European Acquired Haemophilia Registry Research Articles

Acquired Haemophilia A in four north European countries: survey of 181 patients.

Acquired haemophilia A (AHA) is a rare bleeding disorder caused by acquired antibodies against coagulation factor VIII. In the Nordic countries, treatment and outcomes have not been studied in recent times. To collect retrospective data on patients diagnosed with AHA in the Nordic countries between 2006 and 2018 and compare demographic data and clinical outcomes with previously published reports, data were collected by six haemophilia centres: three Swedish, one Finnish, one Danish and one Estonian. The study included 181 patients. Median age at diagnosis was 76 (range 5-99) years, with even gender distribution. Type and severity of bleeding was comparable to that in the large European Acquired Haemophilia Registry study (EACH2). Bleedings were primarily treated with activated prothrombin complex concentrate (aPCC) with a high success rate (91%). For immunosuppressive therapy, corticosteroid monotherapy was used most frequently and this may be the cause of the overall lower clinical remission rate compared to the EACH2 study (57% vs. 72%). Survey data on 181 patients collected from four north European countries showed similar demographic and clinical features as in previous studies on AHA. aPCC was used more frequently than in the EACH2 study and the overall remission rate was lower.

The European Acquired Haemophilia (EACH) Registry.

Acquired hemophilia is a rare autoimmune syndrome, characterized by depletion of FVIII, more rarely of FIX, with high morbidity and mortality. Treatment modalities to control bleeding and to suppress the antibodies synthesis are controversial. The purpose of the EACH registry is to collect data on management of these patients (pts) in European countries in order to provide a basis for accepted guidelines. Method. The following information was requested: underlying condition (primary or secondary), causes (spontaneous or provoked), site, type and severity of bleeding, type and titre of the inhibitor, regimens of the anti-hemorrhagic and immunosuppressive therapy (IST), clinical response, side effects and outcome.Inclusion criteria: pts diagnosed after January 1st, 2003; patients diagnosed before 2003 were included if new bleedings occurred or if already on follow-up.Results. From January 2003 to May 15th, 214 pts from 77 centers in 18 countries were registered; 19 were not evaluable because of missing data. The analysis includes 195 pts (102 males, 93 females). Underlying conditions (pts no): idiopathic 107, seconadary 88 (autoimmune diseases 23, neoplasia 27, pregnancy 23, other 15). Inhibitor type: anti FVIII 193, anti FV 1, anti FIX 1. Laboratory data (median and range) age 72 years (6–95); Hb 10 g/dL (4.9–13.6), inhibitor titre 15.5 BU/mL (1–2,800); no bleedings in 13 pts; bleeding in 182 pts; no anti hemorrhagic therapy in 45 pts; 28 recurrences in the follow up. The evaluable events were 165, treated with one or several therapeutic modalities: 89 rFVIIa, 26 APCC, 35 FVIII, 10 fresh frozen plasma, 9 antifibrinolyticic, 5 DDAVP, 5 immunoadsorption; more than 1 treatment was given in some events. The overall response was 79.3%. IST (steroid alone or in combination with other drugs) was given in 153 pts received with complete remission in 95 pts. To date 10 inhibitor recurrences were registered. Patients mortality (%): 39 (20); 8 (4.1) of bleeding, 7 (3.6) of the underlying condition, 13 (6.6) IST related infections, 11 (5.7) others.Comments. Distribution in primary and secondary is in accordance with the data in the literature; 20% of the pts did not required treatment. The factor level and the inhibitor titre are not correlated with the clinical picture. Control of bleeding and an overall response to IST is achieved in about 80% of the episodes and in 61.4% of the pts respectively. To date bleeding mortality is lower than reported in the literature.

