Hemostatic Abnormalities in Liver Disease

Hemostatic Abnormalities in Patients with Liver Disease

• Presented by Dr. Huda Ayad Mohammed (Hematopathology Board Resident Doctor)
• Supervised by Professor Dr. Israa Mohammed Baqer AL-Bayaa (Consultant Hematopathologist)

Objectives

• Overview of Liver's Role in Hemostasis
• Hemostatic Alterations in Chronic Liver Disease
• A Rebalanced Hemostatic System in Chronic Liver Disease
• Routine Tests of Hemostasis in Patients with Severe Liver Disease
• Pros and Cons of Global Hemostasis Tests in Patients with Severe Liver Disease

Case Scenario

• A patient with chronic liver disease (due to alcohol abuse) is hospitalized for acute decompensation with massive ascites.
• The patient has severe liver disease, as evidenced by a Model for End-Stage Liver Disease (MELD) score of 20 and a Child-Pugh score of C10.
• A paracentesis is scheduled, but the physician is concerned about the patient's coagulopathy.
• International normalized ratio (INR) is 1.8
• Plasma fibrinogen level is 1.4 g/L
• Platelet count is 61,000/μL

Child-Turcotte-Pugh Score

• Clinical and Laboratory Criteria for assessing liver disease severity.
• Scoring system that considers factors like encephalopathy, ascites, bilirubin, albumin, and prothrombin time.
• Total points indicate disease severity:
  • Class A: 5-6 points (least severe)
  • Class B: 7-9 points (moderately severe)
  • Class C: 10-15 points (most severe)

Model for End-Stage Liver Disease (MELD) Score

• Used for allocation policies related to organ donation (liver transplants).
• Predicts 90-day mortality.
• Higher the score, higher the priority for transplant.
• MELD calculation formula provided
• Additional rules when calculating MELD based on bilirubin, creatinine, and INR (all <1.0 use 1.0)

Overview of Liver's Role in Hemostasis

• Liver parenchymal cells synthesize most coagulation factors (except FVIII)
• Liver produces natural coagulation inhibitors (protein C, protein S, antithrombin)
• Liver synthesizes essential components of the fibrinolytic system

Overview of Liver's Role in Hemostasis (continued)

• Liver clears activated coagulation factors and coagulation factor-inhibitor complexes from the circulation
• Changes in primary hemostasis (mediated by platelets, vWF) and metalloprotease (ADAMTS13) may occur.

Primary Hemostasis

• More than 75% of patients with chronic liver disease (especially moderate to severe cirrhosis) have reduced platelet counts ( less than 150,000/μL)
• Reduction in platelet counts is due to splenomegaly, reduced thrombopoietin synthesis by the diseased liver, low-grade activation of the hemostatic system, and the presence of autoantibodies against platelets.
• Other causes for decreased function are bone marrow suppression related to infection or alcohol use, etc or coexisting acute kidney injury, infection, and/or endothelial abnormalities.
• Reduced platelet function may be due to impaired signal transduction, acquired storage pool deficiency, proteolysis of platelet membrane proteins, increased production of endothelial-derived platelet inhibitors

Primary Hemostasis (continued)

• Platelet adhesion defects can be present; often caused by thrombocytopenia and a low hematocrit in some studies.
• vWF antigen levels are strongly elevated in liver disease causing endothelial damage. Elevated levels of vWF may improve the hemostatic defect
• vWF-cleaving protease ADAMTS13 is reduced contributing to impaired regulation of multimer size and activity

Secondary Hemostasis: Coagulation and Anticoagulation

• Liver synthesizes most procoagulant proteins (II, V, VII, IX, X, XI)
• Decreased levels of these factors are commonly observed in liver failure
• Levels of FVIII are increased (due to elevated level of its carrier protein vWF, protecting FVIII degradation)
• Acquired vitamin K-dependent carboxylation deficiency (due to reduced bile salt secretion) results in impaired function of coagulation factors (II, VII, IX, and X).

Secondary Hemostasis: Coagulation and Anticoagulation (continued)

• Decreases in anticoagulant proteins are seen (protein C, protein S, antithrombin, heparin cofactor II, and a2-macroglobulin)
• Fibrinogen levels are frequently in the normal range in patients with chronic liver disease, but may decrease in decompensated cirrhosis, or acute liver failure.

