Antithrombin Deficiency Treatment & Management

  • Author: Arun Rajan, MD; Chief Editor: Emmanuel C Besa, MD   more...
 
Updated: Jan 10, 2012
 

Medical Care

In a patient with a known inherited antithrombin deficiency (AT deficiency), management of the acute thrombotic event depends on the type of antithrombin deficiency, because a variable response to large doses of heparin occurs in some of these patients. When a therapeutic response to intravenous heparin is not achievable, additional support with an antithrombin concentrate may be necessary.[41]

  • Low molecular weight heparins (LMWHs) also require antithrombin for their antithrombotic action. Not much is known about the use of LMWHs in these patients.
  • The synthetic anti–factor Xa pentasaccharide also requires adequate amounts of antithrombin for its action.

Patients who have had an episode of DVT and whose antithrombin deficiency has been recognized should receive lifelong oral anticoagulation to protect them from recurrent VTE, the development of thrombosis at other sites, or both. Patients who present with atypical site thrombosis, such as mesenteric or hepatic vein thrombosis, should be placed on lifelong anticoagulation immediately. A variety of precipitating factors, such as taking oral contraceptives or hormone replacements (which should be discontinued), may precede the development of VTE. Patients with known antithrombin deficiency need aggressive antithrombotic prophylaxis during high-risk situations such as surgery and pregnancy.

In the future, in patients with antithrombin deficiency (AT deficiency), synthetic direct thrombin inhibitors that do not require antithrombin for their anticoagulant effect (eg, argatroban) could be tried. Such inhibitors are also more desirable, because they may obviate the need for exposure to biologic products such as plasma or antithrombin concentrate, currently required for the adequate anticoagulant action of presently available agents.

Few adequate clinical trials have been carried out to answer the question of the possible utility of antithrombin concentrates in pregnancy-related disorders.

In animal models of hepatic failure as well as in human studies, replacement with antithrombin concentrates at variable time points has generated differing results, with some showing control of DIC without any obvious impact on bleeding, whereas others have not had any significant impact on outcome.

In patients undergoing orthotopic liver transplantation, it has been suggested that prophylactic administration of antithrombin concentrates may be beneficial in minimizing the DIC. Once again, large, prospective, multicenter randomized clinical trials are needed, because published clinical data have shown both efficacy and a lack of it. In this context, note that, in a very small study involving children undergoing orthotopic liver transplantation, administration of antithrombin concentrate (along with fresh frozen plasma [FFP], prostaglandin E1, and LMWH) was beneficial in reducing the frequency of hepatic arterial thrombosis.

Antithrombin supplementation has been suggested to be useful in patients with the following conditions or those undergoing the following procedures (The value of replacement in all of these procedures and conditions has not been clearly proven in unbiased trials):

  • Malignancies
  • Sepsis
  • Shock
  • Open heart surgery
  • Orthopedic procedures

A phase III, double-blind, placebo-controlled, randomized multicenter trial found that administration of high-dose antithrombin within 6 hours of the onset of sepsis and septic shock in adults had no effect on 28-day all-cause mortality rates. Increased bleeding occurred in patients who received the antithrombin concentrate and heparin (low or therapeutic doses of heparin).

Each unit of FFP obtained from a blood bank contains whatever "normal" level of antithrombin the individual donor had. If a patient requires 3000 U of antithrombin, that patient would require 3000 mL of FFP given rapidly to raise the level of antithrombin in the recipient. Clearly, volume overload becomes a problem in such patients, particularly more so in patients with an inability to tolerate large volumes. Thus, FFP replacement is not a reasonable source of repeated antithrombin replacement; rather, FFP is a choice only when no concentrate is available.

