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Biomedical subjects

M Andrew

Publications and source records attributed to M Andrew.

At least 217 records · Page 12Linked to original sources
PubMed1987

Abnormal endothelial factor VIII associated with pulmonary hypertension and congenital heart defects.

In patients with pulmonary hypertension associated with congenital heart defects, ultrastructural abnormalities are observed in endothelial cells, which suggest heightened metabolic function. If endothelial production of the von Willebrand factor (vWF) is increased, this may be associated with abnormal interactions with platelets leading to worsening of the pulmonary hypertension. We therefore evaluated vWF in 30 patients with pulmonary hypertension (25 with congenital heart defects) and in 30 individuals with normal pulmonary arterial pressure (12 with congenital heart defects). We measured the antigenic (vWF: Ag) and biologic (VWF: rist) activity of vWF in plasma and assessed endothelial vWF: Ag directly by an immunoperoxidase stain applied to lung biopsy tissue. Because of considerable variance and small size, the group of five patients with pulmonary hypertension and without congenital heart defects were excluded from statistical analyses. Patients with pulmonary hypertension and congenital heart defects had significant higher vWF: Ag levels than individuals with normal pulmonary arterial pressure without congenital heart defects (p less than .05), whereas values in those with normal pressure and congenital heart defects were intermediate. In lung biopsy tissue available from 29 patients in this study and from 11 others we previously reported, immunostain of pulmonary arterial endothelium for vWF was intense (suggesting increased production) in 29 of 32 with pulmonary hypertension and congenital heart defects and in only one of eight with normal pulmonary arterial pressure and congenital heart defects (p less than .01). Only three patients with congenital heart defects and pulmonary hypertension and increased vWF: Ag, however, had increased vWF: rist. Compatible with this discrepancy was a loss of vWF high-molecular weight forms as determined by both crossed immunoelectrophoresis and multimeric analysis. Our results suggest that increased vWF in most patients with congenital heart defects and pulmonary hypertension is associated with increased production of a biologically deficient molecule lacking high-molecular weight forms.

Adolescent↗
PubMed1987

111In-oxine platelet survivals in thrombocytopenic infants.

Thrombocytopenia is a common occurrence (20%) in sick neonates, but the causes have not been well studied. In this report we demonstrate that thrombocytopenia in the neonate is characterized by increased platelet destruction as shown by shortened homologous 111In-oxine-labeled platelet life spans. Thirty-one prospectively studied thrombocytopenic neonates were investigated by measuring the 111In-labeled platelet life span, platelet-associated IgG (PAIgG), and coagulation screening tests. In every infant, the thrombocytopenia was shown to have a destructive component since the mean platelet life span was significantly shortened to 65 +/- 6 (mean +/- SEM) hours with a range of one to 128 hours compared with adult values (212 +/- 8; range, 140 to 260; gamma function analysis). The platelet survival was directly related to the lowest platelet count and inversely related to both the highest mean platelet volume and duration of the thrombocytopenia. In 22 infants the percent recovery of the radiolabeled platelets was less than 50%, which suggested that increased sequestration also contributed to the thrombocytopenia. Infants with laboratory evidence of disseminated intravascular coagulation (n = 8) or immune platelet destruction evidenced by elevated levels of PAIgG (n = 13) had even shorter platelet survivals and a more severe thrombocytopenia compared with the ten infants in whom an underlying cause for the thrombocytopenia was not apparent. Full-body scintigraphic images obtained in 11 infants showed an increased uptake in the spleen and liver, with a spleen-to-liver ratio of 3:1. This study indicates that thrombocytopenia in sick neonates is primarily destructive, with a subgroup having evidence of increased platelet sequestration.

Blood Platelets↗
PubMed1987

Development of the human coagulation system in the full-term infant.

