eMedicine Specialties > Hematology > Coagulation, Hemostasis, and Disorders

Antithrombin Deficiency: Follow-up

Author: Arun Rajan, MD, Clinical Fellow, Medical Oncology Branch, National Cancer Institute/National Institutes of Health
Coauthor(s): Sara J Grethlein, MD, Associate Dean for Graduate Medical Education, Professor, Department of Internal Medicine, Division of Hematology and Oncology, State University of New York Upstate Medical University; Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Contributor Information and Disclosures

Updated: Oct 4, 2009

Follow-up

Further Inpatient Care

  • Treatment of the acute thrombotic event in patients with antithrombin deficiency (AT deficiency) has traditionally been accomplished with intravenous heparin supplemented by antithrombin. With the availability of direct thrombin inhibitors, which do not require antithrombin for their action, a whole new therapeutic arena has opened for these patients.
  • Therapy of the acute thromboembolic event must be followed by the lifelong administration of an oral anticoagulant (vitamin K antagonists) to maintain anticoagulation in the therapeutic range at all times for patients with inherited antithrombin deficiency (AT deficiency) and thrombosis.
  • Discontinuation of oral anticoagulants should be undertaken with great caution and only for essential procedures because of the risk of recurrent thromboembolic events. Replacement with antithrombin concentrate may be needed during such times.

Further Outpatient Care

  • Long-term administration of therapeutic oral outpatient anticoagulants is effective in preventing recurrent thromboembolic episodes in patients with proven antithrombin deficiency (AT deficiency) and an index thromboembolic event. As long as the patient's international normalized ratio (INR) is therapeutic at all times (the authors prefer INRs in the 2.6-3.2 range, using a sensitive thromboplastin), patients do very well.
  • Management of bridge therapy when necessary to discontinue warfarin sodium poses a real problem at this time, as heparin and LMWHs are the only currently available choices. The possible use of subcutaneous hirudin is complicated by antibody formation to the compound. No data are available on the utility of subcutaneous argatroban.
  • Prophylactic care: When oral anticoagulants are temporarily discontinued for a surgical procedure, an alternative method of prophylaxis should be considered. Currently, a non – antithrombin-dependent agent is unavailable. Most physicians use heparin or LMWH despite their expected limitation.

Inpatient & Outpatient Medications

  • Drug and diet interactions are a major problem with vitamin K antagonists.

Transfer

  • Lack of availability of adequate support from a knowledgeable hematologist may require that the patient with antithrombin deficiency (AT deficiency) be transferred to an appropriate facility.

Deterrence/Prevention

  • Identification of the specific mutation in a family with antithrombin deficiency (AT deficiency) may allow a mother to undergo prenatal testing if she or her spouse is affected, using techniques well established for people with hemophilia, but only after the patient fully comprehends the implications and complications of such testing.
  • Patients with an inherited deficiency require lifelong oral anticoagulants to prevent recurrent thrombotic complications.

Complications

  • Serious long-term morbidity can result from the following issues:
    • Venous and arterial thromboembolic events
    • Postphlebitic syndrome due to extensive DVT as the first event
    • Recurrent VTE due to the discontinuation of oral anticoagulants
    • Sudden death due to the lack of prophylaxis in high-risk circumstances
    • Atypical site thrombosis such as Budd-Chiari syndrome
    • Bowel ischemia due to mesenteric vein thrombosis
  • Hepatitis viruses, HIV, acquired immunodeficiency syndrome (AIDS), parvovirus, and prion-induced diseases that are transmitted from blood products can lead to morbidity and mortality.
  • A review by Senior focused attention on concerns about transmission of CJD or nvCJD from blood products.45 The FDA's Transmissible Spongiform Encephalopathies Advisory Committee (TSEAC) proposed limiting donors and excluding those who had resided or traveled in Europe for 5 years starting in 1980 or those who had lived in the United Kingdom for a total of more than 3 months. The availability of new tests to detect nvCJD are also anticipated.

Prognosis

  • The prognosis depends on the sites and types of complications that patients with inherited antithrombin deficiency (AT deficiency) have. Women have the added risks of pregnancy or estrogen use as an early precipitating factor for thrombotic events.
  • The prognosis with acquired causes of antithrombin deficiency depends on the underlying disease.

