Thrombophilia – common variants

Hereditary thrombophilia (also termed inherited thrombophilia) manifests clinically as venous thromboembolism (VTE), most commonly deep-vein thrombosis (DVT) of the legs and pulmonary embolism. Upper-extremity, cerebral, splanchnic, and superficial venous thromboses also occur, and pregnancy- or postpartum-associated VTE is over-represented among affected women. First thrombotic events typically occur in adulthood; recurrent VTE before age 30 years is seen in a minority, particularly in homozygotes, compound heterozygotes, or individuals with additional acquired risk factors. Clinical expression is highly variable: many heterozygous and even homozygous individuals never develop thrombosis, while others present with recurrent events. Risk is modulated by zygosity, coexisting thrombophilic disorders, family history, and circumstantial factors such as pregnancy, estrogen-containing contraception or hormone replacement therapy, surgery, immobilisation, malignancy, and obesity.

The estimated prevalence is 1/13 – 1/33 (GeneReviews, 2024). The Factor V Leiden variant is heterozygous in 3-8% of general United States and European populations, and the F2 20210G>A variant in 1.7-3%; homozygote frequencies are approximately 1/5,000 and 1/10,000, respectively.

Hereditary thrombophilia is caused by certain germline pathogenic variants in F5 or F2. When conducting genetic testing, it is important to note that pathogenic variants in F2 and F5 are typically associated with a deficiency of these factors and, consequently, a tendency to bleed. The F5 c.1601G>A p.(Arg534Gln) variant, known as , substitutes glutamine for arginine at an activated protein C cleavage site; factor V is consequently inactivated approximately tenfold more slowly than normal, producing APC resistance, increased thrombin generation, and a mild hypercoagulable state. The F2 c.*97G>A (G20210A) variant lies in the 3’ untranslated region and increases the efficiency of 3’-end mRNA processing, leading to plasma prothrombin levels approximately 30% higher than in healthy controls and a gain-of-function prothrombotic state.

Both and are inherited in an autosomal dominant manner. Each child of a heterozygous individual has a 50% probability of inheriting the variant. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified; given the typically mild and incompletely penetrant phenotype, requests for prenatal testing are uncommon.

Hereditary thrombophilia is diagnosed primarily by molecular genetic testing of F5 and F2. Low activated protein C (APC) resistance on qualitative and quantitative APC resistance assays is a supportive laboratory finding for Factor V Leiden thrombophilia, but molecular confirmation is required. Plasma prothrombin concentration is not reliable for diagnosis of prothrombin thrombophilia, as the range in heterozygotes overlaps with the normal range.

Main differential diagnoses include:

• Inherited deficiencies of the natural anticoagulants , , and antithrombin, causing increased VTE susceptibility. Approximately tenfold less common than and identified in 1-3% of individuals with a first VTE.
• Hereditary dysfibrinogenemia: rare qualitative fibrinogen disorders that infrequently cause thrombophilia, characterized by abnormal fibrinogen function rather than APC resistance or elevated prothrombin levels.

• Establishing the diagnosis: a molecular genetic diagnosis confirms the clinical suspicion and provides a definitive etiological explanation.
• Clinical management: identification of the causative variant is a prerequisite for targeted medical care, enabling individualized management decisions by the treating physicians in consultation with the affected individual.
• Family member testing: predictive testing of at-risk relatives becomes possible once the familial pathogenic variant has been identified, supporting informed reproductive and clinical decision-making.

• Pastori D, Menichelli D, Valeriani E, Pignatelli P. Factor V Leiden thrombophilia. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. PMID: .
• Kujovich JL. Prothrombin thrombophilia. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. PMID: .