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Biomedical subjects

M Andrew

Publications and source records attributed to M Andrew.

At least 199 records · Page 11Linked to original sources
PubMed1989

The use of indium-111 oxine platelet scintigraphy and survival studies in pediatric patients with thrombocytopenia.

We have utilized 111In-labeled heterologous platelets to investigate the mechanism of thrombocytopenia in ten children. From the scintigraphic findings, platelet survival times, and clinical information, thrombocytopenia was ascribed to decreased production or to increased destruction. Two patients were found to have bone marrow production defects. Two patients with hemangiomas were studied. In one, the hemangioma was shown not to be the cause of thrombocytopenia. In the second, the hemangioma was proven the source of platelet destruction, but was much more extensive than clinically evident. In both, surgical manipulation of the hemangioma was avoided. Six additional patients had thrombocytopenia due to accelerated destruction. In four, the spleen was shown responsible. In two, however, the spleen was shown not to be responsible for the low platelet counts, and splenectomy was avoided. Thus, 111In-platelet scintigraphy and survival studies are valuable in the classification and management of childhood thrombocytopenia. We believe that this study should be performed, when possible, in any child with thrombocytopenia where the mechanism is unclear or the therapeutic intervention involves splenectomy or resection of a hemangioma.

Adolescent↗
PubMed1988

Heparin clearance and ex vivo recovery in newborn piglets and adult pigs.

The newborn infant requires more heparin per kg body weight than the adult to achieve similar heparin plasma levels. Possible mechanisms include altered heparin pharmacokinetics and/or a decreased expression of anticoagulant activity of heparin in new-born plasma because of low levels of antithrombin III (AT-III). We measured the pharmacokinetics and the anticoagulant activity of heparin in the pig (AT-III level: 100%), in the piglet (levels of AT-III: 50% of adult) and the piglet given exogenous porcine AT-III. All pigs were bolused with 125I-heparin (25 or 100 units/kg) and blood samples collected for the measurement of 125I-radioactivity, and antifactor Xa activity. The half-life of 125I-heparin was dose-dependent and similar in pigs and piglets; however, the volume of distribution was greater in the newborn resulting in an increased total clearance compared to the pig. The anti-factor Xa activity disappeared earlier in the piglet than in the pig. Both the kinetics and the absolute recovery of anti-factor Xa activity were normalized to pig values (after correction for different volumes of distribution) when the piglets were infused with exogenous AT-III. Thus apparent heparin resistance of the newborn is due to both an increased volume of distribution and the low AT-III level which limits the measurement of the anticoagulant activity of heparin in conventional anti-factor Xa assays.

Aging↗
PubMed1988

Antithrombotic properties of heparin in a neonatal piglet model of thrombin-induced thrombosis.

The relative deficiency of antithrombin III (AT III) in neonatal plasma results in lower recovery of heparin in some assay systems. It is uncertain whether low AT III levels also limit the antithrombotic effects of heparin in this age group. We therefore compared the antithrombotic properties of heparin in mature pigs and newborn piglets, whose coagulation and inhibitor system closely resembles that of the human neonate. Animals were pretreated with saline, 10 or 25 U/kg heparin (n greater than or equal to 16 per age group and dose). Following an injection of 100 U/kg thrombin, systemic 125I-fibrinogen consumption and local 125I-fibrinogen incorporation into jugular venous stasis thrombi were measured. Significantly more 125I-fibrinogen was consumed in piglets than in pigs systemically (p less than 0.0001), as well as within the occluded vein segment (p = 0.0112), largely because heparin was less effective in piglets than in pigs. This neonatal resistance to heparin could not be explained by lower heparin levels in the newborn animals. However, pretreatment with AT III concentrate significantly improved the antithrombotic properties of heparin in this age group (p less than 0.0001). We conclude that physiologically low AT III levels reduce the efficacy of heparin in neutralizing thrombin activity in newborn piglets. We speculate that AT III deficiency may also limit the antithrombotic properties of heparin in newborn infants with thrombotic disease.

Animals↗
PubMed1988

Defective presentation to class I-restricted cytotoxic T lymphocytes in vaccinia-infected cells is overcome by enhanced degradation of antigen.

