Donald G. McKay

The pathologic anatomy of eclampsia, bilateral renal cortical necrosis, pituitary necrosis, and other acute fatal complications of pregnancy, and its possible relationship to the generalized Shwartzman phenomenon.

Abstract Intravascular fibrin deposition in arterioles and capillaries throughout the body is responsible for the necrosis and hemorrhage seen in eclampsia, bilateral renal cortical necrosis, and pituitary necrosis associated with pregnancy. These cases are often accompanied by severe shock, hemorrhage, and anuria. Fibrinogenopenia and fibrinolysins develop in this group of patients. It is suggested that the mechanism behind the fibrin deposition is similar to that in the generalized Shwartzman reaction. In some cases the source of “toxin” may be a bacterial infection. In some cases, particularly those associated with toxemia of pregnancy, the “toxin” may be similar to the “menstrual toxin” described by the Smiths.

Endotoxin shock and the generalized Shwartzman reaction in pregnancy

Abstract The clinical and pathologic findings in 7 pregnant patients with endotoxin shock have been presented. Escherichia coli was the most common infective organism. The syndrome occurred in 2 clinical situations; namely, (1) infected abortion, and (2) premature rupture of the membranes with chorioamnionitis and placentitis. The presence of bilateral renal cortical necrosis due to disseminated intravascular coagulation in 3 of these patients demonstrates that the human being is subject to the generalized Shwartzman phenomenon. A comparison between the response of the patient and that of the experimental animal to intravenous bacterial endotoxin has been made. Both showed marked alterations in the blood coagulation mechanism associated with disseminated intravascular coagulation and both exhibited profound, sometimes irreversible, shock. Animal experiments suggest that the shock is caused by a decreased venous return to the right side of the heart because of obstruction of the portal circulation by the liver. The obstruction may be due to vasospasm and thrombosis of the central veins of the liver. Acute cor pulmonale may also contribute to the decreased cardiac output and hence to the systemic hypotension. A general discussion of the current armamentarium in the management of these cases has been presented.

Therapeutic implications of disseminated intravascular coagulation

Abstract Disseminated intravascular coagulation is a fundamental pathogenetic mechanism which complicates a wide variety of diseases. The clinical and hematologic problem varies so greatly from one disease process to another and from one patient to another with the same disease that no standard therapy is possible. Each patient must be handled individually. The fact that disseminated intravascular coagulation is an intermediary mechanism of disease indicates that its best prevention or treatment would come from prevention or treatment of the underlying disease process. Since this is not possible at present, treatment directed at the coagulation and fibrinolytic systems is indicated. Evidence of disseminated intravascular coagulation in any disease is obtained from three sources: (1) pathologic anatomy, (2) alterations in the hemostatic mechanism and (3) clinical manifestations. All of these must be understood before therapy is undertaken. Anticoagulants (heparin and Dicumarol) and fibrinolysin activators (streptokinase and urokinase) constitute the therapeutic agents that interfere directly with the coagulation process. Replacement therapy (whole blood, plasma and fibrinogen) and fibrinolysin inhibitors (EACA and Trasylol) are indicated when clotting has ceased and activation of the fibrinolytic system is the major problem. In most diseases clotting and fibrinolysis are superimposed on each other. Actual clinical experience with the use of these agents in disseminated intravascular coagulation is still in a very early stage of development, but promising results have already been obtained. One of the important contributions of these early studies is the demonstration of a rapid return to normal of the clotting factors after heparin has been used. This is valuable information in itself because it constitutes further evidence that disseminated intravascular coagulation is occurring in the patient and in the disease process. Heparin therapy in single cases has apparently been effective in stopping bleeding and in prolonging life. The best clinical and laboratory responses have been achieved in diseases with subacute or recurrent intravascular clotting, including thrombohemolytic thrombocytopenic purpura, hemolytic-uremic syndrome, purpura fulminans and Philippine hemorrhagic fever. Symptomatic response has also been described in cases of cancer, leukemia, cirrhosis of the liver and giant hemangioma. The fears of the dangers of the use of anticoagulants in these syndromes have been exaggerated. The cases in which serious hemorrhage could in any way be attributed to the anticoagulant are practically nil. Attention has been drawn to the risk of maintaining intravascular thrombi by epsilon aminocaproic acid (EACA) in patients who have a continuing intravascular clotting even though the fibrinolytic system has been activated. Several cases of bilateral renal cortical necrosis have been reported after administration of fibrinogen and EACA. The combined use of heparin and EACA is probably safer. EACA is very useful in reducing the hemorrhage from local bleeding sites, as in prostatic resection, whether or not there is a systemic abnormality of the hemostatic process. Many of the reported good results with EACA in patients with disseminated intravascular coagulation must be viewed in the light of the local effect on bleeding sites. In many of the cases reviewed, multiple therapeutic agents have been used, and precise evaluation of the effectiveness of any single agent is obscured. With the exception of heparin therapy following pulmonary embolism, the treated cases are too few to al ow statistical evaluation of therapy. More careful clinical studies are needed to establish the effectiveness of these agents on a statistical basis.

