Fibrinolysis Shutdown and Hypofibrinolysis Are Not Synonymous Terms: The Clinical Significance of Differentiating Low Fibrinolytic States

Abstract

Low fibrinolytic activity has been associated with pathologic thrombosis and multiple-organ failure. Low fibrinolytic activity has two commonly associated terms, hypofibrinolysis and fibrinolysis shutdown. Hypofibrinolysis is a chronic state of lack of ability to generate an appropriate fibrinolytic response when anticipated. Fibrinolysis shutdown is the shutdown of fibrinolysis after systemic activation of the fibrinolytic system. There has been interchanging of these terms to describe critically ill patients in multiple settings. This is problematic in understanding the pathophysiology of disease processes related to these conditions. There is also a lack of research on the cellular mediators of these processes. The purpose of this article is to review the on and off mechanisms of fibrinolysis in the context of low fibrinolytic states to define the importance in differentiating hypofibrinolysis from fibrinolysis shutdown. In many clinical scenarios, the etiology of a low fibrinolytic state cannot be determined due to ambiguity if a preceding fibrinolytic activation event occurred. In this scenario, the term “low fibrinolytic activity” or “fibrinolysis resistance” is a more appropriate descriptor, rather than using assumptive of hypofibrinolysis and fibrinolysis shutdown, particularly in the acute setting of infection, injury, and surgery.

Endogenous and Exogenous Activation of the Fibrinolytic System

Fibrinolysis is a counterbalance to clot formation. Since the 1940s, exogenous fibrinolytic activators have been administered in the clinical setting to treat pathologic clotting in patients.¹ Subsequently lytic therapy has become instrumental in improving outcomes in myocardial infarction,² pulmonary embolism,³ and stroke.⁴ However, excessive fibrinolysis can result in uncontrolled hemorrhage and death.^5,6 This also includes the use of exogenous fibrinolytic activators as therapeutics in which lethal bleeding posttreatment can occur.^7,8

Plasminogen activation occurs with tissue plasminogen activator (tPA) entering the blood stream from vascular endothelium⁹ and peripheral sympathetic nerves innervating the adventitia of blood vessels.¹⁰ The dual source of plasminogen activators allows the activation of fibrinolysis even when one has been eliminated, but at a submaximal response.¹¹ While tPA was originally identified to be present in multiple tissue types,¹² high-concentration tPA-rich cells are present in precapillary arterioles.¹⁰ There are also organ-specific regions of high plasminogen activator content, including the brain, heart, lung, and kidney, while other organs such as the liver have minimal activator present.¹³

Urokinase as a plasminogen activator has a uniquely different role in tissue regeneration and predominantly circulates as a proenzyme.¹⁴ Urokinase does not appear to play a critical role in acute activation of fibrinolysis in the setting of shock. Previous studies have identified tPA^15-17 rather than urokinase as the predominantly elevated plasminogen activator in systemic circulation. However, urokinase at the local clot degradation level cannot be excluded as an important factor in fibrinolysis activity. Fibrinolysis initiated with tPA caters to enhanced fibrin degradation with subsequent urokinase administration due to additional lysine-binding sites created by proteolytic cleavage.¹⁸ This is relevant, as not only circulating cells such as macrophages express urokinase¹⁹ but localization of these cells to fibrin is predominantly tPA dependent.²⁰ This component of cellular-mediated fibrinolysis has not received as much attention in coagulation-based research. Urokinase has been predominantly studied in the context of it binding to its receptors²¹ and downstream effects of tissue remodeling in its association with tumor biology^22,23 and angiogenesis.²⁴ There are also several cell lines applicable to intravascular coagulation in which the urokinase receptor can be upregulated including endothelial cells,²⁵ microparticles released from endothelial cells,²⁶ monocytes, neutrophils, and T lymphocytes.²⁷ This is further complicated by localization of plasminogen, which is also expressed on a large number of circulating cells and endothelium that can modulate local fibrinolytic activity²⁸ (Fig. 1). Mouse knockout models of plasminogen activators demonstrate that a deficiency in one plasminogen activator is tolerated, but the double knock out is associated with extravascular fibrin deposition and decreased survival.²⁹ The recurring theme of overlapping mechanisms of plasminogen activation reflects the biological importance of the fibrinolytic system.

