At a Glance

Protein C deficiency is an inherited venous thrombotic disorder. A history of unexplained venous thrombosis in a patient younger than 50 years of age with a family history of venous thrombosis should prompt consideration of protein C deficiency. First venous thrombosis with protein C deficiency typically occurs in otherwise healthy individuals at around 30 years of age. Thrombosis may be triggered by surgery, trauma, pregnancy, or prolonged immobilization, such as car or plane rides longer than 8 hours. Venous thrombosis associated with protein C deficiency may occur in unusual locations, such as the portal vein, mesenteric vein, superior sagittal sinus, or arm veins, and in multiple veins simultaneously. Any of these indicators of unusual venous thrombosis should prompt consideration of protein C deficiency.

Protein C deficiency occurs in about 1 in 500 individuals. Patients with protein C deficiency are typically heterozygotes with one abnormal and one normal protein C gene, resulting in an autosomal dominant heredity pattern (male and female, each generation showing disorder).

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

The most useful test for evaluating possible protein C deficiency is a protein C activity assay. Protein C activity is preferred over protein C antigen assays, as activity assays will detect both low levels of protein C production and abnormal or dysfunctional protein C that leads to low activity even though antigen levels may be normal. Typically, a protein C activity of less than about 65% of normal suggests a possible protein C deficiency. If the protein C activity is low, it should be repeated to confirm the finding prior to establishing a diagnosis of protein C deficiency.

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If the patient has confirmed low protein C activity, protein C antigen levels can be run to determine whether the patient has type 1 protein C deficiency (low levels of activity and antigen indicative of decreased production of protein C) or type 2 (low levels of activity with normal antigen indicative of an abnormal protein C molecule).

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?

Protein C levels should not be measured in patients with vitamin K deficiency, with prolonged prothrombin time, or on warfarin or asparaginase therapy, as these conditions can reduce protein C levels, leading to falsely low estimates of baseline protein C activity. Wait at least 10 days after the medications have been stopped and check to make sure the prothrombin time is normal before measuring protein C activity.

Protein C levels may also be transiently decreased in patients with extensive venous thrombosis, portal vein thrombosis, or disseminated intravascular coagulation (DIC) due to consumption of protein C in the clotting process. Wait until the patient has recovered from the current thrombotic episode before measuring protein C activity. Protein C levels may be reduced in patients with severe hepatocellular liver disease.

Protein C levels are lower and more variable in infants and small children than in adults. Age-based reference ranges are required to determine protein C deficiency in children, but protein C deficiency is generally not associated with an increased risk of thrombosis in children prior to puberty, unless they have other risk factors for venous thrombosis, such as cancer, infection, or intravascular catheters.

Clot-based protein C activity assays have more false-positive and false-negative results than chromogenic protein C activity assays. Patients on direct thrombin inhibitors, such as argatroban, bivalirudin or dabigatran, may have falsely high protein C activity levels in clot-based assays, so it is better to wait until the patient is off these medications and has a normal prothrombin time and partial thromboplastin time (PTT) before measuring protein C activity using a clot-based method. Patients with lupus inhibitors may have falsely high clot-base protein C activity, whereas patients with acute phase responses due to infection, inflammation, or other causes may have falsely low clot-based protein C activity due to interference from elevated factor VIII levels in the sample.

What Lab Results Are Absolutely Confirmatory?

Genetic testing for protein C mutations is not routinely done, as there are many different mutations that can cause protein C deficiency, the cost of testing is high, clinical availability low, and definitive diagnosis poor, unless the mutation is previously well described and known to be associated with deficiency and increased risk of venous thrombosis.

A protein C activity less than 60% of normal in a patient with a normal prothrombin time and no evidence of going thrombosis is likely to have hereditary protein C deficiency.

Does protein C deficiency predict initial or recurrent venous thrombosis or change recommendations for antithrombotic therapy?

Patients with protein C deficiency have approximately a 5- to 10-fold increased risk of developing venous thrombosis compared to individuals without inherited thrombophilia and tend to develop venous thrombosis at a younger age. However, most individuals with protein C deficiency never develop venous thrombosis. Protein C deficiency is associated with an increased risk of fetal loss and venous thrombosis during pregnancy. Testing for protein C deficiency does not, in practice, identify individuals who definitely develop recurrent venous thrombosis, reduce the incidence of recurrent venous thrombosis, or alter antithrombotic therapy in most cases.

Additional Issues of Clinical Importance

Because protein C levels fall quickly after starting warfarin therapy, patients with protein C deficiency may develop a transient procoagulant state, known as warfarin associated skin necrosis, soon after starting warfarin therapy, unless treated with another anticoagulant like heparin when warfarin is started.

Rare homozygous protein C deficiency may have near undetectable protein C levels at birth, which is associated with severe thrombotic complications, including neonatal purpura fulminans and disseminated intravascular coagulation (DIC).

The association between protein C deficiency and arterial thrombosis is weak, controversial, and has no therapeutic implications at present.

Errors in Test Selection and Interpretation

Protein C activity is preferred over protein C antigen assays, as activity assays detect both low levels of protein C production and abnormal or dysfunctional protein C that leads to low activity even though antigen levels may be normal. The optimal protein C activity assay is a chromogenic assay that is less sensitive to low levels of vitamin K deficiency and lupus inhibitors compared to clot-based protein C activity assays.

The most common error in interpreting protein C activity results is the false diagnosis of hereditary protein C deficiency due to acquired low levels of protein C activity associated with warfarin therapy, vitamin K deficiency, or ongoing thrombosis. Because the prevalence of protein C deficiency in the population is low (pretest probability is low), false positives are likely if the result is near the lower limit of the reference range.