Antibodies to procoagulant factor VIII (anti-VIII:C) occurring in patients with haemophilia neutralise porcine factor VIII:C less readily than human factor VIII: C in vitro. Porcine factor VIII concentrate (porcine VIII) therefore has potential advantages in the treatment of such patients. Polyelectrolyte-fractionated porcine VIII (PE porcine VIII) lacks a major drawback of earlier preparations of porcine VIII in that it contains negligible quantities of platelet aggregating factor (PAF). The purpose of this study was to make a preliminary clinical assessment of the therapeutic value of PE porcine VIII. Over 6 months, 12 courses of treatment were given to four patients with circulating anti-VIII: C. Bleeding episodes treated ranged from the potentially lethal to moderately severe joint and muscle haemorrhages. Duration of courses was from 24 hrs. to more than 3 weeks. Clinical responses were strikingly good and no patient developed thrombocytopenia. Occasional mild pyrogenic-type transfusion reactions were encountered, but these were easily controlled. Dose- response relationships were most favourable in patients with low pre-infusion levels of anti-VIII: C activity against PE porcine VIII but excellent clinical responses could be obtained without achieving high plasma VIII: C levels. Multiple courses of therapy (up to 6) were given to individual patients without evidence of loss of clinical or laboratory efficacy, or an increased tendency to adverse reactions. There was no evidence of resistance in the patient who was treated daily for more than 3 weeks. Only 1 course of therapy was followed by a classical anamnestic rise in anti-VIII: C, and this course had included human factor VIII. PE porcine VIII appears to have a low immunogenic potential, and is a rational and effective therapeutic alternative for patients with anti-VIII: C.

Factor XI deficiency is a rare autosomally transmitted coagulopathy that is associated with a variable bleeding tendency. Recently there have been reports of thrombotic events following the administration of a virally inactivated factor XI concentrate (BPL) to factor XI deficient patients. We have therefore reviewed a single centre's experience of the use of factor XI concentrate over a 6-year period and compared this to our previous experience of either no treatment or treatment with fresh frozen plasma (FFP) in 103 patients. There were 156 procedures performed without haemo- static cover. The incidence of bleeding was greatest following tonsillectomy (71%) and dental extraction (Sl'h). There was a trend for bleeding complications to be associated with lower levels of factor XI but patients with all levels of factor XI suffered bleeding complica- tions. There were 38 procedures carried out under FFP cover, with only one patient suffering excessive bleeding and no serious complications. Factor XI concentrate was given to 25 patients to cover 45 episodes. There were no bleeding complications. Three patients suffered serious complications. One patient, with a previous history of cardiovascular disease, died of a myocardial infarction and a second had an ischaemic episode resulting in a %day hospital admission. These episodes both occurred on the same day as the factor XI infusion. A third patient suffered bilateral pulmonary emboli 7 weeks after a prolonged course of factor XI concentrate. These finding suggest that factor XI concentrate should be contraindicated in patients with a history of cardiovascular disease, when FFP should be used. Guide- lines for the use of factor XI concentrates should be revised, and work performed to establish the mechanism of these thrombotic events.

Circulating antibodies to factor VIII (anti-VIII, “inhibitors”) occurring in patients with hemophilia neutralize porcine factor VIII less readily than human factor VIII in vitro. Over an 18-mo period, 8 patients with anti-VIII were treated with 45 courses (297 infusions) of polyelectrolyte-fractionated porcine factor VIII concentrate (PE porcine VIII). Where no anti-PE porcine VIII was detectable, mean post- infusion rise in plasma factor VIII was 1.29 U/dl/units infused/kg. Above 13 Old Oxford units of anti-PE porcine VIII and 48 Bethesda units of anti-human VIII, there were no postinfusion rises in plasma factor VIII. Where postinfusion rises were detected, clinical responses were good and conventional methods could be used to guide dosage. Ten percent of infusions were followed by febrile reactions, but these were usually mild and decreased in frequency and severity with increasing exposure. Multiple and prolonged courses of therapy were given to some patients without evidence of loss of clinical or laboratory efficacy. PE porcine VIII could provoke anamnestic rises of anti-VIII in susceptible patients, but appeared to have a lower immunogenic potential than human VIII. PE porcine VIII is a rational and effective therapeutic alternative for patients with anti-VIII, particularly those with intermediate level inhibitors who cannot be managed effectively using human factor VIII.

Summary.A retrospective study of the natural history of factor VIII inhibitors in haemophilia A patients experienced in a single comprehensive haemophilia centre over three decades is reported. 431 haemophilia A patients of all severities have been followed-up for a total of 5626 patientyears. The frequency of inhibitors was 10% in the severe haemophilia A patients and 37% occurred in children <10 years. The majority of the patients received several products before developing the inhibitors. 59% of patients had <50 exposure days and 48% were high responders (>5 BU). An 8-year (1987-95) inhibitor-free period was seen during which all previously untreated patients were treated with an intermediate-purity factor VIII concentrate. A moderate haemophiliac with a misense mutation that has not been described in association with inhibitor is reported. Six HIV-positive patients preserved their antibody response to factor VIII even at the advanced stage of their disease.

SummaryIn a study to demonstrate the safety and pharmacokinetics (half-life and recovery) of two different method M purified AHF (Hemofil-M) concentrates processed in the USA and Spain, two different methods of factor VIII assay (one-stage clotting and chromogenic) have been compared in vivo. The study was a single centre blinded, randomised, crossover study. Twelve patients with severe haemophilia A (VIII: C <2 u/dl) were divided into two subgroups of six. None had received factor VIII concentrate within 48 h preceding the study. Twenty-four pharmacokinetic studies were performed in the 12 patients. Each subgroup received two different lots of study material (US and Spanish) at a dose of 50 u/kg seven days apart. A second randomisation was nominal potency, high: 1000 u or mid: 500 u per vial. The potency label was a one-stage clotting assay using the mega I standard. A standard pharmacokinetic study was performed over 24 h and each blinded sample was analysed in duplicate by a one-stage clotting (aPTT) and a chromogenic (Chromogenix AB; CS) assay at the Royal Free and NIBSC. Pharmacokinetic modelling was performed. The mean label for Hemofil-M using the chromogenic substrate assay was 79% that using the one stage assay (Mega I standard). The recovery was 17-28% higher measured by chromogenic compared to the clotting assay. Since most clinicians use the clotting assay, potency labelling using the chromogenic assay, will overestimate predicted Hemofil-M recovery by as much as 25%.