Current Concepts in Coagulation Profile in Cirrhosis and Acute‐on‐Chronic Liver Failure

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Abbreviations

ACLF

acute‐on‐chronic liver failure

ACT

activated clotting time

AD

acute decompensation

ALF

acute liver failure

ALI

acute liver failure

aPTT

activated partial thromboplastin time

AT

antithrombin

CR

clot rate

CYP P450

cytochrome P450

DIC

disseminated intravascular coagulation

DOAC

direct oral anticoagulant

EACA

ε‐aminocaproic acid

F

factor

FFP

fresh frozen plasma

IL

interleukin

INR

international normalized ratio

IV

intravenous

LMWH

low‐molecular‐weight heparin

LT

liver transplantation

Lysis30

lysis index after 30 minutes

MA

maximum amplitude

MELD

Model for End‐Stage Liver Disease

PAI

plasminogen activator inhibitor

PC

platelet concentrate

PF

platelet function

PLT

platelet count

POC

point of care

PPC

prothrombin complex concentrate

PRBC

packed red blood cells

PT

prothrombin time

PVT

portal vein thrombosis

rF

recombinant factor

ROTEM

rotational thromboelastometry

SCT

standard coagulation test

SIRS

systemic inflammatory response syndrome

SMVT

superior mesenteric vein thrombosis

SQ

subcutaneous

TEG

thromboelastography

TIPS

transjugular intrahepatic portosystemic shunt

TNF

tumor necrosis factor

tPA

tissue plasminogen activator

TRALI

transfusion‐related acute lung injury

ULN

upper limit of normal

VE

viscoelastic

VKA

vitamin K antagonist

vWF

von Willebrand factor

Background

Patients with cirrhosis have profoundly altered hemodynamics and hemostatic pathways with procoagulant and anticoagulant mechanisms, resulting in a tenuous “rebalanced” state in the setting of portal hypertension. This balance could be tipped toward either a procoagulant or anticoagulant phenotype by superimposed conditions. ¹

Specific coagulation factor (F) V (FV), FVII, FIX, FX, FXI, prothrombin, protein C, and protein S are reduced with concomitant increased FVIII and von Willebrand factor (vWF) activity in cirrhosis. ² Thrombocytopenia, increased nitric oxide, and prostacyclin inhibit platelet function (PF), and higher vWF and FVIII activity support platelet aggregation. ³ Thrombocytopenia is the result of splenic sequestration in portal hypertension, decreased hepatic thrombopoietin synthesis, and immune‐mediated platelet destruction due to glycoprotein IIb/IIIa platelet surface antigen‐antibody interaction triggered by inflammation or sepsis. ⁴ Patients with acute liver failure (ALF) have a markedly prolonged international normalized ratio (INR) but preserved thrombin generation potential, and they tend not to bleed. In cirrhosis, INR increases modestly with synthetic dysfunction and reflects short‐term patient mortality, but not bleeding risk, during invasive procedures because of adequate thrombin generation potential. ⁵ Acute‐on‐chronic liver failure (ACLF) is associated with organ failure, progressive clinical course, and high 28‐day mortality. ⁶ In ACLF, coagulation switches from a procoagulant to an anticoagulant phenotype with the onset of systemic inflammation and endothelial activation, which is compounded by sepsis. ⁷ , ⁸ , ⁹ In these situations, critical scenarios, such as variceal bleeding, the need for invasive procedures, central line placement, venous thromboembolism, portal vein thrombosis (PVT), and secondary organ failure, often supervene. Standard coagulation tests (SCTs), such as prothrombin time (PT), activated partial thromboplastin time (aPTT), INR, and bleeding time, do not measure the risk for bleeding in liver disease. ³ Hence inappropriate use of blood products to correct these parameters is often ineffective and leads to volume overload and transfusion‐related acute lung injury (TRALI). ¹⁰ , ¹¹

