Description of compensated and uncompensated disseminated intravascular coagulation (DIC) responses (non-overt and overt DIG) in baboon models of intravenous and intraperitoneal Escherichia coli sepsis and in the human modelof endotoxemia: Toward a better definition of DIC

Objective: Work toward a better definition of disseminated intravascular co agulation (DIC) by characterizing the difference between compensated and un compensated responses of the hemostatic system to inflammatory stress in ba boons and human subjects using global coagulation and molecular marker assa ys of hemostatic, inflammatory, and endothelial perturbation. Design: We conducted prospective evaluation of the response of baboons to i ncreasing concentrations of intravenous Escherichia coli, human subjects to intravenous endotoxin, and baboons to intraperitoneal E. coli. Setting: Animal laboratory and medical intensive care facilities, Universit y of Oklahoma Medical School laboratories. Subjects: Cynocephalus baboons; normal healthy male human subjects (age, 24 -37 yrs). Measurements and Main Results: Global coagulation assays, white blood cell counts, and molecular marker assays (ELISA) of components of the inflammato ry and hemostatic systems, neutrophil release products, and endothelial inj ury. A fall in both fibrinogen concentration and platelet counts indicated a decompensated hemostatic response to inflammatory stress (ie, overt DIC). These responses were observed 2-6 hrs after intravenous infusion of 10(9) and 10(10) colony-forming units (CFU)/g of E. cell and after implantation o f 10(11) CFU/g of E. coli into the peritoneal cavity. However, 6 hrs after E. coli challenge, these tests were much less reliable as markers of overt DIC because the fibrinogen underwent an acute phase response and the platel et count fell and remained depressed for 48 hrs in the face of a coagulopat hic response that was already beginning to resolve, as reflected by a risin g fibrinogen concentration. This lack of reliability was particularly evide nt in the E. coli peritonitis studies, in which one third of the animals re covered, one third remained sick for up to 14 days, and one third died. In contrast, fibrin degradation products and the molecular markers thrombin /antithrombin, soluble fibrin monomer, protein C, and activated protein C/i nhibitor complexes responded consistently in a dose-dependent manner regard less of the length of time after challenge. These variables exhibited this dose response to 10(6) and 10(8) CFU/g of E. coli in absence of a fall in f ibrinogen concentration. This was defined as a compensated hemostatic respo nse to inflammatory stress (ie, non-overt DIC). The values of these variabl es correlated closely with rising concentrations of markers of neutrophil a ctivation (elastase/infinity 1 antitrypsin) and endothelial injury (soluble thrombomodulin). This was particularly evident in the human response to en dotoxin, in which there was abundant evidence of hemostatic marker response in absence of a fall in platelet or fibrinogen concentration, both immedia tely after endotoxin infusion (first stage, 0-8 hrs after endotoxin) and la ter (second stage, 12-48 hrs after endotoxin). Conclusion: Global coagulation tests are most useful in detecting overt con sumptive coagulopathy (overt DIC) near the time of challenge or injury (1 t o 6 hrs). Molecular markers can detect and grade the degree of hemostatic s tress of a non-overt consumptive coagulopathy (nonovert DIC). These markers correlate with degree of endothelial cell injury and reveal a reperfusion injury stage (second stage) in the human endotoxin model of compensated hem ostatic stress after all clinical symptoms have subsided and the subjects h ave returned to work.