Anticoagulation in cirrhosis patients: What don't we know?

Patients admitted to the hospital are at high risk for developing venous thrombosis when compared with the general population (1, 2). Prophylaxis with unfractionated heparin or low-molecular-weight heparin (LMWH) decreases the risk of development of venous thrombosis in hospitalized medical patients (3). Current guidelines recommend venous thrombosis prophylaxis for hospitalized medical patients who will be confined to a bed (4). Hospitalized patients with cirrhosis are also known to be at risk to develop deep venous thrombosis (5–9). They are often rendered immobile because of complications like encephalopathy, ascites, oedema or muscle wasting. As it is well established that prophylaxis decreases the risk of venous thrombosis in hospitalized patients, it is currently unclear if a similar benefit would extend to patients with cirrhosis. The article in this issue of Liver International by Bechmann et al. (10) provides one of the first studies to specifically examine the effects of venous thrombosis prophylaxis in this unique population. This study evaluates the efficacy of using anti-Xa values to monitor and guide dosing of LMWH in cirrhotic patients receiving both prophylactic and therapeutic doses of LMWH. Using anti-Xa levels to measure effect in prophylactic or therapeutic dosing of LMWH is only routinely indicated in special patient populations, such as those with renal failure or advanced age. However, cirrhotic patients have not been well studied and pharmacodynamic data regarding LMWH in patients with cirrhosis are scarce. Patients admitted with cirrhosis who met inclusion criteria (prolonged immobilization, advanced age, low levels of protein C and protein S, malignancy, known thrombophilia, stroke, shock, prior thrombotic events) were enrolled. Patients with a recent major bleeding event, creatinine clearance <30 ml/min or history of heparin-induced thrombocytopenia were excluded. A smaller cohort of nine patients that needed full dose therapeutic LMWH for known thrombosis was also followed. Although not powered to evaluate for safety of LMWH, there were no reported deaths and no thrombotic events in either group. The authors cite bleeding events that were similar to previous studies in hospitalized patients with cirrhosis. By measuring levels of anti-Xa activity, they found that only 11 out of 75 patients in the prophylaxis group and zero out of nine in the therapeutic group achieved therapeutic dosing levels using standard weight-based regimens of LMWH, regardless of dose adjustments. Interestingly, a negative correlation was found between levels of anti-Xa and severity of liver disease as defined by Childs–Pugh–Turcotte, model for end-stage liver disease and the presence of ascites. A positive correlation was found between levels of antithrombin (AT) and anti-Xa. Because cirrhotic patients are deficient in AT, the authors argue that these findings may indicate that current dosing guidelines are not effective for cirrhotic patients. The authors conclude that either current assays measuring anti-Xa are inaccurate in cirrhotic patients, or that the acquired deficiency of AT inherent in cirrhosis may lead to reduced efficacy of LMWH. Anti-Xa levels may not be an accurate way to assess the degree of anticoagulation provided by standard dosing of LMWH in cirrhotic patients. Coagulopathy of liver disease is a complex interplay between pro- and anticoagulant factors that are not accurately assessed by currently available biochemical indices (11–14). The apparent propensity to bleed or alternatively to develop clot presents a challenging clinical paradox to physicians that care for this patient population. This study re-inforces the evolving notion among hepatologists that current laboratory tests to evaluate coagulopathy cannot be extrapolated and applied to cirrhotic patients. For example, the commonly held misconception that an elevated INR provides a 'protective' barrier to developing thrombosis remains unfortunately pervasive in the medical community. While coagulation parameters can often be abnormal in patients with cirrhosis, the values per se have little predictive value on bleeding risk (15, 16). In this study, the authors found that the majority of patients did not achieve therapeutic effect as measured by anti-Xa levels with current standard-dose regimens of LMWH. This apparent decreased efficacy of LMWH in cirrhotic patients is an important finding. This study is the first, to our knowledge, to report this in the cirrhosis patient population. While decreased efficacy may indeed argue for altering dosing patterns in cirrhotic patients, the authors also suggest that inaccuracies inherent in classical anti-Xa assays may lead to false