Sections

Antithrombin Deficiency

Workup

Laboratory Studies

Important considerations during the laboratory workup of antithrombin (AT) deficiency include the following:

Appropriate timing of sample collection
Avoid obtaining specimens during acute illnesses or in proximity to heparin administration
Considering the impact of oral anticoagulants in normalizing the levels in some types of AT deficiency
Handle the specimen in prompt fashion
Appropriate methodology of functional and antigenic tests
Use of biologic versus chromogenic substrate assays

The initial workup should include the following routine coagulation studies:

Prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
Fibrinogen level

Special laboratory tests

Two types of biologic assays measure AT activity. The first is the heparin cofactor assay of AT activity, which measures the ability of AT to bind heparin and neutralize thrombin or factor Xa.

The second test measures the ability of AT to progressively neutralize thrombin in the absence of heparin. HCII also has heparin cofactor activity, but it is able to neutralize thrombin only in the presence of a large amount of heparin. Thus, the use of low concentrations of heparin and of factor Xa (rather than thrombin) in the assay system excludes the contribution of heparin cofactor II (HCII) in the heparin cofactor assay of AT activity.

The antigen assay and presence of abnormal molecules by electrophoretic mobility require further immunologic assessment or DNA sequencing to characterize the specific defect present. Assessment of the specific genetic defect allows for early and easy identification of carriers and of risk assessment, as well as provision of genetic counseling and anticipatory guidance.

While the optimal, cost-effective workup for an inherited coagulopathy varies from center to center, currently available tests include the following:

Protein C activity
Free protein S antigen and activity
Activated protein C resistance (factor V Leiden) assay
Thrombomodulin and MTHFR gene mutations
Fasting homocysteine levels
Plasminogen activity
Plasminogen activator inhibitor type 1 (PAI-1)
Tissue factor pathway inhibitor (TFPI) activity

Imaging Studies

Objective documentation of all thromboembolic disease is essential. The various imaging techniques available include compression and color ultrasonography, venography, angiography, computed tomography (CT) scanning, and magnetic resonance imaging (MRI). The specific imaging modality depends on the location of the suspected thrombus.

Other Tests

Decisions about proceeding with additional tests, including genetic tests, are based on the patient's history and their current medications.

Gene-based tests require that the potential implications, such as the inherited nature of the defect and insurance issues, be discussed with the patient before blood is drawn. The need for genetic counseling should be discussed after test results become available.

Treatment & Management

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Media Gallery

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.
Antithrombin sites of action.

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Author

Drew H Barnes, MD Fellow Physician, Hospice and Palliative Medicine, The Ohio State University Wexner Medical Center

Drew H Barnes, MD is a member of the following medical societies: American Academy of Hospice and Palliative Medicine, American College of Physicians, American Medical Association, American Society of Clinical Oncology, American Society of Hematology

Disclosure: Nothing to disclose.

Coauthor(s)

Claudia M da Costa Dourado, MD Clinical Assistant Professor of Medicine, Sidney Kimmel Medical College of Thomas Jefferson University; Program Director, Hematology and Medical Oncology Fellowship Program, Attending Physician, Division of Hematology and Medical Oncology, Department of Medicine, Einstein Medical Center Philadelphia

Claudia M da Costa Dourado, MD is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology

Disclosure: Nothing to disclose.

Specialty Editor Board

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

Disclosure: Received salary from Medscape for employment. for: Medscape.

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, SWOG

Disclosure: Partner received none from No financial interests for none.

Chief Editor

Perumal Thiagarajan, MD Professor, Department of Pathology and Medicine, Baylor College of Medicine; Director, Transfusion Medicine and Hematology Laboratory, Michael E DeBakey Veterans Affairs Medical Center

Perumal Thiagarajan, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Society for Biochemistry and Molecular Biology, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Royal College of Physicians

Disclosure: Nothing to disclose.

Additional Contributors

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, AMDA - The Society for Post-Acute and Long-Term Care Medicine, American Society of Hematology, Infectious Diseases Society of America, Phi Beta Kappa

Disclosure: Nothing to disclose.

Bryan A Mitton, MD, PhD Clinical Instructor, Division of Pediatric Hematology-Oncology, Department of Pediatrics, Stanford University School of Medicine

Disclosure: Nothing to disclose.

Angela Steineck, MD, MS Assistant Professor of Pediatric Oncology, MACC Fund Center for Cancer and Blood Disorders - Children's Wisconsin, Medical College of Wisconsin

Angela Steineck, MD, MS is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Medical Association

Disclosure: Nothing to disclose.

Acknowledgements

Sara J Grethlein, MD Associate Dean for Undergraduate Medical Education, Indiana University School of Medicine

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.

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.

Antithrombin Deficiency Workup

Laboratory Studies

Special laboratory tests

Imaging Studies

Other Tests

References

Tables

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