Diagnosis and management of acquired coagulation inhibitors: a guideline from UKHCDO

Abstract

Acquired coagulation inhibitors result from immune-mediated depletion or inhibition of a coagulation factor. Inhibitors are most commonly directed against factor VIII (FVIII) and von Willebrand factor (VWF) and inhibitors against other coagulation factors are only occasionally reported. Since the publication of previous guidelines (Laffan et al, 2004; Pasi et al, 2004; Hay et al, 2006) substantial new data has been published on acquired FVIII inhibitors, necessitating updated guidelines. The rarity of acquired inhibitors to other coagulation factors means that limited information is available to guide management and the treatment strategies suggested are necessarily by consensus and often extrapolated from data derived from FVIII inhibitors. Inhibitors to VWF will not be covered because a revised von willebrand disease (VWD) guideline is in preparation (Laffan et al, 2004; Pasi et al, 2004). The writing group reviewed publications known to them, supplemented with papers identified through Pubmed, using index terms H(a)emophilia, acquired h(a)emophilia, factors VIII, II, V, VII, IX, X, XI, XIII, fibrinogen, fibrin, inhibitors, autoantibodies, rFVIIa, Novoseven, FEIBA, aPCC, rituximab, management. The writing group produced the draft guideline, which was reviewed and revised by members of the United Kingdom Haemophilia Centre Doctors’ Organization (UKHCDO) Advisory Board. The guideline was also reviewed by a sounding board of approximately 50 UK haematologists, the British Committee for Standards in Haematology (BCSH) and the British Society for Haematology (BSH) Committees and comments incorporated where appropriate. The ‘GRADE’ system was used to quote levels and grades of evidence, details of which can be found at http://www.bcshguidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_GRADES_OF _RECOMMENDATION/43_GRADE.html. The objective of this guideline is to provide healthcare professionals with pragmatic guidance on the management of patients with acquired coagulation factor inhibitors although individual patient circumstances may dictate an alternative approach. Patients should be registered, and treated jointly with a Comprehensive Care Haemophilia Centre (CCC) experienced in the management of inhibitors (National Service Specification available at www.ukhcdo.org). CCCs must provide 24-h access to senior clinicians with experience in inhibitor management and laboratory services for the measurement of factor levels and inhibitor titres. An underlying cause of the acquired inhibitor should be sought and patients should be investigated for autoimmune disease and malignancy. Patients should be offered inclusion in appropriate clinical trials and reported to registries. UK patients must be registered with the National Haemophilia Database. Acquired haemophilia A (AHA) has an incidence of about 1·5/million/year and presents most commonly in the elderly at a median age of 75–80 years (Collins et al, 2004, 2007; Knobl et al, 2012). Other inhibitors are much less common. AHA is associated with polymyalgia, rheumatoid arthritis, systemic lupus erythematosus (SLE) and other autoimmune diseases, malignancy, pregnancy and pemphigoid. No association is identified in about half of patients (Green & Lechner, 1981; Morrison & Ludlam, 1995; Collins et al, 2007). Inhibitors to other coagulation factors have been associated with auto-immune disease and malignancy (Hay, 2012). The mortality associated with AHA has been reported to be between 8% and 42% (Green & Lechner, 1981; Morrison et al, 1993; Hay et al, 1997; Delgado et al, 2003; Collins et al, 2007). In recent studies, 3–12% of deaths were attributed to the effects of immunosuppression and infection whilst 3–8% were attributed to bleeding (Collins et al, 2007; Knobl et al, 2012). An acquired inhibitor should be considered in patients with recent onset of abnormal bleeding. Patients usually present to clinicians with limited experience of the disorder and diagnosis and appropriate treatment is often delayed. Severe and life-threatening bleeding is common in AHA, although, in contrast no haemostatic treatment is required in 25–33% of cases (Lottenberg et al, 1987; Collins et al, 2007; Knobl et al, 2012). Some patients present without clinical bleeding. The severity of bleeding at presentation does not predict future bleeding and patients remain at risk of fatal bleeding until the inhibitor has been eradicated (Collins et al, 2007). The clinical features of AHA differ from those of congenital haemophilia because bruising, retroperitoneal, muscle, gastrointestinal and urogenital bleeding are common whereas haemarthroses are uncommon (Morrison et al, 1993; Hay et al, 1997; Delgado et al, 2003; Collins et al, 2007; Knobl et al, 2012). Fatality is associated with gastrointestinal, intracranial and retroperitoneal bleeds (Collins et al, 2007). Compartment syndromes and critical compression of