Influence of activated factor VII concentrates on thrombin generation in full-term and preterm neonates.
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Factor VIIa↗
Biomedical subjects
M Andrew
Publications and source records attributed to M Andrew.
Influence of exogenous factor VIIa on thrombin generation in cord plasma of full-term and pre-term newborns.
Factor (F) VIIa has been used to treat adults and children with a variety of bleeding disorders. The results from these studies cannot be extrapolated to newborns because their hemostatic system differs significantly from adults, which may influence the effects of FVIIa on thrombin (IIa) generation. We compared the effects of FVIIa concentrates on IIa generation in plasmas from adults, full-term newborns and pre-term newborns. Defibrinated plasma (using arvin) from adults, or umbilical cords from full-term or pre-term deliveries was supplemented with FVIIa (Novo Nordisk, Bagsvaerd, Denmark), mixed with dilute thromboplastin reagent, and the resultant reaction mixture subsampled periodically into ethylenediamine tetraacetic acid, followed by measurement of total IIa activity (S-2238). Thrombin-alpha2 macroglobulin complexes, determined as residual activity after neutralization with heparin and antithrombin, were subtracted from total IIa to give free IIa. Prothrombin (FII) and inhibitor complexes were measured by enzyme-linked immunosorbent assays. Addition of FVIIa caused a reduction in the lag phase for the appearance of free IIa and consumption of FII, which was more pronounced in newborn plasma. There was no increase in peak IIa levels regardless of the amount of FVIIa added. Final inhibitor complex concentrations were increased in plasmas from adults compared with newborns, likely reflecting higher plasma concentrations of FII in adults. Generation of IIa was more rapid in pre-term plasma compared with that in adult and full-term cord plasmas due to increased endogenous tissue factor (TF). In summary, FVIIa enhanced IIa generation in plasma from different age groups, with the effect being more pronounced in plasma from pre-term newborns, possibly due to increased levels of plasma TF.
Adult↗
Improving doctors' prescribing behaviour through reflection on guidelines and prescription feedback: a randomised controlled study.
BACKGROUND: It is difficult to put research findings into clinical practice by either guidelines or prescription feedback. AIM: To study the effect on the quality of prescribing by a combined intervention of providing individual feedback and deriving quality criteria using guideline recommendations in peer review groups. METHODS: 199 general practitioners in 32 groups were randomised to participate in peer review meetings related to either asthma or urinary tract infections. The dispensing by the participating doctors of antiasthmatic drugs and antibiotics during the year before the intervention period provided the basis for prescription feedback. The intervention feedback was designed to describe the treatment given in relation to recommendations in the national guidelines. In each group the doctors agreed on quality criteria for their own treatment of the corresponding diseases based on these recommendations. Comparison of their prescription feedback with their own quality criteria gave each doctor the proportion of acceptable and unacceptable treatments. MAIN OUTCOME MEASURE: Difference in the prescribing behaviour between the year before and the year after the intervention. RESULTS: Before intervention the mean proportions of acceptably treated asthma patients in the asthma group and urinary tract infection (control) group were 28% and 27%, respectively. The mean proportion of acceptably treated patients in the asthma group was increased by 6% relative to the control group; this difference was statistically significant. The mean proportions of acceptable treatments of urinary tract infection before intervention in the urinary tract infection group and asthma (control) group were 12% for both groups which increased by 13% in the urinary tract infection group relative to the control group. Relative to the mean pre-intervention values this represented an improvement in treatment of 21% in the asthma group and 108% in the urinary tract infection group. CONCLUSIONS: Deriving quality criteria of prescribing by discussing guideline recommendations gave the doctors a basis for judging their treatment of individual patients as acceptable or unacceptable. Presented with feedback on their own prescribing, they learned what they did right and wrong. This provided a foundation for improvement and the process thus instigated resulted in the doctors providing better quality patient care.
Asthma↗
Whole blood heparin concentrations do not correlate with plasma antifactor Xa heparin concentrations in pediatric patients undergoing cardiopulmonary bypass.