The investigation of many hemostatic defects in the newborn is limited by the lack of normal reference values. This study was designed to determine the postnatal development of the human coagulation system in the healthy full-term infant. Consecutive mothers of healthy full-term infants born at St Joseph's Hospital in the city of Hamilton were approached for consent. One hundred eighteen full-term infants (37 to 42 weeks' gestational age) were entered into the study. Demographic information and a 2-mL blood sample were obtained in the postnatal period on days 1, 5, 30, 90, and 180. Between 40 and 79 full-term infants were studied on each day for each of the coagulation tests. Plasma was fractionated and stored at -70 degrees C for batch assaying of the following tests: prothrombin time, activated partial thromboplastin time, thrombin clotting time, and factor assays (biologic): fibrinogen, II, V, VII, VIII, IX, X, XI, XII, and high-molecular weight kininogen. Factor XIII subunits A and S, von Willebrand factor, and the inhibitors antithrombin III, alpha 2-antiplasmin, alpha 2-macroglobulin, alpha 1-antitrypsin, C1 esterase inhibitor, protein C, and protein S were measured immunologically. Plasminogen, prekallikrein, and heparin cofactor II were measured by using chromogenic substrates. The large number of infants studied at each time point allowed us to determine the following: the range of normal for each test at five time points in the postnatal period; that coagulation tests vary with the postnatal age of the infant; that different coagulation factors show different postnatal patterns of maturation; and that near-adult values are achieved for most components by 6 months of life. In summary, this large cohort of infants studied consecutively in the postnatal period allowed us to determine the normal development of the human coagulation system in the full-term infant.

Aging↗
PubMed1987

A prospective study investigating the mechanism of thrombocytopenia in preeclampsia.

Hemostatic and platelet function studies were performed prospectively on 61 preeclamptic patients and 24 healthy pregnant control patients to delineate possible causes of thrombocytopenia in preeclampsia. Thrombocytopenia occurred in 50% of the preeclamptic patients, and was accompanied by qualitative platelet defects as shown by an increased bleeding time and decreased biosynthesis of thromboxane A2. All patients had normal routine coagulation and protamine sulphate paracoagulation assays. All nulliparous patients had normal levels of fibrinopeptide A, but approximately 60% of parous patients had slight elevations of fibrinopeptide A. Elevated levels of platelet-associated immunoglobulin G (IgG) were demonstrated in 35% of all preeclamptic patients and were inversely correlated (r = -0.524) with the severity of the thrombocytopenia. This study indicates that, at least in nulliparous patients, thrombin action is not a major contributor to the development of thrombocytopenia in preeclampsia. The observation of elevated levels of platelet-associated IgG suggests that immune mechanisms could contribute to the thrombocytopenia in some patients.

Adult↗
PubMed1986

A randomized controlled trial of a low-molecular-weight heparin (enoxaparin) to prevent deep-vein thrombosis in patients undergoing elective hip surgery.

There is experimental evidence that low-molecular-weight fractions of heparin are as effective as the standard form but cause less bleeding. We therefore performed a double-blind, randomized trial comparing PK10169 low-molecular-weight heparin with placebo for the prevention of venous thrombosis in patients undergoing elective hip surgery. Prophylactic treatment with a fixed dose was begun postoperatively and continued for 14 days. Fifty patients in each treatment group underwent surveillance with [125I]fibrinogen leg scanning and impedance plethysmography. In the first 24 patients, venography was performed only if either surveillance test was positive. Because the rate of venous thrombosis detected in those patients was unexpectedly low, venography was requested in the remaining 76 patients, even if the screening tests were negative. In this latter group, venous thrombosis occurred in 4 patients (10.8 percent) given PK10169 heparin and 20 patients (51.3 percent) given placebo (P = 0.0002); the corresponding rates for proximal-vein thrombosis were 5.4 percent and 23.1 percent, respectively (P = 0.029). In the entire group of 100 patients, venous thrombosis occurred in 12 percent of those given PK10169 heparin and 42 percent of those given placebo (P = 0.0007), and the corresponding rates for proximalvein thrombi were 4 percent and 20 percent, respectively (P = 0.014). The observed hemorrhagic rate was 4 percent in each treatment group. We conclude that prophylaxis with fixed-dose PK10169 heparin is effective and safe for patients undergoing elective hip replacement.

