Search PubMed⌕ Search

Biomedical subjects

S J Machin

Publications and source records attributed to S J Machin.

At least 73 records · Page 4Linked to original sources
PubMed1997

Relationship between preoperative endotoxin immune status, gut perfusion, and outcome from cardiac valve replacement surgery.

STUDY OBJECTIVE: Endotoxin is a powerful trigger of systemic inflammation. Since cardiac surgery exposes patients to endotoxemia, this study was set up to define the relationship between preoperative endogenous endotoxin immune status, gut perfusion, and outcome following cardiac valve replacement surgery. DESIGN: Observational study. SETTING: University hospital. PATIENTS: Fifty-nine consecutive patients undergoing cardiac valve replacement. MEASUREMENTS AND MAIN RESULTS: Blood was assayed for IgG and IgM endotoxin core antibody (EndoCAb) levels preoperatively, immediately postoperatively, and at 4 h and 24 h postoperatively. Intraoperative gut mucosal perfusion was assessed using gastric tonometry. Complications were assessed for groups above and below the median EndoCAb value of a healthy population (100 median units micro/mL). Of the 59 patients, 12 developed at least one of a set of predefined complications. Of these 12, all had preoperative levels of IgM EndoCAb below 100 MU/mL (p<0.025). Eleven had IgG EndoCAb levels below 100 MU/mL (0.05<p<0.1). There was no relationship between the fall in gastric intramucosal pH and exposure to endotoxin as implied by the fall in unbound IgM EndoCAb levels, although the specificity of tonometry for predicting complications could be improved by considering the patient's preoperative EndoCAb status. CONCLUSIONS: Preoperative EndoCAb levels were related to poor outcome following cardiac surgery and may be used to improve the specificity of GI tonometry in predicting postoperative complications.

Adolescent↗
PubMed1997

New antiplatelet drugs.

Antiplatelet drugs are used in a wide range of disorders, either as sole agents or as adjuncts to other therapies. Aspirin has been shown to be clinically effective in a number of ischaemic conditions and has been in use for many years. The newer agents, ticlopidine and clopidogrel (which are thought to inhibit ADP-mediated platelet reactions) are also effective and may prove to be superior to aspirin in certain indications. However, ticlopidine in particular has a different spectrum of side-effects, which may eventually limit its widespread use. The Gp IIb/IIIa antagonists have been most extensively investigated in the acute coronary syndromes, and shown to significantly improve outcome. Most of these studies have utilized agents which need to be given parenterally, and subsequently oral compounds are currently being developed. A number of other antiplatelet drugs such as prostacyclin and its analogues, as well as thromboxane inhibitors have been studied over the years, but overall they have failed to demonstrate any real clinical advantage.

Blood Platelets↗
PubMed1997

Hemostatic-endothelial interactions: a potential anticoagulant role of the endothelium in the pulmonary circulation during cardiac surgery.

The use of extracorporeal circulation during cardiopulmonary bypass (CPB) procedures is associated with significant morbidity and mortality. Exposure of blood to the foreign surface of the extracorporeal circuit results in activation of complement, kinin, fibrinolytic and coagulation systems as well as cellular mediators of inflammation. Without the use of anticoagulants, the extracorporeal circuit would clot; high-dose heparin prevents coagulation, but activation of the coagulation system and consequent thrombin generation still occur. During CPB, the lungs are effectively removed from the circulation, and, hence, heparinized blood remains static within the pulmonary vasculature for this period. It was postulated that under these conditions, the hemostatic system may become activated and could contribute to pulmonary dysfunction in some patients after CPB. However, it appears that during CPB interactions among heparin, the hemostatic system, and the endothelium may exert a protective effect, at least against activation of the tissue factor coagulation pathway. In this article, the effect of CPB on the coagulation system, with particular reference to changes in coagulation proteins occurring in the pulmonary vasculature, are reviewed.

Anticoagulants↗
PubMed1997

Monitoring of oral anticoagulant therapy in lupus anticoagulant positive patients with the anti-phospholipid syndrome.