91-Year-Old Man With Upper Extremity Ecchymoses

91-Year-Old Man With Upper Extremity Ecchymoses

Acquired Factor VIII Inhibitor and Cardiopulmonary Bypass

ACQUIRED HEMOPHILIA A (AHA) may cause massive bleeding during surgical procedures due to the formation of specific autoantibodies most frequently against coagulation factor VIII (FVIII), which decrease its activity and plasma half-life. Whereas up to 30% of chronically substituted patients with inherited hemophilia A develop inhibitor activity during their treatment, the incidence of AHA is extremely low at 1.5 cases per million. 1 Rodriguez-Merchan E.C. Rocino A. Literature review of surgery management in inhibitor patients. Haemophilia. 2004; 10: 22-29 Crossref PubMed Scopus (35) Google Scholar , 2 Collins P.W. Hirsch S. Baglin T.P. et al. Acquired hemophilia A in the United Kingdom: A 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors’ Organisation. Blood. 2007; 109: 1870-1877 Crossref PubMed Scopus (526) Google Scholar Elderly people (aged 60-80 years) are affected especially, although there is another peak at a younger age (20-30 years). 3 Green D. Lechner K. A survey of 215 non-hemophilic patients with inhibitors to factor VIII. Thromb Haemost. 1981; 45: 200-203 Crossref PubMed Scopus (681) Google Scholar AHA is associated with malignancy (11.8%), autoimmune diseases (13.4%), pregnancy (8.4%), drugs (3.4%), and dermatologic diseases (1.4%). In the majority of patients, the cause remains unknown. 4 Knoebl P. Marco P. Baudo F. et al. Demographic and clinical data in acquired hemophilia A: Results from the European Acquired Haemophilia Registry (EACH2). J Thromb Haemost. 2012; 10: 622-631 Crossref PubMed Scopus (316) Google Scholar

Pregnancy‐associated acquired haemophilia A: results from the European Acquired Haemophilia (EACH2) registry

The European Acquired Haemophilia registry (EACH2) collected data on the demographics, diagnosis, underlying disorders, bleeding characteristics, treatment, and outcome of women with acquired haemophilia A (AHA), a rare and often severe bleeding disorder caused by autoantibodies directed against coagulation factor VIII. Prospective, multi-centre, large-scale, pan-European registry. A total of 117 haemophilia centres in 13 European countries. Pregnancy-associated AHA. Data were reported using a web-based electronic case report form. Diagnosis was based on the presence of a prolonged activated partial thromboplastin time, reduced coagulation Factor VIII level and positive inhibitor assay. Presenting characteristics, time to diagnosis, haemostatic treatment and outcome, immunosuppressive treatment and outcome. The EACH2 registry (n = 501) documented 42 (8.4%) cases of AHA associated with the peripartum period, a median Factor VIII level at diagnosis of 2.5 (range 0-25) IU/dl and inhibitor titre of 7.8 (range 0.7-348) BU/ml. Antepartum inhibitors were evident in eight women. Time to diagnosis of AHA after delivery was 89 (range 21-120) days. First-line haemostatic treatment was successful in 20/23 (87%) women treated. Bleeding episodes resolved in 17/18 (94%) women treated with a bypassing agent and 29/39 (74%) women achieved complete remission with first-line immunosuppressive treatment. Two babies experienced postnatal bleeding, suggesting transplacental transfer of the antibody. All women were alive at last follow-up. Although rare, pregnancy-associated AHA may cause severe bleeding-related morbidity. Once diagnosed, women respond well to haemostatic treatment with bypassing agents and immunosuppression. Awareness of peripartum AHA requires improvement to facilitate rapid and appropriate management.

Immunosuppression for acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2)

AbstractAcquired hemophilia A (AHA) is an autoimmune disease caused by an autoantibody to factor VIII. Patients are at risk of severe and fatal hemorrhage until the inhibitor is eradicated, and guidelines recommend immunosuppression as soon as the diagnosis has been made. The optimal immunosuppressive regimen is unclear; therefore, data from 331 patients entered into the prospective EACH2 registry were analyzed. Steroids combined with cyclophosphamide resulted in more stable complete remission (70%), defined as inhibitor undetectable, factor VIII more than 70 IU/dL and immunosuppression stopped, than steroids alone (48%) or rituximab-based regimens (59%). Propensity score-matched analysis controlling for age, sex, factor VIII level, inhibitor titer, and underlying etiology confirmed that stable remission was more likely with steroids and cyclophosphamide than steroids alone (odds ratio = 3.25; 95% CI, 1.51-6.96; P < .003). The median time to complete remission was approximately 5 weeks for steroids with or without cyclophosphamide; rituximab-based regimens required approximately twice as long. Immunoglobulin administration did not improve outcome. Second-line therapy was successful in approximately 60% of cases that failed first-line therapy. Outcome was not affected by the choice of first-line therapy. The likelihood of achieving stable remission was not affected by underlying etiology but was influenced by the presenting inhibitor titer and FVIII level.

Demographic and clinical data in acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2)

Acquired hemophilia A (AHA) is a rare autoimmune disease caused by autoantibodies against coagulation factor VIII and characterized by spontaneous hemorrhage in patients with no previous family or personal history of bleeding. Although data on several AHA cohorts have been collected, limited information is available on the optimal management of AHA. The European Acquired Hemophilia Registry (EACH2) was established to generate a prospective, large-scale, pan-European database on demographics, diagnosis, underlying disorders, bleeding characteristics, treatment and outcome of AHA patients. Five hundred and one (266 male, 235 female) patients from 117 centers and 13 European countries were included in the registry between 2003 and 2008. In 467 cases, hemostasis investigations and AHA diagnosis were triggered by a bleeding event. At diagnosis, patients were a median of 73.9 years. AHA was idiopathic in 51.9%; malignancy or autoimmune diseases were associated with 11.8% and 11.6% of cases. Fifty-seven per cent of the non-pregnancy-related cases were male. Four hundred and seventy-four bleeding episodes were reported at presentation, and hemostatic therapy initiated in 70.5% of patients. Delayed diagnosis significantly impacted treatment initiation in 33.5%. Four hundred and seventy-seven patients underwent immunosuppression, and 72.6% achieved complete remission. Representing the largest collection of consecutive AHA cases to date, EACH2 facilitates the analysis of a variety of open questions in AHA.