This study was designed to test the validity of whole blood heparin concentration (WHBC) measurements using an on-site protamine titration assay with the Hepcon instrument (Medtronic Blood Management, Parker, CO, USA) in pediatric patients less than 1 year old undergoing cardiopulmonary bypass (CPB). The validity of the Hepcon measurements was examined via a test of correlation with the gold standard plasma antifactor Xa activity (anti-Xa) assay. Fifty-one patients (23 females and 28 males) under 1 year old (mean age 5.3 months) were studied prospectively. Blood samples were taken at 5 min into CPB and at the end of CPB for the WBHC, plasma anti-Xa activity, and hematocrit (Hct). The WBHC was converted to plasma heparin level using a formula taking into account the collection of blood into citrate solution and the effect of the citrate on the hematocrit. While a nonparametric statistical analysis revealed that the mean corrected values from the Hepcon instrument were not significantly different from the mean anti-Xa values (p = 0.070 at 5 min on CPB, p = 0.518 at the end of CPB), there was no significant correlation between these values at either 5 min into CPB (r = 0.113, p = 0.429) or at the end of CPB (r = -0.247, p = 0.080). The lack of correlation between the two assays may be related to the extreme hemodilution observed during CPB in small children, which leads to very low concentrations of coagulation proteins. Due to this discrepancy, whole blood heparin monitors should be further evaluated in children undergoing CPB.
Anticoagulants↗
Outcome of pediatric thromboembolic disease: a report from the Canadian Childhood Thrombophilia Registry.
The outcome for children with deep vein thrombosis (DVT) and pulmonary embolism (PE) is unknown. An understanding of morbidity and mortality of DVT/PE is crucial to the development of rational treatment protocols. The Canadian Childhood Thrombophilia Registry has followed 405 children aged 1 mo to 18 y with DVT/PE for a mean of 2.86 y (range, 2 wk to 6 y) to assess outcome. The all-cause mortality was 65 of 405 children (16%). Mortality directly attributable to DVT/PE occurred in nine children (2.2%), all of whom had central venous line-associated thrombosis. Morbidity was substantial, with 33 children (8.1%) having recurrent thrombosis, and 50 children (12.4%) having postphlebitic syndrome. Recurrent thrombosis and postphlebitic syndrome were more common in older children, although deaths occurred equally in all age groups. The incidence of recurrent thrombosis and postphlebitic syndrome are likely underestimated because of difficulties in diagnosis, especially in younger children. The significant mortality and morbidity found in our study supports the need for international multicenter randomized clinical trials to determine optimal prophylactic and therapeutic treatment for children with DVT/PE.
Adolescent↗
Asthma management in five European countries: doctors' knowledge, attitudes and prescribing behaviour. Drug Education Project (DEP) group.
The aim of the study was to examine the relationship between guideline recommendations on asthma management, and the performance of doctors in five different European health care contexts. Knowledge, attitudes and prescribing behaviour of doctors recruited to an educational project was investigated. A total of 698 general practitioners from Germany, The Netherlands, Norway and Sweden, and 94 specialists from the Slovak Republic participated. A questionnaire was used to assess their knowledge and attitudes. Antiasthmatic drugs dispensed to their patients reflected their prescribing behaviour. In response to questions on how to treat chronic asthma, most doctors were in agreement with guideline recommendations. In practice, however, the proportion of asthma patients receiving inhaled steroids varied almost twofold, ranging 31% in Germany to 58% in The Netherlands. On questions related to exacerbation of asthma, German and Slovakian doctors often preferred treatment with antibiotics to steroids. They also more often associated yellow-green sputum with bacterial infection. In conclusion, although many doctors in different health care contexts have accepted the recommendations given in guidelines, the proportion of their patients treated accordingly differed. German and Slovakian doctors seem to attach less importance to the inflammatory features of asthma than the doctors from the other three European countries.
Adolescent↗
Analysis of warfarin therapy in pediatric patients: A prospective cohort study of 319 patients.
