Hemophilia carrier’s awareness, diagnosis, and management in emerging countries: a cross-sectional study in Côte d’Ivoire (Ivory Coast)

Hemophilia is a congenital X-linked recessive bleeding disorder causing low levels of Factor VIII (FVIII, hemophilia A [HA]) or Factor IX (FIX, hemophilia B [HB]), occurring in approximately 1 in 5000 for HA and 1 in 20,000–30,000 for HB) live male births [1], with a similar incidence across ethnic populations [2]. The condition affects men while their female relatives are likely to be hemophilia carriers. It has been estimated that for each male with hemophilia, there are five potential female carriers [3]. Carriers are at risk of having sons with hemophilia but may also carry a bleeding risk [4].

A wide range in clotting FVIII or FIX levels is observed in carriers, independently of hemophilia severity within the family [5], which is attributed to the lyonization phenomenon (random X-chromosome inactivation during embryonic life) [6]. In HA carriers, Factor VIII levels display a considerable variability, ranging from very low to the upper limit of normal [7]. Carriers in the mild hemophilia range are defined by factor levels < 30 IU/mL, though there is no consensus about this threshold, and are labeled “symptomatic carriers” [8]. Carriers may show an increased bleeding tendency [5], even those with normal FVIII levels [9, 10]. Assessing bleeding risk is therefore mandatory in all obligate or potential carriers [5].

Previously, pedigree analysis and clotting FVIII/IX levels were applied for diagnosing hemophilia carriership [11]. Since the 1980’s, DNA analysis has been available, which ascertains hemophilia carriership in most developing countries [12, 13]. Currently, comprehensive care in hemophilia patients comprises carrier factor testing, genetic counseling, and prenatal diagnosis [5, 8, 14]. Detection of carriers is likewise relevant considering the 3.5–4% incidence of intracranial bleeding in affected male newborns [14].

In developing countries, carrier detection proves even more crucial for early hemophilia diagnosis in children, because they often die early in life due to the lack of diagnostic opportunities, absence of care facilities, and limited access to clotting factor concentrates (CFC) [15]. As circumcision generally represents the first surgical intervention in African boys with hemophilia, it is a major cause of bleeding and death [16]. Unawareness of carrier condition and bleeding risk, as well as healthcare givers’ ignorance concerning appropriate management modalities, are also major issues of concern in these countries [4, 17]. In Sub-Saharan Africa, little is known about hemophilia carriers [3, 4, 18, 19], with only very limited access to molecular testing [18, 20], and pedigree and clotting FVIII and IX analyses being often the principal screening and assessment tools.

In 2015, a twinning partnership was established between the Ivorian hemophilia treatment center (HTC) of the Centre Hospitalier universitaire (CHU) of Yopougon in Abidjan and the international HTC of the Cliniques universitaires Saint-Luc in Brussels, Belgium. This collaboration has provided the opportunity to identify and assess potential and obligate hemophilia carriers among families of patients with hemophilia (PWH) in this location.

This study aimed to identify obligate and potential carriers of hemophilia in Côte d’Ivoire and collect detailed information on their demographics, pedigree, bleeding phenotypes, and laboratory results. Yet, its ultimate goal was to provide Ivorian hemophilia carriers with appropriate counseling on the risk of bleeding and of having children with hemophilia.

Based on pedigree analysis of 81 Ivorian PWHs, we identified 83 obligate carriers (12 for HB and 71 for HA) and 248 possible carriers (30 for HB and 218 for HA), resulting in an average of four carriers per PHW. A total of 61 carriers for severe and moderate hemophilia A and B were included with 27 obligate carriers (3 for HB and 24 for HA) and 34 possible carriers (2 for HB and 32 for HA) (Table 1). The median (range) age at evaluation was 34 (13–58) years. None had previously been assessed nor were clotting FVIII or IX levels measured prior to the WFH’s twinning program, with 64% unaware of their carrier status.

Limited research has been conducted so far in Sub-Saharan countries on hemophilia carriers [3, 18, 19, 4]. Accurate and detailed data in this population are highly relevant to prevent and treat bleedings appropriately, offer genetic counseling, and diagnose hemophilia early in life in boys, with the aim to avoid death and severe complications, mainly due to intracranial bleeding and circumcision. This is the first prospective study focused on detection and assessment of Ivorian hemophilia carriers.

Pedigree analysis rendered it possible to identify 331 possible or obligate carriers, of which 61 were considered for analysis. Considering the theoretical 400 carriers linked to the 81 PHWs from the HTC of Yopougon, pedigree was of great value to target carriers within PWH’s families. In the absence of molecular testing availability, pedigree is a cost-effective and useful tool for assessing the carrier status of females from PWH’s families and can be of a great help in providing genetic counselling [24]. Family trees were sometimes large and complex to build up. It was thus repeated trough several family members, be merged, corrected, and updated in order to obtain quality data.

