What Are Common Inherited Thrombophilias?

Patient Presentation
A 6-month-old female came to clinic for her health maintenance visit. She was growing well physically. Her mother had several questions regarding her normal development which were easily answered. The mother was most concerned because the family history was now positive for her sister (patient’s maternal aunt) having a recent deep venous thrombosis during pregnancy. The aunt’s evaluation showed Factor V Leiden and the mother was in the process of being tested. She wanted to know if the patient should also be tested. The past medical history showed no abnormal bruising/bleeding or other problems with the patient or other family members.

The pertinent physical exam showed a smiling infant with growth parameters in the 75-95% for age. Her examination was normal. The diagnosis of a healthy infant was made. The pediatrician recommended that first the mother finish her own evaluation and re-iterated that there were several things the mother could already do to decrease her own risk of blood clots including being active and a non-smoker. The physician said, “Being pregnant like your sister is also a risk, and one you need to discuss with your doctor and your husband about. Once we know if you have Factor V Leiden then we can talk about the baby’s risks. Usually we wait until the child is older to discuss testing, but we can have you talk with the genetic counselor if you would like to. The good news is that infants and children are at low risk for getting blood clots.”

Thrombophilia is the increased risk of thromboembolic disease due to a disorder. Thrombophilia can be inherited or acquired (such as antiphospholipid syndrome). The risk of thromboembolic events is much lower in children than adults.

At-risk patients should avoid:

  • Dehydration
  • Sitting for prolonged time periods during travel
  • Obesity
  • Smoking
  • Estrogen containing oral contraceptives

Common inherited thrombophilias include:

  • Prothrombin (Factor II mutation)
    • Second most common
    • Genetics: 1-2% prevalence is variable depending on location and ethnic background.
    • Cause: Abnormal point mutation of the prothrombin gene that causes increased levels of prothrombin, the precursor of thrombin.
  • Protein C
    • Relatively common
    • Genetics and epidemiology – 0.2% prevalence of general population. Heterozygous state is most common. Can occur in homozygous state but has severe thromboembolic events mainly in neonatal period.
    • Cause: Protein C becomes activated (activated Protein C = APC) and combines with Protein S. This complex then normally inactivates Factors Va and VIIIa. Protein C is Vitamin K dependent.
    • Two types:
      • Type 1 – antigen and activity levels are low (quantitative deficiency, 85% of cases)
      • Type 2 – antigen levels are normal and activity levels are low (qualitative deficiency, 15% of cases)
  • Protein S
    • Relatively uncommon
    • Genetics and epidemiology – 0.03-.13% prevalence of general population. Heterozygous state is most common. Can occur in homozygous state but has severe thromboembolic events mainly in neonatal period.
    • Cause: Free Protein S combines with Protein C. This complex then normally inactivates Factors Va and VIIIa. Protein S is Vitamin K dependent. Protein S is 60% protein bound.
    • Three types:
      • Type 1 – free antigen and total antigen is low (quantitative deficiency)
      • Type 3 – free antigen is low but total antigen is normal (quantitative deficiency)
      • Type 2 – normal free and total antigen levels but activity is low (qualitative deficiency)
  • Antithrombin
    • Least common
    • Genetics and epidemiology: 0.02% prevalence of Caucasian population, Autosomal dominant so heterozygous state is most common. Homozygous Type 1 is incompatible with life.
    • Cause: Acts to inhibit several coagulation factors including IIa, IXa, Xa, XIa, and XIIa.
    • Two types:
      • Type I – low antigen and activity levels (quantitative deficiency)
      • Type II – normal antigen but low activity levels (qualitative deficiency)

Learning Point
Factor V Leiden

  • Most common thrombophilia, named for the city of Leiden, Netherlands where it was discovered.
  • Genetics and epidemiology – Prevalence is variable depending on location and ethnic background. 1% in African American population, 2% in Hispanic population and 5% in European background. Mainly occurs in heterozygous state. Homogygotes have a high risk with thrombosis in up to 80/1000.
  • Cause: Factor V Leiden is an abnormal activated Protein C (APC) caused by a point mutation replacing arginine with glutamine at position 1691 which changes the amino acid at position 506 of the protein. Normally APC inactivates coagulation Factor V which then slows down the clotting process and prevents the clots from becoming too large. Is usually inactivated by activated protein C. Factor V Leiden doesn’t allow the APC to work, so the coagulation Factor V continues to allow the clot to grow.
  • Screening is controversial – Prior to a known thrombotic event, many people recommend to wait until children are adolescent age for screening so patients can make informed choices particularly as epidemiology in children is much different than adults. Screening after a thromboembolic event is less clear and most people would evaluate the patient and screen for thrombophilias as this will also help with treatment decisions.

Questions for Further Discussion
1. What are the Vitamin K dependent coagulation factors?
2. What is the role of imaging in evaluation and treatment of thromboembolic events?
3. What is the role of genetic counseling in thromboembolic events?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Blood Clots and Bleeding Disorders.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Varga EA, Moll S. Prothrombin 20210 Mutation (Factor II Mutation). Circulation. 2004; 110: e15-e18.

Haywood S, Liesner R, Pindora S, Ganesan V. Thrombophilia and first arterial ischaemic stroke: a systematic review. Arch Dis Child. 2005 Apr;90(4):402-5.

Kenet G, Nowak-Gottl U. Venous thromboembolism in neonates and children. Best Pract Res Clin Haematol. 2012 Sep;25(3):333-44.

Heleen van Ommen C, Middeldorp S. Thrombophilia in childhood: to test or not to test. Semin Thromb Hemost. 2011 Oct;37(7):794-801.

Kalpatthi, RV, Kirkland KR, Tarantino CA. Screening for Factor V Leiden Mutation. The Link – Kansas City Mercy Infectious Disease. 2015; April 7(4).


Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital