ACQUIRED HEMOPHILIA - World Federation of Hemophilia

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2Treatment of Hemophilia No. 38The reason for the completely different bleeding patternin acquired hemophilia remains unknown; there is nodemonstrable impairment of platelet function. In a surveyof 24 cases treated in a single centre over a 28-year period,purpura and soft tissue hemorrhage were the presentingproblems in the overwhelming majority (23) of cases[1]. Bleeding into soft tissues can worsen rapidly into acompartment syndrome. Other presentations includedhematuria (4 cases), gastrointestinal bleeding (2 cases),and prolonged postpartum bleeding (4 cases). This studyalso emphasized the potential life-threatening natureof the condition as 3 patients (11% of the cohort) dieddirectly of bleeding complications. Other studies havedemonstrated a similar clinical presentation and mortalityin the range of 8-22%, with the highest risk being withinthe first few weeks after presentation [2].It There is often an underlying medical condition associatedwith this acquired hemophilia. An association withother autoimmune conditions, malignant disease, certaindrugs, and pregnancy has been recognized in varioussurveys. In approximately half of all cases, there is noobvious underlying cause and the condition is labelledas idiopathic.EpidemiologyAcquired hemophilia is significantly rarer than the inheritedform, affecting around 2 per million of the population[2]. As with the conventional inherited form, it appearsin all ethnic groups and has a worldwide prevalence. Thecondition is often not recognized or mistaken for otheracquired bleeding disorders such as disseminated intravascularcoagulation (DIC). Case presentations withininstitutions and conferences can help to increase localawareness of the disorder among healthcare professionalsin other disciplines.Acquired hemophilia typically presents in middle age andbeyond. It rarely arises in childhood, where the presenceof an inhibitor on laboratory screening of a previouslyhealthy child is much more likely caused by the presenceof a lupus anticoagulant (antiphospholipid antibody).In an analysis of pooled data from 20 surveys encompassing249 patients, the median age of patients reportedwith acquired hemophilia was 64, with a range of 8-93years [3]. In a prospective national study from the UnitedKingdom, the median age at diagnosis was 78 years; only15% were less than 65 years-old at the time of diagnosis[2]. An underlying diagnosis such as cancer, autoimmunedisease, or pregnancy was identified in 40% of patientsin this series.Laboratory diagnosisThe typical findings of acquired hemophilia are aprolonged activated partial thromboplastin time (APTT)and a low factor VIII level. The thrombin and prothrombintimes are normal, as are both the platelet count and function.Mixing studies can be used to demonstrate thepresence of a time-dependent inhibitor of factor VIII.Details of the methodology for the screening of plasmasamples for inhibitory antibodies to factor VIII and theirquantification can be found in sections 28 and 34 of theWFH laboratory manual, Diagnosis of Haemophilia andOther Bleeding Disorders [4]. It is important to distinguishanti-factor VIII inhibitors from the more commonlyencountered antiphospholipid antibodies (or “lupus anticoagulant”).In such cases, no correction of the baselineAPTT will be seen immediately after mixing text plasmawith normal plasma.The antibodies in acquired hemophilia are invariablydirected towards factor VIII and not factor IX. The antibodiesare usually polyclonal IgG4 antibodies (rarely IgMor IgA). Most antibodies bind to the 44-kD A2 domainand/or the 72-kD C2 domain of factor VIII, and do notfix complement.The kinetics of the interaction between factor VIII and theinactivating antibody in acquired hemophilia are unusualand differ from the usual pattern seen in congenital hemophiliacomplicated by inhibitor development. The profileshows a non-linear inactivation pattern (type II kinetics),with some residual factor VIII activity identifiable evenafter incubation at high concentrations of antibody forsome time. The lack of complete inactivation of factorVIII even at high concentration is due to the fact thatantibodies in acquired hemophilia may react with factorVIII to form a complex with some residual factor VIIIactivity. What this means in practice is that patients withacquired hemophilia may have measurable factor VIIIbaseline levels even in the presence of high titer inhibitoryantibodies. There is therefore a poor correlation between