Fig. 1.

Cellular mediators of fibrinolysis activation. This figure demonstrates a schematic on the numerous potential cellular regulators of fibrinolysis. Basal levels of plasminogen activators (tPA and uPA) are present in the systemic circulation. There are additional cellular factors that can release tPA and uPA based on stimuli, in addition to neurons that can directly release tPA and also release neurotransmitters for local tPA release. Many circulating cells also have receptors for plasminogen and uPA which further help localize plasminogen activators in proximity to plasminogen. With local fibrin production, additional binding of plasminogen can occur which also enables tPA binding, enabling high concentrations of cellular and non–cellular-mediated fibrinolysis. tPA, tissue plasminogen activator; uPAR, urokinase-type plasminogen activator receptor.

Inhibitors of Fibrinolysis

Circulating inhibitors of fibrinolysis were appreciated to be in high abundance in circulation early in the understanding of the fibrinolytic system.³⁰ The numerous circulating inhibitors of the system have been extensively studied from a biochemical perspective.³¹ Plasminogen activator inhibitor 1 (PAI-1) has recently been proposed as the primary regulator of fibrinolysis, as it can be rapidly upregulated in multiple clinical settings and shutdown fibrinolysis.³² PAI-1 mechanism works by directly binding to plasminogen activators, preventing plasmin activation.³³ It has been known for decades that tPA activity stimulated by surgery, trauma, or myocardial infarct is quickly shutdown from a systemic inhibitor.³⁴ However, the short half-life of tPA in circulation is largely attributed to the liver’s ability to rapidly clear this protease.³⁵ The dual importance of tPA clearance and circulating plasma inhibition is apparent in liver transplant, when peak levels occur during the anhepatic phase of surgery and early reperfusion when limited tPA clearance is achieved.³⁶

Beyond direct inhibition of activators, fibrinolysis is largely mediated by fibrin itself. The formation of plasmin in the presence of tPA is highly dependent of the colocalization of these proteins on the surface of fibrin, forming a tertiary complex.³⁷ Thrombin activatable fibrinolysis inhibitor (TAFI) effectively attenuates this process through cleavage of the lysine domains on fibrin, where plasminogen binding occurs.³⁸ Factor XIII also has a role in fibrinolysis regulation. While this fibrin cross-linking protein has some influence in making fibrin resistant to degradation by modifying its structure, the primary mechanism is through cross-linking α2-antiplasmin (A2AP) into clots.³⁹ A2AP is considered the primary inhibitor of the fibrinolytic system.⁴⁰ While A2AP is a downstream inhibitor after plasmin generation, the rapid neutralization of plasmin is one of the fastest occurring biological reactions in the body.⁴¹ High circulating levels of A2AP and dependence of fibrin for effective plasmin generation are designed for tight regional specificity of fibrinolysis.⁴² Overall, the impact of circulating inhibitors, fibrin clot structure, and integrated inhibitors into the clot have a synergistic effect on clot degradation regulation.⁴³

Cellular mediators of fibrinolysis have received less attention than proteases. Platelets have a critical role in fibrinolysis regulation. The utilization of thrombelastography to quantify fibrinolysis activity in whole blood in the 1960s implicated platelets in down regulating plasmin activity, as large differences in activation were appreciated in plasma versus whole blood.⁴⁴ This has been appreciated in trauma patients, in which inhibition of the ADP pathway of platelet-mediated clot strength was associated with increase susceptibility to tPA-mediated fibrinolysis.⁴⁵ Platelets are known to form a hierarchical clot structure around a fibrin core.⁴⁶ The structure of these platelet aggregates forms a dense central region around fibrin, creating a physical barrier to other cells and creates a micro environment that is prothrombotic.⁴⁷

