Hypercoagulability - Hereditary Thrombophilia and Lupus Anticoagulants Associated With Venous Thrombosis and Emboli Workup

  • Author: Paul Schick, MD; Chief Editor: Emmanuel C Besa, MD   more...
 
Updated: Oct 3, 2011
 

Laboratory Studies

Numerous tests are available for each of the hypercoagulable disorders or thrombophilia. The challenge is first to decide who should be tested. Many of the tests (the coagulation-based tests) should not be done while patients are on anticoagulants and during active thrombosis. The results of the test can be difficult to interpret.

Details of most of these tests have been reviewed in other articles; therefore, only essential points are emphasized below. (See Antiphospholipid Syndrome, Protein C Deficiency, Protein S Deficiency, Antithrombin III Deficiency, and Antiphospholipid Antibody Syndrome and Pregnancy for greater detail.)

In the following lists, * indicates tests that should be done in most evaluations:

  • Thrombosis - D-dimer* (useful for verifying the presence of thrombosis)
  • Lupus anticoagulant[6, 7] - Screening tests are easily performed. Clinical presentation should be considered. However, the criteria for diagnosis are positive results from confirmatory studies as described below:
    • Screening tests* - Activated partial thromboplastin time (aPTT), prothrombin time (PT), and mixing studies
    • Confirmatory tests* - Confirmative laboratory tests include (1) coagulation based tests, an abnormal dilute Russell viper venom time (dRVVT), and the demonstration of phospholipid dependence; (2) an increase in anticardiolipin antibodies (IgG and IgM); and (3) an increase in anti-β(2)glycoprotein 1 antibodies (IgG and IgM). The test(s) should be positive on 2 occasions that are 12 weeks apart. There are efforts to standardize these tests to be able to reliably diagnose lupus anticoagulants and to predict the risk for thrombosis. It has been suggested that the risk of thrombosis is greater when results from several of these tests are positive.[14]
  • APC resistance and factor V Leiden
    • APC resistance (a coagulation test) should be done first because a small fraction of APC resistance disorders are due to mutations other that factor V Leiden.*
    • Genetic tests for factor V Leiden - Polymerase chain reaction (PCR).*
  • Prothrombin G20210A - Diagnosed by PCR*
  • Antithrombin III deficiency: Functional studies should always be performed, because some cases of antithrombin III deficiency may be associated with normal antigen levels.
    • Functional assay - Chromogenic heparin cofactor assay*
    • Antigenic
  • Protein C deficiency: Functional studies should always be performed, because some cases of protein C deficiency may be associated with normal antigen levels
    • Functional assay - Amidolytic*
    • Antigen
  • Protein S deficiency: The following 3 tests should be performed. The reason is that there are variants with low total but normal free protein S, other variants can have low normal total but low free protein S, and other variants can have a normal total and free protein S but functionally abnormal protein S.
    • Antigen: Free*
    • Antigen: Total*
    • Functional*

The above tests are affected by a number of conditions, results can be variable, and they are difficult to interpret. Certain of these tests should not be ordered while patients are on anticoagulant therapy. Therefore, the following precautions are important when ordering laboratory studies to rule out an underlying thrombophilia:

  • Only certain studies can be performed while patients are undergoing anticoagulation therapy.
    • Testing for antithrombin III functional activity should not be done while the patient is on heparin or LMWH.
    • Testing for protein C or S functional activity should not be done while patients are on warfarin since protein C and protein S are vitamin K–dependent proteins.
    • Testing for APC resistance should be deferred when patients are on anticoagulant therapy since this test is a coagulation assay. However, genetic tests of factor V Leiden can be ordered.
    • DRRVT and phospholipid dependence for confirming lupus anticoagulants should not be done while the patient is being anticoagulated since they are coagulation-based tests. Testing for anticardiolipid antibodies for anti-β(2)glycoprotein 1 antibodies can be performed during anticoagulation.
  • Antithrombin III, protein S, and protein C levels may be increased during acute thromboembolism. Therefore, both protein assays and functional assays of these proteins could be inaccurate during the acute phase of thromboembolic disease.
  • The tests should be performed in laboratories that specialize in testing for thrombophilia.
  • These test results are difficult to interpret and are best interpreted by a physician with considerable experience with thrombophilias.

The decision to initiate a laboratory workup for thrombophilia is complex.[15, 16]

A workup for thrombophilia is usually indicated only in patients with a history of recurrent thromboembolic episodes, thromboembolism at a young age (ie, < 40 y), family history for thromboembolism, or thrombosis in an unusual site.

