Clinical features and outcome of acquired haemophilia A

Summary

We 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.

Zusammenfassung

In einer Monocenter-Studie haben wir bei 29 konsekutiven Patienten mit erworbener Hemmkörperhämophilie A, die unserem Hämophilie-Behandlungszentrum zwischen März 2001 und Februar 2010 zur Diagnostik und Therapie zugewiesen wurden, eine Zwischenaus-wertung vorgenommen. Patienten, Methoden: 18 Männer (Alter: 44–86 Jahre), 11 Frauen (Alter: 20–83 Jahre). Die Laboratoriumsanalytik erfolgte nach standardisierter Stufendiagnostik unter Einschluss von APTT, Bestimmung der FVIII:C-Aktivität und-Konzentration, Plasmatauschversuchen mit Patienten- und Normal-plasma sowie quantitativer Bestimmung der Inhibitortiter (Bethesda-Assay). Die Diagnostik umfasste zugleich gezielte Untersuchungen zum Nachweis einer Grunderkrankung. Ergebnisse: Bei 18 (62%) der Patienten mit erworbener Hemmkörperhämophilie A wurde eine Grunderkrankung identifiziert: 9 Patienten mit Atemwegserkrankungen (31%), 7 mit Autoimmunerkrankungen (24%), ein Patient mit Malignom, eine Patientin erkrankte in der Postpartalphase. Hingegen lag bei 11 Patienten (38%) eine idiopathische erworbene Hemmkörperhämophilie A vor. Die Hämotherapie aktiver Blutungen, Suppression bzw. Elimination des Inhibitors und Induktion der Immuntoleranz folgten nach einem festgelegten Behandlungsalgorithmus. Prädefinierte klinische Endpunkte waren: Beherrschung der Blutung, Eradikation des Inhibitors, komplette oder partielle Remission (CR, PR), Rezidiv bzw. Frühmortalität. Von den insgesamt 29 Patienten erreichten 22 Individuen eine CR (76%), drei eine PR, ein Patient erlitt ein Rezidiv, und drei Patienten starben innerhalb der ersten 30 Tage (ein Patient am akuten Myokardinfarkt unter antihämorrhagischer Therapie, ein Patient an einer Sepsis unter Immunsuppression, ein Patient an einer Lungenblutung bei pulmonaler Sarkoidose). Schlussfolgerung: Diese Studie zeigt, dass sich die Behandlungs-ergebnisse bei erworbener Hemmkörperhämophilie A durch Beherrschung lebensbedrohlicher Blutungen, Eradikation des Inhibitors und Toleranzinduktion gegenüber endogenem FVIII signifikant verbessert haben. Im Vergleich zu publizierten Daten weist unse-re Zwischenanalyse darauf hin, dass bei erworbener Hemmkörperhämophilie ein Wandel in der Häufigkeit assoziierter Grund-erkrankungen eingetreten sein dürfte und nunmehr eine relative Zunahme an Atemwegserkrankungen zu beobachten ist.

Keywords

Acquired haemophilia A - autoantibodies - morbidity - mortality - underlying disorder

Schlüsselwörter

Erworbene Hemmkörperhämophilie A - Auto-antikörper - Morbidität - Mortalität - Grunderkrankung

^* Dedicated to Prof. Peter Hanfland, Bonn, on the occasion of his 70^th birthday.

^§ This study is part of the MD thesis of Roya Gheisari.

