The Rebalanced Hemostasis System in End-stage Liver Disease and Its Impact on Liver Transplantation

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There are 3 physiological phases of action in the modern view of hemostasis. Primary hemostasis begins with endothelial injury, exposure of von Willebrand factor (vWF), platelet activation and aggregation, and an initial thrombin “burst.” Coagulation then follows with activation of the coagulation cascade, through extrinsic and intrinsic pathways in a positive feedback loop activated by thrombin and the formation of the fibrin mesh and fortification of the classic clot. Lastly, fibrinolysis must occur through the action of anticoagulant proteins and enzymes to avoid pathologic thrombus formation.
Primary hemostasis is typically measured through platelet counts, vWF levels, platelet function assays, and bleeding time. Coagulation is generally measured by prothrombin time (PT) or international normalized ratio (INR) and activated partial thromboplastin time (aPTT) representing the intrinsic and extrinsic pathways of the clotting cascade, respectively. Although infrequently performed clinically, specific procoagulant factor levels can be measured. Fibrinolysis can generally be measured through fibrinogen levels, protein C and S levels, antithrombin III (ATIII) activity, euglobulin lysis time (ELT), and direct measurements of anticoagulant proteins (PAI-1, TAFI).1 There are also in vitro whole blood measures of the complete clotting system using thromboelastography (TEG), rotational thromboelastometry (ROTEM), and sonorheometry, which can give an overall assessment of the different stages of hemostasis, including the intrinsic fibrinolytic and antifibrinolytic pathways.2
In patients with cirrhosis every stage of hemostasis may be altered, putting them at risk for both bleeding and thrombosis. Classically, patients with cirrhosis have been thought of as “autoanticoagulated” because of an elevated INR and baseline thrombocytopenia owing to splenic sequestration and portal hypertension. Although routine tests such as platelet counts, INR, and aPTT may accurately reflect bleeding risk in general populations, multiple studies have shown that patients with cirrhosis have deficiencies in both the procoagulant and anticoagulant pathways, leading to a “rebalanced” coagulation system.3,4
In regard to primary hemostasis, patients with cirrhosis typically have a decreased number of circulating platelets. This is related to splenic sequestration, more rapid turnover and shorter half-life of platelets secondary to splenomegaly, and decreased production related to lower amounts of hepatic thrombopoetin.5,6 There may also be an immunologic component, although this appears to be a minor contributor.7 The decreased platelet count may be expected to increase the risk for bleeding, but patients with cirrhosis also have elevated levels of vWF, which increases in proportion to the severity of liver disease.8 In addition, there is a decrease in ADAMTS13, the vWF cleaving protein, and despite the underlying thrombocytopenia this increase in vWF may actually increase platelet adhesion.9,10 A study by Tripodi et al11 showed that in patients with cirrhosis a minimum platelet count of around 55×109/L is adequate for thrombin generation, allowing normal clot formation, and levels above 100×109/L have no increased benefit in primary hemostasis or in fibrin mesh formation when compared with controls. In some patients, these compensatory mechanisms may actually result in enhanced platelet adherence rather than dysfunctional primary hemostasis.
In the second stage of hemostasis, clotting factors activate and begin to produce thrombin, predominantly on the surface of activated platelets, leading to subsequent deposition of the cross-linked fibrin mesh. In patients with cirrhosis, decreased levels of procoagulant proteins, such as factors II, V, VII, IX, X, and XI, suggest the potential for an anticoagulated state. In fact, 1 study showed a decrease in the activity of procoagulant proteins to as low as 20% to 46% in correlation with the severity of cirrhosis and portal hypertension.12 These deficiencies are easily seen in the standard clinical laboratory measurements of the INR and PT.

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