Platelets contain prestored proteins such as PAI-1⁴⁸ and TAFI⁴⁹ that functionally inhibit fibrinolysis. There are also additional proteins stored within platelets that can bind tPA and plasminogen that may have a regulatory role in fibrinolysis as well.⁵⁰ The same principle of hierarchical plasminogen and tPA binding also occurs in which only a thin rim of peripheral fibrin is actively degraded.⁵¹ The active zone of fibrinolysis is tPA and plasminogen rich, while a zone of prefibrinolysis has increased plasminogen, but is lacking tPA. Therefore, access to the fibrin surface of tPA in combination with the local fibrin clot surface is critical in determining the rate of clot degradation. This is also impacted by the fibrin–platelet interaction, in which platelet contraction to condense the clot can enhance fibrinolysis resistance, particularly in the presence of factor XIII, via tight localization of A2AP.⁵² Platelets also release microparticles which bind to fibrin strands and can promote fibrinolysis resistance.⁵³ Local PAI-1 release at the site of injury can also occur with direct thrombin release from the extracellular matrix and thrombin-related increased expression of PAI-1 from smooth muscle.⁵⁴

Additional cellular mediators of fibrinolysis inhibition include neutrophil extracellular traps (NETs).⁵⁵ The combination of both histones and DNA reduces clot susceptibility to fibrinolysis. It has been implicated that damage-associated proteins driving sterile inflammation can prime neutrophils for NETs formation.⁵⁶ Recent work in stroke has suggested that cell-free DNA from NETs is a culprit in unsuccessful lytic therapy.⁵⁷ Neutrophil adhesion to fibrin is mediated by MAC-1 which is a shared ligand with other leukocytes.⁵⁸ Cell-to-cell interactions in the region of fibrin represent a challenging but important future area of research to determine their role in fibrinolysis, particularly as these cellular interactions can be modulated by flow.⁵⁹ Just as the cell model of hemostasis in thrombin generation has been transformative in understanding clot formation,⁶⁰ understanding the cellular mediators of fibrinolysis is just as important to address. Tying complex interactions together remains a challenge, as there are no current ways to assess this interaction in a single assay and has been completely clinically neglected. Fig. 2 represents a schematic of the interactions between the potential local negative cellular regulators of fibrinolysis.

Fig. 2.

Cellular mediators of fibrinolysis inhibition. This figure represents a schematic of the potential cellular mediators of decreasing fibrinolytic activity. Local tissue injury exposes platelet activators for aggregation. Based on the level of activation of platelet activity, these platelets form an internal core of tightly bound platelets and release antifibrinolytic proteins, microparticles, and thrombin. This platelet core is buffered by a platelet shell that also incorporates neutrophils that can become activated and release neutrophil extracellular traps, creating a more fibrinolytic resistant clot. The platelet core thrombin release also cleaves PAI-1 from the extracellular matrix, in addition to stimulating PAI-1 expression in underlying vascular smooth muscle cells. PAI-1, plasminogen activator inhibitor 1.

Turning Fibrinolysis On and Off

Despite a clear biological role of fibrinolytic activators, the regulation of their release is poorly understood.⁶¹ Early research on the activation of fibrinolysis found a broad range of conditions that would activate fibrinolysis, including emotions, exercise, surgery, and sudden death, with evidence suggesting that a local neurogenic mechanism drove this process.⁶² This is supported by subsequent work demonstrating that epinephrine,⁶³ DDAVP,⁶⁴ serotonin,^65,66 histamine,⁶⁷ bradykinin,⁶⁸ and acetylcholine⁶⁹ can impact the release of plasminogen activators from blood vessels.

