Invitae Hereditary Thrombophilia Panel


Test description

The Invitae Hereditary Thrombophilia Panel analyzes five genes that are associated with an increased risk for developing thromboembolism. Individuals who have inherited a pathogenic variant in one of these genes have a predisposition to excessive blood clot formation, most often in the legs (deep vein thrombosis). Women with hereditary thrombophilia also have an increased risk of miscarriage and other pregnancy complications.

It can be helpful to identify individuals who have a genetic predisposition to blood clots in order to establish or confirm a diagnosis, help predict risk of future thrombotic events, or guide treatment and management decisions. Identification of a disease-causing variant would also encourage testing and diagnosis of at-risk relatives.

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Primary panel (5 genes)


F2: Analysis is limited to the Prothrombin G20210A variant
F5: Analysis is limited to the Factor V Leiden variant

Add-on F9 gene (1 gene)

Clinicians may also wish to include the gene F9 associated with factor IX thrombophilia for no additional charge.


Add-on MPL gene (1 gene)

Clinicians may also wish to include the gene MPL, associated with familial essential thrombocythemia, for no additional charge.


Factor V Leiden thrombophilia
Prothrombin-related thrombophilia
Protein S deficiency
Protein C deficiency
Antithrombin III deficiency

Hereditary thrombophilia is typically an adult-onset disorder that predisposes individuals to blood clot formation. Once formed, blood clots can travel to and affect blood flow in other parts of the body, such as the lungs (causing pulmonary embolism). Hereditary thrombophilia is incompletely penetrant, meaning that only a small percentage of those who have thrombophilia-associated pathogenic variants develop clinical symptoms; even so, deep vein thrombosis and pulmonary embolism affect as many as 600,000 people each year and are a factor in at least 100,000 deaths. Women who have hereditary thrombophilia have an increased risk of miscarriage or other pregnancy complications. Additionally, some rare forms of hereditary thrombophilia can be life-threatening in infants.

The estimated detection rate of this panel for individuals with venous thrombosis is 26%-51%.

Hereditary thrombophilia can be inherited in an autosomal dominant or autosomal recessive pattern.

While most people with hereditary thrombophilia never develop abnormal blood clots, certain factors can increase the risk, including advanced age, surgery, trauma, inactivity, and pregnancy. Having multiple inherited disorders of blood clotting in can also influence the risk of abnormal blood clotting.

The lifetime risk of developing thrombosis can range from 4 to 80 times higher than the general population, depending on the gene(s) involved.

Estimated prevalence of each hereditary thrombophilia disorder:

  • Factor V Leiden thrombophilia: 1 in 45 individuals of Caucasian ancestry; 1 in 100 individuals of African ancestry; 1 in 2000 individuals of Asian ancestry
  • Prothrombin-related thrombophilia: 1 in 126 individuals of Caucasian ancestry; rare in other populations
  • Protein C deficiency: 1 in 200 to 1 in 500 individuals
  • Antithrombin III deficiency: 7-20 per 10,000 individuals
  • Protein S deficiency: 3-13 per 10,000 individuals

  • reduced protein C activity and/or protein S activity
  • venous thromboembolism (VTE) at an unusual site (e.g., cerebral mesenteric, portal, hepatic)
  • recurrent VTE
  • idiopathic VTE (unrelated to surgery/trauma)
  • VTE under the age of 50
  • VTE during pregnancy or in the postpartum period
  • recurrent fetal loss, especially in the second or third trimesters
  • VTE while on oral contraceptives, hormone replacement, or methotrexate
  • life-threatening venous thrombosis (e.g., pulmonary embolism, cerebral vein thrombosis)
  • infants/children with purpura fulminans
  • family history of VTE in first-degree relatives
  • family history of protein C deficiency, protein S deficiency, antithrombin III deficiency, factor V Leiden, or prothrombin-related thrombophilia

Recommendations on when to test an individual for thrombophilias have been suggested:

