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Keywords:

  • acquired haemophilia;
  • bypassing agents;
  • factor VIII;
  • immunosuppression;
  • inhibitor

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Diagnosis
  5. Clinical associations
  6. Pregnancy related acquired haemophilia
  7. Acquired haemophilia in children
  8. Treatment
  9. Inhibitor eradication
  10. Future developments
  11. Disclosure of Conflict of Interest
  12. References

Summary.  Acquired haemophilia A is an auto-immune disease caused by an inhibitory antibody to factor VIII. The pattern of bleeding varies but patients remain at risk of life threatening bleeding until the inhibitor has been eradicated. The cornerstones of management are; rapid and accurate diagnosis, control of bleeding, investigation for an underlying cause and eradication of the inhibitor by immunosuppression. Patients should always be managed jointly with a specialist centre even if they present without significant bleeding. Despite an extensive literature, few controlled data are available and treatment guidelines are based on expert opinion. To treat bleeds recombinant factor VIIa and activated prothrombin complex concentrate are equally efficacious but both are superior to factor VIII or desmopressin. Immunosuppression should be started as soon as the diagnosis is made. Commonly used regimens are steroids alone or combined with cytotoxic agents. Rituximab is being used more widely but current evidence does not suggest that it improves outcomes or reduces side effects.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Diagnosis
  5. Clinical associations
  6. Pregnancy related acquired haemophilia
  7. Acquired haemophilia in children
  8. Treatment
  9. Inhibitor eradication
  10. Future developments
  11. Disclosure of Conflict of Interest
  12. References

Acquired haemophilia A (AHA) is an autoimmune disease caused by an autoantibody to factor VIII (FVIII). Morbidity and mortality are high due to the age of the patients, underlying diseases, the toxic effects of immunosuppression and bleeding [1–8]. Early recognition, rapid diagnosis and prompt referral to a specialist centre are important to optimise the treatment of bleeds and improve outcomes. Recent data suggest that, in a significant proportion of patients, diagnosis and initiation of appropriate treatment is delayed [9] and this puts patients at unnecessary risk of severe bleeding. Education of specialists such as obstetricians, rheumatologists and care of the elderly physicians with regard to the symptoms and signs of AHA is an important role for haematologists. Furthermore, laboratories should have systems in place that automatically investigate an isolated prolonged activated partial thromboplastin time (aPTT) so that, even if the clinician who has ordered the coagulation test has not considered acquired haemophilia as a differential diagnosis, the patient is identified and treated promptly.

AHA has been reported to have an incidence of 1.48 [7] and 1.34 [10] per million year−1 in the only two studies in which patients are linked to a defined population. Both these studies are from the UK and the incidence in other populations has not been reported although there are no data to suggest that it may be different. The incidence increases with age and is estimated to be 0.045 per million year−1 in children under 16 compared to14.7 per million year−1 in people over 85 years [7]. It is likely, however, that AHA is underdiagnosed, especially in elderly patients. The literature on AHA has recently been significantly expanded by data on 501 patients prospectively reported to European Acquired Haemophilia Registry (EACH2) [9,11,12]. Although, at present, these data are only available in abstract form they are the largest cohort reported to date and the registry was designed to answer questions on the management of bleeds and inhibitor eradication.

Diagnosis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Diagnosis
  5. Clinical associations
  6. Pregnancy related acquired haemophilia
  7. Acquired haemophilia in children
  8. Treatment
  9. Inhibitor eradication
  10. Future developments
  11. Disclosure of Conflict of Interest
  12. References

AHA is usually diagnosed following investigation of abnormal bleeding, although 6% of patients were reported to not be bleeding at presentation in the EACH2 registry [9]. The diagnosis must be made promptly to minimise the time that patients are at risk of bleeding and to avoid non-essential invasive procedures. Interim data from EACH2 reported a median (5th–95th percentile) delay of 3 (0–58) days between onset of bleeding and diagnosis and 1 (0–69) days between the first abnormal aPTT and diagnosis [14] suggesting significant delay in a proportion of patients.