Pathologic activation of fibrinolysis has been implicated as the culprit for terminal pathology in sepsis resulting in disseminated intravascular coagulation (DIC).⁷⁰ DIC has also been proposed to be a driver of mortality in trauma.⁷¹ However, others have postulated a lack of fibrinolysis as the culprit in mortality following these clinical settings.⁷² It has been hypothesized that this is due to a disbalance between prothrombosis, with lack of anticoagulation, and impaired fibrinolysis activity.⁷³ Observational literature has identified that fibrinolysis has a predictable pattern of activation following injury with subsequent inhibition,⁷⁴ which was appreciated in a similar time frame of inhibition of fibrinolysis following exogenous administration.¹ The timing of fibrinolysis activation with subsequent inhibition has previously been reviewed in the context of traumatic injury⁷⁵ and demonstrated in animal models of infection.⁷⁶ This same concept of fibrinolytic activation with subsequent shutdown has also gained attention in severe COVID-19 infections.^77,78 There remains a large gap in the literature in understanding pathologic versus physiologic activation, in addition to how system inactivation is returned to normal homeostasis.

Fibrinolysis Shutdown: A Two-Step Process

Fibrinolysis shutdown was first proposed by Innes and Sevitt in 1964 in the setting of trauma,⁷⁴ but rebound fibrinolysis resistance from a systemic inhibitor had been observed 30 years prior in the setting of streptococcal infection.⁷⁹ Fibrinolysis activity in the study of Innes and Sevitt⁷⁴ was quantified by the time it took citrated whole blood to dissolve, in addition to the timing of whole blood clots to dissolve in streptokinase. This reversal of fibrinolytic activation has been proposed to be an acute phase response.³⁴ An evaluation of circulating protease changes in fibrinolysis shutdown demonstrates that PAI-1 complex with tPA increase by 200-fold at 7 hours after fibrinolytic activation, with PAI-1 levels remaining increased by nearly 100-fold at 21 hours.⁸⁰ A more recent analysis evaluating trauma patients who were hyperfibrinolytic on emergency department arrival based on viscoelastic testing demonstrated that PAI-1 levels are increased at 2 hours following injury with viscoelastic testing demonstrating no fibrinolytic activity in the same time frame.⁸¹ While additional regulators of fibrinolysis inhibition can become markedly depleted following systemic fibrinolytic activation, their recovery returns to normal ranges within 24 hours without excessive production.⁸⁰

Trauma patients with evidence of fibrinolytic activation but subsequent shutdown based on viscoelastic testing have depletion of fibrinolytic inhibitors,⁸² increases in plasmin antiplasmin complex,⁸³ and elevated D-dimer levels.⁸⁴ This cohort of patients, despite having a low fibrinolysis activity, also harbor additional coagulation derangements, including an elevated international normalized ratio (INR), and platelet dysfunction and are at risk of bleeding, but do not bleed as much as hyperfibrinolytic patients.^82-84 Ex vivo assessment of the impact on tranexamic acid in this patient population identifies that there is no benefit in fibrin clot strength with the administration of tranexamic acid.⁸⁵ In this study, only patients who are sensitive to exogenous tPA and have increase fibrinolysis activity (low LY30) demonstrated gain in fibrin clot strength with exogenous antifibrinolytics. Patients with low fibrinolytic activity, or who lacked sensitivity to tPA, had no increase in clot strength with antifibrinolytics. These data support that the clinical benefit of antifibrinolytics in increase fibrin clot strength is in the setting of increased fibrinolytic activity with concurrent loss of systemic inhibitors. After a patient has endogenously shut down the fibrinolytic system, the impact of antifibrinolytics in improving coagulation parameters remains unclear. This is likely why the benefit of antifibrinolytics in trauma are appreciated only when given early after injury in severely hypotensive patients.⁸⁶

