Dismantling the myth of “autoanticoagulation” in cirrhosis: An old dogma dies hard
Authors: Stephen Caldwell, Nicolas Intagliata
Journal: Hepatology (2012)

Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med 2011;365:147-156. (Reprinted with permission.) The reassessment of hemostasis in patients with chronic liver disease challenges the dogma that the major coagulopathy in these patients leads consistently to bleeding. Other changes that accompany chronic liver disease may restore the balance of anticoagulant and procoagulant effects. In certain circumstances, the risk of thrombotic events may be greater than the risk of hemorrhage. We speculate that drugs that are often regarded as contraindicated in patients with chronic liver disease may instead prove beneficial and should be tested in appropriate clinical trials. For any provider who cares for patients with liver disease, whether directly or in a supportive or procedural capacity, bleeding from one site or another has likely left an indelible, and often dour, clinical impression. This feeling is especially amplified when the bleeding originates from one's own puncture or biopsy site. The prothrombin time (PT) and international normalized ration (INR) are reliable measures of coagulation in warfarin-treated patients. It stands to good reason that direct extrapolation and application of PT/INR to cirrhosis patients should provide a practical measure of bleeding risk and serve as a reliable guide for therapy and prevention of bleeding. However, for those who have practiced this concept for many years, the emergence of a contrary body of literature may be difficult to digest. Nonetheless, it is currently evident that the hemostatic system in liver disease patients is far more complex than the PT/INR. Indeed, these patients may be relatively hypercoagulable, in spite of prolongation of the PT/INR. These paradoxical relationships have recently been summarized in an important article from two key investigators in this field, Armando Tripodi and Pier Mannuccio Mannucci. 1 Investigations over the recent past have redefined the "balance" of the coagulation cascade in cirrhosis patients as a more sensitive state of equilibrium, where perturbations can result in either a hypo- or hypercoagulation clinical event. From a simplified perspective (Fig. 1), coagulation in the cell-based model of hemostasis originates at a site of vascular breach from activation of tissue factor and factor VII on the phospholipid membrane of a platelet (or adventitial cell). This, in turn, leads to assembly of activated factors X and V (prothrombinase complex), which results in a "priming" amount of thrombin (factor II) and initiation of fibrin production from fibrinogen. If left unchecked, the priming step results in an assembly of activated factors IX and VIII (the "tenase" complex) which "amplifies" the process through activation of more factor X, leading to a "thrombin burst" and additional fibrin production. The process then "propagates" through the recruitment of additional activated factors unless or until it is inhibited by the anticoagulant system, which provides regulatory control over the process. Key components of the inhibitory system, which are also activated by thrombin, include liver-derived antithrombin acting with endothelial-derived heparinoids and, perhaps more important, a complex composed of liver-derived protein C, protein S, and endothelial-derived thrombomodulin. This complex inhibits factors VIII and V (factors in both the tenase and prothrombinase complexes). Importantly, much of this process is occurring on a negatively charged phospholipid substrate (especially the membrane of the activated platelet). 2 A simplified version of the coagulation cascade in normal conditions and the changes observed in cirrhosis (inset). AT, antithrombin; TFPI, tissue factor pathway inhibitor. Red dotted lines indicate inhibition pathways. Groundbreaking evidence for a rebalanced system in cirrhosis (not reflected by the INR) was reported by Tripodi et al. in 2005. 3 They demonstrated that measurement of thrombin production using the endogenous thrombin potential (ETP) assay, in the presence of thrombomodulin, is not different in stable cirrhosis patients from normal controls irrespective of conventional coagulation test parameters, such as the INR. Using the same assay, expressed as a ratio of ETP with and without thrombomodulin, this group further demonstrated that stable cirrhosis patients have a stepwise increase in resistance to the native anticoagulation system and thus, from the perspective of the clotting cascade, become relatively hypercoagulable with more advanced disease. 4 Extending this unexpected finding, Lisman et al., in The Netherlands, demonstrated that the elevation of von Willebrand factor (vWF) in cirrhosis increases platelet adhesion similarly in a stepwise fashion, compared to control subjects. 5 These relationships can likely explain recent reports of thromboembolic disease in cirrhosis. 6, 7 It is also of relevance that increased vWF parallels endothelial dysfunction and carries prognostic significance. 8 On the other hand, how can this paradigm simultaneously account for the bleeding that we routinely see in cirrhosis patients? It is important to recall that most of the recent studies reviewed in the Tripodi and Mannucci article were performed in relatively stable cirrhosis patients and none of the alternative laboratory tests have undergone sufficient translational research to understand their clinical value. Bleeding in liver disease is influenced by a number of interacting factors that often emerge in the decompensated cirrhosis patient. These include portal hypertension, endothelial dysfunction (i.e., the hyperdynamic state), endogenous heparinoids released especially with infection, renal failure with associated volume overload, vascular congestion and uremic platelet dysfunction, altered pro- and anticoagulant factors caused by cirrhosis, dysfibrinogenemia (an abnormal form of fibrinogen/fibrin observed in cirrhosis), altered phospholipid metabolism, and thrombocytopenia. 9-11 What about prolongation of the INR in cirrhosis patients? Though useful in measuring the effect of vitamin K antagonists, such as warfarin, the PT/INR cannot possibly measure the balance (or imbalance) in cirrhosis. This test only detects the deficiency of procoagulant factors (e.g., II, VII, IX, and X) and does not detect the coexisting deficiency of anticoagulant factors, such as liver-derived protein C and S, nor significant increases in procoagulant factors, such as endothelial-derived factor VIII and vWF. Aside from the limitations evident physiologically and in bleeding-risk studies, 12-14 the test also has another major limitation in cirrhosis patients: poor reproducibility. Trotter et al., Lisman et al., and others have shown that the INR is higher or lower than 1.5 in 30%-40% of patients, depending on which commercial thromboplastin is used in the prothrombin time assay. 15, 16 Thromboplastin is the lipid derivative used as a surrogate for the platelet phospholipid membrane to activate the clotting cascade. Variation in the INR in cirrhosis can be reduced if the ISI (international sensitivity index) for a given thromboplastin is measured against a panel of liver disease patients, rather than warfarin-treated patients. 17-19 However, this approach is not likely to be adopted by clinical laboratories and does not overcome other physiological limitations of the test. Presently, no clinical test is widely available that can accurately measure the bleeding (or clotting) risk in these challenging patients. However, there is emerging consensus that accurate assessment will require a more global perspective accounting for the complex, dynamic interactions between the pro- and anticoagulant systems. The inadequacy and limitations of the PT/INR (and the challenges presented by its unfortunate use in some societal guidelines) are anticipated to be the subject of a position paper from the Coagulation in Liver Disease Group subsequent to a recent meeting in London (www.coagulationinliverdisease.org). Ultimately, as is very evident from the Tripodi and Mannucci article, we must abandon an old, unfounded dogma with its wrong, but widely perpetuated myths and move to a better understanding of the complexity of hemostasis in cirrhosis.