Thrombophilia Testing in Healthy Children with Related Family History

Case

A father brings his 5-year-old son for a well-child visit. During the appointment, he mentions that the boy’s aunt developed a blood clot at age 26 and was found to be heterozygous for the factor V Leiden mutation. He asks you if his son should be tested.

Discussion

Thrombophilia refers to the propensity to form blood clots and may be a result of acquired and/or inherited risk factors. Over the past decades, several inherited risk factors for thrombosis have been identified, improving our understanding of the pathogenesis of venous thromboembolism (VTE). These inherited risk factors have gained increasing attention, and pediatricians may be asked to consider testing in healthy children who have a family history of thrombosis or thrombophilia.

The clinical utility of performing such tests has been increasingly scrutinized, and it is important to understand the potential benefits and limitations of testing. The final decision regarding whether or not to test is likely to vary depending upon the clinical situation and the family’s preference.

Numerous inherited risk factors can be identified through laboratory testing. The most common inherited thrombophilias (IT) are listed below. The defects in which the pathogenic link is best understood include the factor V Leiden mutation, the prothrombin gene mutation, and deficiencies of protein C, protein S, and antithrombin. The strength of the association between each IT and the development of VTE varies, and they are often classified into “weak” or “strong” risk factors, as listed. The weak risk factors are associated with relative risks of 2 to 7, while the stronger risk factors are associated with relative risks of around 10 to 15. Although other inherited defects have been described and may be tested for, none have gained widespread acceptance.

Prevalence of inherited thrombophilias and strength of risk

Inherited thrombophilia: Factor V Leiden*
Prevalence in general population: 4 to 5 percent
Strength of risk factor: Weak (heterozygous), strong (homozygous)

Inherited thrombophilia: Prothrombin G20210A*
Prevalence in general population: 2 percent
Strength of risk factor: Weak (heterozygous), strong (homozygous)

Inherited thrombophilia: Antithrombin deficiency
Prevalence in general population: 0.02 to 0.2 percent
Strength of risk factor: Strong

Inherited thrombophilia: Protein C deficiency
Prevalence in general population: 0.2 to 0.5 percent
Strength of risk factor: Strong

Inherited thrombophilia: Protein S deficiency
Prevalence in general population: 0.1 to 1 percent
Strength of risk factor: Strong

* Applies to Caucasian population; prevalence is lower in other groups. Bauer K. Screening for inherited thrombophilia in asymptomatic individuals. Updated August 9, 2016. Accessed Sept. 8, 2016.

Potential benefits of IT testing in healthy children

• Improved counseling for adolescent females considering oral contraceptive pills (OCPs): The baseline annual incidence of VTE is about 1 per 12,500 for women of reproductive age and increases to 1 per 3,500 for those on OCPs. For subjects who are heterozygous for the factor V Leiden mutation and on OCPs, this baseline annual risk is increased 35-fold to approximately 1 per 350 women. The young woman will be better informed regarding her choices and may choose lower-risk alternatives, such as progesterone-only preparations or an intrauterine device.
• Targeted anticoagulant thromboprophylaxis in high-risk situations, e.g., after a femur fracture in an obese teenager who also has IT, or prior to long-distance (> 6 hours) air travel for teenagers
• Education about signs and symptoms of VTE, which could lead to earlier diagnosis.
• Promotion of lifestyle modifications including avoidance of additional prothrombotic risk factors (sedentary lifestyle, obesity and smoking).

Limitations of IT testing in healthy children

• There is very little opportunity for IT testing to benefit a young child. The incidence of venous thrombosis in healthy children is extremely low (0.07/10,000), so that long-term anticoagulation in a healthy child is unwarranted.
• There are ethical issues of genetic screening in children who may lack the maturity and understanding to make an informed decision, especially when there currently is no demonstrated benefit to IT testing during childhood.
• Interpretation of test results — particularly for protein C, protein S, and AT deficiency — can be challenging because normal ranges change throughout early childhood and reliance on adult normal ranges may result in misdiagnosis.
• If an underlying defect has not been identified in a family member, negative testing may provide a false sense of security.
• Identification of an IT may cause unnecessary anxiety.
• Cost

Recommendations

For healthy children who have a family history of thrombosis or IT, the decision to perform IT testing should be made on an individual basis only after counseling the family regarding the potential benefits and limitations.

Whenever possible, children should not be tested unless there is a first-degree family member with an IT. During the counseling, one should discuss how the results might affect the medical management of the child. Adolescents, particularly females, are likely to have the most to gain from IT testing.

CHOP has a well established Hemostasis and Thrombosis Center in the Division of Hematology. In addition to evaluating and managing children with VTE, we frequently counsel, evaluate, and educate patients and families regarding inherited thrombophilia testing and results.

Reference and suggested reading

Raffini L, Thornburg C. Testing children for inherited thrombophilia: more questions than answers. Br J Haematol. 2009;147:277-288.