nerves and blood vessels may be seen. There is limited information on the clinical features associated with inhibitors to other coagulation factors and this will be covered in specific sections of this guideline. Acquired haemophilia A has been reported in association with anticoagulation and anti-platelet agents and diagnosis may be delayed because the bleeding is assumed to be caused by these agents (Uggla et al, 2003; Dragani et al, 2004; Haj et al, 2004; Vadikolia et al, 2007). Excessive bruising or unexpected bleeding in patients on anticoagulants should be further investigated. Diagnosis of acquired coagulation factor inhibitors, and their differentiation from other coagulation abnormalities, requires specialized investigation, often necessitating referral to a reference laboratory. When investigating abnormal clotting times in patients presenting with bleeding, it is important to exclude treatment with anticoagulant therapy. See Fig 1 for further details. Typical laboratory findings are of abnormal coagulation screening tests that do not correct with normal plasma, either with an immediate or incubated mix. The pattern of abnormality of screening tests depends on the specificity of the inhibitor (Fig 1). The diagnosis is confirmed by assays of specific factors and demonstration of an inhibitor in the Bethesda assay for FVIII or, for other factors, a modification of the Bethesda assay. In all cases, the Nijmegen modification should be employed to improve assay sensitivity. In the absence of a time-dependent inhibitor, it is possible to perform a Bethesda assay without the incubation step. A lupus anticoagulant (LA) should be excluded as a cause of apparently reduced coagulation factor levels (Keeling et al, 2012), especially in the absence of bleeding. Acquired coagulation factor inhibitors may co-exist with a LA, especially antibodies to prothrombin. In some cases an inhibitor to one factor may interfere with the assay of other coagulations factors. This is best documented with FVIII inhibitors, where all intrinsic factors may apparently be low due to inhibition of FVIII in the intrinsic factor-deficient plasma, but this finding could equally apply to any inhibitor. In these cases serial dilution will result in correction of the non-specifically reduced factors whilst the specifically reduced factor will remain low. Thus it is important that factor assay design includes multiple dilutions of test plasma, and an evaluation of linearity against the calibration curve. In some cases, for example for defects of fibrin polymerization, thromboelastometry may be useful. Some highly specialized laboratories may extend investigation to global assays, such as thrombin generation, but this is not recommended outside research studies. FVIII inhibitors are time- and temperature-dependent and mixing studies with normal plasma may demonstrate inhibition on incubation that is not present immediately after mixing. Inhibitors to other coagulation factors have not been reported to be time-dependent. Enzyme-linked immunosorbent assay (ELISA)-based assays have been reported for FVIII inhibitor detection, which may avoid interference by LAs. Chromogenic FVIII assays may be used, because LAs do not interfere with this assay. It is often difficult to define the titre of an acquired FVIII inhibitor due to the complex kinetics, whereby the pattern of inactivation is non-linear, and may therefore lead to the inhibitor potency being underestimated. It is usual to report the dilution that most closely inhibits half the FVIII after 2 h. If recombinant B domain-deleted porcine FVIII becomes available, inhibitor titres to this product should be performed. The laboratory investigation of other acquired inhibitors will be covered in appropriate sections. Delay in diagnosis and treatment is common, putting patients at unnecessary risk of severe bleeding, especially if invasive procedures are undertaken. In AHA, delays were more than 12 d in 25% and more than 4 weeks in 10% of cases and occurred both between the onset of bleeding and investigation and the finding of a prolonged aPTT and diagnosis (Knobl et al, 2012). Coagulation laboratories should have algorithms in place that ensure appropriate investigation of abnormal coagulation screening tests, especially of an isolated prolonged aPTT. If the aPTT does not correct with normal plasma and the LA is negative, factor levels should be done. A possible algorithm is suggested (Fig 1) which can be adapted to local needs. Systems should be in place to inform clinicians of the potential significance of abnormal results and to ensure further investigations are performed rapidly to confirm or refute the diagnosis. Haematologists should take responsibility for managing the bleeding manifestations of the disease as soon as a diagnosis is suspected. Reviews and consensus treatment guidelines on the treatment of AHA have been published (Hay et al, 2006; Huth-Kuhne et al, 2009; Collins, 2011). Patients should not