Hemostatic Abnormalities in Liver Disease

Hemostatic Abnormalities in Patients with Liver Disease

• Hemostatic abnormalities are a significant concern in patients with liver disease, especially those with severe or chronic conditions.
• Liver parenchymal cells are crucial for synthesizing several critical coagulation factors (excluding factor VIII) and natural coagulation inhibitors like protein C, protein S and antithrombin.
• Essential elements of the fibrinolytic system, such as plasminogen, a2-antiplasmin and thrombin activatable fibrinolysis inhibitor (TAFI), are also synthesized in the liver.

Liver's Role in Hemostasis

• The liver regulates hemostasis and fibrinolysis by clearing activated coagulation factors and coagulation factor-inhibitor complexes from the circulation.
• Changes in primary hemostasis, involving platelets, von Willebrand factor (vWF), and a disintegrin-like and metalloprotease with thrombospondin type 1 motif member 13 (ADAMTS13), may occur in liver disease.
• Complications associated with liver dysfunction can lead to bleeding, thrombosis, or a combination of both.

Primary Hemostasis in Liver Disease

• Over 75% of patients with chronic liver disease, specifically in moderate to severe cirrhosis (Child B and C), have reduced platelet counts (below 150,000/µL).
• Other potential causes for reduced platelet counts include splenomegaly (sequestration of platelets in the spleen), reduced thrombopoietin synthesis, and the consumption of platelets and hemostatic proteins due to low-grade activation of the hemostatic system.
• Autoantibodies against platelets might also reduce the half-life of platelets in cirrhosis.
• Bone marrow suppression, viral infections (like HCV), alcohol use, or other infections, or antibiotic/antiviral therapies can also contribute.
• Acute kidney injury, infections and endothelial abnormalities can be additional factors.
• Platelet function can be defective due to impaired signal transduction, acquired storage pool deficiency, proteolysis of platelet membrane proteins, and increased endothelial-derived platelet inhibitors (e.g., nitric oxide and prostacyclin).
• Platelet adhesion defects are sometimes observed in conjunction with thrombocytopenia and low hematocrit conditions.
• vWF antigen levels are often elevated in liver disease, potentially due to endothelial damage from endotoxemia.
• Elevated vWF levels can, in some cases, compensate for thrombocytopenia and improve platelet adhesion to collagen.
• Regulation of vWF multimer size and activity may be compromised due to decreased synthesis by stellate cells in the liver.

Secondary Hemostasis (Coagulation and Anticoagulation)

• The liver is the primary site for synthesizing most procoagulant proteins, including factors II, V, VII, IX, X, and XI.
• Decreased levels of these factors are commonly observed in liver failure.
• In contrast, factor VIII (FVIII) levels are typically elevated, possibly due to increased levels of its carrier protein vWF, protection from degradation, and decreased clearance from circulation by the liver's low-density lipoprotein-related receptor.
• FVIII is primarily synthesized in hepatic sinusoidal endothelial cells, whose function is typically preserved in liver disease.
• Anticoagulant proteins such as protein C, protein S, antithrombin, heparin cofactor II, and a2-macroglobulin are decreased in patients with liver disease.
• Fibrinogen levels might be normal or decreased in chronic liver disease, but lower levels are sometimes seen in decompensated cirrhosis or acute liver failure.
• Qualitative changes in fibrinogen may occur (e.g., paradoxical defects in clot formation and thrombogenic clot structure after clot maturation).
• Vitamin K is important for several clotting factor functions, and reduced vitamin K absorption due to reduced bile salt secretion in liver disease may lead to reduced activity of certain factors (II, VII, IX, and X).

Fibrinolysis

• Factors involved in fibrinolysis (except tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI)-1) are synthesized by the liver.
• Chronic liver disease, therefore, often leads to decreased plasma levels of plasminogen, a2-antiplasmin, TAFI, and factor XIII.
• Plasma t-PA levels are commonly elevated due to increased secretion from endothelial cells and/or decreased clearance by the diseased liver.

A Rebalanced Hemostatic System in Chronic Liver Disease

• The liver plays a delicate role in balancing coagulation/anticoagulation.
• Coagulation factors and anticoagulant factors may decline in liver disease but also are not consistently abnormal.
• Other factors, like high levels of vWF, can compensate for these deficiencies in some cases.
• Bleeding in liver disease is frequently not a result of primary hemostatic failure but more often a consequence of portal hypertension or mechanical injury.

Routine Tests of Hemostasis in Patients with Severe Liver Disease

• Routine diagnostic tests of hemostasis are frequently employed to evaluate the severity of liver disease and guide treatment.
• Prothrombin time (PT)/international normalized ratio (INR) is commonly utilized to evaluate synthetic liver function and to screen for potential deficiencies/defects in certain factors (e.g. factors V, VII, X, prothrombin, and fibrinogen).
• Platelet count is also a useful indicator of portal hypertension and its impact on platelets.
• However using these tests alone as a primary indicator of hemostatic status is not reliable.

Global Tests of Hemostasis (e.g., Whole Blood Viscoelastic Tests, Platelet Function Tests, Thrombin Generation Tests, Plasma Based Fibrinolysis Tests)

• Whole blood viscoelastic tests (ROTEM, TEG) assesses blood clotting in real-time, providing information regarding clotting speed, strength, and breakdown.
• These tests are helpful for detecting early or subtle clotting abnormalities before routine tests (e.g. PT/INR).
• Platelet function tests are often challenging in liver disease patients because platelet count often affects test results.
• Thrombin generation tests assess the balance between pro- and anticoagulant proteins, offering a more comprehensive evaluation of coagulation potential in liver disease.
• Plasma based fibrinolysis tests, evaluate clot breakdown, and have been extensively used to profile fibrinolysis in patients with liver disease.

Drawbacks of Specific Tests:

• Routine tests (PT/INR, aPTT, platelet count, and fibrinogen) might not accurately reflect the overall hemostatic status in liver disease patients.
• Platelet function tests can be affected by platelet count, which frequently decreases in liver patients.

This quiz covers the critical role of the liver in hemostasis and the coagulation process in patients with liver disease. It discusses hemostatic abnormalities, the synthesis of coagulation factors, and the liver's function in regulating fibrinolysis. Understanding these concepts is essential for managing patients with liver conditions.