Introduction of the International Normalized Ratio (INR) has improved the standardization of laboratory control of oral anticoagulant therapy (OAT). However, it has been reported that misleading INR results can be obtained from OAT patients with lupus anticoagulant (LA). To investigate this claim, we studied 35 OAT patients, 14 of whom had anti-phospholipid syndrome (APS) with a documented LA. Attainment of anticoagulation was confirmed by chromogenic assay of factor VII and factor X. Prothrombin times were performed using eight thromboplastins (five derived from rabbit brain, two recombinant human tissue factor and one made from human placenta) with an International Sensitivity Index (ISI) of <1.40. When using the thromboplastin manufacturers' ISI there was a significant difference (ANOVA, P<0.0001) between INR results obtained with the eight reagents for both APS (average CV = 12.4%) and non-APS (average CV = 12.5%) patient groups. Variation using the eight thromboplastins was assessed by calculating the CV for each sample; these values were then pooled for each patient group to give the average CV for all samples with all reagents for the two patient groups. Results for both patient groups exhibited markedly reduced variation (APS group average CV = 6.5%, non-APS group average CV = 5.8%) when locally assigned ISI values were employed in the calculation of INRs. Our data does not support the suggestion that the INR may not reflect the true level of anticoagulation in the long-term warfarin-treated patient, in whom lupus anticoagulant was detected. However, there was strong evidence that thromboplastin use should be restricted to those clot detection systems for which the reagent's manufacturer has assigned an ISI, or local ISI assignment must be undertaken. The inappropriate use of a generic (i.e. optical or mechanical clot detection system without regard to specific analyser type) ISI value can lead to ambiguous results.

Adult↗
PubMed1997

Reticulated platelets.

Young or reticulated platelets contain some residual mRNA, which is rapidly degraded after platelet release into the circulation. They can be easily detected either with supravital dye staining (e.g. new methylene blue) on blood films, or more commonly with fluorescent dyes (e.g thiazole orange) and flow cytometry. Using the latter technique many different groups have demonstrated that the measurement of reticulated platelets has much clinical potential. It is apparent that the level of reticulated platelets gives a relatively simple and non-invasive measurement of the rate of thrombopoiesis in an analogous fashion to the red cell reticulocyte count. Many research groups are currently measuring reticulated platelets but with wide variation in data and methods. An international platelet panel has begun to develop protocols and between laboratory comparisons, which will result in the standardization of the procedure. Platelet reticulocyte analysis should thus become part of accepted haematological practice and provide useful clinical information for the investigation and monitoring of platelet production in various thrombocytopenic conditions. In particular, measurement of reticulated platelets will provide an excellent and simple means for monitoring the response of chemotherapy and transplant patients to growth factors (e.g. thrombopoietin) resulting in a decrease in the demand for platelet transfusion.

Journal Article↗
PubMed1996

The effect of heparin and its neutralisation on functional assays for factor VIIa, factor VII and TFPI.

Recently methods have become available to assay the haemostasis proteins tissue factor pathway inhibitor (TFPI) and activated factor VII (FVIIa). These assays are primarily used in research and in some studies patients may be receiving heparin therapy. We investigated the effect of heparin and its neutralisation by protamine sulphate, hexadimethrine bromide (polybrene) and triethylaminoethyl (TEAE) cellulose, on functional assays for TFPI, FVIIa and also factor VII (FVII). In the clotting assay for FVIIa using truncated recombinant tissue factor, heparin had little effect up to IU/ml, but concentrations higher than this grossly prolonged the clotting time. Protamine and polybrene neutralisation of heparin resulted in some prolongation of the clotting time despite adequate heparin neutralisation, and in addition, in the absence of heparin each of these substances themselves affected the clotting time. TEAE neutralisation of heparin appeared to be effective in the FVIIa assay, although in the absence of heparin we observed a 5% decrease in the clotting time. In the amidolytic substrate assays for TFPI and FVII, heparin with or without neutralisation resulted in only small changes in the optical density at 405nm and hence plasma levels of these factors were not significantly changed.

Anticoagulants↗
PubMed1996

Plasma exchange with solvent/detergent-treated plasma of resistant thrombotic thrombocytopenic purpura.

A patient with unremitting thrombotic thrombocytopenic purpura (TTP), with circulating von Willebrand factor (VWF) multimers of unusually high molecular weight, and refractory to standard plasma exchange therapy, was treated with solvent detergent (S/D) plasma. The patient achieved a sustained clinical and haematological remission, with normal VWF multimeric profile. Spontaneous remission of this patient's condition could not be excluded but would appear unlikely. S/D plasma was efficacious and potentially safe for repeated large-volume plasma exchange with respect to viral safety and reduction of anaphylactoid reactions. We have assayed coagulation factors and physiological inhibitors of haemostasis in S/D plasma, which were comparable to normal plasma except in the distribution of VWF multimers. The use of S/D plasma, previously reported in paediatric chronic relapsing TTP, should be assessed in further cases of adult TTP in the context of a clinical trial.

Adult↗
PubMed1996

Passive immunisation with IgG endotoxin core antibody hyperimmune fresh frozen plasma.

