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The activity of the extrinsic pathway inhibitor (EPI), which is the factor-Xa-dependent inhibitor of the factor VIIa-tissue thromboplastin complex, was serially determined in 13 patients with postoperative/posttraumatic septicemia, and compared to the activity of antithrombin (AT), heparin cofactor II and protein C (PC). In the survivors (n = 8), initial low values for all the inhibitors normalized during recovery. In the demises (n = 5), a progressive increase in EPI activity was observed until death, whereas progressive decreases were observed for the other inhibitors. No correlation was found between the inhibitor values and the endotoxin concentration. We conclude that EPI activities are increased in the late course of fatal septicemia. Apparently, a large EPI-AT gap is a severe prognostic indicator in such patients.

This report describes studies on the activation of coagulation factor VII (FVII) and the inhibition of the extrinsic coagulation pathway in acute ischaemic heart disease. FVII and the inhibitor of the tissue thromboplastin-FVII complex, called extrinsic pathway inhibitor (EPI), were determined in plasma from 68 patients and compared to findings in 37 normal individuals. The mean FVII amidolytic activity, the mean FVII clotting activity, as well as the FVII clotting/FVII amidolytic ratio were not significantly different in the patient groups as compared to the controls. The fraction of FVII clotting activity that is sensitive to phospholipase C, 'the FVII-phospholipid complex', was 8% in controls, 19% (P less than 0.05) in patients with acute myocardial infarction, 15% (n.s.) in angina pectoris and 13% (n.s.) in heart failure/arrhythmia patients. The 'FVII-phospholipid complex' was highly significantly correlated to triglycerides in plasma in patients with acute myocardial infarction (r = 0.88, P less than 0.001) and angina pectoris (r = 0.89, P less than 0.001). The mean EPI levels were significantly increased in patients with acute myocardial infarction (132%), angina pectoris (134%), and heart failure (150%) as compared to the control population (110%). The FVII clotting/EPI ratio was significantly decreased both in patients with acute myocardial infarction and heart failure, whereas the FVII amidolytic/EPI ratio was significantly decreased only in the heart failure group. Apparently, in patients with acute ischaemic heart disease, a moderate increase in the procoagulant activity is accompanied by a marked increase in the anticoagulant activity of the extrinsic coagulation pathway, suggesting a balanced activation system.

The incidence of myosatellite cells associated with "white" and "red" muscle fibres of the parietal muscle and "red" fibres of the craniovelar muscle was estimated by quantitative electron microscopy in the Atlantic hagfish (Myxine glutinosa, L.). Myosatellite cell nuclei constitute 3, 11 and 23% of the total number of nuclei inside the basal lamina of the three types of muscle fibres, respectively. However, the total number of nuclei is highest in "white" fibres, most of the nuclei belonging to striated muscle cells. Myosatellite cell profiles in transverse sections constitute 23, 41 and 61% of the number of muscle fibre profiles of the three types, respectively. The intervals between adjacent myosatellite cells are approximately 135 micrometer in "white" fibres, approximately 55 micrometer in "red" parietal fibres, and only approximately 25 micrometer in craniovelar fibres. Since craniovelar fibres are also comparatively thin, myosatellite cells constitute a significant fraction of the volume inside the basal lamina in these fibres. The myosatellite cells are approximately 30-50 micrometer long and up to 5 micrometer thick. Some myosatellite cells possess few organelles, whereas others appear to contain many free ribosomes, granular endoplasmic reticulum, prominent Golgi apparatus and lysosome-like bodies.

Extrinsic coagulation pathway inhibitor may be an important regulator of haemostasis to prevent thrombosis after tissue damage. The functional activity of this inhibitor was determined using a chromogenic substrate assay, and compared to the activities of antithrombin, heparin cofactor II and protein C during the perioperative period of elective hip replacement (n = 28), cholecystectomy (n = 11), and vascular surgery (n = 5). Peroperatively, all the inhibitors decreased rather similarly and to the same degree as the decrease in albumin concentration. The decreases during hip surgery were about 2-fold the decreases observed during cholecystectomy. A significant peroperative increase in extrinsic pathway inhibitor activity was observed in vascular surgery, probably due to a bolus injection of heparin. Antithrombin, heparin cofactor II and protein C levels normalized on days 3-5 postoperatively in all three patient groups. Sustained low levels of extrinsic pathway inhibitor were observed on postoperative days 1 to 7 in hip surgery patients. Apparently, extrinsic pathway inhibitor is not an acute phase reactant. In uncomplicated surgery, the decreases of the coagulation inhibitor levels are mainly due to hemodilution.

We have previously shown that addition of adsorbed plasma to a mixture of TP and FVII reduces the amount of subsequently added FX that can be activated. We now report that this inhibitory effect of plasma is increased dramatically by first incubating TP and FVII with a minor amount of FX. This results in a progressive loss in the ability of TP-FVIIa to convert subsequently added FX to FXa. An assay system quantitating the inhibitory effect of 1 microliter of heated, citrated plasma is described. Optimal inhibition is obtained when the initial amount of FX added is about 0.00125 U, which is 1/16 of the amount used as reagent to measure remaining TP-FVIIa. FVII and FX must be removed from test plasma prior to assay. The inhibitory activity is reduced more by BaSO4 adsorption than by heating plasma to 56 degrees C for 15 minutes. Gel filtration of plasma separates three distinct fractions with inhibitory activity.

The well-known coagulation inhibitors antithrombin and protein C, and the more recently described inhibitors, heparin cofactor II and extrinsic pathway inhibitor, were measured in plasma during a 7-day observation period, from patients with pneumonia (n = 13), and in stroke patients with infarction (n = 9) and haemorrhage (n = 9). In patients with pneumonia, elevated fibrinopeptide A levels and subnormal antithrombin and protein C levels suggested some degree of consumption of the inhibitors. Later, an increase was observed for all the inhibitors, but was most conspicuous for heparin cofactor II which reached high normal values. C-reactive protein, initially markedly elevated, decreased rapidly. This finding suggests that heparin cofactor II might act as a delayed acute phase reactant. In stroke patients only small, not statistically significant, changes occurred during the observation period, except for heparin cofactor II which increased in patients with haemorrhagic stroke.

We have evaluated the quantitative relationship between lipopolysaccharide (LPS, endotoxin), fibrinopeptide A (FPA), antithrombin (AT), protein C (PC) and extrinsic pathway inhibitor (EPI) in plasma from 39 consecutively admitted patients with systemic meningococcal disease (SMD). The most severely ill patients with fulminant meningococcal septicemia (n = 13, 6 dead) had significantly (p less than 0.01) higher plasma levels of LPS and FPA and lower levels of PC and AT on admission as compared with the less severe clinical presentations (n = 26, 1 dead). The levels of EPI on admission were significantly (p less than 0.05) higher in nonsurvivors vs survivors with fulminant septicemia. As the disease progressed, the levels of LPS, FPA, AT and PC declined, while the levels of EPI increased. Three of six nonsurviving septicemic patients had levels of EPI greater than 200% within 16 hours of admission vs two of 30 survivors (p = 0.02). The results suggest that increasing levels of LPS in SMD elicit increasing consumption coagulopathy, contributing to the organ pathophysiology. The kinetics of EPI, inhibiting the thromboplastin-FVIIa-FXa complex, differs markedly from the kinetics of AT and PC i.e. increases as opposed to decreases.