Hemophilia A and B are X-linked genetic diseases caused by mutation in the factor VIII and factor IX genes leading to coagulation disorders [2], the clinical form of which is identical [14]. They usually present as bleeding after minor insignificant trauma or as a spontaneous hemorrhage [15]. Based on the plasma levels of factors hemophilia patient may develop mild, moderate and severe form of the disease. Hemophilic patients develop various forms of bleeding manifestations and may present at various age depending on severity. But bleeding into a joint space, or hemarthrosis, is the hallmark of hemophilia [8]. Large joints are typically involved in various frequency. This study describes the sites and frequency of bleeding episodes among moderate and severe hemophilia along with sociodemographic profile of patients in Bangladesh.
A total of 44 hemophilia patients were included who had an average age of 21.31 ± 9.78 years (± SD) and a median age of 20 years at inclusion. Maximum patients were aged between 11 to 20 years (45.5%). Similar to our study Singh et al. also found majority (26.85%) patients between 11 to 20 years [16]. John et al. found a median age of 22 years among their participants which is also similar to our study [17]. Being a genetic disease majority of the patients suffer their first episode of bleeding at early age, but often they are late to diagnose their problem. We found a median age of first bleeding 3.5 years but the median age at diagnosis was 5 years. Similar picture was recorded by John and colleagues who reported a median age of first bleeding 1.5 years and median age at diagnosis 3 years [17].
Only moderate and severe hemophilia patients were included in this study—56.8% patient had moderate and 43.2% had severe disease. Contrary to findings from other studies [3, 16] we found a lower proportion of severe disease among our participants. This could be a random finding among the small sample in our study.
Most of the patients hailed from rural areas (56.8%) which might be a reflection of the general rural–urban distribution of the population in the Bangladesh. According to The World Bank estimates by 2019 Bangladesh had 62.9% population living in rural areas [18]. As majority of the participants in our study were young students (43.5%) we found majority having primary education (43.2%) followed by 25% having Secondary School Certificate (SSC). Most of the people came from middle socio-economic category followed by lower socio-economic category. This certainly echoes the public health facility utilization pattern by the people of Bangladesh as described by Mannan [19]. People from lower economic strata usually take services from public health facility and the present study was conducted in the largest government-run facility the country.
We found respectively 90.9 and 9.1% hemophilia A and B patients. This corresponds with the proportion of inherited disorders associated with bleeding where hemophilia A is the most common disorder (72.3%) and followed by hemophilia B (11.5%). An epidemiological study conducted on hemophilia patients in Iraq showed that 72.9 and 24.8% patients were affected by hemophilia A and B respectively [20]. While a hospital-based study in North India found approximately 94% and 6% cases of hemophilia A and B respectively. This indicate that hemophilia B might present less frequently than hemophilia A causing less pursual of hospital services, which is also supported by Franchini and Mannucci [21].
Among our patients, nearly one-third had a delayed diagnosis, and for 14% patients the delay was ≥ 10 years. This indicates there is still a gap in the detection and management of hemophilia cases. The diagnosis is often delayed if the disease is of mild or moderate severity, because the bleeding tendency is manifested at an older age [14, 22]. Moreover, spontaneous bleeding is uncommon in mild cases, and recurrent joint bleed may be present in up to 25% of moderate cases [22] leading to delayed suspicion. Minhas and Giangrande pointed out several important observations for the delay in the diagnosis of hemophilia. According to them failure among physicians to recognize the disease at their presentation is the primary reason for the delay [19]. Diagnostic confusion arises when patient present to the emergency department after accident with bruises or ecchymoses instead of hemarthrosis. However, in countries where circumcision is practiced and preferred at an early age, the first bleeding manifestation may occur during circumcision and hemophilia could be suspected and diagnosed. For instance, Qasim, Asif and Hasan in a study [23] conducted in Pakistan noted that prolonged bleeding during circumcision led to diagnosis of haemophilia in as many as 47.1% of their participants. But, lack of facilities to measure factor VIII, IX, von Williband factor and factor VIII inhibitor levels might often hamper diagnostic evaluation in suspected cases in low resource settings [24].
