Introduction
Protein C is a natural coagulant in the body and is synthesized in the liver. Protein C is converted into activated protein C by proteolysis (protein breakdown into more minor compounds). Activated protein C is circulating in plasma and plays an important role in anticoagulation and regulating the permeability of blood vessel walls with a negative feedback loop. The activated protein C cause degradation of factors Va and VIIIa. Resistance to activated protein C was first discovered in 1993 by Dahl-back, which has improved understanding of thrombosis (blood clot in artery or vein) and embolism (blockage within a blood vessel). The incidence of activated protein C resistance is between 10 to 15 percent. Activated protein C resistance causes venous thrombosis in 40 percent of patients with familial thrombophilia (blood coagulation disorder). Thrombosis can induce cardiac diseases and lead to death.
What Is Activated Protein C Resistance?
Activated protein C resistance is a hematological disease in which poor anticoagulant response to activated protein C can be observed. Individuals suffering from this condition are at an increased risk of developing venous thrombosis, deep vein thrombosis, and pulmonary embolism. Inactivated protein C resistance is the reduced ability of activated protein C to cleave factors Va and VIIIa, leading to increased thrombin generation and clot formation. These changes cause an increased generation of thrombin and lead to a prothrombin state. The condition may develop due to hereditary or acquired factors.
The most common hereditary changes observed are in the single point mutations occurring in factor V, prominently in factor V Leiden. The mutation leads to replacing the amino acid residue arginine with glutamine. The factor V Leiden hereditary mutation is present in more than 95 percent of patients with activated protein C resistance. Individuals with heterozygous mutation for factor V Leiden have a mild to moderate risk for venous thromboembolism and a raised risk for arterial thromboembolism. Patients with homozygous factor V Leiden mutation are at high risk for thrombosis. The hereditary type of activated protein C resistance is inherited in an autosomal dominant (inheritance of a single copy of the mutated gene) manner.
What Are the Causes of Activated Protein C Resistance?
Activated protein C resistance of hereditary type occurs due to factor V Leiden mutation that forms the majority of cases. Other genetic factors for mutations in factor V are Factor V Cambridge and Factor V HR2 haplotypes. The acquired type of activated protein C resistance is primarily due to elevated factor VIII concentrations. Other less significant factors for the acquired type of the condition are the presence of antiphospholipid antibodies, lupus anticoagulant, pregnancy, hormone replacement therapy, hematological malignancies, old age, trauma, surgery, and specific types of estrogen therapy like birth control pills containing ethinylestradiol. Activated protein resistance can be identified during the second and third trimester of pregnancy and are more prominent during the third trimester.
What Are the Symptoms of Activated Protein C Resistance?
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Venous thromboembolism is a major symptom of activated protein C resistance.
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Thrombosis can be seen in unusual areas like the sagittal sinus, hepatic and retinal veins.
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Deep vein thrombosis.
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Central retinal vein occlusion in young adults.
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In pregnant women with activated C resistance, fetal loss may be reported.
How to Diagnose Activated Protein C Resistance?
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Russell Viper Venom Time: The primary basis of the assay depends on the protein C present in the patient's plasma, which, when activated, acts as an anticoagulant that inactivates factors Va and VIIIa. When activated protein C is added to plasma, it prolongs the clotting time compared to plasma without activated protein C. When factor V is mutated, it becomes more resistant to cleavage by activated protein C, and the clotting time is less prolonged. Resistance to activated protein C is measured by calculating the ratio of clotting time with and without activated protein C. The standard reference value for activated protein C is 2.1, and less than 2.1 indicates resistance. The resistance to activated protein C is confirmed if the ratio value is lower.
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Activated Partial Thromboplastin Time-Based Assay (APTT): It measures the time the blood takes to clot, which is raised in individuals with activated protein C resistance. The test is helpful in the identification of factor V mutations and acquired activated protein C resistance. However, for factor V, the mutation sensitivity and specificity of the test is less than 90 percent. The test must be confirmed with controlled preanalytical variables, and the platelet contamination must be below one percent to obtain accurate results.
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Modified Activated Partial Thromboplastin Time Test: The test is performed by diluting sample plasma with factor V deficient plasma. There is less interference from preanalytical variables.
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Chromogenic Factor X Assay: The test is based on measuring the ability of activated protein C to limit the production of factor Xa by inactivating factor VIII in plasma.
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DNA (Deoxyribonucleic Acid)-Based Testing: This test helps confirm or exclude the hereditary type of activated protein C resistance. The mutated factor V gene is analyzed from peripheral blood.
How to Treat Activated Protein C Resistance?
Individuals with heterozygous factor V Leiden resistance with asymptomatic features are not treated unless the risk for thrombosis persists. This type is common in patients undergoing surgery in whom short-term anticoagulant therapy is used. Patients with homozygous factor V Liden and heterozygous factor V Leiden with a risk of antithrombin, protein C, and protein S deficiency are advised with life-long anticoagulant therapy. Individuals with deep vein thrombosis and activated protein C resistance are treated with anticoagulant therapy, including intravenous heparin therapy and oral anticoagulation. Pregnant women with activated protein C resistance who develop acute thrombosis must undergo anticoagulation therapy for their remaining pregnancy period and a minimum of three months after delivery.
What Is the Prognosis for Activated Protein C Resistance?
Since the thrombotic risk depends on the cause of developing activated protein C resistance, the prognosis differs among affected individuals. Patients developing multiple blood clots, arterial or pulmonary thrombosis, and homozygous factor V Leiden have poor outcomes. There is also the possibility of thrombosis to recur even after treatment.
Conclusion
Activated protein C resistance is a predominant factor in inducing thrombophilia. The condition is a common genetic cause of hypercoagulation of blood. Patients with this disease have a mutation in factor V Leiden in most cases. The resistance is diagnosed with activated partial thromboplastin time or assay assessment. The condition is treated with intravenous or oral anticoagulant therapy based on the disease severity.
