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To determine the transmissibility of human T-lymphotropic virus types I and II (HTLV-I and HTLV-II) via transfusion, persons who, from 1983 to 1989, received blood components donated by persons who subsequently tested anti-HTLV-I-positive were evaluated. It was found that 16 (30%) of 54 evaluable recipients of transfused cellular components became infected with one of the HTLVs: 8 had HTLV-I and 8 had HTLV-II. Forty percent of platelet recipients and 28 percent of red cell recipients acquired infection. The rate of transmission of HTLV-I and HTLV-II was significantly correlated with storage age of red cell units prior to transfusion: 47 percent for red cells stored 14 days (p < 0.01). Multiple confirmatory serologic tests performed in 46 anti-HTLV-I enzyme immunoassay-negative recipients revealed that HTLV infection could not be excluded in 3 recipients of blood components from HTLV-II-infected donors. Polymerase chain reaction established HTLV-II infection in one recipient, and the other two recipients could not be classified with respect to HTLV infection status. It appears that some HTLV-II-infected transfusion recipients will not be detected by existing HTLV-I antigen-based reagents. If it is deemed necessary to initiate or continue look-back programs to detect transfusion transmission of HTLV-II infection, it is suggested that the current testing algorithm be modified in selected cases.

In a pilot study designed to evaluate the performance of supplemental hepatitis C virus (HCV) tests, 146 consecutive HCV enzyme immunoassay (EIA)-reactive samples (0.98% of 14,949 donors) were comparatively evaluated with two sets of supplemental tests: HCV antibody neutralization/c100-3 peptide EIA and the first-generation HCV recombinant immunoblot assay (RIBA). Of these samples, 68.5 percent were positive and 17.8 percent were negative on both supplemental assays. Nineteen samples were discordant. Eleven samples were positive on one assay (9 on neutralization/peptide, 2 on RIBA) and negative or indeterminate on the alternate supplemental test, but reacted with two additional HCV antigens outside the c100-3 region in a second-generation dot immunoblot assay. The dot immunoblot assay was used as a reference and reactive samples were considered confirmed. The remaining eight discordant samples were indeterminate or negative on either assay and did not react on the dot immunoblot assay. These data indicate a 0.74-percent prevalence of HCV exposure detected by reactivity with the c100-3 antigen in blood donors in southern Louisiana.

A multicentre study was undertaken in order to determine the reliability of the methods of assay of F VIII:C and the position of the peak value obtained after infusion of F VIII:C concentrates. Blood samples were drawn before and 10, 30 and 60 min after injection of F VIII concentrates in six haemophiliacs in one of the centres. Coded, frozen plasma samples were dispatched to the laboratories of the other four centres. F VIII:C was determined by different one-stage methods using the same international standard but with different activators. The results of the different laboratories differed widely and no agreement was reached on the existence of a lag period. To reach a valid conclusion not only the same sample has to be analysed, as in this study, but also the same laboratory technique has to be used by all participating investigators. To reach agreement on in vivo recovery and on elimination curves for different F VIII concentrates multicentre studies must be based on reliable methods of assay.

This report was presented at the June 1983 meeting of the Blood Transfusion National Consultative Commission at the French Ministry of Health. Clinical and epidemiological data on AIDS as well as problems raised by the lack of specific tests for screening of blood donors were briefly summarized. Out of 49 AIDS patients recorded in France up to April 1983, only one had a history of previous blood transfusion given in Haiti, 4 years before the clinical onset of the disease. Blood donors, all Haitians, had no sign and symptom of AIDS. Retrospective review of 2 300 hemophiliacs followed up in France until April 1983 disclosed no AIDS. However, in 6 patients, the following features, more or less associated, were found to be present: thrombocytopenia, neutropenia, micropolyadenopathy, splenomegaly, hypergammaglobulinemia and low OKT4/OKT8 ratio. No clear correlation could be found between these abnormalities and the origin, commercial or national, of the coagulation factor concentrates used for the treatment. Three main recommendations were proposed: -- information of blood donors and experimental evaluation of some non specific screening tests, in the at risk donor population. -- more cautious use of coagulation factor concentrates -- reduction of importations aiming at complete national self sufficiency concerning factor VIII concentrates.