This study details warfarin use in a large pediatric population followed in a central anticoagulation clinic. A prospective, consecutive cohort of nonselected children were studied. Patients were divided into groups by age, target international normalized ratio (INR) range, disease, medications, and vitamin K supplemented enteral nutrition use. Groups were analyzed on multiple aspects of warfarin therapy using multivariate methods. A total of 319 patients received 352 warfarin courses representing 391 treatment years. Age independently influenced all aspects of therapy. When compared with all older children, the </=1 year of age group required increased warfarin doses, longer overlap with heparin, longer time to achieve target INR ranges, more frequent INR testing and dose adjustments, and fewer INR values in the target range. Although significantly different than children </=1 year, children 1 to 6 years of age showed the same findings when compared with 7- to 18-year-olds. Fontan patients required 25% decreased dosage as compared with other congenital heart disease patients. Children on corticosteroids had less INRs in the target range and children on phenobarbital/carbamazepine required increased maintenance dosages of warfarin. Also, patients receiving enteral nutrition required increased dosages of warfarin. Serious bleeding occurred in 2 children (0.5% per patient year). Recurrent thromboembolic events (TEs) occurred in 8 children. Two children had recurrences while receiving warfarin (1.3% per patient year). This study outlines the profound effect of age and relative complexity of clinical management of warfarin therapy in children.
Adolescent↗
Spontaneous arterial thrombosis in children.
Spontaneous peripheral artery thrombosis in children is rare. We present 2 cases, in both of which the diagnosis was delayed. Acute arterial insufficiency should be considered in children who have clinical symptoms of leg pain, pallor, and reduced pulses. Angiography is the gold standard to confirm or exclude the diagnosis.
Aspirin↗
Prevalence of vitamin K deficiency in cystic fibrosis.
BACKGROUND: Patients with cystic fibrosis (CF) are at risk of developing vitamin K deficiency because of pancreatic insufficiency, hepatobiliary disease, or both. OBJECTIVE: Our objective was to determine the prevalence of vitamin K deficiency in unsupplemented patients with CF and to identify risk factors that might be associated with the deficiency. DESIGN: Ninety-eight patients with CF-83 who were pancreatic insufficient (age: 15.2 +/- 10.7 y; range: 0.6-45.8 y), 15 who were pancreatic sufficient (age: 26.2 +/- 11.6 y; range: 6.5-45.3 y), and 62 healthy individuals (age: 16.2 +/- 12. 8 y; range: 1-45 y)-were studied prospectively. None had taken vitamin K supplements. Eight pancreatic-insufficient patients had advanced CF-associated liver disease. Plasma prothrombin in vitamin K absence (PIVKA-II) was measured by immunoassay. All control subjects had PIVKA-II concentrations <3 microg/L. RESULTS: Seventy-eight percent of pancreatic-insufficient patients had PIVKA-II concentrations >/=3 microg/L (22.8 +/- 35.7 microg/L). All patients with CF-associated liver disease had abnormal PIVKA-II concentrations. The mean PIVKA-II concentration of pancreatic-insufficient patients with liver disease was greater than that of those without liver disease (46.6 +/- 65.3 compared with 15. 3 +/- 26.1 microg/L; P < 0.05). Five pancreatic-sufficient patients had mildly elevated PIVKA-II concentrations. Six (7%) pancreatic insufficient patients (3 with CF-associated liver disease) had mildly prolonged prothrombin time but no clinical bleeding. There was no correlation between PIVKA-II concentrations and severity of fat malabsorption or antibiotic use. CONCLUSIONS: Vitamin K deficiency is common in unsupplemented patients with CF and pancreatic insufficiency and routine supplementation should be considered in all of these patients.
Adolescent↗
Antithrombotic therapy in children.
Thromboembolic events are an increasingly common secondary complication in children who are successfully treated for serious, life-threatening primary diseases. In contrast to adults, thromboembolic events are rare enough in children to hinder clinical trials assessing optimal use of antithrombotic agents. Currently, pediatric patients are treated according to guidelines extrapolated from adults. However, optimal prevention and treatment of thromboembolic events in children likely differs from such treatment for adults. The following review summarizes the available information on commonly used antithrombotic agents in children, which include standard heparin, low molecular heparin, oral anticoagulants, thrombolytic therapy, antiplatelet agents, antithrombin concentrates, and protein C concentrates. The mechanisms, dosing, monitoring, therapeutic range, factors influencing dose-response relationship, and side effects are discussed.
