Hemostasis Defects Associated with Liver Disease

At a Glance

Liver failure is a life-threatening condition that most often arises gradually, over months to years (chronic) or, less often, rapidly over days to weeks (acute). It can result from any type of liver disorder, including viral hepatitis B or C; excessive alcohol use; autoimmune, hereditary, and metabolic causes; infections; cancer; or exposure to drugs, such as acetaminophen or other toxic substances. A large portion of the liver must be damaged before liver failure complications become evident.

Gastrointestinal hemorrhage is one of the most common complications in advanced liver failure patients. Since all of the coagulation factors and the fibrinolytic system proteins are synthesized by the liver, except for factor VIII, which is also released in small amounts by other endothelial cells (i.e., kidney, spleen, lungs, and brain), normal hemostasis is directly linked to liver function.

The extent of coagulation abnormalities in liver disease patients depends on the intensity of the hepatocellular damage. At the early stages, despite the low production of pro- and anticoagulant proteins, mainly the vitamin K-dependent factors (factors II, VII, IX, and X; proteins C and S), a relatively normal hemostasis is maintained. In advanced cases, conversely, a wide spectrum of factor deficiencies and even disseminated intravascular coagulation (DIC) may develop.

Although bleeding becomes more common in advanced stages of liver diseases (i.e., cirrhosis), life-threatening bleeding is often related to portal hypertension more than the low production of coagulation factors.

Several other causes may also contribute to hemostatic defects in liver disease patients, such as thrombocytopenia, alterations in platelet and endothelial cell functions, clotting factors abnormalities (e.g., dysfibrinogenemia), excessive fibrinolysis, and renal failure.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Coagulation screening tests are essential to assess severity, evaluate bleeding tendency, and monitor the response to therapy in liver disease patients.

Because of the low levels of coagulation factors, a prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT) are very common at the early stages of liver disease. The normal to high levels of factor VIII (acute phase reaction protein, APR) in these patients can sometimes conceal aPTT prolongation.

Patients with stable liver disease can have normal to elevated fibrinogen levels (APR), but decreased levels are usually found with more advanced cases.

Dysfibrinogenemia is also common because of the excessive amount of sialic acid, which is metabolized by the liver.

High levels of fibrinogen split products (FSP) can also be seen in advanced cases.

Similar to the procoagulant proteins, synthesis of the natural anticoagulants (protein C, protein S and antithrombin) is also reduced in liver disease patients. However, recent studies have shown that reduced levels of the pro- and anticoagulant proteins do not impair thrombin generation until its concentration is significantly low.

Thrombocytopenia is one of the usual findings in advanced cases due to splenic sequestration, impaired platelet production, abnormal thrombopoietin metabolism, and thrombin mediated consumption (e.g., DIC).

Abnormal platelet function is also commonly observed in these patients because of the increased production of nitric oxide and prostacyclin by endothelial cells, which have an in vivo inhibitory effect on platelet activation. However, the markedly elevated von Willebrand factor (APR) can compensate for any defect in platelet function.

As with the pro- and anticoagulant proteins, the balance between pro- and antifibrinolytic pathways is usually altered in liver disease patients. Although low concentrations of plasminogen, α-2 plasmin inhibitor, thrombin activatable fibrinolysis inhibitor (TAFI), and factor XIII are reported in chronic and acute liver disease, significantly high levels of tissue plasminogen activator (tPA) and plasminogen activator inhibitor (PAI-1) can be seen in advanced cases because of the activated endothelium. As a result, a relatively rare, but not uncommon, hyperfibrinolytic state, characterized by diffuse oozing from puncture wounds, mucosal bleeding and delayed bleeding, may develop.

The presence of other coexisting conditions in advance liver disease patients may enhance bleeding tendency. In renal failure, for instance, which is frequently seen in advanced liver disease, there is a significant role of acquired platelet dysfunction and abnormal platelet-vessel wall interaction on bleeding tendency. Activation of clotting cascade by endotoxin is one of the major effects of bacterial infection that is also very common in these patients (See Table 1).