G. Goldmann

Orthotopic liver transplantation in human immunodeficiency virus (HIV)‐positive patients: Outcome of 7 patients from the Bonn cohort

The outcome and clinical features of 7 HIV‐positive patients who were liver transplanted at Bonn University in the era of highly active antiretroviral therapy (HAART) between 1997 and 2004, analyzed by retrospective chart review, are reported. Reasons for orthotopic liver transplantation (OLT) were end‐stage liver disease due to chronic hepatitis C (n = 4) or hepatitis B (n = 1) or acute liver failure due to fulminant hepatitis B (n = 2). Immunosuppression was based on cyclosporine A and prednisone. HAART was reinitiated 1 month after transplantation, and immunosuppression was carefully adapted to account for drug‐drug interactions between cyclosporine A and protease inihibitors. Prednisone was withdrawn 5 months (median) after OLT when immunosuppression had been reliably established in the presence of HAART. One patient died 95 days after OLT due intrathoracic hemorrhage, whereas 6 patients were alive at a median of 24 months. A single episode of acute rejection was observed. The spectrum of postoperative complications was no different from HIV‐negative patients apart from Kaposis sarcoma and multicentric Castlemans disease in a single patient. Recurrent hepatitis B infection was efficiently prevented, whereas hepatitis C reinfection occurred in all 4 patients who had preexisting hepatitis C. Earlier reports on fatal courses of recurrent hepatitis C infection, high rates of organ rejection, and HAART‐related liver toxicity were not observed in our patients. In conclusion, even though preliminary, our data suggest that outcomes after liver transplantation of HIV‐infected patients can be improved. (Liver Transpl 2005;11:1515–1521.)

The relevance of the bleeding severity in the treatment of acquired haemophilia – an update of a single-centre experience with 67 patients

Summary.  Acquired haemophilia (AH), an autoimmune disorder with clinical features ranging from harmless haematomas to life‐threatening bleedings, still has a mortality rate of up to 25%. Owing to its low frequency (1–4 × 106), standardized treatment protocols for its variable manifestations are not available. In case of prominent severe bleedings, the treatment should aim at rapid elimination of the antibody to protect patients from bleedings and on reinduction of long‐term immune tolerance. Clinical data, short‐ and long‐term treatment results of 67 patients diagnosed by our centre are presented. Patients were treated depending on their bleeding severity either by an immunosuppressive treatment alone, or in case of life‐threatening bleedings, by a combined protocol (modified Bonn–Malmö protocol, MBMP) consisting of antibody depletion through immunoadsorption, intravenous immunoglobulin treatment, immunosuppression and high‐dose factor VIII (FVIII) substitution. Mild bleedings occurred in two patients who were treated successfully alone by immunosuppression. Complete remission (CR) was achieved in 90% of the patients treated with MBMP (60). Of the six patients (10%) who achieved a partial remission (PR), four suffered from cancer. Mortality under MBMP was not seen. In contrast, five patients, in whom diagnosis of AH was delayed, experienced fatal outcome during surgical interventions before initiation of MBMP treatment. Prognosis in AH depends mainly on its prompt diagnosis. Treatment procedures should be adapted to bleeding severity and inhibitor titres. Under these conditions, AH is a potentially curable autoimmune disorder with an excellent prognosis.

Antiviral therapy for hepatitis C virus recurrence after liver transplantation in HIV-infected patients: outcome in the Bonn cohort.

Recurrent hepatitis C is a major cause of mortality in HIV/hepatitis C virus (HCV)-co-infected patients after orthotopic liver transplantation. We report sustained viral clearance in all four transplanted HIV/HCV-positive patients treated with pegylated interferon/ribavirin. Early therapy after HCV recurrence, tailoring treatment duration to the individual decline in HCV-RNA and the management of side effects are key factors for improved efficacy. At experienced centres interferon treatment is a valuable option for recurrent hepatitis C in HIV-positive patients.

Perioperative management and outcome of general and abdominal surgery in hemophiliacs.