Vaccinia infection interferes with the presentation of influenza Haemagglutinin (HA) and Nucleoprotein (NP) to class I-restricted CTL. The inhibitory effect is selective for certain epitopes, and is more profound during the late phase of infection. For influenza A/NT/60/68 NP, the block is present during both early and late phases of infection, and is selective for the COOH-terminal epitope defined by peptide 366-379, having no detectable effect on the presentation of the NH2-terminal epitope 50-63. The presentation of HA is inhibited only during the late phase of vaccinia infection. For both proteins, presentation is partially (NP) or completely (HA) restored by expression of rapidly degraded protein fragments in the vaccinia infected target cell. For HA, deletion of the NH2-terminal signal sequence completely overcomes the block. For NP, either a large NH2-terminal deletion or the construction of a rapidly degraded ubiquitin-NP fusion protein partially restores presentation. These results illustrate the relationship between degradation of viral proteins in the cytoplasm of an infected cell and recognition of epitopes at the cell surface by class I-restricted T cells.

Animals↗
PubMed1988

The effect of hypoxia on platelet survival and site of sequestration in the newborn rabbit.

Thrombocytopenia occurs frequently in sick neonates that have experienced perinatal asphyxia. This study investigated the effect of one component of asphyxia, hypoxia, on platelet lifespan and site of sequestration. 111Indium oxine platelet survivals with scintigraphic imaging were performed in newborn and adult rabbits exposed to room air (normoxia) or following exposure to a 15 minute, severe hypoxic insult (FIO2 = 0.05). Platelet survivals in normoxic adults (n = 27) and newborn rabbits (n = 11) were similar (60 +/- 3.9 hr vs 64 +/- 8.0 hr, m +/- SEM). Inhalation of 5% oxygen for 15 minutes was not associated with an acidemia and did not produce thrombocytopenia but significantly shortened the platelet survival to 34 +/- 3 hr in the adult (n = 18) and 38 +/- 3 hr in the newborn rabbit (n = 7). Postmortem measurement of the sites of 111In-platelet accumulation showed that under normoxic conditions the platelets accumulated in the liver and spleen (23 +/- 4.3% and 8 +/- 1.0% of the total body counts) in the adult with even greater accumulation in the liver (58 +/- 6.8%) and spleen (19 +/- 4.9%) of the newborn (p less than 0.001). The latter observation was likely due to the relatively increased size of the liver and spleen in the newborn compared to the adult. Hypoxia did not alter the site of platelet sequestration in adults or newborns. Our results suggest that the newborn has the same platelet survival as the adult and that acute, severe hypoxia significantly shortens the survival of platelets in both groups. Although the sites of sequestration are qualitatively the same in the newborn, there is greater sequestration in the liver and spleen when compared to the adult.

Animals↗
PubMed1988

Fetal lamb coagulation system during normal birth.

The contribution of the birth process to the unique coagulation system in the young was investigated using the fetal lamb model. Specific components of the coagulation system were measured prior to and immediately following delivery of the lamb. The results show that the birth process itself does not contribute to the physiologically low levels of coagulation factors present in the newborn.

Animals↗
PubMed1988

Fetal lamb coagulation system during birth asphyxia.

Levels of many coagulation factors are low in the healthy infant and even lower in the asphyxiated premature infant. We investigated whether a brief exposure to asphyxia at the time of birth causes the activation and consumption of coagulation factors. Following delivery by caesarean section, premature lambs were asphyxiated by occluding the endotracheal tube for 10 min and then resuscitated. Blood was obtained prior to and following birth for measurement of blood gases and the coagulation system. Birth asphyxia in the premature lamb resulted in thrombin generation and rapid consumption of specific coagulation factors.

Animals↗
PubMed1988

Carrier detection in hemophilia A: ABO blood group, multiple measurements, and application of logistic discrimination.

In healthy 20- to 50-year-old women, the ABO blood group has a significant effect on levels of von Willebrand factor (VWF:Ag, formerly VIIIR:Ag) and on factor VIII activity (F.VIII:C). However, there is no significant effect of ABO group or subject age on the ratio log e(F.VIII:C/VWF:Ag). Multiple measurements of the "ratio" on possible carriers of hemophilia A may be combined with pedigree information using logistic discrimination to yield final risk assessment. To reduce misclassification of carriers as normal women, a lower limit, specified by the logistic model, is set on the logistic carrier probabilities. In this study, the proportion of blood group A for a population of obligate carriers was significantly higher than that expected for the general population (60% vs. 42%); for a population of control women it was lower than expected (22.5 vs. 42%). The effect for the carriers came primarily from daughters of affected fathers, as 81.3% were of blood group A. These observations indicate that a "universal" discriminant should be applied with caution.

ABO Blood-Group System↗
PubMed1988

Fibrinogen has a rapid turnover in the healthy newborn lamb.