Clinical features

Patients present with subcutaneous bruising, mucosal and soft tissue bleeds such as intracranial haemorrhage, muscle bleeds and retroperitoneal haematoma. Bleeding following invasive procedures is almost inevitable but haemarthoses are uncommon [1–5,15] (Figs 1 and 2). The severity of bleeding is very variable and, although between 25% and 33% of patients do not require any haemostatic therapy [7,10,16], patients remain at risk of life threatening bleeding until the inhibitor has been eradicated.

image

Figure 1.  Bleeds observed in acquired haemophilia. Site of bleeding in acquired haemophilia A. Hash is bleeds on presentation [7] and diagonal stripe is bleeds that required treatment [4]. Subcut is subcutaneous, GI is gastrointestinal, GU genitor urinary and ICH is intracranial haemorrhage.

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image

Figure 2.  Bleeding in acquired haemophilia. Typical bleeding in acquired haemophilia. The disorder in this patient was associated with Castlemann’s disease and treatment with alpha interferon. The bleed was caused by venepuncture.

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Patients are at risk of fatal bleeds including intracranial, deep soft tissue, mucosal (gastrointestinal, lung or urogenital) or following invasive procedures. Fatal bleeds may occur at any time after presentation until the inhibitor has been eradicated [7]. The rate of fatal bleeding appears to be decreasing over time with 22% reported in the 1980s but more recently this had decreased to 8% [5,7,16] and EACH2 reports 3% fatal bleeding [9]. The decline in reported fatal bleeding may be because of increased availability of efficacious haemostatic agents and possibly an improved awareness of the disease, although the characteristics of the patients in the studies has varied and the difference may simply be due to this.

There have been reports of anticoagulant and anti-platelet drugs either masking or being associated with AHA [17–20]. Patients who present with bruising or bleeding whilst taking anticoagulants or an anti-platelet agent should have an activated partial thromboplastin time (aPTT) measured in addition to an INR and, if inappropriately prolonged, investigated further with mixing studies and factor levels.

Laboratory diagnosis

Investigation typically reveals a prolonged aPTT and a normal prothrombin time. Because anti-FVIII antibodies are time and temperature dependent the aPTT corrects less after a 1–2 h incubation with normal plasma than after a stat mix. The diagnosis is confirmed by a low FVIII and a raised inhibitor titre on Bethesda assay (Fig. 3). AHA inhibitors often exhibit complex kinetics and residual FVIII can be measured, this makes establishing an accurate inhibitor titre difficult. It is common practice to report the titre based on the dilution in the Bethesda assay that is closest to 50% inhibition [6,21]. The anti-FVIII antibody may interfere with the measurement of other intrinsic factors. Dilution experiments will demonstrate a progressive increase in these apparently decreased coagulation factors whilst FVIII remains low [1–4,22]. A lupus anticoagulant may also interfere with coagulation factor assays potentially leading to diagnostic difficulties [22]. An ELISA assay may be useful in complicated cases [23].

image

Figure 3.  Investigation for possible acquired haemophilia A.

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Clinical associations

  1. Top of page
  2. Abstract
  3. Introduction
  4. Diagnosis
  5. Clinical associations
  6. Pregnancy related acquired haemophilia
  7. Acquired haemophilia in children
  8. Treatment
  9. Inhibitor eradication
  10. Future developments
  11. Disclosure of Conflict of Interest
  12. References

AHA is associated with immune diseases such as rheumatoid arthritis, polymyalgia rheumatica and systemic lupus erythematosis; malignancy (occasionally occult); pregnancy and dermatological disorders such as pemphigoid. The apparent association with commonly used drugs such as penicillin is almost certainly due to chance rather than a genuine association. In about half of cases no underlying cause is found [1–3,5,7,15,24–27], especially in elderly patients [7], possibly because they are less intensively investigated, or that old age is an independent risk factor.

