Consensus-Based Expert Recommendations on the Management of Hemophilia A in the Gulf Region

Abstract

Background

Hemophilia A presents a significant health challenge in the Gulf region, where it has an especially high prevalence. There are several unmet needs associated with the management of hemophilia A in the region. The aim of this manuscript was to contextualize unmet management needs, provide recommendations to optimize care, and specify requirements for the establishment of gene therapy centers in the region.

Summary

An expert panel was assembled comprising ten clinical hematologists from Kuwait, Oman, Saudi Arabia, and the UAE. The Delphi methodology was used to obtain a consensus on statements relating to several aspects of hemophilia A. A consensus was reached for all statements by means of an online, anonymized voting system. The consensus statements pertain to screening and diagnosis, treatment approaches, and requirements for the implementation of gene therapy.

Key Messages

There are significant challenges that hinder the optimal management of hemophilia A in the Gulf region. The consensus statements presented provide specific recommendations to improve diagnostic and treatment approaches, promote multidisciplinary care, and optimize regional data generation and reporting. These statements also delineate the requirements for the establishment of gene therapy centers for hemophilia A in the region.

Introduction

Hemophilia A, a hereditary bleeding disorder characterized by a deficiency of clotting factor VIII (FVIII), presents a significant health challenge in Kuwait, Oman, Saudi Arabia, and the UAE; hereafter referred to as the “Gulf region.” It is a rare, X-linked recessive disorder primarily caused by mutations in the F8 gene located on the X chromosome at Xq28 [1]. The condition presents in 1 in 5,000 live births; however, its frequency is thought to be higher in the Gulf region due to high rates of consanguineous marriage. While consanguinity does not directly influence the incidences of X-linked disorders as it does for autosomal recessive diseases, it may indirectly increase the incidences of X-linked disorders such as hemophilia A by promoting a homogenous gene pool, which increases the frequency of female carriers within populations and in turn also the risk of disorder transmission [2, 3]. Hemophilia A predominantly affects males and leads to absent or reduced production of functional FVIII. FVIII is crucial in the coagulation cascade and is therefore essential in the cessation of bleeding following vascular injury. Consequently, individuals with hemophilia A experience prolonged bleeding episodes, both spontaneous and in response to trauma or post-surgical procedures, leading to the development of arthropathies and potentially life-threatening consequences [4]. Table 1 denotes hemophilia A registered cases in Kuwait, Oman, Saudi Arabia, and the UAE as published in the World Federation of Hemophilia (WFH) 2021 annual global survey report and as per more recent local data from Saudi Arabia [5, 6]. The true numbers of hemophilia A cases in Gulf countries are thought to be higher than the reported figures. This may be attributed to underdiagnosis (especially in mild disease cases), incomplete datasets (many centers are not included in epidemiological studies), and a lack of robust and consistent survey methods.

Table 1.

Reported cases of hemophilia A by country [5, 6]

Country	Population	All hemophilia cases	Hemophilia A cases	Hemophilia A with active inhibitors cases
Kuwait	4,328,553	120	100	Not reported
Oman	Not reported	Not reported	Not reported	Not reported
Saudi Arabia	35,340,680	1,396	1,134	262
UAE	Not reported	Not reported	Not reported	Not reported

Hemophilia A severity varies among affected individuals, classified into mild (6–40% FVIII activity), moderate (1–5% FVIII activity), and severe (<1% FVIII activity) categories based on the residual FVIII activity [7]. While mild and moderate forms may manifest primarily through excessive bleeding following significant trauma or surgery, individuals with severe hemophilia A are at risk of spontaneous hemorrhage and bleeding into joints and muscles, leading to chronic pain, joint damage, and long-term disability if left untreated [2].

Many pathogenic variants of the F8 gene have been characterized, including point mutations, insertions, deletions, and rearrangements/inversions [2, 8]. A recent genotyping study in Saudi Arabia that characterized causative variants of hemophilia A demonstrated that inversion of intron-22 is the most common pathogenic F8 mutation, followed by intron-1 inversion [9].

Female carriers of hemophilia A are those who inherit a pathological variant of the F8 gene. Possible carriers are all females with one or more affected relatives [10]. A recent pilot study conducted in Saudi Arabia demonstrated that 25% of carriers recruited had low FVIII levels; however, none suffered from prolonged bleeding [7]. Nevertheless, it is thought that carriers may experience increased bleeding tendencies, and some female carriers may therefore be candidates for prophylactic intervention. Since carriers can pass on the pathogenic F8 gene variant to their offspring, genetic counseling and comprehensive testing are essential to provide informed reproductive choices and ensure early diagnosis and intervention as required [7].

