ANTITHROMBIN DEFICIENCY

ANTITHROMBIN DEFICIENCY - Marc JeffreyKahn, MD
BASICS
DESCRIPTION
Antithrombin is a protease that inhibits thrombin by forming an irreversible complex. 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 venous thrombosis. Arterial thrombosis is much less common in patients deficient in antithrombin.
• System(s) Affected: Cardiovascular; Nervous; Pulmonary; Reproductive; Hemic/Lymphatic/ Immunologic
• Synonym(s): Antithrombin III deficiency
GENERAL PREVENTION
Patients with antithrombin deficiency without thrombosis do not require prophylactic treatment.
EPIDEMIOLOGY
• Predominant age: Mean age of 1st thrombosis is in the 2nd decade
• Predominant sex: Male = Female
Incidence
4% of patients with thrombophilia
Prevalence
0.16% of normal individuals
RISK FACTORS
• Oral contraceptives, pregnancy, 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 20210 mutation have increased rates of thrombosis.
ALERT
Pregnancy Considerations
Increases thrombotic risk in patients with antithrombin deficiency
Genetics
• Autosomal dominant.
• Heterozygotes have an odds ratio of venous thrombosis of 10-20.
ETIOLOGY
Many mutations in the antithrombin gene have been identified.
• Type I deficiency is characterized by low levels of antigen. Type II deficiency is found when the antithrombin molecule is dysfunctional.
• 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.

DIAGNOSIS
SIGNS AND SYMPTOMS
• Deep or superficial venous thrombosis
• Recurrence rate of thrombosis is 12-17% per year.
TESTS
Lab
• Antithrombin levels in the presence of heparin
• Anti-thrombin-heparin cofactor assay
• Drugs that may alter lab results: Heparin and asparaginase can lower antithrombin levels.
• Disorders that may alter lab results
- Liver disease, DIC, nephritic syndrome, and preeclampsia reduce antithrombin levels.
- Acute thrombosis can lower antithrombin levels.
DIFFERENTIAL DIAGNOSIS
• Factor V Leiden
• Protein C deficiency
• Protein S deficiency
• Dysfibrinogenemia
• Dysplasminogenemia
• Homocysteinemia
• Prothrombin 20210 mutation
• Elevated factor VIII levels
TREATMENT
STABILIZATION
Outpatient
GENERAL MEASURES
• Routine anticoagulation for asymptomatic patients with antithrombin deficiency is not recommended. (1)[A]
• Patients with antithrombin deficiency and a 1st thrombosis should be anticoagulated initially with unfractionated heparin followed by oral anticoagulation with warfarin. (1)[A]
• The role of family screening for antithrombin deficiency is unclear, because most patients with this mutation do not have thrombosis. Screening may be considered for women considering using oral contraceptives or for pregnant women with a family history of factor protein S deficiency. (1)[C]
Diet
No restrictions
Activity
No restrictions
MEDICATION (DRUGS)
First Line
• Heparin initial bolus of 80 U/kg followed by infusion of 18 U/kg/h. Frequent monitoring of the PTT is important as nearly 1/2 of patients deficient in antithrombin require more than 40,000 U of heparin daily to adequately prolong the PTT. (1)[C] After the INR is 2-3, heparin can be stopped after 5 total days of therapy. (1)[A]
• Oral anticoagulant following the initial administration of heparin. Warfarin (Coumadin) 5 mg PO per day and adjusted to INR of 2-3. Patients should be maintained on warfarin for at least 6 months. (1)[A]
• Recurrent thrombosis requires indefinite anticoagulation. (1)[A]
• 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-thrombocytopenia and/or paradoxical thrombosis with thrombocytopenia
• 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, and oral contraceptives
Second Line
• Argatroban 0.4-0.5 mcg/kg/min. Case reports describing the use of the direct thrombin inhibitor in patients with antithrombin deficiency have been published. (2)[C]
• Antithrombin III (ATnativ, Thrombate III) 50-100 IU/min IV titrated to antithrombin level desired. Precise role in therapy remains unclear. (1)[C]
• LMWH is difficult to manage in this population. (1)[C]
FOLLOW-UP
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.
COMPLICATIONS
Recurrent thrombosis (requires indefinite anticoagulation)
PATIENT MONITORING
Warfarin requires periodic (monthly after initial stabilization) monitoring of the INR.
REFERENCES
1. Vinazzer H. Hereditary and acquired antithrombin deficiency. Semin Thromb Hemost. 1999;25(3): 257-263.
2. Dager WE, Gosselin RC, Owings JT. Argatroban therapy for antithrombin deficiency and mesenteric thrombosis: Case report and review of the literature. Pharmacotherapy. 2004;24(5): 659-663.
3. Kottke-Marchant K, Duncan A. Antithrombin deficiency: Issues in laboratory diagnosis. Arch Pathol Lab Med. 2002;126(11):1326-1336.
MISCELLANEOUS
See also: Thrombosis; Deep Vein (DVT); Protein C Deficiency; Protein S Deficiency; Prothrombin 20210 (Mutation); Factor V Leiden