Pregnancy related acquired haemophilia

  1. Top of page
  2. Abstract
  3. Introduction
  4. Diagnosis
  5. Clinical associations
  6. Pregnancy related acquired haemophilia
  7. Acquired haemophilia in children
  8. Treatment
  9. Inhibitor eradication
  10. Future developments
  11. Disclosure of Conflict of Interest
  12. References

AHA is a very rare complication of pregnancy but accounts for most cases of AHA in people below the age of 40 years. It affects about one in 350 000 births in the UK [7] and a survey of 42 specialist Italian centres reported a similar incidence of 20 cases in 15 years [26]. Patients usually present at a median of about 3 months post partum although presentation due to abnormal bleeding at the time of delivery is also relatively common. Cases can present up to a year post partum [25,26,28–30]. One patient out of 42 cases in the EACH2 registry presented ante-partum [30]. The reasons for the late presentations are unclear but may represent delayed diagnosis rather than late onset of AHA in some patients.

Some reports suggest that AHA in pregnancy has a different natural history and response to inhibitor eradication therapy [25]. Retrospective reviews have reported a longer time to remission compared to AHA due to other aetiologies, although this was not seen in the 42 patients reported to EACH2 [30]. Conversely spontaneous remissions are recognised [25,26,29]. Treatment with immunosuppressive agents should take into account the age of the patients and the potential side effects of drugs in women of child bearing age [21]. Rituximab has been used successfully in post partum AHA but there are no data to suggest that it is superior to other treatment modalities [30,31].

Relapse in subsequent pregnancies appears to be relatively uncommon but women should be warned that this is a possibility. In one study AHA recurred in four of six subsequent pregnancies in three patients [29], however no relapses were reported in nine subsequent pregnancies in another study [32] and an Italian Registry reported no relapses amongst four patients [26]. The antibody may affect the FVIII level of the fetus and this must be anticipated at the time of delivery [33,34].

Treatment of bleeds should follow the principles outlined for AHA in general [25,26,29] but caution about the risk of venous thromboembolism associated with bypassing agents in the post partum period should be borne in mind.

Acquired haemophilia in children

  1. Top of page
  2. Abstract
  3. Introduction
  4. Diagnosis
  5. Clinical associations
  6. Pregnancy related acquired haemophilia
  7. Acquired haemophilia in children
  8. Treatment
  9. Inhibitor eradication
  10. Future developments
  11. Disclosure of Conflict of Interest
  12. References

AHA in children is very uncommon, estimated at 0.045 per million year−1 [7]. A survey of haemophilia centres in USA reported six cases and a literature review revealed another eight presumed or definite cases [35]. A large retrospective study reported a further six cases [5]. Patients appeared to present with a bleeding pattern typical for AHA and response to immunosuppression appears to be similar to adults.

Treatment

  1. Top of page
  2. Abstract
  3. Introduction
  4. Diagnosis
  5. Clinical associations
  6. Pregnancy related acquired haemophilia
  7. Acquired haemophilia in children
  8. Treatment
  9. Inhibitor eradication
  10. Future developments
  11. Disclosure of Conflict of Interest
  12. References

Treatment of AHA consists of arresting the bleeding, inhibitor eradication, treatment of an underlying disorder and protecting the patient against trauma and non-essential invasive procedures. Patients should be managed in collaboration with an experienced haemophilia centre even if the initial presentation appears to be benign. It is important to avoid invasive procedures and venepuncture should be kept to a minimum (Fig. 2). Patient education is important so that symptoms are recognised and reported early [6,8,21,36].

Haemostatic management

Bleeding episodes may be very severe and prompt haemostatic control under the supervision of a specialist is important to reduce morbidity and mortality. Available haemostatic agents do not have predictable efficacy, hence regular clinical review supported by appropriate imaging and measurement of haemoglobin level is crucial for optimal outcomes [6]. In contrast, many patients do not need haemostatic treatment and subcutaneous bleeding, even if extensive, can be managed conservatively.

Bleed management depends on site and severity. Haemostatic therapy often needs to be continued at a reduced dose and frequency after the bleeding has been stopped to prevent recurrence. This is particularly important after intracranial, muscle and retroperitoneal bleeds. Local measures to control bleeds should be used. Mucosal haemorrhage will benefit from concomitant therapy with an anti-fibrinolytic agent and topical fibrin glue may be useful in some cases.

The two options for haemostatic control are the use of bypassing agents and strategies to raise the level of circulating FVIII [21], although the use of bypassing agents is more likely to result in effective haemostasis [12].

