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Like many physiological systems, the coagulation cascade is dependent upon a dynamic interplay, which is between multiple opposing procoagulant and anticoagulant drivers so as to maintain physiological haemostasis and prevent unwanted episodes of bleeding or thrombosis. The end product of this proteolytic cascade is the generation of thrombin, which cleaves soluble fibrinogen into fibrin to form a blood clot.1 This process occurs in several phases. Briefly, the initiation phase occurs when tissue factor exposed on cellular surfaces of vascular injury binds circulating factor VIIa,2 which leads to small amounts of thrombin production through activated factor X (Xa). At this stage there is insufficient thrombin to activate fibrinogen, therefore a series of feedback loops through an amplification stage leads to further thrombin generation which is maintained by the propagation phase through generation of large quantities of activated factor X. Soluble fibrin monomers are formed which are cross-linked by activated factor XIII to form a stable fibrin meshwork. To prevent pathological clot formation, thrombin generation is regulated by the anticoagulant system, including proteins C, S and antithrombin. Finally, clot dissolution occurs via activation of the fibrinolytic cascade.
Healthy people have sufficient quantities of coagulation factors, regulatory proteins and platelets to maintain haemostasis, thus preventing bleeding or thrombotic complications. Patients with cirrhosis of the liver have multiple defects in components of the aforementioned pathways, including deficiencies in both procoagulant and anticoagulant factors,3 anaemia,4 thrombocytopenia,5 hypofibrinogenaemia and dysfibrinogenaemia6 as well as evidence of hyperfibrinolysis.7 These derangements, reflected in conventional coagulation indices and haemorrhagic complications seen with cirrhosis, have led to cirrhosis being regarded as a prototypical haemorrhagic disorder.
However, in recent years this interpretation has been challenged,8 leading to a paradigm shift in understanding, owing to increasing evidence of the thrombotic complications associated with cirrhosis,9 …
Competing interests None.
Provenance and peer review Commissioned; externally peer reviewed.