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.

Haemophilia, the journey in search of a cure. 1960-2020.

The single most important step on the path to our modern understanding of blood coagulation and haemophilia in the 20th century was taken by British pathologist Robert Gwyn Macfarlane with his 1964 publication 'An enzyme cascade in the blood clotting mechanism, and its function as a biochemical amplifier'. In the same year, Ratnoff and Davie in the USA reached the same conclusion. Macfarlane and Rosemary Biggs had previously, in 1952, discovered factor IX as the factor deficient in haemophilia B. In 1973, Arthur Bloom defined the distinct role of Factor VIII and von Willebrand factor in haemophilia A and von Willebrand's disease respectively. This inspired the efforts of Tuddenham and his group towards the purification of Factor VIII which reached homogeneity in 1982, leading to the cloning of the Factor VIII gene in 1984 in collaboration with US scientists at Genentech, which in turn enabled development of safe recombinant factor concentrates for patients with haemophilia. Brownlee cloned the factor IX gene in 1982 at the Sir William Dunn Institute of Pathology in Oxford. This led eventually to the first successful trial of gene therapy for haemophilia B in 2011 by the Nathwani group at UCL, which built on pioneering work of US groups and was partnered with St Jude in Memphis where Nathwani started the project. This trial has fuelled the current quest for a functional cure of haemophilia A and B. The UK has, therefore, made a rich contribution to advances in haemostasis over the last 60 years, often in partnership with other groups across the world.

Life expectancy and cause of death in individuals with haemophilia A and B in Norway, 1986-2018.

OBJECTIVES: Evaluate trends over time in age- and cause of death in males with haemophilia (PWH) in Norway compared with the general male population and investigate its correlates with improvements in haemophilia treatment. METHODS: Data about age and cause of death in the period of 1986-2018, from two independent, high-quality national registries: the Norwegian Cause of Death Registry (NCoDR) and the patient registry at Centre for Rare Disorders (CRD), Oslo University Hospital. RESULTS: Life expectancy increased significantly from 1986 to 2018. However, PWH still had a decreased mean age at death of 56.8 years (SD = 24.7) in the NCoDR and 58.6 years (SD = 21.7) in the CRD data, compared with 73.9 years (SD = 16.3) in the general male population. There was a distinct shift in the most frequently reported haemophilia-related causes of death, such as haemorrhage and AIDS, to more age-related causes of death, such as cancer, reflecting an ageing population. CONCLUSION: Haemophilia treatment has improved significantly in the last three decades. Despite treatment-related improvements, PWH in Norway still have a decreased life expectancy compared with the general male population.

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.

Evolution of the Treatments for Hemophilia.

Although hemophilia has been recognized for centuries as an inherited disorder primarily affecting males, advances in treatments have been very recent. Initial availability of plasma-derived therapies offered significant improvements in morbidity and mortality, but the transmission of viruses quickly negated the benefit of early factor replacement products. After developing successful viral inactivation methods and subsequently developing recombinant technology, the manufacturing of factor concentrates became much safer. Access to safer factor products allowed for a shift from the treatment of bleeds to prevention, called prophylaxis. Although dosing and interval vary, prevention of joint disease is now a realistic goal. Unfortunately, despite advances in the safety of therapy, some patients are unable to use factor replacement products because they develop antibodies, known as inhibitors. Eradication of inhibitors is possible in the majority of patients, but it is expensive and takes time. Management of acute bleeding may require significantly higher doses of factor replacement or the use of a bypassing agent. As a result, patients with inhibitors are at increased risk for sequelae, including joint disease, life-threatening bleeding, infectious complications with central vascular access devices, and thrombotic complications.

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.

Legal requirements for optimal haemophilia treatment in Germany.

The clinical benefits of early prophylaxis in the treatment of haemophilia have been unquestioned since publication of the results of the first randomized study. The question of whether or not prophylaxis is cost-effective remains to be proven. For European physicians treating haemophilia patients, and for German clinicians in particular, the law largely supports the use of prophylaxis in haemophilia, but many doctors are unaware of this. The aim of this review was therefore to describe the German legal framework and outline how it can be used to support appropriate clinical decision-making in the treatment of haemophilia and justify the use of prophylaxis to health insurers and third-party payers. The German Disability Equalisation Law and German Social Law Books V and IX outline legal requirements to prevent or ameliorate disability, and support the argument that all haemophilia patients, including adults, have the right to receive appropriate, adequate, and cost-effective treatment. "Appropriate" treatment means that it must be in accordance with state-of-the-art medical knowledge taking into account medical progress. "Adequate" treatment must be conducive to the goals of haemophilia management, which are to prevent bleeds, treat bleeding episodes, maintain and/or restore joint function, and integrate patients into a normal social life. This can only be achieved when long-term treatment is adequately dosed and regularly administered for as long as it is required. Thankfully, with the availability of virus-safe factor concentrates, the introduction of home treatment programmes, and the law on our side, we are in a very strong position to achieve these goals.