Our group has unpublished data demonstrating this early transition to fibrinolysis shutdown in liver transplantation, when viscoelastic testing demonstrates minimal fibrinolytic activity, but there is a heightened sensitivity to exogenous tPA (Fig. 3). This discrepancy in minimal systemic fibrinolytic activity, yet high sensitivity for tPA-mediated fibrinolysis, suggests that the first component of shutting down fibrinolysis is clearance of plasminogen activators. The most likely sources of clearance of plasminogen activator are the multiple liver receptors.³⁵ Delayed tPA clearance in a subcohort of liver transplantation has been appreciated for decades,³⁶ and recently it has been reported that this delayed fibrinolysis shutdown is associated with increased rate of early allograft dysfunction.⁸⁷ Other investigators have identified that hepatic blood flow is directly proportional to tPA clearance,⁸⁸ indicative that both flow and receptor binding play a role in clearance. This is further supported by increased levels of tPA following myocardial infarct with decreased cardiac output reducing blood flow to the liver⁸⁹ and the ability to saturate tPA receptors resulting in impaired clearance.³⁵

Fig. 3.

Differential timing of the fibrinolysis shutdown in liver transplant. This figure represents previously unpublished data in liver transplant in which serial viscoelastic tests demonstrate the shutdown of fibrinolysis activity followed by the increase of fibrinolysis inhibitors. This two-step process is highlighted by the top panel in with LY30 is abruptly decreased at 30 minutes of reperfusion of the liver. In the lower panel, the addition of exogenous tPA to the viscoelastic test demonstrates that the systemic blood is still sensitive to plasminogen activators. Resistance to fibrinolysis activators is not appreciated until 2 hours after reperfusion. These data support that clearance of fibrinolytic activators occurs as the first step of fibrinolysis shutdown, followed by upregulation of fibrinolytic inhibitors hours later. tPA, tissue plasminogen activator; POD, postoperative day.

The liver clears plasminogen activators predominantly through endothelial cells and hepatocytes, and resident macrophages.^35,90 The two predominant receptors that clear tPA in the liver are a mannose-binding receptor and low-density lipoprotein receptor–related protein (LRP).^91,92 TPA clearance is predominantly through hepatocytes and endothelial cells,³⁵ while urokinase clearance appears to have a differential pattern of clearance in which Kupffer cells and hepatocytes clear the majority of this plasminogen activator.⁹⁰ Clearance of tPA complexed with PAI-1 is from hepatocytes from the LRP receptor, which is distinct from free tPA clearance.⁹³ Urokinase complexed with PAI-1 can occur in a similar way, but is also cleared by the urokinase receptor, which is expressed in more ubiquitously than the LRP receptor.⁹⁴

Receptor interactions with plasminogen activators not only clear proteases but also result in downstream cell signaling. tPA has been demonstrated to induce an anti-inflammatory effect on macrophages by binding to the LRP receptor.⁹⁵ Urokinase receptors have been demonstrated to have a diverse role of biological functions through subsequent cell signaling by modulating cellular interaction with the extracellular matrix, cell survival, and tissue remodeling.²¹ The role in these signaling pathways in driving subsequent shutdown of fibrinolysis by increasing transcription of fibrinolytic inhibitors via these pathways is not reported. But alternative agonist of hepatocytes and endothelial cells such as thrombin,⁹⁶ tumor necrosis factor-α,⁹⁷ interleukin-6, and lipopolysaccharide have been demonstrated to increase PAI-1 production. Within 2 hours of liver reperfusion in transplant, most patients have low fibrinolysis activity and tPA resistance (Fig. 3). This timing is comparable to what has been observed in trauma, in which 50% of patients have tPA resistance up to 2 hours after injury, and 75% of patients demonstrate tPA resistance up to 4 hours, which are associated with increased PAI-1 levels.⁸¹ Fibrinolysis shutdown likely represents an acute phase response to controlling hemostasis and activating an innate immune response to prevent the development of infection. The phases of fibrinolysis shutdown are depicted in Fig. 4.

Fig. 4.

