In four children with haemophilia A and antibodies to factor VIII, 18 bleeding episodes were randomized for treatment with factor VIII concentrate (30 units/kg) and 18 for treatment with a prothrombin-complex concentrate (prothrombinex) given in a dose of 30 units of factor IX/kg. Treatment with prothrombinex was associated with a better clinical response, a significantly greater shortening of the kaolin partial thromboplastin time and significantly lower incidence of post-infusion increase of levels of factor VIII antibodies. Although treatment with factor VIII concentrate was clinically successful in 15 episodes, treatment failures occurred in three instances leading to parental request for withdrawal from study in two families.
The recovery and initial half-disappearance rate of factor VIII procoagulant activity (VIIIC) and procoagulant antigen (VIIICAg) were studied in 9 haemophilia A patients following infusion of factor VIII concentrates to varying plasma VIIIC levels. While VIIIC recovery was independent of dose, the VIIICAg recovery varied in a dose-dependent fashion. The excess of VIIICAg relative to VIIIC found in the factor VIII concentrates (VIIICAg/VIIIC ratios of 1.9–3.1) was not observed in plasma samples taken after low level infusions (plasma VIIIC < 1 U/ml) but a significant excess of VIIICAg was observed in higher level infusions. The VIIICAg recovery of post-infusion plasma was not increased by treatment with phospholipase C.
SummaryA factor VIII inhibitor has been found in a patient with an unusual combination of factor VIII-related properties. The inhibitor is directed specifically against the clotting activity (VIII :C) of the factor VIII complex. It behaves in a similar fashion to high responding inhibitors of factor VIII seen in haemophilia A patients and it was characterised as an immunoglobulin of the IgG class. Laboratory results from the patient and his family show considerable variation of factor VUI-related properties between various individuals. Overall, the data suggests the co-existence of haemophilia A and von Willebrand’s disease in the family and the presence of both diseases in the patient.
The ratio of factor VIII coagulant activity (VIIIC) or antigen (VIIICAg) to that of factor VIII related antigen (VIIIRAg) was measured in 15 normals, 21 obligatory and 23 possible carriers of hemophilia. Factor VIII coagulant was measured on fresh plasma samples whereas antigenic properties were measured on frozen and thawed samples. In obligatory carriers only, the mean level of VIIICAg was significantly lower than VIIIC and there was a tendency for low VIIICAg levels to be associated with raised VIIIRAg levels. Using both ratios, 13 obligatory carriers were outside the normal tolerance ellipse. In possible carriers, neither ratio showed superior discriminating power. In reference laboratories that perform carrier studies on stored or transported specimens, measurement of VIIICAg/VIIIRAg is a suitable test for diagnosis of carriers.
Chromatography on Sephadex G-200 of the prothrombin complex concentrate, prothrombinex (Px) showed it to have inhibitor and potentiator fractions when tested by the non-activated partial thromboplastin time (NAPTT). The inhibitory effect was related to the heparin content of Px, as it was removed on ECTEOLA-cellulose. The potentiator fraction clotted fibrinogen and this could be inhibited by hirudin. Thrombin-like activity of this fraction was shown using chromogenic substrates. The effect of the potentiator fraction in the NAPTT was markedly enhanced by platelets. Diluted Px and the potentiator fractions caused aggregation of washed platelets which could be inhibited by hirudin. Aggregation was independent of the prostaglandin pathway, as it occurred in washed aspirin-treated platelets. Neither diluted Px nor potentiator fractions aggregated platelets in platelet rich plasma. Infusion of Px was followed by a rise in β-thromboglobulin (β-TG) in 2 of 3 patients two minutes after infusion. This rise could not be ascribed to the presence of β-TG in Px or to the heparin present in Px. These findings suggest that Px has a thrombin-like activity and that its mode of action in patients with factor VIII antibodies may result from its effect on platelets and their interaction with coagulation enzymes.
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