be exposed to invasive procedures unless they are essential because uncontrollable bleeding may result even from minor procedures. The efficacy of available haemostatic agents is unpredictable and none are universally effective. Even for procedures that would normally be considered unsuitable for delay, the pros and cons of operating in the presence of an inhibitor should be weighed against the risks of conservative management until FVIII levels have increased. Venepuncture and the placement of a venous cannula may also lead to severe bleeding and should be kept to a minimum. Some centres do not allow ward phlebotomists to take blood, in which case samples are taken by haemophilia centre staff. Ward staff should be educated about the risk of inducing bleeds and blood pressure and blood glucose monitoring are only performed if clinically indicated. Patients should be protected against the risk of falls when mobilizing. Intramuscular injections are contraindicated. Treatment of bleeding should be supervized by a clinician experienced in the treatment of patients with inhibitors because bleeds may be very severe and prompt haemostatic control is required to reduce morbidity and mortality. In contrast, many patients do not require haemostatic therapy (Collins et al, 2007; Baudo et al, 2012) and, because of the increased risk of thrombosis associated with bypassing therapy, some bleeds, for example subcutaneous bleeds, may be best managed conservatively. If haemostatic treatment is required it should be with a bypassing agent (Baudo et al, 2012). The available bypassing agents are recombinant factor VIIa (rFVIIa) (Novoseven®, Bagsvaerd, Denmark) and the activated prothrombin complex concentrate (aPCC) Factor Eight Inhibitor Bypassing Activity (FEIBA). Data on the haemostatic efficacy and side effects of bypassing agents in patients with AHA relate to these products and can not necessarily be extrapolated to other rFVIIa molecules or aPCCs. Treatment with human FVIII concentrates is less efficacious than bypassing agents unless combined with immunoadsorption (Baudo et al, 2012). Desmopressin may increase FVIII levels in some patients, although this treatment may be contraindicated in some patients due to comorbidities (Mudad & Kane, 1993; Franchini & Lippi, 2011). Previously, plasma-derived porcine FVIII was shown to be efficacious in treating bleeding in AHA (Morrison et al, 1993). Most data on the treatment of bleeds for patients with FVIII inhibitors relate to congenital haemophilia and focus on haemarthroses (Collins et al, 2013). The autoantibodies that cause AHA have different properties to the allo-antibodies associated with congenital haemophilia and the bleeding pattern differs. In particular, haemarthroses are uncommon. This means that data derived from patients with congenital inhibitors cannot necessarily be extrapolated to AHA. A retrospective study of AHA patients treated with rFVIIa combined data from three sources that had variable inclusion criteria: a compassionate use programme (Hay et al, 1997), the Hemophilia and Thrombosis Research Society Registry and the published literature. It reported on 139 patients and 182 bleeds (Sumner et al, 2007). In the 103 episodes where rFVIIa was used as first-line therapy, treatment was effective or partially effective in 95% of cases (Sumner et al, 2007). Similar results were reported to the European Acquired Haemophilia (EACH2) registry, where 159 prospectively collected bleeds treated first-line with rFVIIa resolved in 92% of cases (Baudo et al, 2012). In EACH2, 64 bleeds were treated first-line with FEIBA with 93% resolution (Baudo et al, 2012). In a retrospective study of FEIBA in 34 patients, moderate bleeds had 100% and severe bleeds 76% haemostatic control at a median of 48 h (Sallah, 2004). When used in 57 surgeries, rFVIIa was reported as effective or partially effective in 86% of cases (Sumner et al, 2007). The haemostatic efficacy of rFVIIa and FEIBA has not been compared directly in AHA. However, an analysis of data in the EACH2 registry, which controlled for bleed and patient characteristics by propensity score matching, found that the two agents were indistinguishable [odds ratio (OR) 1·0, 95% confidence interval (CI) 0·23–4·44] (Baudo et al, 2012). In congenital haemophilia A, studies that compared rFVIIa and FEIBA for treatment of haemarthroses also suggest similar efficacy (Astermark et al, 2007; Young et al, 2008). Either bypassing agent can be used as first-line treatment for bleeding in AHA. The choice of agent will depend on knowledge of the patient's previous response, convenience of dosing, use of plasma-derived products and cost. If response to first-line therapy is inadequate, the alternative bypassing agent may be successful and should be tried at an early stage. The initial dose of rFVIIa should be 90 μg/kg every 2 h and for FEIBA 50–100 u/kg every 6–12 h with a maximum dose of 200 u/kg/d. A period of treatment at reduced dose and frequency after