Analysis of Hemorrhagic Phenotype and Cardiovascular Risk of Severe Hemophilia a Carriers and Difference with Female Working Population Control Group

INTRODUCTION: Recent studies in male subjects with haemophilia have described a prevalence of cardiovascular risk factors (CVRF) and cardiovascular events (CVE) similar to the general population. This finding has not been tested in severe haemophilia A carriers so far. We have little information about whether there is a particular bleeding profile in this group and if this tendency is able to modify cardiovascular risk in these women.

OBJECTIVES: To evaluate bleeding profile from laboratory and clinical point of view in haemophilia A carriers and working population controls; to define and to calculate CVRF, CVE and cardiovascular risk scores in severe haemophilia A carriers and controls; to analyse if there is any difference in cardiovascular risk between symptomatic severe haemophilia A carriers and general population.

PATIENTS AND METHODS: This is a descriptive, cross-sectional, non interventional, single center study. Ethics Committee evaluation and written informed consent are requested to be included for carriers and controls. The target population are severe haemophilia A carriers from our area aged between 18 and 70 years old. The control group are women from regular health laboral checkings. We evaluate bleeding, ischemic and thrombotic personal and familiar history, bleeding profile (ISTH/SSC bleeding assessment tool, ISTH BAT), factor VIII (FVIII) genetic study, complete blood count, basic biochemistry, haemostasis (aPTT, PT, fibrinogen, platelet function tests, FVIIIc, FvWAg and FvWRCo, FXIII, homocysteine, resistence to APC, antithrombin, protein C and S, 20210A prothrombin mutation), cardiovascular risk (Framingham score and Systematic Coronary Risk Evaluation Project, SCORE). The controls have been studied in the same way with the exception of laboratory studies of hemostasis. Only in controls with pathologic ISTH BAT (greater than 3), basic and primary hemostasis have been studied. To describe continuous variables we will use mean, median, standard deviation, maximum and minimum. For categorical variables will be used the percentage of every category.

RESULTS: Out of a total of 81 carriers have been identified between August 2012 to December 2013. We have evaluated 69 carriers. To achieve a confidence level of 95% with 50% heterogeneity we have recruited 138 controls. The mean age of carriers and controls was 43.7+/-15 and 41.5 +/-11.7 years old (p 0.308). In the group of carriers, the mean and standard deviation (SD) of FVIII levels were 87.2+/-35.7%, FvW:RCo 75.6 +/-30% and vWF:Ag 75.6 +/-30, 1%. We found no relationship between levels of FVIII:c and haemophilia genetic defect (34.8% substitutions, 34.8% intron 22, 27.5% mutations). 20.3% of carriers and 2.2% of controls present a pathologic ISTH BAT score (p 0.001). The table describes CVRF and cardiovascular risk scores of carriers and controls.

No personal CVE in carriers group. We found two cases of thrombophilia. They are two women from the same family with high homocysteine levels and family history of heart attack and stroke in haemophiliacs men. Most of family history of ischemia in carriers group comes from haemophiliac male relatives. Among controls only one patient has experienced heart attack and other a deep vein thrombosis. They both were older controls with CVRF. We have analysed separately the 14 symptomatic carriers (pathological ISTH BAT). This particular group has a similar Framingham score to general population but remains in a higher risk of death from vascular event (SCORE) compared to general population.

CONCLUSIONS: Low levels of FVIII do not prevent from developing vascular risk factors in syntomatic carriers of severe haemophilia A. In our media, we describe a higher prevalence of HBP, sedentariness, obesity and overweight in the group of carriers than in controls. The risk of suffering a cardiovascular event and the risk of death because of a cardiovascular events is higher in the group of severe hemophilia A carriers than in the working control population, even in symptomatic carriers.