Search PubMed⌕ Search

Biomedical subjects

Samuel J Machin

Publications and source records attributed to Samuel J Machin.

At least 19 recordsLinked to original sources
PubMed2005

Assessment of the antiplatelet effects of low to medium dose aspirin in the early and late phases after ischaemic stroke and TIA.

Vascular events commonly recur in stroke patients on aspirin, and may reflect incomplete inhibition of platelet function with aspirin therapy. The platelet function analyser (PFA-100) activates platelets by aspirating a blood sample at a moderately high shear rate through a capillary to a biologically active membrane with a central aperture. The membrane is coated with collagen, and either ADP (C-ADP) or epinephrine (C-EPI). The time taken for activated platelets to adhere, aggregate, and occlude the aperture is called the closure time. Previous studies have shown that aspirin prolongs the C-EPI closure time, without prolongation of the C-ADP closure time, in the majority of control subjects. We hypothesised that the PFA-100 would provide a sensitive assay for the detection of early and convalescent phase cerebrovascular disease (CVD) patients who had incomplete inhibition of platelet function with aspirin. We investigated potential cyclooxygenase-dependent and -independent mechanisms that might influence the responsiveness to aspirin using the PFA-100. Patients were studied during the early (< or = 4 weeks, n=57) and convalescent phases ((< or = 3 months, n=46) after ischaemic stroke or TIA. To investigate potential mechanisms that could contribute to aspirin responsiveness on the PFA-100, we measured von Willebrand factor antigen levels, and carried out platelet aggregometry experiments in platelet-rich plasma in response to sodium arachidonate (1 mM) and ADP (5 microM). Sixty percent of patients in the early phase and 43% of patients in the convalescent phase did not have prolonged C-EPI closure times on 75-300 mg of aspirin daily, and were defined as aspirin non-responders. Median C-ADP closure times were significantly shorter in aspirin non-responders than aspirin-responders in both the early and convalescent phases after symptom onset (P=0.008), suggesting platelet hyper-reactivity to collagen or ADP in the aspirin non-responder subgroup. There was a significant inverse relationship between plasma von Willebrand factor antigen levels and C-EPI closure times in both early and convalescent phase CVD patients (P=0.008). Mean von Willebrand factor antigen levels were significantly higher in aspirin non-responders than aspirin responsive patients in the early (P=0.001), but not convalescent phase (P=0.2) after stroke and TIA. None of the patients studied were defined as being aspirin-resistant using sodium arachidonate- or ADP-induced platelet aggregometry. A large proportion of ischaemic CVD patients have incomplete inhibition of platelet function with low to medium dose aspirin using the PFA-100. The results suggest that cyclooxygenase-independent mechanisms, including elevated von Willebrand factor antigen levels, play an important role in mediating aspirin non-responsiveness on the PFA-100.

Adenosine Diphosphate↗
PubMed2005

Platelet hyper-function in acute coronary syndromes.

Previous studies have demonstrated shortened bleeding times in patients with acute coronary syndromes, especially in myocardial infarction (MI). In this study we have investigated platelet hyper-function using the PFA-100 with collagen/adenosine diphosphate and collagen/epinephrine cartridges in 78 patients presenting with acute chest pain. Patients were classified into MI, unstable angina (UA) and non-specific chest pain. All patients received 300 mg aspirin (ASA) more than 2 h before blood samples were collected. Twenty healthy normal subjects were also tested before and 2 h after 300 mg ASA (n = 10). The collagen/adenosine diphosphate closure time was significantly shorter in MI patients (median, 71 s; P = 0.0237) but not in UA patients (median, 81 s; P > 0.05) compared with normal subjects (median, 92.5 s). The collagen/epinephrine closure times were significantly longer in UA patients (median, 233 s) than in untreated controls (median, 125 s; P < 0.0001), as expected, but there was no difference in MI patients (median, 149.24 s; P > 0.05), suggesting that the MI patients were not all responding to ASA. Analysis of a subset of the apparent ASA non-responders (n = 5) by platelet aggregation demonstrated that this was not related to failure of ASA to block cyclo-oxygenase activity. Von Willebrand factor levels were significantly elevated in both UA and MI patients compared with normal subjects (mean, 175.5 and 248.9 versus 89.1 s; P < 0.0001 and P < 0.0001, respectively) and were also significantly higher in the MI group compared with the UA group (P < 0.05). There is evidence for platelet hyper-function and elevated von Willebrand factor levels in the MI group that could explain their decreased responsiveness to ASA on the collagen/epinephrine cartridge.

Administration, Oral↗
PubMed2005

Patient self-testing is a reliable and acceptable alternative to laboratory INR monitoring.