Accurate and timely diagnosis of hemophilia A is paramount to ensuring appropriate care and management. Diagnostic approaches include comprehensive clinical evaluation, family history assessment, and laboratory testing. The measurement of FVIII activity through coagulation factor assays, either through one-stage clotting or chromogenic assays, can help determine the severity of the disorder [2]. Additionally, genetic testing can pinpoint the specific causative mutation within the F8 gene, differentiate between hemophilia A and some types of von Willebrand disease, and facilitate genetic counseling and family planning. It also allows for the identification of potential risk for inhibitors that neutralize exogenously administered FVIII, thereby significantly complicating treatment. Inhibitor formation risk is higher in severe forms of disease associated with gross genetic defects compared with mild and moderate cases [9, 11]. In the Gulf region, most male patients are typically diagnosed very early as circumcision is mandatory from a religious perspective and, therefore, very widely performed. In infants with a family history of hemophilia A, circumcision is usually delayed until a diagnosis is confirmed or ruled out. In a large number of cases caused by de novo mutations in F8, hemophilia A is diagnosed immediately following circumcision [12].

Historically, treatment for hemophilia A primarily involved the replacement of missing or deficient FVIII through intravenous infusions of plasma-derived or recombinant FVIII products with either a standard half-life (SHL) or extended half-life (EHL); however, this approach poses challenges, including the need for frequent injections and the development of inhibitors in a subset of patients [13]. Prophylaxis, a crucial strategy of hemophilia A management, involves regular administration of FVIII clotting factor concentrates (CFCs) to prevent bleeding episodes and their associated complications. This proactive approach is particularly important for individuals with severe hemophilia A as it helps maintain a stable level of FVIII in the bloodstream, reducing the risk of spontaneous bleeding episodes [14].

Recent advances in hemophilia A management have ushered in the era of EHL FVIII products, offering prolonged protection from bleeding and the potential for less frequent infusions. Additionally, non-factor therapies such as monoclonal antibody treatments (e.g., emicizumab) have emerged as promising alternatives to traditional factor replacement therapy and have recently been introduced in the Gulf region. Furthermore, gene therapy represents a highly promising novel treatment approach, with ongoing research focusing on delivering a functional F8 gene to address the underlying genetic defect [2].

This consensus manuscript delves into clinical aspects of hemophilia A in the Gulf region, exploring unmet needs and opportunities specific to the region. There are several factors regional nuances that make the landscape of hemophilia management in the Gulf region unique. For example, FVIII activity and inhibitor detection assays are unavailable in remote areas and are limited to established tertiary centers. Remote areas within the region also suffer from a shortage of specialized staff and sophisticated laboratory facilities. Furthermore, the fragmentation of healthcare systems in the region coupled by frequent staff turnover at treatment centers present significant challenges. Crucially, there is a paucity of region-specific data pertaining to hemophilia and a marked disparity in insurance coverage between local and expatriate subpopulations in these countries. In this manuscript, we also discuss the significance of early diagnosis and access to comprehensive, multidisciplinary care in improving the quality of life for individuals with hemophilia A. Finally, we will highlight current treatment options and provide insights into the emerging therapeutic strategies that hold the potential to transform the landscape of hemophilia A management in the Gulf region.

Methods

Assembly of Expert Panel

An expert panel was established comprising ten consultant hematologists with vast clinical experience in the management of hemophilia A from across the Gulf region, namely Kuwait, Oman, Saudi Arabia, and the UAE. The panel convened on August 10 and 25, 2023 to discuss the landscape of hemophilia A in the region in the context of screening and diagnosis, management options, current unmet needs, and opportunities to optimize care delivery.

Literature Review

A literature review was conducted using the PubMed database to identify pertinent treatment guidelines, recommendations, randomized controlled trials, and observational studies to allow for the generation of evidence-based consensus statements. The 2020 WFH hemophilia management guidelines were used as a basis for the formulation of some statements [13]. All other publications identified were consulted solely as guiding resources.

Survey

The expert panel completed a 12-question survey via an online platform, which aimed to gather insights into their clinical experience managing hemophilia A, with special focus on patient characteristics, disease severity, and treatment selection considerations.

