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).

Table 1.
Test Initial Moderate/Chronic Severe/Acute
PT High High High
PTT Normal High High
TT Normal Normal to high High
FII, VII, IX, X Normal Low Low
FV, XI, XII Normal Low Low
FVIII Normal to High High High
vWF Normal to High High High
Fibrinogen Normal Normal Low
FSP Normal Normal to high High
D-dimers Normal Normal to high High
Protein C, S, AT Normal Normal to low Low
Plasminogen Normal Normal to low Low
tPA/uPA Normal Normal Normal
PAI-1 Normal Normal to low Low
PFA-100 Normal Normal to high High
Platelet Count Normal Normal to low Low
Platelet Function Normal Normal Low

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Among vitamin K dependent factors, factor VII has the shortest half-life and, therefore, is the first to fall and cause a prolonged PT in early stages of liver failure. However, these low concentrations are still sufficient for adequate hemostasis in vivo, since its major role is in secondary hemostasis. Therefore, it’s not uncommon to see a significantly prolonged PT but normal aPTT in some cases of mild to moderate liver failure, which could also be due to the high levels of factor VIII and fibrinogen (APR).

The presence of DIC markers (e.g., prolonged PT, aPTT, elevated D-dimers, and FSP) along with high factor VIII and stable platelet count, which are not usual findings of regular DIC, can be commonly seen in more advanced cases of liver disease.

Although most of the coagulation assays are clotting-based assays, the intense color of icteric samples, due to the high levels of bilirubin, can sometimes interfere with the chromogenic based assays. Thus, careful test reading and interpretation is needed.

What Lab Results Are Absolutely Confirmatory?

In addition to the liver disease indices, prolonged PT and aPTT, along with decreased levels of coagulation factors II, V, and VII and high levels of factor VIII, are strong indicators for hemostatic defects due to liver disease.

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

Despite the abnormal coagulation screening tests (e.g., prolonged PT, aPTT, and thrombin time (TT) in early stages of liver disease, the vast majority of patients do not present with bleeding tendency. Bleeding complications are more evident in advanced cases when the coagulation system becomes fragile and patients are unable to maintain a balanced hemostasis.

As a result, this unbalanced hemostatic status can simply slip into either a hypocoagulable or, less likely, a hypercoagulable state. Furthermore, any additional comorbidity, infection for instance, limits the body’s ability in adjusting this fragile balance.

One of the common findings in severe liver disease patients is a DIC-like picture (pseudo-DIC), which is usually developed due to the imbalance between the accelerated blood coagulation and fibrinolysis. Apparently, coagulopathy of liver disease and DIC are not equally controlled, and they can occur simultaneously in some patients.

Surprisingly, in end-stage liver disease the hemostatic balance is also achieved but in a complicated manner. The defective hepatic clearance of activated procoagulant proteins and the reduced synthesis of anticoagulant proteins, along with low levels of plasminogen and elevated levels of von Willebrand factor and factor VIII, compensate for the low synthesis of procoagulant proteins and thrombocytopenia. Thus, the abnormal bleeding seen in most cases of end stage liver disease that mostly originates from specific sites, such as esophageal or gastric varices, peptic ulcer, and gastric mucosa, emphasizes the important role of portal vein hypertension in addition to the coagulopathy.

Although bleeding tendency has long been linked to cirrhosis, recent findings have shown an association with hypercoagulability, such as portal vein thrombosis, deep vein thrombosis, and pulmonary embolism. In a study of patients with different liver diseases, up to 50% had microthrombi in at least one organ.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Assessment of bleeding tendency in liver disease patients is a clinically significant common practice, despite the current deficiency of reliable bleeding screening tests/methods.

Bleeding time (BT) is one of the oldest tests used to evaluate bleeding tendency in these patients. Because of poor correlation between the corrected BT and decreased clinical bleeding, the practical utility of this test is uncertain.

The platelet function analyzer (PFA-100) is a proposed alternative measure of platelet activity, despite the lack of literature support in liver disease patients.

More reliable data can be obtained from thromboelastography; however, its utilization is still limited mostly to liver transplant procedures.