The paradoxical association between inherited factor VII deficiency and venous thrombosis

Abstract

Inherited factor VII (FVII) deficiency is considered to be a haemorrhagic disease. Nonetheless, some patients paradoxically present with venous thrombosis. We assessed whether there was a link between phenotype and genotype in seven patients with inherited FVII deficiency and thrombosis (eleven venous thrombotic events). For each patient (FVII:C < 50%), clinical data were collected, aetiological assessment of risk factors for thrombosis was investigated, and direct sequencing of the nine exons and promoter of the FVII gene (F7) was performed. We present the second series ever published on FVII patients with thrombosis. In nine of the eleven thrombotic events, there was at least one classical triggering risk factor; clinical (n = 4), familial antecedent (n = 2), or biological, defined by phospholipid-binding antibodies or elevated FVIII:C levels (n = 7). In contrast to a previous series, only two events occurred after surgery, performed both with and without replacement therapy. The thrombotic event remained unexplained in one young patient, highlighting the lack of 'protection' against venous thrombosis by low FVII:C levels. Genetic mutations were found to be heterogeneous. Among the seven F7 sequence alterations identified in the present study, only two (p.Ala354Val and p.Arg364Gln) have previously been reported in FVII-deficient patients presenting with venous thrombosis. Our genetic analyses of the F7 mutations in these patients show the complexity of FVII deficiency associated with thrombosis. These data justify a holistic, clinical and biological approach for patients with these specific symptoms. This series also strongly suggest that mild FVII deficiency should not prevent physicians from using antithrombotic prophylaxis in FVII-deficient patients.

Associated prothrombotic conditions are probably responsible for the occurrence of thrombosis in almost all patients with congenital FVII deficiency. Critical review of the literature

“…Recently, studies of polymorphisms or of mutations in special variants of FVII deficiency have been implicated in an attempt to find a pattern that could explain the lack of bleeding tendency and/or the occurrence of thrombosis. Such studies so far have not reached any conclusion [16][17][18]. The role of Tissue Factor Pathway Inhibitor (TFPI) in the pathogenesis of thrombosis in FVII deficient patients has never been explored.…”

“…In recent years a particular emphasis was placed on the relatively frequent occurrence of thrombosis, mainly venous, in FVII deficiency [3,[9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26].…”

“…Some authors even speculated, on the basis of the observation, that bleeding manifestations in these patients are variable and occasionally absent, that a subtype of FVII deficiency could be classified as prone to thrombosis [16][17][18]. Several polymorphisms were indicated and also a different reactivity of some forms of FVII towards tissue factors was postulated to be present.…”

Thrombin generation in different cohorts: Evaluation of the haemostatic potential

“…For example, DVT, splanchnic thrombosis and arterial thrombosis have been reported even in patients with severe FVII deficiency [169,170,171].…”

Congenital FVII deficiency and thrombotic events after replacement therapy

“…There are a few reported cases of PE in FVII deficiency [16][17][18][19][20][21][22][23][24][25][26][27]. In a few of the latter patients, Prothrombin Complex Concentrates are listed as risk factor [23][24][25].…”