Type IIB von Willebrand's disease is a distinct form of this disorder, in which there are abnormal factor VIII/von Willebrand factor multimers in plasma (but normal multimers in platelets) and heightened interaction between the von Willebrand factor and platelets in the presence of ristocetin. We have found that infusion of desmopressin acetate (1-desamino-8-D-arginine vasopressin [DDAVP]), an agent used in the treatment of von Willebrand's disease, causes platelet aggregation and thrombocytopenia in patients with Type IIB disease. In vitro, platelets in normal plasma and those obtained from patients with Type IIB disease before DDAVP infusion aggregated upon the addition of platelet-poor plasma from Type IIB patients treated with DDAVP. Platelet aggregation was associated with adsorption of multimers of factor VIII/von Willebrand factor onto the platelets and was inhibited by EDTA. We conclude that in Type IIB von Willebrand's disease, DDAVP releases an abnormal factor with platelet-aggregating properties. DDAVP should not be used to treat patients with Type IIB disease, since the presence of platelet aggregates in the circulation may be harmful.

SummaryA comparison was made of intranasal administration of 300 μg desmopressin (DDAVP) by spray, with intravenous administration of 0.2, 0.3 and 0.4 μg DDAVP/kg in 10 healthy volunteers. The effect of DDAVP was measured on F VIII/vWF complex and on plasminogen activator release. In addition, plasma levels of DDAVP were determined using a specific and sensitive radioimmunoassay. Moreover, the reproducibility of the spray effect in 10 healthy volunteers was tested after administration of 300 μg DDAVP intranasally by spray on 5 different occasions.Plasma levels of DDAVP showed a clear dose-response with the maximum levels at 0.4 μg/kg i.v. The effect of the spray approximated the 0.2 μg/kg response. However, the maximum response in both F VIII/vWF complex and plasminogen activator release was obtained after 0.3 μg/kg i. v. The response to 0.4 μg/kg i. v. was not significantly different from the response to 0.3 μg/kg indicating that maximum stimulation was reached with 0.3 μg/kg. There was no correlation between plasma levels of F VIII/vWF and DDAVP indicating that the biological response to DDAVP is subjected to saturation kinetics.The reproducibility of the effect of the spray dose on VIII : C was 21% (c.v.) and 27% for the intra-individual and interindividual variation, respectively, and compared favorably with intravenous administration.Intranasal DDAVP (300 μg) is as effective as 0.2 μg/kg intravenously and provides an accurate, reproducible and convenient alternative to parenteral administration.

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Summary. The present series comprises all families (n 77) with haemophilia B in Sweden and may be considered to be representative for the purposes of a population-based study of mutational heterogeneity. The 77 families (38 severe, 10 moderate, 29 mild) had 51 different mutations in total. Thirteen families had total, partial or small deletions, two had mutations in the promoter, eight families had splice site mutations, 14 had nonsense and the remaining 41 had missense mutations. Ten of the mutations, all C!T or G!A, recurred in 1±6 other families. Using haplotype analysis of seven polymorphisms in the factor IX (FIX) gene, we found that the 77 families carried 65 unique, independent mutations. Of the 48 families with severe or moderate haemophilia, 23 (48%) had a sporadic case of haemophilia compared with 31 families out of 78 (40%) in the whole series. Five of those 23 sporadic cases carried de novo mutations, 11 out of 23 of the mothers were proven carriers and, in the remaining seven families, it was not possible to determine carriership. Eleven of the 48 patients (23%) with severe haemophilia B developed inhibitors and all of them had deletions or nonsense mutations. Thus, 11 out of 37 (30%) patients with severe haemophilia B as a result of deletion/nonsense mutations developed inhibitors compared with 0 out of 11 patients with missense mutations. The ratio of male to female mutation rates was 5´3 and the overall mutation rate was 5´4 Â 10 26 per gamete per generation.

SummaryA chromogenic substrate kit for the determination of factor VIII activity (COATEST® Factor VIII) has been evaluated in five different laboratories, one of them using a semi-automated procedure. This chromogenic method was compared to one-stage clotting assays for factor VIII determination in plasmas from healthy subjects, carriers of hemophilia A, severe, mild and moderate hemophilia A as well as von Willebrand’s patients. In all these cases, a high correlation between these two methods was obtained (r = 0.96-0.99, n = 385) with a good agreement of the assigned potencies at all levels of factor VIII. A good correlation (r = 0.94) was also obtained for the levels of factor VIII after infusion of concentrates in six severe hemophiliacs or after administration of DDAVP to von Willebrand’s patients.The chromogenic method is insensitive to preactivation of factor VIII by thrombin, thus yielding valid potency assignments also in these situations.The precision was higher with the chromogenic method than with the one-stage clotting assays (C.V. = 2-5% vs 4-15%). Altogether, the new chromogenic substrate method has proven itself suitable for determination of factor VIII in plasma and concentrates.