Factor Activation

Bacterial lipopolysaccharides (LPS) I or endotoxins elicit a variety of host responses, the combination of which result in the deposition of fibrin in capillaries and disseminated intravascular coagulation (DIC). These various host responses to endotoxins have recently been summarized (1) and include: (a) aggregation of platelets and release of platelet factor 3; (b) activation of Hageman factor; (c) inhibition of fibrinolysis; (d) aggregation of leukocytes and release of intracellular constituents; (e) stimulation of the a-adrenergic receptor sites in the kidney; and (f) impairment of reticuloendothelial system function. Whereas there exists substantial experimental evidence to support most of these effects of endotoxin, the evidence for the initiation of the intrinsic clotting system by the direct activation of Hageman factor by endotoxin has been limited and indirect. Considerable indirect evidence has inferred that Hageman factor may be activated after the injection or release of endotoxin. Patients in shock from gram-negative bacteremia, but not from hemorrhagic shock, have been estimated to have decreased levels of both Hageman factor and prekallikrein (2). Increased levels of plasma kinins have, in addition, been demonstrated within 30 rain of the intravenous injection of purified LPS into human volunteers (3). Indirect evidence in vitro for endotoxininduced activation of Hageman factor has been demonstrated by the experiments of Rodriquez-Erdmann (4), who showed that LPS significantly altered the thromboplastin-generating times in plasma but had no effect on purified prothrombin. Injections of endotoxin in rabbits have led to a diminution of circulating Hageman factor levels (5, 6). However, the reduction was likely secondary to other effects of the endotoxin since treatment with vitamin K analogues, or depletion of granulocytes prevented the fall of Hageman factor levels. That the activation of Hageman factor in vivo may participate in DIC has been inferred from several studies. Injection of the Hageman factor activators sodium stearate or ellagic acid into rabbits induced DIC when accompanied by administration