Morphologic changes in the developing rat placenta following prednisolone administration

Summary The administration of a relatively high dose of delta-1 hydrocortisone to pregnant rats results in severe morphologic changes in virtually all of the placental tissues. As early as the fifteenth day of pregnancy, there is a marked inhibition of decidua formation and a severe decrease in decidual and “junctional zone” glycogen. In addition, delta-1 hydrocortisone inhibits trophoblastic proliferation and induces morphologic changes in the syncytial trophoblast which resemble “premature aging.” The over-all effect of these changes leads to a failure in placental growth during the eighteenth day of gestation and thereafter. The yolk sac epithelium becomes depleted of glycogen as early as the fifteenth day whereas the apical P.A.S.-positive granulations continue to increase in number until term, a process which leads to marked “clubbing” of the individual epithelial cells. These processes undoubtedly alter placental function severely and are reflected by a significant increase in intrauterine fetal death.

Pathologic Study of Intravascular Coagulation Following Incompatible Blood Transfusion in Dogs I. INTRAVENOUS INJECTION OF INCOMPATIBLE BLOOD

Abstract 1.1. The injection of incompatible blood into the dog results in disseminated intravascular coagulation. 2.2. When blood is injected rapidly intravenously, the animals die instantly with numerous small thrombi predominantly in the small pulmonary vessels but also in the liver, pancreas and gastrointestinal mucosa. 3.3. When the blood is injected slowly intravenously, the animals survive unscathed or die hours later with a few residual thrombi in the lungs and gastrointestinal mucosa. 4.4. These observations offer an explanation for the alterations in the hemostatic mechanism, sudden death, shock, dyspnea and bloody diarrhea which occur following administration of incompatible blood.

The immunologic problem of pregnancy. II. Ultrastructure of isogeneic and allogeneic trophoblastic transplants.

Abstract An analysis of the electron microscopic characteristics of ectopic implants of mouse trophoblast was carried out. Mouse ova transplanted under the kidney capsule of isogeneic and allogeneic male recipients developed into aggregates of trophoblastic giant cells. There was no histologic or electron microscopic difference between isogeneic and allogeneic transplants. Invasion of host tissue took place by expansion of the hemorrhagic mass and infiltration of trophoblastic cells between host cells. Although phagocytosis of intact red blood cells and leukocytes by trophoblast was present, no phagocytosis of renal parenchymal cells could be demonstrated. An electron-dense intercellular “fibrinoid” material was not found around the trophoblast cells or at the trophoblast-host junction. It was concluded that the trophoblast does not owe its privileged immunologic behavior to an extracellular barrier which interferes with antigen detection by the mother. It is likely that the failure of trophoblast to express transplantation antigens is due to a relative intrinsic deficit of such antigens on the cell surface.

