Ernest W. Page

Plasma Throinboplastin Component (PTC) Deficiency A New Disease Resembling Hemophilia

Summary1. A severe hemorrhagic disease, characterized by a prolonged whole blood coagulation time due to the delayed formation of thrombin, has been described. The patient with this disease was found to have normal plasma concentrations of all the previously described coagulation factors. 2. The corrective factor in normal plasma or serum can be removed by barium sulfate adsorption. A method for the partial purification and concentration of the patients missing factor has been outlined. The defect in the patients blood may be corrected by the addition of plasma free of previously described thromboplastin components (e.g. platelet-free hemophilic plasma), as well as by small amounts of tissue thromboplastin. The name plasma thromboplastin component (PTC) has been assigned to this previously undescribed coagulation factor.Summary 1. A severe hemorrhagic disease, characterized by a prolonged whole blood coagulation time due to the delayed formation of thrombin, has been described. The patient with this disease was found to have normal plasma concentrations of all the previously described coagulation factors. 2. The corrective factor in normal plasma or serum can be removed by barium sulfate adsorption. A method for the partial purification and concentration of the patients missing factor has been outlined. The defect in the patients blood may be corrected by the addition of plasma free of previously described thromboplastin components (e.g. platelet-free hemophilic plasma), as well as by small amounts of tissue thromboplastin. The name plasma thromboplastin component (PTC) has been assigned to this previously undescribed coagulation factor.

Accommodation of the human placenta to hypoxia

Abstract In the perfused, term human placenta, the fetal circulation responds to hypoxia by a marked vasodilatation and to a high oxygen concentration by vasoconstriction. This is interpreted as a rapid accommodation resulting in alterations of the effective area for oxygen exchange. When terminal villi are explanted for organ culture, and the concentration of oxygen in the chamber is reduced from 26 to 6 per cent, morphologic changes occur in the syncytiotrophoblast. The nuclei, together with some cytoplasm, cluster at one pole of the villus, leaving only a thin layer of cytoplasm over the basement membrane. The distance from the intervillous space to the nearest fetal capillary is reduced by 25 per cent. In accordance with the law governing diffusion, such a change should permit a comparable increase in the quantity of oxygen transferred per unit of time. The clustering of nuclei and thinning of the syncytial covering is quite marked by 6 hours. If normal oxygen concentration is now restored, the morphologic changes are largely reversible. The changes are interpreted as a slow accommodation of the placenta to chronic hypoxia. The nuclear clustering and “naked” villi are quite identical to those observed in the majority of villi of placentas from women with pre-eclampsia or eclampsia.

ON THE PATHOGENESIS OF PRE-ECLAMPSIA AND ECLAMPSIA*

MAY I express my great appreciation of the honour of presenting this review in memory of V. B. Green-Armytage. His first publication in 1913 was a book on obstetrics and although he turned his attention in later years to problems of infertility, his earliest interests were concerned with pregnancy disorders. Your President has addressed the Royal Society of Medicine on the subject of “Pre-eclampsia and Eclampsia : The Disease of Theories” (Jeffcoate, 1966) and has encouraged me to speak on the same topic. Despite our divergent interests in cricket and baseball, a dissertation on the pathogenesis of eclampsia has been a vigorous Anglo-American sport for over a century. My intention is to assemble the pieces of a jigsaw puzzle into a cohesive pattern as I visualize it in 1972. Professor Jeffcoate said; “In assembling a jigsaw puzzle it is all too easy to delay the solution by misplacing one component; a piece coloured blue may be put in the sky when it ought to be in the sea.” I am quite sure that I will misplace a piece in the sky when it ought to be in the waste basket!

The cause of the blood coagulation defect following abruptio placentae.

Abstract Abruptio placentae is sometimes followed by a hemorrhagic syndrome which results from a sudden depletion of plasma fibrinogen. This defibrination is probably due to the escape of placental or decidual thromboplastin into the maternal circulation. This converts prothrombin to thrombin, which in turn converts fibrinogen to fibrin, and the latter is deposited spottily over a very large vascular surface, sometimes producing serious visceral lesions. The syndrome was reproduced in 18 dogs by the intravenous infusion of human placental thromboplastin. This resulted in fibrinolysin depletion, a variable reduction in prothrombin and accelerator globulin concentrations, an inability of the blood to clot, focal lesions in the liver and kidneys, and oliguria. All of these findings are sometimes encountered in severe cases of abruptio placentae. The administered thromboplastin disappeared almost immediately from the blood and was probably incorporated with the fibrin and fixed by the tissues. No fibrinolytic activity was demonstrated in the undiluted plasma samples from 10 of the dogs in which the syndrome was produced nor in 5 clinical cases of abruptio placentae. Reasons are given for rejecting the hypothesis that an activation of a plasma fibrinolytic enzyme could account for the observed reductions of fibrinogen.

Transfer of materials across the human placenta.

