Hemophilia: a biography on therapeutical approaches

The history of hemophilia is ancient, with descriptions dated to the 2nd century AD. The first modern narratives appeared in 1800s, when total blood transfusion was the only available treatment and life expectancy was remarkably low. Advances occurred with the use of plasma and cryoprecipitate, but only the discovered of factor concentrates revolutionized the treatment. The implantation of prophylaxis allowed hemophilic patients to prevent bleeding and the development of chronic arthropathy, although with a significant burdensome with the regular infusions. In the past 20 years, this field has witnessed major improvements, including the development of gene therapy and other pharmacological approaches.

Comprehensive care for hemophilia and other inherited bleeding disorders.

The World Federation of Hemophilia (WFH) states in its Guidelines for the Management of Hemophilia, Second Edition [1], that people with hemophilia are best managed in a comprehensive care setting. That team is typically comprised of a core group including a hematologist, nurse coordinator, physiotherapist, social worker, specialized lab technologist and data manager, and as needed, by other specialists. Hemophilia is an X-linked congenital bleeding disorder caused by a deficiency of coagulation factor VIII (FVIII) in hemophilia A or factor IX (FIX) in hemophilia B. There are a number of other disorders that are now typically treated in these comprehensive care centers including von Willebrand disease (VWD), rare factor deficiencies (I, II, V, V & VIII, VII, X, XI and XIII), and inherited platelet function disorders. Models of comprehensive care delivery for hemophilia and other inherited bleeding disorders were first defined in the 1960s and have been in constant evolution ever since. Comprehensive care for hemophilia and other inherited bleeding disorders was made possible by the discovery of cryoprecipitate for the treatment of hemophilia A in the mid-1960s and, in the decade that followed, the development of lyophilized clotting factor concentrates. It was quickly realized that treatment at home was far preferable to frequent visits to Emergency Departments or out-patient. Tragically, the same clotting factor concentrates that revolutionized treatment and dramatically improved quality of life exposed thousands of people with hemophilia to HIV-AIDS and hepatitis C in the late 1970s and 1980s [2]. The model of comprehensive care was forced to add specialists in infectious disease and hepatology. At the same time, the crisis accelerated the development of recombinant FVIII and IX clotting factors; these entered the clinic in 1993 and 1997 respectively. The proven safety of both recombinant and plasma-derived products spurred on the expansion of prophylactic care to more patients. Today, with the success of a comprehensive care model that keeps patients out of the hospital (and out of sight), and promises a normal lifespan, there is an emerging impression among many health system managers that the problem of hemophilia is "solved." In 2019, however, even the best care and treatment remains highly burdensome and not entirely efficacious. Emerging innovative therapies are promising yet dramatically different in their modes of action, dosing and administration. Much of what has been learned in terms of management of the disease over the last 50 years may no longer be relevant. Rather than one type of treatment for all, there may well be many different therapies. Comprehensive care centres will not become obsolete. It will remain critically important that specialized staff be able to foster long-term relationships with patients and their families. Indeed, they will need to expand their knowledge and expertise in order to be able to continue to deliver the standards of care so carefully developed since the 1960s.

The history of hemophilia.

Hemophilia A and B are rare inherited bleeding disorders characterized by the deficiency of coagulation factor VIII (FVIII) or factor IX (FIX). While the history of hemophilia dates back to the 2nd century AD, a modern description of hemophilia appeared only at the beginning of the 19th century. The discovery of "antihemophilic globulin" in the middle of the 20th century paved the way to the production of cryoprecipitate and then of FVIII and FIX concentrates. Barring the tragic consequences on the hemophilia community of the transmission of blood-borne viruses by nonvirus inactivated factor concentrates during the 1970s and 1980s, plasma-derived first and recombinant products later revolutionized the treatment of hemophilia through the widespread adoption of home treatment and prophylaxis regimens, which dramatically improved the quality of life and life expectancy of persons with hemophilia during the past decade. This article briefly reviews the most important stages of the management of hemophilia from the past century up to the present days.

Blood clotting and coagulation factors: the work of Yale Nemerson. 1980, 1982.

After developing a blood disorder, Yale Nemerson became interested in hematology. This led to his lifelong study of thrombogenic tissue factor and to his contributions to developing the modern theory of blood coagulation. The two Classic papers reprinted here detail some of Nemerson's studies on coagulation factors IX and VII.