Platelet aggregometry cannot identify uremic platelet dysfunction in heart failure patients prior to cardiac surgery.

BACKGROUND: Patients with heart failure often have concomitant renal disease which can result in uremic platelet dysfunction. Determining whether uremia has affected platelets by platelet aggregometry can be challenging in these patients since they are often on antiplatelet medications. This study was undertaken to determine if platelet aggregation studies could identify heart failure patients at risk for uremic bleeding prior to cardiac surgery. METHODS: Platelet aggregation studies from three groups were studied and compared: 17 heart failure patients with mild to moderate renal impairment, 17 heart failure patients without renal abnormalities and 17 healthy volunteers. RESULTS: Platelet aggregation was severely impaired in both heart failure groups with and without renal abnormalities compared to healthy controls, and there were no significant differences in platelet aggregation in response to any of the agonists. There was a pan-decrease in platelet aggregation to all agonists in all heart failure patients. CONCLUSION: Platelet aggregometry does not appear to be useful in measuring platelet dysfunction in heart failure patients with mild to moderate renal impairment.

Impact of an integrated treatment algorithm based on platelet function testing and clinical risk assessment: results of the TRIAGE Patients Undergoing Percutaneous Coronary Interventions To Improve Clinical Outcomes Through Optimal Platelet Inhibition study.

Assessment of platelet reactivity alone for thienopyridine selection with percutaneous coronary intervention (PCI) has not been associated with improved outcomes. In TRIAGE, a prospective multicenter observational pilot study we sought to evaluate the benefit of an integrated algorithm combining clinical risk and platelet function testing to select type of thienopyridine in patients undergoing PCI. Patients on chronic clopidogrel therapy underwent platelet function testing prior to PCI using the VerifyNow assay to determine high on treatment platelet reactivity (HTPR, ≥230 P2Y12 reactivity units or PRU). Based on both PRU and clinical (ischemic and bleeding) risks, patients were switched to prasugrel or continued on clopidogrel per the study algorithm. The primary endpoints were (i) 1-year major adverse cardiovascular events (MACE) composite of death, non-fatal myocardial infarction, or definite or probable stent thrombosis; and (ii) major bleeding, Bleeding Academic Research Consortium type 2, 3 or 5. Out of 318 clopidogrel treated patients with a mean age of 65.9 ± 9.8 years, HTPR was noted in 33.3 %. Ninety (28.0 %) patients overall were switched to prasugrel and 228 (72.0 %) continued clopidogrel. The prasugrel group had fewer smokers and more patients with heart failure. At 1-year MACE occurred in 4.4 % of majority HTPR patients on prasugrel versus 3.5 % of primarily non-HTPR patients on clopidogrel (p = 0.7). Major bleeding (5.6 vs 7.9 %, p = 0.47) was numerically higher with clopidogrel compared with prasugrel. Use of the study clinical risk algorithm for choice and intensity of thienopyridine prescription following PCI resulted in similar ischemic outcomes in HTPR patients receiving prasugrel and primarily non-HTPR patients on clopidogrel without an untoward increase in bleeding with prasugrel. However, the study was prematurely terminated and these findings are therefore hypothesis generating.

[Cardiology. Platelet function testing for clinicians]. / Cardiologie. Tests de réactivité plaquettaire: mise à jour pour le praticien.

Platelet P2YI2 receptor inhibition with clopidogrel, prasugrel or ticagrelor plays a key role to prevent recurrent ischaemic events after percutaneous coronary intervention in acute coronary syndromes or elective settings. The degree of platelet inhibition depends on the antiplatelet medication used and is influenced by clinical and genetic factors. A concept of therapeutic window exists. On one side, efficient anti-aggregation is required in order to reduce cardio-vascular events. On the other side, an excessive platelet inhibition represents a risk of bleeding complications. This article describes the current knowledge about some platelet function tests and genetic tests and summarises their role in the clinical practice.

Analysis of individualized antiplatelet therapy for patients of acute coronary syndrome after percutaneous coronary intervention under the guidance of platelet function: A one-center retrospective cohort study.

