> Table of Contents > Protein S Deficiency
Protein S Deficiency
Dalia Hammoud, MD
Elie Chalhoub, MD
Maissaa Janbain, MD
image BASICS
DESCRIPTION
  • Protein S is a vitamin K-dependent factor made principally by the liver that acts as a cofactor for protein C.
  • Protein C becomes activated when thrombin binds to the endothelial receptor, thrombomodulin.
  • Activated protein C, with protein S as a cofactor, inactivates clotting factors Va and VIIIa, and it enhances fibrinolysis.
  • Protein S is also able to directly inhibit factors Va, VIIa, and Xa independently of activated protein C.
  • Patients with protein S deficiency have a thrombotic disorder that primarily affects the venous system.
  • System(s) affected: cardiovascular; hematologic/lymphatic/immunologic; pulmonary
EPIDEMIOLOGY
Incidence
  • Predominant age: Mean age of first thrombosis is the 2nd decade of life.
  • Predominant sex: male = female
Prevalence
  • 0.3% of normal individuals
  • Found in 3% of persons with VT
ETIOLOGY AND PATHOPHYSIOLOGY
  • >131 mutations in the protein S gene leading to an inherited protein S deficiency have been described. Protein S reversibly binds to the C4b-binding protein. Only the free form acts as a cofactor for activated protein C. This leads to conditions in which free protein S is low, but total protein S is normal. These individuals are prone to thrombosis.
  • Acquired protein S deficiency from decreased free protein S can occur during pregnancy; in patients taking oral contraceptives or warfarin; and in DIC, liver disease, nephrotic syndrome, inflammation, L-asparaginase chemotherapy, and acute thrombosis.
  • Transient autoantibodies can develop to protein S in patients with acute varicella (1)[C].
Genetics
Autosomal dominant. Heterozygotes have an odds ratio (OR) of venous thrombosis (VT) of 1.6 to 11.5. Arterial thrombosis is more frequent in patients with protein S deficiency who smoke. Homozygotes can have a fulminant thrombotic event in infancy, termed neonatal purpura fulminans. Homozygosity or compound heterozygosity, if untreated, is usually incompatible with adult life.
RISK FACTORS
  • Oral contraceptives, pregnancy, and the use of HRT increase the risk of VT in patients with protein S deficiency (2)[A].
  • Patients with protein S deficiency and another prothrombotic state, such as factor V Leiden, have further increased rate of thrombosis (2)[A].
  • Patients heterozygous for protein S deficiency who are initiated on warfarin without concomitant heparin can develop warfarin-induced skin necrosis because the half-life of other vitamin K-dependent clotting factors (e.g., prothrombin, factor IX, and factor X) is much longer than the anticoagulant protein S (4 to 8 hours), leading to a transient hypercoagulable state when protein S becomes depleted. These patients develop extremely low levels of protein S and develop necrosis of the skin over central areas of the body such as the breast, abdomen, buttocks, and genitalia (2)[A].
Pregnancy Considerations
Increased thrombotic risk in patients with protein C deficiency
GENERAL PREVENTION
Because protein S deficiency is a congenital disease, there are no preventive measures.
COMMONLY ASSOCIATED CONDITIONS
  • Deep and superficial VT, often spontaneous
  • Up to 50% of homozygotes will have thrombosis.
  • Homozygosity is associated with catastrophic thrombotic complications at birth: neonatal purpura fulminans
  • Sites of thrombosis can be unusual, including the mesentery, cerebral veins, and axillary veins.
  • Arterial thrombosis is rare, but reported in several case reports.
  • Skin necrosis can be seen in patients on warfarin.
