para>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 �
DIAGNOSIS
HISTORY
- Previous thrombosis
- Family history of thrombosis
- Family history of antithrombin deficiency
- Recurrent pregnancy loss
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 �
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 long-term anticoagulation
- 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 �
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.
COMPLICATIONS
Recurrent thrombosis (requires indefinite anticoagulation) �
REFERENCES
11 Lipe �B, Ornstein �DL. Deficiencies of natural anticoagulants, protein C, protein S, and antithrombin. Circulation. 2011;124(14):e365-e368.22 Maclean �PS, Tait �RC. Hereditary and acquired antithrombin deficiency: epidemiology, pathogenesis and treatment options. Drugs. 2007;67(10):1429-1440.33 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;5:233-241.44 Rodgers �GM. Role of antithrombin concentrate in treatment of hereditary antithrombin deficiency. An update. Thromb Haemost. 2009;101(5):806-812.55 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
ICD9
- 289.81 Primary hypercoagulable state
SNOMED
- 36351005 Antithrombin III deficiency (disorder)
- 439699000 hereditary antithrombin III deficiency (disorder)
- 439126002 Thrombophilia due to acquired antithrombin III deficiency
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.