Development of Consensus Statements

Consensus statements relating to clinical aspects of hemophilia A were jointly developed by the ten-membered expert panel, of whom nine members comprise the team of authors. The developed statements were largely congruent with international guidelines developed by the WFH; however, evidence-based recommendations were made to align them with regional clinical practice, with consideration of the nuances of specific patient populations and local healthcare infrastructures. The expert panel also reviewed relevant published findings from various randomized controlled trials and observational studies during the development of the consensus recommendations. Each consensus statement was critically evaluated and modified as required by all members of the panel. The Delphi technique was used to reach a consensus on all statements. Panel members anonymously voted on each statement. Voting options were “strongly agree”, “agree,” “neither agree nor disagree,” “disagree,” “strongly disagree,” and “abstain/unable to answer.” A consensus was considered when ≥90% of experts chose to “strongly agree” or “agree” with a particular statement.

Results

The expert panel reached a consensus on four statements pertaining to screening and diagnosis. These statements emphasize the need to enhance the availability of diagnostic and monitoring tests and genetic counseling in the region. They also highlight the need to raise awareness via initiatives aimed at physicians and outreach programs to optimize the detection of disease cases. These statements are listed in Table 2.

Table 2.

Consensus statements pertaining to screening and diagnosis

Consensus statement	Agreement level, %
There is a substantial need to enhance the accessibility and availability of diagnostic and monitoring tests for hemophilia A across treatment centers in the Gulf region. Expanding the infrastructure for laboratory facilities, including assays for accurate diagnosis, inhibitor detection, and monitoring of treatment efficacy is crucial to ensure timely and comprehensive care	100
Whenever feasible, genetic counseling and analysis should be made available to all individuals with clinically suspected hemophilia or in cases with a confirmed laboratory diagnosis to identify the specific genetic variant associated with the disease	100
There is a need to raise awareness about mild bleeding disorders, including hemophilia A, among physicians across various subspecialties and healthcare professionals working in accident and emergency departments within the Gulf region	100
Establishing outreach programs is recommended to optimize the detection of hemophilia. This involves conducting initiatives aimed at enhancing disease awareness among healthcare professionals in different regions and conducting practical workshops and onsite training sessions for laboratory technicians, nurses, physiotherapists, and physicians	100

The panel reached a consensus on nine statements pertaining to the management of hemophilia A. These statements highlight the importance of providing individualized care, using multidisciplinary teams, ensuring the availability of alternative treatment options, and establishing updated management guidelines for use in the Gulf region. These statements are listed in Table 3.

Table 3.

Consensus statements pertaining to management

Consensus statement	Agreement level, %
Prophylaxis with CFCs or emicizumab is recognized as the standard of care for individuals with moderate and severe hemophilia A and is crucial in mitigating bleeding episodes and preserving joint health in affected individuals	100
The choice between SHL and EHL CFCs is dependent on several factors, including patient preferences for infusion frequency, cost, availability, and individual response to treatment	100
In all cases, hemophilia treatment plans should be highly individualized, with decisions made in close consultation with a hemophilia specialist who can recommend the most appropriate and effective treatment approach tailored to the specific needs and clinical profiles of individual patients	100
Patients who develop inhibitors must have ready access to immune tolerance induction (ITI) therapy, as well as appropriate hemostatic agents for bleeding control and surgical interventions when necessary	90
Bypassing agents should be accessible to patients with inhibitors who respond inadequately to increased factor doses, ITI therapy, and emicizumab, thus ensuring the availability of alternative treatment options for individuals with hemophilia A and inhibitors	100
In emergency care situations for bleeding episodes, individuals with hemophilia should receive immediate assessment and attention, irrespective of the perceived severity of the complication, as proactive care is needed to prevent rapid deterioration	100
It is recommended that each patient with hemophilia is provided with an unobtrusive identification card, designed to offer essential information in case of emergencies. These cards should include details about patient condition, the current treatment regimen, and emergency contact information, ensuring prompt and informed medical care during unexpected critical situations	100
Utilizing multidisciplinary care teams that include pediatric/adult hematologists, orthopedic surgeons, physiotherapists, dentists, psychologists, nurses, and social workers as integral components of a comprehensive care approach will significantly enhance patient outcomes and alleviate the disease burden associated with hemophilia. This multidisciplinary care approach promotes holistic, patient-centered care, addressing medical aspects as well as the physical, dental, orthopedic, psychological, and social needs of individuals with hemophilia A	100
It is recommended that healthcare authorities publish updated guidelines pertaining to the management of hemophilia in the Gulf region. These guidelines should include standards of care, protocols for diagnosis and treatment, and directives pertaining to the establishment of multidisciplinary care teams and specialized treatment centers	100

Crucially, the expert panel reached a consensus on 12 statements pertaining to the implementation of gene therapy in the region. These statements specify requirements for gene therapy centers and are listed in Table 4.

Table 4.

