Abstract
A significant amount of clinical and research interest in thrombosis is focused on large vessels (eg, stroke, myocardial infarction, deep venous thrombosis, etc.); however, thrombosis is often present in the microcirculation in a variety of significant human diseases, such as disseminated intravascular coagulation, thrombotic microangiopathy, sickle cell disease, and others. Further, microvascular thrombosis has recently been demonstrated in patients with COVID-19, and has been proposed to mediate the pathogenesis of organ injury in this disease. In many of these conditions, microvascular thrombosis is accompanied by inflammation, an association referred to as thromboinflammation. In this review, we discuss endogenous regulatory mechanisms that prevent thrombosis in the microcirculation, experimental approaches to induce microvascular thrombi, and clinical conditions associated with microvascular thrombosis. A greater understanding of the links between inflammation and thrombosis in the microcirculation is anticipated to provide optimal therapeutic targets for patients with diseases accompanied by microvascular thrombosis.
Abbreviations: ADAMTS13, A disintegrin-like and metalloproteinase with thrombospondin type 1 motif 13; AP, Alternate pathway; APC, Activated Protein C; APS, Antiphospholipid syndrome; CAPS, Catastrophic APS; ASFA, American Society for Apheresis; ATP, adenosine triphosphate; CFH, Complement factor H; Con A, concavalin A; COX, cyclooxygenase; DAMP, Damage-associated molecular pattern; DIC, Disseminated intravascular coagulation; GBM, Glomerular basement membrane; HELLP, Hemolysis, elevated liver enzymes, low platelets; HITT, Heparin-induced thrombocytopenia and thrombosis; HLH, Hemophagocytic lymphohistiocytosis; HUS, Hemolytic-uremic syndrome; ISTH, International Society for Thrombosis and Haemostasis; IVIG, Intravenous immunoglobulin; LDH, Lactate NOS, Nitric Oxide Synthase; NET, Neutrophil extracellular trap; PAI-1, Plasminogen activator inhibitor 1; PF4, Platelet factor 4; PRR, Pattern recognition receptor; RBC, Red blood cell; SCD, Sickle cell disease; SLE, Systemic lupus erythematosus; TLR, Toll-like receptor; TF, Tissue factor; TFPI, Tissue factor pathway inhibitor; TMA, Thrombotic microangiopathy; TNF-α, Tumor necrosis factor-α; TPE, Therapeutic plasma exchange; ULC, ultra large heparin-PF4 complexes; ULVWF, Ultra-large von Willebrand factor; VWF, von Willebrand factor
Introduction
Thrombosis, or the pathologic formation of blood clots, is associated with a significant health and economic impact world-wide. A great deal of clinical and research attention on thrombosis focuses on arteries in common conditions such as stroke or myocardial infarction, or in veins such as in deep venous thrombosis. Thrombosis also affects the microcirculation with significant consequences; this review will focus on the connection between microvascular thrombosis pathogenesis and clinical implications. Microvascular thrombosis often occurs in diseases characterized not only by disordered clot formation but also by disordered inflammation. In fact, many of the diseases discussed in this review are characterized by a “loss of focality” or escape from regulation of the physiologic pathways involved in hemostasis and innate immunity. There is increasing awareness of the close association between inflammation and thrombosis, also referred to as “thromboinflammation.1” The complex pathways of inflammation and coagulation appear to have a common evolutionary origin to defend against deadly insults. This is strikingly illustrated by the horseshoe crab, whose innate immune and coagulation systems are so intertwined that scientists consider them to be the same system.2 , 3 Going forward, a greater understanding of the mechanisms responsible in the links between thrombosis and inflammation is expected to aide in the design and development of more effective therapies for these conditions.
Overview of the microcirculation
In a simplified manner, the microcirculation may be defined as those blood vessels that cannot be observed clearly by the human eye without assistance.4 There are also some suggestions of defining the microvasculature based on topography and hemodynamic responses, corresponding to a upper threshold of arteriole diameter of ∼100 μm5; however, in reality there is no abrupt transition between macro- and microvessels but rather a gradual transition, thus each definition will have limitations. However, particularly when comparing the precapillary arterioles and postcapillary venules to large arteries and veins, there are clear structural and functional differences, discussed below.
The microvasculature is subdivided into 3 main categories of blood vessels: arterioles, capillaries and venules distinguished by location, function and structure. Sequentially the arterioles deliver oxygenated blood to the capillaries, which deliver oxygen to the parenchyma, then the venules collect deoxygenated blood from the capillaries. The arteriolar endothelium is surrounded by dense, circumferential smooth muscle cells; the capillary endothelium is surrounded by sparse pericytes and the venule endothelium is surrounded by sparse smooth muscle cells.6 These cellular configurations are distinct from the 3 defined layers found in large vessels (intima, media, and adventitia). Functionally, arterioles have a primary role of regulating distribution of blood flow, while the capillaries represent the primary site of fluid and solute exchange and the venules are the primary site of interaction with immune cells. The capillary beds do not hold a significant portion of the blood volume – estimated at less than 10% of the total volume – but have an enormous surface area for exchange. For example, morphometric analyses of human lungs estimate a capillary surface area of 126 m2 7 and total body skeletal muscle capillary surface area is estimated to far exceed 180 m2.8 9 To place these estimates in perspective, the sum of capillary surface area of lungs and skeletal muscle is larger than the area of a tennis court for doubles matches (nearly 261 m2). There are densely packed networks of capillaries throughout most organs, facilitating delivery of nutrients to surrounding tissues. Capillaries are in a unique position to directly exchange solutes and fluid with the parenchyma and also have the most organ-specific phenotypes within the vasculature.10 The structure of microvasculature is influenced by biomechanical forces including shear stress and biochemical signals including hormones, growth factors, cytokines, chemokines, complement, and nitric oxide (NO) contribute to the unique highly adaptive microvascular endothelial cell phenotype.11 While some features of endothelial cells are maintained in vitro, a significant amount are dependent on temporal and location specific signals.11, 12, 13
Microvessels are subject to significantly increased wall shear stress, a tangential force exerted on vascular walls as a result of blood flow, as their size decreases.14 Measures of mean wall shear stress in arterioles greatly exceed values in arteries within the same species.14 , 15 For example, within the same microvascular bed, mean wall shear stress measured in arterioles (>100 dyn/cm2 for the smallest arterioles) exceeded that of venules of comparable diameter by about one order of magnitude.16 Higher shear stress is deemed to contribute to significant morphologic differences of endothelial cells between arterioles and venules, with arteriolar endothelium appearing elongated in the direction of flow as compared to a cuboidal appearance of venular endothelium17; this phenomenon is also well described in cultured endothelial cells.18 Of note, blood rheology in the microcirculation is complex and does not follow the assumptions of traditional Newtonian flow; further, measures of microvessel hematocrit (an important determinant of viscosity and thus shear stress) by microscopy often yield values ≤50% than that of systemic hematocrit.19 , 20 These properties impact the validity of wall shear stress measurements based on centerline blood flow velocity (a common experimental technique), although mathematical models have been developed to account for the unique environment.21 In addition to the shear stress-induced differences in endothelial cell morphology between arterioles and venules, endothelium in these microvessels exhibit a variety of functional differences, including those exemplified in Fig 1: leukocytes interact primarily with venular endothelium, and in some experimental models, a dramatic difference in von Willebrand factor (VWF) expression.
Fig 1.
Examples of striking differences between arterioles and venules in vivo. (A) Silver-stained microvessels of rat mesentery outlining endothelial cell borders (arrows) showing long spindle-shaped cells in arterioles (Art.) and polygonal cells in venules (Ven.). Adherent leukocytes (arrowheads) are evident only on venules. (B) Immunofluorescence of mouse cremaster microvessels demonstrating vascular smooth muscle limited to the arteriole (stained with alpha smooth muscle alpha actin, green) and considerably greater von Willebrand factor expression (stained red) in the venule. Bar = 30 μm. From reference,28 with permission.
Endothelial cells demonstrate wide heterogeneity in structure and function between microvessels and large blood vessels, between organs, within individual tissues, within regions of individual vascular networks, and as shown by single-cell analyses, also between cells of individual vessels; these differences are also obvious in the comparison of endothelial cells between healthy and diseased subjects.22, 23, 24 In contrast to thrombosis in large arteries, thrombosis in microvessels can result in a more diffuse impairment of perfusion and widespread dysfunction of the affected organs.
Regulatory mechanisms of the microvascular endothelium that prevent thrombosis
Under resting conditions, the healthy microvascular endothelium is uniquely positioned to provide a powerful regulatory balance against similarly powerful stimuli predisposing to thrombosis. The resting endothelium provides an antiadhesive, anti-inflammatory, and antithrombotic barrier vital to maintaining homeostasis. Endothelial cells possess a broad range of endogenous regulatory mechanisms which can inhibit platelets, their adhesion to vascular walls, leukocyte–endothelial interactions, and/or the coagulation system. These are discussed briefly below with an emphasis on the microcirculation; these concepts are reviewed in greater detail in other publications.1 , 25 , 26
Endothelial glycocalyx
This is a thin, flexible boundary layer between the phospholipid membrane of the endothelial cell and the cellular and macromolecule components of the blood. This endothelial surface layer provides the interface between flowing blood and endothelial cell membranes and represents a hydrodynamically significant layer. The glycocalyx's constituents include proteoglycans, glycoproteins, and glycosaminoglycans containing heparan sulfate, chondroitin sulfate, hyaluronan and various core proteins (eg, glypicans, syndecans, etc.).27 These components, organized in a mesh-like array, provide a steric- and charge-dependent semipermeable barrier to fluid and solute transport and prevents blood cell adhesion to the endothelium. Measurement of the precise thickness of the endothelial glycocalyx is limited by its physicochemical characteristics which may alter its dimensions during preparation for ultrastructural studies. Using a variety of techniques, reported values of glycocalyx thickness in microvascular endothelium in vivo range from 0.1 to > 1 μm.28, 29, 30, 31 Although the endothelial glycocalyx is also present in large blood vessels, the hemodynamic implications of the glycocalyx are considerably greater in the microcirculation since it occupies a significant proportion of the vascular volume in microvessels with diameters as small as 5 μm. While platelets are known to be activated by shear stress through several mechanisms,32 shear stress on the endothelium induces a balancing effect. The endothelial glycocalyx is well recognized as a key mechanotransducer, mediating shear stress-dependent responses in endothelial cells, including release of nitric oxide and prostacyclin,33, 34, 35 which are endothelial-derived inhibitors of platelets mentioned below. Experimental degradation of the endothelial glycocalyx has been shown to promote adhesion of platelets to microvascular endothelium.36 , 37 Preclinical models of conditions associated with thromboinflammation such as sepsis and ischemia/reperfusion injury have been shown to result in degradation of the endothelial glycocalyx.38 , 39 There is increasing interest in measurement of circulating and/or urinary glycocalyx components including syndecans, hyaluronan, heparan sulfate40, 41, 42, 43, 44 as biomarkers in septic humans. Further, a recent study reported an association between syndecan-1 levels and disseminated intravascular coagulation (DIC) in patients with sepsis.45 Overall, these studies suggest that degradation of the endothelial glycocalyx may contribute to the pathogenesis of certain thromboinflammatory conditions such as sepsis, and strategies aimed at preservation of the glycocalyx might represent future therapeutic targets in these conditions.46
Nitric oxide
Is a gaseous signaling molecule initially discovered as an endothelial-derived relaxing factor,47 , 48 but is now known to mediate a myriad of responses on a broad variety of cells. Endothelial cell nitric oxide synthase (eNOS) is one of 3 isoforms of NOS; while it is constitutively expressed, its activity may be regulated by various mechanisms including phosphorylation, protein–protein interactions, and subcellular localization, among others.49 Microvascular endothelial cells release nitric oxide in response to hemodynamic forces mechanotransduced by the glycocalyx and several agonists.50 , 51 Preclinical models suggest that endothelial release of nitric oxide provides endogenous protection against thrombosis and regulates inflammation through various mechanisms, including inhibition of endothelial adhesion molecule expression, release of P-selectin and VWF, and inhibition of platelet activation.52, 53, 54 Of interest to this review, mice with targeted deficiency of endothelial nitric oxide were reported to develop microvascular thrombosis in the kidney during aging55, comparable to thrombotic microangiopathy (TMA) discussed below. Modulating the regulatory functions of the microvascular endothelium, including nitric oxide, has been suggested as potential future therapeutic strategies for TMA.56
Prostacyclin
This product of arachidonic acid metabolism exerts several physiological responses comparable to those of nitric oxide. As in the case of nitic oxide, prostacyclin is released by microvascular endothelium in response to shear stress, resulting in vasodilatation as well as inhibition of platelet activation.57, 58, 59, 60 Prostacyclin synthesis is dependent on cyclooxygenase-1 (COX-1, expressed constitutively) as well as an inducible form, COX-2.61 Endothelial cell-derived prostacyclin is presumed to be primarily dependent on cyclooxygenase-1 (COX-1); however, COX-1 is also expressed on platelets and mediates release of the prothrombotic molecule thromboxane A2.62 Recent data generated from mice with cell-specific deletion of COX-1 and COX-2 have clarified the relative contribution of these enzymes in regulation of thrombotic tone in endothelial cells: endothelial cell COX-1 and COX-2 both prevent thrombosis, albeit via distinct and complementary pathways.63 From a clinical standpoint, the antithrombotic protection induced by low-dose aspirin (an inhibitor of COX-1 and COX-2) is presumed to reflect a balance favoring prostacyclin over thromboxane A2.64 Prostacyclin has been approved for clinical use for pulmonary hypertension in the US since 1995, and isolated case reports of its off-label use for thrombotic microangiopathies describe conflicting findings.65, 66, 67 A greater understanding of the role of cell-specific regulation of COX isoforms may provide insight into therapies targeting prostacyclin for microvascular thrombosis.
Other endothelial antithrombotic mechanisms
Microvascular endothelial cells possess a variety of additional mechanisms that have been proposed to contribute to its endogenous antithrombotic properties. These include CD39/ectoADPase, a membrane bound enzyme that hydrolyzes adenosine triphosphate and adenosine diphosphate to adenosine monophosphate and thus inhibits platelet activation.68 Other antithrombotic molecules expressed in microvascular endothelium include tissue factor pathway inhibitor,69 activated protein C, thrombomodulin,70 and antithrombin.71 Of interest, these molecules failed to improve outcomes in large clinical trials in patients with sepsis,72, 73, 74, 75 including a trial focused on sepsis-induced coagulopathy in which thrombomodulin failed to demonstrate a clinical benefit.75 Despite the failure of past large clinical trials performed on heterogenous groups of patients with sepsis, there is increased interest in targeting these pathways in selected subsets of patients with microvascular thrombosis in sepsis and related thromboinflammatory disorders.76
Experimental models of microvascular thrombosis in vivo
Much of our understanding of the molecular mechanisms responsible for microvascular thrombosis is derived from preclinical studies utilizing intravital microscopy, or microscopy-based observation of biological responses in vivo. Under physiologic conditions, the endogenous antithrombotic mechanisms described above prevent interactions between platelets and microvascular endothelium and prevent activation of coagulation on microvascular walls. A variety of experimental models have been used to induce focal microvascular thrombosis (Fig 2 ), with a general common feature being the disruption of one or more of the normal endogenous antithrombotic mechanisms outlined above. While microvascular thrombosis in human diseases tends to be diffuse and several models discussed here are focal, single vessel models allow for real-time observation of the kinetics of microvascular thrombus formation in vivo. The study of focal insults can provide insight into molecular mechanisms involved in microvascular thrombosis, which can be used for targeted manipulation of these pathways (eg, with genetically modified animal models, monoclonal antibodies, pharmacological agents, etc.) in preclinical models relevant to human diseases. Selected models are outlined very briefly below; for more in-depth discussion of this category of model, readers are referred to other reviews.77 , 78
Fig 2.
Schematic of experimental models of microvascular thrombosis induced by focal stimulation of individual microvessels, adapted from a schematic from reference.78
Physical and electrical models of microvascular injury
Mechanical injury models are used commonly in preclinical studies in large vessels focusing on hemostasis (physiologic cessation of blood flow following vascular injury), particularly transection of the tail to quantify bleeding time.79, 80, 81 Physical injury models have also been used in the microcirculation, mostly decades ago, with techniques including micropuncture or vessel transection.82, 83, 84 Thrombosis in these models occurs as a result of focal damage to microvascular endothelium and exposure of flowing blood to the subendothelium. While these physical models are relevant to hemostasis, challenges involved in standardizing the degree of vascular injury might contribute to their infrequent use in current studies in the microcirculation. As in the case of physical stimulation, electrical injury to microvessels to induce thrombosis was more prevalent in studies performed many decades ago.85, 86, 87 The infrequent use of direct electrical stimulation as a model of microvascular thrombosis may relate not only to the artificial nature of the injury but to the reported variability in responses in vivo.87 , 88
Photochemical and laser injury
The photochemical injury technique involves systemic administration of a fluorescent dye (or dye-labeled macromolecule) and exposure of a segment of the microcirculation to a carefully controlled light dose. The laser-induced model of injury involves laser injury to a carefully defined segment of the microcirculation in vivo. Both photochemical and laser models result in focal damage to microvascular endothelium and formation of platelet-rich thrombi at the site of injury. Electron microscopy studies have demonstrated focal areas of endothelial cell denudation in some models of laser and photochemical injury, though in others, platelet thrombi are evident in the presence of injured, though not denuded, endothelium.78 , 89 , 90 Both methods are used in contemporary studies by various authors to define the kinetics of microvascular thrombosis in both venules and arterioles in vivo.91, 92, 93, 94, 95, 96 Although admittedly photochemical and laser stimulation represent artificial methods of microvascular injury, a significant advantage of both approaches is the ability to standardize the degree of microvascular injury yielding highly reproducible results. Both models depend on dose of stimulation (ie, power and duration of exposure to laser or light) and the photochemical model also depends on dye concentration. Both techniques enable authors to define the influence of various biological conditions on the kinetics of microvascular thrombosis in vivo. Since these techniques are well established in various vascular beds in mice (eg, cremaster, mesentery, and pial), their use in genetically modified mice has greatly expanded our understanding of the molecular mechanisms involved in microvascular thrombosis in normal conditions and in experimental models of disease. It is important to note that mice and humans differ with regards to various parameters relevant to thrombosis, including platelet count (about 3-fold higher in mice), protease-activated receptors, responsiveness to certain agonists, a host of platelet transcriptomes, leukocyte subset number and expression of certain molecules, among others.97, 98, 99 Recognizing these species-specific differences is important in the design and interpretation of microvascular thrombosis experiments in mice. Despite these differences, mice are used commonly for thrombosis studies in vivo and have provided observations relevant to human conditions.97 , 98 Further, preclinical studies in mice enable sophisticated high-resolution multicolor intravital confocal microscopy imaging not feasible in humans, as exemplified by the studies by Kubes et al, which have revealed many novel observations of the links between thrombosis and inflammation in vivo. Two examples include defining the role of platelets in bacterial clearance in the liver during blood-borne infection and characterizing formation of neutrophil extracellular traps in vivo during infection.100 , 101
Biochemical stimulation
A variety of biochemical agents have been applied topically to macro- and microvessels to induce thrombosis in vivo 1 common method involves topical application of ferric chloride, used commonly in microvessels like the carotid artery102, 103, 104 as well as microvessels as in the mesentery104, 105, 106 and quantifying thrombus formation by reduction in arterial flow and/or recruitment of platelets by intravital microscopy. The mechanism of thrombus formation is proposed to involve oxidant injury to endothelium with denudation,102 , 103 although recent findings suggest a more complex mechanism including participation of red cells.107 , 108 Despite the relative uncertainty of the mechanisms resulting in injury, ferric chloride remains a commonly used method to study thrombosis in vivo. Additionally, targeted agonists can be applied topically, such as histamine, calcium ionophore, adenosine diphosphate, among others.109 , 110 However, ferric chloride remains the most commonly utilized biochemical approach to study thrombosis and/or platelet recruitment in single vessels in vivo. In addition to agonists applied topically to microvessels, targeted agonists can also be administered systemically resulting in experimental models of disease associated with microvascular thrombi, which can be utilized in preclinical evaluation of therapeutics. Some examples of these systemic agonists include lipopolysaccharide,111 soluble VWF,112 lectin concanavalin A (Con A) followed by anti-Con A,113 among others.
