> Table of Contents > Prothrombin 20210 (Mutation)
Prothrombin 20210 (Mutation)
Dalia Hammoud, MD
Elie Chalhoub, MD
Maissaa Janbain, MD
image BASICS
DESCRIPTION
  • Prothrombin 20210 mutation is the second most common inherited risk factor for venous thromboembolism after factor V Leiden mutation.
  • Polymorphism (replacement of G by A) in the 3′ untranslated end of the prothrombin gene causes increased translation, resulting in elevated synthesis and secretion of prothrombin. This leads to a 2.8-fold increased risk for venous thrombosis.
  • Heterozygous carriers have 30% higher plasma prothrombin levels than normal
  • System(s) affected: cardiovascular; hemic/lymphatic/immunologic; nervous; pulmonary; reproductive
  • Synonym(s): prothrombin G20210A mutation; prothrombin G20210 gene polymorphism; prothrombin gene mutation; FII A20210 mutation
EPIDEMIOLOGY
  • Found largely in Caucasian population. Found in 2-5% of European and Middle Eastern population, but rarely in nonwhites. Found in 4-8% of persons with venous thromboembolism and in up to 18% of patients with recurrent thrombosis.
  • Predominant age: Mean age of first thrombosis is in the 2nd decade of life.
  • Predominant gender: male = female
Prevalence
3-5% of the population
ETIOLOGY AND PATHOPHYSIOLOGY
  • Replacement of G for A in the 3′ untranslated region of the prothrombin gene resulting in relatively higher plasma prothrombin activity, leading to increased risk for venous thrombosis.
  • Prothrombin Yukuhashi (Arg596Leu) was described in a Japanese thrombophilic family. The mutant prothrombin had moderately lower, but adequate, activity than wild-type prothrombin. The thrombin molecule generated is resistant to inactivation by antithrombin, thereby conferring an increased susceptibility to thrombosis.
  • Gene mutation
Genetics
Autosomal dominant
RISK FACTORS
  • Patients with prothrombin 20210 and another prothrombotic state, such as factor V Leiden, have increased rates of thrombosis (1).
  • The risk of venous thrombosis in patients with prothrombin 20210 mutation increases when added to the use of oral contraceptives, pregnancy, and the use of hormone replacement therapy as well as any status associated with prolonged immobilization (1).
Pregnancy Considerations
  • Increased thrombotic risk in patients with prothrombin 20210.
  • A new mutation C20209T has been described recently in women with recurrent pregnancy loss; the clinical and biochemical implications of this mutation are not fully understood yet (2).
GENERAL PREVENTION
Patients with prothrombin 20210 without thrombosis do not require prophylactic anticoagulation (3)[A], except for pregnant women with family history of venous thromboembolism, who require antepartum and 6-week postpartum prophylaxis with LMWH (4)[B].
COMMONLY ASSOCIATED CONDITIONS
Venous thromboembolism
image DIAGNOSIS
PHYSICAL EXAM
Arterial thrombosis is rare in adults with prothrombin 20210 gene mutation.
DIFFERENTIAL DIAGNOSIS
  • Factor V Leiden mutation
  • Protein C deficiency
  • Protein S deficiency
  • Antithrombin deficiency
  • Other causes of activated protein C resistance (e.g., antiphospholipid antibodies)
  • Dysfibrinogenemia
  • Dysplasminogenemia
  • Homocystinemia
  • Elevated factor VIII levels
DIAGNOSTIC TESTS & INTERPRETATION
Test patients with thrombosis at age <50 years, history of recurrent idiopathic thrombosis, those with thrombosis in unusual locations, or those with strong family history.
Initial Tests (lab, imaging)
  • For evaluation of a new clot in patients at risk: CBC with peripheral smear, PT/INR, aPTT, thrombin time, lupus anticoagulant, antiphospholipid antibodies, factor VIII, anticardiolipin antibody, anti-B2 glycoprotein I antibody, activated protein C resistance, protein S antigen and resistance, antithrombin III assay, fibrinogen, factor V Leiden, prothrombin G20210A, homocysteine
  • DNA analysis for mutation
  • Testing is reliable during acute thrombosis and on any kind of anticoagulation, as is gene analysis (4).
  • As appropriate for suspected site of thrombosis: US, CT scan, and V/Q scan
Follow-Up Tests & Special Considerations
Although prothrombin levels are elevated, this is not a sensitive test to make the diagnosis.
Diagnostic Procedures/Other
MR angiography (MRA), venography, or arteriography to detect thrombosis
Test Interpretation
Venous thrombus
image TREATMENT
For acute thrombosis
GENERAL MEASURES
  • Patients with prothrombin 20210 mutation and a first thrombosis should receive anticoagulation medication initially with heparin or LMWH (1)[A].
  • Treatment with LMWH is recommended over unfractionated heparin, unless the patient has severe renal failure (3)[A].
  • Treat as outpatient, if possible (3)[B].
  • Initiate warfarin on day 1 or 2 of LMWH therapy; discontinue LMWH after minimum of 5 days and 2 consecutive INRs >2 (3)[A].
  • Patients should be maintained on warfarin with an INR of 2 to 3 for at least 3 months (4)[A].
  • Recurrent thrombosis requires indefinite anticoagulation (1)[B].