Aged↗
PubMed1986

A low molecular weight heparin alters the fetal coagulation system in the pregnant sheep.

Standard heparin and a LMWH, CY222 do not cross the placenta nor alter fetal coagulation when injected into the pregnant ewe. We found that another LMWH, Pharmuka-10169 (PK-10169) alters fetal coagulation without crossing the placenta in the pregnant sheep. To characterize this anticoagulant we measured the in vitro and in vivo effects of 125I-PK-10169 in maternal and fetal plasmas following administration of PK-10169 to the mother or fetus. The fetal anticoagulant activity was not neutralizable by protamine sulphate and was attributable to the inhibition of thrombin but not factor Xa. In vitro, the fetal anticoagulant activity had properties similar to dermatan sulphate; both catalyzed the inhibition of thrombin but not factor Xa by sheep plasma; and neither was neutralizable by protamine sulphate. These effects were due to the enhanced neutralization of thrombin by heparin cofactor II. We conclude that PK-10169 does not cross the placenta, but does induce the release of an endogenous dermatan sulphate-like substance which alters fetal coagulation.

Animals↗
PubMed1986

Therapeutic traditions in Northern Ireland, Norway and Sweden: I. Diabetes. WHO Drug Utilization Research Group (DURG).

A questionnaire survey was carried out to explore differences in the approach to treatment of patients with Type II diabetes between physicians in Northern Ireland, Norway and Sweden, and to discover to what extent it could account for the three-fold difference in drug use between the countries. A representative sample of 400 physicians in each country was asked to give their opinions on the choice of therapy for three model cases designed to cover the spectrum of treatment - from diet alone to insulin. Significantly more Swedish (65%) than Northern Irish (51%) and Norwegian (52%) doctors suggested diet alone for uncomplicated diabetes recently discovered in a middle aged, overweight man. For symptomatic diabetes in a 76 year old over-weight woman with few retinal microaneurysms, the majority of physicians in all three countries suggested treatment with sulphonylureas. Biguanides were here a more common alternative in Northern Ireland than in Scandinavia. For suspected secondary treatment failure in a 63 year old woman with no signs of complications, insulin was suggested by 71% of the Norwegian doctors but only by 44 and 49% of those in Northern Ireland and Sweden, respectively. General practitioners tended to suggest oral treatment earlier and to maintain it longer than hospital physicians. The study has demonstrated significant differences in the approach to treatment of Type II diabetes mellitus between physicians in the three countries. However, the differences were more prominent in the choice of drugs than in the threshold of drug treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Diabetes Mellitus↗
PubMed1986

Therapeutic traditions in Northern Ireland, Norway and Sweden: II. Hypertension. WHO Drug Utilization Research Group (DURG).

A questionnaire survey based on hypertension case histories was performed among a representative sample of 400 GP's and hospital doctors in Northern Ireland, Norway and Sweden, countries having markedly different utilization of antihypertensive drugs. We found a greater propensity to start antihypertensive drug treatment in Northern Ireland than in Norway and Sweden. This was true both in mild diastolic and isolated systolic hypertension. Yet the utilization of antihypertensive drugs in Sweden is about 60% higher than in Northern Ireland and 30% higher than in Norway. Swedish physicians preferred beta-blockers as their first choice to a greater extent than physicians in Northern Ireland and Norway who selected thiazides more often. In general, the choice of drugs agreed with the sales and prescribing patterns in the three countries. Besides providing more insight in therapeutic traditions the study indicates that the lower prescribing of antihypertensive drugs in Northern Ireland, and to some extent in Norway, compared to Sweden, might be due to differences in true or apparent morbidity.

