The interaction of blood platelets with collagen is generally considered to be of primary importance in the arrest of bleeding and to have a role in the pathogenesis of thrombosis and atherosclerosis. Following damage to the vascular endothelium, circulating platelets come into contact with exposed collagen fibrils in the subendothelium and spread along it; this is followed by the secretion of several biologically active substances and by aggregation of platelets. The glycoproteins of the platelet plasma membrane have an important role in the mechanisms underlying these processes. So far, two specific defects of platelet function in patients with a bleeding disorder are known to be associated with a glycoprotein defect and the study of these patients has contributed significantly to present concepts of platelet function. The glycoprotein (GP) IIB-III complex, absent or deleted in the aggregation-defective Glanzmann's thrombasthenia, has been identified as the platelet fibrinogen receptor. GPIb, which is absent in the adhesion-defective Bernard-Soulier syndrome, has been identified as the von Willebrand factor receptor on platelets. We now report a defect of the platelet plasma membrane glycoprotein composition in a patient whose platelets are totally unresponsive to collagen.

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In patients with hemophilia A and inhibitory alloantibodies against factor VIII, various dosage schedules are used to obtain immune tolerance. In this study, we have evaluated the results of 13 years of low-dose immune tolerance induction and factors that are predictive of a positive result. The effect of immune tolerance induction in relation to age at inhibitor development, number of exposure days, age at start of therapy, maximum inhibitor titer, factor VIII products involved, and virologic status were determined. We evaluated 24 patients with severe hemophilia A and inhibitors who were treated with regular infusions with low-dose (25 U/kg every other day) factor VIII to obtain immune tolerance. In 21 of 24 patients (87%), immune tolerance induction was successful. The response time was determined by two factors: the highest inhibitor level and the age at inhibitor development. In patients with maximum inhibitor levels of less than 40 Bethesda units (BU)/mL, immune tolerance was obtained sooner than in patients with inhibitor levels exceeding 40 BU/mL (P = .005). Patients in whom an inhibitor developed before the age of 2.5 years also tended to have a quick immune response (P = .014). Immune tolerance with low-dose factor VIII is often successful in hemophilia A patients with inhibitors. Young children and patients with maximum inhibitors of less than 40 BU/mL show a relatively rapid response.

Diabetes mellitus is associated with aggravated development of vascular complications. Yet, it has not been established whether platelet hyperreactivity contributes as a pathogenetic factor. In order to study the role of activated platelets in diabetes mellitus, we investigated the expression of the membrane activation markers CD63 (GP53) and CD62 (GMP-140) as direct indicators of in vivo activation. The CD63-positive fraction was significantly higher in patients (6.1% X 3.7 +/- 1) than in controls (2.7% X 3 +/- 1). In parallel, the CD62-positive fraction was significantly elevated in patients to 5% X 2.5 +/- 1 in comparison to controls (3% X 2 +/- 1). Patients with angiopathy had a mean increase of 304% in CD63-positive and of 223% in CD62-positive platelets. Patients without clinically detectable angiopathy showed a trend to an increased fraction in CD63-/CD62-positive platelets. There was no correlation of the activation markers with fasting blood glucose, HbA1 or platelet count. CD63 platelet bound fluorescence significantly increased with platelet size in the patient group. We conclude that in diabetes mellitus an increased number of large platelets circulate in an activated state predominantly in patients with angiopathy. This could imply that platelets become activated by vascular lesions. The trend in patients without vascular disease, however, suggests that activated platelets may also basically contribute to the prethrombotic state in diabetes mellitus.

Summary. The development of arthropathy is a serious complication of severe haemophilia. With the use of prophylaxis, bleeds can be prevented and arthropathy delayed. We investigated whether an individually tailored prophylactic regimen can prevent arthropathy and whether it had a similar effect on orthopaedic outcome compared with that of a high-dose regimen. Efficacy was determined clinically and by radiographs of six major joints. Prophylaxis was started in 70 patients at a mean age of 4´1 years. Mean follow-up was 15´6 years (range 8±24´5 years). The mean factor VIII consumption was 2319 IU/kg/year. The mean number of joint bleeds was 3´5/year and the mean clinical score (maximum score 90) was 1´0, with a mean Pettersson joint score (maximum score 78) of 3´0 at a mean age of 13´5 years. In conclusion, long-term, early-onset, individualized prophylaxis in haemophilia is feasible and prevents arthropathy.