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Biomedical subjects

P Ockelford

Publications and source records attributed to P Ockelford.

17 recordsLinked to original sources
PubMed2006

Post-treatment residual thrombus increases the risk of recurrent deep vein thrombosis and mortality.

BACKGROUND: Recurrent thromboembolic events after an initial deep vein thrombosis (DVT) are relatively frequent. Residual thrombus in the affected veins on ultrasound scan at the completion of anticoagulant therapy has been described as a recurrence risk factor, and may have utility in stratifying those patients at risk. OBJECTIVES: The aims of the study were to correlate the risk of recurrence of DVT with the results of ultrasound at completion of oral anticoagulant therapy. A secondary aim was to review the mortality in this population. PATIENTS: A cohort of 316 DVT patients was included. The patients were divided into those with completely clear vessels on follow-up scan (45%) and those with residual thrombus identified (55%). RESULTS: The cumulative incidence of recurrence was 10% by 2 years and 23% by 5 years. Patients with residual thrombus on follow-up ultrasound were at higher risk of recurrence (hazard ratio [HR] 2.2, 1.19-4.21; P = 0.012) which remained significant after multivariate adjustment for age, gender and malignancy (HR 2.2, 1.15-4.17; P = 0.018). During follow-up, the cumulative mortality was 12% at 2 years and 27% by 5 years. The risk of death was increased in patients with residual thrombus on follow-up scan (HR 3.9, 1.93-7.71; P < 0.001) and this risk persisted after multivariate analysis of age, gender and malignancy (2.8, 1.37-5.72; P = 0.005). The majority of deaths were due to malignancy (68%) however 10 (18%) died from vascular causes. There was a trend towards increased vascular death in the patients with residual thrombus on follow-up ultrasound scan, which did not reach significance (HR 4.1, 0.87-19.33; P = 0.13). CONCLUSIONS: Consistent with previous cohort studies, recurrence risk is increased in patients with residual thrombus on ultrasound. The increased risk of death in patients with residual thrombus, with a trend towards increased vascular death, may suggest that failure of thrombus resolution is a marker of more global vascular dysfunction.

Anticoagulants↗
PubMed2004

Audit of community-based anticoagulant monitoring in patients with thromboembolic disease: is frequent testing necessary?

Oral anticoagulant monitoring is managed by general practitioners in Auckland. An audit of this service in 452 patients demonstrated that anticoagulant control was in line with recommended international guidelines, with 58.3% of international normalized ratio (INR) measurements in the therapeutic range. However, the frequency of testing was high, with the majority of patients (68%), including those on long-term treatment, having INR measurements at weekly intervals. We question the need for such frequent INR testing.

Adolescent↗
PubMed2001

The influences of obesity and glycemic control on endothelial activation in patients with type 2 diabetes.

The aims of this study were to elucidate the factors that contribute to endothelial activation and fibrinolytic abnormalities in patients with poorly controlled type 2 diabetes and to determine whether improved glycemic control reduces endothelial activation. Adhesion molecules [E-selectin, intracellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1], von Willebrand factor, total nitric oxide (NO), endothelin-1, tissue plasminogen activator, and plasminogen activator inhibitor-1 were measured in 43 type 2 diabetic subjects with hemoglobin A1c of 9.0% or more at baseline (compared with 21 healthy controls) who after 20 wk had been randomized to either improved (IC) or usual (UC) glycemic control. At baseline, type 2 diabetic patients had significant endothelial activation and abnormal fibrinolysis compared with control subjects. Body mass index in the diabetic patients was the only independent predictor of E-selectin (P = 0.007), ICAM-1 (P = 0.01), and NO (P = 0.008) concentrations, but not vascular cell adhesion molecule-1, plasminogen activator inhibitor-1, or tissue plasminogen activator (all P > 0.05). Type 2 diabetic patients with a body mass index of 28 kg/m2 or less had concentrations of E-selectin, ICAM-1, endothelin-1, and NO similar to those in healthy controls. After 20 wk, hemoglobin A1c was significantly lower in IC vs. UC (IC, 8.02 +/- 0.25%; UC, 10.23 +/- 0.23%; P < 0.0001), but there were no significant changes in markers of endothelial activation or indexes of fibrinolysis. Obesity appears to be the most important predictor of endothelial activation in patients with type 2 diabetes. Short-term improvement in glycemic control does not appear to reduce endothelial activation.