Antihypertensive Agents↗
PubMed1986

Frequency and mechanism of neonatal thrombocytopenia.

We performed a 1-year prospective study of 807 consecutive infants admitted to a regional neonatal intensive care unit to determine the frequency, natural history, mechanism(s), and cause of thrombocytopenia. Thrombocytopenia developed in 22% of the infants. The platelet count nadir usually occurred by day 4 and resolved by day 10. Possible mechanisms responsible for the thrombocytopenia were assessed by comparing mean platelet volume, platelet-associated IgG (PAIgG), and coagulation test results in those infants whose platelet count fell below 100 X 10(9)/L (n = 97) with values in age-, weight-, and disease-matched control infants without thrombocytopenia (n = 80). In some thrombocytopenic infants, 111In-labeled-platelet survival, an estimate of megakaryocyte number in bone marrow biopsy specimens obtained at autopsy, and response to platelet infusions were also assessed. The thrombocytopenia was caused by increased platelet destruction, as shown by short 111In-labeled-platelet survival (12 to 128 hours), a rising mean platelet volume during the first week of life, normal numbers of megakaryocytes, and a poorer than predicted response to platelet infusions. A potential cause for the thrombocytopenia could be found in the majority of infants: 52% had elevated levels of PAIgG, 21% had laboratory evidence of disseminated intravascular coagulation, and 12% had had exchange transfusions. In contrast, the control infants had normal coagulation assay results, and only 15% had elevated levels of PAIgG. Birth asphyxia was identified as an associated risk factor for thrombocytopenia. This study demonstrates that transient, destructive thrombocytopenia develops in a large proportion (22%) of infants admitted to a neonatal intensive care unit, and that birth asphyxia is an important risk factor.

Asphyxia Neonatorum↗
PubMed1986

Increases in factor VIII complex and fibrinolytic activity are dependent on exercise intensity.

Components of the factor VIII complex increase and activation of the fibrinolytic system occur during exercise. The relation between the duration and intensity of exercise and the relative changes in the VIII complex and fibrinolytic system have not been previously examined. Five healthy male subjects were exercised with three protocols: a graded progressive exercise test to exhaustion on a cycle ergometer with 50-W increments every 4 min, steady-state exercise, 15 min at 5 and 125 W each, and an acute 30-s maximal exercise test on a cycle ergometer. Venous blood samples were drawn at base line, during the last 30 s of each power output in the graded exercise, at 5-min intervals for the steady-state exercise, and for up to 1 h after completion of exercise in all three protocols. At the maximum exercise intensities, increases in plasma lactate concentration ([La]), O2 uptake, and [H+] were observed. Components of the VIII complex [VIII procoagulant, VIII procoagulant antigen, VIII-related antigen (VIIIR:Ag), VIII ristocetin cofactor activity] abruptly rose at only the highest work intensities, whereas the whole blood clot lysis time began to gradually shorten much earlier at low work intensities. There were no qualitative changes in the factor VIIIR:Ag on crossed immunoelectrophoresis nor was there evidence of thrombin generation as determined by fibrinopeptide A generation. We conclude that during exercise the changes observed in the coagulation and fibrinolytic systems are related to the intensity of the exercise, which is reflected by increases in plasma [La] and [H+], and that the fibrinolytic system is activated before the changes in the VIII complex are observed.

Adult↗
PubMed1986

A comparative study of coagulation systems in newborn animals.

