scholarly journals Determination of Clopidogrel Resistance by Whole Blood Platelet Aggregometry and Inhibitors of the P2Y12 Receptor

2006 ◽  
Vol 52 (3) ◽  
pp. 383-388 ◽  
Author(s):  
Boris T Ivandic ◽  
Philipp Schlick ◽  
Peter Staritz ◽  
Kerstin Kurz ◽  
Hugo A Katus ◽  
...  
Keyword(s):  
Whole Blood ◽  
Adenosine Monophosphate ◽  
Blood Platelet ◽  
P2y12 Receptor ◽  
Fisher Exact Test ◽  
Exact Test ◽  
Clopidogrel Resistance ◽  
Impedance Aggregometry ◽  
Platelet Aggregometry ◽  
Increased Risk

Abstract Background: Inhibition of platelet aggregation by clopidogrel may be insufficient in up to 30% of users. These nonresponders carry an increased risk of cardiovascular events. We reported here a simple assay to study clopidogrel responsiveness. Methods: Electrical impedance aggregometry was performed in diluted whole blood in the presence of 5 and 20 μmol/L ADP. Some samples were incubated with 0.1 mmol/L methyl-S-adenosine monophosphate (MeSAMP), a P2Y12 receptor blocker, to maximize inhibition of aggregation before aggregometry. To validate the assay, we analyzed 6-min impedance in 21 healthy probands and 244 patients with coronary artery disease (CAD). Results: At 5 μmol/L ADP, the imprecision of the assay was 11%. Mean (SD) impedance of the healthy cohort was 12.2 (2.2) Ω. The mean − 3 SD was used to define the cutoff for clopidogrel responsiveness: responders and nonresponders exhibited a 6-min impedance ≤5 Ω and >5 Ω, respectively. Samples from nonresponders were incubated with MeSAMP and analyzed again to distinguish pharmacokinetic and pharmacodynamic types of resistance. Sixteen percent of CAD patients were classified as nonresponders (38 and 2 cases of pharmacokinetic and pharmacodynamic resistance, respectively). Female sex was strongly associated with clopidogrel resistance (P = 0.0002, Fisher exact test). A higher clopidogrel loading dose (P = 0.0353, Mann–Whitney U-test) was given to responders (median, 450 mg) than nonresponders (median, 300 mg). Age and cardiovascular diagnosis showed no significant associations. Conclusions: Impedance aggregometry using 5 μmol/L ADP is a useful tool for studying clopidogrel responsiveness. MeSAMP allows characterization of responsiveness “on treatment” and may be useful for optimizing clopidogrel dosing.

ADP-Induced Whole Blood Aggregometry and Platelet-Associated Thrombin Generation (TG) In Essential Thrombocythemia (ET) and Polycythemia Vera (PV) Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1981-1981
Author(s):  
Marina Panova-Noeva ◽  
Marina Marchetti ◽  
Annamaria Leuzzi ◽  
Laura Russo ◽  
Guido Finazzi ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Whole Blood ◽  
Thrombin Generation ◽  
Blood Platelet ◽  
Jak2v617f Mutation ◽  
Mutation Carriers ◽  
Impedance Aggregometry ◽  
Platelet Aggregometry ◽  
V617f Mutation ◽  
Blood Platelet Aggregation

