Current Observations in the Management of Hypo- and Hypercoagulability in Patients With Acute or Chronic Liver Failure

Summary and Key Points

• Patients with cirrhosis are often hypercoagulable, and thus need surveillance for portal vein thrombosis using Doppler ultrasound every 6 months.

• All patients with cirrhosis or acute liver failure in the emergency room or inpatient service who are bleeding or require an invasive procedure should undergo a thromboelastography (TEG)/rotational thromboelastometry (ROTEM) on evaluation if available and then be scheduled for monitoring of their clinical status. Consider TEG/ROTEM on an individualized basis for other patients. If TEG/ROTEM is not available, integrate the international normalized ratio (INR), platelet count, and fibrinogen with risk of bleeding, risk of transfusion-related acute lung injury (TRALI)/ transfusion-associated circulatory overload, and other transfusion risks, based on the knowledge that INR is a poor signal of coagulation balance (Figure 1).

• TEG/ROTEM may supersede clinical decisions with the INR/prothrombin time (PT) and may eventually make the INR/PT superfluous. The TEG/ROTEM can be supplemented by platelet count and fibrinogen in patients with cirrhosis or acute liver failure.

• Patients with new evidence of portal vein thrombosis should be anticoagulated unless unstable. Among patients with cirrhosis who have an old portal vein thrombosis as documented by cavernous transformation of the portal vein with no fresh clot, a hypercoagulation phased workup should be considered to target the correct anticoagulation treatment and establish a correct risk and diagnosis. If there is evidence that the clot is progressing, strongly consider anticoagulation. Patients with cirrhosis develop portal vein thrombosis far more frequently from sluggish portal flow, hepatocellular carcinoma, and/or abdominal infection rather than a defined hypercoagulable state, which is difficult to evaluate.

• Patients with cirrhosis are probably at the same or higher risk for deep venous thrombosis and pulmonary embolism as other patients; deep venous thrombosis prophylaxis needs to be planned and individualized based on risk.

• Coagulation support for patients with liver disease should not be focused on the INR/PT, nor should fresh frozen plasma be used arbitrarily to “correct” the INR/ PT; instead, the best approach is to replace the INR/ PT test with TEG testing as soon as the TEG/ROTEM device is available.

• Evaluate the platelet count in all patients; if the platelet count is under 60,000 cells/uL, assess with TEG if available and use thrombopoietin receptor agonists (TPORAs) according to platelet level and risk of bleeding with procedures; if available, adjust TPO-RA use depending on the maximum amplitude on the TEG device.

• In the era of the COVID-19 pandemic, planning procedures in order to minimize time in an infusion center would support the use of a TPO-RA among patients at risk of thrombocytopenia.

Figure 1.

An algorithm for the management of coagulation disorders in patients with liver disease. INR, international normalized ratio; RBC, red blood cell; TEG, thromboelastography; TPO, thrombopoietin. aPlease see the article on background and evaluation of hypercoagulability for more information regarding the INR for TEG. Adapted from Stravitz RT. Hepatol Int. 2018;12(5):390-401.¹³

Controversies

There is disagreement among the authors regarding the scope of laboratory testing that should be performed to identify hypercoagulable disorders in patients with cirrhosis and a history of thromboembolism. RG advocates for multiphase hypercoagulable testing in all patients with cirrhosis and portal vein thrombosis, Budd-Chiari syndrome, pulmonary embolism, deep venous thrombosis, or another major clotting episode. He argues that an acquired or inherited thrombophilia can be identified in the majority of patients in whom testing is performed, which can inform the need for genetic testing/counseling, the intensity of periprocedural venous thromboembolism prophylaxis, and the frequency of surveillance for clotting complications post-transplant. JB argues for a more tailored approach. In his opinion, portal vein thrombosis is common in patients with portal hypertension in the absence of a thrombophilia and does not necessarily warrant hypercoagulable testing. Tests such as protein C, protein S, antithrombin, and factor VIII are often positive in patients with cirrhosis due to impaired synthetic function (and enhanced endothelial production in the case of factor VIII) even in the absence of an inherited disorder, confounding interpretation of results. JB advocates hyper-coagulable testing when one of the following criteria is met: 1) it affects choice of anticoagulation (ie, warfarin for patients with antiphospholipid antibody syndrome), 2) it affects decisions regarding duration of anticoagulation, 3) thrombosis is in an unusual location (ie, hepatic vein thrombosis or noncirrhotic portal vein thrombosis), or 4) appropriate clinical history (ie, convincing family history, signs/symptoms of a myeloproliferative neoplasm or paroxysmal nocturnal hemoglobinuria).

