eMedicine Specialties > Hematology > Coagulation, Hemostasis, and Disorders

Antithrombin Deficiency: Differential Diagnoses & Workup

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

Differential Diagnoses

Dysfibrinogenemia
HCII deficiency
Homozygous MTHFR C677T mutation
Hyperhomocysteinemia
Protein C Deficiency
Protein S Deficiency

Other Problems to Be Considered

The following should also be considered in the differential diagnosis:

  • Abnormal protein Z or protein Z protease inhibitor
  • APC resistance, factor V Leiden mutation
  • Histidine-rich glycoprotein (alpha1-acid-rich glycoprotein)
  • Possible TFPI mutations/deficiency
  • Rare inherited defects in the fibrinolytic system (dysplasminogenemia, abnormal PAI-1, defective release of tissue-type plasminogen activator [tPA]) and elevated levels of alpha2-antiplasmin
  • Thrombomodulin gene mutations
  • Other deficiencies yet to be discovered

Other problems that need to be considered include the following acquired causes of antithrombin deficiency and thrombophilia:

  • Estrogens
  • Pregnancy and related conditions
  • Hypotension, acidosis
  • DIC
  • Sepsis
  • Liver disease
  • Extensive surgery, burns
  • ARDS
  • Malignancies
  • Status post open heart surgery
  • Acute hemolytic anemias
  • Kasabach-Merritt syndrome
  • Large aortic aneurysms
  • Catheters and other vascular access devices
  • Reduction in antithrombin levels secondary to heparin
  • Other acquired causes of deficiency of the factors listed above
  • Unknown causes, as with antipsychotic drug use and increased risk of thrombosis
  • Lupus-type anticoagulant/antiphospholipid antibody syndrome

Workup

Laboratory Studies

  • Important considerations during the laboratory workup of antithrombin deficiency (AT deficiency) include the following:
    • Appropriate timing of sample collection
    • Avoiding obtaining specimens during acute illnesses or in proximity to heparin administration: Consider the impact of oral anticoagulants in normalizing the levels in some types of antithrombin deficiency.
    • Considering the impact of oral anticoagulants in normalizing the levels in some types of antithrombin deficiency
    • Handling of the specimen in prompt fashion
    • Using appropriate methodology of functional and antigenic tests
    • Using biologic versus chromogenic substrate assays
  • Initial workup: Routine coagulation tests should include prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen level.
  • Special laboratory tests
    • Two types of biologic assays measure antithrombin activity.
      • The first is the heparin cofactor assay of antithrombin activity, which measures the ability of antithrombin to bind heparin and neutralize thrombin or factor Xa.
      • The second test measures the ability of antithrombin 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 HCII in the heparin cofactor assay of antithrombin activity.
    • The antigen assay and presence of abnormal molecules by electrophoretic mobility require immunologic assessment.
    • Finally, assessment of the specific genetic defect allows for early and easy identification of carriers and of risk assessment.
  • Additional hypercoagulability workup is complex. Some of the currently known thrombophilic factors are as follows:
    • Protein C activity
    • Free protein S antigen and activity
    • Protein Z
    • Protein Z protease inhibitor (proteins C, S, and Z are vitamin K-dependent proteins)
    • APC resistance
    • Factor V Leiden
    • Thrombomodulin and MTHFR gene mutations
    • Fasting homocysteine levels
    • Plasminogen activity
    • PAI-1
    • 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.

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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Further Reading

Related eMedicine Topics

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Clinical Guidelines

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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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