Fibrinolysis

• Liver synthesizes tissue plasminogen activator (t-PA), and plasminogen-activator inhibitor (PAI-1)
• Chronic liver disease decreases plasma levels of plasminogen, a2-antiplasmin, TAFI, and factor XIII
• High t-PA plasma levels may counteract reduced levels of plasminogen, a2-antiplasmin

Fibrinolysis (continued)

• Hyperfibrinolysis in patients with cirrhosis can occur either through low-grade DIC, or through increased levels of prothrombin fragment 1+2, fibrinopeptide A, D-dimer, thrombin-antithrombin complex, and plasmin-antiplasmin complex (argued to be caused by decreased clearance of these markers)

A Rebalanced Hemostatic System in Chronic Liver Disease

• Long-standing dogma is that patients with liver disease are at a high risk of bleeding, due to reduced coagulation factor production.
• Recent studies suggest thrombin generation is usually normal and may even be heightened in patients with reduced liver function and possible pro-thrombotic phenotype
• Both pro-coagulant and anticoagulant proteins decline in chronic liver disease. A balance is reached between these systems
• Reduction of platelet numbers and impaired functioning of the platelets is counteracted by elevated vWF.
• Decline in profibrinolytic factors is balanced by reduced level of inhibitors of fibrinolysis

Routine Tests of Hemostasis in Patients with Severe Liver Disease

• Recent clinical guidance documents advise against routine diagnostic tests for hemostasis.
• This advice is often ignored in clinical practice because prothrombin time (PT), INR and or platelet counts are considered indicators of severity of liver disease, portal hypertension, and can be used to monitor disease progression.

Prothrombin Time (PT)

• Prothrombin time (PT) assesses the functional activity of coagulation factors, including factors V, VII, X, prothrombin, and fibrinogen.
• Prolonged PT can indicate a deficiency or defect in those factors
• PT cannot be used to assess global hemostatic status

Activated Partial Thromboplastin Time (APTT)

• Measures the activity of various coagulation factors (prekallikrein, high-molecular weight kininogen, factors XII, XI, IX, VIII, X, V, prothrombin, and fibrinogen).
• APTT in patients with advanced liver disease is often prolonged, but not significantly more than PT (INR).
• APTT is not an adequate indicator of hemostatic capacity

Fibrinogen

• In patients with advanced cirrhosis, levels are either normal, or sometimes lowered below reference ranges.
• Most bleeding cases related to portal hypertension rather than a lack of fibrinogen, and therefore prophylactic administration of cryoprecipitate does not generally have an effect on bleeding or mortality.

Platelet Count

• Thrombocytopenia is a common finding in patients with cirrhosis but is unusual for the count to be lower than 50,000/μL.
• Some patients may present with hyperfunctional platelets, which can counteract the effects of lower platelet counts.

Global Tests of Hemostasis

• Whole blood viscoelastic tests (ROTEM/TEG): assess clotting in real-time
• Platelet function tests: independent of platelet count (flow cytometry-based tests currently not suitable for routine diagnostics)
• Thrombin generation tests: assesses the balance between procoagulants and anticoagulants.
• Plasma-based fibrinolysis tests: monitor clot formation and fibrinolysis.

Drawbacks of Whole Blood Viscoelastic Tests

• Platelet count is a major determinant of clot formation, but insensitive to plasma VWF levels, obscuring the compensation of thrombocytopenia
• Insensitive to plasma levels of protein C system, and the compensation of low levels of protein C or S.
• Differences in reagent composition (clot initiation) can cause discrepancies.

Platelet Function Tests

• Platelet function tests are strongly affected by platelet counts (usually low)
• Flow cytometry-based platelet function tests are independent of platelet count, but not currently suitable for routine diagnostics

Thrombin Generation Tests

• Has revolutionized assessment of hemostatic status in liver disease
• Measures thrombin generation capacity in patients using thrombomodulin-modified thrombin generation tests.
• Accurately assesses balance of procoagulants and anticoagulants

Drawbacks of Thrombin Generation Tests

• Lacks cellular components
• Thrombin generation, not clot formation, is measured as the endpoint of the test
• Should be interpreted in the context of other tests assessing hemostasis (platelet, clot formation, and clot stability)

Plasma-based Fibrinolysis Tests

• Utilizes tissue factor activation, lysis by tissue-type plasminogen activator, and turbidity measurements to profile fibrinolytic system
• Normal capacity is seen in compensated cirrhosis, and hyperfibrinolysis in decompensated patients
• Hypofibrinolysis is seen in critically ill patients
• Cellular components in testing must be considered

This quiz explores the complex relationship between liver disease and hemostatic abnormalities. It examines the alterations in the hemostatic system due to chronic liver disease, routine tests for hemostasis, and the implications for patient management. Join to enhance your understanding of this critical aspect in hematology and liver pathology.