Cell‐Based Model of Hemostasis

The traditional chemical enzymatic pathways are now superseded by the cell‐based model of hemostasis in which activated platelets are the primary effectors of clot initiation making a platelet plug. A crucial cellular element is endothelial injury, which is a driver for bleeding and thrombosis with activation of the inflammatory cascade. Primary hemostasis is mediated by platelets, whereas secondary hemostasis is characterized by formation of the fibrin mesh with plasma procoagulant proteins. ⁴ Finally, when the vascular repair is complete, plasma anticoagulant proteins break down this fibrin mesh in a third process known as fibrinolysis. In cirrhosis, bleeding is often due to portal hypertension per se rather than being coagulopathy related, like hyperfibrinolysis. The cell‐based model also explains why local hemostatic changes at the site of injury do not override the systemic hemostatic balance, and conventional tests of coagulation remain the same in a patient with liver disease with clinically apparent bleeding. ¹ , ² The clinician’s ability to detect the coagulation defect at the site of portal hypertensive bleeding, such as variceal or mucosal or vessel injury (e.g., after biopsy), remains elusive because conventional tests reveal the global rather than the local defect. ¹²

Pathophysiology of Coagulation Defects in Cirrhosis

Patients with compensated liver cirrhosis have a rebalanced coagulation profile. In patients with cirrhosis, bleeding (mostly variceal) is usually the consequence of portal hypertension (gastropathy/variceal bleeding) or due to vessel injury (biopsy site/paracentesis site) bleeding. ³ This implied that an elevated INR is not a predictor of bleeding, nor is a therapeutic correction target in a bleeding patient. ⁵ Progression of chronic liver failure is associated with derangement of coagulative balance, and the balance shifts from a procoagulant to anticoagulant phenotype. Platelet count (PLT) alone is an incomplete test of coagulation and indirectly correlates with the degree of portal hypertension, splenomegaly, and hepatic decompensation. However, studies have shown that a target PLT of 56 × 10⁹/L suffices to control variceal bleeding because of intact platelet‐dependent thrombin generation in cirrhosis. ¹³ , ¹⁴ A special scenario is liver transplantation (LT) in cirrhosis, where excess transfusion of platelet concentrate (PC), cryoprecipitate, or fresh frozen plasma (FFP) may contribute to the development of hepatic arterial or venous thrombosis. ¹⁵ , ¹⁶

Pathophysiology of Coagulation in ACLF

Recent studies have sparked interest in coagulation in ACLF. ³ , ⁷ , ⁸ , ⁹ , ¹¹ Fisher et al. ⁸ showed lower thrombin generation in patients with ACLF compared with those with acute decompensation (AD). Bedreli et al. ⁹ demonstrated that rotational thromboelastometry (ROTEM) may reduce substitution of coagulation factors in patients with ACLF. Blasi et al. ⁷ described the ROTEM profile in ACLF as compared with cirrhosis. Finally, our group prospectively studied the dynamic global coagulation dysfunction in patients with ACLF in relation to the development of systemic inflammatory response syndrome (SIRS) and sepsis, and found that worsening coagulation failure often preceded the development of sepsis and mortality in these critically ill patients. ³ , ¹⁷ Table 1 summarizes available studies on coagulation in cirrhosis and liver failure. ³ , ⁵ , ⁷ , ⁸ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ Figure 1 shows our understanding of this dynamic model of coagulation in cirrhosis and ACLF.

Table 1.

