Protein C Deficiency

Thrombotic
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Diagnosis and reasoning

This patient has presented for further evaluation of a first episode of venous thromboembolism; given his age, a thrombophilia (either genetic or acquired) is a strong possibility. Note that while his evaluation at the time of the episode failed to turn up an etiology, this is not unusual, as many clotting and anticlotting factors are depleted during acute thrombosis. His basic screening tests should include a complete blood count (CBC) to exclude thrombocytosis (even though this is more likely to give rise to arterial rather than venous thromboses), and a coagulation profile, aiming to see if the activated partial thromboplastin time (aPTT) is elevated (which might indicate antiphospholipid syndrome). As these are normal, the next step should be screening for a genetic thrombophilia such as Protein C deficiency, Protein S deficiency, Antithrombin III deficiency, Activated Protein C resistance, Fibrinogen deficiency, Hyperhomocysteinemia, and Prothrombin G20210A mutation. He should also be screened for acquired thrombophilias such as antiphospholipid syndrome (APS), and systemic lupus erythematosus (SLE), although these are less common in the male gender. These tests subsequently identify a marked reduction in Protein C activity, making Protein C deficiency the probable diagnosis. Note that Protein C deficiency is usually genetic in origin; while acquired deficiency can occur in patients with acute severe infection, severe liver disease or disseminated intravascular coagulation (DIC) these would have been picked up at the time of the first episode. In addition, while therapy with warfarin can also cause a temporary reduction in protein C levels, this is unlikely to persist for 1 month post-cessation. While DNA testing for Protein C deficiency can also be performed, this is generally not available outside of specialized research laboratories, and is not indicated in most patients. However, as the disease is inherited in an autosomal dominant fashion, screening of his close relatives is quite prudent. As he developed a thrombotic episode only following a provocation (i.e. prolonged immobilization), he only requires prophylaxis in high-risk settings. Thus, lifelong warfarin therapy is not indicated; nor is routine fresh frozen plasma (FFP) required. Note also that aspirin prophylaxis only affects platelet function and is of little benefit in this patient.


Discussion

Activated Protein C (APC) is one of the key anticoagulants in the body; the molecule combines with Protein S on the surface of platelets, and subsequently degrades activated factors V and VIII. Protein C is the inactive precursor of APC; it is dependant on vitamin K for synthesis. Combination with thrombomodulin results in transformation into the active form. As the name suggests, Protein C deficiency is characterized by low levels of the molecule in the plasma; the condition results from mutation of the PROC gene (which is involved in the synthesis of protein C), and is inherited in an autosomal dominant fashion. Overall, between 1 in 200 to 1 in 500 persons are believed to carry the disease, although clinical manifestations occur in only 1 in 20,000 individuals. Protein C deficiency is divided into two key forms; in type 1 deficiency, the defect is quantitative, resulting in low protein C levels; in type 2 disease, concentrations are normal, but activity is reduced. In patients who become symptomatic, the exact clinical manifestations depend on whether a heterozygous or homozygous genotype is present. Heterozygous individuals mainly suffer from venous thromboembolism - most often, deep vein thrombosis (DVT), and less frequently, mesenteric vein or cerebral sinus thrombosis. Compound heterozygotes or homozygotes are at risk of both arterial and venous thrombosis; they may initially present with neonatal purpura fulminans (NPF) or venous thromboembolism in late childhood, or with ischemic stroke or myocardial infarction when young adults. In patients in whom the disease is suspected, Protein C activity levels can be assessed via a variety of immunological and functional assays; the presence of decreased activity is suggestive of the diagnosis. Borderline activity levels may be encountered in both normal individuals and heterozygotes; in such patients, a functional assay is essential for differentiation. Note also that functional assays are capable of distinguishing between type 1 and type 2 deficiency. It should be appreciated that the above tests should not be performed in patients with acute thrombosis (as levels of protein C are expected to be low in such a setting anyway); they are best conducted at least 6 months after the acute phase of thrombosis, or 2 or more weeks after anticoagulant therapy has been discontinued. In general, asymptomatic individuals with incidentally diagnosed protein C deficiency do not require treatment; the exception is if there is a strong family history of venous or arterial thrombosis. In patients who are symptomatic, acute thromboses should be managed in accordance with the usual medical protocols; this should be followed by long term anticoagulation initially with heparin, then followed by warfarin. Note that these patients are at risk of developing Warfarin Induced Skin Necrosis (WISN), if warfarin is started without the addition of another anticoagulant such as heparin or fondaparinux. This is because warfarin reduces the synthesis of all vitamin K dependent proteins (including protein C - which is actually affected first), resulting in a transient hypercoagulable state which causes thrombosis of the dermal vessels, and ischemic necrosis of the skin. In such patients, warfarin should be immediately stopped, and fresh frozen plasma (FFP) or Protein C concentrates administered emergently. Note also that prophylactic FFP or protein C concentrates may be considered in situations where the patient might be at increased risk (i.e. surgery, or periods of prolonged immobility). As Protein C deficiency is a genetic thrombophilia, screening of the immediate relatives is also an important component of the management, as is proper counselling of the patient and family.


Take home messages

  1. Protein C deficiency is inherited in an autosomal dominant fashion.
  2. The diagnosis requires demonstration of reduced protein C activity; testing should not be performed immediately following an acute thrombosis.
  3. Most asymptomatic individuals do not require therapy, unless there is a strong family history of thrombotic events.
  4. Initiation of warfarin therapy without heparin cover may result in warfarin induced skin necrosis, a potentially lethal complication.

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