Practices and challenges for hemophilia management under resource constraints in Thailand

Hemophilia is an inherited bleeding disorder caused by deficiency of a specific coagulation factor, i.e., factor VIII (FVIII) for hemophilia A (HA) and factor IX (FIX) for hemophilia B (HB) [1]. Due to insufficient intrinsic tenase activity, hemophiliacs tend to bleed into skeletal muscles and major joints, either spontaneously or following trauma/surgery, based upon the disease severity [1]. In the United States, the age-adjusted prevalence of hemophilia is reported to be 15.7 cases/100,000 male individuals. The incidence of HB is approximately 4–6 times lower than that of HA [2]. A substantially lower epidemiology has been documented among 66.1 million Thai population. As per the 2020 annual global survey by the World Federation of Hemophilia (WFH), only 1828 Thai hemophiliacs (1615 of HA and 213 of HB) have been registered to the Thai national healthcare system. Most of them have severe (51.2%) and moderate hemophilia (30.2%) [3]. The reason for the low number is the underdiagnosis which is a major concern in the real-world practice among Asian countries [4]. Mild hemophiliacs are more likely to be unrecognized due to lack of awareness, both medical and self, about non-severe bleeding phenotypes [5].

In Thailand, most hemophiliacs are diagnosed by general practitioners, pediatricians or internists at rural hospitals and are referred to hemophilia specialists at the Hemophilia Treatment Centers (HTCs). Fewer patients are directly diagnosed at the HTCs. Since several hemostatic disorders can share the same clinical spectrum, establishing an accurate diagnosis is crucial [1]. An isolated prolongation of activated partial thromboplastin time (aPTT) accompanied with significant bleeding symptoms may lead to the diagnosis of hemophilia based upon the evidence of FVIII or FIX deficiency from the local laboratories. At the HTCs, referred new cases are retested for FVIII and FIX coagulant activities as well as von Willebrand factor (VWF) levels by the standardized special coagulation laboratories to validate the assigned diagnosis and disease severity. The family members of each proband are usually advised to undergo screening for the factor levels even if they are asymptomatic. Once the diagnosis is confirmed, a prophylactic factor replacement therapy using clotting factor concentrates (CFCs) is generally offered, particularly for severe and moderate hemophiliacs with frequent bleeds. After initiating factor replacement therapy, factor inhibitors should be monitored every 6–12 months due to the risk of inhibitor development in the first 50 exposure days and thereafter [1]. In patients who need surgery, inhibitor assays should be performed preoperatively. Among those with severe HA and/or high-risk F8 mutations for developing FVIII inhibitors, more frequent inhibitor monitoring is recommended. As reported in 2020, only 5.6% (102/1828) of Thai hemophiliacs had active inhibitors, accounting for 6.2% (100/1615) of HA and 0.9% (2/213) of HB patients [3]. The low inhibitor prevalence among Thai HA population may partially be attributed to a limited accessibility to inhibitor assays in several HTCs.

Prophylactic factor replacement therapy has been recommended as the standard of care for hemophiliacs to minimize risks of bleeding and hemophilic arthropathy [1]. Nevertheless, implementation of adequate prophylaxis remains a major challenge in Thailand due to a limited budget allowance for CFCs (Tables 1, 2). For those requiring prophylactic CFCs more than low-dose practice (10–15 IU/kg for 2–3 times/week) [1], CFC cost exceeds the reimbursable budget and could cause financial burden. Additional challenges faced by the patients and their caregivers include: limited distribution of CFCs and inhibitor testing, increased bleeding risk among adults with hemophilic arthropathy and issues regarding self-infusion of CFCs. Although every hemophiliac and/or caregiver should be trained for venous access and self-infusion, several cases prefer to receive CFC infusions from medical personnel, which can become a hassle for those residing far from the HTCs. The COVID-19 pandemic adversely affected the onsite visits at the HTCs. Therefore, some HTCs alternatively applied telecommunications to help with the follow-ups, referred the patients to the nearest HTC, or delivered CFCs via cold storage to the patients’ residents if feasible. Due to these obstacles, only 38.5% of Thai severe hemophiliacs who regularly used CFC prophylaxis were registered in the 2020 annual global survey (365/947); 67.7% of which were children and teenagers (< 18 years) [3].