Bypassing agents  At the time of writing the available bypassing agents are Novoseven (rFVIIa) and Factor eight inhibitor bypassing activity (FEIBA) although this is a rapidly moving field and many new agents are under investigation. Both agents have been shown to be efficacious in AHA [12,37–41]. A recent retrospective analysis of 139 patients treated with rFVIIa included cases from the compassionate use programme (= 61) [37], the HTRS registry (= 9) and the published literature (= 69). There were 182 bleeding episodes where it was possible to make an assessment of the efficacy of rFVIIa. In the 103 episodes where rFVIIa was used as first line therapy, it was effective or partially effective in 95% [40]. A very similar first line efficacy (91%) in 170 bleeds was reported to the EACH2 registry [12]. When used as second line therapy rFVIIa was reported to have 80% effectiveness and in 57 surgeries an effective or partially effective response was reported in 86% of cases [40]. For the 61 patients in the retrospective analysis in whom data were available, the mean duration of treatment was 6 days (range 1–33) [40].

A retrospective study of FEIBA describes 34 severe and moderate bleeds treated, in the main, with 75 U kg−1 8–12 hourly. A median of six infusions were needed for moderate bleeds with 100% haemostatic efficacy at a median of 36 h compared to 10 infusions for severe bleeds with 76% haemostatic control at a median of 48 h [38]. In the EACH2 registry 64 bleeds were treated with FEIBA for a median (IQR) 5 (2–10) days with 94% efficacy [12].

Although rFVIIa and FEIBA have not been directly compared, a rigorous analysis of data in the EACH2 registry suggests the two agents have indistinguishable haemostatic efficacy in AHA [12]. The choice of agent should depend on considerations such as the patient’s previous response, dosing schedule, use of plasma-derived products and cost. If first line therapy fails the alternative bypassing agent may be successful and should be tried at a relatively early stage.

Both agents are associated with thrombotic events [42,43], although data are predominantly from patients with congenital haemophilia. Analysis of 139 AHA patients treated with rFVIIa reported 12 (8.6%) thrombotic events, mainly arterial, in 10 patients, four of whom died, although the direct relationship with rFVIIa is not clear and the study methodology would tend to overestimate the rate of events [40]. In contrast, EACH2 reported eight arterial thrombotic events associated with haemostatic therapy out of 337 (2.3%) treated patients [12]. A 10 year compilation of thrombotic events associated with FEIBA reported one episode of disseminated intravascular coagulation, one myocardial infarction and one venous thrombosis [13]. It is not possible to compare the rate of thrombosis with that observed in association with rFVIIa because the number of patients treated was not reported. Inevitably the risk of arterial thrombosis in patients with AHA treated with bypassing agents will be higher than in congenital haemophilia, because of the additional cardiovascular risk factors in elderly patients and the complex clinical situation of many patients. Irrespective of the reported thrombotic episodes, treatment of significant bleeding should not be withheld because benefit clearly outweighs the risk. However, minor bleeding, such as subcutaneous, should not be treated without careful consideration of the risk involved because these bleeds will usually resolve spontaneously. A strategy of increasing the dose of rFVIIa up to 270 μg kg−1 has been described in the management of early haemarthroses in congenital haemophilia with inhibitors [44,45]. This approach should be used very cautiously in patients with AHA because this dose has not been shown to be safe in this patient group or efficacious in treating the types of bleeds associated with AHA.

An important limitation of bypassing agents is that there is no currently validated laboratory monitoring technique. The use of thrombin generation assays [46,47] and modified thromboelastographic assays [48,49] hold promise but no data have been published that ties these tests to haemostatic efficacy in AHA. Some preliminary data suggest that thromboelastography does not always predict clinical response [50]. Extrapolation of data from inhibitors in congenital haemophilia to AHA may not be valid due to the different inhibitor kinetics and bleeding phenotypes.