  • Recurrent pregnancy losses (3).
image DIAGNOSIS
PHYSICAL EXAM
Normal
DIFFERENTIAL DIAGNOSIS
  • Factor V Leiden
  • Protein C deficiency
  • Antithrombin deficiency
  • Dysfibrinogenemia
  • Dysplasminogenemia
  • Homocysteinemia
  • Prothrombin 20210 mutation
  • Elevated factor VIII levels
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • For evaluation of new clot in patient at risk: CBC with peripheral smear, PT/INR, aPTT, thrombin time, lupus anticoagulant, antiphospholipid antibodies, factor VIII, anticardiolipin antibody, anti-&bgr;2-glycoprotein I antibody, activated protein C resistance, protein S antigen and resistance, antithrombin III assay, fibrinogen, factor V Leiden, prothrombin G20210A, homocysteine
  • Protein S activity assay (mainly after obtaining APC resistance)
  • Immunoassay for quantitative assessment of total and free protein S levels. Test off vitamin K antagonists.
  • Disorders that may alter lab results: Liver disease and pregnancy-reduce protein S levels.
  • Total protein S levels are markedly decreased in newborns and young infants; use age-adjusted norms.
image TREATMENT
GENERAL MEASURES
  • Routine anticoagulation for asymptomatic patients with protein S deficiency is not recommended (2)[A].
  • Anticoagulation for 6 to 12 months is recommended for patients with protein S deficiency and a first thrombosis.
  • Some argue for lifetime anticoagulation; data are limited.
  • Anticoagulation for life is indicated for patients with protein S deficiency and recurrent thrombosis.
  • The role of family screening for protein S deficiency is unclear because most patients with this mutation do not have thrombosis. Screening should be considered for women considering oral contraceptives or pregnancy, and who have a family history of protein S deficiency (4)[B].
  • Treatment of thrombosis with LMWH is recommended over unfractionated heparin, unless the patient has severe renal failure (5)[B].
  • Treat as outpatient, if possible (5)[B].
  • Initiate warfarin together with LMWH on the first treatment day, and discontinue LMWH after a minimum of 5 days and two consecutive INRs >2 (5)[A].
  • P.863

  • For pregnant women with no prior history of VTE, we suggest antepartum and postpartum clinical vigilance. Postpartum prophylaxis is reserved for patients with positive family history only; in that case, we suggest prophylactic- or intermediate-dose LMWH for 6 weeks (1)[C],(5).
MEDICATION
First Line
  • Low-molecular-weight heparin (LMWH) (2)[A] initially for a minimum of 5 days and two consecutive INRs between 2 and 3, at which time it can be stopped
    • Enoxaparin (Lovenox) 1 mg/kg SC BID:
      • Alternatively, 1.5 mg/kg/day SC
    • Tinzaparin (Innohep) 175 anti-Xa IU/kg/day SC
    • Dalteparin (Fragmin) 200 IU/kg/day
  • Factor Xa Inhibitor
    • Fondaparinux (Arixtra) <50 kg: 5 mg/day SC; 50 to 100 kg: 7.5 mg/day SC; >100 kg: 10 mg/day SC; contraindicated if CrCl <30 mL/min
  • Oral anticoagulant: warfarin (Coumadin): 5 mg/day PO then adjusted to an INR of 2 to 3 for at least 6 months (5)[A]
  • Novel oral anticoagulants (NOACs) (6):
    • Dabigatran 150 mg po BID (after 5 to 10 days of parenteral anticoagulation)
    • Rivaroxaban 15 mg po BID for 21 days then 20 mg PO QID
    • Apixaban 10 mg PO BID for 7 days then 5 mg PO BID
    • Edoxaban 60 mg PO QID (after 5 to 10 days of parenteral anticoagulation)
  • Contraindications
    • Active bleeding precludes anticoagulation; risk of bleeding is a relative contraindication to long-term anticoagulation.
    • Warfarin is contraindicated in patients with a prior history of warfarin-induced skin necrosis.
  • Precautions
    • Observe patient for signs of embolization, further thrombosis, or bleeding.
    • Avoid IM injections.
    • Periodically, check stool and urine for occult blood; monitor CBC, including platelets.