Role of VE Testing in Cirrhosis, ALF, and ACLF

Author (Year)	No. of Patients	Clinical Condition	Findings	Specific Coagulation Parameters	Remarks
Cirrhosis
Papatheodoridis et al. (1999) 22	Cirrhosis: n = 84	Cirrhosis	All TEG parameters worsened with sepsis and recovered with resolution	Successful treatment of infection usually restores hemostasis parameters to preinfection levels in 5 days	Association of coagulation with sepsis
	30 subjects with sepsis
Lloyd‐Donald et al. (2017) 23	Cirrhosis: n = 74	Acutely ill patients with cirrhosis	Delayed clot formation with longer reaction time (P < 0.01), longer kinetic time (P < 0.01), more acute α angle (65 versus 72.2 degrees; P < 0.01), and longer ACT (P < 0.01)	Not done	AD of cirrhosis made the TEG hypocoagulable
Bedreli et al. (2016) 9	Liver cirrhosis: n = 37	Cirrhosis	ROTEM‐guided transfusion before minimally invasive procedures	VE test–based blood transfusion protocols	Supplementation of coagulation factors (PCCs, FFP, and fibrinogen)
LT
Fayed et al. (2015) 24	n = 100	Decompensated cirrhosis during LT	POC test	Thromboelastometry‐based regression equation accounted for 63% of PRBC, 83% of FFP, 61% of cryoprecipitate, and 44% of platelet transfusion requirements	POCs have ability to predict transfusion requirements
			ROTEM
De Pietri et al. (2016) 19	n = 261	Cirrhosis during LT	Greater clot strength was associated with a MELD score <20, hepatitis C virus, and cholestatic‐related cirrhosis
ALF/ALI
Agarwal et al. (2012) 5	ALF: n = 20	ALF	Significant elevation in plasma levels of FVIII and on vWF and microparticles	TEG tracings were consistent with a hypocoagulable state in 20%, normal in 45%, and hypercoagulable in 35%	Coagulation disturbance in patients with ALF is complex
Stravitz et al. (2012) 20	n = 51	ALF/ALI	Markedly decreased procoagulant FV and FVII levels	Despite a mean INR of 3.4 ± 1.7 (range 1.5‐9.6), mean TEG parameters were normal, and MA was higher in patients with ALF than ALI and correlated directly with venous ammonia concentrations	Five individual TEG parameters were normal in 32 patients (63%); low MA was confined to patients with PLTs <126 × 109/L
ACLF
Blasi et al. (2018) 7	ACLF: n = 36	ACLF	More hypocoagulable characteristics compared with cirrhosis with AD	Prolonged time to initial fibrin formation and clot formation time, and decreased maximum clot firmness and α angle values	VE testing in cirrhosis and ACLF
	Decompensated cirrhosis: n = 24	Grade 1: 13
		Grade 2: 13
		Grade 3: 10
Fisher et al. (2018) 8	Stable cirrhosis: n = 8	ACLF subjects	Thrombin generation peak and velocity were also significantly lower in ACLF compared with healthy controls	Increased vWF and lower ADAMTS‐13 in ACLF	Thrombin generation in ACLF reported
	Decompensated cirrhosis: n = 44	Grade 1: 2			Small sample size
	ACLF: n = 17	Grade 2: 9
		Grade 3: 6
Premkumar et al. (2019) 3	ACLF: n = 114	ACLF, followed up prospectively	TEG parameters worsened with SIRS and sepsis	Dynamic coagulation changes predicted sepsis and mortality	Prospective data on individual coagulation factors with 28‐day mortality assessment
	Cirrhosis: n = 25
Goyal et al. (2018) 21	ACLF: n = 68	ACLF	Reduced MA and lysis in patients with ACLF	TEG parameters in patients with ACLF are essentially normal, with the exception of reduced MA	Single time assessment with no assessment of changes with SIRS and sepsis
	Cirrhosis with AD: n = 53

Abbreviations: ACLF, acute‐on‐chronic liver failure; AD, acute decompensation; ADAMTS‐13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; ALF acute liver failure; ALI, acute liver injury; AT, antithrombin; F, factor; FFP, fresh frozen plasma; INR, international normalized ratio; MELD, Model for End‐Stage Liver Disease; PCCs, prothrombin complex concentrates; MA, maximum amplitude; POC, point of care; PT, prothrombin time; ROTEM, rotational thromboelastometry; SIRS, systemic inflammatory response syndrome; TEG, thromboelastography; VWF, von Willebrand factor.

FIG 1.