Abstract Abstract 1981 Patients with ET and PV are characterized by an increased rate of thrombotic complications and by several abnormalities of platelets, more pronounced in JAK2V617F mutation carriers. Platelet function inhibitors are widely utilized for thromboprophylaxis in ET and PV patients. An increased reactivity to ADP of platelets from these patients has previously been shown by light transmission platelet aggregometry studies, which might explain the failure of aspirin to fully protect from thrombosis these patients, mainly those at high risk. While ADP activation pathway is critical for platelet aggregation, less is known about its role to the initiation of blood coagulation by platelets. In this study we wanted to evaluate in a group of patients with ET and PV, the platelet reactivity to ADP in terms of both proaggregating and procoagulant responses. ADP-induced platelet aggregation and platelet procoagulant potential (i.e. thrombin generation capacity) were measured by the whole blood impedance aggregometry (Multiplate analyser) and by the Calibrated Automated Thrombogram (CAT) assay, respectively. Whole blood platelet aggregation was induced by 6.5 μM ADP. Whereas thrombin generation (TG) was measured in platelet rich plasma (PRP: 150,000 platelets/μl) both in resting conditions and after stimulation by 1.6 μM and 8.3 μM ADP. Fifty patients with ET (58% V617F mutation carriers) and 40 patients with PV (95% V617F mutation carriers) were enrolled into the study. The results show that ET and PV patients presented with significantly higher ADP-induced whole blood platelet aggregation compared to control subjects (786±70 AU*min, and 777±54 AU*min, respectively, versus 465±70 AU*min, both p<0.05), the highest values being observed in ET and PV patients carriers of the JAK2V617F mutation (806±75 AU*min; p<0.001 vs controls). In resting conditions, TG in PRP from ET (133±38 nM) and PV (144±54 nM) patients was significantly greater compared to control PRP (103±21 nM; p<0.05). Similarly, in ADP-stimulated conditions, platelet TG was significantly higher (p<0.05) in ET and PV patients at both 1.6 μM ADP (140±32 nM and 154±59 nM; respectively) and 8.3 μM ADP (161±38 nM and 181±65 nM; respectively) compared to controls (1.6 μM ADP: 112±19 nM; 8.3 μM ADP: 132±26 nM). The analysis according to the JAK2 mutational status showed that platelets from JAK2V617F carriers induced significantly higher TG when stimulated by 8.3 μM ADP (185±47nM) compared to 1.6 μM ADP (146±45nM; p<0.001). Differently, this difference was not observed in JAK2 wild type patients. While in resting conditions patients on hydroxyurea (HU) generated less thrombin compared to non-HU treated patients, no effects of patients’ therapy on TG (i.e. aspirin, HU, aspirin+HU) was observed in the ADP-stimulated conditions. In conclusion, for the first time we demonstrated that platelets from ET and PV patients are more reactive to ADP, not only in terms of increased platelet aggregation in a whole blood system, but also as an enhanced thrombin generation, particularly in those carriers of JAK2V617F mutation. These data support the hypothesis that the use of ADP receptor-inhibitors, in addition to aspirin, might be of help in the prevention of thrombosis in these conditions, by allowing a more complete inhibition of platelet functions. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Determination of Aspirin Responsiveness by Use of Whole Blood Platelet Aggregometry

2007 ◽  
Vol 53 (4) ◽  
pp. 614-619 ◽  
Author(s):  
Boris T Ivandic ◽  
Evangelos Giannitsis ◽  
Philipp Schlick ◽  
Peter Staritz ◽  
Hugo A Katus ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Whole Blood ◽  
Stable Coronary Artery Disease ◽  
Blood Platelet ◽  
Platelet Inhibition ◽  
Impedance Aggregometry ◽  
Platelet Aggregometry ◽  
Healthy Control ◽  
Artery Disease