Postoperative complications have been associated with low pre-operative endotoxin core antibody (EndoCAb) status. Seventy-three patients scheduled to undergo elective cardiac surgery were screened for IgG EndoCAb levels 1 week prior to admission. Of these 73 patients, 39 had levels below the median of a healthy population (100 MU = median units/ml). Only 6 received an infusion of IgG EndoCAb hyperimmune fresh frozen plasma (FFP) due to surgical rescheduling or unavailability of compatible hyperimmune FFP. The 6 patients demonstrated significant elevation (p < 0.0001) of their IgG EndoCAb levels from a mean level of 43 MU/ml (range: 26-75) to a posttransfusion mean of 267 MU/ml (range: 227-300), which persisted until at least immediately prior to the operative period. We conclude that passive immunisation with EndoCAb hyperimmune FFP is possible prior to elective surgery and that the kinetic profile of such an administration will allow the FFP to be given the night prior to surgery and still maintain significantly elevated levels for surgery planned the following morning.

Adult↗
PubMed1996

Haemostatic changes in the pulmonary blood during cardiopulmonary bypass.

Pulmonary injury may result from the use of cardiopulmonary bypass (CPB). We investigated changes in the haemostatic system in the pulmonary vein during CPB compared with blood that circulated through the bypass circuit. Paired samples were taken from the pulmonary vein and central venous pressure (CVP) line during the peri-operative period from ten patients. Plasma levels of factor VII (P < 0.001), prekallikrein (P < 0.05), antithrombin III (P < 0.001) and heparin cofactor II (P < 0.005) were decreased in the pulmonary vein after 20 min of bypass compared with pre-operative levels. In the pulmonary vein there was a significant increase in neutrophil expressed CD11b (P < 0.001), neutrophil elastase: alpha 1-antitrypsin complexes (P < 0.001), endothelin-1(P < 0.001) and thrombin-antithrombin complexes (P < 0.001) by the end of bypass compared with pre-operative levels. There was no significant change in monocyte expressed CD11b, factor XII or C1-esterase inhibitor in the pulmonary vein for the study period. None of these variables were significantly different in the pulmonary vein compared with CVP line. In the pulmonary vein plasma levels of activated factor VII decreased following heparin administration (P < 0.001) in the majority of patients which was coincidental to an increase (P < 0.001) in tissue factor pathway inhibitor (TFPI). This increase in TFPI was significantly higher in the pulmonary vein compared with CVP line (P < 0.05) There was a decrease in neutrophil count by 20 min on CPB in both the pulmonary vein and CVP line (P < 0.001) and this did not return to pre-operative levels in the pulmonary vein. Soluble thrombomodulin levels decreased by 20 min on CPB in the CVP line (P < 0.05) but tended to increase in the pulmonary vein, although this was not statistically significant. In conclusion we found evidence of thrombin generation and possible endothelial damage together with increased neutrophil activation and adhesion molecule expression in the pulmonary vein during CPB which may play an important role in the development of post-CPB pulmonary injury.

Adult↗
PubMed1996

Platelets and antiphospholipid antibodies.

The involvement of platelets in the antiphospholipid syndrome is complex and the full pathogenic significance is not fully understood. The binding of aPL antibodies to the platelet membrane may result in the thrombopenia and further haemostatic activation.

Antibodies, Antiphospholipid↗
PubMed1996

beta 2 glycoprotein-I inhibits factor XII activation on triglyceride rich lipoproteins: the effect of antibodies from plasma of patients with antiphospholipid syndrome.

It is now well recognised that antiphospholipid antibodies are associated with thrombosis and recurrent fetal loss. Some antiphospholipid antibodies (aPAs) have been shown to require a cofactor, beta 2 glycoprotein-I (beta 2 GPI), for binding to phospholipids, and recently beta 2 GPI has been identified as the antigenic target for some aPAs. beta 2 GPI possesses in vitro anticoagulant properties and modulation of beta 2 GPI function may therefore result in altered haemostatic regulation. In the present study, the influence of plasma derived aPAs and beta 2 GPI on factor XII activation on the surface of very low density lipoprotein (VLDL) was investigated. Factor XIIa generation was dependent on lipoprotein lipase treatment of VLDL and beta 2 GPI inhibited the factor XIIa generation in a concentration dependent manner. No consistent effects on factor XIIa generation were demonstrated with the IgG fractions from patients with aPAs. Inhibition of the beta 2 GPI activity was demonstrated by some antibodies, and study with cardiolipin affinity purified antibody indicated that antibody concentration is critical. These results suggest that perturbation of beta 2 GPI function may contribute to the pathogenic mechanism for thrombosis in some patients with aPAs.