An intriguing observation derived from several of the models described above is that the ultrastructural organization of microvascular thrombi is highly heterogenous. Several reports have demonstrated that microvascular thrombi in vivo and ex vivo contain a core area of tightly packed platelets with extensive shape change and frequent degranulation and a distal area containing loosely packed platelets with less evidence of activation.84 , 114 , 115 This heterogeneity is deemed to be functionally significant, by influencing transport of biologically active substances across thrombi as well as thrombus stability,114 , 115 likely to have clinical implications. Fig 3 demonstrates the 3-dimensional ultrastructure of a microvascular thrombus generated by our group using the photochemical injury model in a mouse cremaster venule (procedures approved by the Institutional Animal Care and Use Committee of Baylor College of Medicine), using the relatively new imaging technique of serial block-face scanning electron microscopy.116
Fig 3.
Three-dimensional ultrastructure of a photochemical injury-induced thrombus in a mouse cremaster venule (45 μm in diameter) by serial block-face scanning electron microscopy. (A) Longitudinal section demonstrates cellular heterogeneity within the thrombus; the dimensions of the bounding box are 43 × 43 × 107 μm. (B) Cross section of the distal end of the thrombus shows loosely packed, discoid (unactivated) platelets. (C) Cross-section of the center of the thrombus shows densely packed platelets with evidence of significant degranulation. (D) Cross-section of the proximal end of the thrombus shows platelet (Plt)-endothelial cell (EC) adhesion, leukocytes (WBC) and erythrocytes (RBC). Scale bar = 5 μm. Images courtesy of Drs. Alan Burns and Samuel Hanlon, University of Houston College of Optometry.
Many of the experimental models of microvascular thrombosis described above result in platelet-rich thrombi, often with little evidence of fibrin by electron microscopy.78 As described below, the structure of thrombi in clinical conditions associated with microvascular thrombosis varies considerably; for example, platelet-rich thrombi predominate in thrombotic thrombocytopenic purpura and fibrin-rich thrombi in hemolytic-uremic syndrome and DIC.117 , 118 Similarly, the composition of thrombi in large vessels also varies according to vessel type and underlying disease119; of interest, the well-defined fibrin mesh often demonstrated in large vessel thrombi is not characteristic of the experimental microvascular thrombi described above.
Clinical overview of microvascular thrombosis
Imaging of the microvasculature
A key obstacle in effectively treating dysfunctional microvasculature is correctly identifying that there is an issue in that physiologic compartment. There have been significant advances in aids to the human eye, but the microvasculature continues to elude observation by many common clinical imaging techniques. The resolution of a computed tomography angiogram or magnetic resonance angiogram typically does not provide information about the structure of these microscopic vessels. Even a conventional angiogram of the brain does not resolve vessels smaller than 500 µm.120 The nailfold capillaries are grossly visible using commonly available clinical tools such an otoscope, but this does not reveal the internal contents of the capillaries. Dedicated nailfold video capillaroscopy has been utilized in a variety of conditions, particularly rheumatologic; for example, it has been reported to help identify microthrombi and microhemorrhages in some patients with systemic sclerosis or antiphospholipid syndrome.121 , 122 While these approaches may have utility, particularly for screening in a subset of the conditions outlined below, in the vast majority of these conditions defined by and/or accompanied by microvascular thrombosis, the diagnosis is typically made clinically and sometimes confirmed histologically if possible. Early recognition is typically an important factor in delivering effective therapy.
Diseases accompanied by microvascular thrombosis
Many of the diseases characterized by microvascular thrombi were initially classified solely based on clinical phenotype; however, advances in science have broadened understanding of the mechanisms of dysregulation in many diagnoses and subsequent reclassification based on pathogenesis. In some cases, microvascular thrombosis may develop in a previously healthy individual following exposure to a devastating stimulus (eg, Shiga toxin-producing Escherichia coli [E. coli]). In other cases, microvascular thrombosis may develop in individuals with significant medical conditions (eg, cancer, severe systemic lupus erythematous) following a relatively less severe stimulus. In this review, we discuss a variety of clinical entities associated with microvascular thrombosis, although this is not intended to be an exhaustive all-encompassing discussion of such conditions. Similarly, we discuss common therapeutic interventions for various conditions, noting that in many cases of microvascular thrombosis associated with an underlying disease, the standard of care in therapy consists of treatment of the underlying disease.
Thrombotic microangiopathies (TMAs)
TMAs are defined as having microangiopathic intravascular hemolytic anemia, thrombocytopenia, and organ dysfunction (renal or neurological) in the absence of evidence of diffuse intravascular coagulation (DIC). A hallmark of TMA is the presence of mechanically damaged red blood cells (RBCs) in circulating blood, termed schistocytes, deemed to result during passage of highly deformable RBC through porous microthrombi and/or interactions with fibrin strands in the microthrombi.123 , 124 The primary underlying etiology and specific therapy for the TMA subtypes differs. For example, although therapeutic plasma exchange (TPE) has been used for various TMA subtypes, it may be reasonable to bypass TPE for eculizumab for definite cases of TMA-complement mediated, also known as atypical hemolytic-uremic syndrome (aHUS).125 , 126 In TMA characterized by direct endothelial damage such as TMA-infection associated (also HUS) and some types of TMA-drug induced, the endothelium may often spontaneously recover and not require TPE.125 This logic may be less applicable in severe cases of endothelial damage that have pushed other fluid-phase pathways into a dysregulated state.127 , 128 Often, the specific etiology of TMA is not immediately clear and patients require treatment prior to the results of specific laboratory testing. The British Committee for Standards in Haematology and the Mayo Clinic have developed consensus algorithms to guide treatment decision-making while diagnostic evaluation is pending.123 , 129 The specific etiology of the TMA is particularly helpful in long-term management and prognosis.
Thrombotic thrombocytopenia purpura (TTP)
TTP was distinguished as a unique TMA with the discovery of a disintegrin-like and metalloproteinase with thrombospondin type 1 motif 13 (ADAMTS13).130 Endothelial cells are one source of VWF, a large plasma glycoprotein, which serves multiple functions in hemostasis. ADAMTS13 cleaves a specific bond in the VWF-A2 domain—releasing the VWF from endothelial cell surface and reducing the size. The ultra-large VWF multimers are unfolded under high levels of shear stress in the arterioles and capillaries, which induces platelet aggregation specific to the microcirculation.131, 132, 133 The brain is commonly involved clinically, although autopsy studies have revealed diffuse organ involvement.134 The mechanisms behind this organ-specific predominance are unclear, although endothelial heterogeneity is a plausible explanation since a wide range of molecular and functional differences in endothelial cells among organs have been described, including VWF.22 , 135, 136, 137 Deficiency of ADAMTS13 can be congenital or acquired, and the acquired form can occur spontaneously or secondary to an existing inflammatory condition. The standard of care for initial therapy for most forms TTP is TPE. The American Society for Apheresis (ASFA) strongly recommends TPE in TTP with grade 1A evidence. TPE removes potential antibodies targeting ADAMTS13 and replaces ADAMTS13 from healthy plasma.126
Primary TTP-Acquired
Acquired primary TTP is characterized by anti-ADAMTS13 antibodies that results in severe deficiency of ADAMTS13.130 There are 2 types of anti-ADAMTS13 antibodies: neutralizing and clearing, which require different assays for their measurement. Many hospital laboratories do not perform ADAMTS13 panels, requiring that physicians send patient specimens to outside laboratories, delaying diagnosis. The PLASMIC score was developed to rapidly assess TTP risk using rapidly available laboratory results including: platelet count, reticulocyte count, haptoglobin, indirect bilirubin, mean corpuscular volume, international normalized ratio, creatine and clinical characteristics.138 Patients with elevated PLASMIC scores should generally start TPE therapy while awaiting the results of the ADAMTS13 panel. While TPE removes circulating pathogenic anti-ADAMTS13 antibodies, it does not halt their production. Therefore, immunosuppression should be initiated in conjunction with TPE. Corticosteroids are the mainstay of treatment, although there are no comparative trials definitively demonstrating their efficacy.126 While TPE can remove circulating pathogenic anti-ADAMTS13 antibodies, it does not halt their production. There are multiple prospective studies demonstrating the efficacy of B-cell depletion with the anti-CD20 chimeric monoclonal antibody rituximab in acquired primary TTP in shortening the initial episodes.139 , 140 Additionally a retrospective comparison found that patients who received rituximab experienced fewer relapses compared to historical controls who did not receive this therapy.140 There has been a recent phase 3 trial of caplacizumab, a humanized immunoglobulin fragment which targets the A1 domain of VWF to prevent its interaction with the platelet glycoprotein Ib-IX-V receptor, demonstrating efficacy over TPE and steroids alone. Severe ADAMTS13 deficiency was not an inclusion criteria for this trial, although 85% of patients were found to have ADAMTS13 activity of less than 10% of baseline.141 Other potential therapies reported include cyclosporine, azathioprine, vincristine, bortezomib, and other immunosuppressive agents.126 Additionally these patients should be carefully monitored for development of systemic autoimmune conditions such as systemic lupus erythematous, particularly when acquired TTP occurs in childhood.142
Primary TTP - Congenital
If there is no antibody detectable and ADAMTS13 activity is less than 10%, then genetic defects should be considered.123 Congenital TTP comprises approximately 5% of cases of primary TTP and typically presents early, with 50% of cases presenting in infancy. Of interest, it can present at any age, including adulthood, particularly in the setting of common inflammatory stimuli such as trauma and infection or pro-thrombotic stimuli such as pregnancy. The clinical spectrum of disease varies significantly from asymptomatic thrombocytopenia to life threatening organ dysfunction. Depending on the severity of presentation and clinical course, some patients may benefit from prophylactic plasma infusion to minimize relapses.143 Additionally, recombinant ADAMTS13 or BAX 930 is currently being assessed in clinical trials for this indication.144
Secondary TTP
Acquired ADAMTS13 deficiency is known to complicate existing inflammatory diseases, including systemic lupus erythematosus (SLE), systemic sclerosis, polymyositis/dermatomyositis, rheumatoid arthritis (RA), sepsis, and pancreatitis.130 , 145 , 146 A prospective study compared the level of ADAMTS13 in connective tissue disease (CTD)-TMA to primary TTP and found that severe deficiency is more common in primary TTP.130 The subset of patients with severe deficiency of ADAMTS13 in CTD-TMA also had a higher incidence of detectable ADAMTS13 auto-antibodies. These CTD-TMA patients with a phenotype similar to primary TTP were more likely to have a diagnosis of rheumatoid arthritis or SLE. Interestingly, severe deficiency of ADAMTS13 was associated with better outcomes in CTD-TMA compared to mild-moderate deficiency.130 Acute inflammation, chronic inflammation, antiphospholipid antibodies, and immunosuppressive medications are all potential contributors to microvascular endothelial dysfunction that may be additive to a moderate ADAMTS13 deficiency.147 Acquired deficiency of ADAMTS13 has also been described in patients with sepsis and is associated with severity of disease, DIC, and mortality risk.145 , 146 Secondary TTP without anti-ADAMTS13 antibodies typically does not result in undetectable levels of ADAMTS13 or less than 10% of baseline activity130 , 145 , 146 but may be a sign of an extremely dysregulated microvascular environment. The treatment of secondary TTP with severe deficiency consistent with anti-ADAMTS13 autoantibodies is comparable to that of primary TTP with additional attention to treating the underlying condition. Without clinical presentation consistent with anti-ADAMTS13 autoantibody, the treatment should be tailored to triggering factors.148
HUS
This subtype of TMA is unified by the frequent involvement of the microvasculature of the kidney, as indicated by the term “uremic” in its name. To distinguish HUS from TTP, the PLASMIC score includes creatinine of less than 2.0 mg/dL as a point in favor of the diagnosis of TTP.138 Relative to TTP, there is a decreased incidence of cerebral injury in HUS. An in vitro study revealed that human brain microvascular EC displayed a stronger regulatory response when alternative pathway (AP)-related gene expression was increased compared to renal microvascular EC.149 Additionally renal microvascular EC possess a higher baseline level of AP activation compared to human umbilical vein ECs. AP activation was significantly increased in both cell types by the addition of tumor necrosis factor-α.150 HUS is composed of subcategories that share a similar clinical phenotype but with different pathogenesis and initial treatment.
TMA-infection associated (also typical HUS)
In the majority of patients with HUS (90%), the TMA is triggered by Shiga-like toxin (Stx) produced by bacteria, predominately E. coli O157:H7.151 The Stx directly damages the renovascular endothelium by binding to the glycosphingolipid globotriaosylceramide present on renal glomerular endothelial, mesangial and tubular epithelial cells.152 , 153 In contrast to TTP, the dysfunctional component of the microcirculation is not the plasma but the endothelium thus routine use of TPE is not recommended by the ASFA.126 The treatment is primarily supportive care with adequate hydration to account for diarrheal losses and microvascular leakage. In cases of severe diarrhea or neurologic involvement, some retrospective studies suggest a benefit for use of eculizumab.154 The ASFA advises that physicians may consider the use of TPE in patients with severe bloody diarrhea or neurologic involvement as some case reports suggest benefit in this subset (grade III recommendation with grade 2C evidence).126 , 128 The use of antibiotics in OH157:H7 infections was found by a retrospective study to be associated with a higher risk of development of TMA-infection.153 , 155 Another less common cause of TMA-infection is triggered by invasive disease with Streptococcus pneumoniae. The mechanism of TMA development is less well understood in HUS triggered by S. pneumoniae. It has been proposed that S. pneumoniae produce neuramidase that cleaves sialic acid from cell membrane surfaces exposing the Thomsen–Friedenreich antigen (T antigen) which then reacts with naturally occurring anti-T antibodies causing hemolysis.156 , 157 However, another study found that this antigen exposure did not correlate well with HUS development.158 Additionally this mechanism describes the process of an autoimmune hemolytic anemia, which is classically extravascular, in contrast to intravascular TMA.159 The ASFA recommends TPE based on clinician discretion (grade 2C evidence). In this case, treatment of the underlying infection is recommended. Triggering infections tend to be severe and include sepsis, pneumonia and meningitis.
TMA-complement mediated (also atypical HUS)
TMA-complement mediated disorders compromise a group of conditions associated with abnormalities in the complement system, which can either be inherited or acquired. The complement system is a powerful part of the innate immune system and accompanied by a complex regulatory system to prevent inappropriate activation. There are 3 main pathways in which complement activation occurs: the Classical Pathway, Lectin Pathway, and Alternative Pathway, which converge on activation of C3. There are membrane-bound and fluid-phase complement regulators that prevent inappropriate deposition of C3 onto endothelial cells.160 The inherited complement disorders include mutations in complement regulators and activators and often present after an inflammatory trigger.161 The cascade of events typically leads to fibrin-rich thrombi, compared to the more platelet-rich thrombi of TTP.162 The glomerulus of the kidney is especially reliant on soluble complement regulators (such as factor H) due to the unique properties of the glomerular basement membrane. The glomerular basement membrane is directly exposed to blood in the gaps in the fenestrated glomerular endothelium—and therefore lacks endothelial membrane and all regulatory proteins bound by endothelial membrane at these locations.160 Greater than 70% of genetic mutations have been identified in complement factor H (CFH), a soluble regulator of the alternative pathway. Additionally, anti-CFH antibodies have been described in a form of acquired TMA-complement mediated.160 , 163 Other commonly mutated complement regulatory proteins include complement factor I, membrane-cofactor protein (MCP/CD46), and thrombomodulin (discussed below under TMA-coagulation mediated).164 The diagnosis may be suspected based on TMA features with prominent renal findings and the absence of bloody diarrhea or positive stool test for Stx producing bacteria. Measured levels of complement, including C3 and C4, are often low due to consumption but these findings lack specificity to aHUS.165 In some cases it is clinically unclear whether the TMA is due to underlying TTP or HUS—the Mayo clinic consensus guidelines recommend initial TPE in these cases.123 Additionally TMA-complement-mediated with a positive anti-CFH autoantibody can benefit from TPE.126 Eculizumab has been confirmed by phase 3 trials in children and adults to be superior to TPE alone and has significantly reduced the mortality and morbidity in this disease. Earlier initiation (within 1 month of presentation) is associated with improved outcomes compared to months or years after presentation.166 , 167 TMA-complement mediated is a prime example of thromboinflammation, as immune overactivation directly leads to thrombosis.1 The key therapeutic for this class, eculizumab, was actually developed for use in classic rheumatologic/inflammatory conditions such as SLE, rheumatoid arthritis and dermatomyositis.168
TMA-coagulation mediated (also atypical HUS)
A smaller subset of patients within the classification of atypical HUS have been found to have activating defects in the coagulation cascade. During physiologic hemostasis, the coagulation cascade is activated through the tissue factor pathway after the formation of platelet plug at sites of endothelial injury. This process, also known as secondary hemostasis, results in the generation of thrombin, which cleaves fibrinogen into fibrin, which then polymerizes into a stable fibrin plug. One study identified thrombomodulin mutations in 5% of aHUS patients who were sequenced.151 Thrombomodulin is a thrombin cofactor that negatively regulates coagulation activation and fibrinolysis. This study found that thrombomodulin also has regulatory roles in complement activation and binds to C3b and factor H in vitro.151 Additionally thrombomodulin negatively regulates leukocyte trafficking.169 Thrombomodulin provides one of many links between coagulation, complement and innate immunity. An additional coagulation-based mutation identified in aHUS is diacylglycerol kinase epsilon which inhibits protein kinase C and plasminogen.164 , 170 Eculizumab is also used in this category but may be less effective than use in TMA-complement mediated.170 Currently, there is no specific treatment for this subtype of aHUS, but potential future directions could include pharmaceuticals that have been developed for DIC including recombinant thrombomodulin for patients with pathogenic thrombomodulin mutations.75 , 151
TMA-transplantation associated
TMA has been observed after both solid organ and hematopoietic stem cell transplantation (HSCT).171 , 172 TMA after HSCT can affect any organ but typically involves the kidney, resulting in a similar phenotype to aHUS.173 A prospective cohort identified proteinuria and hypertension as the earliest signs of TMA-TA; creatinine was also elevated but not specific in comparison to HSCT recipients without TMA.174 The diagnosis after HSCT is particularly challenging as many of the laboratory hallmarks of TMA are present at baseline, including schistocytes,175 elevated lactate dehydrogenase (LDH), and thrombocytopenia. Severe ADAMTS13 deficiency is not a hallmark of TMA-TA; the etiology is thought be related to endothelial damage from chemotherapy and the post-transplant inflammatory state leading to classical and alternative complement activation.173 , 176 , 177 Alterative pathway dysfunction is supported by complement regulatory mutations and anti-factor H antibodies in a subset of patients.178 TMA-TA also frequently co-occurs with other insults including infection and graft versus host disease so it can be challenging to assess the relative severity of TMA-TA.172 Regarding treatment, retrospective studies on the effectiveness of TPE in TMA-TA have not suggested efficacy.126 , 179 Calcineurin inhibitors are frequently implicated in the development of TMA-TA and it is recommended to reduce the dose or discontinue the medication on an individualized basis.172 Given the prominent role of complement, eculizumab has been used with some success,180 although it may carry increased risk of infection in this vulnerable group.181
TMA-drug associated, or drug-induced (DI)-TMA
This category includes the diagnoses of DI-HUS and DI-TTP. Drug-induced TMA occurs by a variety of mechanisms, dependent on the properties of the individual drug. Two main mechanistic categories have been proposed: immune-mediated reaction and dose- and duration-related toxic reactions. Immune-mediated reactions tend to occur acutely within weeks after drug exposure whereas toxicity-related reactions which could be either acute (with a supra-therapeutic dose or known toxic substance) or gradual (with therapeutic dosing). A literature review in 2015 identified 78 drugs with published evidence of TMA association and found that 22 met their criteria for definite causal association. The top 3 drugs implicated in the literature were quinine, cyclosporine and tacrolimus.182 TPE's efficacy varies with the triggering agent; the mainstay of treatment is avoidance of re-exposure to the triggering agent.126
Hemolysis, elevated liver enzymes and low platelet count
Hemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome is a TMA syndrome typically presenting in the second or third trimester of pregnancy and occasionally postpartum.183 HELLP is a clinical diagnosis which can be aided by the Tennessee classification. The classification requires hemolysis (evidenced by schistocytes or burr cells, elevated serum bilirubin, low serum haptoglobin or elevated LDH) with anemia, liver damage and thrombocytopenia.184 HELLP is characterized by endothelial injury, fibrin deposition, platelet activation and consumption.185 The exact pathogenesis is not well elucidated, however it is thought to be similar to pre-eclampsia, as about 80% of cases with HELLP are preceded by pre-eclampsia.186 At a cellular level, effectors of this syndrome include abnormal placental factors, endothelium, and immune system. Defective spiral artery modeling and abnormal extra villous trophoblast cell proliferation results in hypoxia and shedding of debris.187 The resultant tissue necrosis elicits a strong inflammatory response with cytokine production,188 activation of the complement system,189 and leukocytosis.190 Indeed, germline mutations in the alternative complement pathway (Factor H, MCP/CD46, and Factor I) have been shown to predispose women to HELLP.191 , 192 There is literature suggesting that placental derived antiangiogenic factors contribute to endothelial dysfunction and decreased renewal which results in platelet activation, hemolysis, and microvascular thrombosis.193 The mainstay of treatment of HELLP is prompt delivery.194 In addition, other therapies such as betamethasone for promoting fetal lung maturity, antihypertensives, magnesium sulfate for neuroprotection and supportive care with RBC or platelet transfusions are used prior to delivery.195 Initially, corticosteroids were considered for treatment of HELLP based on the role of leukocytes in its pathophysiology,190 , 196 however, their effect appears to be modest, with improved platelet recovery in those treated with corticosteroids and no effect on maternal-fetal outcomes.197 Despite a role for complement activation, to date no major trials have been conducted using eculizumab, however, case report exists for its efficacy.198 As we gain better understanding of pathogenesis of disease, more targeted treatments are expected to become available.