ABSTRACT: There is controversy in clinical application of antiplatelet drugs by monitoring platelet function. Therefore, we explored whether early and dynamic medication could bring better clinical outcomes for patients under the guidance of platelet function tests (PFT).In this retrospective cohort study, we analyzed the prognostic events of 1550 patients with acute coronary syndrome (ACS) at Tianjin People's Hospital in China. They received dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) from January 2017 to December 2018. The primary endpoint was based on the Bleeding Academic Research Consortium (BARC) 3 or 5 major bleeding. Secondary endpoints included MACCE (all-cause death, nonfatal myocardial infarction, stroke, stent thrombosis, and unplanned target vessel reconstruction) and BARC 1 to 2 minor bleeding. The endpoint events within 1 year after PCI were recorded. Patients were divided into a guided group and a control group according to the drug adjustment by PFT results. After the propensity scores matched, the end points of 2 groups were compared, and subgroup analysis was performed on major bleeding events.After propensity score matching, there were 511 cases in the guided group and the control group, respectively. The primary endpoint events occurred in 10 patients (1.96%) in the guided group and 23 patients (4.5%) in the control group (HR: 0.45; 95% CI, 0.21-0.95; P = .037). After the guided group adjusted drug doses, the risk of major bleeding was lower than standard DAPT of the control group. Although some patients in the guided group reduced doses earlier, the incidence of MACCE events did not increase in the guided group compared with the control group (4.89% vs 6.07%; P = .41). There was no statistical difference in BARC 1 to 2 minor bleeding (P = .22). Subgroup analysis showed that PFT was more effective in patients with diabetes and multivessel disease.Early observation of dynamic PFT in ACS patients after PCI can guide individualized antiplatelet therapy to reduce the risk of major bleeding without increasing the risk of ischemia.

Response to aspirin in healthy individuals. Cross-comparison of light transmission aggregometry, VerifyNow system, platelet count drop, thromboelastography (TEG) and urinary 11-dehydrothromboxane B(2).

Variable biological effect of aspirin is suggested to be related to pharmacological resistance. The incidence of this so-called "resistant" state varies with the study population and the assay used. We determined performance features of five assays used to assess aspirin effects in non-smoking healthy volunteers not taking any drug known to interfere with platelet function. Blood and urine samples were obtained immediately before and after 8-10 days of aspirin 80 mg intake. Forty-five participants 19-59 years old were enrolled. The sensitivity (SE), specificity (SP), and optimal cut-off (CO) value to detect the effect of aspirin were: light transmission aggregometry (LTA) with 1.6 mM arachidonic acid (AA) - SE 100%, SP 95.9%, CO 20%; LTA with adenosine diphosphate (ADP) 10 microM - SE 84.4%, SP 77.8%, CO 70%; VerifyNow Aspirin - SE 100%, SP 95.6%, CO 550 ARU; platelet count drop - SE 82.2%, SP 86,7%, CO 55%; TEG((R)) - SE 82,9%, SP 75,8%, CO 90%; and urinary 11-dehydrothromboxane B(2) levels (11-dHTB(2)) - SE 62.2%, SP 82.2%, CO 60 pg/ml. AA-induced LTA and the VerifyNow assay reliably detected aspirin intake in all subjects; there was wide overlap in pre- and post- aspirin results with ADP-induced LTA, platelet count drop, TEG((R)) and urinary 11-dHTB(2) assays. These results suggest that some of the variability in the reported incidence of "aspirin resistance" is unrelated to aspirin intake but related to inherent limitations of some assays to detect aspirin mediated effects or to underlying platelet reactivity variability independent of aspirin-mediated cyclooxygenase-1 inhibition.

Cross validation of the Multiple Electrode Aggregometry. A prospective trial in healthy volunteers.

Several test systems exist for assessment of platelet function in patients under clopidogrel or aspirin therapy. The objective was to cross-validate the Multiple Electrode Aggregometry (MEA) with three other methods used for determining platelet reactivity under treatment with clopidogrel and aspirin. Platelet function was assessed by the MEA, Vasodilator Stimulated Phosphoprotein (VASP) phosphorylation assay, Platelet Function Analyzer-100 (PFA-100) and the Cone and Platelet Analyzer. Measurements were performed in blood from nine healthy volunteers at baseline, 2, 4, 6 and 72 hours after clopidogrel and aspirin loading. The apparent effect size for clopidogrel and aspirin was greatest for the MEA: treatment induced a 19-fold difference in the arachidonic acid-induced platelet aggregation and an 11-fold difference in the adenosine diphosphate-induced platelet aggregation before/after treatment. For comparison, aspirin and clopidogrel induced only 2.0- to 2.6 -fold changes in other tests (VASP assay, Cone and Platelet Analyzer and PFA-100). Maximal effects were seen 2 hours after aspirin loading and shorter than 72 hours after clopidogrel loading. In conclusion, aspirin and clopidogrel produce stronger signals in the MEA compared to several other methods.

Use of the platelet function analyzer to minimize bleeding complications after renal biopsy.

BACKGROUND: The bleeding time is frequently used to screen primary haemostasis before surgical procedures, although it poorly predicts the risk of hemorrhage. The platelet function analyzer (PFA), which is also used to screen primary haemostasis, has a higher sensitivity and other advantages, like patient friendliness, higher degree of objectivity and analytical reliability, but needs more extensive clinical validation. METHODS: We compared the predictive values of the PFA-CTs (closure times) and bleeding time for bleeding events after renal biopsy. We prospectively evaluated the complications in patients that underwent a renal biopsy and were screened with PFA in advance (n=170). For comparison we used a historical cohort of patients screened with the bleeding time (n=132). RESULTS: When the PFA-CTs were normal, 26.0% of the patients had a mild bleeding event after the biopsy, which did not differ from the event rate with a normal bleeding time (29.4%). When one or both PFA-CTs were prolonged, 51.3% of the patients had post-biopsy bleeding events independently of the measures to correct the closure time(s), significantly more than with either a prolonged bleeding time (26.7%) or normal PFA-CTs (26.0%). CONCLUSION: For bleeding events, the PFA has a higher positive and similar negative predictive value compared to the bleeding time. Taken into account the additional advantages of the PFA like patient friendliness and better analytical qualities, we prefer the PFA over the bleeding time as a screening tool for primary haemostasis before performing a renal biopsy.

Towards a rationale of platelet aggregation monitoring in stroke prophylaxis?

The recurrence of ischemic cerebrovascular events despite treatment with aspirin (ASA) and/or clopidogrel remains a serious problem. Although there is increasing evidence that clinical failure may at least partially result from the nonresponsiveness of platelets to medication, the adjustment of the therapy according to ex vivo platelet responses is not yet common in clinical practice. Here, we compare two commonly used ex vivo platelet function tests under different treatment conditions. Blood samples from 142 patients with cerebrovascular disease receiving either ASA, clopidogrel, or a combined treatment, and 51 controls were evaluated by the platelet function analyzer (PFA)-100 (collagen/epinephrine cartridge), as well as collagen and ADP-induced aggregometry. The tests all demonstrated the interindividual heterogeneity of platelet aggregation inhibition, but the fractions of nonresponsiveness differed considerably with 58-62% of patients being nonresponsive to ASA by PFA-100 compared with 27-33% by collagen-induced aggregation. The clopidogrel nonresponsiveness was 44% by ADP-induced aggregation. The agreement of the test values between PFA-100 and collagen-induced aggregometry was weak (correlation coefficient r= -0.1 to -0.3). Only about half of the patients were consistently identified as either ASA responsive or nonresponsive by both tests. Under dual therapy conditions, the unspecificity of aggregometric tests prevented reliable measurements of platelet responses. In conclusion, there are currently considerable limitations in platelet aggregation monitoring. Nevertheless, we encourage prospective trials to improve the predictive value of platelet aggregation testing and to prove whether a systematic strategy of "platelet aggregation-adapted treatment" will improve the clinical outcome of patients with cerebrovascular events.

An evaluation of methods for determining reference intervals for light transmission platelet aggregation tests on samples with normal or reduced platelet counts.

Light transmission platelet aggregation tests are important for diagnosing platelet function defects. However, uncertainties exist about the best procedures to determine aggregation reference intervals. We investigated methods for determining reference intervals for light transmission aggregation tests, using the % maximal aggregation values for prospectively collected data on healthy control samples. Reference intervals for samples tested at 250 x 10(9) platelets/l were determined by mean +/- 2 standard deviations and non-parametric analyses. To establish reference intervals for tests on thrombocytopenic subjects, regression analyses were used to estimate 95% confidence limits for % maximal aggregation, according to sample platelet counts, using data for control samples diluted to match the platelet count of undiluted thrombocytopenic patient platelet-rich plasma samples. For samples tested at 250 x 10(9) platelets/l, non-parametric analyses described 95% of data for healthy control samples better than mean +/- 2 standard deviations. For samples tested at lower counts, to match thrombocytopenic samples, the % maximal aggregation was influenced by platelet count and derived limits were wider at very low platelet counts for almost all agonists. With ristocetin, it proved feasible to test samples with very low platelet counts to exclude Bernard-Soulier syndrome and type 2B von Willebrand disease. Non-parametric analyses should be the preferred method to establish light transmission aggregation reference intervals for samples tested at normal platelet counts. The derived limits for thrombocytopenic samples provide guidance for evaluating thrombocytopenic platelet function disorders, including which agonists to test, based on the sample platelet count.

Platelet function tests: A 5-year audit of platelet function tests done for bleeding disorders in a tertiary care center of a developing country.

INTRODUCTION: The platelet function disorders remain largely undiagnosed or incompletely diagnosed in developing nations due to lack of availability of tests like lumiaggregometry, granule release assay or molecular testing. We performed a retrospective analysis of all the platelet function test (PFT) carried out in past 5 years by Light transmission aggregometery (LTA) using a panel of agonist. The indications and the test results were analyzed by two hematopathologist with the aim to look into the present diagnostic facilities or lack of it for correct diagnosis. This is essential for better management and genetic counselling. MATERIALS AND METHODS: The PFT was performed both on patients and healthy unrelated age specific controls by light transmission aggregometry on Chronolog platelet aggregometer using platelet rich plasma. The panel of agonists included ADP (10µm/l and 2.0 µm/l), epinephrine (10.0 µm/l), collagen (2µg/ml), arachidonic acid (0.75 mM) and ristocetin (1.25 mg/ml & 0.25 mg/l). RESULTS: The 5 years records of 110 cases were audited, 101 of these were tested for clinical bleeding , 35 adults and 66 children. The adults included 29 women and 6 men, 17 to 82 years of age. The children were 16 years to 3 months of age, 30 girls and 36 boys. Platelet function test abnormality was found in 31.6% (32/101) cases ,a majority remained undiagnosed of these about 21% had clinically significant bleeding.The cases diagnosed included Glanzmann Thromboasthenia-11 , von Willebrand Disease-6, Bernard Soulier'syndrome-1, storage pool disorder-6, mild defect of Epinephrine-3, isolated defect with collagen in1. CONCLUSION: An epidemiologically large proportion of platelet function disorders amongst people living in developing nations remain undiagnosed. This lacunae needs to be highlighted and addressed on larger scale. The options available are to increase the available armamentarium of tests or international collaboration with a specialized laboratory to aid in complete diagnosis.

Using the Platelet Function Analyzer-100 for monitoring aspirin therapy.

INTRODUCTION: The aim of the study was to evaluate the test characteristics of the Platelet Function Analyzer-100 (PFA-100) in patients treated with aspirin. METHODS AND RESULTS: The study consisted of two sub-studies. In study 1, 10 patients with ischemic heart disease (IHD) and 10 controls had platelet function assessed by optical platelet aggregation and the PFA-100 method in two 5-week periods. Patients with IHD were treated with aspirin 150 mg/day (first 5-week period), and 300 mg/day (second 5-week period), whereas the controls only received aspirin (150 mg/day) during the second 5-week period. From the results of study 1, we found that a cut-off value for the PFA-100 collagen/epinephrine cartridge <165 s identified patients not taking aspirin (sensitivity 0.91, specificity 1.00). A good agreement between the PFA-100 method and optical platelet aggregation was found. Within-subject variation for the PFA-100 collagen/epinephrine cartridge was +/-28%, as compared to +/-17% for the optical platelet aggregation. Study 2 included 298 aspirin treated patients who were admitted with symptoms suggestive of an acute myocardial infarction. Platelet function was assessed in duplicate by the PFA-100 collagen/epinephrine cartridge, and a 95% Limit of Agreement interval at [-65%, 65%] indicated a limited precision. CONCLUSION: We defined a cut-off value below which patients not taking aspirin can be identified. However, due to imprecision of the PFA-100 method repeated duplicate assessment of the collagen/epinephrine Closure Time is recommended.

Postoperative bleeding in coronary artery bypass patients on double antiplatelet therapy: predictive value of preoperative aggregometry.

OBJECTIVES: We tested the possible value of routine aggregometry testing for bleeding prediction following coronary artery bypass grafting in patients who received preoperative double antiplatelet therapy. METHODS: In 226 patients undergoing on-pump isolated coronary artery bypass grafting, aggregometry [adenosine diphosphate (ADP) test and ASPI test] was always prospectively performed by Multiplate® analyser immediately before surgery. We assessed the differences in postoperative bleeding according to the type of double antiplatelet therapy [acetylsalicylic acid plus clopidogrel (ASA+C), or plus ticagrelor (ASA+T)], duration of clopidogrel/ticagrelor withdrawal (0-3 days or ≥ 4 days) and results of aggregometry tests. Multivariable predictors of blood losses were sought by linear regressions (drainage amount at 6, 12 and 24 postoperative hours) and logistic regression (increased bleeding: 75th percentile of blood losses at 6 h, i.e. >450 ml). RESULTS: Overall, postoperative blood losses did not significantly differ between treatment groups (median at 6 h: ASA + C = 335 ml, ASA + T = 300 ml, P = 0.21). With longer withdrawal interval, higher rates of patients with normal ADP-related platelet function were observed in both groups (ASA + C: P = 0.04; ASA + T: P = 0.006) but only in the ASA + T group were blood losses significantly smaller at all 3 time points. Bleeders (>450 ml at 6 h) were significantly less frequent among patients with ADP test showing recovered platelet function (ASA + T: P = 0.002; ASA + C: P = 0.053). The correlation between ADP test result and blood losses amount was stronger in the ASA + T group (e.g. at 6 h: r = -0.6; P < 0.001). In multivariable analyses, the ADP test result independently predicted postoperative bleeding in the ASA + T group and the ASPI test in the ASA + C group. CONCLUSIONS: Aggregometry can help in predicting postoperative bleeding in double antiplatelet therapy patients undergoing coronary artery bypass grafting.