initial bleed control is often needed to prevent recurrence and must be assessed on a case-by-case basis. In EACH2, after matching for bleed and patient characteristics, the likelihood of haemostatic failure was lower with bypassing agents compared to FVIII or desmopressin (OR 0·15, 95% CI 0·04–0·53, P = 0·003) (Baudo et al, 2012). Most patients with AHA are resistant to human FVIII and, even if the inhibitor titre is low, the response is unpredictable and the Bethesda assay is not predictive of FVIII recovery. Human FVIII is usually neutralized with an early rapid parabolic reduction to a low level, which is sometimes followed by a slower, second disappearance-phase resulting in a low level of residual FVIII activity that may persist for several hours (Gawryl & Hoyer, 1982). The FVIII level is not a good guide to clinical response. The administered dose of FVIII must be sufficient to overcome the inhibitor and provide an adequate haemostatic level. Although formulae have been suggested for calculating the dose, the inaccuracies inherent in the laboratory measurement of inhibitor titres in AHA make these, at best, very rough approximations. If FVIII is used, a large initial dose is likely to be required with regular boluses or continuous infusion and regular monitoring of plasma FVIII level and clinical response is required. If a poor response is observed an early change to an alternative product is required. The use of high dose human FVIII (100 iu/kg/d) in combination with immunoadsorption may result in haemostatic FVIII levels and rapid control of severe bleeding, despite high anti-FVIII inhibitor titres (Zeitler et al, 2006a, 2010). This treatment strategy may be useful as first-line therapy or if bypassing agents have failed, although it is available in only a very limited number of centres (Guillet et al, 2001; Freedman et al, 2003). Some patients with a low titre inhibitor (<2 Bethesda units, BU) and baseline FVIII above 5 iu/dl may respond to desmopressin infusion: clinical response, however, is unpredictable and haemostatic efficacy is not as good as that seen with bypassing agents (Mudad & Kane, 1993; Franchini & Lippi, 2011; Baudo et al, 2012). Desmopressin may be useful to treat minor bleeds but careful laboratory and clinical monitoring of response is required. In AHA, the inhibitor titre to porcine FVIII is usually 5–10% that of the human titre (Morrison et al, 1993) and so porcine FVIII may achieve haemostasis in situations where human FVIII is ineffective. Plasma-derived porcine FVIII has proven efficacy in AHA (Morrison et al, 1993) but is no longer available. The use of a recombinant B-domain deleted porcine FVIII is currently under investigation in AHA. Tranexamic acid is a useful adjunct therapy, especially for mucosal bleeds. It should be considered for all bleeds apart from renal tract bleeding. Concerns about concomitant use of tranexamic acid with FEIBA exist but reports of complications are very rare and many clinicians use tranexamic acid in combination with FEIBA (Holmstrom et al, 2012). Topical tranexamic acid may be useful for oral or skin bleeding. The use of intravenous immunoglobulin (IVIG) as an adjunct to other haemostatic measures is approved in the current UK IVIG clinical guidelines for patients with acquired inhibitors of coagulation factors and life or limb threatening haemorrhage that has failed to respond to other therapies, although there is only very limited data supporting its efficacy (http://www.ivig.nhs.uk/documents/dh_129666.pdf). Outcome data on the efficacy for this indication will be available in the future as part of the demand management of IVIG use in the UK. Invasive procedures should only be performed at CCCs. Treatment options include the use of bypassing agents or immunoadsorption with FVIII infusion. Haemostasis cannot be guaranteed and life-threatening bleeding may result. Treatment with either rFVIIa or FEIBA is associated with arterial and venous thrombosis and the incidence of thrombosis appears to be higher than when these agents are used in congenital haemophilia A. This is probably due to risk factors associated with the age and the often complex clinical status of these patients. A review of patients with AHA treated with rFVIIa reported 12 thrombotic events, predominantly arterial, in 139 patients (8·6%) (Sumner et al, 2007). EACH2 reported 11 thrombotic events (seven arterial and four venous) in patients treated with a haemostatic agent and two in patients not treated with a haemostatic agent. There were 5/174 (2·7%) events associated with rFVIIa, 3/63 (3·6%) with FEIBA, 0/70 with FVIII or desmopressin and in three cases the haemostatic agent was not reported (Baudo et al, 2012). Although a causal relationship between bypassing agents and the reported thrombotic events cannot be established, caution is required and the decision to use a bypassing agent is not straightforward. Treatment of significant bleeding should not be withheld because the benefit of early