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Protein C Deficiency

BASICS

  • Definition: Rare heritable or acquired prothrombotic disorder, due to deficiency of protein C (vitamin K-dependent anticoagulant).
  • Symptoms: Range from asymptomatic to recurrent VTE, neonatal purpura fulminans, severe DIC.
  • Protein C: Synthesized by the liver; activated protein C (APC) inhibits factors Va & VIIIa (needs protein S as cofactor).

EPIDEMIOLOGY

  • Incidence: 1 in 200–500 (general), clinically substantial 1 in 20,000, severe 1 in 4 million infants
  • Prevalence: 0.3% of population, 3–5% of VTE cases
  • Mean age of first thrombosis: 45 years
  • No gender predominance

ETIOLOGY & PATHOPHYSIOLOGY

  • Heritable (autosomal dominant):
  • Type I: ↓ Protein C levels (most common)
  • Type II: ↓ Protein C function (normal levels)
  • Acquired causes: Liver disease, DIC, severe infection, autoantibodies, cancer/chemo, vitamin K deficiency, initial warfarin use
  • Genetics: >270 mutations in PROC gene; heterozygotes mild/asymptomatic; homozygotes/severe
  • Risk of warfarin-induced skin necrosis (WISN): Shorter half-life of protein C compared to other vitamin K-dependent factors

RISK FACTORS

  • Acquired: Heart failure, severe liver disease, DIC, vitamin K antagonists

GENERAL PREVENTION

  • No preventive measures for congenital forms
  • Avoid warfarin loading/bridge with heparin in known deficiency

ASSOCIATED CONDITIONS

  • VTE (DVT, PE)
  • Purpura fulminans in homozygotes
  • Recurrent pregnancy loss

DIAGNOSIS

History

  • Recurrent/unprovoked VTE (esp. <40–50 yrs)
  • Thrombosis in unusual sites (mesentery, portal vein, sagittal sinus)
  • Family history of VTE, abortion, or WISN

Physical Exam

  • Usually normal unless active thrombosis

Differential Diagnosis

  • Factor V Leiden, Protein S deficiency, antithrombin deficiency, dysfibrinogenemia, prothrombin G20210A, antiphospholipid syndrome, DIC, HIT

Testing

  • Clotting/ELISA/chromogenic assay for protein C levels
  • PROC gene mutational analysis
  • Labs: CBC, INR, aPTT, hepatic/renal function
  • Imaging as needed for VTE

When to Test

  • First VTE <40 yrs
  • Recurrent VTE
  • VTE at unusual sites
  • History of WISN
  • Neonates/children with purpura fulminans

Cautions

  • Acute thrombosis, warfarin, liver disease lower protein C—repeat testing after resolution
  • OCPs can raise levels

TREATMENT

General

  • Educate about VTE signs/symptoms
  • Avoid estrogen OCPs/hormone replacement
  • Progestin-only contraception is allowed
  • Routine anticoagulation not recommended for asymptomatic individuals

Anticoagulation (for VTE):

  • At least 3 months; longer if recurrent
  • LMWH, NOACs, or warfarin (INR 2–3)
  • LMWH preferred in pregnancy (monitor anti-Xa)
  • Heparin bridge if starting warfarin
  • Protein C concentrate for severe/homozygous cases

Pregnancy

  • LMWH/UFH for VTE
  • No routine prophylaxis if no prior VTE
  • Postpartum prophylaxis if other risk factors

Procedures

  • Hold anticoagulation for surgery
  • IVC filter only if contraindication to anticoagulation

ONGOING CARE

  • Monitor: INR (warfarin), anti-Xa (LMWH in pregnancy), kidney function, CBC
  • Diet: Unrestricted, except if on warfarin (monitor vitamin K intake)
  • Avoid NSAIDs with warfarin

PROGNOSIS

  • Normal lifespan if managed appropriately
  • Complications: Primary or recurrent VTE

ICD-10 CODES

  • D68.59 Other primary thrombophilia

CLINICAL PEARLS

  • Do not screen asymptomatic family unless female, childbearing age, no prior pregnancy complications
  • Asymptomatic PCD: No prophylactic anticoagulation
  • First VTE: At least 3 months anticoagulation; indefinite for recurrent VTE
  • Acute thrombosis and warfarin lower protein C—repeat confirmatory testing
  • Warfarin-induced skin necrosis risk: always use heparin bridge