Consensus statements pertaining to gene therapy

Consensus statement	Agreement level, %
It is crucial to establish robust systems for monitoring and efficiently integrating approved advanced therapies for hemophilia A within the healthcare systems of Gulf countries	100
A formal standard of care for hemophilia A should be defined, encompassing clear guidelines that specify when gene therapy is indicated as a viable treatment option	100
Gene therapy centers should collaborate with private biopharmaceutical companies to develop and integrate companion diagnostics designed to assess patient eligibility and monitor treatment response before and after gene therapy	100
Gene therapy centers must have a dedicated team of hematologists and healthcare professionals with expertise in the management of hemophilia A. Staff should have expertise in the complexities of gene therapy, patient care, and the monitoring of treatment outcomes	100
Gene therapy centers should be accredited by national healthcare authorities and compliant with international healthcare standards and regulatory requirements	100
Gene therapy centers should be subject to rigorous quality control measures, including comprehensive tracking of healthcare personnel expertise, workflow and clinical procedures, treatment volumes, patient outcomes, and adverse events. Accreditation renewals should be dependent on findings from regular audits/compliance inspections	100
Gene therapy centers should be equipped with cutting-edge medical facilities, including advanced laboratories for factor activity and inhibitor testing, specialized infrastructure for gene therapy administration, and emergency response capabilities	100
Care provided at gene therapy centers should prioritize patient well-being and include comprehensive support services via multidisciplinary teams, including patient and family education, genetic counseling, management of comorbidities, and psychosocial support	100
Gene therapy centers must have established protocols for managing unexpected adverse events or complications related to treatment, ensuring rapid response and optimizing patient safety	100
Healthcare staff at gene therapy centers should undergo frequent training and education to stay updated on the latest advancements in gene therapy and hemophilia management guidelines	100
Gene therapy should be accessible to all eligible individuals with hemophilia A within the Gulf region to ensure equity in healthcare access	90
Engaging healthcare authorities and the central leadership of countries is crucial in decision-making processes regarding the establishment of gene therapy centers in the Gulf region. Involving these key stakeholders will ensure a coordinated and strategic approach to the introduction and accessibility of gene therapy	100

The expert panel reached a consensus on four statements pertaining to regional data generation and reporting. These emphasize the need to actively engage in data collection and research initiatives and promote comprehensive data reporting to the WFH. These statements are listed in Table 5.

Table 5.

Consensus statements pertaining to data generation and reporting

Consensus statement	Agreement level, %
There is a pressing unmet need for region-specific data generation regarding hemophilia A within the Gulf region. Comprehensive and localized epidemiological, clinical, and genetic data are essential to better understand the prevalence and clinical spectrum specific to the region, thus enabling tailored strategies for improved patient care	100
Existing treatment centers and novel gene therapy centers should actively engage in data collection and research initiatives, potentially in collaboration with dedicated research institutions and universities	100
There is a significant need to establish robust national registries dedicated to storing comprehensive data on hemophilia A and to actively promote data reporting from countries in the Gulf region to the WFH.	100
There is a critical need for enhanced collaboration and data sharing among hemophilia treatment centers in the Gulf region to strengthen the robustness and accuracy of national data reported to the WFH and to facilitate the transition of patients from pediatric to adult care	90

Discussion

Hemophilia A in the Gulf Region

Hemophilia A poses significant challenges to affected individuals and wider healthcare systems in the Gulf region. Left untreated, patients with hemophilia can experience joint and muscle bleeding, leading to pain, disability, and impaired quality of life [4]. The management of hemophilia A has evolved significantly over the years, with advances in diagnosis, treatment modalities, and comprehensive care approaches. FVIII products and bypassing agents have been approved for clinical use by healthcare authorities in the Gulf region for a number of years. Emicizumab was approved in Saudi Arabia in 2020 and is also widely available regionally. However, the disease landscape in the Gulf poses unique challenges that warrant specific considerations. Recent survey data indicate that the number of patients with hemophilia A linked to care varies considerably between clinics/institutions, ranging from 0 to 10 patients at some centers to over 100 patients at large tertiary centers (shown in Fig. 1) [12].

Fig. 1.

Number of hemophilia A patients (pediatric patients and adults) linked to care at the clinic/institution of each panel member (number of respondents = 10) [12].