DIC
DIC is a different, but not mutually exclusive, category of microvascular occlusion than TMA. The fibrin-rich microvascular occlusions in DIC111 are presumed to not allow for a significant percentage of RBCs to extrude through the occlusions resulting in anemia from characteristic mechanical damage.124 Although schistocytes may be present in DIC, they tend to occur at a much lower frequency than in TMA.199 Additionally, DIC is differentiated from TMA by widespread fibrin deposition resulting in low fibrinogen and coagulation cascade factor consumption leading to coagulopathy.200 , 201 Like TMA, DIC can be incited by a variety of insults which result in unique phenotypes of DIC; we will discuss 4 common triggers of DIC including sepsis, trauma, malignancy and hemophagocytic lymphohistiocytosis (HLH). The International Society on Thrombosis and Haemostasis (ISTH) defines DIC as “An acquired syndrome characterized by the intravascular activation of coagulation with loss of localization arising from different causes. It can originate from and cause damage to the microvasculature, which if sufficiently severe, can produce organ dysfunction.” Additionally the ISTH developed scoring criteria for DIC comprised of the platelet count, d-dimer (fibrin degradation marker), prothrombin time and fibrinogen level.202 DIC is associated with both excessive coagulation and enhanced fibrinolysis; the predominance of these pathways can result in a primary phenotype of bleeding, of microvascular thrombosis with organ failure, or both bleeding and microvascular thrombosis simultaneously.203 Although bleeding clearly has significant clinical implications in DIC, we will focus our discussion on microvascular thrombosis, the topic of this review.
DIC-Sepsis
The Society of Critical Care Medicine and the European Society of Intensive Care Medicine third consensus definition of sepsis is life-threatening organ dysfunction caused by a dysregulated response to infection. Organ dysfunction is defined according to the Sequential Organ Failure Assessment score of 2 points or more; one of the parameters being platelet count.204 DIC in sepsis provides a clear connection between the innate immune system and the coagulation cascade. During healthy physiology, the innate immune system and the coagulation cascade cooperate to control infections at the source of inoculation. The innate immune system primarily attacks the invading organism, while the coagulation cascade helps contain the infected area with a fibrin mesh – potentially contributing to an abscess capsule.205 , 206 The crosstalk between inflammation and thrombosis is extensive and covered by several reviews.1 , 207 , 208 During sepsis, interactions between pathogen-associated patterns (PAMPs) and pattern recognition receptors (PRRs), including toll-like receptors (TLRs), on sentinel immune cells result in increased production of a broad array of cytokines via transcription factor nuclear factor-kappa B (NK-kB) and mitogen activated protein (MAP) kinases.209 Key cytokines released include tumor necrosis factor alpha, interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6), and interleukin-8 (IL-8).210 Sepsis is a highly heterogeneous syndrome211 and therefore the path to DIC within sepsis may also be variable. A broad range of mechanisms have been proposed in the pathogenesis of DIC in sepsis. Due to the volume of research invested in understanding DIC, it is not possible to briefly summarize this body of work. We selected 2 from a multitude of interesting pathways with evidence of relevance to DIC: tissue factor and neutrophil extracellular traps (NETs), and do not wish to construe that these are the most relevant. The innate defense against invaders is complex with multiple, redundant pathways to counteract the rapid evolutionary potential of pathogenic microorganisms. Likely numerous different pathways may escape regulation and lead to a clinical phenotype that is currently described as sepsis with DIC. For more in-depth overview of the pathogenesis of DIC, including sepsis, readers are referred to recent reviews.212 , 213
Tissue factor
The coagulation cascade has 2 primary pathways to activation: the contact activation pathway (intrinsic) and the tissue factor pathway (extrinsic). Tissue factor is expressed at a high density on stationary cells protected from exposure to the soluble factor VII.214 , 215 In states of injury, tissue factor is exposed to the circulating components of the blood and aids in physiologic hemostasis. Tissue factor can also be expressed by stimulated monocytes, which has been demonstrated in animal and human models.216 , 217 Whether human platelets express tissue factor remains controversial.216 , 218 Similarly, while tissue factor expression by endothelial cells is well characterized in vitro, there are few reports of its expression endothelial cells in vivo, possibly as a result of lower levels of expression.219 Despite promising preclinical studies, a large phase 3 clinical trial with recombinant tissue factor pathway inhibitor, tifacogin, did not show a decrease in all-cause mortality and was associated with a higher risk of hemorrhagic events.72 As in the case of countless other clinical trials that have failed in sepsis, including several other agents targeting coagulation (with promising preclinical data), it is conceivable that additional insight into phenotyping subsets of patients may identify patients to benefit from this and other therapies in a personalized manner.220
NETs
Neutrophils are the most abundant circulating nucleated cell and respond to cytokines released from initial PAMP–PRR interactions. Neutrophils’ classic roles in pathogen offense is through generation of endogenous reactive oxygen species via nicotinamide adenine dinucleotide phosphate and phagocytosis of pathogens. Neutrophils are also capable of undergoing a unique version of programed cell death called NETosis in which they release a DNA meshwork with attached histones, granular enzymes and cytoplasmic proteins including neutrophil elastase, myeloperoxidase, cathepsin G, proteinase 3, gelatinase, LL-37, lactoferrin and calprotectin. A number of components of NETs, including extracellular DNA and histones, can predispose to thrombosis through multiple potential pathways.221, 222, 223 Extracellular DNA functions as a damage-associated molecular pattern (DAMP) which interacts with the coagulation cascade directly through multiple potential pathways.224 , 225 NETs can function as a scaffold for fibrin deposition analogous to the platelet plug scaffold.226 Additionally, VWF has been shown ex-vivo to interact with extracellular DNA, providing a possible link between NETs and platelet interaction.227 Further, serine proteases attached to the DNA meshwork including neutrophil elastase and cathepsin G have been demonstrated in vitro to promote fibrin deposition by degrading regulators of blood coagulation.228 , 229 NETs have also been shown to be associated with deep vein thrombosis in mouse models.230 , 231 The imbalance of NET formation and NET degradation may contribute to the DIC phenotype in sepsis in humans.225 In mice, DNase1 and DNase1-like 3 (DNase1L3) mediate clearance of NETs. DNase1-/- or DNaDNase1L3-/- mice showed a hemolytic anemia, increased concentrations of LDH, and schistocytes after receiving lipopolysaccharide (LPS) to mimic sepsis—consistent with a TMA or DIC-like clinical phenotype.232
DIC-trauma
While the immediate mortality from severe trauma or “polytrauma” often arises from direct damage, such as hemorrhagic shock or primary brain injuries, delayed mortality is associated with secondary damage from the body's dysregulated response to injury and infection. Trauma patients can develop a systemic inflammatory response that can be complicated by DIC.233 The excessive response to injury may also be followed by an excessive opposing response termed compensatory anti-inflammatory response syndrome.234 In contrast to DIC-Sepsis with an initial PAMP–PRR interaction that can lead to self-induced DAMP–PRR interactions such as NETs, DIC-Trauma is characterized by initial DAMP–PRR interactions. One suggested contributory interaction in DIC-trauma is between mitochondrial DNA and TLR9, which also recognizes viral or bacterial DNA.235 Interestingly, mitochondrial DNA shares similar features to pathogen DNA and may contribute to the similar phenotypes of DIC-trauma and DIC-sepsis.236 , 237 The tissue factor pathway has also been implicated in the pathogenesis, as evidenced by the significant activation of tissue factor in patients with DIC-trauma.238, 239, 240 Additionally, the balance of clot formation and clot breakdown may be different than DIC-Sepsis. In experimental models, TF-induced DIC resulted a compensatory response in fibrinolysis while LPS-induced DIC resulted in suppressed fibrinolysis.241 Plasminogen activator inhibitor 1 (PAI-1) is a potent inhibitor of fibrinolysis secreted by endothelial cells and also present in the alpha granules of platelets.242 While PAI-1 expression increases in LPS models of sepsis,243 a relative reduction in activity during DIC-Trauma can result in DIC with enhanced fibrinolysis or a bleeding predominant phenotype.244 The general management of DIC-trauma includes avoidance of additional DAMP production, for example, avoiding immediate operations on fractures that can be temporarily addressed noninvasively.234 , 245
DIC-cancer
There has been a longstanding association between various types of malignancies and an increased incidence of thrombosis including arterial, venous and microvascular in the form of DIC. In some regards, malignancy may be viewed as even more heterogeneous than sepsis and trauma, so it is difficult to discuss pathogenesis under this broad category of disease. In infection, fibrin deposition functions to defend the body from an invader, but certain cancers may coop this physiologic function to defend themselves from detection by the immune system. One study that analyzed cell lines from patients with pancreatic cancer found that some patients’ cancer expressed TF microparticles into culture medium.246 Another study in human breast cancer cells connected the upregulation of TF expression by nearby vascular endothelial cells as a marker for angiogenesis.247 One study identified the presence of DIC in 6.8% of patients with solid tumors in 3 center cohort with independent risk factors of DIC including older age, male, advanced stage, breast cancer and the presence of necrosis on biopsy.248 Fragmented RBCs were also identified in approximately two-thirds of the patients. Additionally, this study identified an increased prevalence of bleeding manifestations compared to thrombotic manifestations in their cohort.248 For additional insight into the association between cancer and thrombosis, readers are referred to a recent review.249
DIC-HLH
Primary/familial HLH is a form of genetic immunodeficiency, often a malfunction of the cytotoxic machinery of natural killer cells and cytotoxic lymphocytes that results in ineffective removal of intracellular pathogens including viruses.250 This can drive a compensatory over-reaction of other pathways of innate immunity resulting in high fevers, cytokine storm, and overactivation of macrophages. Secondary HLH (also known as macrophage activation syndrome) can be triggered by a variety of conditions including rheumatic disease and malignancy.250 The 2004 classification criteria for HLH include low fibrinogen and thrombocytopenia as 2 of the 8 possible criteria, with a cutoff of 5 criteria being required for inclusion in HLH clinical trials.251 The ISTH guidelines for the clinical diagnosis of DIC including low platelet count, elevated d-dimer, prolonged PT and low fibrinogen have also been described in patients with HLH. One study reported that 50% of a 117 patient HLH cohort met the ISTH diagnostic cutoff for DIC.252 The microvascular histopathologic findings on liver biopsies and autopsy studies in HLH include a cellular lymphohistiocytic infiltrate of sinusoids253 , 254 as opposed to the classic fibrin-rich microvascular occlusion in Sepsis-DIC. Measurement of serum ferritin can help distinguish sepsis-DIC from HLH: the HLH-2004 classification criteria include ferritin levels > 500251 and levels > 10,000 have been demonstrated to have specificity for HLH in isolation.255 Diagnosis may be suspected with hyperferritinemia, but is made clinically, ideally by a specialist or team with experience in identifying HLH and MAS. In contrast to DIC-sepsis, patients with primary HLH and MAS often require immunosuppression for therapy, in many cases prior to clearly meeting published classification criteria. Even with treatment, the mortality rate is high in both conditions: the 5-year survival in the HLH-2004 study was 66%256 while a large multicenter, multinational trial revealed an initial mortality of 8% in MAS complicated systemic juvenile idiopathic arthritis.257 The treatment of HLH can include steroids and chemotherapy per the HLH-2004 protocol and/or newer anti-interferon gamma monoclonal antibody emapalumab, typically followed by bone marrow transplant after remission is achieved.251 , 258 Secondary HLH/MAS is treated with a variety of immunosuppressive agents including steroids, cyclosporine and IL-1 cytokine blockade with anakinra.259 , 260
Treatment of DIC
While DIC may be initiated by various conditions, the mainstay of treatment primarily involves treating the underlying disease (ie, infection, cancer, etc.). A number of specific treatments have been suggested for patients based on the distinct clinical presentations (eg, thrombotic, bleeding, and asymptomatic); however, in many cases the quality of the evidence is not high, resulting in distinct treatment recommendations by various societies.203 A variety of treatments have been examined in clinical trials of patients with DIC, including heparin, antithrombin, activated protein C, and thrombomodulin261, 262, 263 without firm evidence of therapeutic benefit. In patients with DIC and significant thrombosis, therapeutic doses of heparin anticoagulation may be considered, yet this is recommended with a low level of evidence by various society guidelines.203 In contrast, the use of low molecular-weight heparin for prevention of deep venous thrombosis in patients with DIC in the absence of bleeding or thrombocytopenia is generally recommended.203 , 264 , 265 The management of DIC in patients with a predominant bleeding phenotype is beyond the scope of this review and is discussed elsewhere.203
Catastrophic antiphospholipid syndrome
Antiphospholipid syndrome (APS) is typically characterized by macrovascular thrombosis in arteries or veins or focal placental thrombosis resulting in miscarriage. Catastrophic antiphospholipid syndrome (CAPS) is a unique subset of APS that primarily targets the microvasculature resulting in multiorgan dysfunction. The revised Sapporo classification can assist in the clinical diagnosis of APS. The revised Sapporo classification does account for microvascular involvement in APS but does not delineate CAPS as a specific subtype of APS.266 Merrill et al proposed a classification criteria for definite CAPS including (1) 3 or more organ systems involved, (2) development of manifestations in less than one week, (3) histopathological confirmation of small-vessel occlusion in at least 1 organ, (4) laboratory confirmation of lupus anticoagulant or anticardiolipin antibodies twice at least 6 weeks apart.267 These criteria emphasize the fulminant, rapidly progressive or “catastrophic” nature of CAPS as distinct from microvascular thrombi that may be observed in classic APS. The microvascular preference of CAPS and lack of significant coagulopathy (in contrast to DIC) can also create a clinical picture overlapping with TMA.267 CAPS commonly involves the kidneys, skin, brain, cardiovascular system, lung, and liver.268 In classic APS the antibodies are considered pathogenic but not sufficient for disease. However, “triple positivity” with positive lupus anticoagulant, anti-cardiolipin and anti-beta-2-glycoprotein confers increased risk of developing thrombosis.269 A “second hit” hypothesis has been proposed where existing antiphospholipid antibodies become pathogenic under inflammatory conditions leading to thrombus formation.270 In vivo models of APS have used either mechanical, chemical or photochemical trauma or LPS to demonstrate increase in thrombosis in APL-infused animals over the secondary trigger alone.271 , 272 APS antibodies have also been shown to directly interact with endothelial cells in animal models causing endothelial dysfunction.273 It is not clear why a small subset of APS patients (<1%) develop widespread microvascular thrombi as opposed to more focal insults. A recent study identified evidence of increased complement activation in patients with CAPS compared to APS and SLE, with clear statistical significance despite a low number of 7 total CAPS patients.274 Additionally, in this CAPS cohort, there was a high incidence of rare germline variants in complement regulatory genes. This study assessed the anti-B2-glycoprotein-I aPL from 2 of the CAPSs patients and found that these aPLs induced complement activation through the classical complement pathway.274 Due to the rarity of CAPS, an international registry was established and has published demographic, clinical and serologic data from 500 CAPS patients.275 The main identified triggers of CAPS are also inflammatory in nature: infection (47%), malignancy (18%), and surgery (17%). Forty percent of patients had an underlying rheumatic disease, 75% of those having the diagnosis of systemic lupus erythematous. These younger patients with underlying SLE experienced the highest mortality approaching 50%.275 Especially in SLE, the classification criteria of CAPS may overlap with features of secondary TTP.130 Recommended treatment for primary CAPS includes “triple therapy” with heparin, high-dose steroids and TPE or intravenous immunoglobulin (IVIG)275 and typically also includes aggressive treatment of triggering conditions such as rheumatic disease.268 The ASFA strongly recommends TPE with a level I endorsement that is supported by grade 2C evidence.126 Additionally, rituximab has shown potential benefit in a subgroup analysis of the CAPS registry.276
Heparin-induced thrombocytopenia and thrombosis
