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Biomedical subjects

P Monagle

Publications and source records attributed to P Monagle.

36 records · Page 2Linked to original sources
PubMed1998

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↗
PubMed1998

Dalteparin for deep venous thrombosis: a hospital-in-the-home program.

OBJECTIVE: To assess the efficacy, safety and cost savings of home treatment of lower-limb deep venous thrombosis (DVT). SETTING: A hospital-in-the-home treatment program. PATIENTS: One hundred patients with acute lower limb DVT (53 proximal, 47 distal), and no contraindication to home treatment, were entered into the program from March 1995 to February 1997. INTERVENTION: All patients received dalteparin, 200 units/kg subcutaneously, once daily for a minimum of five days, with commencement of oral anticoagulation (warfarin) on Day 2. Patients with proximal DVT had lung ventilation-perfusion scans performed and were admitted to hospital for at least 24 hours. Patients with distal DVT were discharged directly to home treatment. MAIN OUTCOME MEASURES: Clinical responses and the results of sequential duplex ultrasonography at one week, one month, three months and six months. RESULTS: There were no major, but six minor, bleeding complications, two of which led to dalteparin being withdrawn. Sixteen patients had lung ventilation-perfusion scans showing a high probability of pulmonary embolism. All were asymptomatic, and follow-up for at least three months showed no symptomatic thromboembolic events. Duplex ultrasonography showed progression of thrombosis in the first week of therapy in 13.2% of distal and 2.7% of proximal thromboses. Thereafter, distal DVT improved at a much greater rate than proximal DVT; after six months complete resolution was seen in 60.7% of distal and 18.5% of proximal thromboses, respectively. Cost saving was $197 per bed-day equivalent compared with inpatient care. At 15 months' follow-up, swelling and/or pain was reported by 49% of patients with distal DVT and 66% of those with proximal DVT. CONCLUSIONS: Once-daily dalteparin therapy for DVT in a hospital-in-the-home setting was safe, efficacious and cost effective. However, DVT resolution is a slow process, with significant long term morbidity.

Adolescent↗
PubMed1998

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↗
PubMed1998

Prothrombotic disorders in infants and children with cerebral thromboembolism.

BACKGROUND: To our knowledge, the contribution of prothrombotic conditions to cerebral thromboembolism has never been prospectively studied in a large series of pediatric patients. METHODS: The Hospital for Sick Children, Toronto, Ontario, established a program in January 1992 to diagnose and treat children (term newborn to 18 years old) with arterial ischemic stroke or sinovenous thrombosis. The routine evaluation for prothrombotic conditions included plasminogen, antithrombin, protein C, free protein S, activated protein C resistance, IgG and IgM anticardiolipin antibody, and lupus anticoagulant. We analyzed samples taken within 2 years of the event. We report results on patients seen from January 1, 1992, to January 1, 1997. RESULTS: Ninety-two patients (47 males and 45 females) entered the program during the study interval. Patients ranged from newborn to 18 years in age. Arterial ischemic stroke occurred in 78% of patients while sinovenous thrombosis occurred in 22%. All were tested for prothrombotic disorders. One or more abnormal results were present in 35 (38%) of the 92 patients. The majority (21/35) had multiple abnormal test results. The abnormal test results were anticardiolipin antibody (33%), plasminogen (9.5%), activated protein C resistance (9%), protein C (7%), antithrombin (12.5%), lupus anticoagulant (8%), and free protein S (11.5%). Male sex predicted the presence of prothrombotic abnormalities (relative risk, 1.7; 95% confidence interval, 1.2-2.5), but stroke type (relative risk, 0.8; 95% confidence interval, 0.7-1.1), age group, and presence of other risk factors did not predict abnormal testing. CONCLUSIONS: A significant proportion (38%) of children with cerebral thromboembolism had evidence of prothrombotic conditions. In particular, there was a predominance of children with anticardiolipin antibody (33%). These data support a recommendation that children with cerebral thromboembolism be evaluated for prothrombotic disorders.

