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Coagulation Corner


Monday, November 8, 2010

LIVER DISEASE AND COAGULATION OUTCOMES:

The liver plays a central role in the clotting process. Acute and chronic liver diseases are invariably associated with coagulation disorders due to multiple causes including: decreased synthesis of clotting and inhibitor factors, decreased clearance of activated factors, quantitative and qualitative platelet defects, hyperfibrinolysis, and accelerated intravascular coagulation. The liver is the site of production of most coagulation factors, but the response of each factor to liver disease is variable due to differences in biologic half lives and acute phase reactions. The PT is usually prolonged first, then APTT. Factor VII: shortest biologic half life, often affected earliest with largest decrease in plasma level. Factor VII also decreases earliest with warfarin treatment. Factor VIII: may be normal or elevated due to acute phase reactants. Factors XI and XII:have long biologic half lives, and may be normal until liver disease is advanced. 

As a result the PT, APTT, TCT, and all factors are prolonged with the possible exception of fibrinogen (I) and Factor VIII which may be increased, decreased or normal since they are acute phase reactants. Also, FDPs: may be increased due to decreased clearance by liver.  However the D-Dimer is usually normal which is helpful to differentiate liver disease from DIC.  Remember, DIC is a consumptive process in which factors are being consumed, and in this process there is the simultaneous formation of thrombin and plasmin causing increased D-dimers.  Platelets will also be decreased, due to aggregation, while in liver disease platelets will be either normal or decreased. The bleeding tendency accounts for increased risk of morbidity and mortality in patients with liver disease undergoing diagnostic or therapeutic invasive procedures.

Since almost all procoagulants and inhibitors are synthesized in the liver, several conditions can cause acquired bleeding disorders.  Liver disease can be divided into groups with distinctive pathogenesis:

  •  
    1. Decreased synthesis of clotting and inhibitor factors: Cirrhosis
    2. Decreased clearance of activated factors: Chronic liver disease
    3. Quantitative and qualitative platelet defects:  Splenomegaly secondary to liver-induced portal hypertension
    4. Hyperfibrinolysis :  Tumors
    5. Accelerated intravascular coagulation: Acute hepatitis

 The bleeding tendency accounts for increased risk of morbidity and mortality in patients with liver disease undergoing diagnostic or therapeutic invasive procedures. Coagulation disorders in liver disease are extensive, complex and expensive to treat. Many mechanisms can cause the coagulation changes, but many can be attributed to cytokine activation.  Sepsis further impairs hemostasis in patients with liver cirrhosis bleeding from esophageal varices. Thrombotic events, even if rare in cirrhotic patients, occur mainly in the portal and mesenteric veins. 

Liver disease can cause both quantitative and qualitative abnormalities in clotting factors.  Vitamin K-dependent factors (II, VII, IX and X, Protein S, C and Z) undergo posttranslational gamma-carboxylation, which can be impaired by a deficiency of vitamin K or by lack of blood-clotting enzymes in hepatocellular disease. The presence and level of vitamin K-dependent clotting factors that have undergone incomplete or slight carboxylation are also increased.  Levels of factor VIII are typically normal or elevated due to having extra hepatic sites of synthesis.  Fibrinogen is synthesized in a large capacity in the liver, and the level is maintained until late in the disease stage.  Primary fibrinolysis results from reduced clearance of tPA, impaired by increased synthesis of PAI-1 or diminished synthesis of plasminogen.  Conversely, fibrinolysis may be enhanced due to impaired production of alpha-2- antiplasmin.  

Measurement of clotting-factor levels in hepatocellular disease often reveals reduction, even when hemostatic-competency screening tests produce normal results, and the extent of reduction in levels of vitamin K-dependent factors correlates with disease severity. However, clotting factor levels are not uniform in liver disease, and the response is not the same in all forms of the disease.

For example, levels of prothrombin and factors VII and X are often severely lowered in liver disease. Because it has a short half-life (VII has a half life of 4-6 hours) and is unaffected by inflammation or DIC, factor VII is an important early marker of significant parenchymal liver disease; it is usually the first vitamin K-dependent factor to reflect a reduced level. In contrast, factor IX levels typically are only modestly reduced until advanced stages of liver disease. The behavior of factor VIII and V can be a cost effective way to help distinguish between DIC and liver disease.  Since VIII is also produced by endothelial cells, it is not only dependent on hepatocyte function.  Both factors will be consumed in DIC, but in liver disease, V will be low and VIII is either normal or high. Factor V is not a vitamin K dependent factor, as opposed to factors II, VII, IX and X, so it is a cost effective way to look for liver disease.  Acquired dsyfibrinogenemia can be seen in patient with cirrhosis and hepatoma.  They tend to have “flimsy fibrinogen” with increased carbohydrate content, resulting in reduced functional activity.

In liver disease the platelet count is either normal or decreased.  The liver is a source of thrombopoietin which stimulates platelet production .  Mild splenomegaly may be present in cirrhosis resulting in platelet pooling.   Alcohol intake inhibits the production of platelets by megakaryocytes.  Folate deficiency, which may accompany cirrhosis may also cause thrombocytopenia. 

Liver Disease is a complex disorder that impacts coagulation testing.  It must be diagnosed cost effectively and treated appropriately.

Donna Castellone

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About the Author

Donna Castellone,  MS, MT(ASCP)SH

Donna Castellone,
MS, MT(ASCP)SH

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