Makindo Medical Notes

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 PROC gene 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 PROC gene 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.