Human FVIII  Human FVIII will usually be inadequate haemostatic therapy unless the inhibitor titre is low. FVIII has been shown to be significantly worse than rFVIIa and FEIBA for the treatment of bleeds in AHA [12]. The dose of FVIII required will need to be sufficient to overcome the inhibitor and provide an adequate haemostatic level. Although formulae have been suggested for calculating the dose [3] the inaccuracies inherent in the laboratory measurement of inhibitor titres in AHA makes these at best very rough approximations and regular monitoring of plasma FVIII level and clinical response is required.

The use of human FVIII in combination with immunoabsorption is more likely to result in haemostatic FVIII levels despite higher anti-FVIII inhibitor titres. This treatment strategy may be useful as first line or if bypassing agents have failed, although it is available in only a very limited number of centres [51–54].

Porcine FVIII  In AHA the inhibitor titre to porcine FVIII is usually 5–10% of the human titre and so porcine FVIII may achieve haemostatic levels in situations where human FVIII is ineffective [15,55]. Plasma derived porcine FVIII has been shown to have excellent or good haemostatic efficacy in 78% of 74 bleeds but no response in 9% [15], a response rate very similar to that seen with bypassing agents. It has been used successfully as a continuous infusion [56]. This agent is no longer available and a recombinant B-domain deleted porcine FVIII is under investigation but trials in AHA are awaited [57].

Desmopressin  Some patients with a low titre inhibitor and measurable baseline FVIII may respond to a desmopressin (DDAVP) infusion. A literature review of 22 cases found that in 11 patients with FVIII > 5 IU dL−1, DDAVP resulted in an increased FVIII level to between 15 and 140 IU dL−1. The five patients with a Bethesda titre of < 2 BU mL−1 responded best, with peak FVIII levels > 80 IU dL−1 and a half life of 4–6 h. No clinical response was reported in seven of the 22, of these all had a FVIII level < 1 IU dL−1 and a rise following DDAVP to between 0 and 6 IU dL−1. The response to DDAVP is unpredictable but can be considered for minor bleeding episodes [58].

Management of surgery  Invasive procedures are associated with significant risk of severe bleeding and haemostasis can not be guaranteed. Only procedures that are absolutely unavoidable should be considered and even then the benefits carefully weighed against the risks of delaying until the FVIII level has increased. Haemostatic options for surgery include the use of bypassing agents [37,39], immunoabsorption with FVIII infusion and previously porcine FVIII [15].

Inhibitor eradication

  1. Top of page
  2. Abstract
  3. Introduction
  4. Diagnosis
  5. Clinical associations
  6. Pregnancy related acquired haemophilia
  7. Acquired haemophilia in children
  8. Treatment
  9. Inhibitor eradication
  10. Future developments
  11. Disclosure of Conflict of Interest
  12. References

As soon as the diagnosis of AHA has been made, patients should be immunosuppressed to eradicate the inhibitor [6,8,21]. There are numerous publications in the literature but data are often difficult to interpret because different endpoints and definitions are used and studies are almost invariably reports of cohorts without controls. The majority of papers are case reports, single centre cohort studies or retrospective surveys (Table 1) [5,7,10,12,24,27,52,54,59–88]. Most reports are from specialist centres and so the literature is likely to reflect more severely affected patients. Furthermore, good outcomes are more likely to be reported by centres (and accepted by journals) than average or poor outcomes. The literature must, therefore, be treated with caution and the conclusions that can be drawn from many studies are limited.

Table 1.   Literature review of inhibitor eradication therapy
StudySteroidsSteroids and cytotoxicsStudy references
CR/N%CRCR/N%CR
  1. Papers reporting on inhibitor eradication therapy identified from the literature are presented. Although the percentage of patients achieving complete remission does not take into account the length of time patients were followed a broad comparison between treatment groups can be made. Not all patients from each study are included because treatment details or outcome could not be extracted. Results of the EACH2 registry are not included in the aggregate because these data have only been published in abstract form but are included for comparison because this is the largest cohort described to date.

