Clinical profile and outcome of children with haemophilia A: The Royal Hospital, Oman’s experience

A retrospective descriptive cohort study was conducted, including all Omani children, younger than 13 years old, diagnosed with HA, and followed up at the Royal Hospital from 2006 to 2019. Data were retrieved from the electronic chart system, Al-Shifa, which is a comprehensive healthcare information management system implemented by the Ministry of Health. Collected data included: demographic characteristics (sex, age at presentation, nationality, city of origin), bleeding sites, number of bleeding episodes (recorded by paper diaries), FVIII level, and treatment modalities (on-demand and prophylaxis). The local prophylaxis protocol is based on the Malmo Protocol, where 20–40 IU/kg per dose are administered three times a week, usually starting after the first clinically evident joint bleed or after one year of age. The evaluated outcomes were mean annual bleeding rate (ABR) and complications (FVIII inhibitor development, CNS complications, joint arthropathy). ABR was defined as the number of bleeding events occurring per year and was calculated for the whole study population. Based on plasma factor level, persons with haemophilia were classified as mild (> 5 to < 40 IU/dL), moderate (1–5 IU/dL), or severe (< 1 IU/dL). According to the International Society on Thrombosis and Haemostasis (ISTH), a target joint is defined as a joint in which three or more spontaneous bleeds occur within a consecutive six-month period ^[16].

Exploratory analyses were carried out to describe the study population where categorical variables were described using frequencies and percentages, and continuous variables were described using means and standard deviations (SD). Statistical analysis was performed using SPSS 24.0 (SPSS, Inc, Chicago, Illinois). Ethical approval was obtained from the Ethical Committee of the Royal Hospital, Oman.

Forty-four male children diagnosed with congenital HA were identified. Their age ranged from 1 day to 9 years, with a mean of 1 ± 1.7 years. The mean period of follow-up was 7.9 ± 5.6 years. Twenty (45.5%) were diagnosed during a screening test performed in response to positive family history. The two most common complaints at presentation were muscle bleeds (29.5%) and post circumcision-bleeding (11.4%). Two had mild HA (4.5%), 29 moderate HA (66%), and 13 (29.5%) severe HA, respectively. The mean ABR was 1.8 ± 2.3, 4.6 ± 0.4, and 4.6 ± 8.6 for children with mild, moderate, and severe HA, respectively. Most were on regular prophylaxis (63.6%) with a mean ABR of 1.8 ± 4.5. The mean ABR for those who were not on prophylaxis was 4.6 ± 8.6.

Ten (22.7%) chlidren developed at least one target joint and six (13.6%) developed FVIII inhibitors. The majority with moderate (89.7%) and severe (76.9%) HA had joints affected by their haemophilia. Around half of those with moderate or severe HA developed joint arthropathy (Table 1).

The aim of this study was to explore the clinical profile and outcome of children with HA in one of the largest referral centres in Oman. The proportions of those with mild, moderate, and severe HA in our study were 4.5%, 66%, and 29.5%, respectively. A Jordanian study showed that 17%, 15.7%, 67.3% of the included cohort had mild, moderate, and severe HA, respectively ^[17]. Although this could be a random finding due to small sample size, disease severity is important for identifying bleeding patterns and treatment options. Severe HA is associated with serious spontaneous bleeding in joints, muscles, soft tissues, and life-threatening intracranial haemorrhage ^[18,19]; moderate HA causes bleeding after trauma ^[11]. Mild HA may go undiagnosed and only be diagnosed due to because of excessive haemorrhage postoperatively or after a trauma ^[20]. Easy and spontaneous bruising is the most obvious and early sign of haemophilia. This was not reported since the study analysed a hospitalised cohort.

A review article reported that around 70% of people with haemophilia have a positive family history ^[21]. In our study, around half were diagnosed after screening due to positive family history. The activity of FVIII is strongly related to inherited genetic variants. Advanced techniques in genetic analysis in haemophilia has become available in recent decades, allowing faster and more accurate data interpretation. This highlights that adequate carrier detection and genetic counselling are essential to ensure appropriate diagnosis and management; guidelines for the interpretation and classification of gene variants have been established ^[22].

