Quantitative Aspects of Blood Coagulation in the Generalized Shwartzman Reaction: 1. Effects of Variation of Preparative and Provocative Doses of E. Coli Endotoxin

Abstract

The generalized Shwartzman reaction (GSR) is induced in rabbits by two properly spaced intravenous injections of bacterial endotoxin and is characterized by the occurrence of bilateral renal cortical necrosis. This report describes the quantitative changes in the coagulation mechanism in response to variation of preparative and provocative doses of E. coli endotoxin and of the interval between injections. It also correlates the coagulation changes with the pathologic findings of renal cortical necrosis.Renal cortical necrosis was induced in 34 of 49 (70 %) of rabbits using 0.100 mg/kg of endotoxin as the preparative (first) injection and 0.200 mg/kg 24 hours later as the provocative (second) dose. Four hours after the preparative injection white blood cells and platelets fell significantly while fibrinogen, prothrombin time, and Factors V and VIII fell slightly. At 24 hours all determinants except the platelets had recovered and the white cells, Factor V and fibrinogen had risen to significantly higher levels than baseline. Following the second (provocative) injection of endotoxin, a precipitous fall in all factors occurred. Maximal changes developed two hours after the second injection for white cells and platelets and by four hours for the coagulation factors; at this time kidneys show fibrin. By 48 hours all factors except the platelets had returned to 24 hour levels (table I). Rabbits given 0.100 mg/kg of endotoxin and normal saline 24 hours later did not develop cortical necrosis of kidneys or reduction in levels of any of the coagulation factors or platelets (table 11).With 0.1 mg/kg of endotoxin as the preparative dose, the effect of variation in the provocative dose at 24 hours was studied. With 0.2, 0.1, 0.05 mg/kg provocation renal cortical necrosis was observed in 60-100 % of animals. Rabbits given 0.01 mg/kg of endotoxin, or saline, as the second injection did not develop the GSR. Coagulation changes were measured four hours after the provocative injections. With doses of endotoxin of 0.025 mg/kg and greater there was a significant fall in white cells, platelets and each of the coagulation factors measured. With 0.01 mg/kg there was a significant decrease in Factors 11, V and VIII but no significant fall in white cells, platelets or fibrinogen. With saline all of the measured factors rose (table V). Changes in fibrinogen following different provocative doses are demonstrated in fig. 5. Renal cortical necrosis did not occur until a fall in fibrinogen of 66 mg/100 ml was produced.The effect of varying the preparative dose was studied. Groups of rabbits were given either saline, 0.001 mg/kg, 0.01 mg/kg or 0.1 mg/kg endotoxin preparation and all animals received 0.1 mg/kg endotoxin 24 hours later. With saline or 0.001 mg/kg endotoxin as preparation no GSR occurred.

Production of Fibrinogen Following an Endotoxin Injection

“…Several investigators have reported data showing that the fibrinogen level in other species also doesn't change for some hours after endotoxin injections. Rabbits given relatively heavy doses of endotoxin intravenously have no change in the fibrinogen level for over 6 hr, but it is increased twofold by 24 hr (3,4,14,15). In humans, intramuscular injection of typhoid vaccine (1) or of en-dotoxin (16) caused a slight drop in the fibrinogen level during the first few hours, followed by an increase starting after the 12th but before the 24th hour.…”

Effect of Heparin on Endotoxin-Induced Thrombocytopenia

“…The generalized Shwartzman reaction was produced in the classical manner (5). Animals received two intravenous injections of endotoxin (0.1 mg/kg) 24 hr apart.…”

Induction of Intravascular Coagulation and Renal Cortical Necrosis in Rabbits by Simultaneous Injection of Thorotrast and Endotoxin

“…It is now widely accepted that the generalized Shwartzman reaction (GSR) results from induction of intravascular coagulation (McKay, and Shapiro, 1958 ;Kleinmaier, Goergen, Lasch, Krecke and Bohle, 1959;Rodriguez-Erdmann, 1964;Hjort and Rapaport, 1965 ;Corrigan, Abildgaard, Vanderheiden and Schulman, 1967). As classically produced, the reaction requires intravenous injection of two doses of endotoxin administered at least 6 hours apart with the optimum interval being 12-24 hours (Thomas and Good, 1952).…”

“…As classically produced, the reaction requires intravenous injection of two doses of endotoxin administered at least 6 hours apart with the optimum interval being 12-24 hours (Thomas and Good, 1952). Studies on the role of each injection have indicated that although the initial (preparative) injection activates the coagulation mechanism to a slight degree its major effect is to impair the function of the reticuloendothelial system (RES) (Benacerraf and Sebestyen, 1957;Lee, 1962;Levin and Beck, 1966;Corrigan et al, 1967). The second (provocative) dose of endotoxin is then cleared less efficiently as are the intermediates of the coagulation process and fibrin itself.…”

“…The second (provocative) dose of endotoxin is then cleared less efficiently as are the intermediates of the coagulation process and fibrin itself. Massive intravascular clotting results in the formation of large amounts of fibrin which, in rabbits, is deposited in the glomerular capillaries, thus leading to the pathologic hallmark of the GSR, renal cortical necrosis (Rodriguez-Erdinann, 1965 ;Levin and Beck, 1966;Corrigan et al, 1967). Recent studies from this laboratory have demonstrated that the quantitative changes in the coagulation mechanism and the incidence of renal cortical necrosis are dependent upon a critical relationship between the endotoxin dose used in each of the two injections (Corrigan et al, 1967).…”