C. R. Rizza

Mortality from liver cancer and liver disease in haemophilic men and boys in UK given blood products contaminated with hepatitis C

BACKGROUND Most people with haemophilia who were treated with blood products before the introduction of virus-inactivation procedures were infected with the hepatitis-C virus (HCV). However, there is little quantitative information about the long-term effects on mortality of such infection. METHODS We carried out a cohort study of mortality from liver cancer and liver disease in 4865 haemophilic men and boys in the UK. They were treated between 1969 and 1985 with blood products carrying a high risk of HCV infection, and were followed up from first recorded exposure to Jan 1, 1993. FINDINGS Based on death-certificate information, mortality was 16.7 times higher than in the general population for liver disease (95% CI 12.5-22.0; 51 deaths), and 5.6 times higher (1.8-13.0; five deaths) for liver cancer. For men and boys with severe haemophilia who were not infected with HIV-1, the cumulative risks of death from chronic or unspecified liver disease or from liver cancer in the 25 years since first recorded exposure to high HCV-risk products were 1.4% (0.7-3.0) at all ages, and 0.10% (0.01-0.7), 2.2% (0.8-6.1), and 14.3% (4.5-40.9) for those with first recorded exposure at ages under 25, 25-44, and 45 or older. For those with haemophilia and HIV-1 infection, the corresponding risks were 6.5% (4.5-9.5) at all ages, and 3.8% (2.1-6.8), 17.1% (10.0-28.5), and 18.7% (6.4-47.6) in the three age-groups. In those with severe haemophilia, age-standardised all-cause mortality was stable during 1969-84 but increased during 1985-92 in both HIV-1-infected and HIV-1-uninfected groups. Among those not infected with HIV-1, the increase in all-cause mortality resulted largely from deaths attributed to chronic or unspecified liver disease or liver cancer in men aged over 45. INTERPRETATION There is an emerging risk of mortality from liver disease and liver cancer in the UK haemophilia population in individuals both infected and uninfected with HIV-1, which probably results from infection with hepatitis C.

Importance of age at infection with HIV-1 for survival and development of AIDS in UK haemophilia population

BACKGROUND Greater age at infection with HIV-1 is known to be associated with shorter time to development of AIDS, but the size of the differences between people infected in infancy and those infected in old age has not been examined in a single large population of patients with death as an endpoint. We, therefore, investigated the role of age at seroconversion in the entire UK population of haemophiliacs. METHODS We studied 1216 HIV-1-infected haemophilia patients in the UK who were registered with the National Haemophilia Register and were alive on Jan 1, 1985. Their estimated ages at HIV-1 seroconversion ranged from 8 months to 79 years. FINDINGS 10 years after seroconversion 67% (95% Cl 64-69) of the population were still alive. Survival was strongly related to age at seroconversion (86% [82-90], 72% [68-76], 45% [39-51], and 12% [5-21] at 10 years among those patients who seroconverted at ages < 15, 15-34, 35-54, and > or = 55). This steep age-gradient in survival was not explained by deaths expected in the absence of HIV infection or by confounding with other factors such as haemophilia type or severity. The age-gradient was steeper for survival (ie, time from HIV-1 infection to death) than for time to diagnosis of AIDS, partly because survival after an AIDS diagnosis was poorer in older patients, and there was also a substantial increase in mortality among HIV-infected patients who did not satisfy the formal AIDS definition and this increase was greater in older patients. INTERPRETATION Age at infection with HIV-1 is a more important determinant of survival than has previously been appreciated. Age should, therefore, be considered in future studies of disease progression, and studies that compare people infected at different ages should provide insight into the biology of the immune response to HIV-1.

Epsilon-Aminocaproic Acid Therapy for Dental Extractions in Haemophilia and Christmas Disease: A Double Blind Controlled Trial

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.

The mode of action of antibodies which destroy factor VIII. II. Antibodies which give complex concentration graphs.

Summary. Antibodies which destroy factor VIII may follow second‐order kinetics (Biggs et al, 1972) or a more complex type of reaction may occur. The present communication concerns the complex reactions and evidence is presented which supports the hypothesis that these antibodies may react with factor VIII to form a complex with some factor‐VIII activity.

A Variant of Factor VIII Related Antigen

Summary. The factor VIII related antigen in a patient with von Willebrands disease gave qualitatively different precipitation peaks on electroimmunoassay and showed a faster anodal migration on crossed immunoelectrophoresis than antigen obtained from normal subjects, haemophiliacs and other patients with von Willebrands disease. In addition, less of the patients antigen could be recovered from ethanol precipitates and cryoprecipitates of plasma. It is suggested that the patients plasma contained an atypical form of factor VIII related antigen.

Von Willebrand factor multimer patterns in von Willebrand's disease

Summary. 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 Willebrands 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 Willebrands 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 Willebrands 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.

The Mode of Action of Antibodies which Destroy Factor VIII.: I. ANTIBODIES WHICH HAVE SECOND-ORDER CONCENTRATION GRAPHS

Summary. In 1959 Biggs & Bidwell proposed the hypothesis that the reaction between antibody and factor VIII could be interpreted as a second‐order reaction and that in antibody excess the amount of antibody present could be measured using a linear calibration graph relating the logarithm of residual factor VIII to antibody concentration after incubation for a fixed period of time. This hypothesis has been re‐examined because antibody is seldom present in excess in most routine test systems and in view of a new and attractive hypothesis put forward by Pool & Miller (1972). All the evidence seems to suggest that the original hypothesis of Biggs & Bidwell is adequate for assessing the potency of antibodies of the type occurring in many haemophilic patients.

Factor VIII gene explains all cases of haemophilia A

Using an mRNA-based method to examine haemophilia A mutations we provide an explanation for the puzzling report that half of the mutations causing severe disease are not detected by analysis of the putative promoter, exons, and most exon/intron boundaries of the factor VIII gene. An unusual cluster of mutations involving regions of intron 22 not examined earlier leads to defective joining of exons 22 and 23 in the mRNA and caused haemophilia A in 10/24 severely affected UK patients.

The Treatment of Patients who have Factor‐VIII Antibodies

A new method of measuring factor‐VIII antibodies is described. The application of this method in the study and treatment of patients who have antibodies to factor VIII is discussed.

Severe Allergic Pulmonary Oedema after Plasma Transfusion

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.