control of severe bleeding clearly outweighs the risk of thrombosis. However, careful consideration should be given to minor bleeds, such as subcutaneous haemorrhage, which often resolve spontaneously. The use of rFVIIa at doses higher than 90 μg/kg has been shown to be safe and efficacious for the treatment of haemarthroses in congenital haemophilia (Santagostino et al, 2006; Young et al, 2008). Dose escalation should be considered only in exceptional circumstances in patients with AHA because higher dose rFVIIa has not been shown to be safe in this patient group or efficacious for treating the types of bleeds associated with AHA (Huth-Kuhne et al, 2009). However, in the management of severe bleeds unresponsive to conventional doses, escalation may be justifiable on a case-by-case basis. The use of combined rFVIIa and FEIBA should be avoided (Ingerslev & Sorensen, 2011) except in life or limb-threatening situations unresponsive to each agent alone (Teitel et al, 2007). Remission is often associated with high FVIII levels and, because patients are likely to have other risk factors for venous thrombosis, they should be assessed and treated with appropriate venous thromboprophylaxis if indicated. No laboratory tests have been validated for monitoring haemostatic response of bypassing agents in AHA. FVIII levels can be measured and global haemostatic assays used but results do not necessarily correlate with haemostatic efficacy (Dehmel et al, 2008) and should only be used as part of a clinical trial. Monitoring of response is primarily clinical, supported by measurement of haemoglobin and appropriate imaging. Immunosuppression to eradicate an inhibitor should be started as soon as the diagnosis has been made, to reduce the time a patient is at risk of bleeding (Collins et al, 2007), although haemostatic control should be the priority in the acute setting. The choice of immunosuppressive regimen needs to take into account the comorbidities of the patient. Patients should be monitored closely for evidence of infection. Reports on the effectiveness of immunosuppression are difficult to interpret because of the use of variable endpoints and definitions in different studies. Reports are likely to reflect more severely affected patients and publication bias of good outcomes (Collins & Percy, 2010; Collins, 2011). One study reported a spontaneous remission in 25% of patients after a median 19 months follow up, although there was significant associated morbidity and two patients died of bleeding (Lottenberg et al, 1987); this finding has not been replicated. Meta-analyses have identified older age and underlying malignancy as risk factors for mortality (Delgado et al, 2003; Bitting et al, 2009). Patients presenting with higher FVIII levels and lower inhibitor titres are more likely to respond to immunosuppression but the relationship is too weak to be the basis for treatment decisions (Collins et al, 2007). The median time to remission following the start of immunosuppression is about 5 weeks (Collins et al, 2007, 2012). Routine first-line treatment in many centres is with either steroids alone or steroids combined with a cytotoxic agent (Huth-Kuhne et al, 2009). The most robust analysis of first-line immunosuppression comes from the EACH2 registry of 331 patients. Patients treated with prednisone alone were compared to those treated with prednisone and oral cyclophosphamide. The groups were matched by logistic regression and a propensity score for age, gender, inhibitor titre, FVIII level and underlying aetiology. The study reported an OR of 3·25 (95% CI 1·51–6·96), P < 0·001, of achieving a stable remission using combined therapy compared to prednisone, despite the prednisone-alone arm receiving a higher dose of steroids (Collins et al, 2012). A non-randomized, prospective, national consecutive cohort study compared patients treated with steroids versus steroids and cytotoxics. The design of this study reduced selection bias although the groups were not matched for presenting characteristics. The 34 patients treated with steroids had 76% complete remission (CR) at a median of 49 (95% CI, 31–62) days compared to 78% CR at 39 (34–57) days for the steroids and cytotoxics group (Collins et al, 2007). A meta-analysis of 20 studies reported that the use of steroids and cyclophosphamide resulted in more patients achieving CR compared to steroids alone (Delgado et al, 2003). A more recent meta-analysis of 32 non-randomized studies (including the 20 previous studies) found that patients receiving combination immunosuppression had a reduced OR of 0·04 (95% CI 0·01–0·23), for persistent, acquired haemophilia when compared to those receiving no immunosuppression, and an OR of 0·38 (95% CI 0·14–0·94) for steroid therapy alone (Bitting et al, 2009). The only prospective randomized study enrolled 31 patients (Green et al, 1993). This study is often interpreted as providing evidence to support the addition of cyclophosphamide to steroids if a CR