Interprets thrombophilia variant findings for VTE risk stratification and anticoagulation guidance. Note: MTHFR variants should NOT be tested for VTE risk (ACMG 2013).
Thrombophilia Defect Identified
Concurrent Risk Triggers (select all that apply)
Guidelines & Evidence
Clinical Details
Section 1
When to Use
When to Use
Interpreting results from thrombophilia gene panel testing (Factor V Leiden, Prothrombin G20210A, Protein C/S/Antithrombin deficiency).
Assessing VTE recurrence risk after a first thrombotic event.
Guiding duration of anticoagulation therapy after provoked or unprovoked VTE.
Evaluating thrombotic risk in asymptomatic relatives of affected individuals.
Endorsed by ASH, BCSH, ACMG, ISTH for hereditary thrombophilia interpretation.
When NOT to Test
MTHFR C677T/A1298C should NOT be tested for VTE risk assessment — ACMG 2013 position statement explicitly states that MTHFR variants do not independently increase VTE risk and therapeutic intervention based on this result is not evidence-based.
Antithrombin deficiency carries the highest thrombotic risk of all heritable thrombophilias — 25–50× RR; heparin resistance in acute VTE (AT required for heparin to work).
FVL heterozygous is the most common inherited thrombophilia in Europeans (~5% carrier rate in Northern Europe) but absolute risk of VTE without environmental triggers is relatively low (~0.05%/year).
Testing symptomatic relatives of confirmed cases is appropriate. Testing asymptomatic relatives without clear indication for anticoagulation is more controversial — ASH 2023 does not universally recommend.
Testing in context of acute VTE on anticoagulation: Functional protein C/S/ATIII levels are affected by warfarin and heparin — test after anticoagulation completion or use genetic testing (not functional assays) during treatment.
First unprovoked VTE + low-risk thrombophilia (FVL het or PT20210A het): At least 3–6 months anticoagulation; individualise extended therapy with HERDOO2 or Vienna Prediction Model.
03
First PROVOKED VTE (no thrombophilia): 3 months standard; test for thrombophilia if family history or recurrent events.
Mutation in blood coagulation factor V associated with resistance to activated protein C
Bertina RM et al. • Nature. 1994;369(6475): 64–67
Use of laboratory tests for VTE: guidelines from ASH
Lim MY et al. • Blood Advances. 2023;7(22): 7031–7067
Section 6
Literature
Factor V Leiden Discovery (1994)
Factor V Leiden (FVL, p.R506Q) was identified by Rogier Bertina and colleagues at Leiden University Medical Centre (Netherlands) in 1994 as the molecular basis for activated protein C (APC) resistance, itself described in 1993 by Dahlbäck. The variant was found to be remarkably common in European populations (~5%), making it the most prevalent inherited thrombophilia.
Prothrombin G20210A (1996)
The Prothrombin 20210A variant was identified by Poort et al. (Blood 1996) in Leiden, the same institution. Its discovery established the concept that non-coding variants in coagulation genes could have significant clinical impact by altering mRNA stability and elevating plasma prothrombin levels by ~30%. Together, FVL and PT20210A account for ~70% of all identifiable hereditary thrombophilias.
