Louise Lang Phillips

The Fibrinolytic Enzyme System in Normal, Hemorrhagic and Disease States

The recognition that hypofibrinogenemia may be an important factor in the hemorrhagic diathesis which occurs in a number of pathological states has given rise to an increased study of this phenomenon. In many of these conditions an accompanying fibrinolysin has been reported. However, evidence as to the presence of this enzyme varies from investigator to investigator and from method to method. Therefore, a study has been undertaken to investigate as quantitatively as possible the various factors of the fibrinolytic enzyme system. Early in the investigation it became evident that an active fibrinolysin could be detected only transiently in the blood and that a large part of the discrepancy found in the literature may have been a result of the particular time at which the sample was drawn. It has been frequently observed that lysis of plasma clots at all dilutions may occur at one stage, and yet a blood sample drawn an hour later, which has a lower fibrinogen level, may show no evidence of lysis. Indirect evidence obtained from a changing profibrinolysin or inhibitor level may, therefore, give more information as to what is occurring intravascularly than does the presence or absence of an active fibrinolysis. The following set of experimental tests has been set up as a routine for examining blood from patients with hemorrhagic tendencies which are suspected to be in the field of hypofibrinogenemia or fibrinolysin. These tests have also been applied to a number of normal subjects, pregnant women, obstetrical patients with abruptio placentae, patients undergoing portacaval shunt for cirrhosis of the liver, as well as patients with carcinoma and other disease states.

Procoagulant properties of amniotic fluid.

Abstract Amniotic fluids from about 50 patients from 12 to 40 weeks of gestation have been obtained by amniocentesis and studied for procoagulant material. Some of the fluids were fractionated and concentrated by ammonium sulfate precipitation. The fluids and concentrates were able to shorten the recalcification time of normal plasma or those deficient in factors XI, IX, VIII, and VII. Plasma deficient in factor X or V was not shortened significantly. These results and others with the use of prothrombin, Stypven, and partial thromboplastin times have indicated that this procoagulant from amniotic fluid is an activator of factor X and may function in a manner somewhat similar to Russells viper venom (RVV). The factor X activator has been roughly quantitated in terms of RVV equivalents and appears to increase with the increasing period of gestation. The amount of procoagulant in clear amniotic fluid is probably insufficient to cause significant intravascular coagulation in the event of an amniotic fluid infusion but may be sufficient to promote primary hemostasis in the uterus following delivery.

A Study of Cytofibrinokinase and Fibrinolysin in Extracts of Tissue from Human Myometrium, Endometrium, Decidua, and Placenta *

Summary The presence of a fibrinogenolytic enzyme and a cytofibrinokinase has been demonstrated in extracts of human myometrium, placenta, decidua, and endometrium It is suggested that the presence of these enzymes may be partially or wholly responsible for the lack of fibrinogen which occurs in the blood stream of obstetrical patients under certain conditions, and in menstrual blood.

Changes in factor XI (plasma thromboplastin antecedent) levels during pregnancy

Abstract Factor XI (plasma thromboplastin antecedent [PTA]) has been determined in over 50 pregnant women, in 15 nonpregnant women, and in 12 women during the first 3 postpartum days. Values fell as the gestation progressed. There were no statistically significant differences between the nonpregnant women and the ones during the first trimester of pregnancy. However, the difference between the nonpregnant women and those in the second or third trimester of pregnancy was highly significant (p

Coagulation studies in the hypertensive toxemias of pregnancy

Abstract Certain indices of the coagulation-fibrinolytic systems, studied in hypertensive pregnant patients, demonstrated changes consistent with mild disseminated intravascular coagulation. The changes were more marked in severe acute hypertension and included low platelet count, lower factor V, and prolongation of prothrombin, Stypven, partial thromboplastin, and thrombin times. There was acceleration of the retarded thromboplastin-generation test (RTGT). The plasminogen levels were decreased, suggesting a secondary response to intravascular coagulation since no increase in active fibrinolysis was observed. Uncomplicated chronic hypertension revealed certain trends suggesting intravascular coagulation which probably explain or contribute to the much higher incidence of acute toxemia in this group. These include high fibrinogen, marked acceleration of RTGT, and high levels of plasminogen and fibrinolytic inhibitors.

