To Test or Not to Test: The Inherited Thrombophilia Question

December 20, 2017
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When a result provides questionable or limited clinical utility, physicians and genetic counselors must educate patients and providers on the pros and cons of genetic testing.

Between the increased ease of clinical genetic testing and the direct-to-consumer genetic testing kits now available, physicians and genetic counselors face education challenges that simply did not exist a decade ago.

Among the disorders caused by mutations that are easily tested and identified, hypercoagulable mutations are of particular interest. The sense of fear, lack of control and potentially devastating consequences of a blood clot are strong motivators for families and practitioners who may believe that testing and knowledge will mitigate risk.

However, most of the time, screening asymptomatic individuals of any age – but especially children – may result in overtreatment rather than clot prevention.

According to Elizabeth Varga, MS, LGC, genetics counselor at Nationwide Children’s Hospital, genetic testing is helpful in some cases when patients have experienced clots at a young age, or when they have a strong family history of clotting.

“Certain severe thrombophilias – protein C, protein S and antithrombin – also warrant testing for the whole family,” says Sarah O’Brien, MD, hematologist at Nationwide Children’s. “But these are all quite rare.”

Factor V Leiden (FVL) and prothrombin are two of the most common inheritable thrombophilias. And according to the experts, when to test for these mutations is a complicated question.

When to Test for Common Inheritable Thombophilias

FVL, or protein C resistance, is an inherited condition that prevents the protein C/protein S complex from effectively inactivating factor V. FVL is the most common inherited thrombophilia, occurring in approximately 5 percent of Caucasian Americans, 2 percent of Hispanic Americans, 1 percent of African Americans and 0.5 percent of Asian Americans.

Prothrombin, also known as factor II, is a clotting protein that is active in the final stages of the clotting cascade to form fibrin. A single basepair change, often referred to as G20210A in the 3’ untranslated region of the gene results in increased production of prothrombin. This mutation is present in approximately 2 percent of the general population, with slightly higher occurrence in people from southern Europe.

“A positive family history is an independent risk factor for thrombosis,” says Varga. “A detailed, accurate, three-to-four-generation history may help to identify at-risk relatives who are appropriate for increased education about prevention of venous thromboembolism and/or testing for inherited thrombophilia.”

Even though the likelihood of identifying thrombophilia though clinical testing is high, the clinical utility of the result may be minimal. Diagnosis of inherited thrombophilia may or may not influence clinical management.

The American College of Medical Geneticists (ACMG) does not generally recommend genetic testing for FVL or prothrombin mutations prior to adolescence, with the exception of patients with a personal history of venous thrombosis. The College of American Pathologists (CAP) recommends thrombophilia testing for pediatric patients with a personal history of VTE or arterial thrombosis and consideration of testing in their siblings.

Testing Asymptomatic Relatives for Inherited Thrombophilia

Testing asymptomatic relatives for inherited thrombophilia is highly controversial. Most guidelines recommend that requests be considered on a case-by-case basis. One of the key issues related to the controversy is the limited evidence that prophylactic treatment is helpful for preventing VTE.

“In fact, long-term anticoagulation is not standard for asymptomatic individuals because the risk of bleeding outweighs the risk of VTE,” explains Dr. O’Brien. “However, situational anticoagulation may be appropriate in some high-risk situations.”

Test results may also influence a woman’s choices about hormone use.

“All women who use oral contraceptives have an increased risk of VTE,” says Dr. O’Brien. “However, the risk is multiplied in women with thrombophilia.”

According to a publication in the Journal of Genetic Counseling (2007), heterozygotes for FVL who use oral contraceptive pills have a 35-fold increased risk of VTE compared to women without FVL who do not use oral contraceptive pills. Similarly, risk increases 16 fold for individuals who are heterozygous for prothrombin mutation. They also have a higher risk of cerebral vein thrombosis. Risk increases for homozygotes and compound heterozygotes.

“It’s important to remember that the absolute risk of VTE remains low, even for females with thrombophilia on oral contraceptive pills,” says Dr. O’Brien. “The baseline risk for thrombosis for a female of reproductive age is only 1/10,000 per year. So it’s important to weigh the risks of thrombosis during pregnancy with the risks of oral contraceptive use as well.”

Better Education for Patients and Families

Genetic counselors have an essential role in helping physicians, patients and families navigate the pros and cons of testing. Despite the recommendations not to test, many physicians test for FVL in an effort to prevent thrombosis related morbidity. Additionally, direct to consumer genetic testing has led to many patients bringing test results to physicians.

“Physicians are now in situations where they are being brought genetic test results that they didn’t order,” explains Varga. “It’s important that they have the resources and education to appropriately counsel these patients and families about guidelines for further testing and risk.”

“We know that knowledge of genetic test results increases awareness of thrombosis risk, but patients often overestimate the magnitude of risk,” Varga continues. “We have an opportunity to support patients and families, as well as their providers.”


  1. Hellman EA, Leslie ND, Moll S. Knowledge and educational needs of individuals with factor V Leiden mutation. Journal of Thrombosis and Haemostasis. 2003;1:2335-2339.
  2. Varga E. Inherited thrombophilia: key points for genetic counseling. Journal of Genetic Counseling. 2017. DOI: 10.1007/s10897-006-9069-9
  3. Wu O, Robertson L, Twaddle S, Lowe GDO, Clark P, Greaves M, Walker ID, Langhorne P, Brenkel I, Regan L, Greer IA. Screening for thrombophilia in high-risk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study. Health Technology Assessment. 2006;10(11).
  4. Grody WW, Griffin JH, Taylor AK, Korf BR, Heit JA. American College of Medical Genetics Consensus Statement on Factor V Leiden Mutation Testing. Genetic Medicine. 2001 Mar-Apr;3(2):139-148.
  5. CAP Guidelines


Photo credit: Nationwide Children’s