Patient Education

  • Educate patients with antithrombin deficiency (AT deficiency) on a continuing basis, and encourage them to seek appropriate information on the Internet, both for the underlying predisposition and the pitfalls of long-term oral vitamin K antagonist therapy. Genetic testing requires consent from the family because of its many implications.

Miscellaneous

Medicolegal Pitfalls

  • Estrogens are contraindicated in a patient with antithrombin deficiency (AT deficiency) and thrombosis.
  • Patients need to know the risks of the use of plasma-derived concentrates.
  • Repeated heparin exposure may increase the risk of heparin-induced thrombocytopenia and thrombosis syndromes (HIT/HITTS) in these patients.
  • Long-term oral anticoagulant use is associated with an increased risk of bleeding due to the potential for drug-drug or drug-diet interactions. The availability of numerous over-the-counter (OTC) medications increases this risk. Inadequate anticoagulation increases the risk for recurrent thrombotic events. Patients must not be started on oral anticoagulants in the absence of simultaneous, full anticoagulant coverage with heparin or another appropriate thrombin inhibitor.

Special Concerns

  • Inherited antithrombin deficiency can be passed to the next generation; identification of the defect in the young may lead to denial of insurance coverage despite variable laws prohibiting such action. Regardless of the anxiety that identification of a defect may engender in the parents and patient, early identification of the defect allows the pediatrician to provide adequate prophylaxis during high-risk, hypercoagulable states.
  • Pregnancy must be avoided when a female is taking oral anticoagulants because of the teratogenic effects of vitamin K antagonists.
  • Patients treated with plasma-derived products require long-term follow-up care.
 


More on Antithrombin Deficiency

Overview: Antithrombin Deficiency
Differential Diagnoses & Workup: Antithrombin Deficiency
Treatment & Medication: Antithrombin Deficiency
Follow-up: Antithrombin Deficiency
Multimedia: Antithrombin Deficiency
References
Further Reading
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References

  1. Irving JA, Pike RN, Lesk AM, Whisstock JC. Phylogeny of the serpin superfamily: implications of patterns of amino acid conservation for structure and function. Genome Res. Dec 2000;10(12):1845-64. [Medline]. [Full Text].

  2. Irving JA, Steenbakkers PJ, Lesk AM, et al. Serpins in prokaryotes. Mol Biol Evol. Nov 2002;19(11):1881-90. [Medline]. [Full Text].

  3. Olds RJ, Lane DA, Mille B, Chowdhury V, Thein SL. Antithrombin: the principal inhibitor of thrombin. Semin Thromb Hemost. 1994;20(4):353-72. [Medline].

  4. Rosenberg JS, McKenna PW, Rosenberg RD. Inhibition of human factor IXa by human antithrombin. J Biol Chem. Dec 10 1975;250(23):8883-8. [Medline]. [Full Text].

  5. Stead N, Kaplan AP, Rosenberg RD. Inhibition of activated factor XII by antithrombin-heparin cofactor. J Biol Chem. Nov 10 1976;251(21):6481-8. [Medline]. [Full Text].

  6. Rao LV, Nordfang O, Hoang AD, Pendurthi UR. Mechanism of antithrombin III inhibition of factor VIIa/tissue factor activity on cell surfaces. Comparison with tissue factor pathway inhibitor/factor Xa-induced inhibition of factor VIIa/tissue factor activity. Blood. Jan 1 1995;85(1):121-9. [Medline]. [Full Text].

  7. Okajima K, Uchiba M. The anti-inflammatory properties of antithrombin III: new therapeutic implications. Semin Thromb Hemost. 1998;24(1):27-32. [Medline].

  8. Yamashiro K, Kiryu J, Tsujikawa A, et al. Inhibitory effects of antithrombin III against leukocyte rolling and infiltration during endotoxin-induced uveitis in rats. Invest Ophthalmol Vis Sci. Jun 2001;42(7):1553-60. [Medline]. [Full Text].

  9. Dunzendorfer S, Kaneider N, Rabensteiner A, et al. Cell-surface heparan sulfate proteoglycan-mediated regulation of human neutrophil migration by the serpin antithrombin III. Blood. Feb 15 2001;97(4):1079-85. [Medline]. [Full Text].

