The diagnosis and management of factor VIII and IX inhibitors: a guideline from the United Kingdom Haemophilia Centre Doctors Organisation

Abstract

SummaryThe revised UKHCDO factor (F) VIII/IX Inhibitor Guidelines (2000) are presented. A schema is proposed for inhibitor surveillance, which varies according to the severity of the haemophilia and the treatment type and regimen used. The methodological and pharmacokinetic approach to inhibitor surveillance in congenital haemophilia has been updated. Factor VIII/IX genotyping of patients is recommended to identify those at increased risk. All patients who develop an inhibitor should be considered for immune tolerance induction (ITI). The decision to attempt ITI for FIX inhibitors must be carefully weighed against the relatively high risk of reactions and the nephrotic syndrome and the relatively low response rate observed in this group. The start of ITI should be deferred until the inhibitor has declined below 10 Bethesda Units/ml, where possible. ITI should continue, even in resistant patients, where it is well tolerated and so long as there is a convincing downward trend in the inhibitor titre. The choice of treatment for bleeding in inhibitor patients is dictated by the severity of the bleed, the current inhibitor titre, the previous anamnestic response to FVIII/IX, the previous clinical response and the side-effect profile of the agents available. We have reviewed novel dose-regimens and modes of administration of FEIBA (factor VIII inhibitor bypassing activity) and recombinant activated FVII (rVIIa) and the extent to which these agents may be used for prophylaxis and surgery. Bleeding in acquired haemophilia is usually treated with FEIBA or rVIIa. Immunosuppressive therapy should be initiated at the time of diagnosis with Prednisolone 1 mg/kg/d ± cyclophosphamide. In the absence of a response to these agents within 6 weeks, second-line therapy with Rituximab, Ciclosporin A, or other multiple-modality regimens may be considered.Keywords: diagnosis, management, factor VIII/IX inhibitors.Since the publication of the previous guideline on the detection and management of factor (F) VIII inhibitors (Hay et al, 2000), significant diagnostic and therapeutic advances have taken place. The UK Haemophilia Doctors Organisation (UKHCDO) has therefore revised and updated those sections of the earlier guideline covering areas of clinical practice which we felt had developed, to define best current practice internationally. Although all sections of the previous guideline have been reviewed, some sections required little revision whereas others required rewriting. For those areas that did not require revision, the reader is referred back to the previous guideline. The evidence-based approach used highlights the need for future clinical trials in areas where current treatment strategies are based on uncontrolled observations or where there is a dichotomy of clinical opinion. MethodsThe guidelines were drafted by the UKHCDO Inhibitor Working Party and circulated to the Executive Committee of the UKHCDO for consultation. Members of UKHCDO and its working parties make an annual declaration of interest to UKHCDO and to their Ho...

Rituximab in the treatment of autoimmune haematological disorders

“…Acute bleeding episodes in patients with low-titre autoantibodies can be treated with plasma-derived or recombinant human FVIII, whereas FVIII-bypassing agents, such as activated prothrombin complex or recombinant FVIIa, are recommended for patients with high-titre autoantibodies (Sallah & Aledort, 2005;Hay et al, 2006). The long-term goal of therapy is to eliminate the FVIII autoantibodies and thus cure the disease.…”

“…The long-term goal of therapy is to eliminate the FVIII autoantibodies and thus cure the disease. To this end, it is recommended that immunosuppressant therapy be initiated as soon as acquired haemophilia is diagnosed (Sallah & Aledort, 2005;Hay et al, 2006). Prednisone with or without cyclophosphamide is generally the treatment of choice for initial immunosuppressant therapy, with elimination of inhibitors being achieved in approximately 70% of patients (Hay et al, 2006).…”

“…To this end, it is recommended that immunosuppressant therapy be initiated as soon as acquired haemophilia is diagnosed (Sallah & Aledort, 2005;Hay et al, 2006). Prednisone with or without cyclophosphamide is generally the treatment of choice for initial immunosuppressant therapy, with elimination of inhibitors being achieved in approximately 70% of patients (Hay et al, 2006). For those patients who do not respond to initial therapy and the 20% of patients who relapse after a first response, second-line therapy may include 2-chlorodeoxyadenosine, ciclosporin A, azathioprine or IVIG (Sallah & Aledort, 2005;Hay et al, 2006).…”

Acquired haemophilia in a patient with discoid lupus

“…Mortality is rather high in newly diagnosed acquired haemophilia ranging from 8 to 22 % in different studies [2][3][4][5]. A major cause of significant mortality and morbidity is the frequent confusion with other life-threatening conditions such as disseminated intravascular coagulation (DIC), thus often leading to uncontrolled bleeding prior to correct diagnosis of the disease.…”

“…Effective treatment involves not only the initial treatment of acute haemorrhage with factor VIII concentrates, a factor-VIII-bypassing-agent such as recombinant FVIIa or activated prothrombin complex concentrate but also the eradication of the inhibitor by 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 3 immunosuppression, plasmapheresis or immunoadsorption or a combination of these modalities [1,5,6].…”