Hemostatic Abnormalities in Liver Disease

This presentation discusses hemostatic abnormalities in patients with liver disease.
A patient with chronic liver disease related to alcohol abuse, hospitalized for acute decompensation with massive ascites, was presented as a case study.
The patient's liver disease was severe, evidenced by a model for end-stage liver disease (MELD) score of 20 and a Child-Pugh score of C10.
The patient's coagulopathy was a concern, with an international normalized ratio (INR) of 1.8, a plasma fibrinogen level of 1.4 g/L, and a platelet count of 61,000/μL.
A paracentesis was scheduled, but the treating physician was concerned about the patient's coagulopathy.

Liver parenchymal cells synthesize most coagulation factors (except factor VIII).
The liver synthesizes natural coagulation inhibitors, such as protein C, protein S, and antithrombin.
The liver produces essential components of the fibrinolytic system (e.g., plasminogen, a2-antiplasmin, thrombin-activatable fibrinolysis inhibitor).
The liver clears activated coagulation factors and coagulation factor-inhibitor complexes from the circulation.
Changes in primary hemostasis (mediated by platelets, von Willebrand factor, and ADAMTS13) can occur in liver disease.

More than 75% of patients with severe cirrhosis have low platelet counts.
Low platelet counts can be due to splenomegaly, reduced thrombopoietin synthesis, low-grade activation of the hemostatic system, or autoantibodies against platelets.
Bone marrow suppression from hepatitis C, alcohol use, infections, or antibiotic/antiviral therapies are other possible causes.
Coexisting comorbidities like acute kidney injury, infection, and endothelial abnormalities can also contribute.
Platelet function can also be defective due to impaired signal transduction, acquired storage pool deficiency, proteolysis of platelet membrane proteins, and increased production of endothelial-derived platelet inhibitors.
Platelet adhesion defects are also possible, attributed to thrombocytopenia and a low hematocrit in some studies.
vWF antigen levels are often elevated in liver disease, possibly due to endothelial damage from endotoxemia (bacterial infection).
vWF mRNA and protein expression are substantially increased in cirrhosis, but vWF ristocetin cofactor activity varies.
High vWF levels may mitigate hemostatic defects from thrombocytopenia and platelet dysfunction.
The regulation of vWF multimer size and activity is sometimes impaired by reduced synthesis of ADAMTS13 by stellate cells in the liver.
Several studies show that the most active high-molecular weight multimers of vWF are often diminished in cirrhotic plasma, potentially due to plasmin or other proteases.

The liver is the site of synthesis of most procoagulant proteins (factors II, V, VII, IX, X, and XI).
Decreased levels of these factors are commonly found in liver failure.
Factor VIII levels are often elevated due to increased levels of its carrier protein vWF, protection from degradation, and decreased clearance from the circulation through the liver's low-density lipoprotein-related receptor.
Factor VIII is primarily synthesized in hepatic sinusoidal endothelial cells, whose function is preserved in liver disease.
Levels of anticoagulant proteins (e.g., protein C, protein S, antithrombin, heparin cofactor II, and a2-macroglobulin) are decreased in liver disease.
Fibrinogen levels are frequently normal in chronic liver disease, but can be decreased in decompensated cirrhosis or acute liver failure.
Qualitative changes in fibrinogen (e.g., abnormal fibrinogen molecules with paradoxical defects in clot formation speed and thrombogenic clot structure) can be seen.
Acquired vitamin K-dependent carboxylation deficiency (due to reduced bile salt secretion and vitamin K absorption from the gut) can lead to qualitative defects in coagulation factors II, VII, IX, and X.

All fibrinolytic proteins (except t-PA and PAI-1) are synthesized by the liver.
Chronic liver disease leads to decreased plasma levels of plasminogen, a2-antiplasmin, TAFI, and factor XIII.
Plasma levels of t-PA are elevated, likely due to increased secretion from endothelial cells and/or less clearance by the diseased liver.
Plasma PAI-1 levels are also increased but not to the same extent as t-PA, potentially shifting fibrinolytic balance.
Hyperfibrinolysis, related to low-grade DIC and endotoxemia, can occur in cirrhosis, manifesting with increased levels of markers like prothrombin fragment 1+2, fibrinopeptide A, D-dimer, thrombin-antithrombin complex, and plasmin-antiplasmin complex.

It has been a long-held belief that liver disease leads to a high risk of bleeding due to reduced coagulation factor synthesis and altered hemostasis.
Recent studies show that thrombin generation is normal in many with liver failure, and sometimes even prothrombotic.
Both procoagulant and anticoagulant proteins decline in chronic liver disease.
Platelet function reductions are counteracted by high vWF levels, and often, the decline in profibrinolytic factors is balanced by reduced inhibitors of fibrinolysis.
This leads to a rebalanced, though delicate hemostatic system.

Recent clinical guidelines suggest routine hemostasis tests aren't useful in predicting spontaneous or procedure-related bleeding in patients with advanced liver disease. However, this advice isn't always followed.
PT/INR can indicate liver disease severity, relating to the liver's synthetic capacity, and can monitor disease progression.
Platelet count reflects portal hypertension which affects platelet count through splenomegaly or increased platelet sequestration in the spleen.

Global tests of hemostasis, like Whole Blood Viscoelastic Tests (ROTEM/TEG), platelet function tests, thrombin generation tests, and plasma-based fibrinolysis tests, are increasingly utilized.
Whole Blood Viscoelastic Tests (ROTEM/TEG) provide real-time insights into clotting processes and are especially useful for early/subtle clotting issues even before other tests pick up abnormalities.

Platelet count, a major influencer in viscoelastic tests, is often insensitive to plasma vWF levels or compensation for thrombocytopenia.
Viscoelastic tests are insensitive to the protein C system, further underestimating true hemostatic potential.
The initiator of clot formation may affect interpretation of results (i.e., differences in test results between ROTEM and TEG).
Platelet function tests are highly reliant on platelet count which is often decreased in liver diseases.
Thrombin generation tests have potential limitations because clot formation, not just thrombin generation itself, needs to be considered.
The lack of cellular components in plasma-based fibrinolysis tests makes interpretations dependent on an understanding of results in relation to other aspects of hemostasis.

The presentation concludes with a summary of the concept of a "rebalanced" hemostatic system, highlighting the disconnect between routine tests of hemostasis and clinical bleeding tendencies. Clinically significant bleeding in cirrhosis is often unrelated to overall hemostatic function but more likely attributable to portal hypertension and other factors.