Inhibitor Eradication In Acquired Haemophilia A: Final Results of European Acquired Haemophilia Registry (EACH2)

AbstractAbstract 715The optimal first line immunosuppression (IS) for eradicating factor (F)VIII inhibitors in acquired haemophilia A (AHA) is controversial. Steroids and cyclophosphamide are commonly used and there has been recent interest in the role of rituximab. Prospective randomised controlled trials (RCTs) would be challenging and in their absence registries may provide useful data to guide clinical practice. EACH2 collected data on 281 analysable patients who received first line IS. Complete remission (CR) was defined as inhibitor undetectable, FVIII>70IU/dL and IS stopped. Stable CR was defined as CR without relapse. A higher proportion of patients achieved CR with steroids and a cytotoxic (predominantly cyclophosphamide) (77%) than those treated with steroids alone (58%) (P<0.005) or a rituximab based regimen (61%) (P<0.02). The 12 patients treated with rituximab alone had the lowest proportion achieving CR (42%). Median time to normal FVIII and undetectable inhibitor was similar in the steroid alone and steroid and cytotoxic groups (about 5 weeks) but slower in those treated with a rituximab based regimens (about 9 weeks), although this was in part due to the slow response of patients treated with rituximab alone. Relapse was most common after initial treatment with steroids alone (19%). In this group relapse was diagnosed a median (range) 134 (13-695) days after stopping IS. In contrast, only 1 patient (4%) who achieved a CR with a rituximab based regimen relapsed. Stable CR after first line treatment was highest after steroids plus a cytotoxic (67%) and rituximab plus another IS (64%). Stable CR was lower in the steroids alone (48%) and rituximab alone groups (42%). Patients who achieved CR after first line IS had higher FVIII and lower inhibitor titres compared with those who did not, median (IQR) for FVIII 2 (1-7) compared to 1 (1-4)IU/dL (P<0.005) and inhibitor titre 13 (4-45) compared to 31 (7-75)BU/mL P<0.03. To minimise bias, propensity score matched analysis based on age, weight, gender, FVIII level, inhibitor titre and underlying aetiology was performed to compare oral prednisone plus oral cyclophosphamide with oral prednisone alone (n=70 in each arm). This showed an odds ratio (95% CI) of achieving a stable CR of 3.25 (1.51-6.99) (P<0.003) in favour of combined treatment despite the prednisone alone group being treated with a higher mean dose of prednisone/kg (P<0.005). There were insufficient patients to perform a propensity score matched analysis with the rituximab group. There was no statistically significant difference in survival between the groups and similarly a proportion of patients were alive and in CR at final follow up (FU), median (IQR) FU was 246 (66-665) days. In conclusion, stable CR after first line IS was more likely following combination therapy with oral prednisone and cyclophosphamide than oral prednisone alone. Although a lower proportion of patients achieved CR with rituximab based regimens than steroids plus cytotoxics the lower relapse rate resulted in a comparable proportion achieving stable CR. Stable CR after rituximab alone was low, although there were only 12 patients. These are the best data available to date relating to the response to first line IS in AHA and will be useful for informing treatment guidelines and designing future RCTs. Disclosures:Collins:NovoNordisk: Consultancy, Honoraria, The EACH2 registry was funded by Novonordisk; Baxter Healthcare: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: The use of Rituximab for the treatment of acquired haemophilia. Baudo:NovoNordisk: Consultancy, Honoraria, NovoNordisk fund the EACH2 registry, Speakers Bureau; Bayer Healthcare: Honoraria, Speakers Bureau. Knoebl:NovoNordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, NovoNordisk fund the EACH2 registry, Research Funding; Baxter Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Levesque:NovoNordisk: NovoNordisk fund the EACH2 registry. Nemes: NovoNordisk: Novonordisk fund the EACH2 registry. Pellegrini:Novonordisk: Consultancy, Honoraria, Speakers Bureau, The EACH2 registry is funded by Novonordisk. Tengborn:NovoNordisk: NovoNordisk fund the EACH2 registry. Huth-Kuehne:NovoNordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, NovoNordisk fund the EACH2 registry; Baxter Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Acquired Haemophilia: Clinical and Demographic Data.Results of European Acquired Haemophilia Registry (EACH2).