Schematic of the two phases of fibrinolysis shutdown. This figure represents a schematic of the proposed mechanism of fibrinolysis shutdown. Plasminogen activators released in circulating blood are initially controlled by local PAI-1 levels. Activators surpass the local PAI-1 binding and enter the liver. The numerous receptors of cells in the liver that have tPA avidity bind the plasminogen activators. This is the phase I of fibrinolysis shutdown. Following this, the response to tPA from local liver cells increases PAI-1 synthesis, resulting in increased release of PAI-1 up to an hour after activator clearance. Additional peripheral endothelial cells also play a role in increase PAI-1 production from cytokine release. This second phase of shutdown is hallmarked by resistance to fibrinolytic activators. PAI-1, plasminogen activator inhibitor 1; tPA, tissue plasminogen activator; uPA, urokinase-type plasminogen activator.

Resolution of fibrinolysis shutdown may play a role in transitioning from hemorrhage and infection control to anti-inflammatory and tissue regeneration. This is supported by work demonstrating plasmin generation attenuating inflammation in macrophages.⁹⁸ Neutrophils may have a role in the regulation of fibrinolytic shutdown states.⁹⁹ There is a paucity of data that describe recovery from fibrinolysis shutdown in the literature. It remains an important ongoing area of research to identify if interventions to promote early resolution can improve outcomes. Currently, recovery from fibrinolysis shutdown is limited to observational studies in trauma, in which persistent fibrinolysis shutdown is associated with increased mortality, if patients remain in a low fibrinolytic state for days after admission to the intensive care unit.^100,101 Similar data in sepsis have also been reported, in which prolonged tPA resistance is associated with poor outcomes in the intensive care unit.¹⁰²

Lack of Fibrinolysis Activation—Hypofibrinolysis

Hypofibrinolysis reflects a lack of activation of fibrinolysis when anticipated. Hypofibrinolysis is often confused with fibrinolysis shutdown, as a single measurement of low fibrinolytic activity can occur in both settings. To clearly differentiate the two conditions, a known event of anticipated fibrinolysis activation needs to occur. Liver transplant, as previously mentioned, is one of the most predictable ways to generate a fibrinolytic response via proxy of removal of the liver, and results in increased circulating levels of fibrinolytic activators from impaired clearance and should induce a systemic fibrinolytic response. When a lack of activation occurs, hypofibrinolysis can be identified. This occurs in roughly 40% of liver transplant recipients,³⁶ and is associated with early allograft dysfunction.⁸⁷ Recently, hypofibrinolysis in the setting of acute liver failure in cirrhosis patients has also been associated with increased 30-day mortality.¹⁰³

Testing for hypofibrinolysis does not require a liver transplant but is logistically challenging. Assessment of hypofibrinolysis in an individual not undergoing a procedure requires an intervention to stimulate plasminogen activator release. Upper extremity venous occlusion is historically the most common methods of stimulating plasminogen activator release, as forearm appears to have a highest concentration of tPA releasing cells.¹⁰⁴ Assessment of fibrinolysis in this setting has been historically through the euglobulin lysis assay, which fractionates whole blood eliminating cellular components and plasma proteins important for fibrinolysis inhibition.¹⁰⁵ This lack of fibrinolysis activation is found to occur in 30% of patients with a history of deep venous thrombosis (DVT).¹⁰⁶ This can be attributable to either elevated levels of PAI-1 or lack of release of tPA.¹⁰⁷ In a study of 100 patients with a history of DVT, 10% had defective tPA release and 20% had elevated inhibitor levels, suggesting that the most common cause of hypofibrinolysis is due to elevated inhibitors.¹⁰⁸ Viscoelastic testing to quantify hypofibrinolysis using venous occlusion has not been previously reported.