Dynamic coagulation profile changes in cirrhosis and ACLF.

Risk Assessment For Procedures in Liver Disease

Preprocedure correction of SCTs is a double‐edged sword. Assessment of baseline bleeding risk, limitations of prediction by conventional tests, and the benefits of prophylactic correction are to be weighed (Table 2). Correction of the PT/INR may lead to paradoxical bleeding by increasing blood flow in the collateral beds. ²⁵ Standard doses of blood components, such as FFP, can only partially correct SCTs. Common dose ranges are from 15 to 30 mL/kg; however, these data have been extrapolated from critically ill patients with trauma and coagulopathy. ²⁶ , ²⁷ Increased volumes of FFP infusion predispose to transfusion‐associated circulatory overload and TRALI. For every 100‐mL rapid expansion of blood volume, portal pressure increases by 1 mm Hg, which can subsequently cause portal collateral‐related bleeding. ²⁸

Table 2.

Classification of Risk for Bleeding During Procedures

High‐Risk Procedures	Intermediate‐Risk Procedures	Lower‐Risk Procedures
Intrabdominal/orthopedic/cardiac surgery	Invasive endoscopy (biliary sphincterotomy, endoscopic ultrasound‐guided biopsies, cystogastrostomy)	Paracentesis
Intracranial catheter insertion	TIPS	Thoracentesis
Invasive endoscopy (polypectomy)	Lumbar puncture	Dental extraction
Endoscopic submucosal resection	Transarterial chemoembolization or percutaneous locoregional therapies for hepatocellular carcinoma	Endoscopy (e.g., diagnostic, variceal ligation)
	Percutaneous biopsy of extrahepatic organs and lesions	Cardiac catheterization
	Transjugular liver biopsy	Central line placement
		Hepatic venous pressure gradient measurement

Abbreviation: TIPS, transjugular intrahepatic porto‐systemic shunt.

Prothrombin complex concentrates (PPCs) and recombinant FVIIa (rFVIIa) have been designed for specific situations. The use of cryoprecipitate, a small‐volume product having vWF, fibrinogen, and fibronectin without need for cross‐matching, is an attractive option.

PCCs are available as three‐factor (II, IX, X) and four‐factor (II, IX, X, with the addition of VII) products. These products have additional factors (protein C, protein S, antithrombin [AT] III) with or without heparin. The use of PCCs has been standardized only for vitamin K antagonist (VKA)‐treated patients, and the dose is based on body weight, INR, and FIX content. rFVIIa has been studied in acute variceal bleeding; however, no mortality benefit was demonstrated ²⁹ (Table 3). The thrombopoietin receptor agonist eltrombopag can increase PLTs to a variable degree after a 10‐ to 20‐day course but bears a risk for PVT. ³⁰ Two new congeners, avatrombopag and lusutrombopag, are reportedly bereft of this complication, making them of clinical interest. ³¹ , ³²

Table 3.