AbstractAbstract 1398Acquired Haemophilia (AH) is an autoimmune disorder, characterized by autoantibodies against the coagulant activity of Factor VIII: C. Is a rare (estimated frequency 1.5 cases per million/year), but severe hemorrhagic condition. EACH2 is a multinational European registry from 90 centres in 11 countries that recruited between 2003–2009, This abstract describes the demographic, clinical and aetiological data recorded in a web database from EACH2 from the largest cohort described in the literature to date. Outcomes of haemostatic therapy, immunosuppression and during pregnancy are described elsewhere. Data were recorded on consecutive patients from each centre. Informed consent was taken as appropriate to each country. Parametric and non-parametric test, were used to analyse the study. There were 501 AH patients included in the registry. The basic demographic data are shown in Table 1.Table 1:Demographic data of the whole group expressed in median, interquartile range (IQR) and rangeAgeFVIII at diagnosis IU/dLInhibitor titre at diagnosis BU/mLHb g/LFemale/Male ratioWhole group n=50174212.89235/266(62–80)(1–5)(4.3–42.5)(7.5–11.3)1:1.313–1040–400.1–28003–15.7In 93 % of the patients the diagnosis was triggered by bleeding in a variety o locations, these were and mainly spontaneous (details will presented in another abstract).). There was no correlation between FVIII level or titre inhibitor and type or severity of bleeding.Aetiology of AH Table 2The delay in diagnosis, stratified in etiologic groups, after detecting abnormal APTT is shown in Table 3Table 3:Time (days) between abnormal APTT and diagnosisAll groupIdiopathicAutoimmune diseaseMalignancyPregnancyEvaluable patients n=49921.62436108Mean110.511Median(0–8)(0–9)(0–5)(0–7)(0–9)IQR0–10910–7960–10910–930–60RangeSurvival analysis (Kaplan-Meyer curves), after 5 years of follow-up was: 71.5% in patients who had eradicated the inhibitor, 47.7% in patients dependent immunosuppressive therapy, and 37.6% in those who had not eradicated the inhibitor In conclusion this prospective multinational European registry (EACH2) includes a large number of patients affected of AH. Idiopathic remains the more frequent aetiological association. Bleeding is the principal clinical manifestation but in a proportion of patients there is a considerable delay in diagnosis. The finding of an abnormal APTT in a bleeding patient with no history of hemorrhagic condition should raise suspicion of AH. Survival in this patient cohort is clearly related to response to immunosuppressive therapy. Disclosures:Marco:Novo Nordisk: Consultancy. Collins:NovoNordisk: Consultancy, Honoraria, The EACH2 registry was funded by Novonordisk; Baxter Healthcare: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Knoebl:Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, NovoNordisk fund the EACH2 registry, Research Funding; Baxter Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Levesque:NovoNordisk:. Baudo:NovoNordisk: Consultancy, Honoraria, NovoNordisk fund the EACH2 registry, Speakers Bureau; Bayer Healthcare: Honoraria, Speakers Bureau. Nemes:Novo Nordisk: Consultancy. Tengborn:Novo Nordisk: Consultancy. Huth-Kuehne:NovoNordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, NovoNordisk fund the EACH2 registry; Baxter Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees. Pellegrini:Novonordisk: Consultancy, Honoraria, Speakers Bureau, The EACH2 registry is funded by Novonordisk.

TALKING ABOUT…

TALKING ABOUT…

The European acquired haemophilia registry.

Acquired haemophilia is a rare bleeding disorder, occurring in approximately one person in every million. The mortality from bleeding is approximately 20%. The development of autoantibodies to factor VIII is commonly associated with the postpartum period, the presence of other autoimmune disorders, malignancy, lymphoproliferative disorders and previous multiple transfusions. Nevertheless, all these observations are based on a number of rather small case series. In 2001, the United Kingdom Haemophilia Centre Doctors' Organisation initiated a 2-year registry across the UK to provide more robust information on the incidence and clinical features of acquired haemophilia. This registry enrolled almost 200 patients. Analysis and publication of these data are underway. In order to collect data across Europe, the European Acquired Haemophilia Registry has recently been initiated. The Registry is run by an independent steering committee consisting of specialists in the field of acquired haemophilia, and collects data on clinical features and management of the patients, using a secure, Internet-based platform. All clinicians who treat patients with acquired haemophilia are encouraged to enrol consenting patients in the Registry. The data obtained in the Registry will provide a better understanding of acquired haemophilia, and may contribute to improving the treatment.