Another controversy surrounds the use of TEG/ROTEM compared with standard laboratory assessment (PT/INR, activated partial thromboplastic time [aPTT]) in patients with liver disease. Should it replace the use of INR/PT in all patients with advanced liver disease? We believe the answer is yes. The elevated PT and INR/PT that occurs in cirrhotic patients often occurs against the background of a normal or near-normal aPTT. Evaluating PT/INR in isolation does not take into account other issues such as thrombocytopenia and platelet dysfunction, although both of these issues are important in the patient with coagulopathy and advanced liver disease. TEG/ ROTEM integrates these test results into one graphical representation. In patients with liver failure, PT results and INR calculation do not correlate well with more specific assessments of overall coagulation state using TEG. TEG provides the opportunity to determine a true coagulation profile that correlates well with the in vivo clinical presentation. Although TEG/ROTEM is not considered as standard of a technique as PT measurement and INR calculation, it has been shown to provide benefit when guiding procedures such as liver transplant.¹ It also has shown benefit when guiding the management of acute coagulopathy in critical acute settings such as the emergency room and military operations.^2-5 However, additional research is needed to more fully establish the role of TEG in the management of patients with advanced liver disease.

Much debate surrounds the implementation of anticoagulation therapy across all patients with portal vein thrombosis. As the thrombotic complications of advanced liver disease are increasingly recognized, the use of these agents in this setting is likely increasing. Given the limited clinical trials in this area, there are no consensus guidelines to provide recommendations. A nonblinded, single-center study by Villa and colleagues showed successful and safe prevention of portal vein thrombosis using prophylactic enoxaparin.⁶ This study also demonstrated reduced bacterial translocation, a decrease in the incidence of hepatic decompensation, and improved survival. However, in the absence of well-designed clinical trials, other experts are of the opinion that the data are insufficient to justify widespread primary prophylaxis of portal vein thrombosis.⁷ Instead, it may be considered on an individual case-by-case basis at the discretion of the treating physician.

With the availability of newer direct oral anticoagulants (DOACs; including apixaban, dabigatran, edoxaban, and rivaroxaban), there is a school of thought that these agents should completely replace the use of warfarin. Over the past several years, these newer anticoagulant agents have emerged as alternatives to warfarin for the prevention and treatment of venous thromboembolism and for the prevention of stroke in patients with atrial fibrillation. Based on the results of a number of randomized trials, these agents are now recommended as first-line treatment or as alternatives to warfarin for the management of atrial fibrillation and venous thromboembolism across multiple guidelines. However, the efficacy and safety of these drugs in the setting of liver disease have not been well studied, and none of the clinical practice guidelines offer direction regarding their use in patients with liver disease.⁸ Indeed, these randomized trials largely excluded patients with liver disease. All of these agents undergo hepatic metabolism (to varying degrees), and therefore are subject to decreased liver function. In addition, the presence of hepatic coagulopathy may exacerbate the risk of bleeding associated with newer anticoagulant agents. In the wake of their approval for use, the hepatic safety of the newer anticoagulant agents has been followed and reported in clinical practice. It is clear that all of these agents are associated with elevations of transaminases. However, there remains no clear evidence that these agents result in hepatotoxicity, and a Canadian administrative database-linked cohort study recently found no significant difference in the rates of serious liver injury with DOACs compared with warfarin in patients with or without liver disease.⁹