 17/888[94]
 23/475[95]
 34/666[64]
 47/1644[80]
 57/1070[66]
 64/666[62]
 71/333[75]
 811/1292[72]
 95/1145[86]
109/9100[79]
118/8100[61]
126/6100[73]
134/580[69]
148/1275[84]
155/8631/333[63]
161/3336/6100[67]
178/9898/1457[27]
183/4759/1182[83]
193/31004/4100[76]
209/109014/1688[24]
210/107/7100[85]
222/3660/20[65]
232/36610/1283[10]
249/127515/1979[87]
2526/347635/4578[7]
Aggregate of all studies96/13472165/21178 
Studies reporting both treatment arms68/9076109/13978 
EACH2 registry83/1425866/8380[11]

Options for immunosuppression are steroids, cytotoxics (cyclophosphamide, azathioprine, vincristine or combination therapy), rituximab, cyclosporin A, plasmaphoresis or immunoabsorption and FVIII immune tolerance. A regimen may be considered superior if more patients achieve complete remission (CR) or this is achieved more rapidly. About 25% of patients achieve a spontaneous remission, although the associated morbidity was significant, and this must be considered when interpreting outcome data [16]. Recent studies with adequate follow up have reproducibly reported a relapse rate of 10–20% [7,88] and some patients require long term immunosuppression to prevent relapse. The absence of any reported relapses in most published studies further highlights the need to interpret these results very cautiously.

Steroids and cytotoxic agents

The only prospective randomised study performed to date enrolled 31 patients treated initially with prednisolone 1 mg kg−1 for 3 weeks after which 10 patients were in CR. Four patients were randomised to continuing treatment with prednisolone alone and this led to CR in 3 (75%). Of the 10 patients randomised to adding cyclophosphamide 5 (50%) achieved CR and of those in whom cyclophosphamide was replaced by prednisolone three out six (50%) achieved CR. There was no difference between the treatment arms and no suggestion that adding or changing to cyclophosphamide after 3 weeks was better than continuing with steroids alone [89].

A non-randomised, prospective national consecutive cohort study compared patients treated with steroids vs. steroids and cytotoxics. The design of this study makes it less prone to selection bias than other cohort studies. The 34 patients treated with steroids had 76% CR at a median (95% confidence interval) of 49 (31–62) days compared to 78% CR at 39 (34–57) days for the steroids and cytotoxics group. There was no statistically significant difference between the treatment arms and mortality was not different [7].

The aggregated data available from uncontrolled cohorts published to date suggest similar results. For combined steroids and cytotoxic agents the CR rate was 78% compared to 72% for steroids alone. However, if only studies that report the use of both treatments are included the response rates are almost indistinguishable; 78% for steroids and cytotoxic and 76% for steroids alone (Table 1).

In contrast, a review of 20 publications reported that the use of steroids and cyclophosphamide resulted in more patients achieving CR compared to steroids alone. The higher CR rate was not translated into a lower mortality and the authors proposed that this was due to increased toxicity associated with cyclophosphamide [1]. A robust analysis of the 331 patients reported to the EACH2 registry compared patients treated with prednisone alone with those treated with prednisone and oral cyclophosphamide. The groups were matched for age, gender, inhibitor titre, FVIII level and underlying aetiology by logistic regression and propensity score. The study reported an odds ratio (95% confidence intervals) 3.25 (1.51–6.96) < 0.001 in favour of combined therapy despite the prednisone alone arm receiving a high dose of steroids [11]. Of interest the complete remission rate in the 80 patients treated with steroids and cyclophosphamide in EACH2 was 80%, which is very similar to that observed in the aggregate of studies published in the literature at 78% (Table 1). The observed complete remission in EACH2 for steroids alone was lower than the aggregated literature, 58% compared to 76% (Table 1). Despite the different complete remission rates after first line therapy, the final outcome in terms of survival and sustained remission was the same for both treatments in all large studies [1,7,11]. Interpretation of the current data suggest that the combination of steroids and cyclophosphamide is more likely to result in a stable remission than steroids alone but the final outcome is not better [11].

Regimens involving combination chemotherapy have been reported to have high success rates [61,67,73,76,85] but without comparative groups the results must be treated with caution because numbers are very small. Whichever regimen is used, 3 weeks appears to be too short a time to assess outcome because the median time to remission has been reproducibly been shown to be about 5 weeks [7,11].