Appropriate animal experimentation can enhance our understanding of thrombotic and hemorrhagic problems in the human neonate. Which newborn animal species' coagulation system most closely resembles the human neonate is unknown. The objective of the study was to assess the newborn coagulation system in four animal species and compare them with the human neonate. Blood samples were drawn on days 1 and 7 of life from lambs (n = 10), piglets, (n = 12), rabbit pups (n = 12), and beagle pups (n = 7). Coagulation screening tests, specific factor assays, and specific inhibitors of the coagulation system were measured. All factor assays were expressed as a percent of the respective species pooled adult plasma. The results from the animals were compared to normal values from our laboratory for healthy full-term infants. The coagulation systems of all species tested, except the rabbit pup, were immature at birth with most factor levels being lower than the adult of their species. The coagulation systems were influenced by the postnatal age of the animal and the factor levels reached adult values in fewer days relative to the human. The coagulation system for the piglet most closely approximated the human neonate. The shared characteristics were prolonged screening tests, increased factor VIII:C, generally low levels for the contact and vitamin K-dependent factors, and low antithrombin III levels relative to the adult. The beagle pup also showed many similar characteristics but in contrast to the human neonate factor VIII:C and V were low on day 1 of life and prekallikrein was not measurable in the adult or newborn beagle.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

Validation of observed differences in the utilization of antihypertensive and antidiabetic drugs in Northern Ireland, Norway and Sweden.

The amount of antihypertensive and antidiabetic drugs based of defined daily doses per 1000 inhabitants per day varies two to three fold between Northern Ireland, Norway, and Sweden. We explored whether variations based on the universally applied defined daily doses might be accounted for by national differences in the actual average prescribed daily doses. Use of prescribed daily doses for antihypertensive drugs resulted in Northern Irish and Norwegian consumption figures which were respectively 40 and 21% lower than the Swedish one, compared to 38 and 25% when defined daily doses were used. The effect of population age-sex differences on the gross defined daily doses per 1000 inhabitants per day figures was determined by applying the Northern Irish or Norwegian age-sex group proportions to Swedish age-sex specific sales data. Taking population differences into account would have resulted in antihypertensive drug use being 21 rather than 38% less in Northern Ireland and 18 rather than 25% less in Norway. Also adjustment for prescribed daily doses left an unexplained difference of 23% between Sweden and Northern Ireland and 14% between Sweden and Norway. For oral antidiabetics use of prescribed daily doses resulted in a Northern Irish - Swedish difference of 62% compared to 67% when defined daily doses were used. Simultaneous adjustment for population differences and prescribed to defined daily dose variations left a 52% difference.

Adolescent↗
PubMed1985

Placental transport of low molecular weight heparin in the pregnant sheep.

Standard heparin, an effective treatment for antepartum thromboembolic disease, is thought to be safe for the fetus since it does not cross the placenta. Recently, a number of low molecular weight heparins have been prepared which have been shown to produce less bleeding than standard heparin for an equivalent antithrombotic effect in experimental animals. These observations suggest that the low molecular weight heparins may also provide superior antithrombotic therapy in antepartum thromboembolic disease. However, it is not known whether the low molecular weight heparins cross the placenta. To determine this, we examined the pharmacokinetics of 125I-labelled standard heparin and a low molecular weight heparin, and their anticoagulant effects in mother and fetus, using a pregnant sheep model. Catheters were inserted into maternal and fetal femoral arteries at 108-119 d gestation (term: 147 d). 1-3 days later the mothers were given a bolus i.v. injection of 5000 anti-Xa units of 125I-labelled standard heparin or low molecular weight heparin, CY 222. Nine serial blood samples were collected over 4 h from both mother and fetus for measurements of radioactivity, anti-Xa activity (chromogenic) and activated partial thromboplastin times. When therapeutic levels of standard and CY 222 heparins were achieved in the mother, there was no detectable radioactivity or anticoagulant effect in the fetus. We conclude that standard heparin and the low molecular weight CY 222 do not cross the placenta in the pregnant sheep.

Animals↗
PubMed1985

Dysfunctional antithrombin III in sick premature infants.

