Treatment of patients with factor viii autoantibodies by staphylococcal protein a‐based immunoadsorption and immunosuppression (2001)

We read with interest the paper by Jansen et al (2001) and would like to comment on their report, particularly on the basis of our own experiences in the treatment of four patients with factor VIII (FVIII) autoantibodies. Our therapeutic approach consists of two main elements (Mansouri Taleghani et al, 1998). First, it includes a modified Malmö treatment protocol (Nilsson et al, 1993) as induction therapy with removal of FVIII inhibitors by at least three protein A-based immunoadsorptions (PAIA), cyclophosphamide at 12–15 mg/kg bodyweight i.v. (d 1 and 2) and i.v. immunoglobulins 0·4 g/kg/d for 5 d (after the last PAIA). Induction cycles are repeated at intervals of 3–4 weeks until consistent lowering of the inhibitor and sufficient increase of FVIII activity is achieved. The subsequent maintenance therapy comprises daily oral applications of cyclophosphamide and/or corticosteroids, and PAIAs, which are performed once a week. Adjusted to each individual's clinical and laboratory course, the maintenance therapy is adjusted and then tapered off, beginning with the PAIAs. There are several major procedural differences to the treatment described by Jansen et al (2001). First, we utilized Sepharose-bound staphylococcal protein A in columns, which preferentially bind IgG1, 2 and 4 (Immunosorba™, Excorim AB, Lund, Sweden) for the selective IgG immunoadsorption. Second, an automated cell separator and plasma flow monitor was used for plasma separation (Cobe spectra, Cobe Laboratories, Lakewood, USA) and for controlling the flow of plasma and regeneration fluids to the immunoadsorption columns respectively (Citem 10, Cobe Laboratories, Lakewood, USA). Finally, in each immunoadsorption procedure the total amount of treated plasma had to be at least threefold of the patient's body plasma volume in order to achieve an inhibitor reduction of approximately 90% (Gjörstrup et al, 1991). To date, four patients with severe bleeds caused by FVIII autoantibodies have been treated. Patient characteristics, treatment course and results are summarized in Table I. No serious side-effects occurred during PAIA procedures, no infectious or bleeding complications were observed and no FVIII concentrates had to be given. Our results indicate that it may indeed be of minor importance which device is chosen (Ig-Therasorb™ or Immunosorba™ columns) to deplete the FVIII inhibitors efficiently. Because of the fact that most inhibitors have been identified as being of IgG class, usually of subclass IgG4 ± IgG1 (Fulcher et al, 1987), we favour the more selective approach with PAIA and include a preceding Ig subtyping of the inhibitor. In contrast to haemophiliacs, in whom high doses of FVIII seem to be helpful to induce immune tolerance, similar results of this very cost-intensive measure were not seen in patients with autoantibodies to FVIII. Therefore, we would not recommend FVIII substitution for immune modulation in this context. In contrast to membrane-based plasma separation devices, in which a blood flow of at least 50 ml/min is usually necessary, centrifuge-based cell separators may be run with 30 ml/min or even less. Therefore, we recommend the latter system in order to avoid the necessity of thick lumen central venous accesses as often as possible in patients prone to severe haemorrhage. Instead of heparinization we prefer a local anticoagulation of the extracorporeal circuit with regular doses of citrate and calcium neutralization before reinfusion, thus avoiding the well-known side-effects of citrate anticoagulation as well as the rare but potentially life-threatening heparin-induced thrombocytopenia type 2. In conclusion, we would like to confirm the findings of Jansen et al (2001) in patients with FVIII autoantibodies, but recommend the above-mentioned therapeutic modifications and alternatives. We fully agree that the value of Ig immunoadsorption can only be defined in carefully designed randomized trials.