A bleeding diathesis is described which is phenotypically indistinguishable from hemophilia A and which has been transmitted as a dominant trait in three generations of women in a North Carolina kindred. The abnormal phenotype is characterized by clinical mildness and slightly abnormal clotting time, prothrombin consumption, and partial thromboplastin time. Bleeding time, platelet count, clot retraction, tourniquet test, and prothrombin time are normal. Concentration of factors I, II, V, VII, IX, X, and XII are normal, while factor VIII activity is reduced to 2%-5% of control values. De novo synthesis of factor VIII does not occur after transfusion; factor VIII-related antigen is normal; patients'plasmas aggregate platelets normally in the presence of ristocetin, and a typical protein pattern is seen when a chymotryptic digest of cryoprecipitate of the proband is examined by SDS-polyacrylamide gel electrophoresis. Six possible genetic explanations are entertained. Balanced X-autosomal translocation of hemophilia A heterozygotes has been excluded by cytogenetic analysis of metaphase chromosomes. Classes von Willebrand's disease (vWd) is probably excluded on the basis of the laboratory data, and extreme lyonization of hemophilia A heterozygotes on probabilistic grounds. The genetic possibilities which cannot be excluded include a previously unrecognized variant mutation at the vWd locus, a dominant mutation at the hemophilia A locus on the X chromosome, and dominant mutation at a hypothetical fourth locus involved in factor VIII synthesis and control.

Summary The symposium has drawn attention to several risks inherent to multiple infusions with Factor VIII concentrates. The incidence of antibodies to Factor VIII is approximately 12 per cent, 20 per cent of which are low responders and can be regularly treated. Multiple plasmapheresis and porcine Factor VIII concentrates are useful to treat high titer inhibitors. The porcine material induces a severe thrombocytopenia which could possibly be alleviated if the concentrate is prepared with the polyelectrolyte method. The high incidence of B and non A non B hepatitis in the hemophilic population is recognized. Persistant elevation of transaminases is a matter of concern that has lead several groups to perform liver biopsies. Various pathological patterns are found and the principle of liver biopsy in hemophiliac is controversial since the benefit for the patient is doubtful. An abnormally high incidence of hypertension is reported. Its relationship with the number of infusions is suggested. No evidence of accompanying abnormal kidney functions is present. Yet, various anti-serum protein antibodies are found in multitransfused hemophiliacs, the most frequent being anti Gm. Evidence for the presence of circulating immune complexes following transfusions is given both by radioimmunologic tests for the detection of immune complexes and by the presence of elevated levels of complement split products.

The workshop emphasized contributions of genetic engineering in providing reagents and techniques for diagnosing and monitoring HIV infections. Despite a variety of tests for specific antibodies, virus antigens and nucleic acids no consistent serum profile has emerged that correlates well with virus life cycle or clinical course. HIV infections are a great deal more complex than hepatitis B infections where diagnosis and prognosis are very accurately based on serologic profiles. HIV generates at least 15 virus proteins all of which are immunogenic. The workshop emphasized studies on immunogenicity of the proteins. Full understanding of the virus life cycle and the clinical course of disease may require in-depth studies of the production and immunogenicity of the virus-directed catalytic and regulatory gene products. Fortunately, all of these reagents can be produced through biotechnology. The new techniques described in the workshop will allow expanded studies to proceed rapidly.

In order to determine the relationship between different doses of factor VIII and their clinical effect,70 children with severe hemophilia A treated with single doses of cryoprecipitate were studied. Plasma factor VIII levels were tested by a one stage assay on samples taken before, and 30 and 60 min. post-infusion. Clinical failure was defined as an absence of clinical improvement or the occurrence of bleeding in another site within 24 hours post-treatment. The relationship between plasma factor VIII levels or doses injected in u/kg and clinical result followed an exponential curve. Calculated from 153 factor VIII recoveries, plasma factor VIII levels of 0.35 and 0.52 u/ml corresponded to 95 and 99% satisfactory treatment, respectively. The same clinical result was obtained with 20 and 31 u of factor VIII/kg when studied in 1043 infusions of lyophilized cryoprecipitate. The in vivo recovery being 0.015 u factor VIII activity/ml for 1 u/kg injected, these dosages provided plasma factor VIII levels of 0.30 and 0.47 u/ml respectively. Since home treatment is largely based on single infusions of factor VIII, it is suggested that most current bleedings can be adequately treated with a dose of factor VIII providing a plasma factor VIII activity of 0.30-0.35 u/ml.

Increasing physical activity of hemophilic children has resulted in more frequent fractures. Within the last ten years, fourteen severe hemophiliacs (8-19 years)sustained femoral fractures. Four of these hemophiliacs had an inhibitor. Eight were the result of minimal trauma. There was no obvious correlation in these eight cases with prolonged immobilisation and/or treatment with steroids. Co-existing knee hemarthrosis or thigh hematoma often led to a delay in the diagnosis of the fracture. Metaphyseal fractures(8 cases) were treated by plaster cast (4) or, skin or pin traction (4) with good anatomical result and normal union. Replacement therapy was given in 3 cases for 3 days and in 1 case for 2 weeks. No complication occurred in any of the non transfused patients(4). Epiphyseal and femoral shaft fractures were treated by skin or pin traction (3) or internal plate fixation (2)associated with replacement therapy for at least 2 weeks. Unsatisfactory anatomical result was obtained in three cases. One impacted fractured neck of femur was discovered on X-ray examination 3 weeks after trauma. Guide lines for orthopedic and medical treatment of femoral fractures in hemophiliacs are suggested according to the anatomical feature.

