Clinical features and outcome of acquired haemophilia A

SummaryWe have performed a monocenter study on 29 consecutive patients with acquired haemophilia A who were referred for diagnosis and treatment to the Düsseldorf Haemophilia Comprehensive Care Center between March 2001 and February 2010. Patients, methods: 18 men (age: 44–86 years) and 11 women (age: 20–83 years). For laboratory evaluation, a standardized staged protocol of aPTT, FVIII : C activity and concentration, mixing studies with patient and normal plasma, and quantification of inhibitor titers (Bethesda assay) was used. Diagnostic work-up included elaborate examinations for any underlying disease. Results: In 18 (62%) of the 29 patients with acquired haemophilia A, an underlying disorder was identified, including 9 patients with respiratory diseases (31%), 7 patients with autoimmune disorders (24%), one with malignancy, and one with postpartum state, while in 11 patients (38%) acquired haemophilia A remained idiopathic. Haemotherapy of bleeding, suppression or elimination of the inhibitor, and induction of immunotolerance to endogenous FVIII:C were performed according to a treatment algorithm. Predefined clinical endpoints were control of bleeding, eradication of the inhibitor, complete or partial remission (CR, PR), relapse, or early death (≤30 days). Of the 29 patients in total, 22 individuals achieved CR (76%), three had PR, one relapsed, and three died within 30 days (one of acute myocardial infarction while on anti-haemorrhagic treatment, one of sepsis while on immunosuppression due to active acquired haemophilia A, one of lung bleeding in association with pre-existing pulmonary sarcoidosis). Conclusion: This monocenter study demonstrates that control of life-threatening bleeding, eradication of the inhibitor, and induction of tolerance to endogenous FVIII have significantly improved the clinical outcome of acquired haemophilia A. Our data also suggest a shift in underlying disorders associated with acquired haemophilia A, whereby, in comparison to published studies, a relative increase in the proportion of patients with respiratory diseases is present.

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Improved Prognosis of Acquired Hemophilia A: A 10-Year-Experience

Blood ◽

10.1182/blood.v118.21.4348.4348 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4348-4348 ◽

Cited By ~ 1

Author(s):

Rudiger E. Scharf ◽

Barbara Bomke ◽

Holger Seidel ◽

Roya Gheisari ◽

Marie Antonia Scharf ◽

...

Keyword(s):

Immune Tolerance ◽

Respiratory Diseases ◽

Hemophilia A ◽

Conflicts Of Interest ◽

Treatment Algorithm ◽

Factor Vii ◽

Laboratory Evaluation ◽

Acquired Hemophilia A ◽

Acquired Hemophilia ◽

Life Threatening

Abstract Abstract 4348 Background: Acquired hemophilia A (AHA) is a rare but significant hemostatic disorder caused by inhibitory autoantibodies against coagulation factor VIII (FVIII:C). The annual incidence of AHA is low with about 1 to 4 cases per million individuals. However, the mortality rate due to severe hemorrhages and comorbidity is high reaching 22% in several series. In the past, only a few patients were reported in whom an association of AHA with respiratory disorders was observed. Patients, Methods, and Study Protocol: We have performed a monocenter study on 35 consecutive patients with AHA A who were referred for diagnosis and treatment to the Düsseldorf Hemophilia Comprehensive Care Center between March 2001 and June 2011. The cohort included 24 males (age: 44–86 years) and 11 females (age: 20–83 years). For laboratory evaluation, a standardized staged protocol of APTT, FVIII:C activity and concentration, mixing studies with patient and normal plasma, and quantitation of inhibitor titers (Nijmegen modification of the Bethesda assay) was used. Diagnostic work-up for any underlying disease was performed according to a standardized protocol of clinical examinations and imaging procedures (including X-ray examination of thorax, sonography of abdomen, retroperitoneum and thyreoidea and, whenever indicated, computerized tomography of thorax, abdomen, or pelvis). Therapy was performed according to a treatment algorithm consisting of (a) acute antihemorrhagic therapy (irrespective of residual FVIII:C activity and inhibitor titer), (b) immediate immunosuppression (individually tailored to the patients’ risks with regard to age and comorbidity), and, if life-threatening bleedings persisted, (c) inhibitor elimination by immunoadsorption or plasmapheresis, and (d) concomitant immunotolerance regimens. Predefined clinical endpoints were control of bleeding, eradication of the inhibitor, complete or partial remission (CR, PR), relapse, or early death (< 30 days). CR was defined as no inhibitor detectable, FVIII:C activity > 80%, and withdrawal of immunosuppressive therapy. Results: In 21 (60%) of the 35 patients with AHA, an underlying disorder was identified, including 9 patients with respiratory diseases (26%), 8 patients with autoimmune disorders (23%), 3 with malignancies, and one with postpartum state, while in 14 patients (40%) AHA remained idiopathic. Upon admission, 16 of the 35 patients presented with life-threatening hemorrhages. In 13 of these 16 patients, control of bleeding was achieved by high doses of recombinant activated factor VII (rFVIIa; 90–120 μ g/kg every 2–3 h), while 3 patients required combined FVIII bypassing agents (rFVIIa plus bolus injections of activated prothrombin complex concentrates, aPCC; 100 IU/kg every 8–12 h). In the other 19 patients, bleeding also subsided in response to rFVIIa. Concurrent immunosuppression with prednisone alone (2 mg/kg/day) was performed in 11 patients, while 24 patients received cyclophosphamide (2 mg/kg/day) sequentially in combination with prednisone. In 5 patients in whom this first-line immunosuppression failed, 4 doses of rituximab (375 mg/m2) were administered as second-line therapy. Of the 35 patients, 13 required extracorporeal inhibitor elimination procedures due to persisting life-threatening bleeds. Exchange plasmapheresis was performed in 4, daily large-volume immunoadsorption (Ig-Therasorb) for up to 4 weeks in 9 patients. In 3 of them, immune tolerance was concomitantly induced by exogenous FVIII (100 IU/kg/day). Of the 35 patients in total, 28 individuals achieved CR (80%), 3 had PR, one relapsed, and 3 died within 30 days (one of acute myocardial infarction while on antihemorrhagic treatment, one of sepsis while on immunosuppression due to active AHA, one of lung bleeding in assocociation with pre-existing pulmonary sarcoidosis). Conclusions: This monocenter study demonstrates that control of life-threatening bleeding, eradication of the inhibitor, and induction of immune tolerance to FVIII have clearly improved the clinical outcome of AHA. Our data also suggest a shift in underlying disorders associated with AHA, whereby, in comparison to published studies, a relative increase in the proportion of patients with respiratory diseases is observed. Large controlled multicenter studies are required to confirm these findings. Disclosures: No relevant conflicts of interest to declare.