Clinical Scenarios Relating to Coagulation in Cirrhosis and Liver Failure

Clinical Scenario	Management	Coagulation Tests for Diagnosis and Management	Therapeutic Strategy	Pitfalls
Acute variceal bleeding	Timely endoscopic management by variceal ligation, sclerotherapy, glue injection, etc.	SCT: INR	Maintain hemoglobin target of ~7 g/dL in all patients and 8 g/dL in patients with cardiac disease	Failure to control bleed caused by mucosal hemorrhage and early rebleeding due to high pressures
	Resuscitate as needed without increasing portal pressure.	PLT	Platelet transfusion target of at least 56 × 109/L	Role of TIPS
		Fibrinogen level	Fibrinogen level >100 mg/dL	Role of self‐ expanding metal stents is of utility
		Global tests: TEG and ROTEM are not validated
Invasive procedures	Risk‐to‐benefit ratio and ability of the center to control bleeding should be ascertained.	INR and PLT are not a measure of coagulation risk	In high‐risk procedures, PLTs of 50‐60 × 109/L are to be maintained	FFP use in the prescribed dosage of 20‐40 mL/kg is unlikely to correct INR and may lead to volume overload
		Global tests: TEG and ROTEM are not validated	In very high‐risk procedures, a PLT of 100 × 109/L is to be targeted
LT	Blood transfusion requirements are guided by the stage of the procedure with lower central venous pressures maintained during liver dissection.	Global tests: TEG and ROTEM are validated to guide blood component therapy	TEG‐based correction algorithm for platelets and clotting factors in the form of FFP and cryoprecipitate	POC‐based correction is validated
		Assessment of secondary fibrinolysis is essential
PVT	Anticoagulation is indicated in Yerdel grades ≥2, especially in patients who are planned for LT.	Systemic anticoagulation with therapeutic LMWH or fondaparinux	High INR does not indicate an auto‐anticoagulant state, and patients will still require anticoagulation	Patients with cavernomas are less likely to benefit
	In acute PVT and SMVT, catheter‐mediated thrombolysis may be indicated.	Oral anticoagulants to be used include VKAs and DOACs		Conflicting data are available on primary prophylaxis of PVT
Deep vein thrombosis	Consider prophylaxis in all in‐hospital patients with cirrhosis as per risk scores.	Prophylaxis should be with LMWH or fondaparinux	Variceal eradication is necessary	Heparin‐induced thrombocytopenia and appearance of new‐onset clinically evident bleeding at a remote site is challenging
		Therapeutic anticoagulation should be with oral anticoagulants	Anticoagulation is considered for at least 6 months or lifelong in cases of multiple episodes
Systemic thromboembolism	Anticoagulation is indicated to prevent further embolism.	INR and DIC workup is essential to guide therapy	Role of markers of fibrinolysis and DIC
	Assessment of variceal status and likelihood of variceal bleeding is to be weighed.	aPTT target of 2‐3 times ULN measured q4‐6 hours is needed	Oral anticoagulation using VKAs or DOACs may be used for secondary prophylaxis
ALF	Even with increased INR, the patient tends not to bleed because of “rebalanced coagulation.”	Prophylactic correction of INR is NOT recommended in the absence of clinically evident bleeding	Global coagulation tests, such as TEG, often show a procoagulant state	Invasive monitoring of intracranial pressure is rarely performed, which may require correction of INR in the absence of bleeding
				Role of rFVIIa (40 μg/kg) for monitor placement has been described
ACLF	Patients have coagulation failure in addition to portal hypertension and presence of renal dysfunction.	INR >1.5 is part of the definition of ACLF	INR, PLT, and fibrinogen levels are to be corrected in clinical bleeding with the same goals as cirrhosis	Global tests, such as TEG and ROTEM, may have some use in managing clinical bleeding but need further validation
	If postprocedural bleeding occurs in mucosal sites or from puncture wounds, hyperfibrinolysis should be considered.

Abbreviations: ACLF, acute‐on‐chronic liver failure; ALF, acute liver failure; aPTT, activated partial thromboplastin time; DIC, disseminated intravascular coagulation; DOACs, direct oral anticoagulants; FFP, fresh frozen plasma; Hb, hemoglobin; INR, international normalized ratio; LMWH, low‐molecular‐weight heparin; POC, point of care; PVT, portal vein thrombosis; rF, recombinant factor; ROTEM, rotational thromboelastometry; SCT, standard coagulation test; SMVT, superior mesenteric vein thrombosis; TEG, thromboelastography; TIPS, transjugular intrahepatic portosystemic shunt; ULN, upper limit of normal.