The half-lives for coagulation factors in the healthy newborn infant are not known and may be different than for the adult. We measured the half-life for fetal sheep fibrinogen and compared it to the half-life of adult sheep fibrinogen. Fibrinogen was purified from adult and fetal sheep plasma and radiolabeled with either 125I or 131I. The half-lives for these fibrinogens were determined in the adult sheep and newborn lamb. In addition, the fetal and adult sheep fibrinogens were compared by reptilase time, thrombin clotting time, sialic acid content, and the behavior of the N-glycans derived from these fibrinogens on the immobilized lectin, Sepharose-concanavalin A. Finally, the in vivo response of coinjected radiolabeled fibrinogens to increasing doses of infused thrombin was determined. The fetal sheep fibrinogen differed from the adult as indicated by a prolonged reptilase time and an increased sialic acid content (fetal: 10-11 residues/340 Kd versus adult: 8-9 residues/340 Kd). The latter was also reflected in differing chromatographic profiles for the N-glycans on Sepharose-concanavalin A. The half-lives for both the adult and fetal fibrinogen were significantly more rapid in the newborn lamb (fetal: 47 +/- 2.0 h; adult: 46 +/- 2.4 h, mean +/- SEM) than in the adult (fetal: 116 +/- 6.5 h; adult: 121 +/- 6.9 h). Finally, the adult and fetal sheep fibrinogen responded to thrombin in an identical fashion in the intact animal. In summary, both adult and fetal fibrinogen have faster half-lives in the lamb compared tot he adult, despite a higher sialic acid content for the fetal fibrinogen.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1988

Development of the human coagulation system in the healthy premature infant.

This study was designed to determine the postnatal development of the human coagulation system in the healthy premature infant. Consecutive mothers of healthy premature infants born at either St Joseph's Hospital or McMaster University Medical Centre in Hamilton were asked for consent. One hundred thirty-seven premature infants (30 to 36 weeks of gestational age) entered the study. The premature infants did not have any major health problems and did not require ventilation or supplemental oxygen. Demographic information and a 20-mL blood sample were obtained in the postnatal period on days 1, 5, 30, 90, and 180. Between 40 and 96 premature infants were studied on each day for each of the following tests: prothrombin time, activated partial thromboplastin time, thrombin clotting time, plasminogen; 13 factor assays [fibrinogen, II, V, VII, VIII, IX, X, XI, XII, XIII, high-mol-wt kininogen (HMWK), prekallikrein (PK), von Willebrand factor (vWF)] and eight inhibitors [antithrombin III (AT-III), heparin cofactor II, alpha 2-antiplasmin, alpha 2-macroglobulin, alpha 1-antitrypsin, C1 esterase inhibitor, protein C (PC), and protein S (PS)]. A combination of biologic and immunologic assays were used. Between 30 to 36 weeks there was a minimal effect of gestational age for levels of AT-III, PC, and factors II and X only; therefore, the entire data set was used to generate reference ranges for these components of the coagulation system for premature infants. Next, the results for the premature infants were compared with those of a previously published study in 118 fullterm infants and with those for adults. An effect of gestational age was shown for plasminogen, fibrinogen, factors II, V, VIII, IX, XI, XII, HMWK, and all eight inhibitors. In general, the postnatal maturation towards adult levels was accelerated in premature infants as compared with the fullterm infants. By 6 months of age, most components of the coagulation system in premature infants had achieved near adult values.

Age Factors↗
PubMed1988

Standard assays underestimate the concentration of heparin in neonatal plasma.

Heparin is commonly used to treat neonatal thrombosis. Drug monitoring often involves assays that measure the inhibition of added factor Xa or thrombin by the antithrombin III (AT-III) heparin complex. We examined whether the neonatal AT-III deficiency affects heparin recovery in such assays at therapeutic drug concentrations (0.1 to 0.6 U/ml). The chromogenic anti-factor Xa assay (Teien AN, Lie M, Abildgaard U. Thromb Res 1976;8:413-6) and the protamine titration test were performed in eight pooled cord plasma samples and in normal adult plasma. Only 65% to 70% of heparin activity detected in adult plasma was recovered by the assay of Teien et al. In cord plasma; recovery by the protamine test was 80% or less. Heparin recovery in cord plasma was significantly improved by raising the AT-III concentration to normal adult levels in both assays. We conclude that heparin assays underestimate drug levels in neonatal plasma unless the neonatal AT-III deficiency is fully corrected in the test system. The use of standard assays may lead to over-heparinization of newborn infants, thereby placing them at a higher risk of bleeding.