Diagnosis of Hemophilia A

Many typical symptoms of hemophilia A are shared among other bleeding disorders, such as von Willebrand disease and platelet disorders; hence, accurate diagnosis is essential to ensure patients receive the appropriate treatment. Coagulation tests such as prothrombin time and activated partial thromboplastin time are used to assess the function of the coagulation cascade. Additionally, several types of FVIII assay, including chromogenic and fluorogenic clotting assays, are capable of specifically quantifying FVIII activity in the blood and are therefore valuable diagnostic and monitoring tools [15–17]. Other assays such as the Bethesda and Nijmegen-modified Bethesda assays can be used to test for the formation of inhibitors [18, 19]. Testing for inhibitor development, the most serious treatment-associated complication, is a crucial prerequisite for all comprehensive hemophilia treatment programs, and it is recommended that newly diagnosed patients with hemophilia A undergo inhibitor screening every 6–12 months [20]. More frequent screening should be considered for patients experiencing recurrent bleeding or for whom there is clinical suspicion of inhibitor risk [13].

In the Gulf region, there is a significant disparity in access to specialized laboratory tests. FVIII activity assays and inhibitor detection assays are unavailable in remote areas where some centers lack necessary laboratory facilities and trained personnel. These tests are mostly available in established tertiary and some secondary care centers. The shortage of specialized staff in some regions further compounds the challenge of carrying out critical laboratory tests and interpreting results accurately. Consequently, there is an urgent need to improve the accessibility and availability of diagnostic and monitoring tests for hemophilia A across treatment centers in the Gulf region.

Genetic assessment in hemophilia is crucial for diagnosing challenging cases, predicting inhibitor risk, and guiding management decisions [21]. It is recommended that all individuals with clinically suspected hemophilia or a confirmed laboratory diagnosis undergo genetic counseling and assessment to identify the specific genetic variant associated with the disease. This is congruent with global WFH recommendations [13]. Identified female carriers should also receive genetic counseling if available. In the Gulf region, genetic testing facilities are mostly unavailable in treatment centers. In select cases, patient samples are sent abroad for genetic assessment to international reference laboratories, but genetic assessment is typically not conducted for previously diagnosed cases. In the UAE, genetic testing may be available via the Emirati Genome Project; however, it may take several months to obtain results [12]. Crucially, genetic testing strategies are led by phenotypic features assessed via coagulation screening and patient/family history evaluation, so it is essential that these results are made available to the genetic testing laboratory. Accurate genetic variant identification is dependent on supporting clinical and patient/family history data [22]. There is an unmet need to improve the genetic testing capabilities of hemophilia across treatment centers in the Gulf region and to promote data sharing and collaboration between centers to optimize the reliability of genetic assessment.

There was a consensus among the expert voting panel that there is a need to raise awareness about mild bleeding disorders, including hemophilia A, among physicians across various subspecialties and healthcare professionals working in accident and emergency departments within the Gulf region. Establishing outreach programs to optimize awareness and detection of hemophilia is warranted [23]. Outreach programs can utilize several approaches for this purpose, such as conducting awareness-enhancing initiatives and practical workshops for laboratory technicians, nurses, physiotherapists, and physicians across areas within the Gulf region [24]. Furthermore, outreach programs can aim to establish clinics in remote areas attended by experts from established tertiary centers to deliver training to local caregivers on diagnostic techniques in resource-constrained settings and to establish efficient referral pathways to tertiary care [24].

Management of Hemophilia A

In managing moderate and severe hemophilia A, prophylaxis with CFCs or emicizumab is recognized as the standard of care and is crucial in mitigating bleeding episodes and preserving joint health [25]. Episodic treatment is not recommended as a long-term management option as it is ineffective in altering the natural history of spontaneous bleeding and managing associated complications [26, 27]. In resource-constrained settings, low-dose prophylaxis regimes may be adopted in managing individuals with hemophilia A to minimize costs [13]. Low-dose prophylaxis regimes consume therapeutic agents at a similar rate to episodic treatment while significantly lowering spontaneous bleeding rates and better preserving joint health [28–30]. In the Gulf region, intermediate-dose regimes are occasionally used to optimize patient adherence, while low-dose regimes are rarely used.

The choice between SHL and EHL CFCs depends on several factors. Use of SHL products necessitates frequent injections for prophylaxis, which may cause the need for central venous access devices in pediatric patients and reduced adherence in adults [31]. In comparison, EHL products reduce the number of infusions needed to maintain adequate FVIII levels and protect against spontaneous bleeding [13]. In all cases, the choice of therapy is also dependent on patient preference, cost and insurance coverage, availability, and individual responses to specific agents. Treatment decisions must be made jointly by the patient in close collaboration with a hemophilia specialist capable of recommending the most appropriate and effective treatment approaches tailored to the specific needs and clinical profile of the patient. In a survey conducted among members of the expert voting panel, efficacy expressed by annualized bleeding rate was identified as the most important factor considered when recommending treatment to patients with hemophilia A (shown in Fig. 2).

Fig. 2.