Adolescent↗
PubMed1998

Central venous catheter related thrombosis in children: analysis of the Canadian Registry of Venous Thromboembolic Complications.

BACKGROUND: Central venous lines (CVLs) are frequently associated with deep venous thrombosis (DVT) in children; however, little is known about the epidemiologic characteristics or outcome of CVL-related DVT. METHODS: The Canadian Childhood Thrombophilia Registry monitored 244 consecutive patients with objectively diagnosed CVL-related DVT for a median duration of 24 months (range 3 months to 7 years). RESULTS: The incidence of CVL-related DVT was 3.5 per 10,000 hospital admissions. CVL-related DVTs were more frequent in the upper venous system. Ultrasonography or echocardiography were the most commonly used diagnostic tests (n = 183 patients). Venograms were performed on 82 (34%) patients. A variety of therapies were used. Thirty-nine children had pulmonary emboli, but most were not investigated for pulmonary emboli. Nine (3.7%) children died as a consequence of their thromboembolic disease. Recurrent DVT occurred in 16 (6.5%) children, and postphlebitic syndrome occurred in 23 (9.5%) children. CONCLUSION: Currently no uniform guidelines exist for the prevention and management of CVL-related DVT in children. The frequency and clinical consequences of CVL-related DVTs justify controlled trials of primary prophylaxis in children requiring central venous access.

Adolescent↗
PubMed1998

Influence of mechanical stretch on thrombin regulation by fetal mixed lung cells.

Respiratory distress syndrome (RDS) is characterized by intrapulmonary fibrin deposition, which can adversely affect surfactant function, and stimulate fibroblast proliferation, which may contribute to the development of bronchopulmonary dysplasia (BPD). We speculated that the premature lung may have impaired regulation of thrombin, thus making preterm infants susceptible to fibrin formation within the lung. Therefore, we studied the effect of stretch, which simulates fetal breathing movements (FBMs), on the generation and inhibition of a key hemostatic enzyme-thrombin-by rat fetal mixed lung cells (FMLCs). Our results showed that stretch induced glycosaminoglycan production with increased antithrombin activity due to an increase in the concentration of active chondroitin sulfate. Stretch downregulated secretion of tissue factor procoagulant activity, which may lead to decreased thrombin generation on the surface of FMLCs. Overall, stretch enhanced the local control of thrombin by FMLCs. These results suggest that premature infants, who will have experienced less FBM, may have impaired thrombin regulation. Impaired thrombin regulation likely contributes to increased fibrin deposition and, potentially, the development of BPD.

Animals↗
PubMed1998

Morphologic and biochemical features affecting the antithrombotic properties of the inferior vena cava of rabbit pups and adult rabbits.

The incidence of venous thromboembolic disease is reduced in children compared with adults. Thromboprotective mechanisms, some of which have already been identified in plasma, must be present in children. Blood vessel walls have important antithrombotic properties that maintain blood fluidity. This is in part due to proteoglycan (PG)-related glycosaminoglycan (GAG) molecules within vessel walls. PGs are macromolecules with covalently attached GAG chains, either chondroitin, dermatan, heparan, or keratan sulfate. The influence of age on the concentration and anticoagulant activities of PGs and GAGs, within vein walls before puberty has not been previously investigated. We hypothesized that developmental differences in vein walls may contribute to the reduced risk of thrombosis in children. We used a rabbit model to examine morphologic and biochemical features of inferior venae cavae (IVCs). We assessed IVC wall morphology, PG distribution, GAG mass, and GAG antithrombin activity. Morphologically, there were only minor differences between pups and adult rabbits' IVCs. However, there was a significant increase in GAGs by mass in IVCs from pups compared with adult rabbits (p = 0.012). In addition the total antithrombin activity (p = 0.04), and especially that of heparan sulfate (p = 0.01) was significantly increased in pups compared with adult rabbits. These results demonstrate important differences in the antithrombotic properties of IVC walls in pups and adult rabbits. In summary, developmental differences in vein wall PG content and activity exist which may contribute to the reduced risk of venous thromboembolism in children. Further characterization of these differences is required.

