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Keywords:

  • factor V Leiden;
  • genetics;
  • inheritance;
  • mutation;
  • thrombosis

Summary.  Genetic studies in thrombosis started with coining of the term thrombophilia by Jordan and Nandorff in 1956. Next, antithrombin deficiency was identified in 1965 as a simple genetic entity that increased thrombotic risk, albeit in a small subset of patients. This subset was enlarged when, in the 1980s, family studies showed that deficiency of protein C (PC) or its co-factor protein S (PS) increased thrombotic risk. Ten years later activated PC resistance and the underlying genetic trait of factor V Leiden were discovered in a family setting. This genetic risk factor was the first prothrombotic defect in a procoagulant protein and was also more prevalent than abnormalities in anticoagulant proteins. The high incidence induced a shift from family studies to case–control studies. Case–control studies became even more popular after the common prothrombin 20 210 mutation was discovered in 1996. In fact, in the last decade common genetic variations in almost all coagulation proteins were tested in association studies. These common variants impart a small risk, if any risk at all, thereby limiting their usefulness in furthering insight into the pathophysiology of thrombosis. Moreover, common risk factors for venous thrombosis fail to improve prediction models for thrombosis on which prophylactic treatment can be tailored. Now that large-scale sequencing techniques are becoming available that enable many genes to be studied in a single individual, one can expect a revival of the identification of private mutations that are associated with large risks, in particular in genes that have been only poorly studied.