> Table of Contents > Protein C Deficiency
Protein C Deficiency
Elie Chalhoub, MD
Dalia Hammoud, MD
Maissaa Janbain, MD
image BASICS
DESCRIPTION
  • Protein C is a vitamin K-dependent factor made by the liver that becomes activated when thrombin binds to the endothelial receptor thrombomodulin.
  • Activated protein C, with protein S as a cofactor, inactivates factors Va and VIIIa.
  • Patients with protein C deficiency have a thrombotic disorder that primarily affects the venous system but can also affect the arterial system.
  • System(s) affected: cardiovascular, hemic/lymphatic/immunologic, pulmonary
EPIDEMIOLOGY
Prevalence
  • 0.3% of normal individuals
  • 4-5% of persons with venous thrombosis (VT)
  • Predominant age: Mean age of first thrombosis is 45 years.
  • Predominant sex: male = female
ETIOLOGY AND PATHOPHYSIOLOGY
  • Polymorphisms in the promoter region of the protein C gene can affect antigen levels. At least 150 mutations have been described in the protein C gene that can lead to functional deficiency.
  • New mutations have been described associated with late-onset cerebral thrombosis (1).
  • Acquired protein C deficiency can occur with liver disease, ARDS, DIC, chemotherapy with L-asparaginase, 5-FU, methotrexate, and cyclophosphamide, as well as postoperative state and severe infections, especially meningococcemia. Also, rare patients can develop inhibitors to activated protein C. Neonates have lower levels of protein C than adults.
Genetics
Patients heterozygous for protein C deficiency who start warfarin without concomitant heparin can develop warfarin-induced skin necrosis because the half-life of other vitamin K-dependent clotting factors, prothrombin, factor IX, and factor X is much longer than that of protein C (4 to 8 hours). These patients develop extremely low levels of protein C and sub-sequently increased thrombin generation, leading to necrosis of the skin over central areas of the body such as the breast, abdomen, buttocks, and genitalia (2)[A].
GENERAL PREVENTION
Because protein C deficiency is a congenital disease, there are no preventive measures.
COMMONLY ASSOCIATED CONDITIONS
  • Deep and superficial venous thrombosis, often spontaneous
  • Up to 50% of homozygotes will have thrombosis.
  • Homozygosity is associated with catastrophic thrombotic complications at birth (e.g., purpura fulminans).
  • Sites of thrombosis can be unusual, including the mesentery and cerebral veins, especially when combined with other risk factors such as oral contraceptives.
  • Arterial thrombosis is rare.
  • Skin necrosis can be seen in patients on warfarin.
  • Recurrent pregnancy losses
image DIAGNOSIS
HISTORY
  • VT at <40 years of age without another etiology
  • Thrombosis in unusual locations (e.g., mesentery, sagittal sinus, portal vein)
  • Family history of thrombosis or spontaneous abortion
PHYSICAL EXAM
Normal
DIFFERENTIAL DIAGNOSIS
  • Factor V Leiden (causes resistance to activated protein C, not a deficiency of protein C)
  • Protein S deficiency
  • Antithrombin deficiency
  • Dysfibrinogenemia
  • Dysplasminogenemia
  • Homocystinemia
  • Prothrombin 20210 mutation
  • Elevated factor VIII levels
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • For evaluation of new clot in patient at risk (see “History”): 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 C activity assay using a snake venom protease to activate protein C
  • Immunoassay for quantitative assessment of protein C level
  • Drugs that may alter lab results
    • Oral contraceptives can raise protein C levels.
    • Warfarin reduces protein C levels.
    • Patients should be off warfarin for 2 to 3 weeks before reliable testing (3)[C].
  • Disorders that may alter lab results
    • Liver disease reduces protein C levels.
image TREATMENT
Treat active thrombosis; follow-up.
GENERAL MEASURES
  • Routine anticoagulation for asymptomatic patients with protein C deficiency is not recommended (2)[A].
  • Anticoagulation for 6 to 12 months is recommended for patients with protein C deficiency and a first thrombosis.
  • Some argue for lifetime anticoagulation; data are limited.
  • Anticoagulation for life is indicated for patients with protein C deficiency and recurrent thromboses.
  • The role of family screening for protein C deficiency is unclear because most patients with this mutation do not have thrombosis. Screening should be considered for women considering using oral contraceptives or pregnancy and who have a family history of protein C deficiency (4)[B].
  • Treatment 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 minimum of 5 days and two consecutive INRs >2 (5)[A].
  • For pregnant women with no prior history of venous thromboembolism (VTE), we suggest antepartum and postpartum clinical vigilance. Postpartum prophylaxis for 6 weeks with prophylactic- or intermediate-dose LMWH is reserved only for patients with positive family history of VTE (3)[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
    • Enoxaparin (Lovenox) 1 mg/kg SC BID or enoxaparin 1.5 mg/kg/day SC
    • Tinzaparin (Innohep): 175 anti-Xa IU/kg/day SC
    • Dalteparin (Fragmin) 200 U/kg/day
  • Factor Xa inhibitors
    • 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
  • P.861

  • Oral vitamin K antagonist: warfarin (Coumadin), per the most recent chest guidelines, 5mg/day PO then adjusted to an INR of 2 to 3 for at least 3 to 6 months (2)[A],(5)
  • Novel oral anticoagulants (NOACs):
    • 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 QD
    • Apixaban 10 mg PO BID for 7 days then 5 mg PO BID
    • Edoxaban 60 mg PO QD (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 PPT.
  • In patients requiring large daily doses of heparin, measure an anti-Xa level for dose guidance.
  • Alternatively, and for outpatients, unfractionated heparin can be given at 333 U/kg then 250 U/kg SC, without monitoring (5)[C].
ISSUES FOR REFERRAL
Patients with suspected protein C deficiency should be seen by a hematologist.
However, screening and therefore prophylactic treatment of asymptomatic family members is not justified (6).
SURGERY/OTHER PROCEDURES
  • Anticoagulation must be held for surgical interventions.
  • In patients with acute proximal DVT of the leg and an absolute contraindication to anticoagulation, inferior vena cava (IVC) filters are recommended; otherwise, the use of an IVC filter in addition to anticoagulants is not recommended in most patients with acute DVT of the leg (2)[B],(5).
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 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 these patients.
DIET
Unrestricted (except if on warfarin—avoid food with significant amounts of vitamin K)
PATIENT EDUCATION
  • Patients should be educated about the use of oral anticoagulant therapy if taking such.
  • Avoid NSAIDs while on warfarin.
  • Avoid OCPs, as they increase risk of thrombosis.
PROGNOSIS
  • When compared with normal individuals, persons with protein C deficiency have normal life spans.
  • By age 45 years, 50% of the people heterozygous for protein C deficiency will have VT; half will be spontaneous.
REFERENCES
1. Yang LH, Wang MS, Zheng FX, et al. Different impact of two mutations of a novel compound heterozygous protein C deficiency with late onset thrombosis. Genet Mol Res. 2014;13(2):2969-2977.
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. Moll S. Thrombophilias—practical implications and testing caveats. J Thromb Thrombolysis. 2006;21(1):7-15.
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(Suppl 2):7S-47S.
6. 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 C deficiency do not need prophylactic anticoagulation because the risk of thrombosis is low (6).
  • Patients with protein C deficiency who have DVT should be anticoagulated for at least 6 months.