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Importance of Molecular Diagnosis of Inherited Thrombophilia:
The identification of the genetic basis of these inherited causes of thrombophilia ushered in a new way of thinking about thrombosis and the importance of its genetic component. Interest in the genetic basis of VTE was accelerated with the subsequent discovery of Factor V Leiden and Factor II Prothrombin G20210A. These single nucleotide polymorphisms (SNPs) and other genetic variants associated with VTE have become fixtures in the molecular diagnosis of inherited thrombophilia. Because of the large volume of current and anticipated future genetic testing, there has been a push to develop many different genotyping methods which are now used in both clinical and research settings. The identification of new genetic variants that may either directly or indirectly affect coagulation or the anticoagulant pathway, may greatly advance the understanding and clinical management of thrombophilia.


Thrombophilia Facts:

  • Inherited Thrombophilia has an incidence of 4 to 7% in the U.S. Population
  • Preoperative evaluation of patients with a positive family history of Thrombophilia aids physicians in managing post-surgical clotting risks.
  • In combination, Factor V Leiden (FVL) and Factor II Prothrombin(FII) mutation tests diagnose up to 97% of patients with Inherited Thrombophilia
  • Females considering oral contraceptives, hormone replacement therapy or pregnancy management may be recommended for evaluation of Thrombophilia mutation carrier status

Inherited Thrombophilia Testing Recommendations:
The testing recommendations for the FVL and FII mutations are based on the College of American Pathologist's Consensus is that when considering genetic testing for FVL, the FII mutation should also be tested. In combination, these two tests diagnose up to 97% of patients with inherited thrombophilia. Testing for FVL and FII is not recommended as a general screen.


Patients Who Should Be Tested:

  • History of recurrent VTE
  • First VTE at less then 50 years of age
  • First VTE at any age is unprovoked.
  • VTE at an unusual anatomic site (cerebral, mesenteric, portal, or hepatic veins).
  • First VTE at any age, in a patient with a first-degree relative with a VTE before age 50.
  • First VTE related to pregnancy, the puerperium, or oral contraceptive use.
  • First VTE related to hormone replacement therapy.
  • Women with unexplained pregnancy loss during the 2nd or 3rd trimester
  • FVL testing should be considered in patients with unexplained arterial thrombosis.

Patients for Whom Testing is Suggested but Not Required:

  • Family members of patients with confirmed risks for VTE.
  • Females considering oral contraceptives, hormone replacement therapy or where pregnancy management may be desirable because of mutation carrier status.

Added Patients for Whom Testing Maybe Considered:

  • Young women smokers (age < 50) with myocardial infarction
  • Older patients (age > 50) with a first proved VTE event the absence of cancer or an intravascular device
  • First VTE related to SERMs or tamoxifen
  • Women with unexplained severe preeclampsia, placental abruption, or intra-uterine growth retardation (IUGR)

Treatment Considerations:

  • The most common treatment for thrombophilia is either long-term anticoagulant therapy or prophylaxis in temporary periods of high thrombotic risk (e.g. surgery, immobilization)
  • Heterozygous or homozygous FVL individuals with a first deep vein thrombosis or pulmonary embolism are usually treated initially with heparin (either unfractionated or low molecular weight), followed by warfarin (target INR 2.5; therapeutic range 2.0-3.0)
  • Women with FVL and a history of unprovoked VTE should receive prophylactic anticoagulation with heparin or low molecular weight heparin during pregnancy and for at least 6 weeks postpartum.
  • The higher a patient's risk of VTE recurrence (vs. bleeding from anticoagulation)the longer the duration of anticoagulant therapy-generally 3 to 6 months after first VTE in FVL and FII carriers, especially if the VTE was associated with a transient clinical risk factor (e.g. surgery, oral contraceptive use, pregnancy or the puerperium).
  • After orthopedic surgery, FVL or FII carriers with a history of VTE may require a higher intensity and /or more prolonged VTE prophylaxis, especially if the prior VTE was unprovoked or the patient has other persistent VTE risk factors (e.g. obesity, malignant neoplasm, chronic immobility, etc.)
  • The length and strength of anticoagulation is the same for acute management of venous thromboembolic events in patients with inherited thrombophilia as in those without.
  • The need for lifelong anticoagulation after a first episode of VTE in FVL and FII positive individuals alone has not been established by appropriate clinical trials. Indefinite anticoagulation, however, maybe recommended for:
    • Individuals with an idiopathic or life-treating VTE even.(especially with reduced cardiopulmonary functional reserve)
    • Individuals with FVL and another hereditary thrombophilia mutation.
    • Individuals with additional persistent clinical risk factors(e.g. malignant neoplasm or antiphospholipid antibodies)
    • Any patient with recurrent unprovoked VTE.
  • The risk of recurrent VTE associated with a heterozygous FVL mutation (without additional thrombohilic defects) is not firmly established
  • Routine anticoagulation therapy is not recommended for FVL and FII positive individuals with atherosclerotic arterial occlusive disease.

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