Evidence‐Based Role of Viscoelastic Testing in Liver Disease

Global viscoelastic (VE) tests provide a more physiological assessment of coagulation and should be considered to guide blood transfusion requirements in LT and other major surgeries. Its application in patients with ACLF or in a critical care setting requires more data. VE tests, which include TEG, ROTEM, and Sonoclot, offer a means of assessing the activity of procoagulant and anticoagulant pathways, hyperfibrinolysis, and excessive clot lysis. ³ , ³³ A major fallacy in the interpretation of these tests is that they are in vitro assays and cannot assess the in vivo hemostatic milieu of the endothelium, tissue factor, and portal pressure and flow. Assessment of clot formation can be performed in 10 to 20 minutes; however, assessment of clot lysis takes 30 to 60 minutes. ³⁴ VE testing in LT has been described in one randomized controlled trial and several retrospective studies on the basis for which VE test guided transfusion algorithms are recommended by major guidelines. ³⁵

Hypercoagulability Assessment in Liver Disease

Patients with cirrhosis are at an increased risk (0.5%‐2%) for venous thromboembolism. ³⁶ Rates of PVT have been reported as approximately 8% per year, with morbidity and mortality at 1 year impacted by prophylactic anticoagulation. ³⁷ Anticoagulation demonstrates the most utility in patients with more extensive portal vein and mesenteric thrombosis in the absence of other risk factors for bleeding. Low‐molecular‐weight heparin (LMWH) does not appear to increase risk for variceal bleeding and is likely the safest choice. ³⁸ Thromboembolic events occur in 2% to 5% of patients without cirrhosis who receive thrombopoietin receptor agonists, and the risk is apparently higher in patients with cirrhosis. ³¹

Common Clinical Scenarios in Liver Disease

Acute variceal bleeding and portal hypertensive bleeding from gastropathy, vascular ectasia, and colopathy are often challenging in patients with cirrhosis. ¹¹ Another scenario encountered by the clinician is risk assessment and prophylactic correction of coagulation defects before an invasive procedure. ¹⁹ Conversely, patients with cirrhosis and those with liver failure may have bleeding at one site and thrombosis at another. An example of this situation is a patient with acute PVT with extension of thrombus to the superior mesenteric vein causing mesenteric ischemia in the setting of high‐grade esophageal varices. Tables 3 and 4 show these clinical scenarios and the clinical strategy to manage the condition.

Table 4.