HITT (Type 2 HIT) is an immune-mediated, medication-induced prothrombotic disorder characterized by development of auto-antibodies against platelet factor 4 (PF4) and heparin complexes. While HITT is associated with large vessel thrombosis, microvascular thrombosis can occur in addition or isolation. Microvascular thrombosis in HITT has been implicated in skin lesions and surgical flap failure.277 , 278 These lesions may occur without thrombocytopenia.278 It is important for clinicians to be aware of microvascular sequalae for timely diagnosis of HITT. If intermediate or high probability of the clinically based 4T score279 or clinical concern for microvascular complication, further testing with enzyme linked immunosorbent assay for PF4-heparin complex and/or a functional assay such as serotonin release assay is recommended for further confirmation.280 The HIT antibody binds to platelets via FcγRIIa receptors with resultant activation of tyrosine kinases including spleen tyrosine kinase (Syk) which results in platelet aggregation, release of procoagulant microparticles and granules.281, 282, 283, 284, 285 In addition, HIT antibodies can induce expression of TF in monocytes,284 activate neutrophils and promote formation of NETs which independently adds to the prothrombotic milieu.286 , 287 Treatment is primarily focused on avoidance of all heparin products and preventing and/or treating thrombosis with pharmaceuticals including direct thrombin inhibitors (such as bivalirudin and argatroban), danaparoids, fondaparinux, or rivaroxaban.280 Anticoagulation with warfarin is usually not recommended prior to platelet recovery. The alternative anticoagulation is often continued at least until platelet recovery (in some cases up to 4 weeks) in those without thrombosis and up to 3–6 months for those with thrombosis, although optimal duration is unknown.280 , 288 With growing insight into the pathogenesis of disease, adjunctive treatments are being studied and considered. IVIG has been reported to be effective in selected refractory cases of HIT289 and for prophylaxis in patients planned for heparin re-exposure.290 It is believed that IVIG, through competition, prevents binding of HIT antibodies to FcγRIIa receptors,289 a necessary step for platelet activation. TPE can be an adjunctive treatment in patients not responsive to initial therapy or need to undergo emergent surgery.126 TPE removes the activating alloantibodies against PF4-heparin complex.291 Studies inhibiting the Syk pathway have shown promise with decreased platelet aggregation and thrombosis, but to date this finding has not been confirmed in clinical trials.283 , 284 PAD4 inhibition with GSK484 to prevent NETosis have also demonstrated reduction in thrombosis, however, have not been studied in major clinical trials.286 For a broader discussion of HITT, readers are referred to the accompanying review on this topic in this journal.292
Sickle cell disease
Sickle cell disease (SCD) is a group of inherited hemolytic anemias arising from mutation in β-globin gene resulting in an abnormal hemoglobin tetramer HbS.293 , 294 The most frequent cause of hospitalization in SCD are vaso-occlusive crises (VOCs),295 which result from a complex interplay of red cells, endothelial cells (ECs), platelets and leukocytes in the microcirculation that cause characteristic bone pain.294 Other common microvascular events includes acute chest syndrome, pulmonary hypertension and chronic kidney disease.294 Under hypoxia, intraerythrocytic Hb S polymerize to form elongated fibers, which results in changes in cell rigidity, membrane distortion, and hemolysis.296 Sickling in RBCs is not enough to initiate vaso-occlusion and stasis. The sentinel event is thought to be a multi-cellular adhesion between sickle RBCs, endothelial cells, and leukocytes.297 Sickle RBCs have increased cell rigidity and viscosity due to hemoglobin polymerization as well as cytoskeleton remodeling which increases resistance to blood flow.298 This slows the transit time of the sickle RBCs in the micro-circulation such as postcapillary venules and allows them to adhere to endothelium and leukocytes.299 The time for contact between sickle RBCs and the endothelium seems more important than high-affinity receptor–ligand interactions.300 Ex vivo data reveal that the nondeformable (more rigid, not irreversibly sickled RBCs) sickle RBCs tend to adhere more readily to fibronectin (a mimic for vascular endothelium) due to an increase in adhesion molecules from RBC damage resulting from hemoglobin polymerization.301
Sickle RBCs can contribute to coagulation activation in several ways. Sickling-related membrane damage exposes phosphatidylserine and other adhesion molecules such as intercellular-adhesion-molecule-4,302 which contribute to thrombogenesis. Free heme and hemoglobin released from the damaged RBCs can activate platelets, activate neutrophils induce NETs and endothelium dysfunction which promote hypercoagulability.303 In addition, intravascular hemolysis can directly injure the vessel wall, leading to progressive vessel wall thickness, and anemia from hemolysis can raise systolic blood pressure and increase the risk of organ dysfunction such as stroke.304 Subsequently, ECs upregulate expression of adhesion molecules such as E- and P-selection which increases recruitment of leukocytes to the site of hemolysis.297 , 305, 306, 307, 308 A cascade of reactions ultimately result in activation of platelets,309 leukocytes,310 and coagulation cascade.311 Free heme also promotes NETosis,312 IL-8 production,313 and inflammasome activation.314 The activated neutrophils and monocytes can form heterocellular aggregates with platelets and RBCs thus furthering ischemia, vessel occlusion and VOC.306 In SCD, the composition of large and small vessel thrombosis differs by location. Autopsy studies in patients with pulmonary emboli show that fresh large and small arterial vessel thrombosis are mostly composed of sickle RBCs, fibrin, and CD45+ inflammatory cells.315 However, in patients with stroke, thrombus was mostly composed of platelets, fibrin, and sickle RBCs.316 The composition of microthrombi also differ by location. Microthrombi are thought to form from stasis induced by microvascular occlusion and coagulation activation. In one murine model of SCD, vaso-occlusion in the cremaster microcirculation was dependent on sickle RBCs, neutrophils, and endothelium interactions.297 In another study, vaso-occlusion in precapillary pulmonary arterioles was mediated by platelet-neutrophil-rich microthrombi.317 Last, in mucosal-intestinal microcirculation, sickle RBCS directly adhere to endothelium resulting in micro-occlusions in postcapillary venules.307 The difference in contribution of various cellular components may be dependent on local environment such as the presence of high oxygen concentration in lungs. There is no biomarker for VOC in SCD, so the diagnosis relies on patient-reported pain.295 Based on data from surveys, there are often misunderstandings in physicians of the risks of opioid addiction in SCD, which may lead to undertreatment of severe pain.318 Hydroxyurea is helpful in preventing crises; the proposed mechanism is via an increase in fetal hemoglobin which decreases HbS's tendency to polymerize. In addition, hydroxyurea influences neutrophil count, adhesiveness and also promotes NO balance.319 Other FDA approved drugs include L-glutamine, which reduces oxidative stress, ROS and inflammasome activation320, crizanlizumab, a P-selectin inhibitor320, and voxelotor, which reduces HbS polymerization.321 Other emerging therapies such as an E-selectin inhibitor (rivipansel), and inhibitors of RBC-endothelial adhesion (MEK inhibitors) have shown promise.322 , 323 Although drugs targeting IL-1β and IL-1R are already approved for rheumatoid arthritis, their role in SCD is yet to be studied.294 HSCT is currently the only curative option for select group of patients,324 however, preliminary results are promising for gene therapy.325
Degos disease
Systemic malignant atrophic papulosis, also known as Degos disease, is an extremely rare acquired condition, which can present with an intriguing level of microvascular occlusion relative to the level of systemic response, and thus we selected to include it in this review. It is characterized by amyloid-rich microvascular thromboses that accumulate in the brain, skin, and gastro-intestinal tract.326 The age of onset is typically in adulthood but there are several cases described in children as young as 4 years old.327 The etiology is unknown but histological analysis have found complement deposition and increased interferon alpha signal in the surrounding microvasculature.328 However, it is unclear if complement and interferon are present in response to an unidentified insult or are causing the microvasculature damage. There may not be a significant systemic inflammatory response to these severe insults. This condition is also associated with the loss of endothelial progenitor cells, although the method of depletion (lack of production verses destruction) is unknown.328 It does not appear to be clear autoimmune destruction since patients with Degos disease do not respond to broad immunosuppression including steroids. Based primarily on individual case reports, treatment strategies that have been reported include eculizumab to target the complement deposition and treprostinil to increase the supply of endothelial progenitor cells.329 However, the role of these therapeutic approaches on disease progression is unclear. The study of rare diseases such as Degos may lead to a new understanding of relevant pathways in common diseases that are typically obscured by other features.
COVID-19
There has been a great deal of interest in understanding the unique pathophysiology of COVID-19, the disease caused by the novel coronavirus SARS-CoV-2. While some patients present with minimal or no symptoms, others develop a devastating acute respiratory distress syndrome and death. Initial observations of high levels of inflammation led to investigations of immunomodulatory medications for potential treatments.330 More recent observations of an increased frequency of large vessel thrombosis has led to concern that the classically thrombotic pathways are also highly activated.331 Histological examination of postmortem tissue of 5 patients revealed evidence of microvascular thrombosis in skin and lung. Samples from 2 patients with acute respiratory distress syndrome in that study showed severe capillary damage with intra-alveolar fibrin deposition and relative absence of diffuse alveolar damage consistent with pulmonary microvascular thrombosis. These findings were accompanied by terminal complement deposition evidenced by C5b-9 in the pulmonary microvasculature. Skin biopsies of 3 different patients with vasculopathic-appearing rashes revealed a similar pattern of microvascular occlusion without frank vasculitis.332 Another autopsy study revealed a more classic appearance of diffuse alveolar damage and hyaline membrane formation without striking microvascular involvement.333 COVID-19 manifestations further demonstrate the connection between inflammation and thrombosis in the microvasculature. The mechanisms responsible for microvascular thrombosis in COVID-19 are unclear; one intriguing possibility involves NETs. A recent study on 50 patients with COVID-19 demonstrated significant increases in serum of markers of NET release, including cell-free DNA, myeloperoxidase, and citrullinated histone H3.334 Further studies in patients with COVID-19 are needed to define the nature of microvascular dysfunction and thrombosis in this condition.
Conclusion
The diseases characterized by microvascular thrombosis span a wide variety of medical specialties. In many conditions outlined in this review, microvascular thrombosis results from uncontrolled activation of endogenous pathways aimed at protecting the host (Fig 4 ). These powerful pathways require rigorous regulation to ensure they are unharnessed at the appropriate time, site, and duration; otherwise they may become extremely dangerous to the organism they are meant to protect. Despite the close links and common evolutionary origin of inflammation and thrombosis (as exemplified by the horseshoe crab), these pathways are often viewed separately in medical education and also through the historical separation of clinical disciplines (ie, hematology, immunology, rheumatology, infectious disease, etc.). It is helpful to conceptualize inflammation and thrombosis as interconnected not only from a basic science perspective but also from a clinical perspective. A greater understanding of the nature of dysregulation of these inter-related pathways in disease is expected to help identify optimal targets for therapeutic intervention. Historically, the pattern of medicine involves describing a broad category of disease based on clinical similarities, which is then further subdivided into categories as different pathogeneses are discovered. This trend towards increased clinical resolution of pathogeneses could continue to an extreme where pathway dysregulation replaces the concept of diagnosis. As the future continues to trend toward personalized medicine, the ability to precisely define the nature of the dysregulation of these pathways in individual patients will help determine specific treatment dosing and duration to push the microvascular environment back into a self-regulating state.
Fig 4.
Schematic of inter-related pathways that contribute to the clinical conditions associated with microvascular thrombosis discussed in this review; please see the body of the manuscript for details of each condition. The pathways depicted in red circles are traditionally viewed in the context of inflammation, while those depicted in blue circles are traditionally viewed in the context of coagulation/thrombosis.
Acknowledgments
All authors have read the journal's policy on disclosure of potential conflicts of interest and have no conflicts to disclose. All authors have read and agree with the journal's authorship statement. This manuscript has been reviewed and approved by all named authors. This work was supported in part by Merit Review Award Number I01 BX002551 from the United States Department of Veterans Affairs, Biomedical Laboratory Research and Development Service. Monica A. Bray was supported by T32 training program HL139425 from the National Institutes of Health (NIH), National Heart Lung and Blood Institute. Jahnavi Gollamudi was supported by T32 training program DK060445 from the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. The content is solely the responsibility of the authors and does not represent the official views of the Department of Veterans Affairs or the United States government.
References
- 1.Jackson SP, Darbousset R, Schoenwaelder SM. Thromboinflammation: challenges of therapeutically targeting coagulation and other host defense mechanisms. Blood. 2019;133:906–918. doi: 10.1182/blood-2018-11-882993. [DOI] [PubMed] [Google Scholar]
- 2.Iwanaga S. The molecular basis of innate immunity in the horseshoe crab. Curr Opin Immunol. 2002;14:87–95. doi: 10.1016/s0952-7915(01)00302-8. [DOI] [PubMed] [Google Scholar]
- 3.Delvaeye M, Conway EM. Coagulation and innate immune responses: can we view them separately. Blood. 2009;114:2367–2374. doi: 10.1182/blood-2009-05-199208. [DOI] [PubMed] [Google Scholar]
- 4.Johnson PC.Overview of the microcirculation: microcirculation2008; 11-24.
- 5.Smiesko V, Lang DJ, Johnson PC. Dilator response of rat mesenteric arcading arterioles to increased blood flow velocity. Am J Physiol. 1989;257:H1958–H1965. doi: 10.1152/ajpheart.1989.257.6.H1958. [DOI] [PubMed] [Google Scholar]
- 6.Jain RK. Molecular regulation of vessel maturation. Nat Med. 2003;9:685–693. doi: 10.1038/nm0603-685. [DOI] [PubMed] [Google Scholar]
- 7.Gehr P, Bachofen M, Weibel ER. The normal human lung: ultrastructure and morphometric estimation of diffusion capacity. Respir Physiol. 1978;32:121–140. doi: 10.1016/0034-5687(78)90104-4. [DOI] [PubMed] [Google Scholar]
- 8.Poole DC., Edward F. Adolph distinguished lecture. contemporary model of muscle microcirculation: gateway to function and dysfunction. J Appl Physiol. 2019;127:1012–1033. doi: 10.1152/japplphysiol.00013.2019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Gidlof A, Lewis DH, Hammersen F. Fine structure of the human skeletal muscle capillary. A morphometric analysis. Int J Microcirc Clin Exp. 1988;7:43–66. [PubMed] [Google Scholar]
- 10.Aird WC. Phenotypic heterogeneity of the endothelium: II. Representative vascular beds. Circ Res. 2007;100:174–190. doi: 10.1161/01.RES.0000255690.03436.ae. [DOI] [PubMed] [Google Scholar]
- 11.Aird WC. Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms. Circ Res. 2007;100:158–173. doi: 10.1161/01.RES.0000255691.76142.4a. [DOI] [PubMed] [Google Scholar]
- 12.Cleuren ACA, van der Ent MA, Jiang H. The in vivo endothelial cell translatome is highly heterogeneous across vascular beds. Proc Natl Acad Sci U S A. 2019;116:23618–23624. doi: 10.1073/pnas.1912409116. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Marcu R, Choi YJ, Xue J. Human organ-specific endothelial cell heterogeneity. iScience. 2018;4:20–35. doi: 10.1016/j.isci.2018.05.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Seymour RS, Hu Q, Snelling EP, White CR. Interspecific scaling of blood flow rates and arterial sizes in mammals. J Exp Biol. 2019;222:1–10. doi: 10.1242/jeb.199554. [DOI] [PubMed] [Google Scholar]
- 15.Reneman RS, Hoeks AP. Wall shear stress as measured in vivo: consequences for the design of the arterial system. Med Biol Eng Comput. 2008;46:499–507. doi: 10.1007/s11517-008-0330-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Pries AR, Secomb TW, Gaehtgens P. Design principles of vascular beds. Circ Res. 1995;77:1017–1023. doi: 10.1161/01.res.77.5.1017. [DOI] [PubMed] [Google Scholar]
- 17.McDonald DM. Endothelial gaps and permeability of venules in rat tracheas exposed to inflammatory stimuli. Am J Physiol. 1994;266:L61–L83. doi: 10.1152/ajplung.1994.266.1.L61. [DOI] [PubMed] [Google Scholar]
- 18.Davies PF. Flow-mediated endothelial mechanotransduction. Physiol Rev. 1995;75:519–560. doi: 10.1152/physrev.1995.75.3.519. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Akbarzadeh P. Pulsatile magneto-hydrodynamic blood flows through porous blood vessels using a third grade non-Newtonian fluids model. Comput Methods Programs Biomed. 2016;126:3–19. doi: 10.1016/j.cmpb.2015.12.016. [DOI] [PubMed] [Google Scholar]
- 20.Keller MW, Damon DN, Duling BR. Determination of capillary tube hematocrit during arteriolar microperfusion. Am J Physiol. 1994;266:H2229–H2238. doi: 10.1152/ajpheart.1994.266.6.H2229. [DOI] [PubMed] [Google Scholar]