A simple and reproducible method has been developed for rapidly isolating and purifying antibodies to Factor VIII from the plasma of both haemophilic and non-haemophilic patients. The one-step separation of these immunoglobulins makes use of the high affinity binding of staphylococcal cell wall protein A with the Fc region of the human γG1, 2 and 4 subclasses but not with the γG3 subclass. Plasma, as little as 0.5 ml, can be chromatographed on protein A Sepharose CL-4B gel columns. The majority of the plasma proteins, including IgG3, are not bound to the protein A, and are eluted as the first peak at neutral pH. Bound proteins are eluted as a second peak at pH 2.4. Plasmas from ten haemophilic and ten non-haemophilic patients with antibody to Factor VIII have been fractionated by this method. Without exception, the anti-factor VIII activity was bound to the protein A gel and thus eluted in the second peak. The yield of antibody was 70-80%. It is concluded that the great majority, if not all, of the antibodies to factor VIII belong to one or more of the IgG subclasses 1, 2 and 4 and can therefore be efficiently isolated by protein A chromatography. The plasma of a patient with antibody to factor V was also fractionated by protein A gel with similar results.

A high incidence of anatomical alterations of the patellar cartilage is observed in the chronic knee arthropathy of hemophiliacs. A systematic investigation of the role of an abnormal femoro-patellar joint in this knee arthropathy was undertaken. Fifty five knee joints in 38 children and 33 knee joints in 17 adults were studied. Clinical evidence of a femoro-patellar dysfunction was present in 21 children and 6 adults. Pain was the major symptom and this pain often made physiotherapy impossible. A permanent flexion deformity of the knee was frequent. The natural history of this syndrome was documented by regular X-Rays and was correlated with age, number of hemarthrosis, and associated anatomical abnormalities. Surgical procedures were performed in 5 cases in order to improve the knee function and relieve pain : 2 patellectomies, one section of the external patellar ligament and 2 condylar remodelling. After a follow up period of 6 months to 2 years, the clinical and functional results remained questionnable.

In the modern context of hemophilia care the boarding school for hemophiliacs has become a comprehensive center capable of recognizing and adapting to the needs of hemophiliacs through a diversified structure and a multidisciplinary approach. In and out patient care are provided. The duration of stay varies from days to years according to the common project of the child, his parents, and the institution. An educational program for both hemophiliacs and parents has been developed. Since 1972,90 children ranging in age from 10 to 17 participated in the training for self-treatment. Eighty per cent succeeded and guidelines for optimal training were drawn considering age, psychological status and parents involvment. Since 1974 105 families participated in the program. Among 64 families whose children were not involved in self-treatment, 32 are treating their child, 11 were unsuccessful (5 with children under the age of 4, 6 for major psychological problems) and 21 had insufficient attendance. Twice a month, groups of 3-4 families meet successively for an hour with a nurse, a physiotherapist, a physician and an educator. The last two staff members moderate free discussions rather than teach. This training carried out over several months induced profound beneficial changes in the family’s approach to hemophilia.

A comparison of nine commercial and non-commercial Factor VIII preparations was made. They consisted of llyophilized cryoprecipitate, 4 intermediate and 4 high purity concentrates. Protein, Fibrinogen, Factor VIII complex, IgG, anti-A and anti-B antibody levels were measured. Factor VIII:C content varied from 4-7 u/ml in cryoprecipitate, 12-31 u/ml in intermediate and 21-40 u/ml in high purity concentrates. These three categories of Factor VIII preparations can be better defined by 2 ratios: u FVIII/mg proteins and u F VIII/mg fibrinogen. They were respectively < 0.5 and < 1 in cryo, 0.5-1 and 1-3 in intermediate purity concentrates, > 1 and > 3 in high purity concentrates. The F VIII :C/F VIII : AG ratio ranged from 0.3 to 0.6 in any preparation. The F VIII:C/F VIII :VWF ratio was always lower than 1.Each preparation was injected to several classic hemophilia A patients for treatment of minor hemorrhages. The peak of activity was always found 1 hour post-injection and the recovery ranged from 80 to 105%. The Factor VIII half-life ranged from 10 to 12.5 hours. No significant differences in half-life or recovery was found, and the clinical efficacy was similar. With the exception of fibrinogen load, all products carry similar risk for hepatitis, anti-IgG immunization and hemolysis. The differences lie in the ease of injection, the price and the yield of Factor VIII from starting plasma. Nevertheless, high purity concentrates should be used when high doses are reauired for surgery or treatment of patients with inhibitor.