Pooled plasma treated with solvent-detergent (PLAS+SD) is available to treat any condition in which FFP is typically used and for which no factor concentrate is available. Viral inactivation using the solvent-detergent (SD) process has been used in preparation of coagulation factor concentrates in the past. In vitro treatment of donor plasma with 1% of the solvent tri(n-butyl) phosphate (TNBP) and 1% of the detergent Triton X-100 leads to significant inactivation of a broad spectrum of lipid-enveloped viruses.

  • Studies of viral inactivation using the SD process show significant inactivation of the human pathogenic viruses hepatitis B (HBV) and C (HCV) and human immunodeficiency virus (HIV). Other lipid-enveloped viruses (eg, Sindbis virus, bovine viral diarrhea virus) have also been used to monitor inactivation.
  • PLAS+SD is ABO blood type specific, and SD-treated plasma should be ABO compatible with the recipient's red blood cells.
  • The frozen product is supplied in 200-mL bags. Each 200-mL bag has been demonstrated to raise factor levels by approximately 2-3%, with 4-6 bags raising the factor level of a 70-kg person by approximately 8-18%.
  • Monitoring of specific factor levels before and after product infusion is important to ensure that hemostatically adequate levels are achieved and maintained to provide adequate hemostasis.
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Surgical Care

Replacement with antithrombin concentrate is necessary in patients with known antithrombin deficiency (AT deficiency). In patients with acute severe trauma, some studies suggest a beneficial effect with prophylactic replacement. The frequency of antithrombin replacement depends on the half-life of the product, but in the presence of active bleeding, more frequent replacement should be based on antithrombin levels.

In acquired disorders, correction of antithrombin levels allows heparin to exert its full antithrombotic effect. Such replacement is necessary to maintain a minimum of 80% antithrombin activity until the full therapeutic effect of oral anticoagulants is obtained. Serial assessment of antithrombin levels is necessary to assure the adequacy of the dosing.

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Consultations

  • Close consultation with a hematologist is necessary.
  • Obtain consultation with a geneticist as needed.
  • The support of a laboratory equipped to assay antithrombin activity is necessary in patients receiving antithrombin replacement therapy.
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Diet

A healthy, normal diet is appropriate.

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Activity

A patient's activity level depends on the clinical circumstance. Activity in patients with acute venous thromboembolic disease depends on their overall clinical status. Patients with antithrombin deficiency (AT deficiency) and thrombosis should receive in-hospital treatment for their acute illness.

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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  Senior Attending Physician, Cancer Treatment Center, Bassett Healthcare Network

Sara J Grethlein, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Society of Clinical Oncology, and 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.

Specialty Editor Board

David Aboulafia, MD  Medical Director, Bailey-Boushay House, Clinical Professor, Department of Medicine, Division of Hematology, Attending Physician, Section of Hematology/Oncology, Virginia Mason Clinic; Investigator, Virginia Mason Community Clinic Oncology Program/SWOG

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.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Marcel E Conrad, MD  Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

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

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 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: Renal Ventures Ownership interest Other

Chief Editor

Emmanuel C Besa, MD  Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Jefferson Medical College of 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 Clinical Oncology, American Society of Hematology, and New York Academy of Sciences

Disclosure: Nothing to disclose.

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Antithrombin (AT) sites of action.
Antithrombin (AT) neutralizes the enzyme (IIa) by forming a 1:1 stoichiometric complex (AT:IIa) between the arginine-serine sites of the 2 proteins. Binding of heparin to lysyl residues on AT results in a conformational change in AT, which makes it more available to bind thrombin (IIa), IXa, and Xa, thus markedly accelerating the rate of enzyme-inhibitor complex formation. AT also neutralizes XIa and XIIa.
Cell surface–directed hemostasis (image adapted from Hoffman M, Monroe DM 3rd. A cell-based model of hemostasis. Thromb Haemost. 2001). Initially, a small amount of thrombin is generated on the surface of the tissue factor–bearing (TF-bearing) cell. Following amplification, the second burst generates a larger amount of thrombin, leading to fibrin (clot) formation.
 
 
 
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