Study of the Prothrombin Gene 20201 GA Variant in FV:Q ⁵⁰⁶ Carriers in Relationship to the Presence or Absence of Juvenile Venous Thromboembolism

Abstract

Abstract-The G20210A transition of the prothrombin gene has been identified as a common but probably mild hereditary risk factor for venous thromboembolism (VTE). However, the prothrombin gene variant might contribute to the penetrance of thromboembolic disease in many patients with other prothrombotic defects, such as the FV:R506Q mutation. In this investigation, the A20210 allele was found in 9 of 450 healthy controls (2%). Among 89 asymptomatic FV:Q 506 carriers, 3 subjects were doubly affected (3.4%). In contrast, of 263 unrelated carriers of the FV:Q 506 mutant with a history of juvenile VTE, 30 also had the prothrombin gene G20210A variant (11.4%), including 25 of 220 patients who were heterozygous (11.4%) and 5 of 43 homozygous (11.6%) for FV:Q 506 . Thus, the A20210 allele of the prothrombin gene is significantly overrepresented in symptomatic FV:Q 506 carriers compared with healthy controls (PϽ0.0001) and asymptomatic relatives carrying the FV mutant (Pϭ0.02). Persons homozygous for the 20210A allele were not found. A statistically significant increase in the prevalence of more unusual sites of venous thrombosis at clinical onset was found in doubly affected patients (9 of 30; 30%) compared with patients without the prothrombin gene variant (26 of 233; 11.1%) (Pϭ0.004). First VTE occurred spontaneously in 53.3% of all doubly affected patients (16 of 30) and in 28.3% of all simply affected patients (66 of 233) (Pϭ0.005). Among patients with VTE preceded by circumstantial risk factors, the A20210 allele was found in 7.7% (14 of 181). We conclude that the A20210 allele of the prothrombin gene is frequently coinherited in symptomatic FV:Q 506 carriers and possibly influences age, site, and type of thrombotic onset manifestation in these patients. Key Words: genes Ⅲ variation (genetics) Ⅲ prothrombin Ⅲ factor V Ⅲ mutation Ⅲ thrombosis, venous W ithin the last decade, several variant alleles of the genes encoding proteins regulating blood coagulation, such as protein C, protein S, antithrombin, and fibrinogen, have been shown to be relatively strong but uncommon risk factors for thrombosis. [1][2][3][4] Resistance to activated protein C due to the factor (F) V Arg 506 to Gln mutation (FV:R506Q) 5-7 is the most common inherited risk factor for venous thromboembolism (VTE) and has been found at an average prevalence of 22% (range, 20% to 52%) in patients with primary VTE. 1,8 -11 Furthermore, a novel sequence variation in the prothrombin (factor II) gene, which is encoded by a 21-kb-pair-long gene localized on chromosome 11 12 has recently been identified as another common risk factor for VTE. The genetic variation is located at nucleotide position 20210 in the 3Ј-untranslated region of the prothrombin gene at which 1 nucleotide is changed (G to A transition. 13 Carriers of the A20210 allele were found in 0% to 4% of healthy controls and in 5% to 19% of patients with VTE. [13][14][15][16][17][18] Whereas the cosegregation of the FV:R506Q mutation and other well-established thrombotic risk factors has been inves...

Genetic prothrombotic mutations are common in neonates but are not associated with umbilical catheter-associated thrombosis

“…20 The prevalence of MTHFR1298 mutation in our study was comparable to the wide range of incidence reported in the United States population. 33 Previous studies have reported an increased prevalence of FVL and MTHFR mutations in neonates and children with thrombosis compared to the general population 16,34 and have also shown an increased risk of catheter-related thrombosis in patients with FVL; 12,13 however, we found no difference in the prevalence of MTHFR mutations and FVL mutation in infants with and without thrombosis.…”

Prothrombin G20210A Gene Mutation and Further Prothrombotic Risk Factors in Childhood Thrombophilia

“…However, these observations suggest that combined defects of the prothrombin G20210A variant and further prothrombotic risk factors play an important role not only in adult carriers but also in young patients. 12,15,16 Thrombosis during childhood is frequently discussed as being due to nongenetic endogenous or exogenous trigger mechanisms. [17][18][19][20] Because in our study Ϸ62% of patients with thrombosis had an underlying disease, we can support these findings.…”

“…[1][2][3][4][5][6][7][8][9] Moreover, the recently described G20210A mutation within the 3Ј-untranslated region of the prothrombin gene is a common but probably mild risk factor of venous thrombosis. [11][12][13][14][15][16] However, because of the low incidence of childhood vascular accidents, the role of such genetic defects in the childhood population is unclear.…”

Abdominal venous thrombosis in neonates and infants: role of prothrombotic risk factors – a multicentre case–control study

“…Based on various trials, evidence is accumulating that familial thrombophilia, defined as a genetically determined tendency to thrombosis, may be as a result of a combination of clotting defects (Ehrenforth et al, 1999b;Nowak-Go Èttl et al, 1999;Salomon et al, 1999). In particular, evidence has shown that inheritance of FV G1691A combined with deficiencies of protein C, protein S and anti-thrombin, as well as with the PT G20210A variant, the MTHFR T677T genotype in some studies, or enhanced Lp(a) concentrations, further increases the manifestation of early vascular accidents in children and young adults.…”