Factors considered by hematologists in the Gulf region when recommending treatment for hemophilia A (number of respondents = 10) [12].

The formation of inhibitors is the most significant complication associated with hemophilia A management and is associated with higher risks of musculoskeletal complications, pain, overall disease burden, and treatment challenges [13]. Patients who develop inhibitors must have ready access to immune tolerance induction (ITI) therapy, as well as appropriate hemostatic agents for bleeding control and surgical interventions when necessary, as indicated in international guidelines published by the WFH [13]. ITI has an inhibitor eradication success rate of 70–80% in severe hemophilia A [32–34]. Patients with inhibitors who respond inadequately to increased factor doses, ITI therapy, and emicizumab should have access to bypassing agents as treatment alternatives with distinct mechanisms of action.

There was a consensus among the expert panel that individuals with hemophilia A must be able to receive immediate assessment and care in emergency situations for bleeding episodes, irrespective of the perceived severity of the complication as proactive care is needed to prevent rapid deterioration [21, 35]. Healthcare authorities in Gulf states should establish systems and protocols that allow for immediate access to emergency care for individuals with hemophilia. This is in alignment with international WFH guidelines. Furthermore, it is recommended that healthcare authorities in the region establish identification systems using physical cards that are designed to be unobtrusive and convenient for the patient to store and carry. The card should include printed details about the patient condition, current treatment regimen, and emergency contact information. This initiative would ensure prompt and informed medical care delivery for patients with hemophilia A in the region during unexpected critical situations.

Multidisciplinary Care for Hemophilia

Promoting multidisciplinary care for hemophilia in the Gulf region is crucial to enhance patient quality of life and overall outcomes. The utilization of multidisciplinary care teams that encompass orthopedic surgeons, physiotherapists, dentists, nurses, and social workers as integral components of a comprehensive care approach can significantly alleviate the burden of disease on individuals and on the healthcare system via improved health outcomes and optimized resourcing. Adopting a patient-centric approach goes beyond addressing the medical aspects of hemophilia and encompasses the broader spectrum of physical, dental, orthopedic, psychological, and social needs of affected individuals [21].

However, there are challenges associated with adopting multidisciplinary care in the Gulf region. First, it is difficult to identify healthcare personnel of different subspecialties willing to participate in hemophilia clinics. To address this lack of interest, initiatives to engage physicians in hematology must be undertaken, such as organizing conferences for physicians of different subspecialties dedicated to hematology/hemophilia [12]. Another challenge pertaining to the implementation of multidisciplinary care is frequent staff turnover in treatment centers. Finally, fragmentation of healthcare systems also represents a significant challenge, making it difficult to foster collaboration between subspecialties. For example, in Kuwait, there are dedicated medical centers for different subspecialties, and there is a lack of centers wherein physicians of different subspecialties work together [12]. In contrast, other centers in the Gulf region such as the Sultan Qaboos University Hospital in Oman and established tertiary hospitals in Saudi Arabia and the UAE have close collaboration between different departments, providing physiotherapy, dental, and orthopedic services to patients with hemophilia within the same institution. In these centers, it would be easier to establish multidisciplinary care teams for holistic, patient-centric care delivery [12].

It is recommended that healthcare authorities in the region publish updated guidelines pertaining to the management of hemophilia. These guidelines should include standards of care, protocols for diagnosis and treatment, and directives pertaining to the establishment of multidisciplinary care teams and specialized treatment centers, with the aim of ensuring uniform, optimal care for all individuals living with hemophilia in the Gulf region.

Gene Therapy in Hemophilia A

The advent of gene therapy represents a novel approach in the management of hemophilia A. While treatment approaches have historically relied on regular factor replacement infusions to control bleeding episodes, gene therapy seeks to address the underlying genetic cause of the disorder by introducing a functional F8 gene into the patient to enable the production of endogenous FVIII [36]. This reduces the need for frequent infusions and has the potential to significantly improve the quality of life for individuals with hemophilia A [37]. While challenges related to immunogenicity and individual variability exist, gene therapy holds great promise and underscores the evolving landscape of hemophilia A treatment [38].

Gene therapy has demonstrated favorable safety and efficacy outcomes in recent studies [39–41], and holds immense transformative potential in the landscape of hemophilia management, offering patients the prospect of a significantly improved quality of life with reduced treatment burden. Clinical trials for investigational gene therapy products are underway across the world, and it is anticipated that these therapies will obtain widespread regulatory approval for clinical use in the near future. It is crucial that healthcare authorities in the Gulf region establish robust systems for monitoring and integrating advanced therapies for hemophilia A, including gene therapies, within healthcare systems. There was a consensus among the expert panel that the current level of evidence sufficiently demonstrates the efficacy and clinical utility of gene therapy in the context of hemophilia management in the region, with 100% of panel members indicating that “gene therapy is important to advance the care of severe adult patients with hemophilia A [12].” However, there are several barriers that hinder the implementation of gene therapy for severe hemophilia A in Gulf countries. Cost and insurance/reimbursement issues were identified as the two most important barriers to address (shown in Fig. 3).