Impaired vascular release to tPA occurs in the setting of hypertension,¹⁰⁹ smoking,¹¹⁰ obesity,¹¹¹ and renal disease¹¹² and may also be hereditarily acquired.¹¹³ The precise mechanism remains unclear. The muscarinic receptor has been identified to play a role in tPA release in the setting of sympathetic activation in the human forearm.¹¹⁴ Regional differences of this tPA release have been described in animal models in the setting of sympathetic activation¹¹⁵ and it remains unclear in humans how the local distribution of sympathetic neurons can impact tPA release. Muscarinic receptors on the endothelium, through G-coupled signal transduction, have previously been described to control the local vascular tone,¹¹⁶ and could have a dual role in tPA release. The bradykinin 2 receptor has also been proposed to be a regulator of tPA release from endothelial cells.¹¹⁷ This receptor is also known to be activated in specific shear conditions of flow over the surface of the receptor in addition to bradykinin.¹¹⁸

Increased inhibitors of fibrinolysis activation are also appreciated in a wide spectrum of pathology. Diabetes,¹¹⁹ obesity,¹²⁰ inflammatory bowel disease,¹²¹ and specific genetic polymorphisms¹²² are associated with high PAI-1 levels and risk of thrombosis. The source of PAI-1 can come from the adipose tissue,¹²¹ hepatocytes,¹²³ endothelium,¹²⁴ and smooth muscle cells.¹²⁵ Circulating cells can also increase PAI-1 expression for local release including platelets¹²⁶ and macrophages/monocytes.¹²⁷ Stimulation for increased PAI-1 expression has been proposed to come from cytokines, elevated blood glucose, insulin, thrombin, and angiostatin II.¹²⁸ The multiple mechanisms for hypofibrinolysis are displayed in Fig. 5.

Fig. 5.

Schematic of hypofibrinolysis. Hypofibrinolysis occurs from either lack of release of plasminogen activators or increase basal expression of inhibitors, or a combination of both. This figure represents the multiple steps at which tPA release can be impaired from the endothelial cells and local neurons. Increased release of PAI-1 can occur in multiple cell lines, often due to cytokines and other stimuli. PAI-1, plasminogen activator inhibitor 1; tPA, tissue plasminogen activator.

With the projected increased rate of risk factors associated with hypofibrinolysis anticipated to continue to increase over the next 5 years,¹²⁹ the prevalence of hypofibrinolysis is likely to continue to increase overtime as well. Hypofibrinolysis represents an underlying disease process that predisposes individuals to adverse outcomes. This is distinctly different from fibrinolysis shutdown, in which there is activation of fibrinolysis with subsequent inhibition. Patients who are in theory at the greatest risk of adverse events are those patients who are anticipated to have a fibrinolytic response from some sort of insult but fail to generate a response.

Conclusion and Future Direction

Fibrinolysis shutdown and hypofibrinolysis are not interchangeable terms. These are important terms to describe different mechanisms of low fibrinolytic states that have been neglected in more contemporary literature. Hypofibrinolysis is a chronic condition in which an individual has an impaired ability to mount an appropriate fibrinolytic response when anticipated due to either lack of plasminogen activator release or high levels of baseline inhibitors. Fibrinolysis shutdown is the process of shutting down fibrinolysis after prior activation, and its duration appears to be associated with pathology. There is a paucity of data that differentiate these two distinct causes of low fibrinolytic activity in hospitalized patients. Furthermore, there has been a lack of research on the cellular mediators of fibrinolysis and their roles in these processes. Using plasma circulating factors likely neglects critical portions of fibrinolysis that are otherwise unrecognized unless performed in whole blood assays. Whole blood assays are also limited in that they neglect endothelial contribution to fibrinolysis regulation in addition to other vascular and organ-specific factors. There is a large amount of research needed in this field, which is undoubtedly becoming increasingly important to address with the continued obesity epidemic that will likely increase the prevalence of hypofibrinolysis which should not be confused with fibrinolysis shutdown.

Ultimately, understanding which patients have hypofibrinolysis rather than fibrinolysis shutdown provides greater insight into the pathophysiology of these distinct processes. This is important, as it will enable the identification of what is pathologic versus physiologic low fibrinolysis and provide a more effective modality of personalized medicine to treat an underlying cause. Before this can occur, the scientific community needs to begin to appropriately label these terms when used in clinical studies, and, if there is ambiguity, describe the patient cohort as low fibrinolytic activity or resistance based on what measurement is being performed.