BACKGROUND The aim of the current study was to investigate perioperative management and outcome of surgery in hemophiliacs. METHODS Fifty-five hemophiliacs underwent surgery (appendectomy, cholecystectomy, inguinal hernia repair, hemorrhoidectomy). Surgical procedures in hemophiliacs and matched pairs were analyzed for duration of surgery, drainages, hospital stay, factor use (VIII, IX), and complications. Factor substitution was analyzed. Mann-Whitney U and Kruskal-Wallis tests were used (P < .05). RESULTS No significant differences were found for duration of drains and operation time in hemophiliacs versus matched pairs. Significance for duration of hospital stay compared with controls was found in hemophiliacs for appendectomy, inguinal hernia repair, and hemorrhoidectomy but not for cholecystectomy. In both groups, complications were low without significant differences. CONCLUSIONS This study found no significant differences in perioperative data and postoperative outcome in hemophiliacs compared with nonhemophiliacs due to the excellent perioperative interdisciplinary management at our Hemophilia Center with prolonged hospital stay in hemophiliacs.

Total ankle replacement in patients with haemophilia and virus infections--a safe alternative to ankle arthrodesis?

Despite reliable results of ankle fusion for advanced haemophilic arthropathy, total ankle replacement (TAR) may be functionally advantageous. There is only very limited literature data available on TAR in patients with haemophilia. The objective of this study is to evaluate the short‐ and mid‐term results after TAR in patients with end‐stage haemophilic ankle arthropathy and concomitant virus infections. In a retrospective study, results after eleven TAR in 10 patients with severe (n = 8) and moderate (n = 2) haemophilia (mean age: 49 ± 7 years, range, 37–59) were evaluated at a mean follow‐up of 3.0 years (range, 1.2–5.4). Nine patients were positive for hepatitis C, five were HIV‐positive. Range of motion (ROM), AOFAS‐hindfoot‐score, pain status (visual analogue scale, VAS) as well as patient satisfaction were evaluated. In two cases deep prosthesis infection occurred leading to the removal of the implant. In the remaining eight patients the mean AOFAS score improved significantly from 21.5 to 68.0 points (P < 0.0005), the VAS score decreased significantly from 7.6 to 1.9 points (P < 0.0005). ROM increased from 23.2 to 25.0 degrees (P = 0.51). At final follow‐up all patients without any complications were satisfied with the postoperative results. Radiographic examination did not reveal any signs of prosthetic loosening. TAR is a viable surgical treatment option in patients with end‐stage ankle osteoarthritis due to haemophilia. It provides significant pain relieve and high patient satisfaction. However, due to the increased risk of infection and lack of long‐term results, TAR particularly in patients with severe haemophilia and virus infections should be indicated carefully.

Outcome after total knee arthroplasty in haemophilic patients with stiff knees

Advanced haemophilic arthropathy of the knee is associated with progressive joint stiffness. Results after total knee arthroplasty (TKA) in stiff knees are considered to be inferior compared to those with less restricted preoperative range of motion (ROM). There is only very limited data on the results of primary TKA in haemophilic patients with stiff knees.

Immunoadsorption in the treatment of Acquired Haemophilia

In acquired haemophilia (AH) healthy humans can suddenly develop severe bleeding due to autoantibodies (inhibitors) against clotting factors, especially factor VIII. The mortality rate of 21 % is considerable, and standardized treatment protocols have not been developed due to the low disease frequency (1-4 per million). Major goals of treatment are the control of bleeding events and rapid inhibitor elimination. Conventional treatment regimens induce immune tolerance via long-term immunosuppression with success rates between 52% and 82%. However, treatment related mortality can rise to 39%. Lack of complete remission, advanced age, underlying malignancies and infections related to immunosuppressive therapy are regarded as principal risk factors for death. The modified Bonn-Malmö Protocol (MBMP), an immune tolerance protocol consisting of antibody depletion through immunoadsorption, i.v. immunoglobulin treatment, immunosuppression and high dose FVIII supplementation, achieves rapid and safe control of acute bleeding. In the largest published single centre study of high risk patients with AH, we previously demonstrated that complete remission (CR) can be achieved in 88.5% of all patients (54/61) within a median time of 3.9 wks (range: 3.2-4.5 wks) and in 97% (54/56) of AH patients without cancer as an underlying condition. Those 5 patients, who suffered also from cancer, achieved partial remission (PR). Mortality or severe treatment-related side effects were not observed. This study confirmed that MBMP is a safe and effective treatment with a high curative potential for severe AH. However, the severity of bleeding, and therefore the cost-effectiveness of the approach, needs to be considered when initiating this treatment protocol.

