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 manufacture of blood plasma products in Scotland: a brief history.

A number of essential clinical products are derived from human blood plasma, including immunoglobulin products for the treatment of infections and disorders of immunity; albumin for protein and fluid replacement and coagulation factors for the treatment of haemophilia and other disorders of haemostasis. For many years, these protein pharmaceuticals were manufactured by the Scottish National Blood Transfusion Service (SNBTS) at its Scottish Protein Fractionation Centre (PFC) in Edinburgh, a contribution which ended with the closure of the PFC in 2008. The origins and development of plasma fractionation in Scotland are summarised in this article, as well as issues which contributed to the closure of the PFC.

Diagnosing von Willebrand disease: a short history of laboratory milestones and innovations, plus current status, challenges, and solutions.

von Willebrand disease (VWD) is a disorder characterized by deficiency of, or defects in, von Willebrand factor (VWF). VWD was originally identified by Erik Adolf von Willebrand, who in early 1924 investigated a large family suffering from a bleeding disorder that seemed to differ from hemophilia. Erik von Willebrand undertook some initial laboratory investigations to conclude the involvement of a plasma factor, the lack of which prolonged the bleeding time, but failed to impair coagulation times and clot retraction. By the end of the 1960s, VWD was accepted as a combined deficiency of factor VIII (FVIII) and another plasma factor responsible for normal platelet adhesion. Just how these two functions were related to each other was less clear and the diagnostic tests available at the time were poorly reproducible, cumbersome, and unreliable; thus, VWD was poorly delineated from other coagulation and platelet disorders. The early 1970s saw a revolution in diagnostics when ristocetin was identified to induce platelet aggregation, and this formed the basis of the first consistent and reliable VWF "activity" test, permitting quantification of the platelet adhesive function missing in VWD. Concurrently, immunoprecipitating techniques specific for VWF were defined, and the application of such technologies permitted a clearer understanding of both VWF and VWD heterogeneity. Continued exploration of the structure and function of VWF contributed greatly to the understanding of platelet physiology, ligand receptor interaction and pathways of cellular interaction and activation. Recently, additional assays evaluating other functions of VWF, including collagen binding, platelet glycoprotein Ib binding, and FVIII binding, have improved the diagnosis of VWD. The purpose of this narrative review is to explore the history of phenotypic VWD diagnostics, with a focus on laboratory milestones from the past as well highlighting recent and ongoing innovations, and ongoing challenges and possible solutions.

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.

Treatment of haemophilia patients in East Germany prior to and after reunification in 1990.

The reunification of Germany in 1990 brought with it major challenges in terms of unifying the care offered to haemophilia patients. At that time, most of the treatment centres belonged to the largest regional hospitals. The centre for paediatric haemophilia patients in Leipzig was at the University Hospital. In this centre, early prophylaxis was offered to all patients with severe haemophilia A or B. For over 20 years, the treatments of choice in the German Democratic Republic were cryoprecipitate for haemophilia A and prothrombin complex concentrate for haemophilia B. Cryoprecipitate was relatively effective during minor surgery, in cases of mild to moderate bleeding, and for prophylaxis; however, unpleasant, relevant side-effects and hepatitis virus transmission were frequently encountered in clinical practice. Reunification coincided with the availability of virus-safe, high-purity plasma-derived factor VIII concentrates (e.g. Beriate(®) P), which changed the outlook for patients in terms of convenience, tolerability, and virus safety; and these new products quickly became the treatments of choice for haemophilia A patients at the Leipzig Children's Hospital. Today, 20 years later, nearly all of the patients initiated on Beriate(®) P at the time of reunification continue with that treatment, and are still benefitting from its excellent efficacy, tolerability, and virus-safety profile.

The history of haemophilia - a short review.

