Epidemiological Challenges in Rare Bleeding Disorders: FVIII Inhibitor Incidence in Haemophilia A Patients—A Known Issue of Unknown Origin

Abstract

There is a broad range of factor products approved in Germany for haemophilia A treatment. Since the introduction of recombinant coagulation factor VIII (FVIII) products in the 1990s, there has been substantial debate whether there is a difference in inhibitor incidence between single FVIII products or product classes. Neither haemophilia registries nor clinical studies, including a randomised controlled clinical trial, provided a consistent and definite answer. The reasons were mainly related to methodological challenges in conducting controlled studies in a rare disease. In this analysis, the most relevant epidemiological challenges and main problems were examined, including study bias, potential overlap of individual studies and advanced development of therapy and methods in the course of time. Meta-analyses on two levels showed that therapies using recombinant products resulted in different event rates when compared to plasma-derived products. These results are accompanied by substantial study heterogeneity evidenced by Cochran’s Q tests. Only three studies have been identified that meet the standards of current clinical guidance. To finally resolve this ongoing and disputable safety issue of replacement therapy, collaboration among registry owners, academia and regulators must be fostered.

Management of severe peri-operative bleeding: Guidelines from the European Society of Anaesthesiology and Intensive Care

“…Although the preference for plasma-derived or recombinant FVIII products has been highly debated, mainly regarding the risk of inhibitor appearance, 260–262 both proved efficacious for preventing/treating bleeding episodes in haemophilia patients and the WFH recommendations do not express a preference for either recombinant or plasma-derived products 245,257 . However, the SIPPET randomised trial showed an increase in the inhibitor rate in patients using recombinant FVIII products compared with those receiving plasma-derived products in the first exposure days 263 .…”

“…Importantly, 60% of trough and steady-state FIX levels were below the target level in the first 24 h after surgery, whereas 59% of FIX levels were above target more than 6 days after surgery, supporting the need for alternative dosing strategies such as pharmacokinetic monitoring. 259 Although the preference for plasma-derived or recombinant FVIII products has been highly debated, mainly regarding the risk of inhibitor appearance, [260][261][262] both proved efficacious for preventing/treating bleeding episodes in haemophilia patients and the WFH recommendations do not express a preference for either recombinant or plasma-derived products. 245,257 However, the SIPPET randomised trial showed an increase in the inhibitor rate in patients using recombinant FVIII products compared with those receiving plasma-derived products in the first exposure days.…”

Risk factors for coagulation inhibitor development in children with severe hemophilia A

“…Эти антитела нейтрализуют гемостатический эффект введенного фактора, что приводит к рецидивирующим эпизодам кровотечения, прогрессирующему повреждению суставов и иногда к угрожающим жизни неотложным состояниям [3]. Возможная роль, которую играют факторы риска в развитии ингибиторов, такие как характер генетических нарушений [4], возраст начала лечения [5], выбор первого лекарственного препарата, режим и интенсивность введения [6], является предметом длительной дискуссии. Дополнительные факторы риска, такие как массивность кровотечения, хирургическое вмешательство [7], сопутствующие инфекции или вакцинации [8], также вовлечены в контекст обсуждения сигналов иммунологической опасности [9], приводящих к иммунным нарушениям, связанным с введением экзогенного фактора свертывания крови для остановки кровотечения.…”

Progress in the Development of Anti-tissue Factor Pathway Inhibitors for Haemophilia Management

“…Haemophilia is a rare X-linked inherited bleeding disorder characterised by remarkable management progress in the past several decades. Advances in novel haemophilia therapy development have primarily been driven by the efforts to address the many currently unmet needs in haemophilia care, which include the high disease and treatment burden (1-3), the need for intravenous infusion of factor replacement therapy (4)(5)(6)(7)(8), the immunogenicity of factor replacement therapy (9)(10)(11), suboptimal prophylaxis due to poor compliance and adherence (12). The non-factor replacement therapies (NFRT) ware developed to address some of these unmet needs in haemophilia care.…”