Changes in the fibrinolytic enzyme system following intravascular coagulation induced by thrombin and endotoxin

Abstract The intravenous infusion of thrombin into pregnant and nonpregnant rats results in intravascular clotting leading to rapid depletion of circulating fibrinogen and slow activation of the fibrinolytic system. Small doses of bacterial endotoxin (0.075 mg.) injected intravenously into pregnant and nonpregnant rats results in disseminated intravascular coagulation leading to less rapid depletion of circulating fibrinogen and slow activation of the fibrinolytic system. Pregnant rats are more sensitive to bacterial endotoxin than nonpregnant rats. The lethal dose in pregnant rats is 0.4 mg. while in the nonpregnant rat it is 1.6 mg. Lethal (large) doses of bacterial endotoxin cause a more severe and rapid activation of the fibrinolytic system than small doses of endotoxin. The combination of intravascular clotting and activation of fibrinolysis may be an important factor contributing to the rapid onset of endotoxin shock in the rat. The persistence of glomerular thrombi in pregnant rats is probably due to the diminished activatability of the fibrinolytic system in pregnancy.

Hypofibrinogenemia and intrauterine fetal death

Abstract The fibrinolytic system has been studied in 69 pregnancies involving intrauterine fetal death. In 29 of these fibrinogen levels were below the normal 200 mg. per cent. Among the group with hypofibrinogenemia 60 per cent had Rh-positive blood. Therefore, hypofibrinogenemia and severe bleeding can occur in the absence of Rh incompatibility and regardless of the cause of fetal death. In 4 cases the gestational age was 16 weeks or less and in 5 cases the retention of the dead fetus was 5 weeks or less. Therefore, in spite of the fact that in the majority of cases of hypofibrinogenemia the fetus had reached an age of more than 16 weeks and had been retained for longer than 5 weeks following death, these exceptions suggest that the fibrinogen level in all women with intrauterine fetal death should be determined. Fibrinogen was not administered prophylactically in any of the cases reported here and was used therapeutically to control excessive hemorrhage in only 4 cases.

Effects of puff adder venom on the coagulation mechanism—I. in vivo

Abstract A 22-year-old man bitten on the finger by a young puff adder (Bitis arietans) showed within 2 hr a slightly low platelet count, a slightly prolonged prothrombin time and a short euglobulin lysis time. Partial thromboplastin times (PTT) were accelerated. Rats injected with 100 μg of venom per rat intravenously, or 1000 μg intramuscularly showed depressed platelet counts (not prevented by heparin), prolonged PTT and low factor VIII levels. The results suggest that the venom has a direct destructive effect on platelets and on some of the other coagulation factors, particularly factor VIII. Intravascular coagulation, if it occurred in vivo, was of only minor significance.

The efficacy of intramuscular 15 methyl prostaglandin E2 in second-trimester abortion: Coagulation and hormonal aspects

Termination of pregnancy in the second trimester is sometimes associated with serious complications. This led to clinical investigation seeking methods superior to the traditional technique utilizing hypertonic saline. Intra-amniotic administration of naturally occurring prostaglandin F2-alpha has been developed and appears to be advantageous--especially in the area of coagulation stability. This study describes a technique for intramuscular administration of a prostaglandin analogue--15 methyl prostaglandin E2. This analogue is much more potent than the natural compound. Administration to 32 patients resulted in abortion in 28. The coagulation milieu remained completely intact and all other parameters were similar to previous published data for prostaglandin administration. There were no infections in this group of patients.

Transport of radioactive sodium across the rat placenta in experimental toxemia of pregnancy

Abstract The placental permeability of rats in the third trimester of pregnancy has been evaluated by determination of the radioactivity of placenta and fetus following intravenous injection of Na24Cl. Rats that were fed a vitamin E-low diet containing oxidized cod liver oil during pregnancy had a lower placental permeability to sodium ion than control animals in the fifteenth through seventeenth days of gestation. A toxic effect of the oxidized cod liver oil diet on the trophoblast is postulated as the etiology of diet-induced experimental toxemia of pregnancy. In the early stages of the development of the generalized Shwartzman reaction in pregnant rats, placental lesions have caused a severe depression in placental permeability before glomerular thrombi have impaired sodium exchange in the kidney. The alterations of placental transport effect in rats by an oxidized cod liver oil diet are similar to those which have been reported in human toxemia of pregnancy.