Abstract Background: Insufficient platelet inhibition is associated with an increased cardiovascular risk in up to 30% of patients taking regular doses of aspirin. We describe an assay to study aspirin responsiveness. Methods: We performed impedance aggregometry on diluted whole blood with 1 mg/L collagen and 0.5 mmol/L arachidonic acid (AA). We measured thromboxane B2 (TXB2) by RIA. We examined 66 healthy control individuals, 144 aspirin users with stable coronary artery disease (CAD), and 245 CAD patients treated with aspirin and clopidogrel. Nonresponsive samples were incubated with excess dl-lysinmonoacetylsalicylic acid. Results: Assay imprecision (CV) was 9.8% and 8.2% at mean (SD) 6-min impedance of 13.7 (2.8) Ω and 13.6 (2.3) Ω for collagen and AA, respectively. Collagen induced stronger aggregation (P = 0.0199) in women [n = 28, 14.6 (2.4) Ω] than in men [n = 38, 13.1 (2.9) Ω], even after sample incubation with 0.1 mmol/L acetylsalicylic acid (ASA) or 1 μmol/L terbogrel, a combined inhibitor of thromboxane synthase and receptors. The sex association persisted in aspirin users, but not if clopidogrel was also taken. A 6-min impedance &gt;8 Ω with collagen (mean − 2 SD of the controls) was taken as evidence of nonresponsiveness, particularly if incubation with ASA did not inhibit aggregation further (&gt;2 Ω). Compared with AA, collagen identified more nonresponsive samples among aspirin users (15%) and CAD patients who also received clopidogrel (10%). Incubation with ASA improved inhibition of aggregation in 70% of samples and consistently reduced TXB2 formation during aggregation. Conclusions: Impedance aggregometry may prove useful to study aspirin responsiveness, and incubation with ASA may help to identify nonresponders and classify resistance.

Multiple electrode aggregometry: A new device to measure platelet aggregation in whole blood

2006 ◽  
Vol 96 (12) ◽  
pp. 781-788 ◽  
Author(s):  
Andreas Calatzis ◽  
Sandra Penz ◽  
Hajna Losonczy ◽  
Wolfgang Siess ◽  
Orsolya Tóth
Keyword(s):  
Platelet Aggregation ◽  
Whole Blood ◽  
Blood Platelet ◽  
Platelet Inhibition ◽  
New Device ◽  
Platelet Aggregometry ◽  
Spontaneous Platelet Aggregation ◽  
Induced Aggregation ◽  
Blood Platelet Aggregation ◽  
Multiple Electrode

SummarySeveral methods are used to analyse platelet function in whole blood. A new device to measure whole blood platelet aggregation has been developed, called multiple electrode platelet aggregometry (MEA). Our aim was to evaluate MEA in comparison with the single platelet counting (SPC) method for the measurement of platelet aggregation and platelet inhibition by aspirin or apyrase in diluted whole blood. Platelet aggregation induced by different concentrations of ADP, collagen and TRAP-6 and platelet inhibition by apyrase or aspirin were determined in citrateor hirudin-anticoagulated blood by MEA and SPC. MEA indicated that spontaneous platelet aggregation was lower, and stimulated platelet aggregation was higher in hirudin- than citrate-anticoagulated blood. In hirudin-anticoagulated, but not citrate-anticoagulated blood, spontaneous platelet aggregation measured by MEA was inhibited by apyrase. For MEA compared with SPC the dose response-curves of agonist-induced platelet aggregation in citrate- and hirudin-blood showed similar EC50 values for TRAP, and higher EC50 values for ADP (non-significant) and collagen (p<0.05). MEA and the SPC method gave similar results concerning platelet-inhibition by apyrase and aspirin. MEA was more sensitive than SPC to the inhibitory effect of aspirin in collagen-induced aggregation. In conclusion, MEA is an easy, reproducible and sensitive method for measuring spontaneous and stimulated platelet aggregation, and evaluating antiplatelet drugs in diluted whole blood. The use of hirudin as an anticoagulant is preferable to the use of citrate. MEA is a promising technique for experimental and clinical applications.

scholarly journals An introduction to point-of-care testing in extracorporeal circulation and LVADs

Hematology ◽  
2018 ◽  
Vol 2018 (1) ◽  
pp. 516-521 ◽  
Author(s):  
Rachel Sara Bercovitz
Keyword(s):  
Whole Blood ◽  
Point Of Care ◽  
Blood Platelet ◽  
Ventricular Assist Devices ◽  
Bleeding Complications ◽  
Future Research ◽  
Ventricular Assist ◽  
Assist Devices ◽  
Platelet Aggregometry ◽  
Coagulation Tests