Intravenous immunoglobulin

Intravenous immunoglobulin (IVIG) has not been shown to be effective in the treatment of AHA. A study of 16 patients treated with IVIG reported that three subjects with an inhibitor titre ≤ 1 BU mL−1 achieved an undetectable inhibitor titre and normal FVIII level, although one patient also received concomitant steroids. This means that for patients treated with IVIG alone 2/16 (12.5%) responded, a rate lower than that seen for spontaneous remission (25%) [16,78]. A study of six patients treated with steroids and IVIG reported a CR rate of 66% [64] similar to other reports of steroids alone (Table 1). A larger study that compared non-randomised patients who either did or did not receive IVIG [7], the EACH2 registry and a literature review all show no benefit of IVIG [1]. The available evidence strongly supports the view that IVIG as a single agent or in combination with steroids and cytotoxics is not useful in inhibitor eradication in AHA.

Rituximab

Rituximab is becoming a popular treatment for AHA but data have not demonstrated that it is superior to other regimens [8,90]. In one study three patients treated with rituximab and either steroids or steroids plus a cytotoxic agent achieved CR [82]. Another study reported on 10 patients, of whom eight achieved CR and the two non-remitters responded to subsequent intravenous cyclophosphamide [81]. A study in six patients treated with rituximab and steroids with or without cytotoxic agents found a CR rate of 100%. CR occurred at 1, 2, 4, 8, 36 and 52 weeks, response times very similar to those previous reported with other immunosuppressive agents and remission at 36 weeks might be spontaneous [91]. A literature review of 71 patients treated with rituximab and a variety of immunosuppressive agents found a response rate of over 90% but the authors were cautious about interpreting the results and suggested that rituximab should be used as a second line agent in combination with steroids [8]. Data from EACH2 confirm the need for caution, 30 of 51 (59%) patients treated with a regimen that contained rituximab and another immunosuppressive agent achieved a stable remission and this was significantly lower than for patients treated with steroids and cyclophosphamide. The 12 patients treated with rituximab alone had only a 42% response rate [11].

The current data on rituximab are very difficult to interpret, however, there is no published evidence to support the suggestion that rituximab based regimens result in more patients achieving CR or a more rapid response. Some patients resistant to standard first line regimens respond to second line rituximab. There is no evidence to support the use of ritiximab in patients with high titre inhibitors as has been suggested by some authors [59].

Cyclosporin A

A number of cases have been reported in which cyclopsorin A has induced CR following failed first line therapy [60,68,74,77,92].

Immune tolerance

The use of FVIII in conjunction with immunosuppressive agents in AHA has been reported. The rationale is that FVIII may stimulate antibody producing cells into division making them more susceptible to cytotoxic agents [72]. The lack of adequate controls in these studies means that direct assessment of the role of FVIII can not be made.

A report of patients treated with three weekly infusions of FVIII combined with vincristine, cyclophosphamide and steroids resulted in a 92% complete remission rate in 12 patients after 1–3 courses [72]. The same group, however, later published a report in six patients who were treated with vincristine, cyclophosphamide and steroids without FVIII and found 83% remission after one to seven courses [73]. These data are difficult to interpret, the remission rates are similar to other studies, given the number of patients involved, but the time to remission appears to be relatively short. The effect of FVIII is unclear because the intensity of immunosuppression was greater than for many other protocols.

Infusion of FVIII on a daily basis (30 IU kg−1 day−1 for 1 week, 20 IU kg−1 day−1 for a second week and 15 IU kg−1 day−1 for a third week) combined with intravenous cyclophosphamide and methylprednisolone reported complete remission in 93% of 14 patients after a median 4.6 weeks, compared to 67% remission at a median of 28.3 weeks in six historical controls treated with steroids ± cyclophosphamide [93]. Although this is a relative high CR rate the median time to response is similar to studies that did not use FVIII and the median time of 28.3 weeks to CR in the controls is long. 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 should be taken into account. Controlled studies appear to be the only way that this question can be answered.

