Excerpt from Protein C Deficiency

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Background

Protein C deficiency, a deficiency of the anticoagulant protein C, is associated with a variably increased risk of thrombosis. In the rare inherited homozygous or compound heterozygous state, protein C deficiency is associated with severe life-threatening neonatal purpura fulminans or massive venous thrombosis. The inherited heterozygous state of protein C deficiency most frequently is associated with deep venous thrombosis of the lower limb but also may manifest in other venous locations. A significant percentage of patients with protein C deficiency remain asymptomatic. A family history is essential in assessing the association of a patient's deficiency with the patient's risk of thrombotic disease. Acquired protein C deficiency occurs in certain clinical scenarios, but this most often is associated with a transient predisposing factor.

Protein C is a 62-kD glycoprotein, synthesized in the liver as a zymogen, which circulates in the blood at a concentration of 4 mcg/mL. Activation of protein C requires conversion of the single-chain zymogen into a 2-chain serine-protease–like enzyme required for catalytic activity. Physiologically, this activation occurs on phospholipid cell surfaces by the action of thrombin when bound to the endothelial cell proteoglycan, thrombomodulin.

Additionally, endothelial cell protein C receptor, primarily located in major blood vessels, augments thrombin/thrombomodulin activity. Once activated, activated protein C (APC) binds to the cell-surface–bound anticoagulant cofactor, protein S. The APC/protein S complex then proteolyses activated procoagulant cofactors factor VIII and factor V, thereby retarding fibrin formation by preventing activation of procoagulant proteins, factor X and prothrombin.

Pathophysiology

The hemostatic system is comprised of multiple procoagulant and anticoagulant plasma proteins that interact with platelets, along with cellular phospholipids to promote physiological coagulation. The formation of a fibrin clot depends on thrombin generation, the key regulator in the hemostatic process. Protein C inhibits thrombin generation through its proteolysis of key cofactors required in procoagulant enzymatic complexes.

Anticoagulant proteins are particularly important in areas where there may be prolonged exposure of procoagulant factors and platelet phospholipids to the vessel wall, which predisposes to thrombotic disease, largely due to this prolonged exposure. Deficiencies of anticoagulant proteins thus place a patient at increased risk for thrombosis in the slowly flowing venous circulation. In the rapidly flowing arterial circulation, laminar flow largely prevents prolonged interaction between platelets and vessel walls. However, occasional reports of protein C deficiency document an increased incidence of arterial thrombosis, particularly in pediatric patients.

Protein C also plays profibrinolytic, anti-inflammatory, and anti-ischemic roles. Additionally, in patients with severe sepsis, a decrease in the generation of APC contributes to the dysregulation of physiological clot formation.

Frequency

United States

The frequency in the United States is similar to that found internationally.

International

Incidence of protein C deficiency by plasma levels alone is between 1 in 200 and 1 in 500 persons in the general asymptomatic population. Incidence of symptomatic protein C deficiency is approximately 1 in 16,000 to 1 in 32,000 persons. Frequency of protein C deficiency in patients with hypercoagulability and venous thrombosis is approximately 5%. Incidence of severe protein C deficiency occurs in approximately 1 in 500,000 to 1 in 750,000 live births.

Mortality/Morbidity

Despite the morbidity of thrombosis associated with homozygous protein C deficiency, overall 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, when patients are at greater risk for thrombotic events.

• Deep venous thrombosis is the most common symptomatic manifestation of protein C deficiency. Pulmonary embolism and postphlebitic syndrome may occur subsequent to deep venous thrombosis. Mortality in protein C deficiency most often is due to pulmonary embolism subsequent to deep venous thrombosis.
• Morbidity and mortality in homozygous or compound heterozygous protein C deficiency include neonatal purpura fulminans and massive thrombosis. Blindness secondary to vitreous hemorrhages may occur in patients with these severe conditions. Morbidity and mortality in acquired protein C deficiency usually are related to the inciting agent of the deficiency. However, treatment of the acquired protein C deficiency can greatly aid other therapeutic measures.
• Complications secondary to anticoagulant therapy also represent a significant cause of both morbidity and mortality. Anticoagulation exposes the individual to significant risk of major and/or fatal hemorrhage. Warfarin-induced skin necrosis may occur in protein C deficiency subsequent to initiation of oral anticoagulant therapy. Precautions can be taken by administering heparin prior to or concomitantly with oral anticoagulants.

Race

Protein C deficiency is recognized as a significant cause of thrombophilia in most populations. However, APC resistance, briefly discussed in Lab Studies, is very frequent in whites (incidence of approximately 5%) but rare in Asian and African populations (incidence of <1%).

Sex

Incidence of protein C deficiency is similar in men and women. However, pregnancy and postpartum periods increase the risk of thrombosis in patients with protein C deficiency, although the protein C levels are not further decreased during these times.

Age

The median age of onset of thrombosis in heterozygous protein C deficiency is 30-40 years. Homozygous or compound heterozygous deficiency usually manifests several hours to days after birth, with purpura fulminans or massive venous thrombosis. However, some patients with inherited homozygous or compound heterozygous deficiency with low protein C levels (<20%) present during childhood or early adulthood.

Preterm infants, neonates, and adolescents have protein C levels approximately 10-15%, 35%, and 80%, respectively, of normal adult levels. Protein C levels increase approximately 4% per decade in adulthood. Despite the lower protein C levels during childhood, thrombosis associated with heterozygous protein C deficiency is uncommon in individuals younger than 20 years.

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