The history of haemophilia dates back to the 2nd century AD, with the first "modern" descriptions of the condition appearing during the 1800s. At that time, transfusion medicine and haemophilia became closely linked, with blood transfusion being the only possible treatment option. A turning point in the history of haemophilia came in the middle of the 20th century when researchers identified an "antihaemophilic globulin" that could reduce the clotting time in haemophilic blood, thereby paving the way for the introduction of cryoprecipitate and the first clotting factor concentrates for the treatment of haemophilia A, haemophilia B and von Willebrand disease. The availability of pasteurized, and therefore virus-safe, plasma-derived, clotting factor concentrates, such as Haemate P(®) and Beriate(®) P in Germany and other countries, dramatically improved the quality of life and life expectancy of haemophilia patients. These and other treatment advances enabled home treatment, with many centres introducing prophylaxis to younger patients. Today, thanks to the support from patient organizations, such as the German Haemophilia Society, which was founded by Prof. Rudolf Marx from Munich, haemophilia patients can be assured of good bleeding control using products with established efficacy and safety profiles. Work on improving factor concentrates continues, with efforts directed towards extending their half-lives using recombinant albumin-fused proteins and other modern technologies. The past 20 years has witnessed major improvements in almost all aspects of haemophilia treatment. It is hoped the next 20 years will add promising new chapters to the haemophilia book of history.

Cryoprecipitate: an outmoded treatment?

Cryoprecipitate is an allogeneic blood product prepared from human plasma. It contains factors VIII, von Willebrand factor (vWF), fibrinogen, fibronectin and factor XIII. Its use was first described in the 1960s for treatment of patients with factor VIII deficiency. It has also been used to treat patients with congenital hypofibrinogenaemia. Now, the most common use of cryoprecipitate is fibrinogen replacement in patients with acquired hypofibrinogenaemia and bleeding. Despite almost 50 years of use, evidence of efficacy is limited. This review provides an overview of the history of cryoprecipitate use, the current debates on the use of this product and future developments.

Quantifying the source of infection for HIV-infected hemophiliacs in the U.K. from 1979 to 1984.

There is considerable literature on the risk of HIV infection for individuals suffering from hemophilia A in the United Kingdom (U.K.) during the period 1979-1984 when the sources of Factor VIII clotting factor were contaminated with HIV. Toward the end of this period, several investigators reported HIV prevalence among hemophiliacs, often classified by the severity of disease and, to some extent, the source of the clotting factor with which individuals were infused. In the U.K., hemophilia A patients typically received clotting factor from the local National Health Service (NHS) supplies or from commercial product usually imported from the United States. Litigation on behalf of U.K. hemophiliacs, their survivors, and estates remains unresolved, cases in which it becomes important to quantify the fraction of U.K. hemophiliac HIV infections attributable to imported blood product. For HIV-infected individuals who received Factor VIII from one source exclusively, the source of infection is clear, assuming no other risk factors. For patients who used both types of clotting factor, the source of infection is uncertain. For the U.K. as a whole, we produce quantitative estimates of the conditional probability of infection due to a specific source, based on HIV prevalence in groups exclusively exposed to a specific source and the percentage of clotting factor that was imported. With plausible estimates of these input parameters, an estimate of the conditional probability of infection due to imported product is 0.93 (95 per cent CI: 0.90-0.96). This estimate is relatively insensitive to changes in input parameters, but may vary over subgroups of hemophiliacs.

Haemate P von Willebrand factor/factor VIII concentrate: 25 years of clinical experience.

Although von Willebrand disease (VWD) has a very long history, our understanding and treatment of the bleeding disorder has only evolved during the past 50 years or so. It was not until the 1920s that VWD was first recognized as a disease separate from that of classical haemophilia. It then took another 30 years before the first effective treatment was developed. Since then, the medical management of VWD has evolved considerably, but not without its ups and downs. One of the key milestones in the evolution of the treatment of VWD was the development of Haemate P/Humate-P (CSL Behring) - the first virus-inactivated factor VIII plasma product. For 25 years, this concentrate has demonstrated excellent clinical efficacy and safety for patients with VWD and for those with haemophilia. This article provides an historical overview of the early landmark efforts to ensure a safe plasma-derived replacement product and outlines the clinical evolution in the use of Haemate P.