  10. Foy P, Moll S. Thrombophilia: 2009 update. Curr Treat Options Cardiovasc Med. Apr 2009;11(2):114-28. [Medline].

  11. Egeberg O. Inherited antithrombin deficiency causing thrombophilia. Thromb Diath Haemorrh. Jun 15 1965;13:516-30. [Medline].

  12. Abildgaard U. Antithrombin--early prophecies and present challenges. Thromb Haemost. Jul 2007;98(1):97-104. [Medline]. [Full Text].

  13. Picard V, Nowak-Gottl U, Biron-Andreani C, et al. Molecular bases of antithrombin deficiency: twenty-two novel mutations in the antithrombin gene. Hum Mutat. Jun 2006;27(6):600. [Medline]. [Full Text].

  14. Steiner M, Steiner B, Rolfs A, et al. Antithrombin gene mutation 5356-5364*delCTT with type I deficiency and early-onset thrombophilia and a brief review of the antithrombin alpha-helix D molecular pathology. Ann Hematol. Jan 2005;84(1):56-8. [Medline].

  15. Wang WB, Fu QH, Ding QL, et al. Characterization of molecular defect of 13387-9delG mutated antithrombin in inherited type I antithrombin deficiency. Blood Coagul Fibrinolysis. Mar 2005;16(2):149-55. [Medline].

  16. Patnaik MM, Moll S. Inherited antithrombin deficiency: a review. Haemophilia. Nov 2008;14(6):1229-39. [Medline].

  17. Lijfering WM, Brouwer JL, Veeger NJ, Bank I, Coppens M, Middeldorp S, et al. Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives. Blood. May 21 2009;113(21):5314-22. [Medline].

  18. Picard V, Chen JM, Tardy B, Aillaud MF, Boiteux-Vergnes C, Dreyfus M, et al. Detection and characterisation of large SERPINC1 deletions in type I inherited antithrombin deficiency. Hum Genet. Sep 17 2009;[Medline].

  19. Huntington JA, Read RJ, Carrell RW. Structure of a serpin-protease complex shows inhibition by deformation. Nature. Oct 19 2000;407(6806):923-6. [Medline].

  20. van Boven HH, Lane DA. Antithrombin and its inherited deficiency states. Semin Hematol. Jul 1997;34(3):188-204. [Medline].

  21. Maclean PS, Tait RC. Hereditary and acquired antithrombin deficiency: epidemiology, pathogenesis and treatment options. Drugs. 2007;67(10):1429-40. [Medline].

  22. Undas A, Brummel K, Musial J, Mann KG, Szczeklik A. Blood coagulation at the site of microvascular injury: effects of low-dose aspirin. Blood. Oct 15 2001;98(8):2423-31. [Medline]. [Full Text].

  23. Roemisch J, Gray E, Hoffmann JN, Wiedermann CJ. Antithrombin: a new look at the actions of a serine protease inhibitor. Blood Coagul Fibrinolysis. Dec 2002;13(8):657-70. [Medline].

  24. van Boven HH, Vandenbroucke JP, Briët E, Rosendaal FR. Gene-gene and gene-environment interactions determine risk of thrombosis in families with inherited antithrombin deficiency. Blood. Oct 15 1999;94(8):2590-4. [Medline]. [Full Text].

  25. Bayston T, Lane D, for the Plasma Coagulation Inhibitors Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Antithrombin mutation database. Imperial College London. Available at http://www1.imperial.ac.uk/medicine/about/divisions/is/haemo/coag/antithrombin/. Accessed December 12, 2008.

  26. Wickstrom K, Edelstam G, Lowbeer CH, Hansson LO, Siegbahn A. Reference intervals for plasma levels of fibronectin, von Willebrand factor, free protein S and antithrombin during third-trimester pregnancy. Scand J Clin Lab Invest. 2004;64(1):31-40. [Medline].

  27. Morikawa M, Yamada T, Kataoka S, et al. Changes in antithrombin activity and platelet counts in the late stage of twin and triplet pregnancies. Semin Thromb Hemost. Jun 2005;31(3):290-6. [Medline].

  28. D'Uva M, Di Micco P, Strina I, Ranieri A, Alviggi C, Mollo A, et al. Etiology of hypercoagulable state in women with recurrent fetal loss without other causes of miscarriage from Southern Italy: new clinical target for antithrombotic therapy. Biologics. Dec 2008;2(4):897-902. [Medline].