Despite numerous affected relatives or hemophilia-related deaths (31% after circumcision), at least in the familial forms, 64% of participants were unaware of their carrier status. None had ever been clinically assessed, nor had FVIII or IX level measurements been conducted prior to the twinning program. No carrier had ever had DDAVP testing, with only one carrier previously treated with tranexamic acid for bleeding. These data highlight the lack of the carriers’ knowledge of hemophilia inheritance and their bleeding risks, along with the ignorance of healthcare providers concerning their increased bleeding risk and bleeding management. This highly-relevant unawareness about carrier condition has already been reported in studies conducted in India and South Africa [4, 16, 25].

In our study, 44.3% of carriers reported spontaneous bleeding, with menorrhagia the most common symptom. This is in line with data from other studies focused on hemophilia carriers [9, 10], several of which were conducted in African countries [3, 4]. The rate of other unprovoked bleedings, such as epistaxis 5%, gingivorrhagia 5%, and bruising 3%, proved low in our cohort, in comparison with previous studies [4, 10]. No hemarthrosis was reported. Postpartum bleeding frequency, reported to vary in the scientific literature [4, 10, 19], was estimated at 19.6% in our cohort. Postoperative hemorrhage was reported in 4.9% of cases and dental extraction hemorrhage in 20%. In published reports, there were higher postsurgical bleeding rates, occurring mainly after tonsillectomy [5] and tooth extraction [9, 10]. Several studies conducted in Africa demonstrated lower tooth extraction bleeding rates [4, 19]. In our study, however, the number of surgical procedures was limited, with only appendectomy, caesarian section, and non-surgical tooth extractions considered. Another hypothesis to account for the low frequency of hemorrhagic symptoms could be the fact that it was the first time Ivorian carriers were questioned about their bleeding symptoms, or due to their unawareness of increased bleeding risk.

Although most carriers exhibited normal-range factor levels, a significant proportion displayed decreased factor activity (between 40 and 60 IU/mL in 12.5% ​​of HA carriers and 60% of HB carriers and < 40 IU/mL in 9% of HA carriers and 0% of HB carriers). Bleeding was recorded in the three factor level categories. Our findings are consistent with literature data indicating that carriers may exhibit variable factor levels [7], with an increased bleeding tendency for those with clotting factor levels at the distribution extremes (< 0.40 IU/mL), with mildly-reduced clotting factor levels (0.41–0.60 IU/mL) [5] or even normal FVIII activity [9, 10].

Our study displays several limitations: 1) molecular testing was unavailable to formally establish or confirm the carrier diagnosis; 2) factor levels were measured only once in 62% and twice in 38%, and this measurement could not be repeated at distance of hormonal therapy; 3) the factor activity testing was performed using only a one-stage coagulation assay; 4) we had no information on blood group and von Willebrand antigen/activity; 5) anemia interpretation proves difficult in Ivory Coast where malaria is endemic [22].

Given our study data and within the frame of the WFH’s twinning program, actions have been implemented at Yopougon’s HTC designed to improve the care of hemophilia carriers. All the participants were personally informed, using either oral or written support, about their carrier status, bleeding risk, preventive and therapeutic hemostatic measures to apply if necessary, need for a medical follow-up especially during pregnancy and upon delivery, as well as the relevance to screen all male children for hemophilia early in life and at least before circumcision. The seven carriers with a FVIII level < 50 IU/mL underwent DDAVP testing, and the use of tranexamic acid was encouraged as necessary. Educational booklets and workshops were developed and provided, highlighting the need to actively screen carriers among PWH’s families, and assess their bleeding risk by factor level measurements.

Possible and obligate carriers were provided with the same information, as there is actually no regular access to DNA analysis in Côte d’Ivoire. Mother education proves to be the cornerstone towards improving PWH’s care, as gender plays a key role in shaping the burden of care in Africa, with women more likely than men to take on caregiving activities [3]. Moreover, these educational sessions offered the opportunity to address carriers’ personal and familial psychosocial burden - not to be underestimated in developing countries [4]. This awareness campaign is scheduled to be repeated over time, with its outcome monitored trough surveys and corresponding data published.

The current study illustrates the lacking awareness of the hemophilia carrier condition and its implications for carriers, PWH’s families, and medical community in Côte d’Ivoire and by extension in other developing countries. The data highlight the need for implementing dedicated care and developing guidelines taking in account local conditions and priorities, enabling carriers to be identified, their factor levels to be assayed, and counseling on the possible chances of bleeding and having children with hemophilia.

This work underlines the significance of repeated and detailed pedigrees in carrier screening, especially in countries with limited molecular testing. Providing access to individual assessment, establishing appropriate hemostatic treatment plans, and using adjunctive hemostatic drugs (DDAVP, antifibrinolytics) should be actively promoted. Education and information of the carriers, their families, and healthcare givers form the basis enabling us to carry out this major project in Côte d’Ivoire.

This research demonstrates the benefits and strengths of a multidisciplinary and comprehensive approach in holistic hemophilia care involving all family members including females in the WFH twinning program setting.