Antithrombin III↗
PubMed1987

Double-blind randomised trial of Org 10172 low-molecular-weight heparinoid in prevention of deep-vein thrombosis in thrombotic stroke.

In a double-blind, randomised trial Org 10172 low-molecular-weight (LMW) heparinoid was compared with placebo in the prevention of deep-vein thrombosis in patients with acute thrombotic stroke. Prophylaxis was started within 7 days of the onset of stroke with a loading dose of 1000 anti-factor-Xa units intravenously followed by a fixed dose of 750 anti-factor-Xa units twice a day subcutaneously; it was continued for 14 days or until hospital discharge, if earlier. 50 patients were randomised to receive Org 10172 and 25 to receive placebo. All patients underwent surveillance with I125-fibrinogen leg scanning and impedance plethysmography. Venography was carried out if either test became positive. Venous thrombosis occurred in 2 of 50 patients (4.0%) given Org 10172 and 7 of 25 patients (28.0%) given placebo (p = 0.005); the corresponding rates of proximal-vein thrombosis were 0% and 16%, respectively (p = 0.01). There was one major haemorrhage in the Org 10172 group and one minor bleed in the placebo group.

Acute Disease↗
PubMed1987

Clinical impact of neonatal thrombocytopenia.

In a 1-year prospective study, the outcome in infants with a platelet count less than 100 X 10(9)/L (n = 97) was compared with the outcome in an age-, weight-, and disease-matched nonthrombocytopenic control group (n = 80). The hemostatic impact of the thrombocytopenia was assessed by modified template bleeding time, hemorrhage score, and determination of the presence and extent of intraventricular hemorrhage (IVH) in thrombocytopenic infants weighing less than 1500 at birth (n = 39) compared with all nonthrombocytopenic infants less than 1500 g (n = 122) admitted during the study period. The development outcome in infants less than 1500 g was compared at 12 months after delivery. Neonatal thrombocytopenia had a major impact on hemostatic integrity: bleeding time was inversely related to platelet count (r = -0.56, P less than 0.001) and became prolonged when the platelet count fell to less than 100 X 10(9)/L. In addition, many infants (40%) had evidence of platelet dysfunction with prolonged bleeding times despite only moderately reduced platelet counts (75 to 150 X 10(9)/L). The hemorrhage score was greater in the thrombocytopenic infants compared with the sick control infants, and increased as the platelet count fell (r = -0.58, P less than 0.001). The incidence of IVH in thrombocytopenic infants less than 1500 g was 78%, compared with 48% in the nonthrombocytopenic infants (P less than 0.01). In addition, the more severe grades of IVH were more frequent in the thrombocytopenic infants. The serious neurologic morbidity for the surviving infants less than 1500 g was 41% in the thrombocytopenic infants and 7% in the nonthrombocytopenic infants. Thus, on the basis of three indices of abnormal bleeding, thrombocytopenic infants are at greater risk for bleeding than equally sick nonthrombocytopenic infants. The thrombocytopenia itself may have contributed to the high mortality and neurologic morbidity.

Bleeding Time↗
PubMed1987

Operation Everest II: coagulation system during prolonged decompression to 282 Torr.

Thromboembolic phenomena may occur as humans ascend to high altitude. To investigate the role of the coagulation cascade and its inhibitors in these disorders, venous blood was obtained from eight subjects who participated in the Operation Everest II project. Samples were obtained before and 5 min after completion of a progressive incremental exercise test to exhaustion at sea level and atmospheric pressures of 380 (18,000 ft) and 282 Torr (25,000 ft). Plasma was analyzed for the activity or concentration of factors II, V, VII, VIII complex, IX-XIII, prekallikrein, high-molecular-weight kininogen, fibrinogen, antithrombin III, alpha 2-macroglobulin, alpha 2-antiplasmin, C1-esterase inhibitor, alpha 1-antitrypsin, and protein C. Prolonged exposure to simulated high altitude did not alter the concentration of any of the coagulation factors or inhibitors. Exercise increased the circulating concentrations of the factor VIII complex at sea level, 380, and 282 Torr. However, the increment was less at the simulated high altitudes. The increase in the factor VIII complex was inversely related to arterial O2 saturation and directly related to the work load achieved and blood pH and plasma lactate concentrations. These studies suggest that the gradual development of marked chronic hypoxia does not affect the coagulation cascade.

Adult↗