Adult↗
PubMed1995

Increased levels of beta 2 glycoprotein-I antigen and beta 2 glycoprotein-I binding antibodies are associated with a history of thromboembolic complications in patients with SLE and primary antiphospholipid syndrome.

beta 2 Glycoprotein-I (beta 2GPI), a plasma component with in vitro anticoagulant properties, has been identified as a cofactor for the binding of some antiphospholipid antibodies (aPAs). In order to determine whether beta 2GPI changes were associated with the thromboembolic complications of aPAs, we measured beta 2GPI antigen (beta 2GPI:Ag), beta 2GPI aPA cofactor activity (beta 2GPI:Cof) and antibodies to beta 2GPI (alpha beta 2GPI) in 44 systemic lupus erythematosus (SLE) patients, of whom 19 had evidence of aPAs (SLE-aPA+) and 17 patients with primary antiphospholipid syndrome (PaPS). beta 2GPI:Ag levels were significantly increased in SLE-aPA+ patients and PaPS patients compared with SLE-aPA- patients and normal healthy controls. The ratio of beta 2GPI:Cof/Ag was significantly reduced in SLE-aPA+ patients compared with SLE-aPA- patients, indicating functional modification of beta 2GPI in SLE-aPA+ patients. Eighty per cent of patients with anticardiolipin (aCL) IgG also had alpha beta 2GPI, and 13% patients with no detectable aCL IgG had alpha beta 2GPI. Increased beta 2GPI:Ag and alpha beta 2GPI were associated with a clinical history of thrombosis or recurrent fetal loss. The results of these investigations suggest that beta 2GPI may play a role in the pathogenic mechanism of thrombosis associated with aPAs.

Adult↗
PubMed1995

Elevated levels of beta 2 glycoprotein-I (beta 2 GPI) in antiphospholipid antibody syndrome are due to increased amounts of beta 2 GPI in association with other plasma constituents.

beta 2 glycoprotein-I (beta 2 GPI) is a 50 kDa plasma protein which associates with a number of anionic plasma constituents and has been identified as a cofactor for the binding of some antiphospholipid antibodies (aPAs). beta 2 GPI antigen levels are increased in some patients with aPAs. In order to examine the distribution of beta 2 GPI in these patients, we developed a method for measurement of free beta 2 GPI. Forty-three patients with SLE, of whom 18 had laboratory evidence of aPAs, and 22 normal healthy subjects were studied. Plasma was filtered by centrifugation at 650 x g through a 100 kDa filter in order to allow separation of free and complexed beta 2 GPI, and beta 2 GPI levels were measured in the starting plasma and filtrate by a standardized ELISA. Total beta 2 GPI levels of the SLE aPA positive patients (253.3 mg/l) were significantly increased compared with the SLE aPA negative patients and normal controls (188.0, P < 0.001 and 194.9 mg/l, P < 0.01, respectively), but there were no significant differences between free beta 2 GPI levels of these groups (20.8, 24.0 and 20.5 mg/l, respectively). These results suggest that levels of complexed beta 2 GPI are increased in patients with aPAs, perhaps as a result of immune complex formation, or altered binding to other plasma constituents.

Adult↗
PubMed1995

Low plasma heparin cofactor II levels in thalassaemia syndromes are corrected by chronic blood transfusion.

Low plasma heparin cofactor II (HCII) levels are associated with a thrombotic tendency, and we have previously shown these to be decreased in a variety of haemolytic conditions. The risk of thrombosis is recognized to be increased in both thalassaemia major (TM) and intermedia (TI), although the exact mechanisms are poorly understood. HCII levels have therefore been compared in 20 untransfused patients with TI and 20 regularly transfused TM patients to determine the influence of transfusion on HCII. Additionally, untransfused TI patients have been commenced on regular red cell transfusion and the effects on correction of low HCII levels investigated. HCII levels were significantly lower in the untransfused TI patients (mean 0.56 +/- 0.06 U/ml) compared to TM patients (mean 0.85 +/- 0.1 U/ml; P < 0.001). Levels in TI were significantly less than in healthy age-matched controls (P < 0.001) and correlated with Hb values (r = 0.8), whereas levels in TM were at the lower end of the normal range. ATIII values were within the normal reference range in both TI and TM, and HCII antigen showed a parallel reduction to HCII activity, indicating that reduction in HCII is not a consequence of increased thrombin consumption. Three patients with TI were commenced prospectively on hypertransfusion programmes which resulted in a slow normalization of their levels taking 2-3 months. These findings support a hypothesis that the low HCII levels are related to increased red cell turnover and can be normalized once this turnover has been suppressed by hypertransfusion. The thrombotic risk to patients with low HCII levels in the presence of haemolysis might in principle be decreased by such transfusion regimes.

Adolescent↗