Training for home treatment has profound psychological implications. This study was undertaken to determine the optimal time in the hemophilic child’s development to begin this training. Nineteen preadolescents and 31 adolescents were trained during short weekly sessions and followed for a year. They also had interviews with a psychologist. During this one year period, parents of both groups were invited to participate in information sessions including technical training and informal discussions. Eleven of 12 preadolescents whose parents participated were successful in self-treatment whereas only 1 of 7 whose parents did not participate succeeded. Even when parents were not actively present during the training period, the adolescents had a success rate of 75%. In both groups, a positive psychotherapeutic effect was observed but since preadolescent were more flexible, an organizing psychological process was induced which involved both their approach to the disease and the child-parent relationship. The parents benefited from the information program, relieving their anxiety and gaining a better intellectual and gemotional approach to hemophilia. Although the adolescents were highly successful, it is suggested that the training be started during preadolescence with active help from the parents. Then, maximum benefit and success rate would be expected.

In the last two experimental campaigns, the low aspect ratio NSTX has explored physics issues critical to both toroidal confinement physics and ITER. Experiments have made extensive use of lithium coatings for wall conditioning, correction of non-axisymmetric field errors and control of n = 1 resistive wall modes (RWMs) to produce high-performance neutral-beam heated discharges extending to 1.7 s in duration with non-inductive current fractions up to 0.7. The RWM control coils have been used to trigger repetitive ELMs with high reliability, and they have also contributed to an improved understanding of both neoclassical tearing mode and RWM stabilization physics, including the interplay between rotation and kinetic effects on stability. High harmonic fast wave (HHFW) heating has produced plasmas with central electron temperatures exceeding 6 keV. The HHFW heating was used to show that there was a 20–40% higher power threshold for the L–H transition for helium than for deuterium plasmas. A new diagnostic showed a depletion of the fast-ion density profile over a broad spatial region as a result of toroidicity-induced Alfvén eigenmodes (TAEs) and energetic-particle modes (EPMs) bursts. In addition, it was observed that other modes (e.g. global Alfvén eigenmodes) can trigger TAE and EPM bursts, suggesting that fast ions are redistributed by high-frequency AEs. The momentum pinch velocity determined by a perturbative technique decreased as the collisionality was reduced, although the pinch to diffusion ratio, V pinch/χϕ, remained approximately constant. The mechanisms of deuterium retention by graphite and lithium-coated graphite plasma-facing components have been investigated. To reduce divertor heat flux, a novel divertor configuration, the ‘snowflake’ divertor, was tested in NSTX and many beneficial aspects were found. A reduction in the required central solenoid flux has been realized in NSTX when discharges initiated by coaxial helicity injection were ramped in current using induction. The resulting plasmas have characteristics needed to meet the objectives of the non-inductive start-up and ramp-up program of NSTX.

Summary A clinical, immunologic and virologic work-up was undertaken in 425 symptom free multi-transfused patients with haemophilias or hemoglobinopathies. Patients were entered into 5 groups according to the type of blood product they received : domestic Factor VIII (group 1), a mixture of domestic and imported Factor VIII (group 2), imported Factor IX (group 3), domestic Factor IX (group 4) and washed red blood cells (group 5). A lymphopenia below 1 000 mm 3 was observed in 10 patients and was associated with other immunologic disturbances in 8. All groups of haemophiliacs had elevated T suppressor lymphocytes (TS) as compared to controls and patients in group 2 only had a significantly higher TS counts and lower TH/TS ratio than other haemophilic groups. IgG serum levels were significantly higher than control in all groups of patients and higher than haemophilic groups in group 2. Nine patients had cutaneous anergy always associated to other immunologic abnormalities. A correlation between treatment intensity and immune dysfunction was observed in patients treated with Factor VIII. The overall incidence of anti lymphadenopathy associated virus (LAV) IgG antibodies was 45%. The highest incidence was observed in group 2. Lymphadenopathies, abnormal skin tests and lymphopenia was detected at a significantly higher rate in LAV antibody positive subjects. This study has shown the prominent role of LAV in the occurrence of immunologic disturbances in multitransfused patients. However, allogenic proteins, present in Factor VIII but not in Factor IX preparations, seem to play a role of immuno-compromising agent. The interplay between LAV and additional factors possibly leading to AIDS remains to be analyzed.