Age Factors↗
PubMed1998

Homozygous protein C deficiency: description of a new mutation and successful treatment with low molecular weight heparin.

We present a kindred with a new mutation of the protein C gene, in which the proband had an unusual clinical presentation. The relationship between warfarin induced skin necrosis and level of anticoagulation was investigated. The pharmacokinetics of protein C concentrate was assessed to determine frequency of replacement therapy. The clinical and biochemical efficacy of therapy with low molecular weight heparin (LMWH) was assessed. The effect of long-term LMWH on bone density in the growing child was monitored using whole body densitometry. Warfarin therapy required an INR of greater than 3.5 to avoid skin necrosis. If protein C replacement was to be used, doses of 100 U/kg/day would have been required to maintain protein C levels consistently at or above 0.20 U/ml. While receiving prophylactic therapy with LMWH for almost 3 years, there were no episodes of recurrent thrombosis, no skin necrosis and no bleeding. Biochemical markers of in vivo thrombin generation were suppressed and within the normal range. Bone density continued to increase at the normal rate throughout the treatment period. LMWH is an effective form of long-term therapy for homozygous protein C deficient patients with measurable protein C levels.

Adult↗
PubMed1998

Morphological and biochemical features affecting the antithrombotic properties of the aorta in adult rabbits and rabbit pups.

We hypothesised that there are important physiologic differences in arterial wall structure and function with respect to antithrombotic activity in the very young (pre-puberty) compared to adults. Electron microscopy, gel electrophoresis, and activity assays were used to examine differences in aorta structure and function comparing prepubertal rabbits (pups) to adult rabbits. Differences in endothelial function, extracellular matrix structure, proteoglycan (PG) distribution and glycosaminoglycan (GAG) content and function were shown. In both intima and media, total PG, chondroitin sulfate (CS) PG and heparan sulfate (HS) PG content were significantly increased in pups compared to adult rabbits. These findings corresponded to increased concentrations by mass analyses of CS GAG and DS GAG in aortas from pups. There was also a significant increase in antithrombin activity in pups due to HS GAG. In conclusion, differences in both structure and antithrombin activity of aortas from pups compared to adult rabbits suggest that young arteries may have greater antithrombotic potential that is, at least in part, related to increased HS GAG.

Aging↗
PubMed1997

Covalent antithrombin-heparin complexes with high anticoagulant activity. Intravenous, subcutaneous, and intratracheal administration.

Although heparin has been used clinically for prophylaxis and treatment of thrombosis, it has suffered from problems such as short duration within compartments in vivo that require long term anticoagulation. A covalent antithrombin-heparin complex has been produced with high anticoagulant activity and a long half-life relative to heparin. The product had high anti-factor Xa and antithrombin activities compared with noncovalent mixtures of antithrombin and heparin (861 and 753 units/mg versus 209 and 198 units/mg, respectively). Reaction with thrombin was rapid with bimolecular and second order rate constants of 1.3 x 10(9) M-1 s-1 and 3.1 x 10(9) M-1 s-1, respectively. The intravenous half-life of the complex in rabbits was 2.6 h as compared with 0.32 h for similar loads of heparin. Subcutaneous injection of antithrombin-heparin resulted in plasma levels (peaking at 24-30 h) that were still detectable 96 h post-injection. Given the increased lifetime in these vascular and intravascular spaces, use of the covalent complex in the lung was investigated. Activity of antithrombin-heparin instilled into rabbit lungs remained for 48 h with no detection of any complex systemically. Thus, this highly active agent has features required for pulmonary sequestration as a possible treatment for thrombotic diseases such as respiratory distress syndrome.

Animals↗
PubMedDate not supplied

A survey of pediatric cardiology nurses' understanding of warfarin therapy.