Biomarkers↗
PubMed2000

Defective fibrinogen polymerization associated with a novel gamma279Ala-->Asp mutation.

A woman with menorrhagia was investigated for a suspected fibrinogen mutation when coagulation tests revealed prolonged thrombin (55 s) and reptilase (43 s) times together with a functional and an antigenic fibrinogen concentration of 0.7 and 2.8 mg/ml respectively. Heterozygosity for a gamma-chain mutation was suggested by a doublet gamma band on SDS-PAGE and an increased negative charge was observed on isoelectric focusing of HPLC-isolated gamma-chains. Electrospray ionization mass spectrometry revealed a gamma-chain mass of 48 411 Da, which was 20 Da more than the control value of 48 391 Da. Because the normal and variant gamma-chains were not resolved, this implied a 40-Da increase in 50% of the gamma-molecules. An increased negative charge and a 44-Da increase in mass was verified when DNA sequencing showed heterozygosity for an Ala (GCC)-->Asp (GAC) substitution at codon 279 of the gamma-gene. Fibrin polymerization curves indicated a delay in the onset, and a decrease in the rate, of polymerization. Examination of crystal structures showed that the adjacent Tyr-gamma280 side chain is involved in bonding across the D-D interface, and from the proximity of the gamma279Ala-->Asp mutation it would appear that this perturbs the end-to-end DD interactions between fibrin units of the growing polymer.

Adult↗
PubMed1999

Screening for a prothrombotic diathesis in patients attending family planning clinics.

AIMS: 1. To determine the frequency of prothrombotic markers in young women seeking a new or a repeat prescription of the oral contraceptive pill and perceived to be at high risk of thrombosis. 2. To assess cost-effectiveness of thrombophilia testing within this population. 3. To determine the frequency of acquired activated protein C (APC) resistance. METHODS: Results of thrombophilia testing were retrospectively reviewed on 220 consecutively referred patients' plasmas. Women tested were clients attending local family planning clinics for a new or repeat contraceptive prescription. Samples for testing were collected by the Community Laboratory Service. Investigations included: antithrombin III (AT III), protein C, protein S, APC resistance, factor V Leiden mutation analysis and anti-cardiolipin antibodies. RESULTS: Abnormalities were detected in 35 (15.9%) of the 220 women tested. No patient had all tests performed. The most frequently detected abnormality was an increased APC resistance in 6.8% of the women tested. Three of the 13 patients with an abnormal APC resistance had a discrepancy between the low APC ratio and a negative mutation analysis result for factor V Leiden, suggesting acquired APC resistance. Deficiency of protein C was found in 1.2% (of 162), protein S in 2.0% (of 140), antithrombin III in 0.6% (of 159). Low-titre anti-cardiolipin antibodies were detected in 13.9% of this group (115 tested). CONCLUSIONS: The frequency of abnormal thrombophilia markers detected in this cohort of young women is not significantly different from that seen in a control population. This low incidence suggests that testing has been applied on a population screening basis, rather than preselecting a high-risk group. Thrombophilia screening in this patient group cannot be justified when the clinically relevant end-point is death from pulmonary embolism. The cost of preventing one fatal pulmonary embolism arising as a consequence of screening for activated protein C resistance due to the commonly occurring factor V Leiden is a minimum $25,000,000. This compares very unfavourably with the estimated cost per life saved in the National Breast Screening Programme.

Activated Protein C Resistance↗
PubMed1998

A 20.7 kb deletion within the factor VIII gene associated with LINE-1 element insertion.

Large deletions within the factor VIII gene account for approximately 5% of the mutations causing haemophilia A. The characterization of such mutations can provide insights into the molecular mechanisms of these and other deletions in man. We have analyzed a 20.7 kb deletion spanning exons 15 to 20 within the factor VIII gene in a patient with severe haemophilia A. Long range PCR was used to investigate the extent of the deletion and to provide a template for sequencing across the deletion breakpoint. A 38-base insertion homologous to the 3' region of a LINE-1 (L1) element was detected at the breakpoint of the deletion. Normal sequence at the 5' breakpoint in intron 14 was homologous to an L1 flanking region and normal sequence at the 3' breakpoint in intron 20 was homologous to an adjacent sequence within the same L1 flanking region. A molecular mechanism for the deletion involving retrotransposition of a readthrough product of an L1 element plus its 3' flanking region is suggested.