Extracorporeal Treatment for the Acute und Long-Term Outcome of Patients with Life-Threatening Acquired Hemophilia

Objectives: In acquired hemophilia (AH), autoantibodies (inhibitors) impede blood coagulation factors leading to severe bleedings. Cornerstones of a successful treatment are the control of bleeding and an eradication of autoantibodies. The present study is an update of our previous documentation of the treatment of high-titer AH patients with severe life-threatening bleeding undergoing the modified Bonn-Malmö-Protocol (MBMP). Methods: 64 AH patients were treated by a standard combination protocol (MBMP) consisting of antibody depletion through immunoadsorption, i.v. immunoglobulin, immunosuppression, and high-dose FVIII substitution. They underwent a long-term follow-up. Results: Primary study endpoints loss of detection of the activity of the inhibitor and FVIII recovery ≥ 5% were reached in a median time of 3 days (95% CI: 2.6–3.4 days), the median time of FVIII substitution was 13 days (95% CI 10.6–15.3 days), and the median time of immunoadsorption was 16 days (95% CI 13–18.9 days). In 5 patients the AH occurred as paraneoplastic syndrome, and partial remission was achieved. Relapses without bleeding event occurred only in second-line MBMP. Those responded excellently to short time treatment. Overall patients remained in remission over a median follow-up time of 8 years. Conclusion: Except for paraneoplastic AH, MBMP-treated patients have a remarkable prognosis which is confirmed by long-term follow-up with a complete response rate of 93% (53/57) in the first year post MBMP and 100% during long-term follow-up. These outcome in life-threatening AH is unique and until now not achievable via other treatment schedules. In life-threatening bleedings physicians should take into account MBMP as a first line treatment.

Treatment of Factor VIII Inhibitors with Selective IgG Immunoadsorption – a Single Center Experience in 50 Patients with Acquired Hemophilia*

Background: Acquired hemophilia (AH) is a potentially lifethreatening disease in which severe bleeding events lead to a mortality of up to 22%. In AH autoantibodies of the IgG subtype inactivate clotting factors. Although the incidence of this disease is low (1-3 per 106), the treatment cost can be immense due to long-term clotting factor substitution. The treatment should aim at a rapid and permanent elimination of autoantibodies and the induction of a new immune tolerance to prevent further bleedings. Patients and Methods: 50 high-titer (>5 Bethesda Units(BU)/ml) AH patients were treated by the following protocol: i) inhibitor elimination via IgG immunoadsorption, ii) immunosuppression, iii) i.v. immunoglobulin, and iv) high-dose factor VIII substitution. Follow-up time ranged between 12 months and 7 years. Results: A complete remission was achieved in 46 of 50 patients (92%). Neither bleeding nor therapy-associated mortality occurred after initiation of treatment. The median time to reach undetectable inhibitor levels was 3 days (95% CI 3-6 days), coagulation factors were given at a median of 15 days (95% CI 12-18 days). The median treatment duration was 17 days (95% CI, 14-20 days). Conclusions: IgG immunoadsorption allows for a fast and permanent inhibitor elimination, being the basis of the high immunomodulatory potency of our protocol which results in long lasting complete remissions in 92% of our patients.

Muscular compartment syndrome of the forearm in a haemophilia inhibitor patient

DGOOC 2003. 17. Rosendaal G, van den Berg HM, Lafeber FPJG et al. Pathologie der Synovitis und hämophilien Arthropathie. Orthopäde 1999; 28: 323–328. 18. Scharrer I, Bray GL, Neutzling O. Incidence of inhibitorsin hemophilia A patients – a review of recent studies of recombinant and plasma-derived factor VIII concentrates. Haemophilia 1999; 5: