Protein C Deficiency

Protein C is a vitamin K-dependent glycoprotein that is synthesized in the liver. Before activation by the thrombin-thrombomodulin complex on the endothelial cell surface, it circulates as a two-chain zymogen.¹ By inactivating clotting factors V and VIII, activated Protein C (APC) is one of the major inhibitors of the coagulation system. Activated Protein C also stimulates fibrinolysis. Activated Protein C is regulated by Protein S on the surface of endothelial cells and requires calcium as a co-factor.

Protein C deficiency is a condition in which there is a deficiency of Protein C and is therefore associated with a variably increased risk of thrombosis. Protein C deficiency may be inherited or acquired. The clinical features of congenital and acquired Protein C deficiency are similar.

• Inherited (autosomal dominant): familial Protein C deficiency can be classified into two types:
  • Type I: decreased levels of Protein C.
  • Type II (rare): there is normal level of Protein C, but decreased functional activity.
• Acquired Protein C deficiency is most often associated with a transient predisposing factor:
  • Severe infection, including meningococcal septicaemia
  • Disseminated intravascular coagulation
  • Ill preterm infants
  • Severe liver disease
  • Haemolytic-uraemic syndrome
  • Adult respiratory distress syndrome
  • Post-operative
  • Malignancy
  • Vitamin K deficiency, warfarin therapy

• The prevalence of heritable Protein C deficiency in the general population is approximately 0.2-0.3% and in unselected patients with venous thromboembolism is about 3%.²
• The relative risk of venous thromboembolism is between 10 and 15 fold for individuals with Protein C deficiency.³
• Protein C deficiency is rare in Asian and African populations.

A significant number of patients with Protein C deficiency remain asymptomatic.⁴
• The homozygous or compound heterozygous state is associated with severe life-threatening neonatal purpura fulminans (widespread severe purpura with extensive tissue damage and sloughing of skin) or massive venous thrombosis.
• The inherited heterozygous state is most often associated with deep vein thrombosis of the lower limb or elsewhere.
• Venous thrombosis: during early life in homozygotes; variable in heterozygotes but uncommon before age 20 years; include deep vein thrombosis, pulmonary embolus, cerebral venous thrombosis.
• Pregnancy and postpartum periods increase the risk of thrombosis but do not alter Protein C levels.
• Family history of thrombosis.
• Blindness secondary to vitreous haemorrhages may occur in homozygotes.
• Recurrent superficial thrombophlebitis and deep vein thrombosis.
• Postphlebitic syndrome: chronic complication of thrombosis; pain, swelling, and possibly skin ulceration and induration in the leg.⁴

Other causes of thrombophilia.

• A family history is essential in assessing the association of a patient's deficiency with the patient's risk of thrombotic disease.⁴
• Protein C activity:
  • Normal ranges must be established at each laboratory.
  • Both quantitative and qualitative abnormalities of Protein C have been identified. For this reason, functional tests are preferred over antigenic tests for Protein C.³
  • There is a wide overlap in Protein C activity between heterozygous carriers and their unaffected relatives in families with Protein C deficiency.³
  • Normal functional Protein C levels range from approximately 60-130% of the level of pooled plasma from 20 non-pregnant non-clotting individuals who are not taking medications known to affect the Protein C level, e.g. warfarin.
  • Many variables may alter the Protein C level. Therefore each patient must be tested in the context of their clinical situation.
  • A decreased activity level should be repeated on a separate specimen to help rule out any irrelevant variables affecting the result.
  • Protein C levels are decreased during childhood and so a definitive diagnosis of heterozygous disease should not be made until adulthood. Family studies help in making the diagnosis.
• Coagulation tests: including APTT, prothrombin time, fibrinogen level, fibrin degradation D-dimer test.
• Tests for other thrombotic risk factors, including antithrombin level, free Protein S level, a plasma-based test for APC resistance, or a genetic test for factor V Leiden and prothrombin G20210A. Tests for plasminogen, dysfibrinogenaemia, lupus anticoagulant and an anticardiolipin antibody may be required.
• Investigation of thrombotic disease including doppler, contrast venography, MRI, chest ventilation/perfusion scan.

• Asymptomatic patients with low Protein C usually require no specific treatment.
• Prophylactic treatment should be considered at times of increased thrombotic risk, e.g. peri-partum, peri-operatively, prolonged immobilization.
• The potential increased risk of thrombotic disease during oral contraceptive therapy should also be considered.

Symptomatic patients

• Warfarin treatment may cause a further decrease in Protein C levels and therefore an increased risk of thrombosis, Warfarin treatment should be covered with concurrent heparin treatment during the initial 10 days.
• The risks of thrombotic disease should also be considered against the risk of haemorrhage. In most patients, the risk of major haemorrhage associated with anticoagulant therapy is higher than the risk of thrombosis.
• One thrombotic episode: anticoagulant therapy for 3 months to 1 year to prevent further thrombotic episodes.
• Recurrent thrombotic disease or have a strong positive family history of thrombotic disease: long-term anticoagulant therapy.
• Severe homozygous or compound heterozygous Protein C deficiency: aggressive anticoagulation treatment is required because of the high risk of thrombosis in these patients.
• Patients with congenital Protein C deficiency or those with acquired Protein C deficiency associated with other medical problems, e.g. disseminated intravascular coagulation, may be treated with protein C concentrate.

• Protein C deficiency results in a 10-15 fold increased risk of thrombosis.²
• Anticoagulation causes a significant risk of major haemorrhage. Warfarin-induced skin necrosis may occur. Problems with anticoagulants can be reduced by giving heparin before or with oral anticoagulants.

• Homozygous protein C deficiency has a high morbidity and mortality. Homozygotes lacking Protein C die in the early neonatal period, if not before, from overwhelming coagulation.
• Mortality in families with heterozygous Protein C deficiency is similar to that of the general population. Morbidity in Protein C deficiency greatly increases with advancing age, with increasing risk for thrombotic events.
• It is estimated that 50% of individuals who are heterozygous for Protein C deficiency, who have a family history of thrombosis, will experience a thrombotic event.