has not been achieved by 3 weeks. The study data, however, do not provide evidence that this strategy is superior to any other. Despite reports showing that patients treated first-line with a combination of steroids and cyclophosphamide were more likely to achieve a CR than steroids alone, the final outcome in terms of survival and sustained remission is the same in all large studies (Delgado et al, 2003; Collins et al, 2007, 2012). Regimens involving combination immunosuppression have been reported to have high success rates but without comparative groups the results must be treated with caution because numbers are very small (Lian et al, 2002). Rituximab is becoming a common treatment for AHA but there are no data to support the contention that alone, or with other agents, it results in more patients achieving remission or a more rapid response to treatment. A literature review of 71 patients treated with rituximab and a variety of other immunosuppressive agents reported a response rate of over 90%, however, reporting bias towards good outcomes is likely and no controls were included (Franchini & Lippi, 2008). A more recent study reported that 42 patients treated with rituximab had similar outcomes to 44 control patients treated with cyclophosphamide and steroids (Sperr et al, 2007). EACH2 reported that 25 of 39 (64%) patients treated with rituximab and another immunosuppressive agent achieving a stable remission compared to (58/83, 70%) treated with steroids and cyclophosphamide (Collins et al, 2012). Of the patients treated with rituximab alone 5/12 (42%) had a stable remission (Collins et al, 2012). Based on current data, rituximab is not associated with more rapid remission. The 30 patients who responded in the EACH2 registry had a median (inter-quartile range) time to a negative inhibitor of 65 (29–144) days, which is a slower response compared to other regimens (median time to remission 32–40 d) (Collins et al, 2012). In a study of 12 patients treated with rituximab alone 75% achieved CR but with a median (interquartile range) time to remission of 106 (26–184) days (Boles et al, 2011). Some patients who are resistant to standard first-line regimens respond to second-line rituximab (Collins et al, 2012). There is no evidence to support the use of rituximab in patients with high titre inhibitors, as has been suggested by some authors (Aggarwal et al, 2006). The combination of ciclosporin or tacrolimus and steroids has been reported as successful first-line treatment with stable remission in 10/11 (91%) patients at a median of 3 weeks, though no controls were reported in this study (Pardos-Gea et al, 2012). A number of cases have been reported in which ciclosporin has induced CR following failed first-line therapy (Pfliegler et al, 1989; Schulman et al, 1996; Au et al, 2004; Haj et al, 2004). The available evidence does not support the use of IVIG as a single agent or in combination with steroids and cytotoxics as an immunosuppressive agent. The UKHCDO and EACH2 studies both showed no benefit for adding IVIG to other immunosuppression as first-line therapy (Collins et al, 2007, 2012) and a literature review reached the same conclusion (Delgado et al, 2003). FVIII in conjunction with immunosuppressive agents has been reported. The lack of controls in these studies means that the role of FVIII is difficult to assess. A study of daily infusion of FVIII (30 iu/kg/d for 1 week, 20 iu/kg/d for a second week and 15 iu/kg/d for a third week) combined with intravenous cyclophosphamide and methylprednisolone reported CR in 95% of 20 patients after a median 4·7 weeks, compared to 67% remission at a median of 28·3 weeks in six historical controls treated with steroids ± cyclophosphamide (Nemes & Pitlik, 2003). A report of patients treated with 3 weekly infusions of FVIII combined with vincristine, cyclophosphamide and steroids resulted in a 92% CR rate in 12 patients after 1–3 courses (Lian et al, 1989). The same group later reported six patients who were treated with vincristine, cyclophosphamide and steroids without FVIII and found 83% remission after 1–7 courses (Lian et al, 2002). The effect of FVIII is unclear because the intensity of immunosuppression was greater than for many other protocols (Lian et al, 1989, 2002). Taken together these reports are insufficient to conclude that immune tolerance with FVIII is beneficial in AHA and the high cost of FVIII in these protocols must be taken into account. A cohort of 35 patients with severe bleeding was treated with a combination of oral cyclophosphamide 1–2 mg/kg daily, prednisolone 1 mg/kg daily, immunoadsorption on day 1–5 weekly, IVIG 0·3 g/kg day 5–7 weekly and FVIII 100 iu/kg daily. Rapid control of bleeding was reported with an undetectable inhibitor at a median of 3 d (95% CI 2–4) and CR in 88% of patients at a median of 14 d (95% CI 12–17) (Zeitler et al, 2006b). The same group has published updated data on 67 patients with similar outcomes (Zeitler et al, 2010). Although