Therapeutic Agents for Bleeding or Thrombosis in Liver Disease

Therapeutic Agent	Dose and Route of Administration	Mechanism of Action	Advantages	Disadvantages	Remarks
Agents for Hemostasis
FFP	15‐30 mL/kg IV	Partial correction of deficient coagulation factors	Cost‐effective and available at all blood banks as a product of fractionating whole blood	Volume overload	At least 10 mL/kg is needed to effectively raise plasma protein value
Cryoprecipitate	10‐20 mL plasma IV	FVIII, FXIII, fibrinogen, fibronectin, and vWF replacement	Same as FFP and provides large dose of fibrinogen in patients with DIC	Transfusion reactions	Low volume and cost‐effective
			No cross‐match needed
Single‐donor apheresis platelet unit	Platelets in a dose of 8000‐12,000 cells/unit IV	Platelet boost to improve number and function	Small volume	Transfusion reactions and TRALI	Use of random donor platelet units is not recommended in cirrhosis
PCCs	Typical dose is 25‐30 units of FIX per kg body weight IV	Three‐factor (II, IX, X) and four‐factor (II, IX, X, with the addition of FVII) products	Concentrated volume	Expensive	Not widely available
		Also have proteins C and S	Has been used in cirrhosis with good results	Risk for thrombosis
rFVIIa	40‐90 µg/kg IV	FVII as a driver of the coagulation cascade	Concentrated volume	Expensive	Used in acute variceal bleeding, but no mortality benefit was demonstrated
				Risk for thrombosis: cerebrovascular and myocardial infarction and DIC Risk for thrombosis: cerebrovascular and myocardial infarction and DIC
Thrombopoietin Agonists
Eltrombopag	25‐75 mg qd po × 10‐20 days	Increases PLT	Expensive	Risk for PVT	Newer congeners, avatrombopag and lusutrombopag, may pose lower risk for development of PVT
			Short‐lived effect
Antifibrinolytic Agents
Tranexamic acid	500 mg q6 hours IV or po	Disrupts the plasminogen/plasmin interaction with fibrin preventing lysis of clot	Relatively inexpensive	Doubtful risk for thrombosis or urinary clots if used in hematuria	Tests of fibrinolysis are still unclear
			Effective topically
EACA	Initial: 4‐5 g IV/po during first hour	Inhibits fibrinolysis through inhibition of plasminogen binding to fibrin and conversion to plasmin, which causes fibrinolysis	Effective topically		Efficacy in cirrhosis with fibrinolysis is not yet established
	Maintenance: 1‐4 g po/IV q4‐8 hours
Anticoagulation in Liver Disease
Unfractionated heparin	IV or SQ injection	Inactivates FXa and thrombin	Not well studied in cirrhosis but commonly used	Needs frequent monitoring of aPTT	Reversal agent available and safe in renal disease
LMWH (enoxaparin, dalteparin)	SQ injection	Inactivates FXa and thrombin	Monitoring not needed	Extensively used in cirrhosis but expensive and possibility of heparin‐induced thrombocytopenia	Reversal agent not available
VKA	po	Inhibits vitamin K–dependent FII, FVII, FIX, and FX	Cost‐effective	Dosing requirement varies	Unclear dosing variables
			INR is standard monitoring		Dietary restrictions
					CYP P450 interactions
DOACs	po	Direct thrombin inhibition by drugs such as dabigatran	Oral drugs	Role in PVT	Monitoring and dosing protocols in cirrhosis need validation
FXa inhibitors	SQ injection (fondaparinux 7.5 mg qd)	Direct inhibition of FXa	po or SQ administration	Role in heparin‐induced thrombocytopenia	Monitoring and dosing protocols in cirrhosis need validation
	po (rivaroxaban 10 mg qd)

Abbreviations: aPTT, activated partial thromboplastin time; CYP P450, cytochrome P450; DIC, disseminated intravascular coagulation; EACA, ε‐aminocaproic acid; F, factor; FFP, fresh frozen plasma; INR, international normalized ratio; IV, intravenous; LMWH, low‐molecular‐weight heparin; PCCs, prothrombin complex concentrates; PVT, portal vein thrombosis; rF, recombinant factor; SQ, subcutaneous; TRALI, transfusion‐related acute lung injury; VWF, von Willebrand factor.

Dynamic Coagulation Profile in SIRS and Sepsis

Most coagulation enzymes are also components of the inflammatory cascade. The cell‐based model suggests that coagulation is one aspect of systemic inflammation. The interaction of platelets and inflammatory cytokines released from damaged endothelium triggers the adhesion of neutrophils and macrophages, and activation of inflammation. Hence patients with cirrhosis or ACLF with SIRS or sepsis are bound to have coagulation defects with an anticoagulant or procoagulant or mixed phenotype. The changes in the coagulation profile are dynamic, with resolution of global coagulation defects once sepsis resolves. Recurrence of a coagulation defect, such as platelet dysfunction, or occurrence of a new defect, such as fibrinolysis, is seen with new‐onset sepsis. Prior studies have described reduced coagulation FV, FVII, FIX, FX, FXI, and prothrombin, and increased FVIII activity in cirrhosis. ³ , ⁷ , ⁸ , ⁹ Two other divergent agents of the cascade affected by sepsis are tissue plasminogen activator (tPA) and plasminogen activator inhibitor (PAI). In liver failure, tPA is elevated because of endothelial activation and reduced hepatic clearance. Levels of PAI, a blocker of fibrinolysis, are also increased, but to a lesser extent than tPA. ¹² Low fibrinogen is associated with a 29% increase in mortality for every 1‐g/L (100‐mg/dL) reduction in decompensated cirrhosis. ³⁹ Hypofibrinogenemia predisposes to increased risk for bleeding after prophylactic endoscopic variceal band ligation. ⁴⁰ Dysfibrinogenemia (i.e., an altered fibrinogen molecule) may cause decreased permeability of the formed clot compared with controls and may even confer hypercoagulable features, causing scenarios such as portal vein or deep vein thromboses. ⁴¹

