Summary Previous studies have shown that haemorrhage in Lassa fever is associated with abnormal in vitro platelet aggregation and a high mortality. In Sierra Leone we studied platelet aggregation in healthy local subjects, patients with laboratory‐confirmed Lassa fever and febrile patients in whom Lassa virus infection was excluded. There were no significant differences in the mean platelet counts of these groups. Patients with fulminant Lassa virus infection showed a gross depression of in‐vitro platelet responsiveness to 1 and 5 μm ADP and 4 μg/ml collagen compared to other groups (P=0·0004–0·0008 when compared to healthy controls, P=0·002–0·0008 when compared to mild Lassa fever patients). When plasma samples from five of these patients were mixed 1:1 with control platelet‐rich plasma, a marked inhibition of ADP‐induced aggregation was observed. No inhibitory activity was detected in plasma obtained from healthy subjects or febrile control patients. The presence of inhibitor was strongly associated with the occurrence of haemorrhage (P=0·03), depression of platelet aggregation (P=0·004) and severity of Lassa fever (P=0·007).
The effects of two cyclically administered, triphasic, combined low dosage oestrogen and progestogen oral contraceptives on haemostasis have been compared in a longitudinal study, over 6 months, in 26 healthy females aged 16-30 years. Subjects received either Logynon (ethinyl oestradiol and Levonorgestrol, n = 14) or SHD 415G (Schering U.K., n = 12), which contains a similar dosage of ethinyl oestradiol, but in combination with a new progestogen, gestodene. Both groups showed increases in biological activities of procoagulant factors fibrinogen, X and XII and decreased activity of the naturally occurring coagulation inhibitor antithrombin III (AT-III). The majority of these changes were statistically significant (P less than 0.05 to less than 0.001), apparent after one cycle and maintained over the six cycle period. FVII activity increased in both groups, achieving statistical significance (P less than 0.01) by cycle 6 in the SHD 415G group but not in the females receiving Logynon. Protein C activity remained unchanged in both groups. Between-group comparisons showed no differences in the procoagulant factor changes, but protein C was lower (P less than 0.05) in the SHD 415G group after three cycles of therapy. These findings indicate that both triphasic oral contraceptives Logynon and SHD 415G induce increases in procoagulant factor activities which are not balanced by increased biological levels of the two most important physiological coagulation inhibitors AT-III and protein C. These prothrombotic changes are not modified by the new progestogen, gestodene.
SUMMARY Two patients with low random serum vitamin K, concentrations but with normal prothrombin times and normal biological assays of the vitamin K dependent coagulation proteins were treated with an N-methyl-thiotetrazole cephalosporin (cefotetan) postoperatively. Four to six days later both patients developed a prolonged prothrombin time and a noticeable and specific lowering of the clotting activities of factors II, VII, IX and X, though the serum vitamin K, concentrations remained unchanged. Crossed immunoelectrophoresis of prothrombin showed the appearance of a second peak corresponding to descarboxyprothrombin (PIVKA II). These abnormalities corrected after vitamin K administration. These data are consistent with the hypothesis that cephalosporins with an N-methyl-thiotetrazole side chain inhibit the hepatic utilisation of vitamin K but that this only causes hypoprothrombinaemia when liver reserves of vitamin K are low.
A recurrent theme in studies of the pathology of fatal Lassa fever in man is the lack of histological lesions to explain disordered cell function and death. Recently, we demonstrated the existence of a factor in the plasma of patients with Lassa fever which markedly inhibits the aggregation responses of normal platelets in vitro. To assess whether this factor could mediate more global cellular dysfunction, we studied the effects of Lassa plasma on the respiratory burst of neutrophils. Thirteen of 15 samples from patients in the acute phase of Lassa fever profoundly inhibited the amount of superoxide generated by normal neutrophils in response to the chemotactic peptide, f-met-leu-phe (FMLP) (mean superoxide generated = 54.7 +/- 6.1% of control). In contrast, eight of nine samples from patients who had infections other than Lassa fever enhanced the neutrophil response to the peptide. All Lassa samples which inhibited the ADP-induced aggregation responses of normal platelets inhibited the neutrophil response to FMLP. Unlike the effect on platelets, however, the inhibition of neutrophils was only apparent when the cells were stimulated within 5 min of exposure to the plasma. The inhibition of neutrophils is not due to either interference with FMLP-neutrophil binding or an effect on the NADPH-oxidase, suggesting a suppression of signal transduction. Our data suggest the inhibitory factor in Lassa plasma has global effects on cellular function, and may play a central role in the pathogenesis of this often fatal illness.
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