> Table of Contents > Antithrombin Deficiency
Antithrombin Deficiency
Ryan Wargo, PharmD, BCACP
Michelle I. Henne, MD
Holly L. Baab, MD
image BASICS
DESCRIPTION
  • Antithrombin is a glycoprotein that inhibits thrombin by forming an irreversible complex.
  • There are two active sites: one that binds to heparin and one that binds to thrombin/target enzyme
  • Antithrombin can also inhibit factors Xa, IXa, and XIa. This process is catalyzed by the presence of heparin.
  • Patients deficient in antithrombin have an increased incidence of venous thrombosis, including deep vein thrombosis (DVT) of the lower extremity. Arterial thrombosis is much less common in patients deficient in antithrombin.
  • System(s) affected: cardiovascular, nervous, pulmonary, reproductive, hematologic, lymphatic/immunologic hemic/lymphatic/immunologic
  • Synonym(s): antithrombin III deficiency
EPIDEMIOLOGY
  • Predominant age: Mean age of 1st thrombosis is in 2nd decade, usually after puberty.
  • Predominant sex: male = female
  • No racial or ethnic predisposition
Incidence
1/20 to 1/200 with thrombophilia (1)
Prevalence
1/2,000 to 1/5,000 of normal individuals (1)
ETIOLOGY AND PATHOPHYSIOLOGY
  • Hereditary deficiency (2)
    • Type I deficiency is characterized by low levels of antigen (decreased synthesis). Plasma levels of antithrombin are often <50%.
    • Type II deficiency is found when the antithrombin molecule is dysfunctional (decreased function).
    • Type II deficiencies are due to mutations in either the active center of antithrombin that binds the target enzyme or the heparin-binding site.
    • No patients homozygous for defects in the active center have been described, suggesting that this is a lethal condition. Patients heterozygous for mutations in the heparin-binding site rarely have thrombotic episodes.
  • Acquired deficiency (2)
    • Many clinical conditions are associated with antithrombin deficiency, such as those listed under “Follow-Up Tests & Special Considerations," but limited evidence suggests these deficiencies contribute to increased thrombosis.
Genetics
Autosomal dominant with variable clinical penetrance
RISK FACTORS
  • Oral contraceptives, pregnancy, surgery, trauma, and the use of hormone replacement therapy (HRT) increase the risk of venous thrombosis in patients with antithrombin deficiency.
  • Patients with antithrombin deficiency and another prothrombotic state, such as factor V Leiden or the prothrombin G20210A mutation, have increased rates of thrombosis.
Pregnancy Considerations
Increased thrombotic risk from 18% to 70% and specific complications may include preeclampsia, eclampsia, placental abruption, HELLP, premature birth, and recurrent pregnancy loss (3).
GENERAL PREVENTION
Patients with antithrombin deficiency without a history of thrombosis do not require prophylactic treatment.
COMMONLY ASSOCIATED CONDITIONS
Venous thromboembolism
image DIAGNOSIS
PHYSICAL EXAM
Signs consistent with a deep or superficial venous thrombosis or pulmonary embolism
DIFFERENTIAL DIAGNOSIS
  • Factor V Leiden
  • Protein C deficiency
  • Protein S deficiency
  • Dysfibrinogenemia
  • Dysplasminogenemia
  • Homocystinemia
  • Prothrombin G20210A mutation
  • Elevated factor VIII levels
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • For evaluation of a new clot in a patient at risk: CBC with peripheral smear, PT/INR, aPTT, thrombin time, lupus anticoagulant, antiphospholipid antibodies, factor VIII, anticardiolipin antibody, anti-B2 glycoprotein antibody, activated protein C resistance, protein S antigen and resistance, antithrombin III assay, fibrinogen, factor V Leiden, prothrombin G20210A, homocysteine
  • Testing should be done off heparin and at least 2 weeks after the 3 to 6 months course of oral anticoagulation.
  • Another test to consider in the workup of antithrombin deficiency:
    • Antithrombin-heparin cofactor assay measures the ability of heparin to bind to antithrombin, which neutralizes the action of thrombin and factor Xa. This is an indirect measure of factor Xa and thrombin inhibition; the factor Xa inhibition activity being more specific. This assay will detect all currently recognized subtypes of hereditary antithrombin deficiency.
  • Drugs that may alter lab results: heparin (increased clearance), estrogen, and L-asparaginase (decreased synthesis) can lower antithrombin levels.
Follow-Up Tests & Special Considerations
  • The role of family screening for antithrombin deficiency is unclear because most patients with this mutation do not have thrombosis. Screening may be offered to pregnant women with a family history of factor protein S deficiency considering using oral contraceptives or pregnancy.
  • Antithrombin levels are low in:
    • DIC
    • Sepsis
    • Burns
    • Severe trauma
    • Acute thrombosis
    • Pregnancy or postpartum
    • Liver disease
    • Nephrotic syndrome
    • Malignancy
    • Myeloproliferative disorders
  • Antithrombin levels could be elevated by oral contraceptive pills.
  • US to diagnose DVT if clinically indicated
  • If DVT diagnosis in question, a negative D-dimer will help to rule out DVT.
  • Spiral CT or V/Q scan to diagnose pulmonary embolism (PE) if clinically indicated
  • V/Q scan may be difficult to interpret in patients with other lung disease.
Test Interpretation
Venous thrombosis
image TREATMENT
GENERAL MEASURES
Routine anticoagulation for asymptomatic patients with antithrombin deficiency is not recommended (3,4)[C].