Abstract A tentative classification of transport mechanisms across the human placenta is proposed, based upon (a) the primary physiologic significance of the substances transferred, (b) the relative rates of transfer, (c) the actual mechanisms of transport, and (d) the equality or inequality of distribution. The proposed schema, together with some examples, is as follows: Group I.—Substances concerned with the maintenance of biochemical homeostasis or protection against sudden fetal death. Rates of transfer: Milligrams per second. Predominant mechanism of transport: Rapid diffusion. 1.1.1. Equilibrium attained.Examples: Water and electrolytes. 1.2.2. Unequal distribution due to differences in rates of removal and/or different disassociation constants of complexes formed.Examples: Oxygen and carbon dioxide. 1.3.3. Unequal distribution due to destruction by the placenta.Example: Amines. Group II.—Substances concerned primarily with fetal nutrition. Rates of transfer: Measured in milligrams per minute. Predominant mechanism of transport: Carrier systems (plus diffusion). 2.1.1. Carrier systems operating equally in both directions.Example: Glucose. 2.2.2. Carrier systems operating against the concentration gradient.Example: Amino acids. 2.3.3. Unequal distribution with resultant molecular alteration during active transport.Example: Riboflavin. Group III.—Substances concerned primarily with modifications of fetal growth and the maintenance of pregnancy. Rates of transfer: Measured in milligrams per hour. Predominant mechanism: Slow diffusion.Examples: Steroid and protein hormones of maternal or placental origin. Group IV.—Substances of immunologic importance only. Rates of transfer: Measured in milligrams per day. Mechanisms of transport: Leakage through large pores; droplet transfer by pinocytosis(?). 4.1.1. Cell transfer.Example: Red blood cells. 4.2.2. Pinocytosis (?).Example: Plasma proteins.

Amino acid concentrations in fetal and maternal plasma

Summary Fetal and maternal plasma samples, obtained at the time of cesarean section, were analyzed by column ion exchange chromatography for individual amino acids. The oncentrations of 9 individual and 3 paired amino acids, plus taurine and urea, are compared. Each amino acid with the exception of proline was found to exist in higher concentration in the fetal blood. This was found to be true when fetal and maternal blood samples were drawn simultaneously and also when maternal samples were compared to blood samples obtained from the newborn infants of other mothers. The data are presumed to be evidence favoring an active, mediated transport of the amino acids across the placental barrier. The relationship of these findings to the rate of fetal protein synthesis and to the endocrine control of the cellular uptake of free amino acids is discussed.

Cyclic biochemical changes in the human endometrium: With special reference to the fibrinolytic enzyme☆

Abstract The biochemical changes occurring in the human endometrium during a menstrual cycle have been reviewed and classified into four patterns. The amount of beta-glucuronidase parallels the estrogen curve, whereas the content of protease is greatest during the regressive phase of estrogen withdrawal. The intracellular concentration of fat and of glycogen follows the progresterone pattern, while the amount of ribonucleic acid and alkaline phosphatase present in the endometrium increases under the influence of estrogen, then declines with the addition of progesterone. A method for measuring the concentration of fibrinolytic enzyme in tissue is described. When applied to human endometrial samples, it was found that the fibrinolytic activity increased in the latter part of the menstrual cycle, regardless of progesterone influence, and was highest during the bleeding phase. The stimulative influence of estrogens and of estrogen withdrawal upon the fibrinolytic activity of uterine extracts was confirmed in rabbits. Increased activity following estrogen administration is due to an increase in total enzyme concentration and not to a reduction of antifibrinolysin. Endometrial fibrinolysin bears a relation to the fluidity of menstrual blood and might be concerned with the process of endometrial disintegration and shedding.

Human fetal nutrition and growth

A review of intrauterine nutrition of the fetus must involve the areas of fetal metabolism, placental transfer, alterations of maternal metabolism affecting the fetus, maternal nutrition, and the factors which regulate or interfere with fetal growth. These are the topics which are summarized in this review. Most of the data are derived from man, but where information is lacking the results of experimentation with mammals are discussed.

Plasma aminopeptidase activity (oxytocinase) in pregnancy and labor

Abstract The primary oxytocinase activity of pregnancy plasma is apparently due to a cystine aminopeptidase. The latter activity may be measured by a chemical procedure which utilizes the synthetic substrate cystine-di-β-naphthylamide. The results of 110 determinations during pregnancy indicate a progressive rise of this aminopeptidase activity in plasma, paralleling the oxytocinase curves obtained by biologic assay methods. Contrary to some reports, there is no decline of activity during early or late labor, parturition, or the early puerperium. The onset of spontaneous labor in women can hardly be attributed to a diminished ability of the plasma to inactivate endogenous oxytocin.

Precipitation of ventricular arrhythmias due to digitalis by carbohydrate administration.

Abstract Administration of carbohydrate orally or intravenously in seven patients at or near the point of digitalis intoxication precipitated ventricular premature beats in six patients and ventricular tachycardia in one patient. This effect is attributed to reduction in the arterial plasma potassium level after carbohydrate administration.