© 2009 Schattauer GmbH, Stuttgart 586 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 Marcus Stockschläder 1 ; Leilani Ruf 2 ; Anne Linderer 3 ; Thomas Schroeder 2 ; Wolfram T. Knoefel 3 ; Rainer Haas 2 ; Günther Giers 1 ; Andrea Gerhardt 1 ; Christoph Sucker 1 ; Rainer B. Zotz 1 ; Rüdiger E. Scharf 1 1 Department of Haemostasis and Transfusion Medicine, Heinrich Heine University Medical Center, Düsseldorf, Germany; 2 Department of Haematology, Oncology, and Clinical Immunology, Heinrich Heine University Medical Center, Düsseldorf, Germany; 3 Department of General Surgery, Heinrich Heine University Medical Center, Düsseldorf, Germany Case Report Correspondence to: Marcus Stockschlaeder University Medical Center Duesseldorf Institue of Hemostasis and Transfusion Medicine Moorenstr. 5, 40225 Duesseldorf, Germany Tel.: +49 6421 394661, Fax: +49 6421 394146 E-mail: marcus.stockschlaeder@uni-duesseldorf.de Received: Novembre 2, 2008 Accepted after major revision: December 9, 2008 Prepublished online: February 9, 2009 doi:10.1160/TH08-11-0716 Thromb Haemost 2009; 101: 586–590 A cquired haemophilia is a rare, clinically significant hae- mostatic disorder caused by spontaneous development of autoimmune antibodies (inhibitors) against factor VIII coagulant protein (FVIII:C) (1). There is a recognized associ- ation between development of acquired antibodies to factor VIII:C and a number of diseases, especially those with an auto- immune basis. Other risk factors include malignancy, certain drugs, pregnancy and the postpartum period (2–4). In about half of the cases, however, the inhibitor is idiopathic (5). Circulating inhibitors to factor VIII:C may lead to an ac- quired haemophilic state and life-threatening bleeding compli- cations. Fatality is high, reaching 22% in some series depending on age, inhibitor titer levels, and response to treatment (6–8). Pa- tients in whom the inhibitor cannot be eliminated may have a mortality rate as high as 42% (8). Since the inhibitors have com- plex type 2 kinetics with a nonlinear inactivation of factor VIII:C making it difficult to saturate the inhibitor by adding antigen (2, 9), factor VIII:C substitution therapy is unsuccessful in the pres- ence of high-titer inhibitors unless very high-dose factor VIII:C is given (10). Control of bleeding is usually achieved with FVIII bypassing activity such as activated prothrombin complex con- centrates (aPCC; e.g. FEIBA) or recombinant factor VIIa (rFVIIa; e.g. NovoSeven). The primary objective for treating pa- tients should be the safe and rapid elimination of the inhibitor and the development of long-term immune tolerance. Here, we report two factor VIII inhibitor patients who pres- ented with life-threatening bleeding complications and failed in- itial high-dose haemostatic treatment with NovoSeven. New bleeding complications were controlled by addition of FEIBA. After successfully reducing high-titer inhibitors by immunoad- sorption, immunotolerance to endogenous factor VIII:C was achieved by combined immunosuppressive treatment with cor- ticosteroids, cytotoxic drugs, and rituximab. Without adminis- tration of exogenous plasmic or recombinant factor VIII, the in- hibitor disappeared and factor VIII:C activity returned to normal levels. Case 1 A 60-year-old male patient developed spontaneous macrohema- turia. Since imaging of the abdomen revealed a polycystic mass in the left renal pelvis, he underwent laparotomy. Postoperative bleeding complications necessitated two surgical revisions. A subsequent thorough coagulation screen showed a significantly prolonged aPTT (92 seconds [sec]; normal range 29–37 sec) which was due to factor VIII:C activity of less than 1%. After ob- taining a positive plasma mixing, quantitation of the factor VIII:C inhibitor revealed a titer of 36 Bethesda units (BU). For immediate control of bleeding, the patient was treated with No- voSeven (90 μg/kg body weight). Despite shortening of the ad- ministration intervals of rFVIIa (7.2 mg) to every three hours, the patient developed epistaxis and haematothorax necessitating the transfusion of altogether 20 units of packed red blood cells. While maintaining the rFVIIa dose, FEIBA (5,000 IE four times a day) was added (Fig. 1B). Bleeding complications subsided and the dose of rFVIIa was slowly tapered. Daily physical exam- ination and laboratory investigations evaluating the platelet count, fibrinogen, and D-dimers did not reveal any signs of thromboembolic complications or disseminated intravascular coagulation. Concurrent immunosuppressive therapy consisted of prednisone (2 mg/kg body weight per day), cyclophospha- mide (2 mg/kg body weight per day), and four weekly doses of ri- tuximab (375 mg/m 2 BSA). Daily immunoadsorption (Ig-Thera- sorb, Miltenyi Biotec, Teterow, Germany; Sepharose CL-4B coupled with polyclonal sheep antibodies to human immunoglo- bulins; 25 sessions; processed plasma volume of approx. 7,000 ml) was performed to accelerate inhibitor elimination. Factor VIII:C activity increased steadily and remained within the nor- mal range after discontinuation of immunosuppressive therapy (Fig. 1A). For personal or educational use only. No other uses without permission. All rights reserved. Downloaded from www.thrombosis-online.com on 2018-04-06 | ID: 1001066444 | IP: 54.70.40.11