Although prophylactic regimen should be based upon the disease severity and bleeding phenotypes, individualized CFC prophylactic scheme in Thailand is largely influenced by the Thai national budgets for hemophilia care. Since 2019, the Thai National Health Security Office (NHSO) has paid for CFCs, used for both prophylactic/on-demand home treatment (Table 1) and episodic treatment of breakthrough bleeds requiring urgent HTC visits or hospitalization (Table 3). Some adults with hemophilia get reimbursed for these expenses from the Thai Social Security Office (SSO) instead of NHSO (Tables 2, 4). For home treatment in children below 10 years of age, NHSO has provided an annual budget of 288,000 Thai Baht (THB; 8180 USD) and 226,800 THB (6240 USD) per patient for severe HA and HB, respectively. Based upon market prices of CFCs, each patient could receive standard half-life (SHL) FVIII concentrate of 28,500–46,000 IU/year (approximately 500–750 IU/week) or SHL FIX concentrate of 17,500–18,500 IU/year (approximately 500 IU/10 days) for prophylaxis. For children above 10 years of age and adults, the budget allotment from NHSO for home treatment increases to 345,600 THB (9830 USD) and 302,400 THB (8590 USD) per patient for severe HA and HB, respectively. Therefore, SHL FVIII concentrate of 34,500–55,500 IU (approximately 750–1000 IU/week) and SHL FIX concentrate of 23,000–24,000 IU (approximately 500 IU/week), intended for prophylaxis, are reimbursable annually. However, a fixed-dose SHL FVIII concentrate of 500 IU prophylactically given to children with severe HA once weekly does not meet the lowest regimen recommended by the WFH [1], and is insufficient for adults with body weight > 50 kg or advanced-stage hemophilic arthropathy. For severe HB, FIX prophylaxis is more hindered due to a lower budget allocation and a higher cost of SHL FIX concentrate. As a consequence, pediatric hemophiliacs are likely to be undertreated, and joint damages would not be effectively prevented. Although the efficacy data on prophylactic treatment in Thai HB population remain to be determined, a multicenter study on 50 Thai patients with severe HA has suggested that the low-dose prophylaxis using SHL FVIII concentrate of 500 IU twice weekly for 3 months is effective and resulted in zero bleeds in 48% of all subjects and 38% of subjects with preexisting target joints [6]. Future revisions of the Thai national hemophilia budgets should therefore be considered to promote adequate CFC prophylaxis, at least 10 IU/kg twice weekly, and dose escalation should be allowed if needed.

Recombinant (43.3%) and plasma-derived (50.4%) SHL CFCs have been widely used in Thailand while the availability of extended half-life (EHL) CFCs is limited [3]. As of 2023, recombinant CFCs remain more expensive than plasma-derived CFCs in Thailand (Table 5). Nonacog alpha, a recombinant SHL FIX concentrate which was recently approved by the Thai Food and Drug Administration for HB treatment, has a potential for the low-dose HB prophylaxis (e.g., 500 FIX IU/week) based upon the reimbursable budgets [7], despite the limited local experience. For HA patients with inhibitors, although emicizumab prophylaxis—outside NHSO and SSO coverage—could be used in Thailand, only 7% of patients were able to afford its out-of-pocket costs [3, 8]. Nevertheless, compared with on-demand consumption of bypassing agents during breakthrough bleeding episodes, it is believed that the efficacy of low-dose emicizumab prophylaxis (1 mg/kg emicizumab administered monthly) may reduce the total treatment expenses [8, 9].

For social mobilization, the National Hemophilia Foundation of Thailand in cooperation with the Thai Hemophilia Patient Club are actively promoting self-engagement and use of digital technology, i.e., smartwatch monitoring and hemophilia mobile applications, to foster improvement of aerobic exercise capacity and muscle strength among Thai hemophiliacs during the age of digital technology [10]. A study to evaluate the impact of increased physical activities monitored by these modalities during low-dose CFC prophylaxis in Thai hemophiliacs is ongoing (ClinicalTrials.gov NCT05728528). Other innovative technologies, including factor replacement therapy (e.g., EHL CFCs, efanesoctocog alfa), rebalancing non-factor replacement therapy and gene therapy, have a potential role to further improve hemophilia care [11, 12]. Rondaptivon pegol, a VWF-binding aptamer, might be a particularly useful option in supplementing low-dose CFC prophylaxis [13]. Moreover, since the Thai Society of Hematology (TSH) started the national registry of thrombotic and hereditary bleeding disorders in 2016, medical professionals across Thailand could register their patients to collate the real-world hemophilia data. Recently, a sub-registry of hereditary bleeding disorders has been electronically linked with the World Bleeding Disorders Registry endorsed by the WFH. These international collaborative data would hopefully be utilized for the evidence-based advocacy initiatives in the future [14].