The use of intermediate and high purity factor VIII products in the treatment of von Willebrand disease.

Since 1985, viral-attenuated blood products have been available for the treatment of patients with hemophilia. Unfortunately, similar viral-attenuated blood products, enriched for von Willebrand factor (vWF), have not been readily available for the treatment of patients with von Willebrand disease (vWD). In the current study, we examined the clinical efficacy and in vivo properties of two viral-attenuated factor VIII products, Koate-HS and Koate-HP, in the treatment of patients with vWD. Twenty-one (21) infusions were evaluated in 17 different vWD patients (4 with type IA; 8 with Type IIA; 1 with Type IID; 4 with type III). Seven (7) patients received Koate-HS and 12 patients received Koate-HP (2 patients received both products; 1 patient was studied three times). Von Willebrand factor antigen, ristocetin cofactor, bleeding time, and the multimeric composition of vWF were determined pre- and post-infusion. Complete or partial correction of prolonged bleeding times was observed in 2 of the 6 patients tested following treatment with Koate-HS and in 7 out of 11 patients tested following treatment with Koate-HP. Surgery was performed on five of these patients, two of whom were treated with Koate-HS and three of whom were treated with Koate-HP. In the surgical patients, clinical hemostasis was achieved regardless of whether the bleeding time was corrected. We conclude that both Koate-HS and Koate-HP can be utilized successfully in the treatment of patients with vWD in spite of the lack of high molecular weight multimers of vWF in these products.(ABSTRACT TRUNCATED AT 250 WORDS)

Prenatal diagnosis of haemophilia A by factor VIII gene analysis.

Cloned factor VIII deoxyribose nucleic acid (DNA) sequences were used as probes in the prenatal diagnosis of haemophilia A. Fetal DNA from cultured amniotic fluid cells was examined for a DNA polymorphism within the factor VIII gene which marked the haemophilia A gene in the pregnant obligate carrier. The fetus was predicted to be an affected male, and the diagnosis of haemophilia A was confirmed both in utero and after termination of the pregnancy.

Prenatal diagnosis of classic hemophilia (hemophilia A) by immunoradiometric assays.

During the period from 1978 to 1983, 92 pregnancies have been evaluated by fetoscopy for the prenatal diagnosis of hemophilia A. Satisfactory fetal plasma samples were obtained in 80 instances and the diagnosis--or exclusion--of hemophilia was made by immunoradiometric assay of the factor VIII coagulant protein (VIII:CAg). The accuracy of the diagnosis established by fetoscopy has been verified after delivery or termination, and there have been no misdiagnoses resulting from laboratory error. Additional evidence for the accuracy of the analysis was the observation that the frequency of hemophilia in pregnancies of obligate carriers of the hemophilia gene, and of women whose plasma assays were indicative of the carrier state, was 29 of 59 fetuses at risk. In one case of cross-reacting material-positive hemophilia, samples obtained at fetoscopy and from the newborn infant had normal VIII:CAg levels but the infant had decreased factor VIII procoagulant activity. There were five fetal deaths resulting from fetoscopy in 55 pregnancies not intentionally terminated. Although only a small percentage of pregnant hemophilia carriers in the United States have elected to undergo fetoscopy for prenatal diagnosis, this procedure has allowed a number of pregnancies to go to term with delivery of normal males in families that were not willing to accept the risk of a hemophilic child. In eight instances, fetoscopic evaluation was sought for two successive pregnancies.

Von Willebrand factor multimer patterns in von Willebrand's disease.

The von Willebrand factor antigen (factor VIII-related antigen, VIIIR:Ag) multimer pattern has been analysed by SDS-agarose electrophoresis of plasmas from 116 patients (47 families) with von Willebrand's disease. In addition to previously recognized patterns, a subclassification was established between plasmas that had a type Ia pattern (VIIIR:Ag multimer pattern like that of normal plasma) and those that had a type Ib pattern in which there was a relative reduction in the concentration of the larger VIIIR:Ag multimers even though all multimeric forms were present. The different patterns were consistent within families and were inherited by autosomal dominant transmission. Von Willebrand's disease heterogeneity was apparent in the distribution of these plasmas: type Ia, 43 patients in 18 families; type Ib, 39 patients in 15 families; type II, 22 patients in 10 families, one of which was further classified as type IIB, one of which was type IIC, and three were IIA. Seven patients with severe von Willebrand's disease were also studied. In general, the interpretation of SDS-agarose multimer patterns corresponded to those previously obtained by crossed immunoelectrophoresis, but the former technique was more sensitive and could identify differences that were not apparent by crossed immunoelectrophoresis.

Detection of hemophilia carriers during pregnancy.

The accuracy of hemophilia A carrier detection during pregnancy has been determined using combined measurement of VIII:CAg and VIIIR:Ag. These immunoassays detect determinants that are sufficiently stable in plasma that the assays could be done on frozen samples that had been obtained when women were seen for antenatal diagnosis studies (carrier women) or for routine prenatal care (controls). A linear discriminant was calculated that best separated the data for 32 normal women and 25 obligate carriers of the hemophilia gene. Twenty-three of 25 carriers (92%) and all 32 control women were correctly identified in this analysis. The overall classification accuracy (55/57, 96%) is comparable to that obtained by VIII:C and VIIIR:Ag measurements using freshly drawn blood samples in nonpregnant individuals. This study demonstrates that hemophilia A carriers can be detected during pregnancy with sufficient accuracy that the information may be used for genetic counseling.