The Impact of Prothrombotic Mutations on Factor Consumption in Adult Patients with Severe Hemophilia

Abstract

About 10% of patients with severe hemophilia exhibit a milder clinical phenotype with less frequent bleeds. Among many other factors, coinheritance of prothrombotic mutations have been proposed to act as modulators of clinical severity in severe hemophilia. We conducted a study to evaluate the impact of 3 prothrombotic mutations (factor V Leiden, factor II, and methylenetetrahydrofolate reductase mutations) on clinical phenotype of patients with severe hemophilia in our institution. For this purpose we compared the average annual factor concentrate consumption between carriers and noncarriers of prothrombotic mutations. A total of 38 hemophilia A and B patients with factor levels less than 1 were recruited between October 2006 and October 2007. Prothrombotic mutations were detected in venous blood using polymerase chain reaction amplification technique. Eighteen patients (47%) carried no prothrombotic mutations. The remaining 20 patients (53%) were found to be carriers of either 1 or 2 mutations. Median age in both carrier and the non-carrier groups was 27 years. None of the patients in either group gave a history of thromboembolic event. Median annual factor concentrate consumptions in carriers and noncarriers were 610 +/- 530 units/kg and 770 +/- 670 units/kg, respectively (P = .203). Our results demonstrated no significant difference in annual factor concentrate consumption between carriers and noncarriers of prothrombotic mutations. Considering that average annual factor consumption is a surrogate indicator of clinical phenotype, we concluded that coinheritance of prothrombotic mutations was not associated with occurrence of different clinical phenotypes in severe hemophilia.

Correlation between phenotype and genotype in a large unselected cohort of children with severe hemophilia A

“…Several retrospective studies have looked at the effect of coinheritance of prothrombotic mutations, with contradictory results. 6,9,[14][15][16][17][18][19][20][21][22][23][24][25] Some studies have found that severe hemophiliacs carrying a prothrombotic mutation have a milder phenotype characterized by older age at diagnosis, 25 older age at first bleed, 15,17,26 lower annual bleeding frequency, and less arthropathy. 21,22 In contrast, other studies failed to find significant differences in severity of disease attributable to the presence of a prothrombotic mutation.…”

“…21,22 In contrast, other studies failed to find significant differences in severity of disease attributable to the presence of a prothrombotic mutation. 6,14,23,24 These conflicting results, together with the low prevalence of inherited prothrombotic mutations in hemophiliacs, is such that it is unlikely that such prothrombotic risk factors will account for much of the heterogeneity in disease severity seen in patients with hemophilia.…”

Interpatient Phenotypic Inconsistency in Severe Congenital Hemophilia: A Systematic Review of the Role of Inherited Thrombophilia

“…In contrast with these observations, several other groups did not observe a decrease in bleeding frequency in severe hemophiliacs carrying the factor V Leiden. [30][31][32][33][34][35][36][37][38] Arbini and colleagues 30 evaluated 21 patients with severe hemophilia A or B and a milder clinical phenotype and found that only one patient (with hemophilia B) was a carrier of the factor V Leiden mutation. Similarly, Arruda and colleagues 32 found that 3 of 113 patients with hemophilia of different severity had coinherited the factor V Leiden mutation, but the researchers did not detect any difference in the frequency of bleeding episodes or response to therapy between patients who did or did not have the mutation.…”

Influence of Imprinting of an X Chromosome and of the Methylene Tetrahydrofolate Reductase (MTHFR) 677C>T Polymorphism on FVIII Activity

“…The MTHFR 677TT genotype was previously reported to slightly improve the clinical phenotype in severe hemophilia A patients [42][43][44][45]. In 2009 Ar et al described a lower annual factor concentrate consumption in hemophilia A and B patients who carried a prothrombotic mutation -either factor V Leiden, factor II or a MTHFR genetic variant [46]. However, the difference was not statistically significant (p=0.203).…”