The Hemostatic and Hematopoietic System in Liver Disease

The Hemostatic System: Normal Physiology and Pathophysiology in Liver Disease

The coagulation system maintains homeostasis that continually repairs sites of vessel injury with clot formation and subsequent endothelial remodeling. Importantly, this system relies on simultaneous counterregulatory systems to prevent unchecked clot propagation. The main components of the hemostatic system include platelets, vascular endothelium, and protein constituents of the soluble coagulation and fibrinolytic systems. Additionally, other components including monocytes, erythrocytes, cell fragment–derived microvesicles, and other effectors contribute directly to hemostasis and thrombosis.

When vascular endothelium is injured, tissue factor (TF) is exposed on the phospholipid membrane, which triggers the coagulation cascade to begin the process of primary hemostasis with platelet plug formation ( Fig. 19-1 ). Platelets adhere to sites of endothelial injury via von Willebrand factor (vWF) bound to endothelial cells and platelet glycoprotein IIb/IIIa receptors. This results in activation and degranulation of platelets with release of effectors such as adenosine diphosphate (ADP). Additional platelets are recruited to the site and a platelet plug begins to form. Notably, the platelet plug may be transient and requires activation of the coagulation cascade for stable clot formation.

Secondary hemostasis occurs as the coagulation cascade is simultaneously generated on the phospholipid surface of the activated platelets at the site of injury via the interaction between exposed TF and factor VII (VII), which is converted to an activated extrinsic tenase complex (TF-VIIa). This complex then activates factors IX (IXa) and X (Xa). Once activated, Xa binds to its cofactor factor V (Va) to form a prothrombinase complex (Xa-Va). Platelets express binding sites in the lipid membrane for Va and the prothrombinase complex binds prothrombin (factor II) and converts it to its active form (IIa). Next, IIa cleaves fibrinogen (factor I) to form fibrin, which is then cross-linked to provide the necessary support of the platelet plug, and a clot begins to form. This process is fueled initially by small amounts of thrombin (IIa) which primes the cascade and feeds back to the extrinsic (TF-VIIa) and the intrinsic (IXa-VIIIa) tenase complex on anionic cell surfaces, further propagating the signal via a thrombin burst. Circulating monocytes and microparticles generated from monocytes provide another important source of circulating TF that contributes to hemostasis. Meanwhile, as fibrin is produced and a clot is propagated, thrombomodulin, proteins C and S, antithrombin (AT), and the fibrinolytic system act to impede this cycle and counterbalance clot formation (see Fig. 19-1 ).

Thrombomodulin (TM), a surface protein on endothelial cell membranes, binds and inactivates thrombin and the TM-thrombin complex activates protein C. Anticoagulant proteins C and S inactivate and degrade Va and VIIIa promoting a regulatory balance to the coagulation cascade. Whereas the anticoagulation system serves to impede the cycle, the fibrinolytic system works to reverse formed thrombus once endothelial function is restored at the site of injury. In the presence of fibrin, tissue plasminogen activator (tPA) enzymatic activity increases significantly allowing interaction with plasminogen. Plasminogen is converted to plasmin, which degrades fibrin. This system is inhibited by alpha-2 antiplasmin and thrombin-activated fibrinolysis inhibitor (TAFI). TAFI interacts with thrombin bound to TM on endothelial cells to attenuate fibrinolysis.

In cirrhosis, the capacity for hepatocyte production of proteins integral to both the coagulation and the anticoagulation systems is compromised ( Fig. 19-2 ). Conventional clinical measures of hemostasis and coagulopathy involve in vitro systems that mimic, but do not replicate in vivo systems. In particular, the prothrombin time (PT) and INR which derives from the PT are often elevated in patients with cirrhosis due to underproduction of liver-derived coagulation factors. Whereas the INR is useful to predict warfarin effect, it measures only procoagulant factors and not the coexisting deficit of anticoagulant factors. As a result, it is a poor marker for net clot formation in cirrhosis. This has been amply demonstrated by Tripodi et al. who used a thrombin generation assay (TGA) to show that patients with cirrhosis demonstrate normal capacity for thrombin generation despite an abnormal INR. Other investigators showed similar propensity to maintain thrombin generation at normal or even increased levels despite abnormal conventional tests of coagulopathy. Decreased production of protein C by the liver and increased production of VIII by the endothelium in cirrhosis are the principle compensatory mechanisms that rebalance the coagulation system. Additionally, Lisman et al. demonstrated that high levels of vWF in cirrhosis patients compared with healthy controls promote increased platelet adhesion and aggregation. Taken together, these studies reveal important mechanisms that explain the rebalanced state in the hemostatic system of cirrhosis patients. It is thought that this equilibrium is maintained in a more precarious and fragile state that can be tipped into bleeding or thrombosis by exogenous factors like infection or renal failure.

From another perspective, intrahepatic activation of the coagulation system may directly contribute to the progression of chronic liver disease and fibrosis. Wanless et al. noted microthrombi in the hepatic and portal venules of explanted livers and postulated that relative ischemia may promote development of hepatic fibrosis. This process, termed parenchymal extinction, may also explain one underlying pathologic mechanisms of fibrogenesis in liver disease. Beyond microthrombi, ischemia, and necrosis, stellate cells may also be stimulated to generate more fibrosis by thrombin-mediated mechanisms. In support of this new concept, clinical studies examining populations of liver disease patients with inherited thrombophilia disorders (e.g., factor V Leiden mutation) reveal a higher risk of developing advanced fibrosis. Recent prospective clinical data showing a reduction in hepatic decompensation and mortality with prophylactic treatment using low molecular weight heparin (LMWH) in cirrhosis provides an additional and compelling clinical correlation. Furthermore, animal models of liver disease treated with anticoagulant therapeutics such as dabigatran (thrombin inhibitor) and LMWH provide additional experimental evidence that factors in coagulation potentiate fibrogenesis, probably as a physiologic part of the body's efforts at wound healing in chronic disease states. Inhibiting intrahepatic coagulation may impede the process that leads to development of fibrosis in liver disease.

Bleeding in Cirrhosis Patients