Related Subjects: Thrombophilia testing
|Antiphospholipid syndrome
|Protein C Deficiency
|Protein S Deficiency
|Prothrombin 20210A mutation
|Factor V Leiden Deficiency
|Antithrombin III deficiency (AT3)
|Cerebral Venous Sinus thrombosis
|Budd-Chiari syndrome
Introduction
- Protein C deficiency is a rare inherited thrombophilia characterized by a deficiency of protein C, a vitamin K-dependent anticoagulant glycoprotein.
- Protein C plays a crucial role in regulating coagulation by inactivating factors Va and VIIIa, thus preventing excessive clot formation.
- Deficiency of protein C leads to a hypercoagulable state, increasing the risk of venous thromboembolism (VTE), including deep vein thrombosis (DVT), pulmonary embolism (PE), and cerebral venous sinus thrombosis (CVST).
- In severe cases, particularly in neonates, it can cause life-threatening conditions such as purpura fulminans.
Epidemiology
- Prevalence:
- Heterozygous protein C deficiency occurs in approximately 0.2-0.5% of the general population.
- Homozygous deficiency is extremely rare, estimated at 1 in 500,000 to 1 in 750,000 live births.
- Inheritance Pattern: Autosomal dominant for heterozygous deficiency; autosomal recessive inheritance in severe homozygous cases.
- Ethnic Distribution: Affects all ethnic groups equally.
Genetics and Pathophysiology
Protein C deficiency results from mutations in the PROCgene located on chromosome 2q13-14. The deficiency can be classified into two types:
- Type I Deficiency: Quantitative deficiency with reduced levels of protein C antigen and activity.
- Type II Deficiency: Qualitative deficiency with normal antigen levels but reduced functional activity due to dysfunctional protein C molecules.
The reduced activity of protein C impairs the inactivation of coagulation factors Va and VIIIa, leading to increased thrombin generation and a predisposition to thrombosis.
Clinical Features depend on the severity of the deficiency
Heterozygous Protein C Deficiency
- Venous Thromboembolism (VTE):
- Increased risk of DVT and PE, often occurring in young adults.
- Thrombotic events may be spontaneous or triggered by risk factors such as surgery, trauma, pregnancy, oral contraceptives, or prolonged immobilization.
- Cerebral Venous Sinus Thrombosis (CVST): Presenting with headaches, seizures, focal neurological deficits, and signs of increased intracranial pressure.
- Recurrent Thrombosis: Higher likelihood of recurrent VTE episodes.
- Warfarin-Induced Skin Necrosis:
- Rare complication occurring shortly after initiation of warfarin therapy.
- Due to a rapid decline in protein C levels leading to a transient hypercoagulable state.
- Characterized by painful skin lesions that progress to necrosis, typically affecting breasts, thighs, buttocks, and abdomen.
Homozygous Protein C Deficiency
- Neonatal Purpura Fulminans:
- Severe, life-threatening condition presenting within hours to days after birth.
- Characterized by disseminated intravascular coagulation (DIC), widespread thrombosis of small vessels, purpuric skin lesions, and necrosis.
- High mortality rate without prompt treatment.
- Severe Thrombotic Episodes: Including VTE and DIC in infants and children.
Risk Factors and Triggers:Additional factors that increase the risk of thrombosis
- Hormonal factors: Use of estrogen-containing contraceptives or hormone replacement therapy.
- Pregnancy and the postpartum period.
- Surgery and trauma.
- Prolonged immobilization.
- Obesity.
- Cancer.
- Other inherited thrombophilias (e.g., Factor V Leiden mutation, prothrombin G20210A mutation).
Diagnosis
- Clinical History: Personal and family history of thrombotic events, especially at a young age.
- Laboratory Tests:
- Protein C Activity Assay: Measures the functional activity of protein C; reduced levels indicate deficiency.
- Protein C Antigen Level: Differentiates between type I and type II deficiency.
- Other Coagulation Tests: Including PT, aPTT, fibrinogen levels, D-dimer to assess for DIC.
- Genetic Testing: Identification of mutations in the PROCgene confirms the diagnosis.
