C Thomas Kisker

Development of blood coagulation--a fetal lamb model.

Summary: To study the normal development of blood coagulation factor activities in a growing fetus while avoiding the effects of labor and delivery, a chronic fetal lamb model was developed in which serial blood samples from 10 fetuses were studied during the third trimester of pregnancy and 24 hr after birth. Under operating room conditions with sterile technique, a polyethylene catheter to which heparin had been bound to both internal and external surfaces was inserted into the femoral artery of the fetus. The catheter was brought out through a skin pouch to the side of the ewe and enclosed in a zip lock bag. Blood samples were withdrawn from the catheter three times each week for measurement of coagulation factor activities. Levels of coagulation factor activities at birth in noncatheterized animals were not different from those found in catheterized animals except for factor IX activity which was 12% higher in the catheterized animals (0.02 < P < 0.05). The patterns of development for each of the coagulation factors were similar in all 10 animals studied. Fibrinogen, prothrombin, and factor VII show a decrease in activity early in the last trimester of pregnancy whereas other factors V, VIII, IX, X, XI, XII, and XIII show a gradual increase in activity throughout the last trimester of pregnancy. Both factors VIII and IX show a significant increase in activity (23% factor VIII and 12% factor IX) associated with the process of delivery. The levels of coagulation factor activities at birth in the lamb relative to adult sheep normals are similar to those found in humans with the exception of factor XIII. Factor XIII is at normal levels in the newborn lamb and is reported to be at levels approximately 50% of the adult level in human infants.Speculation: The development of a chronic fetal lamb preparation has allowed the construction of developmental patterns for coagulation factor activities throughout the last trimester of pregnancy. Further studies into the biology of the changes in coagulation factor activities observed and the influences of such stresses as hypoxemia and premature delivery should enhance our understanding of the bleeding neonate.

A silver-catalyzed cis-trans isomerization☆

Abstract A silver (Ag+) catalyzed conversion of 4-maleylacetoacetate and of maleylacetone to their trans isomers has been demonstrated in dilute aqueous solutions at 25°. Parallel increases in the degree of catalysis, in the ionization of adjacent (maleyl) carboxyl group, and in the enolization of the carbonyl group adjacent to the double bond accompanied elevation of the pH from 1 to 6. The conversion of maleic to fumaric acid was not catalyzed by Ag+.

Effects of Acidosis on Fetal and Maternal Blood Coagulation: A Fetal Lamb Model

ABSTRACT: The effects of fetal acidosis (mean pH 6.93) on fetal and maternal blood coagulation were measured. Test results from 10 fetal lambs and mother ewes (127 ± 2 days mean gestation) before and after fetal lactic acid infusions were compared to test results from eight control fetal lambs and mother ewes (127 ± 3 days mean gestation) before and after control glucose infusion. Significant changes found in acidotic fetal lambs not seen in control fetuses included an increase in the white blood cell count (mean 2800/mm3 before to 3600/mm3 after acidosis; p = 0.0009), a shortening of the thrombin time (mean 17.8 s before to 11.2 s after acidosis;p = 0.0001), and decreases in the activities of factor V (mean 57% before to 37% after acidosis; p = 0.0014) and factor IX (mean 35% before to 29% after acidosis;/) = 0.0128). There was also a reduction in the concentration of fibrinogen (mean 147 mg/100 ml before to 125 mg/100 ml after acidosis; p = 0.0492) but no significant changes in the levels of fibrin monomer, fibrinogen/fibrin degradation products, or antithrombin III. In vitro exposure of five different fetal whole blood samples to a pH of 6.9 for 2 h at 37°C did not result in significant changes in any of the coagulation factor activities. A significant decrease in the level of factor V was also found in the mother ewes of the acidotic fetuses (mean 141% before to 113% after acidosis; p = 0.006) and a decrease in the level of maternal factor IX approached significance (mean 119% before to 102% after acidosis; p = 0.0564). Two hours of severe fetal lactic acidosis induces changes in blood coagulation, but not the usual findings of disseminated intravascular coagulation. Corresponding decreases in factor Y and IX activities in the mothers of acidotic fetal lambs suggest the liberation of a mediator capable of crossing the placenta and influencing maternal coagulation.

Blood coagulation changes following hypoxemia in the near-term fetal lamb.