Fig. 3.

Barriers to implementing gene therapy for severe hemophilia A in Gulf countries as per a panel of expert hematologists in the region (number of respondents = 10) [12].

Moreover, a formal standard of care should be defined, encompassing clear guidelines that specify when gene therapy is indicated as a viable treatment option. These treatment eligibility criteria should be aligned with the latest international recommendations. Currently, there are challenges associated with utilizing gene therapies in specific populations that warrant special consideration. First, preexisting immunity to AAV vectors represents a challenge. Studies demonstrate that the presence of antibodies against AAV significantly diminishes vector delivery [42]. There is a need to investigate the seroprevalence of AAV vectors among subpopulations within the Gulf region to assess the potential utility of gene therapy. In addition, impaired liver function may be a deterrent for gene therapy eligibility as transient liver toxicity as well as elevated serum aminotransferase and other liver enzyme levels have been reported in patients following AAV transduction [43]. It is noteworthy that these effects can likely be controlled effectively with corticosteroids [38]. It is recommended that healthcare authorities collaborate with biopharmaceutical companies to develop companion diagnostics for hemophilia that can be used to assess patient eligibility for gene therapy.

Future of Gene Therapy for Hemophilia A in the Gulf Region

The panel of expert hematologists specified key requirements for potential gene therapy centers in the region to ensure that care delivery adheres to the highest international standards. First, gene therapy centers must employ dedicated teams of specialist hematologists and healthcare professionals with expertise in the management of hemophilia. These centers must also be subject to stringent compliance/quality control measures and frequent inspections by national healthcare authorities to determine accreditation status. These approaches would ensure that each center maintains international standards and meets regulatory requirements for quality and consistency of care delivery.

It is also recommended that gene therapy centers have access to the latest medical facilities, including advanced laboratories for coagulation, factor activity, and inhibitor testing, as well as the specialized infrastructure required for gene therapy administration and monitoring. It is crucial that comprehensive care centers for hemophilia possess advanced laboratory testing capabilities for timely diagnosis and treatment initiation [13, 20]. Furthermore, care provided at novel gene therapy centers should prioritize patient well-being and include comprehensive support services via multidisciplinary teams, including patient and family education, genetic counseling, management of comorbidities, and psychosocial support. These aspects are vital components of comprehensive care, a key principle of care outlined by the WFH [13]. Other recommendations specified by the expert panel pertaining to gene therapy centers include establishing protocols for management of adverse events or treatment-related complications and ensuring that healthcare personnel at gene therapy centers receive ongoing training and education to stay updated on the latest advancements in gene therapy and hemophilia management guidelines.

Finally, there was a consensus among the panel of hematologists that gene therapy should be accessible to all eligible individuals with hemophilia A within the Gulf region to ensure equity in healthcare access. This is a major challenge in Gulf countries due to the disparity in insurance coverage between expatriate and local subpopulations. In most Gulf countries, including Saudi Arabia and the UAE, nationals are fully covered by governmental medical insurance policies, whereas expatriates must pay via private insurers. Large proportions of expatriate subpopulations in Gulf countries are unable to afford premium insurance. As such, many reimbursement policies for expatriates often do not cover essential services and medications. Due to the high cost of advanced gene therapies, eligible patients with hemophilia may be unable to access the care they need. In a survey conducted among the panel of expert hematologists, 40% of respondents indicated that over 20% of their adult patients with severe hemophilia A were expatriates (shown in Fig. 4) [12].

Fig. 4.

Proportion of adult patients with severe hemophilia A who are expatriates as per a panel of expert hematologists in the region (number of respondents = 10) [12].

