Elsevier

The Lancet

Volume 388, Issue 10040, 9–15 July 2016, Pages 187-197
The Lancet

Seminar
The past and future of haemophilia: diagnosis, treatments, and its complications

https://doi.org/10.1016/S0140-6736(15)01123-XGet rights and content

Summary

Haemophilia A and B are hereditary haemorrhagic disorders characterised by deficiency or dysfunction of coagulation protein factors VIII and IX, respectively. Recurrent joint and muscle bleeds lead to severe and progressive musculoskeletal damage. Existing treatment relies on replacement therapy with clotting factors, either at the time of bleeding (ie, on demand) or as part of a prophylactic schedule. The major complication of such therapy is the development of neutralising antibodies (ie, inhibitors), which is most frequent in haemophilia A. Treatment might improve considerably with the availability of new modified drugs, which might overcome existing prophylaxis limitations by reducing dosing frequency and thereby rendering therapy less distressing for the patient. Subcutaneous administration of some new therapies would also simplify prophylaxis in children with poor venous access. Gene therapy has the potential for a definitive cure, and important results have been obtained in haemophilia B. Despite improvements in haemophilia care, the availability of clotting factor concentrates for all affected individuals worldwide remains the biggest challenge.

Introduction

Haemophilia is an inherited bleeding disorder caused by deficiency or dysfunction of the coagulation proteins factor VIII, leading to haemophilia A, and factor IX, leading to haemophilia B. Since these plasma glycoproteins have an essential role in coagulation, faults cause decreased and delayed generation of thrombin, giving rise to defects in clot formation that lead to haemorrhagic diathesis. These defects are associated with bleeding episodes affecting soft tissue, joints, and muscles. Repeated haemorrhages result in chronic arthropathy, with loss of joint movement.1 At present, patients receive intravenous replacement therapy of the deficient coagulation factors, either at the time of bleeding (ie, on-demand therapy) or as a prophylactic regimen. These disorders are inherited as X-linked recessive traits—ie, male individuals are affected and female individuals are asymptomatic or mildly affected carriers. Globally, the prevalence of haemophilia A is around 1 in 5000 male births, and 1 in 30 000 male births for haemophilia B.1, 2 These figures are similar throughout the world regardless of ancestry or ethnic origin. In this Seminar, we provide an overview of the diagnosis of haemophilia and describe the clinical manifestations and treatment (both on-demand and prophylactic). Finally, we discuss inhibitor formation as a complication of replacement therapy and its treatment.

Section snippets

Diagnosis

Coagulation screening tests typically reveal a prolonged activated partial thromboplastin time with a normal prothrombin time.3 Measurement of factor VIII or IX clotting activity is used for diagnosis. On the basis of the residual coagulant activity in blood (factor VIII C or factor IX C), haemophilia is classified into three main forms: severe, moderate, and mild. Patients with a coagulation factor level of less than 1 IU/dL (ie, <1% of normal) are classified as severe and constitute about

Clinical manifestations

The clinical pictures of patients with haemophilia A and B are largely similar, and conflicting data are reported in the literature. Some evidence suggests that patients with haemophilia B have a lower bleeding frequency and better long-term outcomes than those with haemophilia A,39, 40 although a 2014 study41 suggested similar severity and variation in bleeding phenotype.

The risk of haemorrhage depends both on the severity of clotting factor deficiency and on the age of the patient. The

Treatment strategies

The main treatment is replacement therapy (also known as substitution therapy)—ie, administration of the deficient clotting factor to achieve adequate haemostasis. On-demand treatment is infusion of the deficient clotting factor at the time of bleeding. The appropriate dose, frequency, and number of concentrate infusions depend on the type and severity of the bleed. In 2013, the World Federation of Haemophilia Treatment Guidelines Working Group published detailed recommendations on disease

Development of treatment

The first treatment for haemophilia consisted of direct blood transfusion in 1840. In the 1950s and much of the 1960s, bleeding episodes were treated with fresh frozen plasma. Modern treatment started in 1965 with identification of the cryoprecipitate fraction of fresh frozen plasma by Judith Pool.68 Subsequently, technologies to separate factor VIII or IX from large pools of donor plasma resulted in freeze-dried, lyophilised factor VIII or IX concentrates,69 which made home therapy possible

Conclusion

Over the past 20 years, the diagnosis and treatment of haemophilia have improved considerably. The production of novel therapeutic proteins has been a topic of great interest to biopharmaceutical companies, and several methods have been developed to optimise and ensure the safety and effectiveness of these products. The half-life limitations of haemostatic drugs have led to the redesign of therapeutic proteins to increase their clinical potential. Although the half-lives of recombinant factor

Search strategy and selection criteria

We searched MEDLINE and PubMed for articles published in English between Jan 1, 1980, and March 31, 2015, with the following search terms: “Hemophilia/diagnosis[Majr] OR Hemophilia/hemorrhage[Majr] OR Hemophilia/drug therapy/therapy[Majr] OR Hemophilia [Majr] AND Antibodies[Majr]”, and “(haemophilia [TI] OR hemophilia [TI]) AND (diagnos* OR therap* OR treatmen*) AND “2015/03/30”[PDAT]”. After excluding articles on the basis of their titles or abstracts, the remaining articles and those

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