• References

• 1 Aggarwal A, Grewal R, Green RJ. et al. Rituximab for autoimmune haemophilia: a proposed treatment algorithm. Haemophilia 2005; 11: 13-19.
• 2 Boggio LN, Green D. Acquired hemophilia A. Rev Clin Exp Hematol 2001; 05: 389-303.
• 3 Boye J, Elter T, Engert A. An overview of the current clinical use of the anti-CD20 monoclonal antibody rituximab. Ann Oncol 2003; 14: 520-525.
• 4 Collins P, Macartney N, Davies R. et al. A population based, unselected, consecutive cohort of patients with acquired hemophilia A. Br J Haematol 2004; 125: 69-73.
• 5 Collins PW, Hirsch S, Baglin TP. 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.
• 6 Delgado J, Jimenez-Yuste V, Hernandez-Navarro F, Villar A. Acquired hemophilia: review and meta-analysis focused on therapy and prognostic factors. Br J Haematol 2003; 121: 21-35.
• 7 Franchini M, Lippi G. Acquired factor VIII inhibitors. Blood 2008; 112: 250-255.
• 8 Gerhardt A, Scharf RE, Zotz RB. Effect of hemo static risk factors on the individual probability of thrombosis during pregnancy and the puerperium. Thromb Haemost 2003; 90: 77-85.
• 9 Green D, Lechner K. A survey of 215 non-hemophilic patients with inhibitors to factor VIII. Thromb Haemost 1981; 45: 200-2003.
• 10 Hubbard AR, Heath AB. Calibration of the proposed 5th international standard for blood coagulation factor VIII and von Willebrand factor in plasma, human. WHO and International Society on Thrombosis and Haemostasis. www.isth.org 2003 SSC-WHO document 02/150: 1-30.
• 11 Huth-Kühne A, Baudo F, Collins P. et al. International recommendations on the diagnosis and treatment of patients with acquired hemophilia A. Haematologica 2009; 94: 566-575.
• 12 Huth-Kühne A. Klinik und Therapie der erworbenen Hemmkörperhämophilie A: update 2010. Vasc Care 2010; 19: 14-23.
• 13 Kasper CK, Aledort LM, Counts R. et al. A more uniform measurement of factor VIII inhibitors. Thromb Diath Haemorrh 1975; 34: 869-872.
• 14 Kessler CM, Ludlam CA. The treatment of acquired factor VIII inhibitors: wordwide experience with porcine factor VIII concentrate. International Acquired Hemophilia Study Group. Semin Hematol 1993; 30 (Suppl. 01) 22-27.
• 15 Lottenberg R, Kentro TB, Kitchens CS. Acquired hemophilia. A natural history study of 16 patients with factor VIII inhibitors receiving little or no therapy. Arch Intern Med 1987; 147: 1077-1081.
• 16 Mannucci PM, Peyvandi F. Autoimmune hemophilia at rescue. Haematologica 2009; 94: 459-461.
• 17 Scharf RE. Acquired platelet function defects: an underestimated but frequent cause of bleeding complications in clinical practice. In: Scharf RE. ed Progress and Challenges in Transfusion Medicine, Hemostasis, and Hemotherapy. Freiburg: Karger; 2008: 296-316.
• 18 Scharf RE. Management of bleeding in patients using antithrombotic agents. Prediction, prevention, protection, and problem-oriented intervention. Hämostaseologie 2009; 29: 388-398.
• 19 Scharf RE, Gheisari R, Bomke B, Hoffmann T. The prognosis of acquired hemophilia A has been significantly improved: results of the Dusseldorf Study (in preparation).
• 20 Shaffer LG, Phillips MD. Successful treatment of acquired hemophilia with oral immunosuppressive therapy. Ann Intern Med 1997; 127: 206-209.
• 21 Stasi R, Brunetti M, Stipa E, Amadori S. Selective B-cell depletion with retuximab for the treatment of patients with acquired hemophilia. Blood 2004; 103: 4424-4428.
• 22 Stockschläder M, Scharf RE. Challenges in life-threatening hemorrhages: the acquired hemophilia. In: Scharf RE. ed Progress and Challenges in Transfusion Medicine, Hemostasis, and Hemotherapy. Freiburg: Karger; 2008: 274-287.
• 23 Stockschläder M, Ruf L, Linderer A. et al. Induction of tolerance after combined immunosuppression and -adsorption in two patients with acquired haemophilia after severe haemorrhages controlled by sequential administration of rFVIIa and FEIBA. Thromb Haemost 2009; 101: 586-590.
• 24 Verbruggen B, Novakova I, Wessels H. et al. The Nijmegen modification of the Bethesda assay for factor VIII:C inhibitors. Thromb Haemost 1995; 73: 247-251.
• 25 Wiestner A, Cho HJ, Asch AS. et al. Rituximab in the treatment of acquired factor VIII inhibitor. Blood 2002; 100: 3426-3428.