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Protein S Deficiency

BASICS

  • Definition: Congenital thrombophilia (autosomal dominant), causing increased venous thromboembolism (VTE) risk.
  • Protein S: Vitamin K-dependent glycoprotein, mainly liver-derived, cofactor for activated protein C (APC), inhibits Va/VIIIa (with APC), and can directly inhibit Va, VIIa, Xa.
  • Only the "free" (unbound) protein S is anticoagulant; low free (but normal total) protein S = thrombosis risk.

EPIDEMIOLOGY

  • Incidence: Mean first thrombosis in 2nd decade of life; affects both sexes equally
  • Prevalence: ~0.2% of population; ~1% of patients with VTE

ETIOLOGY & PATHOPHYSIOLOGY

  • Genetics: PROS1 gene (chromosome 3), usually heterozygous; homozygotes: neonatal purpura fulminans
  • Free protein S is functional (30–40%); rest bound to C4b
  • Acquired low protein S: Pregnancy, DIC, liver disease, nephrotic syndrome, HIV, acute thrombosis, varicella, OCPs, warfarin, L-asparaginase
  • Risk of warfarin-induced skin necrosis: Due to shorter half-life of protein S (4–8h) vs other vitamin K factors

RISK FACTORS

  • Oral contraceptives, pregnancy, HRT
  • Concomitant thrombophilias
  • Smoking (arterial thrombosis risk)
  • Initiation of warfarin without heparin bridging

GENERAL PREVENTION

  • No true primary prevention for inherited forms
  • Family screening only for women considering OCPs/pregnancy with family history

ASSOCIATED CONDITIONS

  • DVT, PE, superficial thrombophlebitis
  • Neonatal purpura fulminans (homozygotes)
  • Unusual sites: mesentery, cerebral/axillary veins
  • Recurrent pregnancy losses
  • Warfarin-induced skin necrosis

DIAGNOSIS

History

  • Unprovoked VTE <50 yrs
  • VTE with family history or known protein S deficiency
  • VTE at unusual sites (mesenteric, cerebral)
  • Recurrent VTE

Physical Exam

  • Typically normal unless active thrombosis

Differential Diagnosis

  • Other hereditary thrombophilias (Protein C, ATIII, Factor V Leiden, prothrombin G20210A, dysfibrinogenemia, etc.)
  • Acquired VTE risks (immobility, cancer, surgery, pregnancy, HRT, trauma, antiphospholipid syndrome)

Testing

  • Labs: CBC, PT/INR, aPTT, thrombin time, lupus anticoagulant, antiphospholipid Abs, factor V Leiden, prothrombin G20210A, antithrombin, fibrinogen, protein S antigen (total/free), protein S activity
  • Timing: Avoid during acute thrombosis, pregnancy, VKA therapy, liver disease, acute illness—these lower protein S.
  • Heparin does NOT affect protein S testing.
  • Newborns have low protein S—use age-adjusted norms.

TREATMENT

General

  • No routine anticoagulation for asymptomatic patients
  • VTE treatment:
  • At least 3–6 months for first VTE (longer if low/moderate bleeding risk, or recurrent VTE)
  • Extended anticoagulation for 2nd unprovoked VTE or low bleeding risk
  • Preferred agents:
  • NOACs (rivaroxaban, apixaban, dabigatran, edoxaban) for VTE w/o cancer
  • LMWH, rivaroxaban, edoxaban for VTE + active cancer
  • Warfarin only after bridging with LMWH and INR 2–3 (never use alone in protein S deficiency)
  • LMWH preferred over UFH (unless severe renal failure)
  • Treat as outpatient if possible
  • Prophylaxis: Consider in high-risk situations (surgery, immobility, postpartum, +family history)

Medications

  • LMWH: enoxaparin 1 mg/kg SC BID or 1.5 mg/kg SC QD; adjust for renal function
  • Fondaparinux, NOACs, warfarin (after bridging)
  • Warfarin contraindicated in history of skin necrosis
  • Monitor for bleeding, embolization, thrombocytopenia

ISSUES FOR REFERRAL

  • Hematology for suspected cases
  • Family screening: Only justified for women considering OCPs or pregnancy and with a family history

PROCEDURES/SURGERY

  • Hold anticoagulation for surgery
  • IVC filter: Only if anticoagulation contraindicated

ONGOING CARE

  • INR monitoring for warfarin (target 2–3)
  • Monitor anti-Xa if on LMWH in pregnancy/renal dysfunction
  • Education: Avoid daily alcohol with warfarin, avoid NSAIDs

PROGNOSIS

  • Normal lifespan
  • By age 45: ~50% of heterozygotes have VTE, half are spontaneous

COMPLICATIONS

  • Recurrent VTE (may require indefinite anticoagulation)

ICD-10 CODES

  • D68.59 Other primary thrombophilia

CLINICAL PEARLS

  • No prophylactic anticoagulation for asymptomatic protein S deficiency
  • VTE in protein S deficiency: At least 6 months anticoagulation for first episode
  • Always bridge with heparin when starting warfarin
  • Routine family screening not indicated except select women (OCP/pregnancy with family history)