- 21.Sriram K, Intaglietta M, Tartakovsky DM. Non-Newtonian flow of blood in arterioles: consequences for wall shear stress measurements. Microcirculation. 2014;21:628–639. doi: 10.1111/micc.12141. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Aird WC. Endothelial cell heterogeneity. Cold Spring Harb Perspect Med. 2012;2 doi: 10.1101/cshperspect.a006429. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Chavkin NW, Hirschi KK. Single cell analysis in vascular biology. Front Cardiovasc Med. 2020;7:42. doi: 10.3389/fcvm.2020.00042. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Augustin HG, Koh GY. Organotypic vasculature: from descriptive heterogeneity to functional pathophysiology. Science. 2017;357:1–12. doi: 10.1126/science.aal2379. [DOI] [PubMed] [Google Scholar]
- 25.Jin RC, Voetsch B, Loscalzo J. Endogenous mechanisms of inhibition of platelet function. Microcirculation. 2005;12:247–258. doi: 10.1080/10739680590925493. [DOI] [PubMed] [Google Scholar]
- 26.Gutterman DD, Chabowski DS, Kadlec AO. The human microcirculation: regulation of flow and beyond. Circ Res. 2016;118:157–172. doi: 10.1161/CIRCRESAHA.115.305364. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Reitsma S, Slaaf DW, Vink H, van Zandvoort MA, oude Egbrink MG. The endothelial glycocalyx: composition, functions, and visualization. Pflugers Arch. 2007;454:345–359. doi: 10.1007/s00424-007-0212-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Rumbaut RE, Thiagarajan P. Integrated systems physiology: from molecule to function to disease. Platelet-vessel wall interactions in hemostasis and thrombosis. San Rafael Morgan Claypool Life Sci. 2010, 1-67 [PubMed] [Google Scholar]
- 29.van den Berg BM, Vink H, Spaan JA. The endothelial glycocalyx protects against myocardial edema. Circ Res. 2003;92:592–594. doi: 10.1161/01.RES.0000065917.53950.75. [DOI] [PubMed] [Google Scholar]
- 30.Leskova W, Pickett H, Eshaq RS, Shrestha B, Pattillo CB, Harris NR. Effect of diabetes and hyaluronidase on the retinal endothelial glycocalyx in mice. Exp Eye Res. 2019;179:125–131. doi: 10.1016/j.exer.2018.11.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Schmidt EP, Yang Y, Janssen WJ. The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis. Nat Med. 2012;18:1217–1223. doi: 10.1038/nm.2843. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Kroll MH, Hellums JD, McIntire LV, Schafer AI, Moake JL. Platelets and shear stress. Blood. 1996;88:1525–1541. [PubMed] [Google Scholar]
- 33.Pahakis MY, Kosky JR, Dull RO, Tarbell JM. The role of endothelial glycocalyx components in mechanotransduction of fluid shear stress. Biochem Biophys Res Commun. 2007;355:228–233. doi: 10.1016/j.bbrc.2007.01.137. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Russell-Puleri S, Dela Paz NG, Adams D. Fluid shear stress induces upregulation of COX-2 and PGI2 release in endothelial cells via a pathway involving PECAM-1, PI3K, FAK, and p38. Am J Physiol Heart Circ Physiol. 2017;312:H485–h500. doi: 10.1152/ajpheart.00035.2016. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Bartosch AMW, Mathews R, Tarbell JM. Endothelial glycocalyx-mediated nitric oxide production in response to selective AFM pulling. Biophys J. 2017;113:101–108. doi: 10.1016/j.bpj.2017.05.033. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Vink H, Constantinescu AA, Spaan JA. Oxidized lipoproteins degrade the endothelial surface layer: implications for platelet-endothelial cell adhesion. Circulation. 2000;101:1500–1502. doi: 10.1161/01.cir.101.13.1500. [DOI] [PubMed] [Google Scholar]
- 37.Pries AR, Secomb TW, Jacobs H, Sperandio M, Osterloh K, Gaehtgens P. Microvascular blood flow resistance: role of endothelial surface layer. Am J Physiol. 1997;273:H2272–H2279. doi: 10.1152/ajpheart.1997.273.5.H2272. [DOI] [PubMed] [Google Scholar]
- 38.Yang X, Meegan JE, Jannaway M, Coleman DC, Yuan SY. A disintegrin and metalloproteinase 15-mediated glycocalyx shedding contributes to vascular leakage during inflammation. Cardiovasc Res. 2018;114:1752–1763. doi: 10.1093/cvr/cvy167. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Chappell D, Jacob M, Hofmann-Kiefer K. Antithrombin reduces shedding of the endothelial glycocalyx following ischaemia/reperfusion. Cardiovasc Res. 2009;83:388–396. doi: 10.1093/cvr/cvp097. [DOI] [PubMed] [Google Scholar]
- 40.Smart L, Bosio E, Macdonald SPJ. Glycocalyx biomarker syndecan-1 is a stronger predictor of respiratory failure in patients with sepsis due to pneumonia, compared to endocan. J Crit Care. 2018;47:93–98. doi: 10.1016/j.jcrc.2018.06.015. [DOI] [PubMed] [Google Scholar]
- 41.Hippensteel JA, Anderson BJ, Orfila JE. Circulating heparan sulfate fragments mediate septic cognitive dysfunction. J Clin Invest. 2019;129:1779–1784. doi: 10.1172/JCI124485. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Anand D, Ray S, Srivastava LM, Bhargava S. Evolution of serum hyaluronan and syndecan levels in prognosis of sepsis patients. Clin Biochem. 2016;49:768–776. doi: 10.1016/j.clinbiochem.2016.02.014. [DOI] [PubMed] [Google Scholar]
- 43.Iba T, Levy JH. Derangement of the endothelial glycocalyx in sepsis. J Thromb Haemost. 2019;17:283–294. doi: 10.1111/jth.14371. [DOI] [PubMed] [Google Scholar]
- 44.Schmidt EP, Overdier KH, Sun X. Urinary glycosaminoglycans predict outcomes in septic shock and acute respiratory distress syndrome. Am J Respir Crit Care Med. 2016;194:439–449. doi: 10.1164/rccm.201511-2281OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Ikeda M, Matsumoto H, Ogura H. Circulating syndecan-1 predicts the development of disseminated intravascular coagulation in patients with sepsis. J Crit Care. 2018;43:48–53. doi: 10.1016/j.jcrc.2017.07.049. [DOI] [PubMed] [Google Scholar]
- 46.Uchimido R, Schmidt EP, Shapiro NI. The glycocalyx: a novel diagnostic and therapeutic target in sepsis. Crit Care. 2019;23:16. doi: 10.1186/s13054-018-2292-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288:373–376. doi: 10.1038/288373a0. [DOI] [PubMed] [Google Scholar]
- 48.Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327:524–526. doi: 10.1038/327524a0. [DOI] [PubMed] [Google Scholar]
- 49.Shu X, Keller TCt, Begandt D. Endothelial nitric oxide synthase in the microcirculation. Cell Mol Life Sci. 2015;72:4561–4575. doi: 10.1007/s00018-015-2021-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50.Chilian WM, Kuo L, DeFily DV, Jones CJ, Davis MJ. Endothelial regulation of coronary microvascular tone under physiological and pathophysiological conditions. Eur Heart J. 1993;14(Suppl I):55–59. [PubMed] [Google Scholar]
- 51.Mooij HL, Cabrales P, Bernelot Moens SJ. Loss of function in heparan sulfate elongation genes EXT1 and EXT 2 results in improved nitric oxide bioavailability and endothelial function. J Am Heart Assoc. 2014;3 doi: 10.1161/JAHA.114.001274. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52.Matsushita K, Morrell CN, Cambien B. Nitric oxide regulates exocytosis by S-nitrosylation of N-ethylmaleimide-sensitive factor. Cell. 2003;115:139–150. doi: 10.1016/s0092-8674(03)00803-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 53.Broeders MA, Tangelder GJ, Slaaf DW, Reneman RS, oude Egbrink MG. Endogenous nitric oxide protects against thromboembolism in venules but not in arterioles. Arterioscler Thromb Vasc Biol. 1998;18:139–145. doi: 10.1161/01.atv.18.1.139. [DOI] [PubMed] [Google Scholar]
- 54.Yao SK, Ober JC, Krishnaswami A. Endogenous nitric oxide protects against platelet aggregation and cyclic flow variations in stenosed and endothelium-injured arteries. Circulation. 1992;86:1302–1309. doi: 10.1161/01.cir.86.4.1302. [DOI] [PubMed] [Google Scholar]
- 55.Nakayama T, Sato W, Yoshimura A. Endothelial von Willebrand factor release due to eNOS deficiency predisposes to thrombotic microangiopathy in mouse aging kidney. Am J Pathol. 2010;176:2198–2208. doi: 10.2353/ajpath.2010.090316. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56.Goldberg RJ, Nakagawa T, Johnson RJ, Thurman JM. The role of endothelial cell injury in thrombotic microangiopathy. Am J Kidney Dis. 2010;56:1168–1174. doi: 10.1053/j.ajkd.2010.06.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57.Walshe TE, Ferguson G, Connell P, O'Brien C, Cahill PA. Pulsatile flow increases the expression of eNOS, ET-1, and prostacyclin in a novel in vitro coculture model of the retinal vasculature. Invest Ophthalmol Vis Sci. 2005;46:375–382. doi: 10.1167/iovs.04-0806. [DOI] [PubMed] [Google Scholar]
- 58.Higgs EA, Higgs GA, Moncada S, Vane JR. Prostacyclin (PGI2) inhibits the formation of platelet thrombi in arterioles and venules of the hamster cheek pouch. Br J Pharmacol. 1978;63:535–539. doi: 10.1111/j.1476-5381.1978.tb07809.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 59.Broeders MA, Tangelder GJ, Slaaf DW, Reneman RS, Egbrink MG. Endogenous nitric oxide and prostaglandins synergistically counteract thromboembolism in arterioles but not in venules. Arterioscler Thromb Vasc Biol. 2001;21:163–169. doi: 10.1161/01.atv.21.1.163. [DOI] [PubMed] [Google Scholar]
- 60.Spier SA, Delp MD, Stallone JN, Dominguez JM, 2nd, Muller-Delp JM. Exercise training enhances flow-induced vasodilation in skeletal muscle resistance arteries of aged rats: role of PGI2 and nitric oxide. Am J Physiol Heart Circ Physiol. 2007;292:H3119–H3127. doi: 10.1152/ajpheart.00588.2006. [DOI] [PubMed] [Google Scholar]
- 61.Ruan CH, So SP, Ruan KH. Inducible COX-2 dominates over COX-1 in prostacyclin biosynthesis: mechanisms of COX-2 inhibitor risk to heart disease. Life Sci. 2011;88:24–30. doi: 10.1016/j.lfs.2010.10.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62.Armstrong PC, Truss NJ, Ali FY. Aspirin and the in vitro linear relationship between thromboxane A2-mediated platelet aggregation and platelet production of thromboxane A2. J Thromb Haemost. 2008;6:1933–1943. doi: 10.1111/j.1538-7836.2008.03133.x. [DOI] [PubMed] [Google Scholar]
- 63.Mitchell JA, Shala F, Elghazouli Y. Cell-specific gene deletion reveals the antithrombotic function of COX1 and explains the vascular COX1/prostacyclin paradox. Circ Res. 2019;125:847–854. doi: 10.1161/CIRCRESAHA.119.314927. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 64.Mitchell JA, Ali F, Bailey L, Moreno L, Harrington LS. Role of nitric oxide and prostacyclin as vasoactive hormones released by the endothelium. Exp Physiol. 2008;93:141–147. doi: 10.1113/expphysiol.2007.038588. [DOI] [PubMed] [Google Scholar]
- 65.Au WY, Lie AK, Lam CC. Tacrolimus (FK 506) induced thrombotic thrombocytopenic purpura after ABO mismatched second liver transplantation: salvage with plasmapheresis and prostacyclin. Haematologica. 2000;85:659–662. [PubMed] [Google Scholar]
- 66.Gateley DR, McAnulty GR, Martin DL. Intravenous infusion of prostacyclin to prevent platelet thrombus during microvascular anastomoses. Br J Plast Surg. 1996;49:249–250. doi: 10.1016/s0007-1226(96)90061-2. [DOI] [PubMed] [Google Scholar]
- 67.Salvi F, Baraldi A, Allione B, Santi R, Inverardi D, Levis A. Unsuccessful treatment of resistant thrombotic thrombocytopenic purpura with prostacyclin. Haematologica. 2000;85:1329–1330. [PubMed] [Google Scholar]
- 68.Kaczmarek E, Koziak K, Sevigny J. Identification and characterization of CD39/vascular ATP diphosphohydrolase. J Biol Chem. 1996;271:33116–33122. doi: 10.1074/jbc.271.51.33116. [DOI] [PubMed] [Google Scholar]
- 69.Broze GJ, Jr., Girard TJ. Tissue factor pathway inhibitor: structure-function. Front Biosci (Landmark Ed) 2012;17:262–280. doi: 10.2741/3926. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 70.Scaldaferri F, Sans M, Vetrano S. Crucial role of the protein C pathway in governing microvascular inflammation in inflammatory bowel disease. J Clin Invest. 2007;117:1951–1960. doi: 10.1172/JCI31027. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 71.Felsch JS, Owen WG. Endogenous antithrombin associated with microvascular endothelium. Quantitative analysis in perfused rat hearts. Biochemistry. 1994;33:818–822. doi: 10.1021/bi00169a024. [DOI] [PubMed] [Google Scholar]
- 72.Abraham E, Reinhart K, Opal S. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. Jama. 2003;290:238–247. doi: 10.1001/jama.290.2.238. [DOI] [PubMed] [Google Scholar]
- 73.Ranieri VM, Thompson BT, Barie PS. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med. 2012;366:2055–2064. doi: 10.1056/NEJMoa1202290. [DOI] [PubMed] [Google Scholar]
- 74.Warren BL, Eid A, Singer P. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA. 2001;286:1869–1878. doi: 10.1001/jama.286.15.1869. [DOI] [PubMed] [Google Scholar]
- 75.Vincent JL, Francois B, Zabolotskikh I. Effect of a recombinant human soluble thrombomodulin on mortality in patients with sepsis-associated coagulopathy: the SCARLET randomized clinical trial. JAMA. 2019;321:1993–2002. doi: 10.1001/jama.2019.5358. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 76.Murao S, Yamakawa K. A systematic summary of systematic reviews on anticoagulant therapy in sepsis. J Clin Med. 2019;8:1–9. doi: 10.3390/jcm8111869. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 77.Whinna HC. Overview of murine thrombosis models. Thromb Res. 2008;122(Suppl 1):S64–S69. doi: 10.1016/S0049-3848(08)70022-7. [DOI] [PubMed] [Google Scholar]
- 78.Rumbaut RE, Slaaf DW, Burns AR. Microvascular thrombosis models in venules and arterioles in vivo. Microcirculation. 2005;12:259–274. doi: 10.1080/10739680590925664. [DOI] [PubMed] [Google Scholar]
- 79.Saito MS, Lourenco AL, Kang HC. New approaches in tail-bleeding assay in mice: improving an important method for designing new anti-thrombotic agents. Int J Exp Pathol. 2016;97:285–292. doi: 10.1111/iep.12182. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 80.Gushiken FC, Han H, Li J, Rumbaut RE, Afshar-Kharghan V. Abnormal platelet function in C3-deficient mice. J Thromb Haemost. 2009;7:865–870. doi: 10.1111/j.1538-7836.2009.03334.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 81.Bellio M, Garcia C, Edouard T. Catalytic dysregulation of SHP2 leading to Noonan syndromes affects platelet signaling and functions. Blood. 2019;134:2304–2317. doi: 10.1182/blood.2019001543. [DOI] [PubMed] [Google Scholar]
- 82.van Gestel MA, Reitsma S, Slaaf DW. Both ADP and thrombin regulate arteriolar thrombus stabilization and embolization, but are not involved in initial hemostasis as induced by micropuncture. Microcirculation. 2007;14:193–205. doi: 10.1080/10739680601139294. [DOI] [PubMed] [Google Scholar]
- 83.Arfors KE, Arturson G, Bergqvist D, Svensjo E. The effect ofinhibition of prostaglandin synthesis on microvascular haemostasis and macromolecular leakage. Thromb Res. 1976;8:393–402. doi: 10.1016/0049-3848(76)90032-3. [DOI] [PubMed] [Google Scholar]
- 84.van Gestel MA, Heemskerk JW, Slaaf DW. Real-time detection of activation patterns in individual platelets during thromboembolism in vivo: differences between thrombus growth and embolus formation. J Vasc Res. 2002;39:534–543. doi: 10.1159/000067208. [DOI] [PubMed] [Google Scholar]
- 85.Lewis GP, Smith JR. Prostaglandin endoperoxides and thromboxane A2 in thrombus formation in the hamster cheek pouch in vivo. Prostaglandins. 1984;28:29–41. doi: 10.1016/0090-6980(84)90111-4. [DOI] [PubMed] [Google Scholar]
- 86.Takano S, Suzuki T. A study on the in vivo production ofthrombosis in rat mesenteric arterioles and action of prostaglandin (PG) I2 on the thrombosis. Jpn J Pharmacol. 1982;32:439–444. doi: 10.1254/jjp.32.439. [DOI] [PubMed] [Google Scholar]
- 87.Gordon JL, Evans RJ, Gresham GA. Experimental thrombus formation in mesenteric microvessels: evaluation of a method. Microvasc Res. 1973;6:108–115. doi: 10.1016/0026-2862(73)90011-3. [DOI] [PubMed] [Google Scholar]
- 88.Brooks AM, Fulton GP. A comparison of vascular smooth muscle reactivity, thrombus formation and fragility in response to electrical stimuli in the hamster cheek pouch and mesocaecum. Angiology. 1965;16:470–477. doi: 10.1177/000331976501600807. [DOI] [PubMed] [Google Scholar]
- 89.Hechler B, Nonne C, Eckly A. Arterial thrombosis: relevance of a model with two levels of severity assessed by histologic, ultrastructural and functional characterization. J Thromb Haemost. 2010;8:173–184. doi: 10.1111/j.1538-7836.2009.03666.x. [DOI] [PubMed] [Google Scholar]
- 90.Rumbaut RE, Randhawa JK, Smith CW, Burns AR. Mouse cremaster venules are predisposed to light/dye-induced thrombosis independent of wall shear rate, CD18, ICAM-1, or P-selectin. Microcirculation. 2004;11:239–247. doi: 10.1080/10739680490425949. [DOI] [PubMed] [Google Scholar]
- 91.Bekendam RH, Iyu D, Passam F. Protein disulfide isomerase regulation by nitric oxide maintains vascular quiescence and controls thrombus formation. J Thromb Haemost. 2018;16:2322–2335. doi: 10.1111/jth.14291. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 92.Zhou J, Wu Y, Chen F, Wang L. The disulfide isomerase ERp72 supports arterial thrombosis in mice. Blood. 2017;130:817–828. doi: 10.1182/blood-2016-12-755587. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 93.Yeung J, Tourdot BE, Adili R. 12(S)-HETrE, a 12-Lipoxygenase oxylipin of dihomo-gamma-linolenic acid, inhibits thrombosis via galphas signaling in platelets. Arterioscler Thromb Vasc Biol. 2016;36:2068–2077. doi: 10.1161/ATVBAHA.116.308050. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 94.Senchenkova EY, Ansari J, Becker F. Novel role for the AnxA1-Fpr2/ALX signaling axis as a key regulator of platelet function to promote resolution of inflammation. Circulation. 2019;140:319–335. doi: 10.1161/CIRCULATIONAHA.118.039345. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 95.Kim S, Dangelmaier C, Bhavanasi D. RhoG protein regulates glycoprotein VI-Fc receptor gamma-chain complex-mediated platelet activation and thrombus formation. J Biol Chem. 2013;288:34230–34238. doi: 10.1074/jbc.M113.504928. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 96.Patel KN, Soubra SH, Bellera RV. Differential role of vonWillebrand factor and P-selectin on microvascular thrombosis in endotoxemia. Arterioscler Thromb Vasc Biol. 2008;28:2225–2230. doi: 10.1161/ATVBAHA.108.175679. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 97.Ware J. Dysfunctional platelet membrane receptors: from humans to mice. Thromb Haemost. 2004;92:478–485. doi: 10.1267/THRO04090478. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 98.Rowley JW, Oler AJ, Tolley ND. Genome-wide RNA-seq analysis of human and mouse platelet transcriptomes. Blood. 2011;118:e101–e111. doi: 10.1182/blood-2011-03-339705. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 99.Mestas J, Hughes CC. Of mice and not men: differences between mouse and human immunology. J Immunol. 2004;172:2731–2738. doi: 10.4049/jimmunol.172.5.2731. [DOI] [PubMed] [Google Scholar]