SAn ageing population and the continuing expansion of clinical indications for coumadin therapy have increased pressure on hospital anticoagulant clinics. One solution is patient self-testing (PST) of the international normalized ratio (INR) using capillary blood samples on point-of-care coagulation monitors at home. We conducted a prospective study to determine whether patients can achieve accurate INR values through PST, using the CoaguChek S (Roche Diagnostics, Lewes, UK). The main outcome measurements were: comparability of INR values obtained by PST and the hospital laboratory, patient acceptability as assessed by a questionnaire and anticoagulant control. Eighty-four patients [53 men, 31 women; median age 59 years (range 26-83)], receiving long-term oral anticoagulation (warfarin), were recruited from our Anticoagulation Clinic. Patients were randomized to weekly self-testing or continuing 4-weekly hospital laboratory monitoring of INR. Comparison of INRs (n = 234) showed no significant differences between the CoaguChek (median INR 3.02) and laboratory testing (median INR 3.07). There was excellent correlation between the two methods (r = 0.95), with 85% of CoaguChek results within 0.5 INR units of the laboratory method. On four occasions, differences of >1 unit INR were obtained, but in each case the patient's anticoagulation was unstable (INR >4.5 by both methods) and the differences in INR would not have altered patient management. 87% of patients found self-testing straightforward, 87% were confident in the result they obtained and 77% preferred self-testing. We conclude that PST is a reliable alternative to hospital clinic attendance and is acceptable to the majority of suitably trained patients.

Adult↗
PubMed2005

An evaluation of rapid D-dimer assays for the exclusion of deep vein thrombosis.

We evaluated the performance of eight d-assays for the exclusion of deep vein thrombosis (DVT); Biopool AutoDimer, Biopool MiniQuant, bioMèrieux MDA D-Dimer, VIDAS, Dade Behring D-Dimer Plus, Trinity Biotech AMAX, NycoCard D-dimer and IL Test D-Dimer. The assays were evaluated both as stand-alone tests, and in combination with pretest probability (PTP). D-dimer assays and PTP assessment were performed on 410 patients presenting to the emergency department with suspected acute DVT. DVT was diagnosed in 76 of 410 patients (18.5%) by compression ultrasound or other imaging techniques, as required. Receiver operator characteristics analysis established optimum cut-off values and these were compared with manufacturer's cut-off values where provided. As stand-alone tests, the assays varied immensely regarding cut-off value, negative predictive value (NPV 93-100%) and specificity (0-67%). At least one patient with confirmed DVT had a low d-dimer level by each method: to achieve 100% sensitivity it would be necessary to reduce cut-off values to levels below clinical usefulness. When low d-dimer was used in combination with PTP, six of eight methods achieved > or =98% NPV, with a diagnosis of DVT excluded in 16-44% of patients without the requirement for diagnostic imaging. The highly variable diagnostic performance of these d-dimer assays means that some assays are unsuitable for certain diagnostic strategies. However, our data suggest that the combination of sensitive D-dimer assays with an assessment of PTP may be used to exclude a diagnosis of DVT.

Fibrin Fibrinogen Degradation Products↗
PubMed2005

Stomatocytic haemolysis and macrothrombocytopenia (Mediterranean stomatocytosis/macrothrombocytopenia) is the haematological presentation of phytosterolaemia.

Phytosterolaemia (sitosterolaemia) is a recessively inherited metabolic condition in which the absorption of both cholesterol and plant-derived cholesterol-like molecules at the gut is unselective and unrestricted. In haematology, Mediterranean stomatocytosis or Mediterranean macrothrombocytopenia is a poorly understood haematological condition that combines stomatocytic haemolysis with the presence of very large platelets. Five pedigrees showing this haematology were identified. Gas chromatography mass spectrometry (GC-MS) showed that all of the patients with this highly specific haematology had grossly elevated levels of phytosterols in the blood, diagnostic of phytosterolaemia. All showed mutations in the ABCG5 and ABCG8 previously linked to phytosterolaemia. Three pedigrees showed five new mutations, while two pedigrees showed the common W361X mutation in ABCG8. We draw the following four conclusions: (i) that Mediterranean stomatocytosis/macrothrombocytopenia is caused by an excess of phytosterols in the blood; (ii) that phytosterolaemia, which does not respond to standard statin treatment, can be diagnosed via the distinctive haematology described here, even when the cholesterol is normal; (iii) that phytosterolaemia should be considered in the differential diagnosis of all patients with large platelets; and (iv) that the platelet size should be noted in patients with hypercholesterolaemia.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2005

Coagulation factor levels in cryosupernatant prepared from plasma treated with amotosalen hydrochloride (S-59) and ultraviolet A light.