Comparing the clinical profile of subgroups in our cohort showed that joint, muscle, and mucosal involvement was more commonly reported in children with moderate HA than those with severe HA. This may indicate that factors other than the level of FVIII may interfere in the clinical phenotype. Further studies are required to identify these factors and establish their correlation with bleeding rate and HA clinical manifestation.

Most children in our study were receiving prophylaxis. Conversely, results from studies in Iraq and Saudi Arabia showed that the majority of people with haemophilia received on-demand treatment ^[23,24]. A randomised clinical trial comparing prophylactic with on-demand treatment demonstrated the effectiveness of prophylaxis in young boys with severe HA; 93% of those in the prophylaxis arm had normal joints by the age of six compared with 55% in the on-demand arm ^[12]. Prophylaxis in children has shown better outcomes when initiated at early age ^[25]. Early administration of continuous prophylaxis may decrease the risk of inhibitor formation, reduce the number of bleeding events, and reduce physical impairment due to arthropathy. Consequently, this may lead to improved quality of life ^[26]. However, in our cohort, a considerable proportion of children with severe HA (39%) were not receiving prophylactic treatment, mostly due to family decisions. In our institution, prophylactic treatment is initiated for people with moderate HA after developing recurrent bleeds, especially joint bleeds. A subgroup comparison of the percentages of patients with arthropathy and target joints among those receiving prophylaxis or on-demand therapy showed comparable results. However, a definitive conclusion cannot be derived because of the small sample size and number of events.

Haemarthrosis (bleeding into joints) is one of the clinical hallmarks of HA and occurs particularly in knees, elbows, and ankles ^[3]. Our findings showed that 84% of our cohort had HA with joint involvement (bleeding and/or arthropathy). The proportion with at least one target joint (22.3%) was lower than that reported by a study carried out in six West European countries (50.3%) ^[27]. Around half of our cohort developed joint arthropathy, of whom 60% had moderate HA. This finding is uncommon. A cross-sectional study from Netherlands reported that 20% of children with moderate haemophilia had joint impairment ^[28]. However, a systematic literature review reported a prevalence of 15–77% of overt arthropathy in people with moderate haemophilia ^[29]. Variability in the reported results among studies from different countries may be explained by whether or not national management protocols recommend early prophylaxis. Moreover, people with moderate haemophilia may manifest with heterogenous bleeding phenotypes. In other words, some people with moderate HA may clinically experience severe bleeding events leading to the development of joint arthropathy. This indicates that modulators other than factor level may interfere in bleeding phenotype ^[26]. Haemophilic arthropathy is associated with chronic joint deformity, pain, muscle atrophy, impaired mobility and disability, and consequently a poor quality of life ^[4,10]. Early prophylaxis with recombinant FVIII can prevent joint damage and decrease the frequency of joint bleeding ^[12]. The introduction of a novel non-factor agent, emicizumab, has provided more protection and preservation of joints health and improved patient’s quality of life and treatment adherence ^[30,31].

We reported that around 13% of the cohort developed inhibitors; those who developed inhibitors were equally distributed between moderate and severe groups. A previous study aiming to screen for the prevalence of inhibitor development among Omani persons with severe HA reported a prevalence of 35% ^[32]. Many patient-related factors (e.g., genetic factors, immune response, ethnicity, history of preceding surgical procedure, and massive bleeding) and treatment-related factors (e.g., duration and intensity, age at the first exposure, and product types) influence the development of inhibitors ^[32,33]. Controlling the factors that are manageable may improve patient management, as inhibitor development remains a challenge with significant morbidity.

The clinical phenotype of Omani children with HA is milder compared to other studies but with similar clinical outcomes. Most of the children in this single-centre study have moderate HA, receive prophylactic treatment, and show joint arthropathy. Exploring the clinical characteristics of children with HA may help in improving diagnostic algorithms and disease management, thus improving patient care and clinical outcomes.