  1. Baglin, T, et al. Clinical guidelines for testing for heritable thrombophilia. Br. J. Haematol. 2010; 149(2):209-20. doi: 10.1111/j.1365-2141.2009.08022.x. PMID: 20128794
  2. Borgel, D, et al. Protein S deficiency. Thromb. Haemost. 1997; 78(1):351-6. doi: 10.1016/s0899-7071(97)84577-9. PMID: 9198178
  3. Caspers, M, et al. Deficiencies of antithrombin, protein C and protein S - practical experience in genetic analysis of a large patient cohort. Thromb. Haemost. 2012; 108(2):247-57. doi: 10.1160/TH11-12-0875. PMID: 22627591
  4. Crowther, MA, Kelton, JG. Congenital thrombophilic states associated with venous thrombosis: a qualitative overview and proposed classification system. Ann. Intern. Med. 2003; 138(2):128-34. doi: 10.7326/0003-4819-138-2-200301210-00014. PMID: 12529095
  5. Dykes, AC, et al. A study of Protein S antigen levels in 3788 healthy volunteers: influence of age, sex and hormone use, and estimate for prevalence of deficiency state. Br. J. Haematol. 2001; 113(3):636-41. doi: 10.1046/j.1365-2141.2001.02813.x. PMID: 11380449
  6. Emmerich, J, et al. Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism--pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Study Group for Pooled-Analysis in Venous Thromboembolism. Thromb. Haemost. 2001; 86(3):809-16. PMID: 11583312
  7. Gerson, WT, et al. Severe acquired protein C deficiency in purpura fulminans associated with disseminated intravascular coagulation: treatment with protein C concentrate. Pediatrics. 1993; 91(2):418-22. PMID: 8424021
  8. Lijfering, WM, et al. Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives. Blood. 2009; 113(21):5314-22. doi: 10.1182/blood-2008-10-184879. PMID: 19139080
  9. Margaglione, M, et al. Increased risk for venous thrombosis in carriers of the prothrombin G-->A20210 gene variant. Ann. Intern. Med. 1998; 129(2):89-93. doi: 10.7326/0003-4819-129-2-199807150-00003. PMID: 9669991
  10. Martinelli, I, et al. Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families. Blood. 1998; 92(7):2353-8. PMID: 9746774
  11. Miletich, J, et al. Absence of thrombosis in subjects with heterozygous protein C deficiency. N. Engl. J. Med. 1987; 317(16):991-6. doi: 10.1056/NEJM198710153171604. PMID: 3657866
  12. Pintao, MC, et al. Protein S levels and the risk of venous thrombosis: results from the MEGA case-control study. Blood. 2013; 122(18):3210-9. doi: 10.1182/blood-2013-04-499335. PMID: 24014240
  13. Price, VE, et al. Diagnosis and management of neonatal purpura fulminans. Semin Fetal Neonatal Med. 2011; 16(6):318-22. doi: 10.1016/j.siny.2011.07.009. PMID: 21839696
  14. Reich, LM, et al. Role of the geneticist in testing and counseling for inherited thrombophilia. Genet. Med. 2003; 5(3):133-43. doi: 10.1097/01.GIM.0000067987.77803.D0. PMID: 12792420
  15. Tait, RC, et al. Prevalence of protein C deficiency in the healthy population. Thromb. Haemost. 1995; 73(1):87-93. PMID: 7740502
  16. Ten, Kate, MK, et al. PROS1 analysis in 87 pedigrees with hereditary protein S deficiency demonstrates striking genotype-phenotype associations. Hum. Mutat. 2008; 29(7):939-47. doi: 10.1002/humu.20687. PMID: 18435454
  17. Varga, EA, Kujovich, JL. Management of inherited thrombophilia: guide for genetics professionals. Clin. Genet. 2012; 81(1):7-17. doi: 10.1111/j.1399-0004.2011.01746.x. PMID: 21707594
  18. ten, Kate, MK, van, der, Meer, J. Protein S deficiency: a clinical perspective. Haemophilia. 2008; 14(6):1222-8. doi: 10.1111/j.1365-2516.2008.01775.x. PMID: 18479427

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
F2* NM_000506.3
F5* NM_000130.4
F9 NM_000133.3
MPL NM_005373.2
PROC NM_000312.3
PROS1 NM_000313.3
SERPINC1 NM_000488.3

F2: Analysis is limited to the Prothrombin G20210A variant
F5: Analysis is limited to the Factor V Leiden variant