Summary: The effects of severe hypoxemia on blood coagulation factor activities and other physiologic parameters were examined in ten near-term chronically catheterized fetal lambs (135–140 days gestation). Six lambs were subjected to a mean Po2 of 13.8 ± 1.4 mmHg for 60 min. The other four served as controls. Before, during and after hypoxemia, the white blood cell count, hemoglobin, hematocrit, platelet count, pH, Pco2, Po2, mean arterial pressure, heart rate, norepinephrine and epinephrine were measured. Measures of coagulation factor activities including platelet counts, partial thromboplastin times, prothrombin times and quantitation of plasma activities for factors I, II, V, VII, VIII, IX, X, XI, XII, fibrin degradation products (FDP), antithrombin III, fibrin monomer and ristocetin cofactor activity were also done. An increase in mean arterial pressure from 48 ± 2 mmHg to 56 ± 2 mmHg, and an increase in epinephrine from 22 ± 9 pg/dl to 419 ± 199 pg/dl, and norepinephrine from 431 ± 98 pg/dl to 2408 ± 868 pg/dl occurred in the hypoxemic animals. There was also a slight decrease in the pH from 7.37 ± 0.01 to 7.32 ± 0.03 in the hypoxemic animals. The only significant change in blood coagulation factors during hypoxemia was a slight increase in fibrin monomer from 5.6 ± 0.8 ±g/ml to 12.6 ± 2.0 μg/ml. After the experiment, the animals were allowed to go to term and deliver spontaneously. Delivery occurred from 2–12 days after the experiment (mean 6 days). Blood coagulation factor activities I, II, V, VII, VIII, IX, X, XI, XII, antithrombin III, fibrin monomer, and fibrin degradation products were measured after delivery in the hypoxemic and control animals. Except for factor XII, values obtained from ten previously catheterized control fetal lambs after spontaneous delivery did not differ from the current control animals after delivery.Values on postdelivery samples for the two control groups were therefore pooled for analysis. Factors VIII, and IX were found to show increased activity during the 2 wk after delivery in hypoxemic animals when compared with controls. In contrast, the values for factors II, V, VII, X and fibrinogen showed lower activity in hypoxemic as compared to control animals during the early neonatal period. The study demonstrates that though there are no severe acute effects on blood coagulation during severe hypoxemia in the near-term fetus except perhaps transient low-grade disseminated intravascular coagulation, the episode of hypoxemia appears to alter the future development of blood coagulation factor activities during the early neonatal period.Speculation: Hypoxemia in the near-term fetus delays the normal development of prothrombin, factors V, VII, X, and fibrinogen during the early neonatal period and accelerates the development of factors VIII and IX. The differences in factor responses may help explain the variable results reported in human infants. The results also suggest that both thrombotic and hemorrhagic tendencies might be a consequence of prenatal hypoxemia.

Disseminated intravascular coagulation in a newborn infant with Listeria sepsis

D i s s E ~ i N A T E D intravascular coagulation (DIC) has been reported in the newborn infant associated with abruptio placenta, stillbirths, twin pregnancies with dead fetus, toxemia, shock states, central nervous system hemorrhage, idiopathic respiratory distress syndrome, herpes simplex virus infections, and the septicemia of many gramnegative bacteria. However, DIC associated with Listeria monocytogenes infection has not been reported in the newborn infant , although babies with Listeria sepsis may develop a bleeding disorder? We have observed an infant with Listeria sepsis who developed petechiae and abnormalit ies of coagulation consistent with the diagnosis of disseminated intravascular coagulation. Although all previously reported cases of neonatal Listeria sepsis with petechiae died, our infant was treated with heparin and survived.

Shared Management of Children with Cancer: A Quality of Care Comparison 774

The University of Iowa Division of Pediatric Hematology/Oncology has had more than 20 years of experience delivering care to children with cancer in which academic pediatric/oncologists share management with primary-care physicians. To evaluate the quality of care under this delivery system, we compared survey data from 242 shared cancer management patients with a statistically matched control sample of children from other pediatric oncology centers where cancer management is done by sub-specialists only. Survival outcomes, Goodwins Pediatric Oncology Quality of Life Scale for children with cancer, currently reported health problems, and the parents direct ratings of their childs health are not significantly different by shared or specialist management. We also compared the childrens developmental perspectives, family evaluation of care and transportation costs. From this analysis, we conclude that shared management is equal to specialist management in quality but is preferable from the familys perspective when medical and travel costs are lower. We suggest shared management also supports the transition of children with cancer back to their primary-care physician for management of the childs other medical needs and post-cancer care.

SHARED MANAGEMENT OF CHILDREN WITH CANCER: A 15 YEAR REASSESSMENT. 928

Background: In 1976, to provide access to modern treatment for children with cancer in a rural setting, a system was designed to divide treatment responsibilities between university-based pediatric oncologists and community-based primary care physicians. Under this system, the diagnosis and assignment to a treatment regimen is carried out at the university while community-based physicians delivery over 75% of the chemotherapy. Because managed care limits access to subspecialists and reduces the flexibility for collaboration between subspecialists and primary care physicians, assessment of the shared management system was undertaken.

