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 S deficiency is a rare inherited or acquired thrombophilia characterized by a decrease in the levels or function of protein S, a vitamin K-dependent glycoprotein that plays a crucial role in the anticoagulation pathway. Protein S acts as a cofactor to activated protein C (APC) in the inactivation of coagulation factors Va and VIIIa, thereby regulating thrombin generation and preventing excessive clot formation. Deficiency of protein S 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).

Epidemiology

• Prevalence:
  • Inherited protein S deficiency is estimated to occur in approximately 0.03% to 0.13% of the general population.
  • Among patients with a history of VTE, the prevalence ranges from 1% to 7%.
• Inheritance Pattern: Autosomal dominant with variable penetrance.
• Ethnic Distribution: Affects all ethnic groups equally.

Genetics and Pathophysiology

Protein S deficiency results from mutations in the PROS1 gene located on chromosome 3q11.2. Protein S exists in two forms in plasma: free protein S (active form) and protein S bound to complement component C4b-binding protein (inactive form). Only free protein S functions as a cofactor for APC.The deficiency can be classified into three types:

• Type I Deficiency (Quantitative): Decreased total and free protein S antigen levels with reduced functional activity.
• Type II Deficiency (Qualitative): Normal antigen levels but reduced functional activity due to dysfunctional protein S molecules.
• Type III Deficiency (Quantitative): Normal total protein S antigen levels but decreased free protein S antigen and reduced functional activity.

The deficiency impairs the regulation of coagulation, leading to increased thrombin generation and a predisposition to thrombosis.

Clinical Features:Protein S deficiency primarily presents with thrombotic events:

• Venous Thromboembolism (VTE):
  • Increased risk of DVT and PE, often occurring at a young age (<50 years).
  • Thrombosis may be spontaneous or triggered by risk factors such as surgery, trauma, pregnancy, oral contraceptives, or prolonged immobilization.
  • Recurrent VTE episodes are common.
• Cerebral Venous Sinus Thrombosis (CVST):
  • Headache, visual disturbances, seizures, focal neurological deficits, signs of increased intracranial pressure.
  • Protein S deficiency is a recognized risk factor for CVST, particularly in young adults.
• Arterial Thrombosis:
  • Less common but may occur, leading to stroke or myocardial infarction, especially in combination with other risk factors.
• Pregnancy Complications:
  • Increased risk of miscarriage, stillbirth, preeclampsia, placental abruption, and intrauterine growth restriction.
  • Higher risk of VTE during pregnancy and postpartum period.
• Warfarin-Induced Skin Necrosis:
  • Rare complication occurring shortly after initiation of warfarin therapy.
  • Due to a rapid decline in protein S levels leading to a transient hypercoagulable state.
  • Characterized by painful skin lesions progressing to necrosis.

Risk Factors and Triggers

Factors that increase the risk of thrombosis in individuals with protein S deficiency include:

• Hormonal factors: Use of estrogen-containing contraceptives or hormone replacement therapy.
• Pregnancy and the postpartum period.
• Surgery and trauma.
• Prolonged immobilization.
• Obesity.
• Smoking.
• Cancer.
• Other inherited thrombophilias (e.g., Factor V Leiden mutation, prothrombin G20210A mutation).
• Antiphospholipid antibody syndrome.

Diagnosis involves a combination of clinical evaluation and laboratory testing:

• Clinical Assessment: Personal and family history of thrombotic events, especially at a young age.
• Laboratory Tests:
  • Protein S Antigen Levels:
    • Total Protein S Antigen: Measures both free and bound forms.
    • Free Protein S Antigen: Measures the active form; decreased levels indicate deficiency.
  • Protein S Activity Assay: Assesses the functional activity of protein S.
  • Other Coagulation Tests:
    • Activated Protein C (APC) resistance assay.
    • Antithrombin III levels.
    • Protein C levels.
    • Testing for Factor V Leiden and prothrombin G20210A mutations.
• Imaging Studies:
  • Doppler Ultrasound: For detection of DVT.
  • CT Pulmonary Angiography (CTPA): For suspected PE.
  • Magnetic Resonance Venography (MRV): For diagnosing CVST.