  29. Hara T, Naito K. Inherited antithrombin deficiency and end stage renal disease. Med Sci Monit. Nov 2005;11(11):RA346-54. [Medline].

  30. Bushman JE, Palmieri D, Whinna HC, Church FC. Insight into the mechanism of asparaginase-induced depletion of antithrombin III in treatment of childhood acute lymphoblastic leukemia. Leuk Res. Jul 2000;24(7):559-65. [Medline].

  31. McColl M, Tait RC, Walker ID, et al. Low thrombosis rate seen in blood donors and their relatives with inherited deficiencies of antithrombin and protein C: correlation with type of defect, family history, and absence of the factor V Leiden mutation. Blood Coagul Fibrinolysis. Oct 1996;7(7):689-94. [Medline].

  32. Martinelli I, Mannucci PM, De Stefano V, et al. Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families. Blood. Oct 1 1998;92(7):2353-8. [Medline]. [Full Text].

  33. Tait RC, Walker ID, Perry DJ et al. Prevalence of antithrombin III deficiency subtypes in 4000 healthy blood donors [abstract]. Thromb Haemost. 1991;65:839.

  34. Kurihara M, Watanabe K, Inoue S, et al. Characterization of two novel mutations of the antithrombin gene observed in Japanese thrombophilic patients. Thromb Res. 2005;115(5):351-8. [Medline].

  35. Roozendaal B, Schoorlemmer GH, Wiersma A, et al. Opposite effects of central amygdaloid vasopressin and oxytocin on the regulation of conditioned stress responses in male rats. Ann N Y Acad Sci. Jun 12 1992;652:460-1. [Medline].

  36. Alvi AR, Khan S, Niazi SK, Ghulam M, Bibi S. Acute mesenteric venous thrombosis: improved outcome with early diagnosis and prompt anticoagulation therapy. Int J Surg. Jun 2009;7(3):210-3. [Medline].

  37. Dunbar NM, Chandler WL. Thrombin generation in trauma patients. Transfusion. Aug 4 2009;[Medline].

  38. Hoffman M, Monroe DM 3rd. A cell-based model of hemostasis. Thromb Haemost. Jun 2001;85(6):958-65. [Medline].

  39. Rodgers GM. Role of antithrombin concentrate in treatment of hereditary antithrombin deficiency. An update. Thromb Haemost. May 2009;101(5):806-12. [Medline].

  40. Azzi A, De Santis R, Morfini M, et al. TT virus contaminates first-generation recombinant factor VIII concentrates. Blood. Oct 15 2001;98(8):2571-3. [Medline]. [Full Text].

  41. MediView Express. Recombinant therapy enhances safety and quality of life for hemophilia patients. Paper presented at: 53rd Annual Meeting of the National Hemophilia Foundation; November 16, 2001; Nashville, Tennessee.

  42. Rigas B, Hasan I, Rehman R, et al. Effect on treatment outcome of coinfection with SEN viruses in patients with hepatitis C. Lancet. Dec 8 2001;358(9297):1961-2. [Medline].

  43. PLAS+SD (Pooled Plasma, (Human) Solvent Detergent Treated) [package insert]. Watertown, Mass: V. I. Technologies, Inc. (VITEX). Distributed by the American National Red Cross, Blood Services, Washington, DC; 2000.

  44. [Best Evidence] Fergusson DA, Hebert PC, Mazer CD, et al. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med. May 29 2008;358(22):2319-31. [Medline]. [Full Text].

  45. Senior K. New variant CJD fears threaten blood supplies. Lancet. Jul 28 2001;358(9278):304. [Medline].

  46. Bertina RM. Molecular risk factors for thrombosis. Thromb Haemost. Aug 1999;82(2):601-9. [Medline].

  47. Coukos G, Rubin SC. Gene therapy for ovarian cancer. Oncology (Williston Park). Sep 2001;15(9):1197-204, 1207; discussion 1207-8. [Medline].

  48. Di Bisceglie AM. SEN and sensibility: interactions between newly discovered and other hepatitis viruses?. Lancet. Dec 8 2001;358(9297):1925-6. [Medline].

