IngaMarie Nilsson

Tolerance induction using the Malmo treatment model 1982-1995

The ultimate goal in the treatment of haemophilia patients with inhibitors is to eradicate permanently the inhibitor and induce tolerance. Here we summarize our experience at the Malmö centre regarding tolerance induction according to the Malmö Treatment Model. The protocol includes immunoadsorption if needed, neutralization of inhibitor and replacement with factor concentrates, cyclophosphamide intravenously for 2 days (12–15 mg kg−1 bw) and then orally (2–3 mg kg−1 bw) for an additional 8–10 days and intravenous gammaglobulin daily at dosages of 0.4 g kg−1 bw for 5 days. This protocol has been applied in 23 haemophilia patients with inhibitors, 16 haemophilia A patients and seven haemophilia B patients. Altogether 36 attempts have been made to induce tolerance. Ten of the 16 haemophilia A (62.5%) and 6/7 patients with haemophilia B (86%) became tolerant after the treatment. The chances of success or failure are roughly equal, if the series is considered in a historical perspective. The data showed that the chances of success in tolerance induction with the Malmö protocol were best in those patients with low inhibitor titres, with relatively low historical inhibitory peak and with a long interval since the previous replacement therapy. This was especially true where no inflammatory state was present at the start or during tolerance induction. The advantage with this method compared to the high‐dose regimen is that in the successful cases tolerance can be achieved within 3–4 weeks.

Immunoadsorption for removal of inhibitors: update on treatments in Malmo-Lund between 1980 and 1995

Treatment of severe bleeding and the performance of surgery in Haemophilia patients with inhibitors creates severe problems. It is generally agreed that treatment is most effective if circulating levels of factor VIII/IX can be achieved long enough for control of heamostasis. Immunoadsorption with protein A for the removal of inhibitor has improved treatment for patients with initial inhibitor titres too high to neutralize by infusion alone.

DDAVP‐induced enhancement of platelet retention: Its dependence on platelet‐von Willebrand Factor and the platelet receptor GP IIb/IIIa

Abstract: Although DDAVP has been shown to be haemostatically efficacious in patients with various congenital or acquired platelet disorders, no reasonable explanation has been found for this effect. We have previously shown DDAVP to increase platelet adhesiveness as measured with a platelet retention test. The aim of the present study was to investigate the mechanism of action responsible for the increased platelet retention in response to DDAVP. Patients with vWD type III and type Ia, severe haemophilia and severe thrombasthenia, as well as healthy controls, were included in the study. The effect of different concentrations of vWF in plasma and platelets was explored, as was the effect on platelet function of apyrase and monoclonal antibodies against GP IIb/IIIa and GP Ib. We found the effect of DDAVP on platelet retention to be unaffected by changes in the plasma concentration of vWF. The enhanced platelet retention after DDAVP is apparently dependent on the presence of platelet‐vWF and on a normal function of the GP IIb/IIIa. The effect is not mediated via ADP or thrombin. The platelet‐stimulating effect of DDAVP may be one explanation for the positive haemostatic effect in patients with certain platelet disorders.

FACTOR VIII AND GLOMERULONEPHRITIS

To find out if determination of factor VIII,which most probably is synthetised in the intima of blood-vessesls, is of value for predicting the severity of vessel damge in glomerulonephritis, factor-VIII activity, factor-VIII-related antigen, and glomerular filtration-ratewere esto,ated om 85 patients with early glomerulonephritis on admission, and in 70 of these at follow-up for up to 4 years. The levels of factor-VIII activity and factor-VIII-related antigen on admission were normal in those patients who recovered. Where renal function was impaired on admission or becaome so during follow-up, factor VIII was high. Determination of factor VIII might thus be of prognostic value in early glomerulonephritis.

HIV seroconversion in Swedish haemophiliacs: relation to type and dosage of factor concentrate

Human immunodeficiency virus (HIV) seroconversion among 40 Swedish haemophilia A patients has been investigated by retrospective sera testing. 22/40 patients had developed HIV antibodies before 1983, i.e., when heat‐treatment of American factor concentrates was introduced. All patients had received American and Swedish factor concentrates, thus no case of seroconversion was seen among patients treated exclusively with non‐heat‐treated Swedish concentrates. Of 79 patients with severe or moderate haemophilia, all of whom had received both American and Swedish concentrates, the 36 seropositives were compared with the 43 seronegatives. The total number of units received did not differ between the two groups, though the seropositive group had received significantly more American concentrate. Two batches of concentrate were proved to have been infected. 29 seropositive and 13 seronegative patients had been treated with at least one of these batches. As expected, and unlike most of the seronegative patients, patients in the seropositive group generally had abnormal lymphocyte subsets.

Natural history of HIV infection in Swedish haemophiliacs

The longitudinal follow‐up is described of 36 anti‐HIV positive haemophiliacs who had seroconverted in the period 1980–82, and of 41 seronegative controls. Laboratory variables were followed up for a mean duration of 2.5 years (1985–87). Of the 36 seropositive patients, AIDS developed in 3, and generalised persistent lymphadenopathy in 9. The HIV‐seropositive patient group had lower CD4:CD8 ratios and CD4 counts but higher CD8 counts than the seronegative group. However, there was no deterioration in the values for the lymphocyte subsets during follow‐up. Titration on paired sera showed an increase in anti‐HIV titre with time. Testing for the presence of HIV antigen was positive in 5 patients, including 2 who later developed AIDS. We conclude that anti‐HIV positive haemophiliacs, though actively immunised, often show no symptoms even as long as 7 yr after seroconversion and that, in certain patients, the immune system may even show signs of improvement.