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Antibodies against factor VIII occur in about 15-35% of hemophilia A patients and induce refractoriness to factor VIII substitution. In most cases, these antibodies are of the IgG class. Strategies to avoid or to treat such inhibitors are controversial. In very rare cases, factor VIII inhibitors also develop in nonhemophilic patients. Although there are anecdotal reports that these antibodies may disappear spontaneously without occurrence of bleeding tendencies, in the majority of patients the clinical course is characterized by severe hemorrhages. From 1980 to 1995, we observed ten nonhemophilic patients with acquired factor VIII inhibitors at our hospital. In most cases, a sudden bleeding tendency was observed shortly after an injury or surgery. Coagulation tests showed a prolonged aPTT and a decreased F VIII level. Other deficiencies of blood-clotting factors and acquired or hereditary von Willebrand's disease were excluded. Therapy with F VIII concentrates did not produce the expected increase. Measurement of F VIII inhibitor levels in Bethesda units/ml (BU/ml) revealed maximal values in the range of 2-128 BU/ml. Immunosuppressive therapy with azathioprine or cyclophosphamide in combination with methylprednisolone led to complete disappearance of the inhibitor, normalization of the coagulation tests, and complete remission of the bleeding tendency in seven treated patients within 6 weeks. Although the clinical course is not predictable and inhibitors may disappear spontaneously, combined therapy with methylprednisolone and azathioprine or cyclophosphamide is recommended for patients with bleeding tendency. In pregnancy, therapy should be started only with methylprednisolone; post-partum, azathioprine should be used additionally if methylprednisolone as a single drug does not lead to complete remission. In emergency situations, therapy with high doses of human factor VIII concentrate may be used. When bleeding does not cease, the additional use of activated prothrombin-complex concentrates or porcine factor VIII is indicated. Possible side effects may include hepatitis and short-lived intravascular thrombin production.

There is experimental evidence for recombinant human granulocyte colony-stimulating factor (rhG-CSF)-induced stimulation of hemostaseologic parameters including platelets. Using the closure time of the in vitro bleeding test (IVBT, Thrombostat 4000, VDG, Seeon) and different hemostaseologic parameters, our results are suggestive of a directly or indirectly induced in vivo stimulation of platelets following rhG-CSF stimulation in healthy stem cell donors. According to the negative transcranial Doppler microembolic monitoring of the middle cerebral artery, there is no evidence for clinically silent cerebral microembolism supporting a prothrombotic state facilitating the formation of arterial thrombi with subsequent cerebral embolization.

Allogeneic BMT was performed in a 33-year-old man because of CML. Donor was his HLA-identical brother. GVHD prophylaxis consisted of short-term MTX and i.v. CsA. On day 17 cutaneous GVHD grade-III developed and high-dose methyl-prednisone was added. Initial daily dose of CsA was 4 mg/kg i.v. CsA dosage was adapted to maintain blood trough levels between 200 and 350 ng/ml. On day 27 the patient developed severe musculoskeletal pain of knees, legs, feet, hands, shoulders and ellbows. Only high-dose opioids and dextropropoxyphen were effective for analgesia. Additional medication besides CsA consisted of parenteral nutrition, steroids and antibiotics for total intestinal decontamination. Clinical and radiological examinantion revealed no causes for musculoskeletal pain. Serum levels for lactate-dehydrogenase, aldolase, alkaline-phosphatase, creatinphosphokinase with isoenzymes, electrolytes including magnesium were within normal ranges. Pain decreased within 4 days after switching, from intravenous to oral application. This case indicates that CsA in high dosage given intravenously combined with steroids can cause severe musculoskeletal pain as side effect in allogeneic BMT.