Activated protein C resistance as an additional risk factor for thrombosis in protein C-deficient families

Abstract

Heterozygous protein C deficiency is associated with an increased risk for thrombosis. This association is restricted to a minority of protein C-deficient families, which have been defined as clinically dominant protein C-deficient. In contrast, in the clinically recessive protein C- deficient families, only the homozygous family members are (severely) affected. One possible explanation for this difference in thrombotic risk between families may be the presence of a second hereditary risk factor. A good candidate for this second risk factor is the recently identified resistance to activated protein C (APC). APC resistance, which is associated with a mutation in the FV gene (FV Leiden), is a common and strong risk factor for thrombosis. We show here that the prevalence of the FV Leiden mutation is high among symptomatic protein C-deficient probands (19%). In 6 clinically dominant protein C- deficient families, the segregation of the FV Leiden mutation and the protein C gene mutation was studied. A thrombotic episode had been experienced by 73% of the family members having both the protein C gene mutation and the FV Leiden mutation. In contrast, respectively, 31% and 13% of the family members having either the protein C gene mutation or the FV Leiden mutation had experienced a thrombotic episode. Moreover, the result of a two locus linkage analysis support the assumption that the FV gene and the protein C gene are the two trait loci responsible for the thrombophilia. These results indicate that carriers of both gene defects have an increased risk for thrombosis compared with related carriers of the single defect.

Management of inherited thrombophilia: guide for genetics professionals

“…Factor V Leiden was found in 20% and 39% of thrombophilic families with deficiencies of protein C and protein S, respectively. Relatives with multiple thrombophilic disorders had a significantly higher incidence of VTE (72%) than those with protein C deficiency (31%) or protein S deficiency (19%) alone (15,16). Similar gene-gene interactions occur in families with inherited antithrombin deficiency (17).…”

The factor V Leiden mutation in children with cancer and thrombosis

“…The only child heterozygous for the factor V Leiden mutation did have thrombosis in association with an indwelling venous catheter. It has been suggested that the factor V Leiden mutation may be a cofactor for thrombosis in association with other haemostatic abnormalities or prothrombotic conditions (Nowak-Gottl et al, 1995;Petaja et al, 1995;Zoller et al, 1995a, b;Koeleman et al, 1994;Gandrille et al, 1995). Indwelling central venous catheters are often associated with thrombotic events ( Johnston-Anderson et al, 1989;Moss et al, 1989;Mueller et al, 1992;David & Andrew, 1993;Krafter-Jacobs et al, 1995), even in the absence of other obvious risk factors for thrombosis.…”

Modifier genes in haemophilia: their expansion in the human genome

“…It has been observed that combined FVIII and FXI deficiency is associated with more severe bleeding manifestations than those found when the defects are present separately [1]. Families with factor V (FV) Leiden and protein C deficiency are more prone to thrombophilia than are those patients with only one of these defects [2]. Accordingly, concomitant mutations in two coagulation genes or two thrombotic genes can worsen the clinical severity of their respective clinical pictures.…”