ACQUIRED HEMOPHILIA Revised Edition
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TREATMENT OF HEMOPHILIA November 2012 · No. 38 ACQUIRED HEMOPHILIA Revised edition Paul Giangrande Oxford Haemophilia & Thrombosis Centre Oxford, U.K. Table of Contents Summary ................................................................................................................................1 Clinical features ........................................................................................................................1 Epidemiology ...........................................................................................................................2 Laboratory diagnosis ..................................................................................................................2 Clinical management ..................................................................................................................3 Treatment of acute bleeding ......................................................................................................3 Suppression of inhibitor formation .............................................................................................4 Postpartum acquired hemophilia ...................................................................................................5 References ...............................................................................................................................6 Glossary ..................................................................................................................................7 Published by the World Federation of Hemophilia (WFH) 2005, revised 2012. © World Federation of Hemophilia, 2012 The WFH encourages redistribution of its publications for educational purposes by not-for-profit hemophilia organizations. In order to obtain permission to reprint, redistribute, or translate this publication, please contact the Communications Department at the address below. This publication is accessible from the World Federation of Hemophilia’s web site at www.wfh.org. Additional copies are also available from the WFH at: World Federation of Hemophilia 1425, boul. René-Lévesque O. Bureau 1010 Montréal, Québec H3G 1T7 Canada Tel. : (514) 875-7944 Fax : (514) 875-8916 E-mail: [email protected] Internet: www.wfh.org The Treatment of Hemophilia series is intended to provide general information on the treatment and management of hemophilia. The World Federation of Hemophilia does not engage in the practice of medicine and under no circumstances recommends particular treatment for specific individuals. Dose schedules and other treatment regimes are continually revised and new side effects recognized. WFH makes no representation, express or implied, that drug doses or other treatment recommendations in this publication are correct. For these reasons it is strongly recommended that individuals seek the advice of a medical adviser and/or to consult printed instructions provided by the pharmaceutical company before administering any of the drugs referred to in this monograph. Statements and opinions expressed here do not necessarily represent the opinions, policies, or recommendations of the World Federation of Hemophilia, its Executive Committee, or its staff. Treatment of Hemophilia Series Editor: Dr. Johnny Mahlangu ACQUIRED HEMOPHILIA Revised edition Summary Clinical features Classical hemophilia is an inherited coagulation disorder The classical form of hemophilia results in a congen- caused by a deficiency of either factor VIII or factor IX. ital bleeding tendency associated with a reduction in It is usually associated with bleeding problems from an the factor VIII (or factor IX) level. Like colour blind- early age, and bleeding into joints is a typical feature. ness, the inheritance of hemophilia is sex-linked. Males Acquired hemophilia is a rare condition that is due to are predominantly affected by the severe form of hemo- the production of autoantibodies, in adult life, which philia, which is transmitted by carrier females who do not inactivate factor VIII. Typical clinical manifestations of usually have significant bleeding problems themselves. By the acquired form are extensive cutaneous purpura and contrast, acquired hemophilia is typically a disorder of internal hemorrhage: bleeding into the joints is not a middle age and occurs equally in both sexes. It is due to prominent feature. Both sexes are affected and there may the development of autoantibodies directed against factor be identifiable underlying conditions. Diagnosis is based VIII and the resulting reduction in factor level is associ- on the finding of a low factor VIII level associated with ated with a significant bleeding tendency. the presence of a time-dependent inhibitor in the plasma. Treatment of the condition involves the use of an acti- However, the pattern of bleeding seen in acquired hemo- vated prothrombin complex concentrate (e.g., FEIBA) or philia is quite distinct from that seen in the more common recombinant activated factor VII (NovoSeven) to control congenital form. Whereas bleeding into joints (hemar- bleeding episodes. In addition, immunosuppression with throsis) is the hallmark of severe congenital hemophilia, steroids is usually effective at reducing inhibitor produc- this is unusual in acquired hemophilia where the prin- tion and bringing about a sustained rise in the factor VIII cipal manifestations are bleeding into skin (purpura) and level. The monoclonal antibody rituximab may also be soft tissues. Figures 1 and 2 illustrate typical examples of used for suppression of autoantibody production. extensive purpura due to acquired hemophilia. FIGURE 2. Extensive purpura over the chest and abdomen of a 78 year-old woman with FIGURE 1. Extensive purpura over the flanks of a acquired 62 year-old man with acquired hemophilia. hemophilia. 2 Treatment of Hemophilia No. 38 The reason for the completely different bleeding pattern Kingdom, the median age at diagnosis was 78 years; only in acquired hemophilia remains unknown; there is no 15% were less than 65 years-old at the time of diagnosis demonstrable impairment of platelet function. In a survey [2]. An underlying diagnosis such as cancer, autoimmune of 24 cases treated in a single centre over a 28-year period, disease, or pregnancy was identified in 40% of patients purpura and soft tissue hemorrhage were the presenting in this series. problems in the overwhelming majority (23) of cases [1]. Bleeding into soft tissues can worsen rapidly into a compartment syndrome. Other presentations included Laboratory diagnosis hematuria (4 cases), gastrointestinal bleeding (2 cases), and prolonged postpartum bleeding (4 cases). This study The typical findings of acquired hemophilia are a also emphasized the potential life-threatening nature prolonged activated partial thromboplastin time (APTT) of the condition as 3 patients (11% of the cohort) died and a low factor VIII level. The thrombin and prothrombin directly of bleeding complications. Other studies have times are normal, as are both the platelet count and func- demonstrated a similar clinical presentation and mortality tion. Mixing studies can be used to demonstrate the in the range of 8-22%, with the highest risk being within presence of a time-dependent inhibitor of factor VIII. the first few weeks after presentation [2]. Details of the methodology for the screening of plasma samples for inhibitory antibodies to factor VIII and their It There is often an underlying medical condition associ- quantification can be found in sections 28 and 34 of the ated with this acquired hemophilia. An association with WFH laboratory manual, Diagnosis of Haemophilia and other autoimmune conditions, malignant disease, certain Other Bleeding Disorders [4]. It is important to distin- drugs, and pregnancy has been recognized in various guish anti-factor VIII inhibitors from the more commonly surveys. In approximately half of all cases, there is no encountered antiphospholipid antibodies (or “lupus anti- obvious underlying cause and the condition is labelled coagulant”). In such cases, no correction of the baseline as idiopathic. APTT will be seen immediately after mixing text plasma with normal plasma. Epidemiology The antibodies in acquired hemophilia are invariably directed towards factor VIII and not factor IX. The anti- Acquired hemophilia is significantly rarer than the inher- bodies are usually polyclonal IgG4 antibodies (rarely IgM ited form, affecting around 2 per million of the population or IgA). Most antibodies bind to the 44-kD A2 domain [2]. As with the conventional inherited form, it appears and/or the 72-kD C2 domain of factor VIII, and do not in all ethnic groups and has a worldwide prevalence. The fix complement. condition is often not recognized or mistaken for other acquired bleeding disorders such as disseminated intra- The kinetics of the interaction between factor VIII and the vascular coagulation (DIC). Case presentations within inactivating antibody in acquired hemophilia are unusual institutions and conferences can help to increase local and differ from the usual pattern seen in congenital hemo- awareness of the disorder among healthcare professionals philia complicated by inhibitor development. The profile in other disciplines. shows a non-linear inactivation pattern (type II kinetics), with some residual factor VIII activity identifiable even Acquired hemophilia typically presents in middle age and after incubation at high concentrations of antibody for beyond. It rarely arises in childhood, where the presence some time. The lack