Every participant in our study had at least one episode of spontaneous bleeding, and bleeding from minor and major trauma. The most common target joint of spontaneous bleeding was knee joint (70.5%) which was disproportionately higher than other target sites including elbow, ankle, shoulder, and hip. Joint swelling was present in nearly all patients. But three-quarter patients had any episodes of soft tissue/muscle swelling, and skin bleeding. These findings are higher than that of Mishra and colleagues who noted knee as the target joint in 57.1% participants and joint swelling in 76.6% patients [25]. Nevertheless, joint bleed or hemarthrosis is commonly the first presentation as John and colleagues found [17] and knee is the most common affected joint as Singh et al. [19] as well as Payel and colleagues [3] noted. We noted that 36.4% patients had restricted schooling or work and one patient were restricted to self-care and 59.1% had some limitation constituting 97.7% patients having at least some compromise in the joint movement due to hemophilic arthropathy.
Clinically severe disease presents with frequent spontaneous bleeding with a high frequency of joint crippling, whereas joint crippling is less common among moderate hemophilia patients [14]. We found that knee is the most common (88.6%) bleeding site followed by ankle and elbow (68.2%) and this was true for both severe and moderate disease. Median bleeding episode was high for elbow in severe disease and knee for moderate disease where bleeding episodes ranged from 1 to 40 in case of knee and 1 to 32 in case of elbow. Thigh was the most common site to have muscle hemorrhage naturally as it has the most muscle bulk and is subjected to repeated movements. Gum bleeding was present in fifty percent of the participants and was more common among severe hemophiliacs (median episode 4 vs 1 in cases of moderate disease). A considerable number of patients also had genitourinary bleeding (36.4% of total). Other forms of bleeding were less common but nonetheless present. However, we found that our pattern corresponds with the conventional knowledge regarding hemophilia [14] where large synovial joints are most commonly and frequently affected by spontaneous bleeding. The only unintuitive finding was a significantly higher median frequency of bruises and ecchymosis in moderate hemophilia patients compared to severe ones. However, the proportion of participants who had at least one event of bruise and/or ecchymosis was relatively higher in severe cases. It indicates that in the preceding two years participants of our study with moderate hemophilia had a higher number of bruising/ecchymosis events. One possibility of such an aberrant finding is the underreporting of such events by the participants with severe hemophilia. As participants were asked to recall such events from their memory the possibility of recall bias could not be excluded. Probably small bruises passed unnoticed among the severe hemophiliacs on the background of joint bleeds. Because, a careful survey of the frequency of joints bleeds among the participants indicate a non-significantly higher median number of bleeding episodes among severe cases. The major concern for hemophilia is intracranial bleeding, and sub-pharyngeal hematoma causing blockage of respiratory airway which was not found in our study.
None of the patients in our study were on prophylactic treatment. Hence a comparison of bleeding patterns between patients undergoing on-demand treatment and prophylactic treatment was not possible. However, previous studies conducted in experimental [26] and real-world settings [27] suggest that prophylactic treatment are effective in reducing bleeding frequency among hemophilia patients. So further studies exploring effectiveness of prophylactic factor replacement in hemophilia patients could be explored in the country.
In the light of our findings, and because of the fact that not all hemophilia patients and their families are enlisted in the registry, any event of sudden onset joint swelling, particularly of knee and elbow joint, in previously undiagnosed or unsuspected cases of hemophilia should be considered for exclusion of hemarthrosis and consequently of hemophilia as a priority. People with suspected thigh muscle pain and swelling should also be explored for possible presence of hemophilia.
Hemophilia has moved from a neglected and often fatal hereditary hemorrhagic disorder to that of a defined group of well-characterized molecular entities over the last three decades [28]. Developments in biotechnology and genetics have revolutionized the treatment of hemophilia by making available factors that are defective in this group of patients. Hence, an early diagnosis of hemophilia patients could be life-saving for many people as well as reduce the disability associated with the disorder. This study sorted the frequency of different forms of bleeding among severe and moderate hemophilia patients, thereby giving aid to developing a diagnostic protocol to decrease the diagnostic delay in nearly one-third of the patients.
Our study was limited in that it was conducted in a single center and only moderate or severe patients visiting the facility were included. Thus, we could study a small sample of hemophilic population. Moreover, inhibitor screening could not be done due lack of facility. However, the strength of our study is that a few studies reported a detailed history of sites of bleeding with their frequency of bleeding episodes among hemophilia patients in Bangladesh.