- Imaging Studies:
- Doppler Ultrasound: For detection of DVT.
- CT Pulmonary Angiography (CTPA): For suspected PE.
- Magnetic Resonance Venography (MRV): For diagnosing CVST.
- It is important to note that protein C levels can be influenced by acute thrombosis, anticoagulant therapy, liver disease, vitamin K deficiency, and DIC. Therefore, testing should be performed when the patient is not on anticoagulants and is in a steady state.
Differential Diagnosis
- Protein S deficiency
- Antithrombin III deficiency
- Factor V Leiden mutation
- Prothrombin G20210A mutation
- Antiphospholipid antibody syndrome
- Disseminated intravascular coagulation (DIC)
- Heparin-induced thrombocytopenia (HIT)
Management: Prevention
- Lifestyle Modifications:
- Maintain a healthy weight and engage in regular physical activity.
- Smoking cessation.
- Avoid prolonged immobilization; encourage movement during long periods of travel or bed rest.
- Avoid Hormonal Risk Factors:
- Use non-estrogen-containing contraceptives when possible.
- Cautious use of hormone replacement therapy; consider alternatives.
- Risk Assessment during Pregnancy:
- Prophylactic anticoagulation may be indicated in high-risk women.
- Close monitoring for signs of thrombosis.
Treatment of Acute Thrombosis
- Anticoagulation Therapy:
- Initial treatment with low molecular weight heparin (LMWH) or unfractionated heparin.
- Transition to oral anticoagulants such as warfarin; however, caution is required due to the risk of warfarin-induced skin necrosis.
- Consider overlapping heparin and warfarin therapy until therapeutic INR is achieved and protein C levels are stable.
- Direct oral anticoagulants (DOACs) may be an alternative, though data are limited; consultation with a hematologist is recommended.
- Protein C Replacement:
- For severe deficiency and in cases like neonatal purpura fulminans.
- Use of fresh frozen plasma (FFP) or concentrated protein C concentrates.
- Initiation of anticoagulation alongside replacement therapy.
- Management of Warfarin-Induced Skin Necrosis:
- Discontinue warfarin immediately.
- Administer vitamin K to reverse warfarin effects.
- Provide alternative anticoagulation with heparin.
- Consider protein C replacement therapy.
- Surgical consultation for debridement if necessary.
Long-Term Anticoagulation
- Individualized based on risk of recurrence and bleeding risks.
- Patients with recurrent thrombosis or high-risk profiles may require indefinite anticoagulation.
- Regular monitoring and follow-up are essential.
Management in Neonates
- Immediate Treatment: Replacement therapy with protein C concentrates or FFP.
- Anticoagulation: Use of LMWH or unfractionated heparin.
- Long-Term Management: Consider liver transplantation in severe cases as a definitive treatment.
Genetic Counseling and Family Screening
- Provide genetic counseling to affected families.
- Screen family members for protein C deficiency, especially if they have a history of thrombosis.
- Educate on recognizing signs of thrombosis and preventive measures.
Prognosis varies depending on the severity of the deficiency:
- Heterozygous Individuals:
- With appropriate management, individuals can lead normal lives.
- Risk of thrombosis remains elevated; vigilance is necessary.
- Homozygous Individuals:
- High mortality in neonates without prompt treatment.
- Early intervention improves outcomes.
References
- Dahlbäck B. Inherited thrombophilia: resistance to activated protein C as a pathogenic factor of venous thromboembolism. Blood. 1995;85(3):607-614.
- Bertina RM. Protein C deficiency and other congenital defects of natural anticoagulants associated with thrombosis. Thromb Haemost. 1993;70(1):145-150.
- Goldenberg NA, Manco-Johnson MJ. Protein C deficiency. Haemophilia. 2008;14(6):1214-1221.
- Kyrle PA, Minar E, Hirschl M, et al. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med. 2000;343(7):457-462.
- National Organization for Rare Disorders (NORD). Protein C Deficiency. Available from: [NORD Website](https://rarediseases.org/rare-diseases/protein-c-deficiency/).
- Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. National Heart, Lung, and Blood Institute.