Base Sequence↗
PubMed1996

Experience with recombinant factor VIIa in Australia and New Zealand.

Recombinant factor VIIa (rFVIIa; NovoSeventrademark) was availablefor compassionate use in Australia and New Zealand from 1991 to 1994. Over this period there were 18 treatment episodes in 9 patients, age 8-66 years, with haemophilia A and high titre inhibitors cross-reacting with porcine factor VIII. There were no significant adverse effects. Treatment with rFVIIa resulted in a successful outcome in 8 potentially life-threatening (retroperitoneal, subdural, gastro-intestinal) bleeds. Elective cystoscopy, repair of a cranial flap, yttrium synovectomy and inguinal herniotomy were performed successfully, as was surgical decompression of a flexor pollicis longus bleed. Treatment of a patient with an infected haematoma had limited success, attributed to intermittent suboptimal doses. In 2 patients, satisfactory haemostasis was achieved for multiple dental extractions; subsequent oozing was attributed to suboptimal rFVIIa and/or antifibrinolytic therapy.

Adult↗
PubMed1993

Orgaran (Org 10172) or heparin for preventing venous thrombosis after elective surgery for malignant disease? A double-blind, randomised, multicentre comparison. ANZ-Organon Investigators' Group.

This double-blind, randomised, multicentre trial in 513 patients having elective surgery for intra-abdominal or intrathoracic malignancy compared the efficacy and safety of venous thrombosis (VT) prophylaxis using 750 anti-factor Xa units of Orgaran (a mixture of low molecular weight heparinoids) given subcutaneously (sc) twice-daily with that of twice-daily injections of 5,000 units standard heparin. The main study endpoints were the development of postoperative VT detected by 125I-fibrinogen leg scanning, and the onset of clinically significant venous thromboembolism or bleeding. "Intent to treat" analysis showed a statistically non-significant trend towards less VT during Orgaran prophylaxis (10.4%) than after heparin (14.9%) and there was no difference in bleeding complications between the two study groups. Results remained similar if only patients who completed the intended course of therapy ("compliant patients") were analysed. Other trials have shown that Orgaran prevents VT after hip surgery and stroke. We now show it is also safe and effective in patients having major surgery for cancer.

Aged↗
PubMed1986

Heparin 1986. Indications and effective use.

Heparin is a complex polysaccharide, consisting of repeating dissacharide subunits, which exerts its anticoagulant effect by potentiating the inhibition of activated clotting proteins by the naturally occurring inhibitor antithrombin III. The primary indication for its use is venous thromboembolic disease where an average 20,000 to 40,000 USP units are initially administered by constant infusion over 24 hours to prevent extension of an established thrombus. Subsequent treatment is based on the therapeutic response, usually monitored by a global clotting test such as the activated partial thromboplastin time (APTT). The chromogenic assay based on heparin-induced inhibition of activated factor X (Xa) is a particularly useful alternative monitoring test where thrombosis complicates pregnancy or is associated with the lupus anticoagulant. Subcutaneous heparin has also been used for the primary treatment of venous thrombosis but is more frequently used either for primary or secondary prophylaxis. Primary prophylaxis schedules usually employ a low dose (5000 units) administered 8- or 12-hourly without anticoagulant control, but a titrated subcutaneous heparin regimen has been successfully reported in elective hip surgery. Although arterial thrombosis is primarily initiated by platelet aggregates forming in vivo, heparin is commonly administered for acute arterial thromboembolism including peripheral arterial occlusion and repeated transient cerebral ischaemic events. The potential efficacy of heparin in disseminated intravascular consumption (DIC) remains to be firmly established, but is indicated where symptomatic thrombotic complications occur. Thrombocytopenia and haemorrhagic side effects may complicate heparin therapy, but bleeding complications may be minimised with the development of modified low molecular weight heparin which is currently undergoing clinical trial.

Clinical Trials as Topic↗
PubMed1984

A comparison of the antithrombotic and haemorrhagic effects of low molecular weight heparin fractions: the influence of the method of preparation.