Anticoagulants↗
Vitamin K deficiency bleeding (VKDB) in infancy. ISTH Pediatric/Perinatal Subcommittee. International Society on Thrombosis and Haemostasis.
TERMINOLOGY: Replace the term "Hemorrhagic Disease of the Newborn" (HDN) by "Vitamin K Deficiency Bleeding" (VKDB), as neonatal bleeding is often not due to VK-deficiency and VKDB may occur after the 4-week neonatal period. DEFINITION: VKDB is bleeding due to inadequate activity of VK-dependent coagulation factors (II, VII, IX, X), correctable by VK replacement. DIAGNOSIS: In a bleeding infant a prolonged PT together with a normal fibrinogen level and platelet count is almost diagnostic of VKDB; rapid correction of the PT and/or cessation of bleeding after VK administration are confirmative. WARNING SIGNS: The incidence of intracranial VKDB can be reduced by early recognition of the signs of predisposing conditions (prolonged jaundice, failure to thrive) and by prompt investigation of "warning bleeds". CLASSIFICATION: VKDB can be classified by age of onset into early (<24 h), classical (days 1-7) and late (>1 week <6 months), and by etiology into idiopathic and secondary. In secondary VKDB, in addition to breast feeding, other predisposing factors are apparent, such as poor intake or absorption of VK. VK-PROPHYLAXIS: BENEFITS: Oral and intramuscular VK (one dose of 1 mg) protect equally well against classical VKDB but intramuscular VK is more effective in preventing late VKDB. The efficacy of oral prophylaxis is increased with a triple rather than single dose and by using doses of 2 mg vitamin K rather than 1 mg. Protection from oral doses repeated daily or weekly may be as high as from i.m. VK. VK-PROPHYLAXIS: RISKS: VK is involved in carboxylation of both the coagulation proteins and a variety of other proteins. Because of potential risks associated with extremely high levels of VK and the possibility of injection injury, intramuscular VK has been questioned as the routine prophylaxis of choice. Protection against bleeding should be achievable with lower peak VK levels by using repeated (daily or weekly) small oral doses rather than by using one i.m. dose. BREAST FEEDING MOTHERS TAKING COUMARINS: Breast feeding should not be denied. Supervision by pediatrician is prudent. Weekly oral supplement of 1 mg VK to the infant and occasional monitoring of PT are advisable. CONCLUSION: VKDB as defined is a rare but serious bleeding disorder (high incidence of intracranial bleeding) which can be prevented by either one i.m. or multiple oral VK doses.
Humans↗
The influence of developmental haemostasis on the laboratory diagnosis and management of haemostatic disorders during infancy and childhood.
The physiology of the hemostatic system in children is different from that in adults. Reference ranges for components of the hemostatic system are age dependent. During early childhood, physiologic values may overlap with values observed in congenital deficiencies of acquired pathological conditions. Physiologically decreased plasma concentrations of hemostatic components also influence the response to antithrombotic therapy. The relevance of developmental hemostasis for the laboratory diagnosis and management of hemorrhagic and thrombotic disorders during childhood is discussed.
Adolescent↗
Investigation of the anticoagulant mechanisms of a covalent antithrombin-heparin complex.