    • Heparin: thrombocytopenia and/or paradoxical thrombosis with thrombocytopenia
    • Warfarin: necrotic skin lesions (typically breasts, thighs, and buttocks)
    • LMWH: Adjust dose in renal insufficiency.
  • Significant possible interactions
    • Agents that intensify the response to oral anticoagulants: alcohol, allopurinol, amiodarone, anabolic steroids, androgens, many antimicrobials, cimetidine, chloral hydrate, disulfiram, all NSAIDs, sulfinpyrazone, tamoxifen, thyroid hormone, vitamin E, ranitidine, salicylates, acetaminophen
    • Agents that diminish the response to oral anticoagulants: aminoglutethimide, antacids, barbiturates, carbamazepine, cholestyramine, diuretics, griseofulvin, rifampin, oral contraceptives
Second Line
Heparin 80 mg/kg IV bolus, followed by 18 mg/kg/hr; adjust dose depending on aPTT:
  • In patients requiring large daily doses of heparin, measure an anti-Xa level for dose guidance.
  • Alternatively, in outpatients, unfractionated heparin can be given at 333 units/kg then 250 units/kg SC, without monitoring (5)[C].
  • It does not alter plasma protein S concentration.
ISSUES FOR REFERRAL
  • Patients with suspected protein S deficiency should be seen by a hematologist.
  • Screening and prophylactic treatment of asymptomatic family members is not justified (7).
SURGERY/OTHER PROCEDURES
  • Anticoagulation must be held for surgical interventions.
  • For most patients with DVT, recommendations are against routine use of vena cava filter in addition to anticoagulation; IVC filter is only recommended in case of contraindication to anticoagulation (5)[A].
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
  • Life-threatening VT
  • Significant bleeding while on anticoagulant therapy
Nursing
Look for signs of bleeding while on anticoagulation therapy.
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • Warfarin requires periodic (monthly after initial stabilization) monitoring of the INR.
  • Periodic measurement of INR to maintain a range of 2 to 3.
  • LMWH is the treatment of choice in pregnancy. Periodic monitoring with anti-Xa levels is recommended in some cases, such as overweight and borderline renal failure.
DIET
Unrestricted
PATIENT EDUCATION
  • Patients should be educated about use of oral anticoagulant therapy if taking such.
  • Patients undergoing warfarin therapy should avoid drinking alcohol on a daily basis.
  • Avoid NSAIDs while on warfarin.
PROGNOSIS
  • Persons with protein S deficiency have normal lifespan.
  • By age 45 years, 50% of the people heterozygous for protein S deficiency will have VT; half will be spontaneous.
REFERENCES
1. Moll S. Thrombophilias—practical implications and testing caveats. J Thromb Thrombolysis. 2006;21(1):7-15.
2. Bick RL. Prothrombin G20210A mutation, antithrombin, heparin cofactor II, protein C, and protein S defects. Hematol Oncol Clin North Am. 2003;17(1):9-36.
3. Parand A, Zolghadri J, Nezam M, et al. Inherited thrombophilia and recurrent pregnancy loss. Iran Red Crescent Med J. 2013;15(12):e13708.
4. Langlois NJ, Wells PS. Risk of venous thromboembolism in relatives of symptomatic probands with thrombophilia: a systematic review. Thromb Haemost. 2003;90(1):17-26.
5. Guyatt GH, Akl EA, Crowther M, et al. Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2)(Suppl):7S-47S.
6. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799-808.
7. Hornsby LB, Armstrong EM, Bellone JM, et al. Thrombophilia screening. J Pharm Pract. 2014;27(3):253-259.
Codes
&NA;
ICD10
D68.59 Other primary thrombophilia
Clinical Pearls
&NA;
  • Asymptomatic patients with protein S deficiency do not require prophylactic anticoagulation because the risk of thrombosis is low; asymptomatic patients do not require anticoagulation (6).
  • Patients with protein S deficiency and DVT should be anticoagulated for at least 6 months, especially if first episode.