One of the aims of research in the area of thrombosis has been to design an effective anticoagulant that would function in a predictable and direct manner. In evaluating the role of coagulation in sepsis we used factor Xa blocked in the active center with [5-(dimethylamino)1- naphthalenesulfonyl]-glutamylglycylarginyl+ ++ chloromethyl ketone (DEGR-Xa). We infused 1 mg/kg of DEGR-Xa together with LD100 concentrations of Escherichia coli (4 x 10(10) organisms/kg) into five baboons. As controls, we infused E coli alone into five baboons. The inflammatory, coagulant, and cell injury responses to E coli of both the treated and control groups were lethal and were similar in every respect except for the complete inhibition of the consumption of fibrinogen in the DEGR-Xa group. The half life of DEGR-Xa was approximately 10 hours and 2 hours, as determined by isotopic and enzyme-linked immunosorbent assays, respectively. These results for the first time demonstrate that, although coagulation occurs in E coli sepsis, fibrin formation per se did not influence the lethal outcome in this model. These results also show the effectiveness of DEGR-Xa as an anticoagulant and raise the possibility that it could serve as an alternative to anticoagulants currently in use.

Previous studies showed that infusion of C4b-binding protein with sublethal Escherichia coli (E. coli) in the primate produced a consumptive coagulopathy followed by microvascular thrombosis and renal failure. The first objective of this study was to characterize the pathophysiology and mechanism of this phenomena following infusion of both these agents with emphasis on defining the role of free protein S. The second objective was to examine the relevance of this model to the hemolytic uremic syndrome. Infusion of C4b-binding protein alone reduced free protein S and decreased platelet concentration to 20% of baseline, whereas infusion of the C4b-binding protein/protein S complex did not. There was no activation of other inflammatory or coagulant factors. Infusion of sublethal E coli alone produced a transient inflammatory response with no reduction of free protein S. However, coinfusion of C4b-binding protein with sublethal E coli reduced free protein S and produced a thrombocytopenia, anemia, and a microvascular thrombotic response, whereas infusion of the C4b-binding protein/protein S complex with sublethal E coli did not. Studies comparing the effects of neutralizing (S-163) and nonneutralizing (S-145) antibodies with protein S coinfused with sublethal E coli produced similar contrasting results. Therefore, we concluded that neutralization of free protein S, and not some other property of C4b-binding protein influenced by protein S, accounted for this microvascular thrombotic response. This response is similar to the hemolytic uremic syndrome characterized by thrombocytopenia, anemia, shistocytosis, and renal glomerular thrombosis with uremia. Comparison of the respective renal histopathologic appearance supports this conclusion. This raises the possibility that inhibition of protein S activity (possibly by one of the forms of C4b-binding proteins) might be one of the factors contributing to microvascular thrombotic disorder, such as the hemolytic uremic syndrome.

In a study comparing indium-111 platelet scintigraphy and two-dimensional echocardiography as methods of identifying left ventricular thrombi, the results obtained with both techniques were verified at surgery or autopsy in 53 patients--34 with left ventricular aneurysms, and 19 with mitral-valve disease. Left ventricular thrombi were found at surgery or autopsy in 14 of the patients with aneurysms and in none of those with mitral-valve disease. Thirteen of 53 echocardiograms (25 per cent) were technically inadequate and excluded from the analysis. In the group with aneurysms, the sensitivity of scintigraphy in detecting thrombi was 71 per cent, and that of echocardiography was 77 per cent. The specificity of scintigraphy was 100 per cent, and that of echocardiography was 93 per cent. We conclude that indium-111 platelet scintigraphy and two-dimensional echocardiography have useful and complementary roles in the detection of left ventricular thrombi. Both these noninvasive techniques can be used to monitor therapy.

SUMMARY Indium-111 ("'In) bound to 8-hydroxyquinoline can be used to label platelets without impairing their ability to participate in active thrombosis. The purpose of this study was to identify intracardiac thrombi using "'In platelet scintigraphy. Twenty-nine patients were studied. Twenty-one had discrete left ventricular aneurysms (group 1). The remaining eight patients (group 2) had normal or minimally narrowed coronary vessels (< 50%) and a global ejection fraction of 54 ± 14% (mean i SD) without segmental dysfunction on contrast ventriculography. Six of the eight patients with insignificant coronary disease had severe mitral valve disease requiring surgery. Each intravenous injection contained 3.4 ± 1.6 X 109 platelets labeled in a solution of acid citrate dextrose and saline (1:7, pH 6.5) with 454 ± 144 ,Ci (mean ± SD) "'In complexed to 8-hydroxyquinoline with a final labeling efficiency of 67 ± 17%. Platelet recovery at 15 minutes was 37.8 + 14.5% (mean i SD; n = 15). Imaging was performed in the anterior, left anterior oblique 450 and left lateral views (the right anterior oblique 450 view was included in all except patients 1-5 in group 1) on the day of injection and at 1-2-day intervals for a maximum of 8 days. In group 1, nine patients had abnormal areas of increased activity within the left ventricle. Four required aneurysmectomy and had left ventricular thrombi; a fifth died and at autopsy evidence of a thrombus was found. In four patients (the only patients in whom these data were obtained), surface thrombus "'In activity was at least 9.7 times greater than that of blood, noninvolved myocardium and deeper aspects of the thrombus. Twelve patients with aneurysms had normal scintiphotos. Six required aneurysmectomy and were negative for thrombi. All the patients in group 2 had negative platelet scintiphotos. The six patients who required mitral valve replacement had no thrombi at surgery. Therefore, the diagnostic accuracy of platelet scintigraphy (both groups) in the 17 patients in whom surgical or postmortem confirmation of thrombi could be obtained, five of whom had positive scintiphotos, was 100%. We conclude from this preliminary study that "1'In platelet scintigraphy promises to be a reliable method for the identification of left ventricular thrombi.INDIUM-111 ("'In) is a gamma-emitting radionuclide that emits two photons per disintegration with energies of 173 and 247 KeV and has a half-life of 67 hours. It is well suited for scintigraphic imaging. When bound to 8-hydroxyquinoline, it forms a lipidsoluble compound that is an effective platelet label and does not appear to affect the ability of the cell to participate in thrombus formation.' Therefore, platelets labeled in this way seem suitable for the detection of hematologically active intracardiac thrombi.Thirty to 70 percent5"8 of patients with left ventricular aneurysms, proved at autopsy or surgery, have mural thrombi. In clinical studies, systemic emboli occur in 6-13%5 9, 10 of patients with aneurysms, and the incidence is even higher...

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