Antithrombin III, a major inhibitor of activated coagulation factors has low immunologic levels in the human infant. The objective of this study was to determine if the antithrombin III molecule is fully functional in sick premature infants. The populations studied included: adult controls (n = 20), full term healthy infants (n = 18), sick premature infants on day 1 (n = 16) and at greater than 7 days of age (n = 10), and infants with disseminated intravascular coagulation (n = 11). This was diagnosed in the presence of prolonged screening tests, decreased levels of fibrinogen, and platelets along with elevated fibrin degradation products. Plasma antithrombin III levels were measured biologically (chromogenic substrate S2238) and immunologically (radialimmunodiffusion), and expressed as a percent of adult pooled plasma. Crossed immunoelectrophoresis were performed in the presence and absence of heparin. The antithrombin III biologic/immunologic ratios for adults, healthy full term infants, and sick premature infants on day 1 of life were all near unity. In contrast sick premature infants beyond the 1st wk of life and infants with disseminated intravascular coagulation had lower biologic activity compared to immunologic (B/I = 0.77 +/- 0.28, 0.78 +/- 0.17, p less than 0.01), respectively. In all groups, the antithrombin III molecule was normal on crossed immunoelectrophoresis except for one infant with disseminated intravascular coagulation. Sick premature infants may acquire a dysfunctional antithrombin III molecule in the postnatal period.

Adult↗
PubMed1985

Hypoxia-induced vasopressin release and coagulopathy in a normal subject.

Humans exposed to hypoxia usually increase their plasma procoagulant VIII activity (VIII:C) with no change in the concentration of VIII related antigen (VIIIR:Ag). This case report describes an apparently normal subject who developed marked qualitative and quantitative changes in all components of the factor VIII complex while inhaling an 11% oxygen/balance nitrogen gas mixture for 2 h. Blood from fresh venepunctures was drawn at baseline, during and after exposure to hypoxia for the following: a partial thromboplastin time, a prothrombin time, fibrin monomer, factor VIII:C, VIII procoagulant antigen (VIII:CAg); ristocetin cofactor activity (VIIIR:Co); VIII von Willebrand factor (VIII:vWF) multimer pattern; and arginine vasopressin. During hypoxia VIII:C, VIII:CAg, VIIIR:Ag and VIIIR:Co increased 4 to 5 fold; the VIII:vWF multimer pattern showed increasing low molecular weight complexes, fibrin monomer appeared and arginine vasopressin (AVP) levels increased from 5.5 pg . ml-1 to 73.8 pg . ml-1. These changes are compatible with both the release of the VIIIR:Ag by AVP and protease induced fragmentation of the VIII complex.

Arginine Vasopressin↗
PubMed1985

Fluosol-DA causes pulmonary hypertension and increased lung lymph flow in unanesthetized sheep.

Test doses (0.5 ml) of the perfluorochemical blood substitute Fluosol-DA causes pulmonary hypertension in some patients. To investigate this phenomenon we infused Fluosol-DA into unanesthetized sheep with chronic vascular catheters on ten occasions. In six of these experiments lung lymph flow was measured. Since other fluorochemical blood substitutes alter the coagulation cascade we also sampled blood to perform coagulation screening tests and look for evidence of thrombin generation as assessed by the survival of 125I labelled sheep fibrinogen. Test doses (0.5 ml) of Fluosol-DA resulted in transient but marked pulmonary hypertension in nine of ten experiments (17 +/- 1.2 SE to 43 +/- 3.9 SE torr). Cardiac output decreased by an average of 30%, and lung lymph flow transiently increased without a change in the lymph to plasma protein concentration (L/P) ratio in five of six experiments. When 50 ml of Fluosol-DA was administered one hour later the pulmonary hypertension was more prolonged but less severe (18 +/- 1.0 SE to 34 +/- 3.2 SE torr). Lymph flow again increased without a change in the L/P ratio for protein. The activated partial thromboplastin and prothrombin times, and survival in plasma of 125I labelled sheep fibrinogen were unaffected by administration of Fluosol-DA. We conclude that Fluosol-DA causes pulmonary hypertension in sheep and increases lung lymph flow. This results from vasoconstriction of the pulmonary vessels and subsequent recruitment of the pulmonary microvasculature and not from thromboembolic phenomena.

Animals↗