Thrombophilia FlexPanel

Thrombophilia or hypercoagulability is an inherited or acquired susceptibility to thrombosis (blood clots) due to an abnormality in the system of coagulation.

PrintPrint

Thrombophilia or hypercoagulability is an inherited or acquired susceptibility to thrombosis (blood clots) due to an abnormality in the system of coagulation.

Although most people with an inherited thrombophilia never develop abnormal blood clots, they are at increased risk over the general population for venous thrombosis, especially deep vein thrombosis (DVT), pulmonary embolism (PE), arterial thrombosis (e.g. stroke and heart attack), as well as pregnancy loss and complications such as placental abruption. The inheritance of thrombophilia is complex, and abnormalities associated with an inherited thrombophilia include those that cause insufficient inhibition of the blood clotting cascade or cause increased clotting activity.

The Ambry Test: Thrombophilia FlexPanel tests for the following mutations and variants associated with inherited thrombophilia: Factor V Leiden (F5 G1691A), Prothrombin (F2 G20210A), MTHFR C677T, and MTHFR A1298C.  Testing options are flexible, so the health care provider can select any combination of these 4 common disease-associated mutations, and those patients already tested for one or more of the disease mutations do not have to be retested. . Pricing is based on the number of disease-associated mutations tested.

Disease Name 
Thrombophilia (Factor V-Leiden, Prothrombin-Factor II G20210A, MTHFR C677T, and MTHFR A1298C)
Factor V-Leiden
Disease Information 

Thrombophilia or hypercoagulability is an inherited or acquired susceptibility to thrombosis (blood clots) due to abnormal coagulability of the clotting system. The inheritance of thrombophilia is complex, and abnormalities associated with an inherited thrombophilia include those that cause insufficient inhibition of the blood clotting cascade or enhancement of clotting activity. The R506Q mutation of the F5 gene, commonly known as factor V Leiden, is found in 20-25% of patients with venous thromboembolism (VTE) and in 40-50% of patients with familial thrombophilia. Heterozygosity for R506Q confers 5-fold increased risk for venous thrombosis.1

The carrier frequency for R506Q is 3-8% for the general European and US populations; however, this mutation is extremely rare in Asian, African, and indigenous Australian populations. The G20210A mutation of the coagulation factor II gene (F2), also known as prothrombin, is the second most common cause of familial thrombophilia after factor V Leiden. The prevalence of G20210A in the general population ranges from 0.7% to 4% in Caucasian populations.2

Approximately 20% of families with a history of venous thrombosis have G20210A, and heterozygous individuals have a 3-fold increase in risk for venous thrombosis.3 MTHFR mutations dramatically increase risk for venous thrombosis when present with other genetic thrombophilic factors.4   Approximately 35% of U.S. Caucasians are heterozygous, and 12% are homozygous, for the A222V variant.5 Approximately 9-20% of all ethnic groups are heterozygous for the E429A variant.6 The majority of the available evidence suggests that it is the elevated plasma homocysteine levels that are useful for clinical risk assessment, and not MTHFR genetic status alone.7, 8

Testing Benefits & Indication 

Diagnostic testing may be considered for patients with a personal history of idiopathic or recurrent venous thromboembolism, family history of venous thromboembolism, recurrent pregnancy loss or history of pregnancy complications, such as placental abruption. Genetic testing may impact on management and treatment options for patients affected with thrombophilia. Testing options are flexible, and the health care providers can select any combination of these 4 common disease-associated mutations.

Test Description 

Four common known disease-causing mutations on the three genes that cause thrombophilia are analyzed and listed below. Novel variants at or immediately adjacent to the site of the known mutations may be detected. The panel detects the following mutations/variants: Factor V Leiden (F5 R506Q), Prothrombin (F2 G20210A), MTHFR A222V, and MTHFR E429A.

Mutation Detection Rate 

The factor V Leiden (F5 R506Q) mutation is found in 20-25% of patients with venous thromboembolism (VTE) and in 40-50% of patients with familial thrombophilia. The carrier frequency for R506Q is 3-8% for the general European and US populations; however, this mutation is extremely rare in Asian, African, and indigenous Australian populations.1 The prevalence of the prothrombin (F2 G20210A) mutation ranges from 0.7% to 4% in Caucasian populations. Approximately 20% of families with history of venous thrombosis have G20210A.2 Approximately 35% of U.S. Caucasians are heterozygous, and 12% are homozygous, for the A222V variant in the MTHFR gene.5  Approximately 9-20% of all ethnic groups are heterozygous for the E429A variant in the MTHFR gene.6

Specimen Requirements 

Blood: Collect 3-5 cc from adult or 2 cc minimum from child into EDTA purple-top tube (first choice) or ACD yellow-top tube (second choice). Store at room temperature or refrigerate. Ship at room temperature.
Saliva: Collect 2 ml into Oragene™ DNA Self-Collection container. Store and ship at room temperature.
DNA: Minimum DNA Amount of 5μg of DNA at a concentration of ~100ng/μl in 50μl TE (10mM Tris-Cl pH 8.0, 1mM EDTA); preferred 20μg. Store frozen and ship on ice or dry ice. 

Turnaround Time 
Technique Days
Thrombophilia Mutation Panel 7-14
Factor II Mutation Panel  7-14
Factor V Leiden Mutation Panel 7-14
 Mutation Panel 7-14

 

Genes 
Techniques 
References 

1. Gohil R, Peck R, et al. The genetics of venous thromboembolism. A meta-analysis involving approximately 120,000 cases and 180,000 controls. Thromb Haemost. 2009;102(2):360-70. [PMID: 19652888]

2. Rosendaal FR, Doggen CJ, et al. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost.  1998;79(4):706-8. [PMID: 9569177]

3. Poort SR, Rosendaal FR, et al. A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood. 1996;88(10):3698-703. [PMID: 8916933]

4. Varga EA, Sturm AC, et al. Cardiology patient pages. Homocysteine and MTHFR mutations: relation to thrombosis and coronary artery disease. Circulation. 2005;111(19):e289-93. [PMID: 15897349]

5. Moll S. Thrombophilias--practical implications and testing caveats. J Thromb Thrombolysis. 2006;21(1): 7-15. [PMID: 16475036]

6. Esfahani ST, Cogger EA, et al. Heterogeneity in the prevalence of methylenetetrahydrofolate reductase gene polymorphisms in women of different ethnic groups. J Am Diet Assoc.  2003;103(2):200-7. [PMID: 12589326]

7. Ray JG, Shmorgun D, et al. Common C677T polymorphism of the methylenetetrahydrofolate reductase gene and the risk of venous thromboembolism: meta-analysis of 31 studies. Pathophysiol Haemost Thromb.  2002;32(2):51-8. [PMID: 12214149]

8. Klerk M, Verhoef P, et al. MTHFR 677C-->T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA. 2002;288(16):2023-31. [PMID: 12387655]