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Review of recombinant anti-haemophilic porcine sequence factor VIII in adults with acquired haemophilia A

Therapeutic Advances in Hematology ◽

10.1177/2040620717720861 ◽

2017 ◽

Vol 8 (9) ◽

pp. 263-272 ◽

Cited By ~ 11

Author(s):

Emma Fosbury ◽

Anja Drebes ◽

Anne Riddell ◽

Pratima Chowdary

Keyword(s):

Treatment Algorithm ◽

Individual Variability ◽

Response To Treatment ◽

Factor Vii ◽

Fixed Dose ◽

Haemophilia A ◽

Recombinant Activated Factor Vii ◽

Acquired Haemophilia ◽

Activated Factor Vii ◽

Activated Prothrombin Complex Concentrates

Acquired haemophilia A (AHA) is a rare, serious bleeding disorder most often encountered in elderly patients. The mainstay of haemostatic management is with bypassing agents (BPAs) including recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrates (aPCCs). Their major limitation is incomplete efficacy, potential risk for thrombosis and the lack of routine laboratory assays for monitoring treatment response. Plasma-derived porcine FVIII (pd-pFVIII, Hyate C®), first used in the 1950s for the management of congenital haemophilia, has sufficient sequence homology to be haemostatic in humans, but the lack of complete homology facilitates efficacy even in the presence of human allo- and autoantibodies against human FVIII (hFVIII). In a small phase II/III study, recombinant porcine FVIII (rpFVIII, Obizur®, OBI-1, susoctocog alfa) was shown to be safe and effective for the management of bleeding episodes in patients with AHA with anti-porcine FVIII (anti-pFVIII) antibody levels of 20 BU/ml or less. Treatment outcome was judged on clinical response and FVIII levels after an initial fixed dose of 200 IU/kg. The rise in FVIII levels showed considerable inter-individual variability and was significantly influenced by the presence of anti-pFVIII antibodies. Based on the baseline levels of anti-pFVIII antibodies and response to treatment, three potential patient groups were identifiable. In the first group, the absence of cross-reacting antibodies was associated with supra-therapeutic FVIII levels, fewer infusions and lower rpFVIII utilization per treatment episode. The second group had patients with low levels of cross-reacting anti-pFVIII antibodies (0.8–5 BU/ml) with near-normal response to rpFVIII. The last group had higher titres of anti-pFVIII antibody (10–30 BU/ml) associated with lower FVIII levels, more infusions and higher consumption of rpFVIII. We propose a new treatment algorithm for the haemostatic management of AHA that includes the potential first-line clinical use of rpFVIII that takes into account availability of anti-pFVIII antibody results, titre of anti-pFVIII antibodies and severity of bleeding episode.

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