Idiopathic venous thrombosis is defined as venous thromboembolism without any obvious risk factor. About 50% of patients with idiopathic venous thrombosis have an underlying thrombophilia. Therefore, some studies have recommended that a thrombophilia workup should be done in patients with idiopathic venous thrombosis.

The decision to order a thrombophilia workup can be difficult since the identification of an underlying thrombophilia might not affect therapeutic strategy. If thrombophilia is detected in a patient with no history of thromboembolism, anticoagulation is usually not necessary.

Conversely, patients with recurrent thromboembolic events should be anticoagulated even though there is no evidence of an underlying thrombophilia or a lupus anticoagulant.

Some benefits may exist with testing patients for thrombophilia and lupus anticoagulants.

Some organizations recommend that patients with lupus anticoagulants be treated more aggressively. For example, the American College of Chest Physicians recommends 12 months of anticoagulation and consideration of long-term anticoagulation after a single thrombotic event in patients with antiphospholipid syndromes.[17] There are conflicting reports on the optimal international normalized ratio (INR) level in patients with lupus anticoagulants who are on warfarin. In most cases, an INR between 2.0 and 3.0 is adequate. However, a higher INR might be desirable in patients with severe recurrent thromboembolic disease.

The risk of thrombosis should outweigh the risk of bleeding, especially in older patients, when deciding on anticoagulation.

Patients with more than one risk factor have a greater incidence for venous thrombosis than the sum of the individual risks. For example, women with a prothrombotic mutation who are taking oral estrogen have a 25-fold greater risk of venous thrombosis than women without the mutation who are on estrogen.[18]

Patients who have an identifiable thrombophilic risk factor should be advised to have blood relatives tested. This information would be important when deciding whether to recommend oral contraception or hormonal replacement therapy. Also, this will help decide whether to initiate anticoagulation during surgery or immobilization.

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Contributor Information and Disclosures
Author

Paul Schick, MD  Emeritus Professor, Department of Internal Medicine, Jefferson Medical College of Thomas Jefferson University; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital

Paul Schick, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Society of Hematology, International Society on Thrombosis and Haemostasis, and New York Academy of Sciences

Disclosure: Nothing to disclose.

Coauthor(s)

Barbara P Schick, PhD  Professor, Department of Medicine, Cardeza Foundation; Professor, Department of Biochemistry and Molecular Pharmacology, Professor, Department of Biochemistry and Molecular Biology, Jefferson Medical College of Thomas Jefferson University

Disclosure: Nothing to disclose.

Specialty Editor Board

Pradyumna D Phatak, MBBS, MD  Chair, Division of Hematology and Medical Oncology, Rochester General Hospital; Clinical Professor of Oncology, Roswell Park Cancer Institute

Pradyumna D Phatak, MBBS, MD, is a member of the following medical societies: American Society of Hematology

Disclosure: Novartis Honoraria Speaking and teaching

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

Ronald A Sacher, MB, BCh, MD, FRCPC  Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MB, BCh, MD, FRCPC is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, and Royal College of Physicians and Surgeons of Canada

Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; Talecris Honoraria Board membership

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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Table 1. Thrombophilic or Hereditary Hypercoagulable Disorders in the General Population and in Persons With Venous Thrombosis[10]
ConditionPrevalence in General Population, %Relative Risk of VTE, %Relative Risk of Recurrent VTE, %
Factor V Leiden3-74.31.3
Prothrombin 20210A1-31.91.4
Protein C0.02-0.0511.32.5
Protein S0.01-132.42.5
Antithrombin III0.02-0.0417.52.5
VTE = Venous thromboembolism.
Table 2. Several Commonly Used Antithrombotic Agents
AnticoagulantRisksMonitoringAntidote for BleedingHalf-life
HeparinBleeding HITaPTTProtamine< 60 min
LMWHBleeding HITFactor XaProtamine (< 60%) and in some cases is ineffectiveVariable
WarfarinBleedingPTVitamin K & FFP*Several days
FondaparinuxBleedingFactor XaNone15 h
Lepirudin



Argatroban



BleedingNoneNone1-3 h



30-60 min



PT = Prothrombin time.



*Fresh frozen plasma (FFP) can be used to reverse acute bleeding in patients with high INRs due to warfarin overdose. Recombinant factor VIIa and prothrombin complex concentrates also have been used in these patients, but the risk of thrombosis due to these agents is being evaluated.[28, 29]



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