Immunoadsorption

A cohort of 45 patients with severe bleeding was treated with a combination of oral cyclophosphamide 1–2 mg kg−1 daily, prednisolone 1 mg kg−1 daily, immunoadsorption on day 1–5 weekly, IVIG 0.3 g kg−1 day 5–7 weekly and FVIII 100–200 IU kg−1 daily. Rapid control of bleeding was reported with an undetectable inhibitor at a median of 3 days (95% CI 2–4) and CR in 88% of patients at a median of 14 days (95% CI 12–17) [54]. Although no control patients are reported and the cost of the FVIII is very high, this treatment appears to rapidly control bleeding and induce CR in those that respond. It should be considered in severely bleeding patients, especially those unresponsive to bypassing agents.

Venous thromboprophylaxis

Remission of AHA is often associated with high FVIII levels and because patients are likely to have additional risk factors for venous thrombosis they should be treated with appropriate venous thromboprophylaxis [6].

Relapse

Relapse has been reported in 20% of 102 patients at a median of 7.5 months (range 1 week to 14 months) [7]. This finding has been confirmed by data from the EACH2 registry which reported relapse in 18% of those treated first line with steroids, 12% for steroids and cylcophosphamide and 1% in those treated with first line rituximab after a median of 4 months [11]. Patients, therefore, require prolonged follow up and should be advised to report symptoms of bleeding or bruising early.

Conclusions on inhibitor eradication

There is consensus that immunosuppression to eradicate the inhibitor should be started as soon as the diagnosis of AHA has been made [1–4,6,21]. Available data suggest that a combination of steroids and cyclophosphamide may result in a higher remission rate than steroids alone. Rituximab based regimens have no advantage over other treatments. However, long term outcome is not affected by the choice of first line therapy. Until further data become available it is not possible to make definitive recommendations and first line therapy is at the discretion of the clinician based on the clinical circumstances and taking into account the potential side effects of each treatment. If a patient does not respond to first line steroids then a cytotoxic agent or rituximab can be added. Similarly, if a patient fails first line rituximab then steroids and cytotoxic agents may be successful. Cyclosporin A is a useful second line option. A regimen based on high dose FVIII and immunoadsorption should be considered for patients with severe life-threatening bleeding.

Future developments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Diagnosis
  5. Clinical associations
  6. Pregnancy related acquired haemophilia
  7. Acquired haemophilia in children
  8. Treatment
  9. Inhibitor eradication
  10. Future developments
  11. Disclosure of Conflict of Interest
  12. References

Clinical progress in AHA is hampered by small numbers of patients and difficulties in performing randomised studies. In the area of bleed control it is recognised that the haemostatic efficacy of all agents is unpredictable. A laboratory assay that has been clinically validated to predict successful haemostasis would be a very significant step forward. Understanding why the bleeding phenotype in AHA differs from congenital haemophilia may lead to a better understanding of the mechanism of haemostatic failure and possibly translate into improved haemostatic management. Access to new haemostatic agents is important and studies on the safety and efficacy of recombinant porcine FVIII and longer or enhanced acting rFVIIa molecules are awaited.

Studies in the field of inhibitor eradication are a major challenge, demonstrated by the fact that the literature contains only one randomised prospective clinical trial which was unable to recruit sufficient patients to provide interpretable data [89]. Trials that compare conventional steroid and cytotoxic agents with rituximab or investigate the role of FVIII would be useful. These trials will need to recruit hundreds of patients to be adequately powered and require international collaboration and significant resources to perform. It must be recognised that these trials may not be feasible and that registry data will be the best available data for the foreseeable future.

Disclosure of Conflict of Interest

  1. Top of page
  2. Abstract
  3. Introduction
  4. Diagnosis
  5. Clinical associations
  6. Pregnancy related acquired haemophilia
  7. Acquired haemophilia in children
  8. Treatment
  9. Inhibitor eradication
  10. Future developments
  11. Disclosure of Conflict of Interest
  12. References

The author has received honoraria from Baxter Healthcare and Novonordisk for talking at symposia and acted as a paid consultant to Baxter Healthcare, Novonordisk and Inspiration Pharmaceuticals.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Diagnosis
  5. Clinical associations
  6. Pregnancy related acquired haemophilia
  7. Acquired haemophilia in children
  8. Treatment
  9. Inhibitor eradication
  10. Future developments
  11. Disclosure of Conflict of Interest
  12. References