  49. Hedner U, Ginsburg D, Lusher JM, High KA. Congenital hemorrhagic disorders: new insights into the pathophysiology and treatment of hemophilia. Hematology Am Soc Hematol Educ Program. 2000;241-65. [Medline]. [Full Text].

  50. Kearon C, Julian JA, Kovacs MJ, Anderson DR, Wells P, Mackinnon B, et al. Influence of thrombophilia on risk of recurrent venous thromboembolism while on warfarin: results from a randomized trial. Blood. Dec 1 2008;112(12):4432-6. [Medline].

  51. Lane DA, Bayston T, Olds RJ, et al. Antithrombin mutation database: 2nd (1997) update. For the Plasma Coagulation Inhibitors Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost. Jan 1997;77(1):197-211. [Medline].

  52. Reitsma PH. Genetic principles underlying disorders of procoagulant and. In: Colman RW, Hirsh J, Marder VJ, Clowes AW, George JN, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001:60-87.

  53. Rosenberg RD, Edelberg JM, Zhang L. The heparin-antithrombin system: a natural anticoagulant mechanism. In: Colman RW, Hirsh J, Marder VJ, Clowes AW, George JN, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001:711-31.

  54. Rosendaal FR. Risk factors for venous thrombotic disease. Thromb Haemost. Aug 1999;82(2):610-9. [Medline].

  55. Warren BL, Eid A, Singer P, et al. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA. Oct 17 2001;286(15):1869-78. [Medline]. [Full Text].

  56. Zhou A, Huntington JA, Carrell RW. Formation of the antithrombin heterodimer in vivo and the onset of thrombosis. Blood. Nov 15 1999;94(10):3388-96. [Medline]. [Full Text].

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Further Reading

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Keywords

antithrombin deficiency, AT deficiency, antithrombin III, AT III, ATIII, antithrombin 3, anticoagulation, anticoagulant, coagulation factors, hemostatic pathway, coagulation pathway, serine protease inhibitor, deep vein thrombosis, DVT, venous thrombosis, pulmonary embolism, PE, venous thromboembolism, VTE, thrombotic disease,

acute respiratory distress syndrome, ARDS, venoocclusive disease, veno-occlusive disease, VOD, bone marrow transplantation, BMT, chronic leg ulcerations, severe venous varicosities, postphlebitic syndrome, low molecular weight heparin, low-molecular-weight heparin, LMWH, pooled plasma treated with solvent-detergent, PLAS+SD, ATryn, Budd-Chiari syndrome, estrogen, hormone replacement therapy, HRT

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Contributor Information and Disclosures

Author

Arun Rajan, MD, Clinical Fellow, Medical Oncology Branch, National Cancer Institute/National Institutes of Health
Arun Rajan, MD is a member of the following medical societies: American Medical Association and American Society of Clinical Oncology
Disclosure: Nothing to disclose.

Coauthor(s)

Sara J Grethlein, MD, Associate Dean for Graduate Medical Education, Professor, Department of Internal Medicine, Division of Hematology and Oncology, State University of New York Upstate Medical University
Sara J Grethlein, MD is a member of the following medical societies: American Society of Hematology
Disclosure: Nothing to disclose.

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Medical Editor

David Aboulafia, MD, Medical Director, Bailey-Boushay House; Clinical Professor, Department of Medicine, Division of Hematology, University of Washington
David Aboulafia, MD is a member of the following medical societies: American College of Physicians, American Medical Association, American Medical Directors Association, American Society of Hematology, Infectious Diseases Society of America, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Marcel E Conrad, MD, (Retired) Distinguished Professor of Medicine, University of South Alabama
Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, and Southwest Oncology Group
Disclosure: No financial interests None None

CME Editor

Rebecca J Schmidt, DO, FACP, FASN, Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine
Rebecca J Schmidt, DO, FACP, FASN is a member of the following medical societies: American College of Osteopathic Internists, American College of Physicians, American Medical Association, American Society of Nephrology, International Society of Nephrology, National Kidney Foundation, Renal Physicians Association, and West Virginia State Medical Association
Disclosure: Abbott Grant/research funds Speaking and teaching; Genzyme Honoraria Consulting; Amgen Honoraria Speaking and teaching; Ortho Biotech Honoraria Speaking and teaching

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

 
 
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