MEDICATION
First Line
  • Patients with antithrombin deficiency and a first thrombosis should be anticoagulated initially with unfractionated heparin followed by oral anticoagulation with warfarin (5)[C].
  • Heparin can be stopped after 5 total days of therapy provided the INR is 2 to 3 (5)[C].
  • Oral anticoagulant should be started with the initial administration of heparin. Warfarin (Coumadin) 10 mg/day PO for the first 2 days, then adjusted to INR of 2 to 3. Patients should be maintained on warfarin for at least 6 months (5)[C].
  • Recurrent thrombosis requires indefinite anticoagulation.
  • Contraindications:
    • Active bleeding precludes anticoagulation; risk of bleeding is a relative contraindication to longterm anticoagulation.
  • P.67

  • Precautions:
    • Observe patient for signs of embolization, further thrombosis, or bleeding.
    • Avoid IM injections.
    • Periodically check stool and urine for occult blood and monitor CBCs, including platelets.
    • Heparin-induced thrombocytopenia and/or paradoxical thrombosis with thrombocytopenia
  • Significant possible interactions:
    • Agents that intensify the response to oral anticoagulants: Common anti-infective agents that potentially increase the effect of warfarin include ciprofloxacin, clarithromycin, erythromycin, metronidazole, trimethoprim-sulfamethoxazole, and azole antifungals. Additional interacting agents include alcohol, allopurinol, amiodarone, anabolic steroids, androgens, cimetidine, chloral hydrate, disulfiram, all NSAIDs, sulfinpyrazone, tamoxifen, thyroid hormone, vitamin E, ranitidine, salicylates, and acetaminophen
    • Agents that diminish the response to oral anticoagulants: aminoglutethimide, antacids, barbiturates, carbamazepine, cholestyramine, diuretics, griseofulvin, rifampin, oral contraceptives
    • See “Diet.”
Second Line
  • Argatroban: 0.4 to 0.5 µg/kg/min. Case reports describing the use of this direct thrombin inhibitor in patients with antithrombin deficiency have been published (5)[C].
  • Antithrombin III (ATnativ, Thrombate III): 50 to 100 IU/min IV titrated to antithrombin level desired. Precise role in therapy remains unclear (5)[C].
  • Low-molecular-weight heparin (LMWH) is difficult to manage in this population but is preferred during pregnancy (3,5)[C].
ISSUES FOR REFERRAL
  • Recurrent thrombosis on anticoagulation
  • Difficulty anticoagulating
  • Genetic counseling
ADDITIONAL TREATMENT
  • Patients with severe antithrombin deficiency may require plasma replacement of thrombin in order for heparin to be effective.
  • Compression stockings for prevention
SURGERY/OTHER PROCEDURES
Thrombectomy may be indicated in complicated cases.
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
Complicated thrombosis, such as PE. Heparin initial bolus of 80 U/kg followed by infusion of 18 U/kg/hr. Frequent monitoring of the partial thromboplastin time (PTT) is important, as ˜50% of patients deficient in antithrombin require >40,000 U of heparin daily to adequately prolong PTT.
Discharge Criteria
Stable on anticoagulation
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
Warfarin use requires periodic INR measurements (monthly after initial stabilization) with a goal of 2 to 3.
DIET
Foods high in vitamin K may interfere with anticoagulation on warfarin. Consider nutrition consultation.
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 factor V Leiden, consider screening during pregnancy or if considering oral contraceptive use.
PROGNOSIS
  • The odds ratio of thrombosis in a patient with antithrombin deficiency is much higher than in patients with other thrombophilic conditions. The recurrence rate is similarly high.
  • There is no difference in clinical severity between patients with type I defects and type II mutations.
  • Overall, prognosis is good, if appropriately anticoagulated.
REFERENCES
1. Lipe B, Ornstein DL. Deficiencies of natural anticoagulants, protein C, protein S, and antithrombin. Circulation. 2011;124(14):e365-e368.
2. Maclean PS, Tait RC. Hereditary and acquired antithrombin deficiency: epidemiology, pathogenesis and treatment options. Drugs. 2007;67(10): 1429-1440.
3. James AH, Konkle BA, Bauer KA. Prevention and treatment of venous thromboembolism in pregnancy in patients with hereditary antithrombin deficiency. Int J Womens Health. 2013;5:233-241.
4. Rodgers GM. Role of antithrombin concentrate in treatment of hereditary antithrombin deficiency. An update. Thromb Haemost. 2009;101(5):806-812.
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.
Additional Reading
De Stefano V, Rossi E. Testing for inherited thrombophilia and consequences for antithrombotic prophylaxis in patients with venous thromboembolism and their relatives. A review of the guidelines from Scientific Societies and Working Groups. Thromb Haemost. 2013;110(4):697-705.
See Also
Deep Vein Thrombophlebitis
Codes
ICD10
D68.59 Other primary thrombophilia
Clinical Pearls
  • Antithrombin levels will be low on heparin and during acute thrombosis.
  • Diagnosis can be difficult. Conditions causing low levels of antithrombin III, such as pregnancy, liver disease, sepsis, and DIC, must be ruled out.
  • Testing should be done off heparin and at least 2 weeks after the 3 to 6 months course of oral anticoagulation.
  • For pregnant women with antithrombin deficiency but no prior history of VTE, antepartum and postpartum vigilance are recommended. Postpartum prophylaxis with prophylactic or intermediate-dose LMWH or vitamin K antagonists with target INR 2 to 3 for 6 weeks is only recommended if there is positive family history of VTE.