- 100.Wong CH, Jenne CN, Petri B, Chrobok NL, Kubes P. Nucleation of platelets with blood-borne pathogens on Kupffer cells precedes other innate immunity and contributes to bacterial clearance. Nat Immunol. 2013;14:785–792. doi: 10.1038/ni.2631. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 101.Kolaczkowska E, Jenne CN, Surewaard BG. Molecular mechanisms of NET formation and degradation revealed by intravital imaging in the liver vasculature. Nat Commun. 2015;6:6673. doi: 10.1038/ncomms7673. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 102.Li W, McIntyre TM, Silverstein RL. Ferric chloride-induced murine carotid arterial injury: a model of redox pathology. Redox Biol. 2013;1:50–55. doi: 10.1016/j.redox.2012.11.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 103.Kurz KD, Main BW, Sandusky GE. Rat model of arterial thrombosis induced by ferric chloride. Thromb Res. 1990;60:269–280. doi: 10.1016/0049-3848(90)90106-m. [DOI] [PubMed] [Google Scholar]
- 104.Bonnard T, Hagemeyer CE.Ferric chloride-induced thrombosis mouse model on carotid artery and mesentery vessel. J Vis Exp. 2015:e52838. [DOI] [PMC free article] [PubMed]
- 105.Sorvillo N, Mizurini DM, Coxon C. Plasma peptidylarginine deiminase IV promotes VWF-platelet string formation and accelerates thrombosis after vessel injury. Circ Res. 2019;125:507–519. doi: 10.1161/CIRCRESAHA.118.314571. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 106.Faraday N, Schunke K, Saleem S. Cathepsin G-dependent modulation of platelet thrombus formation in vivo by blood neutrophils. PLoS One. 2013;8:e71447. doi: 10.1371/journal.pone.0071447. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 107.Ciciliano JC, Sakurai Y, Myers DR. Resolving the multifaceted mechanisms of the ferric chloride thrombosis model using an interdisciplinary microfluidic approach. Blood. 2015;126:817–824. doi: 10.1182/blood-2015-02-628594. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 108.Barr JD, Chauhan AK, Schaeffer GV, Hansen JK, Motto DG. Red blood cells mediate the onset of thrombosis in the ferric chloride murine model. Blood. 2013;121:3733–3741. doi: 10.1182/blood-2012-11-468983. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 109.Andre P, Denis CV, Ware J. Platelets adhere to and translocate on von Willebrand factor presented by endothelium in stimulated veins. Blood. 2000;96:3322–3328. [PubMed] [Google Scholar]
- 110.Lu Y, Li Q, Liu YY. Inhibitory effect of caffeic acid on ADP-induced thrombus formation and platelet activation involves mitogen-activated protein kinases. Sci Rep. 2015;5:13824. doi: 10.1038/srep13824. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 111.Nguyen TC, Gushiken F, Correa JI. A recombinant fragment of von Willebrand factor reduces fibrin-rich microthrombi formation in mice with endotoxemia. Thromb Res. 2015;135:1025–1030. doi: 10.1016/j.thromres.2015.02.033. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 112.Adili R, Holinstat M. Formation and resolution of pial microvascular thrombosis in a mouse model of thrombotic thrombocytopenic purpura. Arterioscler Thromb Vasc Biol. 2019;39:1817–1830. doi: 10.1161/ATVBAHA.119.312848. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 113.Hohenstein B, Braun A, Amann KU, Johnson RJ, Hugo CP. A murine model of site-specific renal microvascular endothelial injury and thrombotic microangiopathy. Nephrol Dial Transplant. 2008;23:1144–1156. doi: 10.1093/ndt/gfm774. [DOI] [PubMed] [Google Scholar]
- 114.Mirramezani M, Herbig BA, Stalker TJ. Platelet packing density is an independent regulator of the hemostatic response to injury. J Thromb Haemost. 2018;16:973–983. doi: 10.1111/jth.13986. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 115.Welsh JD, Muthard RW, Stalker TJ, Taliaferro JP, Diamond SL, Brass LF. A systems approach to hemostasis: 4. How hemostatic thrombi limit the loss of plasma-borne molecules from the microvasculature. Blood. 2016;127:1598–1605. doi: 10.1182/blood-2015-09-672188. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 116.Courson JA, Smith I, Do T. Serial block-face scanning electron microscopy reveals neuronal-epithelial cell fusion in the mouse cornea. PLoS One. 2019;14 doi: 10.1371/journal.pone.0224434. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 117.Hosler GA, Cusumano AM, Hutchins GM. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are distinct pathologic entities. A review of 56 autopsy cases. Arch Pathol Lab Med. 2003;127:834–839. doi: 10.5858/2003-127-834-TTPAHU. [DOI] [PubMed] [Google Scholar]
- 118.Esaki Y, Hirokawa K, Fukazawa T, Matsuda T. Immunohistochemical study on the liver in autopsy cases with disseminated intravascular coagulation (DIC) with reference to clinicopathological analysis. Virchows Arch A Pathol Anat Histopathol. 1984;404:229–241. doi: 10.1007/BF00694889. [DOI] [PubMed] [Google Scholar]
- 119.Chernysh IN, Nagaswami C, Kosolapova S. The distinctive structure and composition of arterial and venous thrombi and pulmonary emboli. Sci Rep. 2020;10:5112. doi: 10.1038/s41598-020-59526-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 120.Beuker C, Schmidt A, Strunk D. Primary angiitis of the central nervous system: diagnosis and treatment. Ther Adv Neurol Disord. 2018;11 doi: 10.1177/1756286418785071. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 121.Aslanidis S, Pyrpasopoulou A, Doumas M, Triantafyllou A, Chatzimichailidou S, Zamboulis C. Association of capillaroscopic microhaemorrhages with clinical and immunological antiphospholipid syndrome. Clin Exp Rheumatol. 2011;29:307–309. [PubMed] [Google Scholar]
- 122.Andracco R, Irace R, Zaccara E. The cumulative number of micro-haemorrhages and micro-thromboses in nailfold videocapillaroscopy is a good indicator of disease activity in systemic sclerosis: a validation study of the NEMO score. Arthritis Res Ther. 2017;19:133. doi: 10.1186/s13075-017-1354-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 123.Go RS, Winters JL, Leung N. Thrombotic microangiopathy care pathway: a consensus statement for the Mayo Clinic Complement Alternative Pathway-Thrombotic Microangiopathy (CAP-TMA) Disease-Oriented Group. Mayo Clin Proc. 2016;91:1189–1211. doi: 10.1016/j.mayocp.2016.05.015. [DOI] [PubMed] [Google Scholar]
- 124.Bull BS, Kuhn IN. The production of schistocytes by fibrin strands (a scanning electron microscope study) Blood. 1970;35:104–111. [PubMed] [Google Scholar]
- 125.Winters JL. Plasma exchange in thrombotic microangiopathies (TMAs) other than thrombotic thrombocytopenic purpura (TTP) Hematology Am Soc Hematol Educ Program. 2017;2017:632–638. doi: 10.1182/asheducation-2017.1.632. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 126.Padmanabhan A, Connelly-Smith L, Aqui N. Guidelines on the use of therapeutic apheresis in clinical practice - evidence-based approach from the writing committee of the American Society for Apheresis: The eighth special issue. J Clin Apher. 2019;34:171–354. doi: 10.1002/jca.21705. [DOI] [PubMed] [Google Scholar]
- 127.Kreuter J, Winters JL. Drug-associated thrombotic microangiopathies. Semin Thromb Hemost. 2012;38:839–844. doi: 10.1055/s-0032-1328886. [DOI] [PubMed] [Google Scholar]
- 128.Colic E, Dieperink H, Titlestad K, Tepel M. Management of an acute outbreak of diarrhoea-associated haemolytic uraemic syndrome with early plasma exchange in adults from southern Denmark: an observational study. Lancet. 2011;378:1089–1093. doi: 10.1016/S0140-6736(11)61145-8. [DOI] [PubMed] [Google Scholar]
- 129.Scully M, Hunt BJ, Benjamin S. Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol. 2012;158:323–335. doi: 10.1111/j.1365-2141.2012.09167.x. [DOI] [PubMed] [Google Scholar]
- 130.Matsuyama T, Kuwana M, Matsumoto M, Isonishi A, Inokuma S, Fujimura Y. Heterogeneous pathogenic processes of thrombotic microangiopathies in patients with connective tissue diseases. Thromb Haemost. 2009;102:371–378. doi: 10.1160/TH08-12-0825. [DOI] [PubMed] [Google Scholar]
- 131.Schneider SW, Nuschele S, Wixforth A. Shear-induced unfolding triggers adhesion of von Willebrand factor fibers. Proc Natl Acad Sci U S A. 2007;104:7899–7903. doi: 10.1073/pnas.0608422104. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 132.Tsai HM. Pathophysiology of thrombotic thrombocytopenic purpura. Int J Hematol. 2010;91:1–19. doi: 10.1007/s12185-009-0476-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 133.Dong JF, Moake JL, Nolasco L. ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions. Blood. 2002;100:4033–4039. doi: 10.1182/blood-2002-05-1401. [DOI] [PubMed] [Google Scholar]
- 134.George JN. Clinical practice. Thrombotic thrombocytopenic purpura. N Engl J Med. 2006;354:1927–1935. doi: 10.1056/NEJMcp053024. [DOI] [PubMed] [Google Scholar]
- 135.Bajaj MS, Kuppuswamy MN, Manepalli AN, Bajaj SP. Transcriptional expression of tissue factor pathway inhibitor, thrombomodulin and von Willebrand factor in normal human tissues. Thromb Haemost. 1999;82:1047–1052. [PubMed] [Google Scholar]
- 136.Yamamoto K, de Waard V, Fearns C, Loskutoff DJ. Tissue distribution and regulation of murine von Willebrand factor gene expression in vivo. Blood. 1998;92:2791–2801. [PubMed] [Google Scholar]
- 137.Mbagwu SI, Filgueira L. Differential expression of CD31 and Von Willebrand Factor on endothelial cells in different regions of the human brain: potential implications for cerebral malaria pathogenesis. Brain Sci. 2020;10:1–12. doi: 10.3390/brainsci10010031. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 138.Bendapudi PK, Hurwitz S, Fry A. Derivation and external validation of the PLASMIC score for rapid assessment of adults with thrombotic microangiopathies: a cohort study. Lancet Haematol. 2017;4:e157–ee64. doi: 10.1016/S2352-3026(17)30026-1. [DOI] [PubMed] [Google Scholar]
- 139.Froissart A, Buffet M, Veyradier A. Efficacy and safety of first-line rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange. Experience of the French Thrombotic Microangiopathies Reference Center. Crit Care Med. 2012;40:104–111. doi: 10.1097/CCM.0b013e31822e9d66. [DOI] [PubMed] [Google Scholar]
- 140.Scully M, McDonald V, Cavenagh J. A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura. Blood. 2011;118:1746–1753. doi: 10.1182/blood-2011-03-341131. [DOI] [PubMed] [Google Scholar]
- 141.Scully M, Cataland SR, Peyvandi F. Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura. N Engl J Med. 2019;380:335–346. doi: 10.1056/NEJMoa1806311. [DOI] [PubMed] [Google Scholar]
- 142.Muscal E, Edwards RM, Kearney DL, Hicks JM, Myones BL, Teruya J. Thrombotic microangiopathic hemolytic anemia with reduction of ADAMTS13 activity: initial manifestation of childhood-onset systemic lupus erythematosus. Am J Clin Pathol. 2011;135:406–416. doi: 10.1309/AJCP5BVL4FCLCGLU. [DOI] [PubMed] [Google Scholar]
- 143.Lotta LA, Garagiola I, Palla R, Cairo A, Peyvandi F. ADAMTS13 mutations and polymorphisms in congenital thrombotic thrombocytopenic purpura. Hum Mutat. 2010;31:11–19. doi: 10.1002/humu.21143. [DOI] [PubMed] [Google Scholar]
- 144.Scully M, Knobl P, Kentouche K. Recombinant ADAMTS-13: first-in-human pharmacokinetics and safety in congenital thrombotic thrombocytopenic purpura. Blood. 2017;130:2055–2063. doi: 10.1182/blood-2017-06-788026. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 145.Nguyen TC, Liu A, Liu L. Acquired ADAMTS-13 deficiency in pediatric patients with severe sepsis. Haematologica. 2007;92:121–124. doi: 10.3324/haematol.10262. [DOI] [PubMed] [Google Scholar]
- 146.Azfar MF, Khan MF, Habib SS. Prognostic value of ADAMTS13 in patients with severe sepsis and septic shock. Clin Invest Med. 2017;40:E49–E58. doi: 10.25011/cim.v40i2.28195. [DOI] [PubMed] [Google Scholar]
- 147.Lansigan F, Isufi I, Tagoe CE. Microangiopathic haemolytic anaemia resembling thrombotic thrombocytopenic purpura in systemic lupus erythematosus: the role of ADAMTS13. Rheumatology (Oxford) 2011;50:824–829. doi: 10.1093/rheumatology/keq395. [DOI] [PubMed] [Google Scholar]
- 148.Li A, Makar RS, Hurwitz S. Treatment with or without plasma exchange for patients with acquired thrombotic microangiopathy not associated with severe ADAMTS13 deficiency: a propensity score-matched study. Transfusion. 2016;56:2069–2077. doi: 10.1111/trf.13654. [DOI] [PubMed] [Google Scholar]
- 149.Sartain SE, Turner NA, Moake JL. Brain microvascular endothelial cells exhibit lower activation of the alternative complement pathway than glomerular microvascular endothelial cells. J Biol Chem. 2018;293:7195–7208. doi: 10.1074/jbc.RA118.002639. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 150.Sartain SE, Turner NA, Moake JL. TNF regulates essential alternative complement pathway components and impairs activation of protein C in human glomerular endothelial cells. J Immunol. 2016;196:832–845. doi: 10.4049/jimmunol.1500960. [DOI] [PubMed] [Google Scholar]
- 151.Delvaeye M, Noris M, De Vriese A. Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:345–357. doi: 10.1056/NEJMoa0810739. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 152.Lingwood CA. Verotoxin-binding in human renal sections. Nephron. 1994;66:21–28. doi: 10.1159/000187761. [DOI] [PubMed] [Google Scholar]
- 153.Tarr PI, Gordon CA, Chandler WL. Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet. 2005;365:1073–1086. doi: 10.1016/S0140-6736(05)71144-2. [DOI] [PubMed] [Google Scholar]
- 154.Percheron L, Gramada R, Tellier S. Eculizumab treatment in severe pediatric STEC-HUS: a multicenter retrospective study. Pediatr Nephrol. 2018;33:1385–1394. doi: 10.1007/s00467-018-3903-9. [DOI] [PubMed] [Google Scholar]
- 155.Wong CS, Jelacic S, Habeeb RL, Watkins SL, Tarr PI. The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N Engl J Med. 2000;342:1930–1936. doi: 10.1056/NEJM200006293422601. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 156.Klein PJ, Bulla M, Newman RA. Thomsen-Friedenreich antigen in haemolytic-uraemic syndrome. Lancet. 1977;2:1024–1025. doi: 10.1016/s0140-6736(77)92915-4. [DOI] [PubMed] [Google Scholar]
- 157.McGraw ME, Lendon M, Stevens RF, Postlethwaite RJ, Taylor CM. Haemolytic uraemic syndrome and the Thomsen Friedenreich antigen. Pediatr Nephrol. 1989;3:135–139. doi: 10.1007/BF00852894. [DOI] [PubMed] [Google Scholar]
- 158.Geary DF. Hemolytic uremic syndrome and streptococcus pneumoniae: improving our understanding. J Pediatr. 2007;151:113–114. doi: 10.1016/j.jpeds.2007.04.057. [DOI] [PubMed] [Google Scholar]
- 159.Hill A, Hill QA. Autoimmune hemolytic anemia. Hematology Am Soc Hematol Educ Program. 2018;2018:382–389. doi: 10.1182/asheducation-2018.1.382. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 160.Ricklin D, Reis ES, Lambris JD. Complement in disease: a defence system turning offensive. Nat Rev Nephrol. 2016;12:383–401. doi: 10.1038/nrneph.2016.70. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 161.Noris M, Caprioli J, Bresin E. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol. 2010;5:1844–1859. doi: 10.2215/CJN.02210310. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 162.Sethi S, Fervenza FC. Pathology of renal diseases associated with dysfunction of the alternative pathway of complement: C3 glomerulopathy and atypical hemolytic uremic syndrome (aHUS) Semin Thromb Hemost. 2014;40:416–421. doi: 10.1055/s-0034-1375701. [DOI] [PubMed] [Google Scholar]
- 163.Clark SJ, Ridge LA, Herbert AP. Tissue-specific host recognition by complement factor H is mediated by differential activities of its glycosaminoglycan-binding regions. J Immunol. 2013;190:2049–2057. doi: 10.4049/jimmunol.1201751. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 164.Bu F, Maga T, Meyer NC. Comprehensive genetic analysis of complement and coagulation genes in atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2014;25:55–64. doi: 10.1681/ASN.2013050453. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 165.Sridharan M, Go RS, Abraham RS. Diagnostic utility of complement serology for atypical hemolytic uremic syndrome. Mayo Clin Proc. 2018;93:1351–1362. doi: 10.1016/j.mayocp.2018.07.008. [DOI] [PubMed] [Google Scholar]
- 166.Greenbaum LA, Fila M, Ardissino G. Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome. Kidney Int. 2016;89:701–711. doi: 10.1016/j.kint.2015.11.026. [DOI] [PubMed] [Google Scholar]
- 167.Fakhouri F, Hourmant M, Campistol JM. Terminal complement inhibitor eculizumab in adult patients with atypical hemolytic uremic syndrome: a single-arm, open-label trial. Am J Kidney Dis. 2016;68:84–93. doi: 10.1053/j.ajkd.2015.12.034. [DOI] [PubMed] [Google Scholar]
- 168.Patriquin CJ, Kuo KHM. Eculizumab and beyond: the past, present, and future of complement therapeutics. Transfus Med Rev. 2019;33:256–265. doi: 10.1016/j.tmrv.2019.09.004. [DOI] [PubMed] [Google Scholar]
- 169.Conway EM, Van de Wouwer M, Pollefeyt S. The lectin-like domain of thrombomodulin confers protection from neutrophil-mediated tissue damage by suppressing adhesion molecule expression via nuclear factor kappaB and mitogen-activated protein kinase pathways. J Exp Med. 2002;196:565–577. doi: 10.1084/jem.20020077. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 170.Lemaire M, Fremeaux-Bacchi V, Schaefer F. Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nat Genet. 2013;45:531–536. doi: 10.1038/ng.2590. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 171.Verbiest A, Pirenne J, Dierickx D. De novo thrombotic microangiopathy after non-renal solid organ transplantation. Blood Rev. 2014;28:269–279. doi: 10.1016/j.blre.2014.09.001. [DOI] [PubMed] [Google Scholar]
- 172.Oran B, Donato M, Aleman A. Transplant-associated microangiopathy in patients receiving tacrolimus following allogeneic stem cell transplantation: risk factors and response to treatment. Biol Blood Marrow Transplant. 2007;13:469–477. doi: 10.1016/j.bbmt.2006.11.020. [DOI] [PubMed] [Google Scholar]
- 173.Elsallabi O, Bhatt VR, Dhakal P, Foster KW, Tendulkar KK. Hematopoietic stem cell transplant-associated thrombotic microangiopathy. Clin Appl Thromb Hemost. 2016;22:12–20. doi: 10.1177/1076029615598221. [DOI] [PubMed] [Google Scholar]
- 174.Jodele S, Davies SM, Lane A. Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults. Blood. 2014;124:645–653. doi: 10.1182/blood-2014-03-564997. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 175.Kanamori H, Takaishi Y, Takabayashi M. Clinical significance of fragmented red cells after allogeneic bone marrow transplantation. Int J Hematol. 2003;77:180–184. doi: 10.1007/BF02983218. [DOI] [PubMed] [Google Scholar]