MEDICATION
First Line
  • Low-molecular-weight heparin (LMWH) (3)[A]
    • Enoxaparin (Lovenox): 1 mg/kg SC BID; tinzaparin (Innohep): 175 anti-Xa IU/kg SC daily; dalteparin (Fragmin): 200 IU/kg SC daily
    • Initiate warfarin on day 1 or 2 of LMWH therapy; continue LMWH for a minimum of 5 days and 2 consecutive INRs >2
    • Fondaparinux (Arixtra): <50 kg: 5 mg SC daily; 50 to 100 kg: 7.5 mg SC daily; >100 kg: 10 mg SC daily
  • Oral anticoagulant
    • Warfarin (Coumadin) 5 mg PO daily; then adjusted to an INR of 2 to 3 (4)
  • P.867

  • Contraindications
    • Active bleeding precludes anticoagulation (3)[A].
    • Risk of bleeding is a relative contraindication to long-term anticoagulation (3)[A].
    • Warfarin is contraindicated in patients with history of warfarin skin necrosis (3)[A].
    • Fondaparinux: severe renal impairment (CrCl <30 mL/min)
  • Precautions
    • Observe patient for signs of embolization, further thrombosis, or bleeding.
    • Avoid IM injections. Periodically check stool and urine for occult blood; monitor CBCs, including platelets.
    • Heparins: thrombocytopenia
    • Warfarin: necrotic skin lesions (typically breasts, thighs, or buttocks)
    • LMWH: Adjust dosage 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 anticoagulants: aminoglutethimide, antacids, barbiturates, carbamazepine, cholestyramine, diuretics, griseofulvin, rifampin, oral contraceptives
Second Line
  • Heparin 80 mg/kg IV bolus followed by 18 g/kg/hr continuous infusion
  • Adjust dose, depending on aPTT.
  • In patients requiring large daily doses of heparin, measure an anti-Xa level for dose guidance.
  • Alternatively, unfractionated heparin can be given for outpatients at 333 U/kg then 250 U/kg SC (4)[A].
ISSUES FOR REFERRAL
  • Recurrent thrombosis on anticoagulation
  • Difficulty anticoagulating
  • Genetic counseling
SURGERY/OTHER PROCEDURES
  • Anticoagulation must be held for surgical interventions.
  • For most patients with deep venous thrombosis (DVT), recommendations are against routine use of vena cava filter in addition to anticoagulation, except in case with contraindication to anticoagulation (4)[A].
  • Thrombectomy may be necessary in some cases.
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
Complicated thrombosis, such as pulmonary embolus; heparin
Discharge Criteria
Stable on anticoagulation
image ONGOING CARE
Compression stockings for prevention
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • Warfarin use requires periodic (monthly after initial stabilization) INR measurements, with a goal of 2 to 3 (3)[A].
  • Heterozygous prothrombin 20210 mutations increase the risk for recurrent venous thromboembolism (VTE) only slightly once anticoagulation is stopped and should have the same length of anticoagulation as in someone without the mutation.
DIET
  • No restrictions
  • Food rich in vitamin K may interfere with warfarin anticoagulation.
PATIENT EDUCATION
  • Patients should be educated about:
    • Use of oral anticoagulant therapy.
    • Avoidance of NSAIDs while on warfarin
  • The role of family screening is unclear, as most patients with this mutation do not have thrombosis. In a patient with a family history of prothrombin 20210, consider screening during pregnancy or if considering oral contraceptive use.
PROGNOSIS
  • When compared with normal individuals, persons with prothrombin 20210 have normal lifespan.
  • Carriage of the PT20210 mutation has been linked to an increased rate of liver fibrosis in HCV patients (5).
REFERENCES
1. Girolami A, Simioni P, Scarano L, et al. Prothrombin and the prothrombin 20210 G to A polymorphism: their relationship with hypercoagulability and thrombosis. Blood Rev. 1999;13(4):205-210.
2. Prat M, Morales-Indiano C, Jimenez C, et al. “20209C-T” a variant mutation of prothrombin gene mutation in a patient with recurrent pregnancy loss. Ann Clin Lab Sci. 2014;44(3):334-336.
3. 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.
4. Moll S. Thrombophilias—practical implications and testing caveats. J Thromb Thrombolysis. 2006;21(1):7-15.
5. Maharshak N, Halfon P, Deutsch V, et al. Increased fibrosis progression rates in hepatitis C patients carrying the prothrombin G20210A mutation. World J Gastroenterol. 2011;17(45):5007-5013.
Additional Reading
&NA;
Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med. 2001;344(16): 1222-1231.
See Also
&NA;
Antithrombin Deficiency; Deep Vein Thrombophlebitis; Factor V Leiden; Protein C Deficiency; Protein S Deficiency
Codes
&NA;
ICD10
D68.52 Prothrombin gene mutation
Clinical Pearls
&NA;
  • Prothrombin 20210 mutation is the second most common inherited risk factor for VTE after factor V Leiden mutation.
  • Asymptomatic patients with prothrombin 20210 mutation do not need anticoagulation.
  • Testing for the prothrombin G20210 mutation may be done while the patient is anticoagulated, as it is a genetic assay.
  • For pregnant women homozygous for factor V Leiden, or heterozygous for factor V and prothrombin G20210 mutation, but no prior history of VTE, postpartum prophylaxis with prophylactic or intermediate-dose LMWH or vitamin K antagonists with target INR 2 to 3 for 6 weeks is recommended. Antepartum prophylaxis is added if there is positive family of VTE.