Abstract There is a delicate balance between bleeding and clotting in patients on circuits such as ventricular assist devices or extracorporeal membrane oxygenation. Traditional coagulation tests, prothrombin time, activated partial thromboplastin time, and anti-factor Xa levels, are used to monitor patients on these devices. However, turnaround times and inability to assess global hemostasis, including platelets and fibrinogen have contributed to a recognition that faster, accurate, and more informative coagulation tests are needed. Activated clotting time is used to monitor heparin in patients on circuits and has the advantages of being a near-patient point-of-care test. However, its utility is limited to heparin monitoring. Viscoelastic tests (thromboelastometry and thromboelastography) are global, whole-blood coagulation tests, and whole-blood platelet aggregometry evaluates platelet function. Ideally, these tests can ensure that patients are within the therapeutic range of their antithrombotic medications, identify patients at risk for hemorrhagic or thrombotic complications, and guide management of acute bleeding complications. This ideal is currently hampered by a lack of studies that delineate clear ranges that are clinically relevant. Future research is needed to better understand the optimal use of point-of-care coagulation testing in patients on extracorporeal circuits and ventricular assist devices.

Increased risk for abnormalities on perioperative colon screening in patients with microsatellite instability–positive endometrial carcinoma

2006 ◽  
Vol 16 (6) ◽  
pp. 1980-1986 ◽  
Author(s):  
B. M. Buttin ◽  
M. A. Powell ◽  
P. J. Goodfellow ◽  
S. N. Lewin ◽  
R. K. Gibb ◽  
...  
Keyword(s):  
Regression Analysis ◽  
Microsatellite Instability ◽  
Medical Records ◽  
Fisher Exact Test ◽  
Exact Test ◽  
Molecular Stratification ◽  
Colon Cancers ◽  
Increased Risk ◽  
Primary Colon ◽  
Endometrial Cancers

Microsatellite instability (MSI) is a feature of certain hereditary and sporadic endometrial and colon cancers. We set out to determine whether molecular stratification of endometrial cancers based on tumor MSI status could help identify patients at increased risk for abnormalities found on perioperative colon screening. From a prospectively accrued series of 413 patients, medical records were reviewed from 94 patients with MSI positive (MSI+) and 94 patients with MSI negative (MSI−) endometrial cancers, matched by year of diagnosis. We reviewed clinicopathologic data and results of perioperative colon screening. Differences were analyzed using Fisher exact test and logistic regression analysis. There were no significant clinicopathologic differences between the two cohorts. Sixty-five percent of patients in each group underwent perioperative colon screening. However, patients with MSI+ cancers had a twofold increase in the frequency of colonic abnormalities (30% versus 14.8%, P= 0.044) over those with MSI− cancers. Furthermore, the only primary colon cancers (N= 2) were found in women with MSI+ endometrial cancers that were unmethylated at the MLH1 promoter. Our data suggest that patients with MSI+ endometrial cancers are at increased risk for abnormalities on perioperative colon screening. Those with MSI+MLH1 unmethylated cancers appear to be at highest risk.

scholarly journals Polymorphisms in Phase I (CYP450) Genes CYP1A1 (rs4646421), CYP1B1 (rs1056836), CYP19A1 (rs749292) and CYP2C8 (rs1058930) and Their Relation to Risk of Breast Cancer: A Case-Control Study in Mazandaran Province in North of Iran

2019 ◽  
Vol 7 (15) ◽  
pp. 2488-2496 ◽  
Author(s):  
Golpar Golmohammadzadeh ◽  
Abbas Mohammadpour ◽  
Nematollah Ahangar ◽  
Mohammad Shokrzadeh
Keyword(s):  
Breast Cancer ◽  
Case Control Study ◽  
Control Group ◽  
Fisher Exact Test ◽  
Mazandaran Province ◽  
Chi Square ◽  
Exact Test ◽  
Cyp1b1 Gene ◽  
Increased Risk ◽  
Control Study