Note: Protein S levels can be influenced by acute thrombosis, anticoagulant therapy, liver disease, vitamin K deficiency, pregnancy, and oral contraceptive use. Testing should ideally be performed when the patient is not on anticoagulants and is in a steady state.

Differential Diagnosis: similar presentations include:

• Protein C deficiency
• Antithrombin III deficiency
• Factor V Leiden mutation
• Prothrombin G20210A mutation
• Antiphospholipid antibody syndrome
• Disseminated intravascular coagulation (DIC)
• Lupus anticoagulant presence
• Heparin-induced thrombocytopenia (HIT)

Management focuses on preventing thrombotic events and treating acute thrombosis:

Preventive Measures

• Lifestyle Modifications:
  • Maintain a healthy weight and engage in regular physical activity.
  • Smoking cessation.
  • Avoid prolonged immobilization; encourage mobility during long 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:
  • Consider prophylactic anticoagulation in high-risk women.
  • Close monitoring for signs of thrombosis.
  • Regular obstetric care with attention to fetal growth and placental function.

Treatment of Acute Thrombosis

• Anticoagulation Therapy:
  • Initial treatment with low molecular weight heparin (LMWH) or unfractionated heparin.
  • Transition to oral anticoagulants such as warfarin; careful monitoring is required due to potential warfarin-induced skin necrosis.
  • Direct oral anticoagulants (DOACs) like rivaroxaban or apixaban may be considered, although data are limited; consult a hematologist.
• Monitoring and Duration of Therapy:
  • Duration of anticoagulation depends on the individual risk profile; often at least 3-6 months for a first VTE.
  • Extended or indefinite anticoagulation may be necessary in cases of recurrent thrombosis or high-risk patients.
  • Regular monitoring for efficacy and adverse effects.
• Management of Warfarin-Induced Skin Necrosis:
  • Discontinue warfarin immediately.
  • Administer vitamin K to reverse warfarin effects.
  • Provide alternative anticoagulation with heparin.
  • Consider protein C concentrate if protein S levels are critically low (though protein S concentrates are not widely available).
  • Surgical consultation if necessary.

Long-Term Anticoagulation

• Individualized based on risk of recurrence and bleeding risks.
• Patients with recurrent thrombosis or additional risk factors may require long-term or indefinite anticoagulation.
• Regular follow-up with a healthcare provider is essential.

Genetic Counseling and Family Screening

• Provide genetic counseling to affected individuals and families.
• Screening of family members may be considered, especially if there is a strong history of thrombosis.
• Educate on recognizing signs of thrombosis and implementing preventive measures.

Prognosis varies:

• With appropriate management and preventive measures, many individuals lead normal lives.
• Risk of recurrent thrombosis remains; ongoing vigilance and adherence to management plans are crucial.
• Pregnancy requires careful monitoring but can be successful with appropriate care.

Conclusion

Protein S deficiency is a significant risk factor for thrombotic events. Early recognition, appropriate management, and patient education are essential to reduce morbidity and mortality associated with this condition. Collaboration between patients and healthcare providers ensures optimal outcomes.

References

• Dahlbäck B. The discovery of protein S and its cofactor function in activated protein C-mediated anticoagulation. Arterioscler Thromb Vasc Biol. 2007;27(6):1172-1177.
• Patel JP, Cooper N, Whyte S, et al. Protein S deficiency and pregnancy. Thromb Haemost. 2015;113(1):123-128.
• Miles JS, Harper PL, Ebdon JE, et al. Clinical importance of free protein S measurements. Br J Haematol. 1996;92(4):1139-1142.
• National Institute for Health and Care Excellence (NICE). Venous thromboembolic diseases: diagnosis, management and thrombophilia testing. NICE guideline [NG158]; 2020.
• James AH. Thrombophilia in pregnancy: a review of the risks and recommendations for management. Obstet Gynecol Surv. 2001;56(10):703-715.