Intravascular Clotting After Endotoxin in Rabbits With Impaired Intrinsic Clotting Produced by a Factor VIII Antibody

Abstract

A rabbit model in which intrinsic clotting was selectively impaired by injection of a human factor VIII antibody was used to evaluate the mechanism of endotoxin-induced intravascular clotting in cortisone-treated rabbits. Three groups of animals were studied: a control group given factor VIII antibody followed by saline; a second control group given an inert material followed by endotoxin; and an experimental group given factor VIII antibody followed by endotoxin. The following parameters were measured: 125I-fibrinogen kinetics, fibrinogen levels, factor VIII, factor VII, factor V, WBC, platelets, and hematocrit. The kidneys were examined for deposition of fibrin. Mean values for factor VIII at the time of injection of the second test material and mean values for fibrinogen consumed in the 6 hr after the second injection were as follows: antibody-saline group, 8.5% and 11.0 mg/kg; control material-endotoxin group, 90% and 29.6 mg/kg; and antibody endotoxin group, 7.0% and 32.7 mg/kg. Factor V, factor VII, granulocytes, and platelets fell in both groups of animals given endotoxin. One animal in each group given endotoxin developed gross renal cortical necrosis. These data establish that selective impairment of the intrinsic clotting reactions does not reduce the amount of clotting induced by a single injection of endotoxin in the cortisone-treated rabbit.

Disseminated Intravascular Coagulation and Related Syndromes: A Clinical Review

“…Endotoxin (bacterial coat lipopolysaccharide) is capable of inducing a granulocyte release of procoagulant or coagulation-activating enzymes, of directly converting Factor XII to Factor XIIa, may induce a platelet release reaction, and may cause en dothelial sloughing with subsequent exposure of sub endothelial collagen. [161][162][163][164][165][166] Any one of these insults may independently initiate an episode of acute DIC; however, what is most likely clinically seen is a sum mation of several or all of these events in patients with endotoxemia and DIC. Table 9 depicts the clinical consequences of activating Factor XII to Factor XIIa in an episode of DIC.…”

Direct Evidence for Hageman Factor (Factor Xii) Activation by Bacterial Lipopolysaccharides (Endotoxins)

“…Rabbits, depleted of factor VIII of the extrinsic clotting system with heterologous antibody, demonstrated a fall in fibrinogen levels after injection of endotoxin that equalled the drop found in normal rabbits. In fact, one of the factor VIII-depleted rabbits developed a generalized Schwartzman reaction (12). The use of lysozyme to block contact activation of Hageman factor in vivo failed to block DIC of the generalized Schwartzman reaction in endotoxin-treated rabbits (5), although lysozyme, together with vitamin K analogues did inhibit DIC after the injection of liquoid (1,13).…”

Pathophysiology of Generalized Intravascular Coagulation

“…Furthermore, the inhibition of Hageman factor activation by lysozymes did not prevent GIC after endotoxin injection [162], whereas lysozymes inhibited GIC induced by Liquoid, indicating the primary activation of Hageman factor by Liquoid [158,160,165]. If endotoxin was injected into rabbits with an impaired intrinsic coagulation system, GIC still occurred [231]. The cited experiments demonstrate the minor role of contact factors in the activation of GIC by endotoxin.…”