The high cost of gene therapies and issues regarding insurance coverage for expatriate subpopulations are significant barriers to the adoption of gene therapy for hemophilia in the Gulf region. A potential solution to these challenges is the conception of value-based agreements to balance investment responsibilities and ease financial constraints for multiple stakeholders, including healthcare authorities and insurance providers. Adopting gene therapy in the region will likely result in cost savings to the healthcare systems in the long term due to improved patient outcomes, lowered consumption of prophylactic FVIII therapies, and fewer hospitalizations for bleeding episodes and emergency care. A cost-effectiveness analysis based on the healthcare system of the USA forecasted that over a period of 10 years, the cost of gene therapy is USD 700,000 less than standard prophylactic factor replacement therapy. The model also predicted that gene therapy provides 1.71 additional quality-adjusted life years compared with prophylaxis [44]. This study demonstrates that adoption of gene therapy has the potential to be cost saving, improve the quality of life and reduce bleeding events for patients, and produce long-term benefits for the overall healthcare system. It is important that cost-effectiveness studies specific to the Gulf region are conducted to demonstrate the feasibility of adopting gene therapy in these countries. Additionally, to recognize the full potential of gene therapy for hemophilia, it is crucial to engage healthcare authorities and the central leadership of countries in joint decision-making processes regarding the establishment of gene therapy centers in the Gulf region. Involving these key stakeholders will ensure a coordinated and strategic approach to the introduction and accessibility of gene therapy, ultimately benefiting individuals with hemophilia A.

Regional Data Generation and Reporting

There is a pressing unmet need for region-specific data generation within the Gulf region. Comprehensive and localized epidemiological, clinical, and genetic data are essential to better understand the prevalence and clinical spectrum of hemophilia specific to the region, thus enabling tailored strategies for improved patient care. Existing treatment centers and novel gene therapy centers should actively engage in data collection and research initiatives, potentially in collaboration with dedicated research institutions and universities. There are also pressing needs to establish robust national registries dedicated to storing comprehensive data on hemophilia and to actively promote data reporting from countries in the Gulf region to the WFH. However, there are significant regulatory challenges associated with data collection and reporting in the Gulf region. Local regulations pertaining to medical data are highly restrictive and mostly prohibit data sharing with external third parties. The prospective establishment of national hemophilia registries in the region will therefore require alignment with local health ministries. While Kuwait already has approved pathways for patient data reporting to international data registries, other countries in the region mostly lack effective systems for data reporting.

The expert panel also highlighted that there is a critical need for enhanced collaboration and data sharing among hemophilia treatment centers in the Gulf region to facilitate the transition of patients from pediatric to adult care. As per survey data, patients in the region mostly transition from pediatric to adult care between 14 and 16 years of age [12]. The effective transition to adult care is an important component of comprehensive care as per WFH guidelines [13]. It also represents a challenging period for patients in the Gulf region due to the fragmentation of healthcare systems and lack of collaboration between centers. While some reputed centers such as the Sultan Qaboos University Hospital in Oman and other well-established tertiary hospitals have pediatric and adult hematology departments within the same center, most hemophilia treatment centers do not offer services for pediatric patients and adults within the same facility. When transitioning to adult care, patients must therefore present at a new treatment center, and there are often logistical challenges such as transportation issues and the unavailability of patient data. To ensure effective continuity of care and optimized patient adherence, it is crucial to implement initiatives to foster collaboration and data sharing among treatment centers in the region.

Conclusion

There are several unmet needs that hinder the optimal management of hemophilia A in the Gulf region. The panel of experts in clinical hematology reached a consensus on statements pertaining to screening and diagnosis, treatment approaches, gene therapy requirements, and data generation in this disease area.

Acknowledgments

Medical writing support was provided by Luqman Khan of Connect Communications, Dubai, UAE, and funded by BioMarin Pharmaceuticals, Dubai, UAE. The authors acknowledge the valuable insights shared by Dr. Murtadha Al-Khabori, Consultant Hematologist at Sultan Qaboos University Hospital, Oman, and thank him for his attendance and participation in the consensus meetings conducted on August 10 and 25, 2023.

Conflict of Interest Statement

Ali Mullah-Ali, Ashraf Warsi, Ghazi Alotaibi, Hazzaa Abdulla Alzahrani, Mahmoud Abu-Riash, Mohammad Alshahrani, Mustaqeem Siddiqui, Shahrukh Hashmi, and Tarek Owaidah received honoraria fees from BioMarin Pharmaceuticals as advisory board members.

Funding Sources

This work, including publication and open access fees, was funded by BioMarin Pharmaceuticals, Dubai, UAE.

Author Contributions

Ali Mullah-Ali, Ashraf Warsi, Ghazi Alotaibi, Hazzaa Abdulla Alzahrani, Mahmoud Abu-Riash, Mohammad Alshahrani, Mustaqeem Siddiqui, Shahrukh Hashmi, and Tarek Owaidah contributed to the development of the consensus statements and to the preparation and review of the manuscript.

Funding Statement

This work, including publication and open access fees, was funded by BioMarin Pharmaceuticals, Dubai, UAE.