The optimal management of patients with a baseline INR value higher than 2 who have an indication for therapeutic anticoagulation is unclear. Some advocate targeting an INR 1 unit above the patient’s baseline INR value, but no higher than 3.5. However, evidence supporting this approach is lacking, and maintaining such a narrow therapeutic window in patients with advanced cirrhosis is often not feasible. Use of DOAC therapy to avoid the need for INR monitoring is appealing, but these agents have not been well-studied in patients with advanced cirrhosis. A tailored approach using individualized INR targets, reduced-dose DOAC therapy, or daily prophylactic dose low-molecular-weight heparin is often considered. Sometimes, no safe anticoagulant can be recommended.

Another controversy exists regarding the use of TPO-RAs in patients with low platelets (<50,000) as a prophylaxis prior to invasive procedures. Recently, this strategy was explored in ADAPT 1 and ADAPT 2, which were 2 identically designed, multicenter, randomized, double-blind, placebo-controlled studies.¹⁰ A total of 435 patients with chronic liver disease were stratified according to baseline platelet count, with 184 in a high cohort (mean baseline platelet count of 40 to <50 × 10⁹/L) and 251 in a low cohort (mean baseline platelet count <40 × 10⁹/L). Patients in both cohorts were randomized in a 2-to-1 ratio to treatment with either avatrombopag or placebo. Avatrombopag was associated with a significant reduction in the primary endpoint, the need for platelet transfusion, or any rescue procedure for bleeding. Among patients with a high baseline platelet count in ADAPT 1 and ADAPT 2, the primary endpoint was met by 88% of those treated with avatrombopag, compared with 38% in the placebo arm of ADAPT 1 and 33% in the placebo arm of ADAPT 2. A similar pattern was observed in patients with a low baseline platelet count. The primary endpoint was met by 66% of the treatment arm in ADAPT 1 and 69% of the treatment arm in ADAPT 2, vs 23% and 35%, respectively, of the placebo arms. Additionally, up to 93% of high-platelet patients and up to 69% of low-platelet patients who were treated with avatrombopag reached the secondary endpoint of a target platelet count of ≥50 × 10⁹/L. In pooled analysis of the 2 trials, the most common (>5%) adverse events reported with avatrombopag were pyrexia, abdominal pain, nausea, and headache.

Lusutrombopag was evaluated in the L-PLUS 2 trial, a global, phase 3, randomized, double-blind, placebo-controlled study, for its ability to raise platelet counts in patients with chronic liver disease and thrombocytopenia who were undergoing invasive procedures.¹¹ A total of 215 patients were randomly assigned to treatment with lusutrombopag or placebo. The primary endpoint of avoidance of preprocedure platelet transfusion and avoidance of rescue therapy for bleeding was met by 64.8% of the lusutrombopag group compared with 29.0% of the placebo group (P<.0001). A key secondary endpoint, the number of days that platelet counts were ≥50 × 10⁹/L throughout the study, was also significantly longer with lusutrombopag (without platelet transfusion) vs placebo (with platelet transfusion). The median duration of platelet counts of ≥50 × 10⁹/L was 19.2 days with lusutrombopag vs 0.0 days with placebo (P=.0001). Most adverse events were mild or moderate in severity; headache was the only treatment-emergent adverse event reported in more than 5% of lusutrombopag-treated patients.

Although TPO-RAs have proven to be effective in raising platelet counts and reducing use of preoperative platelet transfusion, their effect in reducing procedure-related bleeding is less clear. No randomized trials have demonstrated reduction in the risk of procedural bleeding by raising the platelet count above a specific threshold. The safety profile of the 2 approved TPO-RAs is comparable to that of placebo, and these treatments can obviate the risks of platelet transfusion. Although these therapies are expensive, costing approximately $4,000 to $10,000 for a course of treatment (according to list price), the cost compares favorably with that of prophylactic platelet transfusion.¹²

Acknowledgment

Dr Gish would like to acknowledge Timothy Halterman, MD, for reviewing this article.