Recently, we developed a covalent antithrombin-heparin complex (ATH) as a possible treatment for respiratory distress syndrome. ATH reacted rapidly with thrombin and efficiently catalyzed the inhibition of either thrombin or factor Xa by exogenous antithrombin. In order to investigate mechanisms for the conjugate's unusual anticoagulant properties, changes in fluorescence due to covalent linkage or addition of exogenous antithrombin were studied in relation to reaction with thrombin derivatives or factor Xa. The emission spectrum of ATH was similar to that of antithrombin plus heparin mixtures. ATH quickly inhibited thrombin or factor Xa activities, as measured by a fluorogenic substrate. Fluorescein-labeled heparin was displaced from either thrombin or active site blocked thrombin by ATH, indicating that thrombin must bind to the conjugate's heparin moiety. Interaction of thrombin with ATH's heparin component was confirmed by a slow reaction rate of conjugate with a thrombin mutant that has weak heparin binding. Total intrinsic fluorescence increased when exogenous antithrombin was added to ATH, indicating that the catalytic mechanism may occur through a second inhibitor binding site. Thus, ATH reacts directly with thrombin through a bridge mechanism and probably catalyzes the reaction of thrombin with antithrombin by a second binding sequence on its heparin chain.
Anticoagulants↗
Covalent heparin cofactor II-heparin and heparin cofactor II-dermatan sulfate complexes. Characterization of novel anticoagulants.
Heparin cofactor II is a naturally occurring anticoagulant that acts by specifically inhibiting thrombin and is facilitated by the binding of glycosaminoglycans such as heparin and dermatan sulfate. In vivo, heparin cofactor II-glycosaminoglycan complexes dissociate, leaving the inhibitor less active in its ability to function as a component of the anticoagulation pathway. We have produced permanently activated heparin cofactor II molecules by covalent linkage to either heparin or dermatan sulfate. Covalent heparin cofactor II-heparin and heparin cofactor II-dermatan sulfate complexes had catalytic antithrombin activities similar to those of the corresponding starting heparin and dermatan sulfate (86% and 110% of standard heparin and dermatan sulfate activity, respectively). Both heparin cofactor II-heparin and heparin cofactor II-dermatan sulfate had fast bimolecular rate constants of 1.4 x 10(7) M-1 s-1 and 1.3 x 10(7) M-1 s-1, respectively, for reaction with thrombin. The intravenous half-life of the covalent complexes in rabbits was significantly longer than that of free heparin or dermatan sulfate (4.4, 3.4, 0.33, and 0.50 h for heparin cofactor II-heparin, heparin cofactor II-dermatan sulfate, heparin, and dermatan sulfate, respectively). Given their unique properties, these conjugates may have a clinical application for long term, selective inhibition of thrombin.
Animals↗
Anticoagulant dermatan sulfate proteoglycan (decorin) in the term human placenta.
Normal pregnancy is characterized by increased in vivo thrombin generation. A greater proportion of endogenously generated thrombin is complexed to heparin cofactor II in plasma from pregnant women compared to plasma from nonpregnant ones. The increase in thrombin-heparin cofactor II complexes suggests that the site of the additional thrombin generation is relatively rich in dermatan sulfate. We postulated that the site of thrombin generation may be the placenta since endogenous thrombin generation returns rapidly to normal after delivery. This report describes the isolation and characterization of placental dermatan sulfate proteoglycan from villous tissue of the term human placenta. Placental dermatan sulfate was isolated by guanidine HCI extraction and anion exchange chromatography. The isolated material was found to have anticoagulant activity with a relative activity of approximately 40% of that of a porcine mucosal dermatan sulfate which is undergoing clinical trial as an antithrombotic agent. The dermatan sulfate was present as a proteoglycan with a molecular mass of 90-150 kD. Upon degradation with chondroitin ABC lyase, the core protein was demonstrated to be a doublet with molecular masses of 42 and 44 kD. This core protein reacted with antiserum against the core protein of decorin on Western analysis. The role of this placental dermatan sulfate in local regulation of thrombin in the placenta warrants further study.
Alcian Blue↗
The use of lectin-dependent lysis for detection of cytotoxic T lymphocytes in outbred animals.
The assessment of cytotoxic T lymphocyte (CTL) specificity and levels of activity is often important in the analysis of an immune response to viral infection or vaccination. However, the restriction of CTL lysis to cells bearing self major histocompatibility complex proteins makes this analysis difficult in outbred animals. The data presented here demonstrate that lysis by CTL can be measured on allogeneic or xenogeneic target cells in the presence of Concanavalin A, if the CTL are first restimulated in vitro with specific antigen. Using this method, CTL from a large number of animals could be conveniently assayed on a single target cell line.