BACKGROUND: The standard treatment for thrombotic thrombocytopenic purpura (TTP) is plasma exchange with fresh-frozen plasma (FFP). Exposure to large volumes of FFP increases the risk of transfusion-transmitted infections. Cryosupernatant (CSP) offers a theoretical advantage over FFP, because it lacks the large von Willebrand factor (VWF) forms implicated in the pathogenesis of TTP. This study compared the hemostatic variables of CSP prepared from FFP treated with a photochemical pathogen inactivation process to CSP prepared from conventional FFP. STUDY DESIGN AND METHODS: Forty CSP units were prepared from North American blood group A donor FFP. Twenty-one of the FFP units were individually treated with amotosalen hydrochloride (S-59) and ultraviolet A light (test, photochemically treated FFP), and 19 units were not treated (control, FFP). RESULTS: Hemostatic variables of test and control CSP were similar and within reported ranges for conventional FFP with the exception of those properties depleted in CSP. VWF-cleaving protease activity (VWF:CP) and protein S (PS) levels (total and free antigen and activity) were within the conventional FFP reference range for test and control CSP. There were statistical differences between test and control CSP for alpha(2)-antiplasmin, antithrombin, protein C, and VWF:CP on a per-volume basis, but all levels were within the reference range for FFP, and the differences were not significant when expressed per gram of CSP protein. CONCLUSION: S-59-treated CSP retained adequate levels of critical plasma proteins for plasma exchange therapy in acute TTP. The data indicate good preservation of hemostasis control proteins such as PS, alpha(2)-antiplasmin, and VWF:CP activity (ADAMTS13).

Bacterial Infections↗
PubMed2004

Platelet degranulation and monocyte-platelet complex formation are increased in the acute and convalescent phases after ischaemic stroke or transient ischaemic attack.

Flow cytometric studies suggest that platelets are activated in ischaemic stroke or transient ischaemic attack (TIA). However, few studies have measured circulating leucocyte-platelet complexes in this patient population. Whole blood flow cytometry was used to quantify the expression of CD62P-, CD63-, and PAC1-binding, and the percentages of leucocyte-platelet complexes in acute (1-27 d, n = 79) and convalescent (79-725 d, n = 70) ischaemic cerebrovascular disease (CVD) patients compared with controls without CVD (n = 27). We performed a full blood count, and measured plasma levels of soluble P-selectin, soluble E-selectin, and von Willebrand factor antigen (VWF:Ag) as additional markers of platelet and/or endothelial cell activation. The median percentage CD62P expression and the median percentage monocyte-platelet complexes were higher in both acute and convalescent CVD patients than controls (P </= 0.02). The mean white cell count and mean VWF:Ag levels were significantly elevated in the acute and convalescent phases after ischaemic stroke or TIA (P </= 0.02). Otherwise, there was no significant increase in any other marker of platelet or endothelial activation in CVD patients. There was a positive correlation between the percentage expression of CD62P and the percentages of both neutrophil-platelet and monocyte-platelet complexes in the acute phase, and the percentages of all leucocyte-platelet complexes in the convalescent phase after ischaemic CVD. This study provides evidence for ongoing excessive platelet and/or endothelial activation in ischaemic CVD patients despite treatment with antithrombotic therapy.

Acute Disease↗
PubMed2004

Assessment of an immature platelet fraction (IPF) in peripheral thrombocytopenia.

A new automated method to reliably quantify reticulated platelets, expressed as the immature platelet fraction (IPF), has been developed utilizing the XE-2100 blood cell counter with upgraded software (Sysmex, Kobe, Japan). The IPF is identified by flow cytometry techniques and the use of a nucleic acid specific dye in the reticulocyte/optical platelet channel. The clinical utility of this parameter was established in the laboratory diagnosis of thrombocytopenia due to increased peripheral platelet destruction, particularly autoimmune thrombocytopenic purpura (AITP) and thrombotic thrombocytopenic purpura (TTP). Reproducibility and stability results over 48 h were good. An IPF reference range in healthy individuals was established as 1.1-6.1%, with a mean of 3.4%. Patients in whom platelet destruction might be abnormal, were studied and two of these patients followed serially during the course of treatment. The IPF was raised in several disease states. The most significant increases in IPF values were found in patients with AITP (mean 22.3%, range 9.2-33.1%) and acute TTP (mean 17.2%, range 11.2-30.9%). Following patients during treatment demonstrated that as the platelet count recovered the IPF% fell. These results show that a rapid, inexpensive automated method for measuring the IPF% is feasible and should become a standard parameter in evaluating the thrombocytopenic patient.

Blood Platelets↗
PubMed2004

Circulating reticulated platelets in the early and late phases after ischaemic stroke and transient ischaemic attack.