The development of sepsis in patients with cirrhosis changes the coagulation factors and cellular elements, including endothelium, macrophages, and lymphocytes. Endotoxins inhibit PF by increased prostacyclin and nitric oxide production. ¹² SIRS and sepsis trigger the release of endogenous heparinoids, or a heparin‐like effect, caused by small endothelium/mast cell–derived glycosaminoglycans, which can be detected on heparinase‐treated VE assays. One study demonstrated the presence of heparan sulphate–like molecules in patients with variceal bleeding. ⁴² Senzolo et al. ³³ showed that these glycosaminoglycans affect hemostasis in patients with cirrhosis and bacterial infection as seen by a hypocoagulable native thromboelastography (TEG). This can be corrected by using heparinase‐treated TEG. Bacterial sepsis predisposes patients to new bleeding events and results in difficult‐to‐control bleeds or endoscopic treatment failure. ¹¹ Endotoxin also activates the clotting cascade and results in disseminated intravascular coagulation (DIC). After appropriate treatment, the coagulation profile resolves and endogenous heparinoids are cleared, emphasizing the complementary association of the coagulation cascade and the inflammatory pathways. ¹⁷

Laboratory Testing in Liver Disease

SCTs, such as INR and PT, are determined by liver‐synthetized coagulation FI, FII, FV, FVII, and FX. The anticoagulation system (low protein C and protein S) is not tested, which may result in a hypercoagulable state despite increased INR in ACLF. Effective thrombin generation potential has been demonstrated to be normal in cirrhosis, AD of cirrhosis, and even uncomplicated ACLF because of higher levels of FVIII and low protein C. ³ , ⁷ , ⁸ , ⁹ VE assays provide a physiological estimation of coagulation; however, their use has been validated only in the setting of LT. New research has demonstrated the use of global coagulation tests, such as TEG, ROTEM, and Sonoclot, in the setting of cirrhosis, ALF, AD of cirrhosis, and ACLF; thus, VE tests are finding mention in newer guidelines for hemostatic resuscitation, but more validation is needed before they can be recommended as standard of care. ³ , ⁵ , ⁶ , ⁷ , ⁸ , ⁹ , ²⁵ Table 4 shows the therapeutic targets and agents available for evidence‐based management of bleeding or thromboses in liver disease. Figure 2 shows a clinical decision algorithm to determine coagulation correction targets using VE assays and SCTs.

FIG 2.

Coagulation correction algorithm using global coagulation tests.

Key elements of the whole blood TEG include the reaction time (R time), which reflects the quantity of available factors; clot formation time (K); alpha angle (α) reflecting the rate of clot formation and indirectly indicating fibrinogen levels; maximum amplitude (MA), which is an indicator of platelet activity; and finally, a measure of clot lysis. ³ Thrombin generation assays provide the rate of thrombin formation in the presence of a triggering agent, such as phospholipid, a tissue factor that indicates a preserved coagulation milieu in cirrhosis or liver failure. ¹³

Summary and Future Directions

The dogmatic practice of conventional testing and treatment of coagulation defects is being challenged in light of new clinical evidence of the cell‐based hemostasis model in cirrhosis and liver failure. The use of global coagulation tests has provided more credible data for practical use of blood component therapy. Appreciation of the role of fibrinolysis in bleeding and effective use of antifibrinolytic agents to control mucosal bleeding are of interest in clinical practice, reducing the need for component transfusions. The pitfalls of the use of INR to guide transfusion strategies are well recognized. Hypercoagulable states in the setting of cirrhosis and liver failure are often undiagnosed. Prospective studies are needed to examine the utility of current risk models in patients with liver disease with a goal of improving knowledge of the incidence and natural history of venous thromboembolism.