Rosemary Biggs MD FRCP (1912-2001) and Katharine Dormandy MD FRCP (1926-78): from laboratory to treatment and care of people with haemophilia.

In 1977 the Haemophilia Society presented the first RG Macfarlane Award to Katharine Dormandy for her outstanding contribution towards the social and physical wellbeing of people with haemophilia and related disorders. In 1978 Rosemary Biggs was the second recipient of the Award given for similarly outstanding personal contributions. Dr Biggs worked under Dr RG Macfarlane at Oxford and in 1952 devised a laboratory test that identified two forms of haemophilia. Macfarlane realized the potential for replacement therapy which subsequently transformed the lives of haemophiliacs in the UK. Dr Biggs was director of the Oxford Haemophilia Centre (1967-77) and instrumental in documenting the increase in incidence of jaundice with the import of concentrates for infusion. Katharine Dormandy, Consultant Haematologist at the Royal Free Hospital in London, set up one of the country's foremost haemophilia centres, pioneered home treatment for haemophilic children and with Rosemary Biggs was involved in the social and educational welfare of affected families.

Haemophilia B: current pharmacotherapy and future directions.

INTRODUCTION: Hemophilia B is a rare hereditary hemorrhagic disorder characterized by deficiency of the clotting factor IX (FIX). Hemophilia B patients experience mild to severe bleeding complications according to the degree of FIX defect. Nowadays, the most challenging complication of individuals with hemophilia B is the development of alloantibodies, which render the standard replacement therapy with FIX concentrates ineffective, exposing them to a significantly increased morbidity and mortality. AREAS COVERED: This review summarizes the most important events leading to the development of the current FIX products available for the treatment of hemophilia B patients. In addition, it focuses on the more recent advances in the production of new FIX molecules aimed at improving the clinical management of such patients. EXPERT OPINION: Although the availability of plasma-derived FIX concentrates has greatly improved the clinical management of hemophilia B patients, the introduction of FIX products using recombinant DNA technology has represented the most significant therapeutic progress in hemophilia B therapy, ensuring an advanced level of safety. The development of rFIX products with extended half lives will further improve the therapeutic armamentarium for hemophilia B patients.

Marathon of eponyms: 24 Xmas (Christmas) disease.

The use of eponyms has long been contentious, but many remain in common use, as discussed elsewhere (Editorial: Oral Diseases. 2009: 15; 185). The use of eponyms in diseases of the head and neck is found mainly in specialties dealing with medically compromised individuals (paediatric dentistry, special care dentistry, oral and maxillofacial medicine, oral and maxillofacial pathology, oral and maxillofacial radiology and oral and maxillofacial surgery) and particularly by hospital-centred practitioners. This series has selected some of the more recognised relevant eponymous conditions and presents them alphabetically. The information is based largely on data available from MEDLINE and a number of internet websites as noted below: the authors would welcome any corrections. This document summarises data about Christmas disease.

The 'royal disease'--haemophilia A or B? A haematological mystery is finally solved.

'History can change blood. And blood can change the course of history'. Haemophilia is an illustration of this, as this congenital hereditary coagulation disorder, passed through the majority of royal European families at the beginning of the 20th century by Queen Victoria of England and Empress of the Indies, had indisputable political consequences, which led to one of the most defining moments of contemporary history: the Bolshevik Revolution. Today, none of Queen Victoria's living descendents carry haemophilia. Because of this, the characterization of haemophilia (deficit of either factor VIII or XI) and the identification of the causal mutation are rendered impossible. In 1991, a tomb containing the remains of Czar Nicolas II's entire family was discovered. A second tomb was discovered in 2007, allowing Russian and American scientists to fill in this gap in medical history. Following a scientific approach combining current genetic experimentation tools and the development of biological information technology, researchers were able to identify each body, allowing them to obtain precious genetic material from the young Czar Alexis, who was stricken by the disease, which revealed a causal substitution in the splice acceptor site of exon 4 in the F9 gene. This mutation that is responsible for haemophilia B had traumatized European royal families throughout the 20th century!

Genotype analysis identifies the cause of the "royal disease".

The "royal disease," a blood disorder transmitted from Queen Victoria to European royal families, is a striking example of X-linked recessive inheritance. Although the disease is widely recognized to be a form of the blood clotting disorder hemophilia, its molecular basis has never been identified, and the royal disease is now likely extinct. We identified the likely disease-causing mutation by applying genomic methodologies (multiplex target amplification and massively parallel sequencing) to historical specimens from the Romanov branch of the royal family. The mutation occurs in F9, a gene on the X chromosome that encodes blood coagulation factor IX, and is predicted to alter RNA splicing and to lead to production of a truncated form of factor IX. Thus, the royal disease is the severe form of hemophilia, also known as hemophilia B or Christmas disease.

Bleeding disorders

The primary objective of this chapter is to deal with the most important bleeding disorders from a dental point of view. An understanding of the disorders discussed in this section hinges upon a basic knowledge of the various physiological processes involved in normal haemostasis (AU)