Platelet adhesiveness in toxemia of pregnancy

Abstract Indices of platelet adhesiveness in vitro were obtained from 10 nonpregnant women, 25 normal pregnant women, 10 with essential hypertension, 10 with mild pre-eclampsia, and 10 with severe pre-eclampsia. Platelet adhesiveness in normal pregnancy was slightly greater than in the nonpregnant state but lacked statistical significance. No alteration was found in patients with essential hypertension, but in toxemia of pregnancy the indices were significantly higher than in normal pregnancy. There appears to be a direct relationship between the severity of the disease and the platelet adhesiveness index. Increased platelet adhesiveness has been interpreted as evidence of slight platelet damage. It has been suggested that platelet damage in toxemia may be caused by damaged placental trophoblast, and that it is related to a slowly progressive, low grade process of disseminated intravascular coagulation in pre-eclampsia.

Metachromasia in the endometrium

Abstract The changes in the metachromatic substance in the endometrium during the menstrual cycle have been described. Intercellular stromal metachromasia is present during the proliferative phase, diminished or absent during the early secretory phase, and reappears between the predecidual cells of the late stages of secretion. There appears to be a reciprocal relation between intercellular stromal metachromasia and edema of the stroma. Mast cells are present during the proliferative phase, diminish in number or are absent in the early stages of secretion and reappear in moderate numbers in late secretion. They are present in slightly increased numbers in hyperplasia. Metachromatic granules appear in predecidual cells in late secretory endometrium and these are probably ribonucleoprotein particles. Faint metachromasia was observed in the cytoplasm of epithelial cells in a few examples of proliferative endometrium. Intense metachromasia was present in the cytoplasm of epithelial cells in hyperplastic endometrium. This probably represents ribonucleoprotein in part but some may be mucopolysaccharide. Incubation with hyaluronidase failed to abolish any metachromasia in the endometrium.

Electron microscope studies of the absorption of lipids: II. Medium chain saturated triglycerides☆

Abstract The absorption of saturated long chain triglycerides across the jejunal epithelium of the rat has been studied by electron microscope. The absence of lipid droplets in the microvilli, the terminal web and the absence of phagocytosis of lipid droplets at the cell surface is consistent with the concept that the majority of the triglyceride is hydrolyzed in the intestinal lumen, is transferred across the cell surface as fatty acids, glycerol, and monoglyceride. Visible lipid first appears in the channels of the endoplasmic reticulum, probably as a triglyceride resynthesized from the absorbed fatty acids. As with the saturated medium chain acids, the long chain acids also produced a negative image in the electron micrographs due to the absence of the double bonds necessary to reduce osmium. The chylomicrons developed by the intestinal epithelial cells are ellipsoidal or elongated in comparison to those formed with MCT and unsaturated fatty acids, which are spherical. These unstained chylomicrons were visible only because of the formation of a tiny “membrane” immediately investing each chylomicron. These “membranes” have been interpreted as lipoprotein or phospholipid acquired by the chylomicron in its transit through the epithelial cell. One of the major differences in the absorption of LCT in comparison with other lipids is the development of large cleft-like deposits of this lipid within the cytoplasm of the epithelial cells. This ultimately causes damage to the cell as evidenced by the destruction of mitochondria and the development of “myelin” forms within the cytoplasm of some of the cells.

Pulmonary embolism and disseminated intravascular coagulation

Abstract Two patients who died suddenly of pulmonary embolism have been presented. The immediate cause of death in both was an episode of disseminated intravascular coagulation. Evidence for such a mechanism, fibrin thrombi in the capillary beds of the lungs, kidneys and gastric mucosa, was obtained at autopsy. Disseminated intravascular coagulation accounts in part for the cyanosis, dyspnea, hypotension and death in these patients and probably in many patients in whom thrombosis of the microcirculation has not been documented. The hemostatic evidence of disseminated intravascular coagulation following pulmonary embolism has been provided by Merskey and Johnson. The dramatic response of patients treated with heparin following pulmonary embolism constitutes further evidence of intravascular coagulation in this syndrome and indicates that the clotting episode in some patients is the lethal factor. It is postulated that the clotting episode is initiated by the release of thrombin adsorbed onto the fibrin, or contained within pockets of serum within the clot, at the time of impaction of the embolus against the walls of the pulmonary artery. Anoxia, endothelial damage and the release of serotonin from damaged platelets may be contributory factors.