Animals↗
Benefit of heparin in peripheral venous and arterial catheters: systematic review and meta-analysis of randomised controlled trials.
OBJECTIVE: To evaluate the effect of heparin on duration of catheter patency and on prevention of complications associated with use of peripheral venous and arterial catheters. DESIGN: Critical appraisal and meta-analysis of 26 randomised controlled trials that evaluated infusion of heparin intermittently or continuously. Thirteen trials of peripheral venous catheters and two of peripheral arterial catheters met criteria for inclusion. MAIN OUTCOME MEASURES: Data on the populations, interventions, outcomes, and methodological quality. RESULTS: For peripheral venous catheters locked between use flushing with 10 U/ml of heparin instead of normal saline did not reduce the incidence of catheter clotting and phlebitis or improve catheter patency. When heparin was given as a continuous infusion at 1 U/ml the risk of phlebitis decreased (relative risk 0.55; 95% confidence interval 0.39 to 0.77), the duration of patency increased, and infusion failure was reduced (0.88; 0.72 to 1.07). Heparin significantly prolonged duration of patency of radial artery catheters and decreased the risk of clot formation (0.51; 0.42 to 0.61). CONCLUSIONS: Use of intermittent heparin flushes at doses of 10 U/ml in peripheral venous catheters locked between use had no benefit over normal saline flush. Infusion of low dose heparin through a peripheral arterial catheter prolonged the duration of patency but further study is needed to establish its benefit for peripheral venous catheters.
Adolescent↗
Anticoagulation therapy in pediatric patients with sinovenous thrombosis: a cohort study.
OBJECTIVE: To assess the use of anticoagulant therapy in a consecutive cohort study of children with sinovenous thrombosis (SVT). METHODS: A single institutional pilot study of anticoagulant therapy was conducted from January 1992 to December 1996 at the Hospital for Sick Children, Toronto, Ontario. Consecutive children with the diagnosis of SVT, made by computed tomography, magnetic resonance imaging (MRI), MRI with venography, ultrasonography, nuclear brain scanning, or conventional angiography were eligible for anticoagulant therapy. RADIOGRAPHIC EVALUATION: Most children underwent multiple radiographic tests for evaluation of the central nervous system. Of the 32 episodes of SVT, CT was performed in 30, MRI with or without venography in 26, ultrasonography in 11, and nuclear brain scanning in 5. The majority of the SVTs were located at the superior sagittal sinus (50%) and right lateral sinus complex (44%). RESULTS: There were 30 consecutive children with 32 episodes of SVT during the 5-year study (2 girls had recurrent SVT). The median age was 6.2 years (age range, 3 days to 18 years), and the sex of the patients was evenly distributed (15 girls and 15 boys). The primary associated clinical conditions consisted of systemic lupus erythematosus (n = 5), renal disease (n = 3), perinatal distress (n = 2), congenital heart disease (n = 1), cerebral arteriovenous malformation (n = 1), and neurosurgery for refractory seizures (n= 1). The remainder were previously healthy children older than 1 month (n = 10) and newborns (n = 7). Eight children were ineligible for anticoagulant therapy because of an associated intracranial hemorrhage (n = 6), a postoperative bleeding risk after neurosurgery (n = 1), or a prolonged delay from the diagnosis to the time of referral (n = 1). Ten children received standard heparin, and 12 children received low-molecular-weight heparin (LMWH) (enoxaparin sodium). Eighteen children were treated with oral anticoagulants for 3 months after initial heparin therapy, and 4 patients received LMWH for the entire course of treatment. There was no intracranial hemorrhage in the 12 patients treated with LMWH, but there was 1 case of clinically silent bleeding in the standard heparin group. CONCLUSIONS: The results of this pilot study suggest that anticoagulant therapy, in particular LMWH, is safe and may have a role in the treatment of children with SVT. A randomized controlled trial is warranted.
Adolescent↗