The percentage of reticulated platelets (% RP) could be a useful marker of increased platelet production and/or turnover in patients with increased platelet activation, but few flow cytometric studies have measured the % RP in patients with ischaemic cerebrovascular disease (CVD). Whole blood flow cytometry using thiazole orange was performed to compare the % RP in patients in the early (1-27 d, n = 79) and late phases (79-725 d, n = 70) after ischaemic stroke or transient ischaemic attack (TIA) with controls without CVD (n = 27). The impact of aspirin dose escalation (75-300 mg/d) on the % RP was investigated in 10 patients in the late phase after stroke/TIA. The platelet count and mean platelet volume (MPV) were similar in CVD patients and controls. Compared with controls, the unadjusted % RP was not significantly higher in early or late phase CVD patients (P < or = 0.3). However, having adjusted for age, the % RP was higher in early (P = 0.047) and late phase CVD patients (P = 0.01). There was a positive correlation between % RP and MPV in EDTA- and citrate-anticoagulated blood in both early and late phase CVD patients (P< or = 0.01). The % RP was not significantly influenced by aspirin dose. These data do not convincingly support an excessive stimulus to platelet production in the early or late phases after ischaemic stroke/TIA, but are consistent with the hypothesis that reticulated platelets are larger than more mature 'non-reticulated' platelets in ischaemic CVD.

Aged↗
PubMed2003

Paradoxical association between the 316 Trp to Ser beta 2-glycoprotein I (Beta2GPI) polymorphism and anti-Beta2GPI antibodies.

We report a woman with an obstetric history of a stillbirth at 28 weeks, associated with hypertension and severe intrauterine growth restriction and a miscarriage at 9 weeks. She was persistently positive for immunolgobulin G (IgG) anticardiolipin antibodies and IgG anti-Beta-2-glycoprotein I (anti-Beta2GPI) antibodies. She has delivered three healthy babies when managed antenatally with aspirin and low-molecular-weight heparin prophylaxis. Genotyping revealed that she was homozygous for the 316 Trp to Ser Beta2GPI polymorphism. Studies examining the binding of her plasma Beta2GPI to purified cardiolipin showed markedly reduced binding in comparison with Beta2GPI in pooled normal plasma.

Adult↗
PubMed2003

Lack of association of beta2-glycoprotein I polymorphisms Val247Leu and Trp316Ser with antiphospholipid antibodies in patients with thrombosis and pregnancy complications.

Beta2-glycoprotein I (beta2GPI) is an important target antigen for antiphospholipid antibodies (aPL) and thus beta2GPI polymorphisms may influence aPL production and the development of antiphospholipid syndrome. We have studied the relationship between the Val247Leu and Trp316Ser beta2GPI polymorphisms and the aPL status of 230 patients referred for aPL screening. Sixty-one (26.5%) had persistent aPL [anticardiolipin antibodies (IgG and/or IgM), lupus anticoagulants and/or IgG anti-beta2GPI antibodies]. A comparison of the genotypic and allelic frequencies of these two polymorphisms between the Caucasian patient population and an ethnic-matched normal control group (n = 308) showed no significant differences between aPL-positive patients, aPL-negative patients and the normal control group. This suggests that the Val or Leu allele at position 247 and the Trp or Ser allele at position 316 of beta2GPI do not play a role in the production of aPL. There was a significantly decreased prevalence of the Ser316 allele in aPL-negative women (n = 98) when compared with female normal control subjects (n = 249) [0.020 [95% confidence interval (CI) 0.00-0.04]vs 0.060 (95% CI 0.04-0.08), P = 0.0286]. Subgroup analysis showed no significant difference between female patients with thrombosis and female normal control subjects. Thus, the Ser316 allele may protect women from developing pregnancy complications by influencing an anticoagulant function of beta2GPI via a mechanism distinct from aPL production.

Adolescent↗
PubMed2003

Venous thromboembolism associated with the management of acute thrombotic thrombocytopenic purpura.

Venous thromboembolism (VTE) is not a feature of thrombotic thrombocytopenic purpura (TTP), but there has been a recent report of VTE in association with plasma exchange (PEX) treatment for TTP using the solvent detergent (SD) plasma, PLAS+SD. We reviewed the occurrence of VTE in 68 consecutive patients with TTP (25 men, 43 women). Eight documented VTE events [six deep venous thromboses (DVTs), three pulmonary emboli] were identified in seven patients (all female) during PEX therapy. All six DVTs were associated with central lines at the site of thrombosis. Other known precipitating factors included pregnancy, immobility, obesity and factor V Leiden heterozygosity. VTE occurred at a mean of 53 d following the first PEX. The European SD plasma, Octaplas was the last plasma to be used in PEX prior to the VTE in 7/8 events. This is the first report of VTE following Octaplas infusion. VTE is a multifactorial disease and, although several known precipitating factors were present in all patients in this study, the use of large volumes of SD plasma in PEX may be an additional risk factor. We recommend prevention of VTE with graduated elastic compression stockings (class I) at diagnosis and prophylactic low-molecular-weight heparin once the platelet count rises above 50 x 10(9)/l.

Adult↗