Progress in the contemporary management of hemophilia: The new issue of patient aging

Highlights

• Persons with hemophilia enjoy nowadays a normal life expectancy.

• This goal was achieved through the availability of safe and efficacious therapies.

• Gene replacement therapy is promising to offer a cure to this scourge.

• Multimorbidity and related polypharmacy are a forthcoming in older patients.

• Thus, hemophilia management requires also the holistic approach of internists and geriatricians.

Abstract

The management of inherited coagulation disorders such as hemophilia A and B has witnessed dramatic progresses since the last few decades of the last century. Accordingly, persons with hemophilia (PWH) now enjoy a life expectancy at birth not different from that of males in the general population, at least in high income countries. Nowadays, a substantial proportion of PWH are aging, like their peers in the general population. This outstanding progress is accompanied by problems that are in part similar to those of any old person (multiple concomitant diseases and the resulting intake of multiple drugs other than those specific for hemophilia treatment). In addition, older PWH suffer from the consequences of the comorbidities that developed when their treatment was at the same time poorly available and unsafe. Typical hemophilia comorbidities affect the musculoskeletal system following joint and muscle bleeds, but also the liver and kidney are often impaired due to previous bloodborne infections such as viral hepatitis and HIV. Thus, the comorbidities of hemophilia superimposed on the multimorbidity and polypharmacy associated with aging create peculiar problems in the current management of these patients, that demand the coordinated holistic intervention of internists, geriatricians and clinical pharmacologists in addition to the care traditionally provided by pediatricians and hematologists.

Introduction

Hemophilia A and B are rare bleeding disorders caused by mutations in the genes encoding coagulation factor VIII (FVIII) and factor IX (FIX) [1]. The prevalence of hemophilia A is 1 in 5000 male live births and that of hemophilia B is 1 in 40,000 [1], [2]. Patients with plasma factor levels < 1 IU/dL (< 1% of normal) are classified as severe hemophilia, those with levels between 1 and 5 IU/dL (1–5% of normal) and those with > 5 but < 40 IU/dL (> 5%–<40% of normal) are moderate and mild hemophilia [3]. Although the bleeding phenotype may be heterogeneous [4], [5], this classification reflects rather closely the severity of clinical symptoms [6]. Traditionally hemophilia A and B have been considered clinically indistinguishable from each other [7], [8], [9]. Recent evidence, however, suggests that severe hemophilia B may have a milder clinical phenotype than severe hemophilia A [8], [9], reflected by less factor consumption, less deleterious gene mutations and less need for orthopedic surgery [9]. The latter is often necessary in poorly managed patients with hemophilia (PWH) because recurrent bleeding into muscles and joints is the hallmark of severe disease. The long-term consequences of these bleeds are the development of arthropathy through synovial hypertrophy, cartilage destruction and bone damage [10], that leads to relevant physical and psychosocial handicaps [11]. This review provides a general overview of the current knowledge of the comorbidity and the multiple chronic diseases associated with aging that may occur in PWH who are becoming older as consequence of the improved management of hemophilia.