BACKGROUND: The second leading cause of cancer-related death in women is breast cancer. Xenobiotic Metabolizing Enzymes (XMEs) contribute to the detoxification of numerous cancer therapy-induced products. In the metabolism of xenobiotic, cytochrome P450s or monooxygenases perform an important function by catalysing the hydroxylation reaction. In this study, the susceptibility and genetic polymorphisms of CYP450 isoenzymes was investigated that may have an etiological role in breast cancer. AIM: The main purpose of this study was to evaluate the association of CYP1A1 (rs4646421), CYP1B1 (rs1056836), CYP2C8 (rs1058930), and CYP19A1 (rs749292) polymorphisms with the risk of breast cancer in Mazandaran province. MATERIAL AND METHODS: This cross-sectional case-control study were recruited 72 patients and 51 healthy individuals and was performed between March 2018 to May 2018 in the Oncology Department at Imam Hospital in Sari city, Iran. Peripheral blood samples were collected in EDTA tube, and DNA extraction was performed using the salting-out method and WizPrep extraction kits. Breast cancer patients with known clinicopathological characters and healthy women as control group were genotyped for genes polymorphisms by PCR-RFLP technique, using restriction enzymes. Chi-square, Fisher exact test and Logistic regression model, were applied for statistical analysis. RESULTS: The results of the experiments showed that there was a significant relationship between two groups and the age of the patients is significantly higher than the control group (p = 0.044). According to the chi-square and Fisher exact test, education, pregnancy, menopause status and oppose were significant between the two groups. Based on using a logistic regression model in two normalized and age-adjusted models to finding relationship between the genotypes of each gene and breast cancer risk, it was determined that in the CYP2C8 genotype, those who have the CG allele have a 7.74 degree increased risk of breast cancer (CI = 95% 0.95-62.5) and in the CYP19A1 gene, individuals with GA genotype, increased risk of breast cancer (CI = %95 1.52-27.21), about the CYP1B1 gene, people with two genotypes of CG + GG had higher risk of breast cancer (CI = %95 1.19-5.71) and allele G has decreased risk of breast cancer in this gene (P = 0.0271), also allele G in CYP2C8 gene had the protective effect (P = 0.02). In the age-adjusted model, for the CYP2C8 gene, GG genotype increased risk of breast cancer (CI = %95 1.11-75.84) as well as, the CG + GG genotype in CYP1B1 gene (CI = %95 1.31-6.57). CONCLUSION: Our results confirm the association between CYP2C8 (rs1058930), CYP19A1 (rs749292) and CYP1B1 (rs1056836) gene polymorphisms and increased risk of breast cancer in women in Mazandaran province.

Improving Ambulatory Health Care Proxy Completion Rates: Implementing an Interdisciplinary Clinic-Based Process

2020 ◽  
Vol 35 (6) ◽  
pp. 491-499
Author(s):  
Lauge Sokol-Hessner ◽  
Griffen Allen ◽  
Jennifer Cluett
Keyword(s):  
Primary Care ◽  
Health Care ◽  
Care Practice ◽  
Fisher Exact Test ◽  
Health Care Proxy ◽  
Exact Test ◽  
The North ◽  
Increased Risk ◽  
Physician Leaders ◽  
Interdisciplinary Process

All adults should complete a health care proxy (HCP), especially those who are seriously ill or otherwise at increased risk of losing capacity. This study describes the implementation of an interdisciplinary process for helping patients complete HCPs during nonurgent visits at a large urban academic primary care practice between July 2014 and May 2017. The process was mapped using direct observations. Pre- and post-implementation measurement of the percent of patients who completed HCPs during their visit revealed significant improvement (1.4% vs 26.1% in the North Suite, special cause variation). Over the study period, the percentage of patients with HCP information rose significantly across the entire clinic (eg, 37% to 80% in the North Suite, Fisher exact test P < .0001; similar findings in other suites). Key facilitators and barriers to implementation were identified by physician leaders. An interdisciplinary process can sustainably improve the percentage of primary care patients with a completed HCP.

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