Children with underlying cardiac defects represent the largest cohort of pediatric patients requiring oral anticoagulant therapy. This study aimed to determine how much pediatric cardiology nurses understood about warfarin therapy, given their role as patient educators. Surveys were sent to four Australian pediatric hospitals that provided inpatient cardiac services. Data are presented descriptively, with relationship between variables analyzed using linear regression analysis. Forty-one completed questionnaires were received from 94 registered nurses. The majority of nurses held an undergraduate degree in nursing and were classified as senior registered nurses. Nurses did not demonstrate a good understanding of warfarin therapy. Knowledge deficits were identified across a broad spectrum of areas, with only 30% of nurses reporting that they felt equipped to provide families with education regarding oral anticoagulant therapy. Nurses regularly provide patients with education regarding medication regimes; however, the effectiveness of that education is rarely evaluated. This study suggests that pediatric nurses working with patients who are often prescribed oral anticoagulant therapy have significant knowledge deficits about anticoagulant therapy. The impact of this lack of knowledge on the effectiveness of patient education has not been evaluated, but it is unlikely to be helpful.

Anticoagulants↗
PubMedDate not supplied

Capillary whole blood monitoring of oral anticoagulants in children in outpatient clinics and the home setting.

A whole blood prothrombin time/international normalized ratio (PT/INR) monitor (CoaguChek, Roche Diagnostics Corp., Indianapolis, IN) was assessed in children for its accuracy, reliability, safety, and acceptance by health care personnel and patient's families. The PT/INR values measured by the CoaguChek monitor showed an excellent correlation with PT/INR values measured by the Hospital for Sick Children (HSC) laboratory (r = 0.96) and Hamilton Civic Hospitals Research Centre (HCHRC) laboratory (r = 0.92) in clinic patients and a close correlation with PT/INR values measured by the HSC laboratory (r = 0.76) and HCHRC laboratory (r = 0.74) in patients at home. Reduced correlation in the home setting did not adversely affect clinical management. The whole blood PT/INR monitor is safe and accurate for children requiring oral anticoagulation therapy in either the outpatient clinic or home setting.

Administration, Oral↗
PubMedDate not supplied

Heparin-induced thrombocytopenia in children.

OBJECTIVE: To audit the frequency of heparinoid (standard heparin and low molecular weight heparin) use in a tertiary paediatric hospital, and to determine the occurrence of heparin-induced thrombocytopenia (HIT). METHODS: A 1-week cross-sectional audit of all heparinoids given to inpatients at a tertiary paediatric hospital was undertaken and a retrospective medical record review of all suspected HIT cases at the tertiary paediatric centre over a 2-year period was carried out. RESULTS: One hundred and sixteen patients received heparinoid medications over a 7-day period. An average of 29 children received heparin daily. The retrospective medical record review identified four patients with suspected HIT over a 2-year period. Two patients developed thrombotic complications, which were fatal in one patient. CONCLUSION: Heparin is used frequently in paediatric tertiary hospitals, yet the occurrence of HIT in children is much lower than that reported in adults. Improved laboratory techniques could facilitate improved screening and diagnosis of this serious adverse drug reaction.

Adolescent↗
PubMedDate not supplied

Cerebral sinus venous thrombosis in children.

OBJECTIVE: Cerebral sinus venous thrombosis (cerebral SVT) is rare in children. Information on clinical characteristics, radiological findings and outcome is emerging. METHODS: Cases of cerebral SVT diagnosed between 1995 and 2001 were identified by a computer-assisted search using International Classification of Disease codes. Medical records were reviewed to collect information on clinical presentation, investigations, treatment and outcome. RESULTS: Sixteen cases of cerebral SVT were identified. All cases presented in association with head and neck pathology. The majority of cases presented with symptoms of raised intracranial pressure and focal neurological signs. Magnetic resonance imaging identified all cases of cerebral SVT whilst CT scanning failed to demonstrate the diagnosis in two cases. Management with anticoagulation was associated with radiological resolution of the thrombosis and normal neurological outcome. Long-term follow up demonstrated neurological deficits in greater than 40% of patients. CONCLUSION: Cerebral SVT in children is associated with significant residual neurological morbidity. Prospective studies to identify predictors of outcome and effective management interventions are required.

Adolescent↗