- 176.George JN, Li X, McMinn JR, Terrell DR, Vesely SK, Selby GB. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome following allogeneic HPC transplantation: a diagnostic dilemma. Transfusion. 2004;44:294–304. doi: 10.1111/j.1537-2995.2004.00700.x. [DOI] [PubMed] [Google Scholar]
- 177.Sartain S, Shubert S, Wu MF, Wang T, Martinez C. The alternative complement pathway activation product Ba as a marker for transplant-associated thrombotic microangiopathy. Pediatr Blood Cancer. 2020;67:e28070. doi: 10.1002/pbc.28070. [DOI] [PubMed] [Google Scholar]
- 178.Jodele S, Licht C, Goebel J. Abnormalities in the alternative pathway of complement in children with hematopoietic stem cell transplant-associated thrombotic microangiopathy. Blood. 2013;122:2003–2007. doi: 10.1182/blood-2013-05-501445. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 179.Sartain S, Shubert S, Wu MF. Therapeutic plasma exchange does not improve renal function in hematopoietic stem cell transplantation-associated thrombotic microangiopathy: an institutional experience. Biol Blood Marrow Transplant. 2019;25:157–162. doi: 10.1016/j.bbmt.2018.08.016. [DOI] [PubMed] [Google Scholar]
- 180.Jodele S, Fukuda T, Vinks A. Eculizumab therapy in children with severe hematopoietic stem cell transplantation-associated thrombotic microangiopathy. Biol Blood Marrow Transplant. 2014;20:518–525. doi: 10.1016/j.bbmt.2013.12.565. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 181.Bohl SR, Kuchenbauer F, von Harsdorf S. Thrombotic microangiopathy after allogeneic stem cell transplantation: a comparison of eculizumab therapy and conventional therapy. Biol Blood Marrow Transplant. 2017;23:2172–2177. doi: 10.1016/j.bbmt.2017.08.019. [DOI] [PubMed] [Google Scholar]
- 182.Al-Nouri ZL, Reese JA, Terrell DR, Vesely SK, George JN. Drug-induced thrombotic microangiopathy: a systematic review of published reports. Blood. 2015;125:616–618. doi: 10.1182/blood-2014-11-611335. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 183.Hay JE. Liver disease in pregnancy. Hepatology. 2008;47:1067–1076. doi: 10.1002/hep.22130. [DOI] [PubMed] [Google Scholar]
- 184.Ditisheim A, Sibai BM. Diagnosis and management of HELLP syndrome complicated by liver hematoma. Clin Obstet Gynecol. 2017;60:190–197. doi: 10.1097/GRF.0000000000000253. [DOI] [PubMed] [Google Scholar]
- 185.Barton JR, Riely CA, Adamec TA, Shanklin DR, Khoury AD, Sibai BM. Hepatic histopathologic condition does not correlate with laboratory abnormalities in HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count) Am J Obstet Gynecol. 1992;167:1538–1543. doi: 10.1016/0002-9378(92)91735-s. [DOI] [PubMed] [Google Scholar]
- 186.Baxter JK, Weinstein L. HELLP syndrome: the state of the art. Obstet Gynecol Surv. 2004;59:838–845. doi: 10.1097/01.ogx.0000146948.19308.c5. [DOI] [PubMed] [Google Scholar]
- 187.Polsani S, Phipps E, Jim B. Emerging new biomarkers of preeclampsia. Adv Chronic Kidney Dis. 2013;20:271–279. doi: 10.1053/j.ackd.2013.01.001. [DOI] [PubMed] [Google Scholar]
- 188.Simsek Y, Gul M, Celik O. Nuclear transcription factor-kappa beta-dependent ultrastructural alterations within the placenta and systemic inflammatory activation in pregnant patients with hemolysis, elevated liver functions and low thrombocyte count (HELLP) syndrome: a case-control study. Hypertens Pregnancy. 2013;32:281–291. doi: 10.3109/10641955.2013.806538. [DOI] [PubMed] [Google Scholar]
- 189.Vaught AJ, Gavriilaki E, Hueppchen N. Direct evidence of complement activation in HELLP syndrome: a link to atypical hemolytic uremic syndrome. Exp Hematol. 2016;44:390–398. doi: 10.1016/j.exphem.2016.01.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 190.Terrone DA, Rinehart BK, May WL, Moore A, Magann EF, Martin JN., Jr. Leukocytosis is proportional to HELLP syndrome severity: evidence for an inflammatory form of preeclampsia. South Med J. 2000;93:768–771. [PubMed] [Google Scholar]
- 191.Vaught AJ, Braunstein EM, Jasem J. Germline mutations in the alternative pathway of complement predispose to HELLP syndrome. JCI Insight. 2018;3 doi: 10.1172/jci.insight.99128. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 192.Fakhouri F, Jablonski M, Lepercq J. Factor H, membrane cofactor protein, and factor I mutations in patients with hemolysis, elevated liver enzymes, and low platelet count syndrome. Blood. 2008;112:4542–4545. doi: 10.1182/blood-2008-03-144691. [DOI] [PubMed] [Google Scholar]
- 193.Fang CJ, Richards A, Liszewski MK, Kavanagh D, Atkinson JP. Advances in understanding of pathogenesis of aHUS and HELLP. Br J Haematol. 2008;143:336–348. doi: 10.1111/j.1365-2141.2008.07324.x. [DOI] [PubMed] [Google Scholar]
- 194.Sibai BM. Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver enzymes, and low platelet count. Obstet Gynecol. 2004;103:981–991. doi: 10.1097/01.AOG.0000126245.35811.2a. [DOI] [PubMed] [Google Scholar]
- 195.American College of O, Gynecologists Task force on hypertension in P. hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy. Obstet Gynecol. 2013;122:1122–1131. doi: 10.1097/01.AOG.0000437382.03963.88. [DOI] [PubMed] [Google Scholar]
- 196.van Runnard Heimel PJ, Kavelaars A, Heijnen CJ. HELLP syndrome is associated with an increased inflammatory response, which may be inhibited by administration of prednisolone. Hypertens Pregnancy. 2008;27:253–265. doi: 10.1080/10641950802174953. [DOI] [PubMed] [Google Scholar]
- 197.Woudstra DM, Chandra S, Hofmeyr GJ, Dowswell T. Corticosteroids for HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome in pregnancy. Cochrane Database Syst Rev. 2010 doi: 10.1002/14651858.CD008148.pub2. Issue 9. Art. No.: CD008148. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 198.Elabd H, Elkholi M, Steinberg L, Acharya A. Eculizumab, a novel potential treatment for acute kidney injury associated with preeclampsia/HELLP syndrome. BMJ Case Rep. 2019;12 doi: 10.1136/bcr-2018-228709. e228709. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 199.Lesesve JF, Martin M, Banasiak C. Schistocytes in disseminated intravascular coagulation. Int J Lab Hematol. 2014;36:439–443. doi: 10.1111/ijlh.12168. [DOI] [PubMed] [Google Scholar]
- 200.Katz J, Lurie A, Kaplan BS, Krawitz S, Metz J. Coagulation findings in the hemolytic-uremic syndrome of infancy: similarity to hyperacute renal allograft rejection. J Pediatr. 1971;78:426–434. doi: 10.1016/s0022-3476(71)80222-6. [DOI] [PubMed] [Google Scholar]
- 201.Sakurai S, Kato H, Yoshida Y. Profiles of coagulation and fibrinolysis activation-associated molecular markers of atypical hemolytic uremic syndrome in the acute phase. J Atheroscler Thromb. 2019;27:353–362. doi: 10.5551/jat.49494. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 202.Taylor FB, Jr., Toh CH, Hoots WK, Wada H, Levi M. Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost. 2001;86:1327–1330. [PubMed] [Google Scholar]
- 203.Wada H, Matsumoto T, Yamashita Y. Diagnosis and treatment of disseminated intravascular coagulation (DIC) according to four DIC guidelines. J Intensive Care. 2014;2:15. doi: 10.1186/2052-0492-2-15. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 204.Singer M, Deutschman CS, Seymour CW. The third international consensus definitions for sepsis and septic shock (Sepsis-3) JAMA. 2016;315:801–810. doi: 10.1001/jama.2016.0287. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 205.Lehman MK, Nuxoll AS, Yamada KJ, Kielian T, Carson SD, Fey PD. Protease-mediated growth of staphylococcus aureus on host proteins is opp3 dependent. mBio. 2019;10 doi: 10.1128/mBio.02553-18. e02553–18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 206.Malachowa N, Kobayashi SD, Porter AR. Contribution of staphylococcus aureus coagulases and clumping factor A to abscess formation in a rabbit model of skin and soft tissue infection. PLoS One. 2016;11 doi: 10.1371/journal.pone.0158293. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 207.Levi M, van der Poll T. Inflammation and coagulation. Crit Care Med. 2010;38:S26–S34. doi: 10.1097/CCM.0b013e3181c98d21. [DOI] [PubMed] [Google Scholar]
- 208.Witkowski M, Landmesser U, Rauch U. Tissue factor as a link between inflammation and coagulation. Trends Cardiovasc Med. 2016;26:297–303. doi: 10.1016/j.tcm.2015.12.001. [DOI] [PubMed] [Google Scholar]
- 209.Tartey S, Takeuchi O. Pathogen recognition and Toll-like receptor targeted therapeutics in innate immune cells. Int Rev Immunol. 2017;36:57–73. doi: 10.1080/08830185.2016.1261318. [DOI] [PubMed] [Google Scholar]
- 210.Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med. 2003;348:138–150. doi: 10.1056/NEJMra021333. [DOI] [PubMed] [Google Scholar]
- 211.Carcillo JA, Berg RA, Wessel D. A multicenter network assessment of three inflammation phenotypes in pediatric sepsis-induced multiple organ failure. Pediatr Crit Care Med. 2019;20:1137–1146. doi: 10.1097/PCC.0000000000002105. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 212.Gando S, Levi M, Toh CH. Disseminated intravascular coagulation. Nat Rev Dis Primers. 2016;2:16037. doi: 10.1038/nrdp.2016.37. [DOI] [PubMed] [Google Scholar]
- 213.Levi M, Sivapalaratnam S. Disseminated intravascular coagulation: an update on pathogenesis and diagnosis. Expert Rev Hematol. 2018;11:663–672. doi: 10.1080/17474086.2018.1500173. [DOI] [PubMed] [Google Scholar]
- 214.Drake TA, Morrissey JH, Edgington TS. Selective cellular expression of tissue factor in human tissues. Implications for disorders of hemostasis and thrombosis. Am J Pathol. 1989;134:1087–1097. [PMC free article] [PubMed] [Google Scholar]
- 215.Fleck RA, Rao LV, Rapaport SI, Varki N. Localization of human tissue factor antigen by immunostaining with monospecific, polyclonal anti-human tissue factor antibody. Thromb Res. 1990;59:421–437. doi: 10.1016/0049-3848(90)90148-6. [DOI] [PubMed] [Google Scholar]
- 216.Grover SP, Mackman N. Tissue factor: an essential mediator of hemostasis and trigger of thrombosis. Arterioscler Thromb Vasc Biol. 2018;38:709–725. doi: 10.1161/ATVBAHA.117.309846. [DOI] [PubMed] [Google Scholar]
- 217.Franco RF, de Jonge E, Dekkers PE. The in vivo kinetics of tissue factor messenger RNA expression during human endotoxemia: relationship with activation of coagulation. Blood. 2000;96:554–559. [PubMed] [Google Scholar]
- 218.Osterud B, Bouchard BA. Detection of tissue factor in platelets: why is it so troublesome? Platelets. 2019;30:957–961. doi: 10.1080/09537104.2019.1624708. [DOI] [PubMed] [Google Scholar]
- 219.Bode M, Mackman N. Regulation of tissue factor gene expression in monocytes and endothelial cells: thromboxane A2 as a new player. Vascul Pharmacol. 2014;62:57–62. doi: 10.1016/j.vph.2014.05.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 220.Marshall JC. Why have clinical trials in sepsis failed? Trends Mol Med. 2014;20:195–203. doi: 10.1016/j.molmed.2014.01.007. [DOI] [PubMed] [Google Scholar]
- 221.Elaskalani O, Abdol Razak NB, Metharom P. Neutrophil extracellular traps induce aggregation of washed human platelets independently of extracellular DNA and histones. Cell Commun Signal. 2018;16:24. doi: 10.1186/s12964-018-0235-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 222.Lam FW, Cruz MA, Leung HC, Parikh KS, Smith CW, Rumbaut RE. Histone induced platelet aggregation is inhibited by normal albumin. Thromb Res. 2013;132:69–76. doi: 10.1016/j.thromres.2013.04.018. [DOI] [PubMed] [Google Scholar]
- 223.Lam FW, Cruz MA, Parikh K, Rumbaut RE. Histones stimulate von Willebrand factor release in vitro and in vivo. Haematologica. 2016;101:e277–e279. doi: 10.3324/haematol.2015.140632. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 224.Gould TJ, Vu TT, Swystun LL. Neutrophil extracellular traps promote thrombin generation through platelet-dependent and platelet-independent mechanisms. Arterioscler Thromb Vasc Biol. 2014;34:1977–1984. doi: 10.1161/ATVBAHA.114.304114. [DOI] [PubMed] [Google Scholar]
- 225.Liaw PC, Ito T, Iba T, Thachil J, Zeerleder S. DAMP and DIC: the role of extracellular DNA and DNA-binding proteins in the pathogenesis of DIC. Blood Rev. 2016;30:257–261. doi: 10.1016/j.blre.2015.12.004. [DOI] [PubMed] [Google Scholar]
- 226.Fuchs TA, Brill A, Duerschmied D. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A. 2010;107:15880–15885. doi: 10.1073/pnas.1005743107. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 227.Grassle S, Huck V, Pappelbaum KI. von Willebrand factor directly interacts with DNA from neutrophil extracellular traps. Arterioscler Thromb Vasc Biol. 2014;34:1382–1389. doi: 10.1161/ATVBAHA.113.303016. [DOI] [PubMed] [Google Scholar]
- 228.Massberg S, Grahl L, von Bruehl ML. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med. 2010;16:887–896. doi: 10.1038/nm.2184. [DOI] [PubMed] [Google Scholar]
- 229.Papayannopoulos V. Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol. 2018;18:134–147. doi: 10.1038/nri.2017.105. [DOI] [PubMed] [Google Scholar]
- 230.von Bruhl ML, Stark K, Steinhart A. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med. 2012;209:819–835. doi: 10.1084/jem.20112322. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 231.Brill A, Fuchs TA, Savchenko AS. Neutrophil extracellular traps promote deep vein thrombosis in mice. J Thromb Haemost. 2012;10:136–144. doi: 10.1111/j.1538-7836.2011.04544.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 232.Jimenez-Alcazar M, Rangaswamy C, Panda R. Host DNases prevent vascular occlusion by neutrophil extracellular traps. Science. 2017;358:1202–1206. doi: 10.1126/science.aam8897. [DOI] [PubMed] [Google Scholar]
- 233.Gando S, Nanzaki S, Kemmotsu O. Disseminated intravascular coagulation and sustained systemic inflammatory response syndrome predict organ dysfunctions after trauma: application of clinical decision analysis. Ann Surg. 1999;229:121–127. doi: 10.1097/00000658-199901000-00016. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 234.Keel M, Trentz O. Pathophysiology of polytrauma. Injury. 2005;36:691–709. doi: 10.1016/j.injury.2004.12.037. [DOI] [PubMed] [Google Scholar]
- 235.Krishnan J, Selvarajoo K, Tsuchiya M, Lee G, Choi S. Toll-like receptor signal transduction. Exp Mol Med. 2007;39:421–438. doi: 10.1038/emm.2007.47. [DOI] [PubMed] [Google Scholar]
- 236.Zhang Q, Raoof M, Chen Y. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464:104–107. doi: 10.1038/nature08780. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 237.Sauaia A, Moore FA, Moore EE. Postinjury inflammation and organ dysfunction. Crit Care Clin. 2017;33:167–191. doi: 10.1016/j.ccc.2016.08.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 238.Goodnight SH, Kenoyer G, Rapaport SI, Patch MJ, Lee JA, Kurze T. Defibrination after brain-tissue destruction: a serious complication of head injury. N Engl J Med. 1974;290:1043–1047. doi: 10.1056/NEJM197405092901903. [DOI] [PubMed] [Google Scholar]
- 239.Gando S, Nanzaki S, Sasaki S, Kemmotsu O. Significant correlations between tissue factor and thrombin markers in trauma and septic patients with disseminated intravascular coagulation. Thromb Haemost. 1998;79:1111–1115. [PubMed] [Google Scholar]
- 240.Gando S, Nanzaki S, Morimoto Y, Kobayashi S, Kemmotsu O. Systemic activation of tissue-factor dependent coagulation pathway in evolving acute respiratory distress syndrome in patients with trauma and sepsis. J Trauma. 1999;47:719–723. doi: 10.1097/00005373-199910000-00017. [DOI] [PubMed] [Google Scholar]
- 241.Asakura H. Classifying types of disseminated intravascular coagulation: clinical and animal models. J Intensive Care. 2014;2:20. doi: 10.1186/2052-0492-2-20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 242.Horrevoets AJ. Plasminogen activator inhibitor 1 (PAI-1): in vitro activities and clinical relevance. Br J Haematol. 2004;125:12–23. doi: 10.1111/j.1365-2141.2004.04844.x. [DOI] [PubMed] [Google Scholar]
- 243.Biemond BJ, Levi M, Ten Cate H. Plasminogen activator and plasminogen activator inhibitor I release during experimental endotoxaemia in chimpanzees: effect of interventions in the cytokine and coagulation cascades. Clin Sci (Lond) 1995;88:587–594. doi: 10.1042/cs0880587. [DOI] [PubMed] [Google Scholar]
- 244.Gando S, Wada H, Thachil J. Differentiating disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype from coagulopathy of trauma and acute coagulopathy of trauma-shock (COT/ACOTS) J Thromb Haemost. 2013;11:826–835. doi: 10.1111/jth.12190. [DOI] [PubMed] [Google Scholar]
- 245.Ertel W, Eid K, Keel M, Trentz O. Therapeutical strategies and outcome of polytraumatized patients with pelvic injuries: a six-year experience. Eur J Trauma. 2000;26:278–286. [Google Scholar]
- 246.Wang JG, Geddings JE, Aleman MM. Tumor-derived tissue factor activates coagulation and enhances thrombosis in a mouse xenograft model of human pancreatic cancer. Blood. 2012;119:5543–5552. doi: 10.1182/blood-2012-01-402156. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 247.Contrino J, Hair G, Kreutzer DL, Rickles FR. In situ detection of tissue factor in vascular endothelial cells: correlation with the malignant phenotype of human breast disease. Nat Med. 1996;2:209–215. doi: 10.1038/nm0296-209. [DOI] [PubMed] [Google Scholar]
- 248.Sallah S, Wan JY, Nguyen NP, Hanrahan LR, Sigounas G. Disseminated intravascular coagulation in solid tumors: clinical and pathologic study. Thromb Haemost. 2001;86:828–833. [PubMed] [Google Scholar]
- 249.Hisada Y, Mackman N. Cancer-associated pathways and biomarkers of venous thrombosis. Blood. 2017;130:1499–1506. doi: 10.1182/blood-2017-03-743211. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 250.Freeman HR, Ramanan AV. Review of haemophagocytic lymphohistiocytosis. Arch Dis Child. 2011;96:688–693. doi: 10.1136/adc.2009.176610. [DOI] [PubMed] [Google Scholar]
- 251.Henter JI, Horne A, Arico M. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124–131. doi: 10.1002/pbc.21039. [DOI] [PubMed] [Google Scholar]
- 252.Valade S, Azoulay E, Galicier L. Coagulation disorders and bleedings in critically Ill patients with hemophagocytic lymphohistiocytosis. Medicine (Baltimore) 2015;94 doi: 10.1097/MD.0000000000001692. e1692. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 253.Favara BE. Histopathology of the liver in histiocytosis syndromes. Pediatr Pathol Lab Med. 1996;16:413–433. doi: 10.1080/15513819609168681. [DOI] [PubMed] [Google Scholar]
- 254.Chen JH, Fleming MD, Pinkus GS. Pathology of the liver in familial hemophagocytic lymphohistiocytosis. Am J Surg Pathol. 2010;34:852–867. doi: 10.1097/PAS.0b013e3181dbbb17. [DOI] [PubMed] [Google Scholar]
