SummaryTo elucidate the mechanisms triggering disseminated intravascular coagulation (DIC) in shock, acidosis was produced in dogs by intravenous infusions of lactic acid over a period of 4 h. As the pH of the blood dropped, the blood pressure increased and the heart rate fell. The platelet counts dropped and whole blood clotting times shortened. The partial thromboplastin times and prothrombin times decreased as did the r-times and maximal amplitudes of the thrombelastograms. Simultaneously, the levels of prothrombin, fibrinogen, factors V and VIII decreased with time in acidosis. There was no evidence of a systemic activation of the fibrinolytic system. The euglobulin lysis times increased as did the thrombin times and there was no lysis observed in the thrombelastograms.Thrombi in the lungs, liver, spleen and kidneys, together with the coagulation changes indicated that the infusion of acid produced DIC, with the changes being similar to those produced in shock. The glomeruli were especially affected and the pictures were identical to those described in kidneys of animals having experienced a generalized Sanarelli-Shwartzman phenomenon.A pH value of 7.20 or lower appeared to be a potent trigger of intravascular coagulation. The lower the pH, the more thrombi were found in the tissues. The consumption of clotting factors and thrombus formation thus corresponded to the degree of acidosis.A generalized fibrinolytic state was induced using Streptokinase, after a 4 h period of acidosis and 1 h of compensation with sodium bicarbonate. Streptokinase was infused along with human euglobulin fractions on the basis of the streptokinase tolerance test of each dog’s blood and plasma. Thrombolysis was maintained for 3-4 h and this was reflected in the reduction of fibrin deposits in the tissues. Of 100 glomeruli counted/dog’s kidney, the average containing fibrin was 44 ± 11% after acidosis and 0.4 ± 0.3% after thrombolysis.

SummaryThe clinical course of a young patient is described who developed a thrombophlebitis migrans associated with pulmonary embolism after a pneumonia. Circulating antibodies against fibrinogen were found, and the possible mechanisms of the formation of these antibodies, as well as the possible role of these antibodies in the development of the thrombophlebitic process are discussed. A combined intravenous therapy with heparin and steroids in high doses was successful in eliminating a further antibody production and clotting.

The pathophysiology of sepsis and septic shock is extremely complex and ultimately involves every physiological pathway. The initiating event is the entrance of endotoxin or similar substances into the blood which initiates the release of multiple mediators. These are designed to react locally and to protect the organism. Their constant release, however, sets in motion up- and down regulations, ultimately resulting in "metabolic anarchy". Tumor necrosis factor alpha and other cytokines trigger several systems, especially coagulation to yield DIC, and the complement system. Many treatment modalities have been developed, most recently those which substitute inhibitors of various systems. Antithrombin III concentrates and potentially protein C concentrates are designed to arrest DIC. C1-esterase inhibitor concentrates should intercept the activation of the complement system and the contact phase of coagulation and its relationship to kinin generation. Even newer approaches entail antibodies to tumor necrosis factor alpha or endotoxin itself. The complex process of sepsis will undoubtedly require a multifaceted therapeutic approach.

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SummaryBy using glass wool absorption followed by elution in strong salt solution and various precipitation methods and DEAE cellulose column chromatography, Hageman factor was purified from bovine plasma. Physico-chemical properties were studied in native protein and in 6 M urea (denatured) which was used in order to prevent monomer - polymer conversion. S°20,w was 7.07 in 0.1 M KC1 and 5.84 in 6 M urea. The intrinsic viscosity by Kragh’s method was 0.0540 ml/g inNaCl-phosphate buffer and 0.0815 ml/g in 6 M urea. Partial specific volume (v) by method based on amino acid residues in undenatured protein, was 0.724 cc/g. By using differential sedimentation equilibrium in 6 M urea-H20 and 6 M urea - D20 solution, v was determined as 0.740 cc/g. In urea, molecular weight (MW) was 142,000 as determined by meniscus depletion method. Similar values were obtained for nondenatured and denatured protein by Sephadex gel filtration, from amino acid composition using Brand’s method and Schachman’s equation. For undenatured and denatured Hageman factor, molar frictional ratios (f/fo) were 1.39 and 1.58, axial ratios were 5.0 and 7.0 and estimation of diffusion constant (D°20, w) based on S-rate, MW and v, gave values of 4.45 x 10-7 and 3.88 x 10-7 cm2/sec respectively. Our data indicate that the molecule was unfolded in 6 M urea solution. Two N-terminal groups, glycine and valine, were demonstrated by Edman procedure. Carbohydrate analysis revealed the following: hexosamine 0.8%, protein- bound hexose 1.9%, fucose 0.19% and sialic acid 0.35%. Isoelectric point was determined as 7.9 by electrofocussing technique. This protein migrated with gamma globulin on electrophoresis. Hageman factor was found to be a powerful immunogen. Anti Hageman factor reacted with both a plasma and a serum protein but not with purified IgG.