Acquired hemophilia 3the measureable factor VIII level and bleeding severityin acquired hemophilia, as opposed to what is seen withcongenital hemophilia. A patient with acquired hemophiliaand a factor VIII level of, say, 5% can still haveserious hemorrhagic episodes.Clinical managementAcquired hemophilia is a rare disorder and the potentialfor significant bleeding problems is high. It is thereforerecommended that such patients be managed in specialisthemophilia units, which have the necessary expertise andblood products available.It needs to be remembered that many of the patientswith this condition are elderly and frail, and may thusbe particularly vulnerable to the adverse effects of treatmentwith steroids such as diabetes mellitus, psychosis,osteoporosis, and cataract development. There may wellalso be ethical issues involved in decisions regarding howfar to pursue investigations for underlying pathologyand getting truly informed consent, as well as the cost oftreatment. At the very least, a thorough medical history,physical examination with a limited panel of blood tests,and radiological studies should be conducted to identifyany underlying condition.Recent medication use should be carefully reviewedas the development of acquired hemophilia has beenreported as a very occasional adverse reaction to certaindrugs. Drugs that have been implicated in published casereports include antibiotics (such as penicillin, sulphonamidesand ciprofloxacin), immune-modifying drugs(interferon, fludarabine), psychotropic drugs (phenytoin,flupentixol, zuclopenthixol), and the antiplatelet agent,clopidogrel. However, this is by no means an exhaustivelist and the possibility that any recent drug couldhave provoked the bleeding disorder must be considered.Many elderly patients may be prescribed medicationsthat can exacerbate the bleeding tendency in acquiredhemophilia through inhibition of platelet function, fore.g. anti-inflammatory drugs for osteoarthritis or aspirinor clopidogrel for cardiac disease.Treatment of acquired hemophilia is two-pronged [5].The immediate priority is to control acute bleeding withbypassing agents. Immunosuppression should then beused to control antibody production. Human factor VIIIis likely to be very rapidly inactivated by a significant titerof inhibitory antibody and therefore of no practical use,even at high doses.Treatment of acute bleedingThe principal products available for the treatment ofbleeding episodes are activated prothrombin complexconcentrates (such as FEIBA, which contains activatedfactors VII, IX, and X) or recombinant activated factor VII(NovoSeven). The efficacy of both agents is very similarand the choice of product and dose is determined by thesite and severity of the bleeding. It should be noted thateven extensive cutaneous purpura do not necessarilyrequire treatment.FEIBA is a plasma-derived concentrate which is subjectedto dry heat vapour treatment and nanofiltration. Dosesin the range of 50-100 units every 8-12 hours are givenby intravenous infusion, but it is important not to exceeda total of 200 units/kg within a 24-hour period as thismay be associated with a risk of venous thromboembolism.Tranexamic acid should not be given together withthis agent.A recent retrospective survey of 34 patients with acquiredhemophilia documented an overall complete responserate of 86%, with a typical dosage regime of 75 units/kggiven every 8-12 hours [6]. The median number of dosesrequired to control a severe bleed was 10, compared to amedian of 6 doses for an episode classified as “moderate”.There is no easy way to monitor the response to FEIBA inthe laboratory and clinical judgement must be relied on.Recombinant activated factor VII is an alternative agent,which has the advantage of freedom from the risk of transmissionof blood-borne viruses and other pathogens. Areview of its use in acquired hemophilia reported an efficacyrate of 95% in 139 patients when used as first linetherapy [7]. A typical dose regime would be 90-120 µg/kgadministered every 3 hours until bleeding is controlled.Tranexamic acid may be safely used in combination withrecombinant activated factor VII to inhibit fibrinolysisand thus enhance hemostasis. As with FEIBA, laboratorymonitoring is not easy and response to treatment is bestassessed on purely clinical grounds. Shortening of theprothrombin time (PT) will be observed after administrationof recombinant activated factor VII.
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ACQUIRED HEMOPHILIA - World Federation of Hemophilia

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