Page 31 - Haematologica March 2020

Hemophilia therapy: the future has begun
Ferrata Storti Foundation
Pier Mannuccio Mannucci
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
ABSTRACT
The success story of hemophilia care first began in the 1970s, when the availability of plasma-derived concentrates of coagulation fac- tor VIII (FVIII) and factor IX (FIX) provided efficacious treatment of bleeding in patients with hemophilia A and B. This positive scenario was consolidated in terms of greater safety and availability in the 1990s, when the first recombinant coagulation factors were produced. This meant that, instead of only treating episodic bleeding events, prophylaxis regimens could be implemented as a preventive measure. Following the demonstration of its superiority in the frame of two randomized clinical trials, prophylaxis became evidence-based standard of care. In high- income countries, these achievements have led to a patients’ life expectancy being extended to close to that of the general male popula- tion. Alongside this, the last decade has witnessed further spectacular therapeutic progress, such as the availability of coagulation factors with a longer plasma half-life that allow for wider intervals between treat- ment. Moreover, new therapeutic products based on new mechanisms other than the replacement of the deficient factor, have become available (emicizumab) or are at an advanced stage of development. This review celebrates the success story of hemophilia care, while also discussing cur- rent limitations, issues and as yet unmet needs. The prospects of cure by means of gene therapy are also outlined.
Introduction
Among the more than 6,000 human diseases caused by single gene defects,1 the plasma deficiencies of coagulation proteins are of great importance to the hematol- ogist, entailing as they do a lifelong bleeding tendency with important morbidity and mortality if not adequately managed. Inherited coagulation deficiencies are rare diseases according to the definitions adopted in the United States (less than 200,000 cases nationwide) and Europe (less than 5 cases per 10,000 persons in the general population).2 The hemophilias are clinically relevant rare diseases: hemo- philia A (HA), which results from the deficiency or dysfunction of coagulation fac- tor VIII (FVIII), and hemophilia B (HB) of factor IX (FIX). Both are due to mutations in genes located on chromosome X and thus largely affect males, with bleeding symptoms roughly proportional to the degree of factor deficiency in plasma. The main sites of spontaneous bleeding are joints and muscles, which, if inadequately treated, cause chronic damage to the musculoskeletal system resulting in severe handicaps and disability. Furthermore, trauma and surgical interventions are accompanied by uncontrolled bleeding.
A recent report on the worldwide distribution3 shows that the hemophilias are more frequent than previously estimated: 17.1 cases per 100,000 males with HA for all degrees of FVIII deficiency, 3.8 cases per 100,000 of HB, with a prevalence of 6 per 100,000 for HA and 1.1 per 100,000 for HB of cases with complete plasma fac- tor deficiency, and thus a more severe clinical phenotype (Table 1).3 Inherited coag- ulation disorders are much rarer. These are due to defects in genes encoding other factors, such as fibrinogen, prothrombin, factors V, VII, X, XI and XIII.4 The defec- tive genes are transmitted with an autosomal recessive pattern of inheritance and thus affect both sexes at similar rates. Prevalence rates in the general population range between 1 case per 500,000 for the more frequent factor VII deficiency and 1 in 2-3 million for the rarest prothrombin and factor XIII deficiencies (Table 1).4
Haematologica 2020 Volume 105(3):545-553
The natural history and clinical phenotype of rarer coagulopathies are less accu-
Correspondence:
PIER MANNUCCIO MANNUCCI
piermannuccio.mannucci@policlinico.mi.it
Received: December 4, 2019. Accepted: January 20, 2020. Pre-published: February 14, 2020.
doi:10.3324/haematol.2019.232132
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/3/545
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