conclusions. It is becoming increasingly apparent that cirrhotic patients are prone to developing venous thrombosis. This study shows us that future investigation aimed at evaluation of safety, dosing and monitoring of these medications are desperately needed before definitive recommendations for prophylaxis and treatment of thrombosis can be developed. While they did not specifically state their dosing adjustment methods in this study, it is an interesting, and perhaps a somewhat disturbing conclusion, that only a few patients were able to reach the prophylactic goal and no patients reached the therapeutic goal as defined by anti-Xa levels. Whether this is evidence of reduced efficacy of LMWH in this population or just a shortcoming of the assay remains unknown. The fear of the practitioner caring for the cirrhosis patient is clinical bleeding. Bleeding events, especially gastrointestinal bleeding, are often life threatening and are generally more frequent than true systemic thromboembolic events (excluding portal vein thrombosis). Nonetheless, gastrointestinal bleeding related to portal hypertension is related to many aetiologies. The most dangerous acute bleeding typically arises from the rupture of gastroesophageal varices. While coagulopathy (either innate or therapeutic) certainly can make variceal bleeding more severe, the initiation of this type of bleeding is generally thought to be because of mechanical issues, not the severity of coagulation defect in an individual patient. The mere presence of anticoagulation should not increase the risk of variceal bleeding. This notion is re-inforced in the present article showing a bleeding rate similar to what would be expected in the non-anticoagulated cirrhosis population. No mention is made in the article about severity of bleeding other than the fact that there were no fatalities from variceal bleeding. It should also be noted that none of the patients suffering from bleeding reached the therapeutic range of anticoagulation as measured by anti-Xa levels. The notion that mechanical or procedure-related bleeding is not predictable by traditional measures of coagulation in the cirrhosis patient is becoming more established within the Hepatology community (17–19). Be that as it may, it would seem prudent to eradicate gastroesophageal varices before undertaking long-term anticoagulation in the decompensated cirrhosis patient. Unfortunately, this study is underpowered to prove either efficacy or safety of the use of LMWH in this population. The present work addresses an important question about the utility and pharmacokinetics of LMWH in cirrhosis patients but this article raises more questions than answers. Is the assay for anti-Xa invalid in patients with an acquired AT deficiency (like cirrhosis)? Is LMWH still efficacious in cirrhosis patients despite the fact that standard dosing regimens do not bring the anti-Xa levels to traditionally acceptable therapeutic ranges? Does the reduced innate factor X activity in cirrhosis patients make therapeutic anticoagulation inherently more unpredictable? What does the role of the functional decrease in protein C activity in these patients play in anticoagulation? These questions all revolve around a fundamental lack of understanding of how the pathophysiology of chronic liver disease interacts with the complex coagulation cascade. This cascade is inadequately described by simple coagulation protein levels and involves such complicated issues as platelet dysfunction, innate heparinoids, procoagulant protein activity, endothelial dysfunction and many other factors. Articles such as this help to support the notion that a systematic, prospective study of coagulation profiles in patients with acute and chronic liver disease is needed to help to define the nature of the coagulation defects. A full understanding of the coagulation disorder in this disease is needed before we undertake therapeutic studies. With the burden of cost and therapy targeted towards coagulation defects in liver disease patients, funding for translational and clinical research in this area is overdue. In conclusion, the study by Bechmann and colleagues provides us with a prospective study to investigate thrombotic prophylaxis and treatment in cirrhotic patients with LMWH. The evidence in this study re-inforces prior conclusions that have called for special coagulation profile studies to be developed that will guide risk assessment and treatment strategies in cirrhotic patients. Further studies are needed to evaluate safety and efficacy once more knowledge is gained related to pharmacokinetics of LMWH in cirrhotic patients. A better understanding of the role of medical prophylaxis is necessary to aid in preventing thrombosis in this unique and complex population.