Summary. The results are reported of a pilot study and two separate double blind controlled trials of the effectiveness of epsilon‐aminocaproic acid (EACA) in dental extractions in patients with haemophilia and Christmas disease. In the major trial 31 patients were studied; 23 at Oxford and eight at Cardiff. All patients received either EACA (6 g four times daily for 10 days at Oxford or for 7 days at Cardiff) or a placebo, in conjunction with a single preoperative dose of therapeutic materials expected to raise the plasma factor‐VIII or factor‐IX level to 50%. Post‐operative therapeutic materials were withheld unless intraoral bleeding occurred. Despite the fact that plasma factor‐VIII or factor‐IX levels were, on average, lower, the number of teeth extracted larger, the amount of therapeutic concentrates less and the postinfusion plasma factor‐VIII or factor‐IX levels lower in the EACA group at Oxford, the incidence of postoperative intraoral bleeding was lower and the requirements for postoperative therapeutic materials less in the group treated with EACA. Side‐effects were not a major problem. The number of patients studied at Cardiff was too few for statistical analysis but the results were similar to those at Oxford. The total conservation of therapeutic materials at Oxford in comparison to the amount utilized before EACA was used is estimated on the basis of these results to be approximately 12 000 factor‐VIII or factor‐IX units/patient, or approximately 190 units/kg/patient, equivalent, for each patient, to the amount derived from approximately 120 blood donations. These results show that EACA in conjunction with preoperative therapeutic concentrates sufficient to raise the plasma factor‐VIII or factor‐IX level to 50% can be useful for all patients with haemophilia and Christmas disease undergoing tooth extraction. In some patients EACA therapy is contraindicated and for these patients adequate cover with therapeutic materials must be provided during the postoperative period.

SummaryFactor XI deficiency is an uncommon bleeding disorder usually manifested by excessive bleeding after surgery or trauma. Until recently the only effective therapy has been fresh-frozen plasma (FFP) infusion. We describe the efficacy and safety of a new factor XI concentrate produced from human donor plasma by a modification of the method used for antithrombin III concentrate. The mean recovery of factor XI in the circulation measured on 62 occasions was approximately 91% of the injected dose, and the mean half-disappearance-time was 52 h. The concentrate was used for 31 invasive procedures in 30 patients, including 16 patients who had a definite bleeding tendency on previous occasions, with normal haemostasis being achieved in all but 1. Only 1 patient (previously experiencing allergy to FFP) experienced adverse effects during infusion. Monitoring of liver function tests and viral antibody status in suitable patients has shown no evidence of transmission of hepatitis viruses, HIV-1 or parvovirus B19.We conclude that this concentrate provides effective treatment for patients with factor XI deficiency. Preliminary results suggest safety from virus transmission, but this needs to be established in further studies of previously untreated patients.

Desmopressin acetate may be useful in correcting defects in primary haemostasis in chronic liver disease.

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.

Factor XI deficiency is a rare bleeding diathesis found predominantly in Ashkenazi Jewish kindreds. A recent study of six Jewish patients identified three distinct mutations (Types I, II, and III) in the factor XI gene that were sufficient to fully define the genotypes of the patients. We have investigated 63 patients with factor XI deficiency and find overall allele frequencies of 44% for the type II mutation, 31% for the type III mutation, and 0% for the type I mutation. Therefore, 25% of the mutant factor XI alleles in our sample remain undefined. However, the distribution of mutant alleles is significantly different between Jewish and non-Jewish populations with hitherto undefined mutations accounting for 84% of the disease alleles in non-Jewish patients. Plasma factor XI:C levels were found to differ significantly between different homozygous and compound heterozygous genotypes and the inheritance of the II/III genotype was found to carry an increased risk of the most severe bleeding tendency.

Summary. Three patients with haemophilia suffered severe febrile reactions after transfusions of fresh frozen plasma and developed pulmonary oedema which did not appear to be due to circulatory overload. The chest radiographs were characterized by widespread patchy rounded opacities resembling bronchopneumonia. In one of the patients the reaction proved fatal; in the other two, treatment was followed by the rapid resolution of symptoms, clinical signs and the abnormal chest radiograph. In two of the patients there was evidence that the reactions might have been caused by transfer of antibodies to white cell or Gm factors from the donor to the recipient. It is recommended that haemophiliacs with a history of transfusion reactions should only be treated with concentrated preparations of factor VIII and not with fresh frozen plasma.

Orally administered dihomo-gamma-linolenic acid (DHLA) is well absorbed in man; it appears in blood after ca. 4 hr first as triglyceride ester and later as phospholipid. After sustained-dosing, DHLA penetrated membrane pools and all phospholipid components but, depending on the dosage, reached a metabolic equilibrium in 4-16 days. Intact platelets do not accumulate arachidonate following DHLA administration, and species differences occur in the capacity of animals to metabolize DHLA to arachidonic acid (AA). The rat appears to be unusual in having a very active hepatic delta5-desaturase enzyme system. Potentially antithrombotic changes in platelet function which followed the administration of DHLA to man were accompanied by a significant increase in the capacity of platelets to synthesize PGE1. Concomitant increases in PGE2 synthesis do not apparently result from an increased production of AA and suggest that DHLA, or a DHLA metabolite, interferes with the metabolism of AA. Effects on thromboxane and prostacyclin synthesis are being studied.

SummaryThe effects of orally ingested dihomo---linolenic acid (DHLA), the natural biosynthetic precursor of prostaglandin El (PGE,), were assessed in human volunteers. Single doses of DHLA (0 1-2g) increased the proportion of DHLA relative to arachidonic acid in plasma and platelets and also increased the ex-vivo capacity of platelets to produce PGE, and PGE2. More pronounced effects were observed during sustained treatment (five days to four weeks) when DHLA also accumulated in red cell membranes. These biochemical changes were accompanied by potentially antithrombotic changes in haemostatic function. The most common effect, which was consistently detected after 0 1-g single doses of DHLA or its methyl ester, was a decrease in plasma heparin-neutralising activity. Inhibition of platelet aggregation induced by adenosine diphosphate was also detected, though this was generally less pronounced. Sustained treatment in one subject also produced definite inhibition of ristocetininduced platelet aggregation. There was only one possible adverse effect-a transient cough in a subject with a history of asthma.