792 COMPARISON OF DATA COLLECTION CAPABILITIES BETWEEN COMPUTER ASSISTED PEDIATRIC CANCER MANAGEMENT AND STANDARD PEDIATRIC CANCER MANAGEMENT

This three-year study was made of local and university based physician encounter records of 270 visits by 15 randomly selected computer assisted medical management childhood cancer patients and 246 visits by 14 randomly selected standard management patients. Both groups of patients were treated according to the same research protocols. The amount of clinical research data obtained through use of self-coding, self-auditing computer printed encounter records tailored to the patient-care and data collection requirements of specific protocols was compared to the yield obtained through use of a standard generalized partially structured encounter record. The computer assisted medical management encounter forms yielded 4411 (78%) physician responses to 5670 requests for coded toxicity severity information. The standard management encounter forms yielded 1469 (66%) physician responses to 2214 requests for toxicity information. The computer assisted forms requested specific coded lymph node, liver, spleen, and kidney data4050 times and the information was supplied by the physicians3640 (89.9%) of the times requested. The standard management group forms requested the same uncoded data 984 times, the physicians supplied the data 595 (60.4%) of the times requested. Clearly this computer assisted management system increases the amount of physician supplied clinical data for patients on cancer research treatment protocols.

EFFECTS OF FETAL ACIDOSIS ON FETAL & MATERNAL BLOOD COAGULATION |[lpar]|A FETAL LAMB MODEL|[rpar]|

The effects of two hours of fetal acidosis (mean pH 6.93) on fetal and maternal blood coagulation were measured. Coagulation test results from 10 fetal lambs and mother ewes (127 ± 2 days mean gestation) before and after fetal lactic acid infusion were compared with test results from 8 control fetal lambs and mother ewes (127 ± 3 days mean gestation) before and after control glucose infusion. Tests included Hb, Hct, WBC, platelet count, pH, pCO2, pO2, PT, PTT, thrombin time, fibrinogen, factors II, V, VII, VIII, IX, X, XI, XII activities, fibrin monomer (FM), AT III, and FDP levels. Significant changes in acidotic fetal lambs not seen in controls included increased WBC (mean 2800/mm3 to 3600/mm3; p=.0009), shortened thrombin time (mean 17.8 sec to 11.2 sec; p=.0001), decreased factor V (mean 57% to 37%; p=.0014), factor IX (mean 35% to 29%; p=.0128), and fibrinogen (mean 147 mg % to 125 mg %; p=.0492). There were no increases in FM or FDP and no decreases in platelet counts or AT III levels. Although there was no change in pH or lactate, a decrease in factor V was found in ewes with acidotic fetuses (mean 141% to 113%; p=.006) and a decrease in factor IX (mean 119% to 102%) approached significance (p=.0564). Fetal acidosis thus induces a hypercoagulable state in the fetus by shortening the thrombin time. Decreases in the levels of factor V and IX are also observed in both fetus and mother, suggesting the liberation of a mediator capable of crossing the placenta.

Development of chemotactic factor inactivation - a fetal lamb model.

Summary: To study the developmental pattern of chemotactic factor in-activator (CFI) activity, although avoiding the effects of labor and delivery, serial blood samples were obtained from eight chronically catheterized lamb fetuses, 13 pregnant, and 13 nonpregnant ewes. The biologic profiles of adult sheep neutrophils in response to sheep C5-derived chemotactic fractions (C5-fr) were determined by the chemotactic and lysosomal enzyme release assays. CFI activity in sheep plasma was characterized and measured by the % inhibition of C5-fr-induced neutrophil lysosomal enzyme release.The chemotactic and enzyme release profiles of sheep neutrophils paralleled those of human neutrophils. Sheep plasma was shown to contain a CFI-like activity similar to that in human plasma.Mean CFI activity was higher in the plasma of pregnant ewes as compare to nonpregnant ewes (7.60 versus 5.15%, P < 0.001). Higher CFI levels (39.5%) were shown in the plasma of chronically catheterized fetuses early in the third trimester of pregnancy (109 days gestational age). These fetal levels decreased progressively to attain normal adult levels at fetal maturity (147 days gestational age) and no significant changes were noted at or after birth. Because identical changes occurred in all chronically catheterized fetuses, a developmental pattern was defined for CFI. Control CFI levels from six acutely catheterized fetuses did not differ from those predicted by the developmental pattern. Thus, the changes in CFI activity were not related to the chronic catheterization or to events surrounding labor and delivery; rather CFI levels correlated best with fetal immaturity.CFI levels correlated inversely with ability of zymosan activated plasma to induce neutrophil chemotaxis (r = —0.96, P < 0.01), suggesting that CFI plays a major role in the regulation of leukocytes chemotaxis.These data confirm previous findings in human neonates and provide a model for future studies. Further studies into the biology of the changes in CFI activity in the fetus and the influence of such high risk factors as prematurity, fetal distress or premature rupture of membranes should enhance our understanding of the immunocompromised neonate.