Bleeding is an important complication of heparin therapy. A number of low molecular weight heparin fractions produce less bleeding than standard heparin for an equivalent antithrombotic effect in experimental animals. Low molecular weight heparin fractions and fragments are produced by a number of different procedures but their relative effects on haemostasis and thrombosis have not been evaluated. We have compared the antithrombotic and haemorrhagic effects of two low molecular weight heparin fragments and of a heparinoid with porcine mucosa heparin and related these in vivo findings to the results of ex vivo tests of blood coagulation and in vitro tests of platelet vivo tests of blood coagulation and in vitro tests of platelet function. Haemorrhage was assessed using a rabbit ear bleeding model. The antithrombotic effects were assessed by measuring inhibition of a tissue thromboplastin-induced jugular vein thrombus and by inhibition of fibrin and platelet accumulation in an arterial-venous shunt. The ex vivo anticoagulant effects were assessed with the thrombin clotting time, activated partial thromboplastin time and anti-Xa assay, and the effect of these glycosaminoglycans on platelet function was assessed by measuring collagen-induced platelet aggregation. For a similar antithrombotic effect, standard heparin produced significantly more bleeding than the other 3 glycosaminoglycans. The antithrombotic effects of all 4 glycosaminoglycans occurred at similar levels of anti-Xa activity but there was no relationship between blood loss and the effects of these glycosaminoglycans on any of the other tests of blood coagulation. Standard heparin had a greater inhibitory effect on collagen-induced platelet aggregation than the low molecular weight glycosaminoglycans, supporting the possibility that the increased bleeding observed with heparin is related in part to its inhibitory effect on platelet function.

Animals↗
PubMed1984

Neonatal antithrombin III.

Antithrombin III (AT-III) heparin cofactor activity and its antigen levels have been determined in 106 plasma samples from 42 term and preterm neonates. In contrast to healthy adult controls, a reduced activity/antigen (act/ag) ratio (ranging from 0.26 to 0.86) was observed in 90% of the samples and was independent of the state of health of the infant. By modifying the routine assay techniques, laboratory artefacts were excluded as the cause of the observed discrepancy. The relative increase in antigenic AT-III could not be accounted for by circulating AT-III-thrombin complexes, or by increased heparin cofactor II plasma levels in neonates.

Adult↗
PubMed1983

Identification of a contaminant protein in the purification of human factor V. Comparison of two purification methods.

Coagulation factor V has been isolated from human plasma by the methods of Bolhuis and of Kane to investigate reported differences in purity and specific activity. The specific activities of the preparations are 10 and 40 units/mg, respectively. The Kane preparation shows a single band (Mr 330 000) in polyacrylamide gel electrophoresis in the presence and absence of dithiothreitol, but the Bolhuis preparation shows an additional band at Mr 190 000 upon reduction with dithiothreitol. This suggests the presence of a contaminant which could account for the lower specific activity. Modification of the Bolhuis technique to include ion-exchange chromatography on DEAE-Sepharose resulted in separation of the two isolated proteins. The proteins were identified as factor V, with characteristics indistinguishable from Kane factor V, and a dimeric subunit of alpha 2-macroglobulin (Mr 350 000). Contamination by alpha 2-macroglobulin may explain the I2-component described in some preparations of bovine factor V, which is the basis of speculation that bovine factor V has a second polypeptide chain modulating stability and activity.

Blood Proteins↗
PubMed1982

Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis.

We have previously reported that long-term therapy with warfarin is effective for preventing recurrent venous thromboembolism in patients with proximal-vein thrombosis but that there is an appreciable risk of hemorrhage. To determine whether that risk could be reduced without a loss of effectiveness, we randomly allocated 96 patients with proximal-vein thrombosis to a group receiving less intense anticoagulant therapy, with a mean prothrombin time of 26.9 seconds using the Manchester comparative reagent (corresponding Simplastin time, 15 seconds), or a group given more intense therapy, with a mean Simplastin time of 19.4 seconds (corresponding prothrombin time 41 seconds with the Manchester comparative reagent) (P less than 0.001). Two of 47 patients (4 per cent) in the less intensely treated group had hemorrhagic complications, as compared with 11 of 49 patients (22 per cent) in the more intensely anticoagulated group (P = 0.015 by the two-tailed test). This difference was due to minor bleeding episodes. The frequency of recurrent venous thromboembolism was low in both groups (2 per cent). Our findings indicate that less intense anticoagulant therapy is associated with a low frequency of recurrent venous thromboembolism (2 per cent) and a reduced risk of hemorrhage.

Administration, Oral↗