- 255.Allen CE, Yu X, Kozinetz CA, McClain KL. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2008;50:1227–1235. doi: 10.1002/pbc.21423. [DOI] [PubMed] [Google Scholar]
- 256.Bergsten E, Horne A, Arico M. Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood. 2017;130:2728–2738. doi: 10.1182/blood-2017-06-788349. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 257.Minoia F, Davi S, Horne A. Clinical features, treatment, and outcome of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a multinational, multicenter study of 362 patients. Arthritis Rheumatol. 2014;66:3160–3169. doi: 10.1002/art.38802. [DOI] [PubMed] [Google Scholar]
- 258.emapLocatelli F, Jordan MB, Allen C. Emapalumab in children with primary hemophagocytic lymphohistiocytosis. N Engl J Med. 2020;382:1811–1822. doi: 10.1056/NEJMoa1911326. [DOI] [PubMed] [Google Scholar]
- 259.Boom V, Anton J, Lahdenne P. Evidence-based diagnosis and treatment of macrophage activation syndrome in systemic juvenile idiopathic arthritis. Pediatr Rheumatol Online J. 2015;13:55. doi: 10.1186/s12969-015-0055-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 260.Eloseily EM, Weiser P, Crayne CB. Benefit of anakinra in treating pediatric secondary hemophagocytic lymphohistiocytosis. Arthritis Rheumatol. 2020;72:326–334. doi: 10.1002/art.41103. [DOI] [PubMed] [Google Scholar]
- 261.Gando S, Saitoh D, Ishikura H. A randomized, controlled, multicenter trial of the effects of antithrombin on disseminated intravascular coagulation in patients with sepsis. Crit Care. 2013;17:R297. doi: 10.1186/cc13163. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 262.Aoki N, Matsuda T, Saito H. A comparative double-blind randomized trial of activated protein C and unfractionated heparin in the treatment of disseminated intravascular coagulation. Int J Hematol. 2002;75:540–547. doi: 10.1007/BF02982120. [DOI] [PubMed] [Google Scholar]
- 263.Mori S, Ai T, Sera T, Ochiai K, Otomo Y. Human soluble recombinant thrombomodulin, ART-123, resolved early phase coagulopathies, but did not significantly alter the 28 day outcome in the treatment of DIC associated with infectious systemic inflammatory response syndromes. J Clin Med. 2019;8:1–12. doi: 10.3390/jcm8101553. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 264.Levi M, Levy M, Williams MD. Prophylactic heparin in patients with severe sepsis treated with drotrecogin alfa (activated) Am J Respir Crit Care Med. 2007;176:483–490. doi: 10.1164/rccm.200612-1803OC. [DOI] [PubMed] [Google Scholar]
- 265.Squizzato A, Hunt BJ, Kinasewitz GT, Wada H, Ten Cate H, Thachil J. Supportive management strategies for disseminated intravascular coagulation. An international consensus. Thromb Haemost. 2016;115:896–904. doi: 10.1160/TH15-09-0740. [DOI] [PubMed] [Google Scholar]
- 266.Miyakis S, Lockshin MD, Atsumi T. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS) J Thromb Haemost. 2006;4:295–306. doi: 10.1111/j.1538-7836.2006.01753.x. [DOI] [PubMed] [Google Scholar]
- 267.Merrill JT, Asherson RA. Catastrophic antiphospholipid syndrome. Nat Clin Pract Rheumatol. 2006;2:81–89. doi: 10.1038/ncprheum0069. [DOI] [PubMed] [Google Scholar]
- 268.Carmi O, Berla M, Shoenfeld Y, Levy Y. Diagnosis and management of catastrophic antiphospholipid syndrome. Expert Rev Hematol. 2017;10:365–374. doi: 10.1080/17474086.2017.1300522. [DOI] [PubMed] [Google Scholar]
- 269.Pengo V, Ruffatti A, Legnani C. Clinical course of high-risk patients diagnosed with antiphospholipid syndrome. J Thromb Haemost. 2010;8:237–242. doi: 10.1111/j.1538-7836.2009.03674.x. [DOI] [PubMed] [Google Scholar]
- 270.Meroni PL, Borghi MO, Raschi E, Tedesco F. Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nat Rev Rheumatol. 2011;7:330–339. doi: 10.1038/nrrheum.2011.52. [DOI] [PubMed] [Google Scholar]
- 271.Pierangeli SS, Liu SW, Anderson G, Barker JH, Harris EN. Thrombogenic properties of murine anti-cardiolipin antibodies induced by beta 2 glycoprotein 1 and human immunoglobulin G antiphospholipid antibodies. Circulation. 1996;94:1746–1751. doi: 10.1161/01.cir.94.7.1746. [DOI] [PubMed] [Google Scholar]
- 272.Jankowski M, Vreys I, Wittevrongel C. Thrombogenicity of beta 2-glycoprotein I-dependent antiphospholipid antibodies in a photochemically induced thrombosis model in the hamster. Blood. 2003;101:157–162. doi: 10.1182/blood-2002-05-1310. [DOI] [PubMed] [Google Scholar]
- 273.Ramesh S, Morrell CN, Tarango C. Antiphospholipid antibodies promote leukocyte-endothelial cell adhesion and thrombosis in mice by antagonizing eNOS via beta2GPI and apoER2. J Clin Invest. 2011;121:120–131. doi: 10.1172/JCI39828. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 274.Chaturvedi S, Braunstein EM, Yuan X. Complement activity and complement regulatory gene mutations are associated with thrombosis in APS and CAPS. Blood. 2020;135:239–251. doi: 10.1182/blood.2019003863. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 275.Rodriguez-Pinto I, Espinosa G, Erkan D, Shoenfeld Y, Cervera R. The effect of triple therapy on the mortality of catastrophic anti-phospholipid syndrome patients. Rheumatology (Oxford) 2018 doi: 10.1093/rheumatology/key082. [DOI] [PubMed] [Google Scholar]
- 276.Berman H, Rodriguez-Pinto I, Cervera R. Rituximab use in the catastrophic antiphospholipid syndrome: descriptive analysis of the CAPS registry patients receiving rituximab. Autoimmun Rev. 2013;12:1085–1090. doi: 10.1016/j.autrev.2013.05.004. [DOI] [PubMed] [Google Scholar]
- 277.Segna E, Bolzoni AR, Baserga C, Baj A. Free flap loss caused by heparin-induced thrombocytopenia and thrombosis (HITT): a case report and literature review. Acta Otorhinolaryngol Ital. 2016;36:527–533. doi: 10.14639/0392-100X-1188. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 278.Warkentin TE, Roberts RS, Hirsh J, Kelton JG. Heparin-induced skin lesions and other unusual sequelae of the heparin-induced thrombocytopenia syndrome: a nested cohort study. Chest. 2005;127:1857–1861. doi: 10.1378/chest.127.5.1857. [DOI] [PubMed] [Google Scholar]
- 279.Cuker A, Gimotty PA, Crowther MA, Warkentin TE. Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis. Blood. 2012;120:4160–4167. doi: 10.1182/blood-2012-07-443051. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 280.Cuker A, Arepally GM, Chong BH. American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia. Blood Adv. 2018;2:3360–3392. doi: 10.1182/bloodadvances.2018024489. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 281.Reilly MP, Taylor SM, Hartman NK. Heparin-induced thrombocytopenia/thrombosis in a transgenic mouse model requires human platelet factor 4 and platelet activation through FcgammaRIIA. Blood. 2001;98:2442–2447. doi: 10.1182/blood.v98.8.2442. [DOI] [PubMed] [Google Scholar]
- 282.Warkentin TE, Hayward CP, Boshkov LK. Sera from patients with heparin-induced thrombocytopenia generate platelet-derived microparticles with procoagulant activity: an explanation for the thrombotic complications of heparin-induced thrombocytopenia. Blood. 1994;84:3691–3699. [PubMed] [Google Scholar]
- 283.Reilly MP, Sinha U, Andre P. PRT-060318, a novel Syk inhibitor, prevents heparin-induced thrombocytopenia and thrombosis in a transgenic mouse model. Blood. 2011;117:2241–2246. doi: 10.1182/blood-2010-03-274969. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 284.Lhermusier T, van Rottem J, Garcia C. The Syk-kinase inhibitor R406 impairs platelet activation and monocyte tissue factor expression triggered by heparin-PF4 complex directed antibodies. J Thromb Haemost. 2011;9:2067–2076. doi: 10.1111/j.1538-7836.2011.04470.x. [DOI] [PubMed] [Google Scholar]
- 285.Huang MM, Indik Z, Brass LF, Hoxie JA, Schreiber AD, Brugge JS. Activation of Fc gamma RII induces tyrosine phosphorylation of multiple proteins including Fc gamma RII. J Biol Chem. 1992;267:5467–5473. [PubMed] [Google Scholar]
- 286.Perdomo J, Leung HHL, Ahmadi Z. Neutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia. Nat Commun. 2019;10:1322. doi: 10.1038/s41467-019-09160-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 287.Gollomp K, Kim M, Johnston I. Neutrophil accumulation and NET release contribute to thrombosis in HIT. JCI Insight. 2018;3:1–17. doi: 10.1172/jci.insight.99445. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 288.Linkins LA, Dans AL, Moores LK. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141 doi: 10.1378/chest.11-2303. e495S-e530S. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 289.Greinacher A, Selleng K, Warkentin TE. Autoimmune heparin-induced thrombocytopenia. J Thromb Haemost. 2017;15:2099–2114. doi: 10.1111/jth.13813. [DOI] [PubMed] [Google Scholar]
- 290.Vender JS, Matthew EB, Silverman IM, Konowitz H, Dau PC. Heparin-associated thrombocytopenia: alternative managements. Anesth Analg. 1986;65:520–522. [PubMed] [Google Scholar]
- 291.Welsby IJ, Um J, Milano CA, Ortel TL, Arepally G. Plasmapheresis and heparin reexposure as a management strategy for cardiac surgical patients with heparin-induced thrombocytopenia. Anesth Analg. 2010;110:30–35. doi: 10.1213/ANE.0b013e3181c3c1cd. [DOI] [PubMed] [Google Scholar]
- 292.Arepally GM, Cines DB. Pathogenesis of heparin-induced thrombocytopenia. Transl Res. 2020 doi: 10.1016/j.trsl.2020.04.014. S1931-5244(20)30077-3. Online ahead of print. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 293.Bunn HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med. 1997;337:762–769. doi: 10.1056/NEJM199709113371107. [DOI] [PubMed] [Google Scholar]
- 294.Sundd P, Gladwin MT, Novelli EM. Pathophysiology of sickle cell disease. Annu Rev Pathol. 2019;14:263–292. doi: 10.1146/annurev-pathmechdis-012418-012838. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 295.Solomon LR. Treatment and prevention of pain due to vaso-occlusive crises in adults with sickle cell disease: an educational void. Blood. 2008;111:997–1003. doi: 10.1182/blood-2007-07-089144. [DOI] [PubMed] [Google Scholar]
- 296.Barabino GA, Platt MO, Kaul DK. Sickle cell biomechanics. Annu Rev Biomed Eng. 2010;12:345–367. doi: 10.1146/annurev-bioeng-070909-105339. [DOI] [PubMed] [Google Scholar]
- 297.Turhan A, Weiss LA, Mohandas N, Coller BS, Frenette PS. Primary role for adherent leukocytes in sickle cell vascular occlusion: a new paradigm. Proc Natl Acad Sci U S A. 2002;99:3047–3051. doi: 10.1073/pnas.052522799. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 298.Mozzarelli A, Hofrichter J, Eaton WA. Delay time of hemoglobin S polymerization prevents most cells from sickling in vivo. Science. 1987;237:500–506. doi: 10.1126/science.3603036. [DOI] [PubMed] [Google Scholar]
- 299.Du E, Diez-Silva M, Kato GJ, Dao M, Suresh S. Kinetics of sickle cell biorheology and implications for painful vasoocclusive crisis. Proc Natl Acad Sci U S A. 2015;112:1422–1427. doi: 10.1073/pnas.1424111112. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 300.Montes RA, Eckman JR, Hsu LL, Wick TM. Sickle erythrocyte adherence to endothelium at low shear: role of shear stress in propagation of vaso-occlusion. Am J Hematol. 2002;70:216–227. doi: 10.1002/ajh.10145. [DOI] [PubMed] [Google Scholar]
- 301.Alapan Y, Little JA, Gurkan UA. Heterogeneous red blood cell adhesion and deformability in sickle cell disease. Sci Rep. 2014;4:7173. doi: 10.1038/srep07173. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 302.Kaul DK, Finnegan E, Barabino GA. Sickle red cell-endothelium interactions. Microcirculation. 2009;16:97–111. doi: 10.1080/10739680802279394. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 303.Villagra J, Shiva S, Hunter LA, Machado RF, Gladwin MT, Kato GJ. Platelet activation in patients with sickle disease, hemolysis-associated pulmonary hypertension, and nitric oxide scavenging by cell-free hemoglobin. Blood. 2007;110:2166–2172. doi: 10.1182/blood-2006-12-061697. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 304.DeBaun MR, Armstrong FD, McKinstry RC, Ware RE, Vichinsky E, Kirkham FJ. Silent cerebral infarcts: a review on a prevalent and progressive cause of neurologic injury in sickle cell anemia. Blood. 2012;119:4587–4596. doi: 10.1182/blood-2011-02-272682. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 305.Li J, Kim K, Hahm E. Neutrophil AKT2 regulates heterotypic cell-cell interactions during vascular inflammation. J Clin Invest. 2014;124:1483–1496. doi: 10.1172/JCI72305. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 306.Zhang D, Xu C, Manwani D, Frenette PS. Neutrophils, platelets, and inflammatory pathways at the nexus of sickle cell disease pathophysiology. Blood. 2016;127:801–809. doi: 10.1182/blood-2015-09-618538. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 307.Embury SH, Matsui NM, Ramanujam S. The contribution of endothelial cell P-selectin to the microvascular flow of mouse sickle erythrocytes in vivo. Blood. 2004;104:3378–3385. doi: 10.1182/blood-2004-02-0713. [DOI] [PubMed] [Google Scholar]
- 308.Belcher JD, Mahaseth H, Welch TE. Critical role of endothelial cell activation in hypoxia-induced vasoocclusion in transgenic sickle mice. Am J Physiol Heart Circ Physiol. 2005;288:H2715–H2725. doi: 10.1152/ajpheart.00986.2004. [DOI] [PubMed] [Google Scholar]
- 309.Gladwin MT, Ofori-Acquah SF. Erythroid DAMPs drive inflammation in SCD. Blood. 2014;123:3689–3690. doi: 10.1182/blood-2014-03-563874. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 310.Belcher JD, Chen C, Nguyen J. Heme triggers TLR4 signaling leading to endothelial cell activation and vaso-occlusion in murine sickle cell disease. Blood. 2014;123:377–390. doi: 10.1182/blood-2013-04-495887. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 311.Sparkenbaugh E, Pawlinski R. Interplay between coagulation and vascular inflammation in sickle cell disease. Br J Haematol. 2013;162:3–14. doi: 10.1111/bjh.12336. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 312.Kono M, Saigo K, Takagi Y. Heme-related molecules induce rapid production of neutrophil extracellular traps. Transfusion. 2014;54:2811–2819. doi: 10.1111/trf.12700. [DOI] [PubMed] [Google Scholar]
- 313.Graca-Souza AV, Arruda MA, de Freitas MS, Barja-Fidalgo C, Oliveira PL. Neutrophil activation by heme: implications for inflammatory processes. Blood. 2002;99:4160–4165. doi: 10.1182/blood.v99.11.4160. [DOI] [PubMed] [Google Scholar]
- 314.Dutra FF, Alves LS, Rodrigues D. Hemolysis-induced lethality involves inflammasome activation by heme. Proc Natl Acad Sci U S A. 2014;111:E4110–E4118. doi: 10.1073/pnas.1405023111. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 315.Adedeji MO, Cespedes J, Allen K, Subramony C, Hughson MD. Pulmonary thrombotic arteriopathy in patients with sickle cell disease. Arch Pathol Lab Med. 2001;125:1436–1441. doi: 10.5858/2001-125-1436-PTAIPW. [DOI] [PubMed] [Google Scholar]
- 316.Balkaran B, Char G, Morris JS, Thomas PW, Serjeant BE, Serjeant GR. Stroke in a cohort of patients with homozygous sickle cell disease. J Pediatr. 1992;120:360–366. doi: 10.1016/s0022-3476(05)80897-2. [DOI] [PubMed] [Google Scholar]
- 317.Bennewitz MF, Jimenez MA, Vats R. Lung vaso-occlusion in sickle cell disease mediated by arteriolar neutrophil-platelet microemboli. JCI Insight. 2017;2:e89761. doi: 10.1172/jci.insight.89761. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 318.Labbe E, Herbert D, Haynes J. Physicians' attitude and practices in sickle cell disease pain management. J Palliat Care. 2005;21:246–251. [PubMed] [Google Scholar]
- 319.Almeida CB, Scheiermann C, Jang JE. Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice. Blood. 2012;120:2879–2888. doi: 10.1182/blood-2012-02-409524. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 320.Morrone K, Mitchell WB, Manwani D. Novel sickle cell disease therapies: targeting pathways downstream of sickling. Semin Hematol. 2018;55:68–75. doi: 10.1053/j.seminhematol.2018.04.007. [DOI] [PubMed] [Google Scholar]
- 321.Vichinsky E, Hoppe CC, Ataga KI. A phase 3 randomized trial of voxelotor in sickle cell disease. N Engl J Med. 2019;381:509–519. doi: 10.1056/NEJMoa1903212. [DOI] [PubMed] [Google Scholar]
- 322.Telen MJ, Wun T, McCavit TL. Randomized phase 2 study of GMI-1070 in SCD: reduction in time to resolution of vaso-occlusive events and decreased opioid use. Blood. 2015;125:2656–2664. doi: 10.1182/blood-2014-06-583351. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 323.Zhao Y, Schwartz EA, Palmer GM, Zennadi R. MEK1/2 inhibitors reverse acute vascular occlusion in mouse models of sickle cell disease. FASEB J. 2016;30:1171–1186. doi: 10.1096/fj.15-278481. [DOI] [PubMed] [Google Scholar]
- 324.Bernaudin F, Socie G, Kuentz M. Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease. Blood. 2007;110:2749–2756. doi: 10.1182/blood-2007-03-079665. [DOI] [PubMed] [Google Scholar]
- 325.Ribeil JA, Hacein-Bey-Abina S, Payen E. Gene therapy in a patient with sickle cell disease. N Engl J Med. 2017;376:848–855. doi: 10.1056/NEJMoa1609677. [DOI] [PubMed] [Google Scholar]
- 326.Amato C, Ferri R, Elia M. Nervous system involvement in Degos disease. AJNR Am J Neuroradiol. 2005;26:646–649. [PMC free article] [PubMed] [Google Scholar]
- 327.Huang YC, Wang JD, Lee FY, Fu LS. Pediatric malignant atrophic papulosis. Pediatrics. 2018;141:S481–S4s4. doi: 10.1542/peds.2016-4206. [DOI] [PubMed] [Google Scholar]
- 328.Magro CM, Poe JC, Kim C. Degos disease: a C5b-9/interferon-alpha-mediated endotheliopathy syndrome. Am J Clin Pathol. 2011;135:599–610. doi: 10.1309/AJCP66QIMFARLZKI. [DOI] [PubMed] [Google Scholar]
- 329.Smadja DM, Mauge L, Gaussem P. Treprostinil increases the number and angiogenic potential of endothelial progenitor cells in children with pulmonary hypertension. Angiogenesis. 2011;14:17–27. doi: 10.1007/s10456-010-9192-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 330.Luo P, Liu Y, Qiu L, Liu X, Liu D, Li J. Tocilizumab treatment in COVID-19: a single center experience. J Med Virol. 2020;92:814–818. doi: 10.1002/jmv.25801. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 331.Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18:844–847. doi: 10.1111/jth.14768. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 332.Magro C, Mulvey JJ, Berlin D. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. Transl Res. 2020 doi: 10.1016/j.trsl.2020.04.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 333.Xu Z, Shi L, Wang Y, Zhang J. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020;8:420–422. doi: 10.1016/S2213-2600(20)30076-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 334.Zuo Y, Yalavarthi S, Shi H. Neutrophil extracellular traps in COVID-19. JCI Insight. 2020;5 doi: 10.1172/jci.insight.138999. [DOI] [PMC free article] [PubMed] [Google Scholar]