Protein C deficiency resulting from possible double heterozygosity and its response to danazol

A unique family with protein C (PC) deficiency is described. The proband had a history of renal vein thrombosis as a newborn and iliofemoral thrombosis at the age of 6 years. After 6 months of heparin treatment, discontinuation of anticoagulation therapy was accompanied by persistent hypofibrinogenemia with increased fibrinogen consumption. With continuous infusion of heparin, fibrinogen turnover normalized, and the child has remained free of thrombosis. Both the immunologic level of PC and the functional activity measured by amidolytic assay were moderately reduced (47% and 34%, respectively). Functional activity of PC measured by its anticoagulant activity was disproportionately lower (14%). A 3-year-old asymptomatic sibling had a similar disproportionate reduction of PC anticoagulant activity compared with the amidolytic activity or immunologic level. The mother demonstrated type I PC deficiency with a proportionate reduction in immunologic protein levels (59%), anticoagulant activity (52%), and amidolytic activity (46%), whereas the father had type II PC deficiency with normal immunologic protein levels (102%), normal amidolytic function (98%), but a low anticoagulant function (50%). An abnormal PC molecule was detected by two-dimensional immunoelectrophoresis in the father and two children. These data are consistent with the hypothesis that the children are doubly heterozygous for two different types of PC deficiency inherited from each of the parents. A 14-day trial of danazol in the proband resulted in a rise in the PC antigen concentration from 66% to 98% but no change in PC anticoagulant function.     

Lymphadenopathy-associated virus antibodies and T cells in hemophiliacs treated with cryoprecipitate or concentrate

Evidence for exposure to lymphadenopathy-associated virus (LAV) was investigated in 48 patients with hemophilia, 15 of whom had been treated exclusively with single-donor cryoprecipitate. The prevalence of antibodies to LAV in all patients was 53% in 1983 and 63% in 1984, while in patients treated only with cryoprecipitate, the prevalence was 31% in 1983 and 40% in 1984. Patients treated with any concentrate had a seroprevalence of 65% in 1983 and 77% in 1984. Seropositive patients were more likely to have a significant reduction in the ratio of helper to suppressor T cells, absolute numbers of helper T cells, and T cell function in vitro. Seven of 18 patients who were seronegative in 1983 had seroconverted by 1984. The relative risk of seroconversion for patients using any concentrate since 1981 compared with those using cryoprecipitate only was 3.9 (P = .04). Nevertheless, the rate of conversion in the latter group was 18% per year.     

Effect of recombinant human interleukin-6 (rhIL-6) and rhIL-3 on hematopoietic regeneration as demonstrated in a nonhuman primate chemotherapy model

Using a recently developed hepsulfam-induced pancytopenia model in rhesus macaques, we have studied the effects of recombinant human interleukin-6 (rhIL-6) and rhIL-3 on marrow regeneration. Control animals were given hepsulfam (1.5 g/m2 by a single 30-minute intravenous [i.v.] injection, n = 4), while study animals received hepsulfam followed by rhIL-6, rhIL-3, or a combination of rhIL-6 and rhIL-3 (n = 3 per study group). Each cytokine was administered by once- daily subcutaneous (SC) injection (15 micrograms/kg/d) for 3 weeks beginning the day after chemotherapy (days 2 through 22). Mean platelet counts in control animals were < 100,000/microL on days 15 through 24, with 50% of the counts < 50,000/microL and two of four animals requiring platelet transfusion. In the rhIL-6- and rhIL-6/rhIL-3- treated groups, the nadir mean platelet counts were 164,000 +/- 58,700/microL and 162,300 +/- 23,800/microL, respectively, and occurred on day 15. Platelet counts in the rhIL-3-treated group were similar to those in controls. Mean absolute neutrophil counts (ANCs) < 1,000/microL occurred on days 10 through 29 in control animals, days 8 through 15 in rhIL-6-treated animals, and days 6 through 8 and 13 in rhIL-6/rhIL-3-treated animals. The frequency of ANCs < 500/microL was significantly less in the rhIL-6- and rhIL-6/rhIL-3-treated groups versus control groups (2.7 +/- 0.6 and 2.0 +/- 1.0 vs 7.0 +/- 1.4 occurrences, respectively; P < .05). rhIL-3-treated animals had ANCs similar to those in controls; one animal died with septicemia on day 21. Monkeys receiving rhIL-6 were significantly more anemic during the cytokine administration period; however, the anemia resolved by day 24. Coadministration of rhIL-3 and rhIL-6 partially corrected the anemia. The data indicate that rhIL-6 prevents significant thrombocytopenia and shortens the neutropenic period in this chemotherapy model.     

Adenosine dialdehyde and nitrous oxide induce HL-60 differentiation

Adenosine dialdehyde and nitrous oxide, specific S-adeno- sylhomocysteine hydrolase and methionine synthetase inhibitors, respectively, induced differentiation of the human promyelocytic cell line HL-60. Their effect did not appear to be mediated through changes in transmethylation or decreased S-adenosylmethionine synthesis because (1) there was little correlation between the concentrations of adenosine dialdehyde that induced differentiation and those that changed the ratio of the intracellular concentrations of S- adenosylmethionine to S-adenosylhomocysteine, and (2) inhibition of methionine adenosyltransferase by cycloleucine did not induce differentiation. The differentiation induced by adenosine dialdehyde was prevented by homocysteine and that by nitrous oxide was inversely related to the medium methionine concentration. This suggested that differentiation was secondary to decreased methionine synthesis.