Analysis of Bleeding Phenotype of Severe Hemophilia a Carriers and Comparation with a Working Population Group. Impact on Quality of Life

INTRODUCTION: We have little information about if there is a particular bleeding phenotype of severe haemophilia A female carriers. In the literature, an increased bleeding tendency is described in this group, justified even by levels of factor VIII (FVIII) very close to normal values, in absens of primary hemostasis evaluation in many cases. There is no published evidence about quality of life (QoL) of these women and the relationship between QoL and this bleeding tendency.

OBJECTIVES:

• To evalute the hemorrhagic phenotype of severe haemophilia A carrier and to compare them with the general population.

• To identify symptomatic carriers and to study from laboratory point of view the reasons for that bleeding tendency.

• To define the bleeding profile of symptomatic carriers.

• To analyze the quality of life and state of anxiety/depression in carriers and to compare them with the 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 will evaluate family bleeding, ischemic and thrombotic personal and familiar antecedents, bleeding profile (ISTH/SSC bleeding assessment tool, ISTH BAT, and pictorial blood assessment chart, PBAC), carrier genetic study, complete blood count, basic biochemistry, haemostasis (aPTT, PT, fibrinogen, platelet function tests, FVIIIc, FvWAg and FvWRCo, FXIII). QoL has been studied trough SF-36 (Spanish version 1,4 1999) and anxiety and depression states using Goldberg questionary (1998, Spanish version Gzempp, 1993).The controls have been studied in the same way except for laboratory studies of hemostasis. Only in controls with pathological ISTH BAT (greater than 3) basic and primary hemostasis have been studied.

RESULTS: Out of a total of 81 carriers 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 and standard deviation (SD) age of the carrier and controls was 43.7+/-15 and 41.5+/-11.7 years old (p 0.308). In the population of carriers, the mean and SD of FVIII levels are 87.2+/-35.7%. 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). There are 14 carriers with a pathologic ISTH BAT score (median 5.5, range 4-11). In this group we found FVIII levels less than 40% in 4 carriers, 1 thrombopathy and levels of VWF:RCo and VWF:Ag compatible with von Willebrand disease in other 4 carriers. The remaining 5 present ISTH BAT score between 4 and 6 (low), FVIII levels above 60% and no other laboratory abnormal results to justify bleeding tendency. In the 3 controls with pathologic ISTH BAT score (4-5), we have not found any hemostatic disorder from laboratory point of view. The carrier group has a higher incidence of abnormal bleeding at wounds (1.5% vs. 14.5% p 0.000), tooth extraction (3.6% vs. 11.6%, p 0.028), surgery (0% vs. 11.6 %, p 0.028) and methrorragia (13.8% vs 43.5%, p 0.000). However when methrorrragia is analysed with an objective scale of menstrual bleeding as PBAC, methrorragia incidence in carriers is similar to controls (23.2% carriers vs 31.5% controls, p 0.071). Regarding quality of life, the population of carriers presented worse scores in the domains of social activity (p 0.01) and mental health (p 0.014). In the group of symptomatic carriers there are no differences in quality of life with the control group. The control population has a higher incidence of anxiety (42.3% vs 21.7%, p 0.002), with no differences in the presence of depression.

CONCLUSIONS: In our series, women with symptomatic severe hemophilia A are those with FVIII lower than 40% or another disorder of hemostasis associated to carrier condition. The hemorrhagic symtoms able to define a severe haemophilia A carrier could be abnormal bleedings from wounds (surgical or traumatic) and in dental extractions. Quality of life in women with hemophilia is worse in the mental health and social activity fields, but for reasons other than their own bleeding phenotype.