Assessment of the efficacy and tolerability of clopidogrel napadisilate in Korean patients with coronary stenting: a multicenter, prospective, open-label, randomized trial.

OBJECTIVE: Clopidogrel is indicated for the treatment and prevention of peripheral vascular, cerebrovascular, and coronary artery diseases. This clinical trial was designed to demonstrate that clopidogrel napadisilate (CN) is not inferior to clopidogrel bisulfate (CB) with respect to its effectiveness in inhibiting platelet aggregation. METHODS: This 4 week multi-center, prospective, open-label, randomized trial was conducted at five clinical centers in South Korea. Patients were randomized into the 75 mg CN group or the 75 mg CB group. Platelet aggregation was assessed by the VerifyNow assay. The primary outcome was the difference of the percentage P2Y12 inhibition and the secondary outcome was the baseline and change in P2Y12 reaction units (PRU). RESULTS: There was no significant difference in the percentage P2Y12 inhibition (CN vs. CB, 34.92 ± 21.33% vs. 30.43 ± 17.90%, p=0.203). The mean difference of the percentage P2Y12 inhibition between groups was 4.49%, their two-sided 95% confidence interval was -2.45% to 11.44%, and the lower bound (-2.45%) was greater than the acceptable non-inferiority margin of -9.0%. The baseline PRU was 96.67 ± 76.76 in the CN group and 216.95 ± 68.86 in the CB group (p=0.121), and the change in the PRU was -3.32 ± 51.71 in the CN group and 10.52 ± 43.31 in the CB group (p=0.106). Four subjects experienced AEs (6.3%, 5 events) in the CN group and 7 subjects (11.11%, 13 events) in the CB group without statistical significance (p=0.364). With respect to serious adverse events, 2 events were reported in 2 subjects, 1 in each group. CONCLUSION: Clopidogrel napadisilate was not inferior to clopidogrel bisulfate in terms of antiplatelet efficacy and tolerability, and there were no clinically significant adverse events.

Comparison between urinary 11-dehydrothromboxane B2 detection and platelet Light Transmission Aggregometry (LTA) assays for evaluating aspirin response in elderly patients with coronary artery disease.

Aspirin is widely used in the primary and secondary prevention of cardiovascular diseases. The aim of our study was to compare between two established methods of aspirin response, urinary 11-dehydrothromboxane B2 (11dhTXB2) and platelet Light Transmission Aggregometry (LTA) assays in elderly Chinese patients with coronary artery disease (CAD), and to investigate the clinical significance of both methods in predicting cardiovascular events. Urinary 11dhTxB2 assay and arachidonic acid-induced (AA, 0.5mg/ml) platelet aggregation by Light Transmission Aggregometry (LTAAA) assay were measured to evaluate aspirin responses. High-on aspirin platelet reactivity (HAPR) was defined as urinary 11dhTxB2>1500pg/mg or AA-induced platelet aggregation≥15.22%-the upper quartile of our enrolled population. The two tests showed a poor correlation for aspirin inhibition (r=0.063) and a poor agreement in classifying HAPR (kappa=0.053). With a mean follow-up time of 12months, cardiovascular events occurred more frequently in HAPR patients who were diagnosed by LTA assay as compared with no-HAPR patients (22.5% versus 10.6%, P=0.039, OR=2.45, 95% CI=1.06-5.63). However, the HAPR status, as determined by urinary 11dTXB2 measurement, did not show a significant correlation with outcomes.

Patients with coronary artery disease who present with chest pain have significantly elevated platelet contractile force and clot elastic modulus.

Rapid laboratory markers that correlate with patient risk would facilitate the decision making regarding admission of patients with chest pain (CP). Platelet contractile force (PCF) and clot elastic modulus (CEM) are elevated in patients undergoing coronary bypass grafting. This study assessed PCF, CEM, and platelet aggregation in patients presenting to the emergency department with chest pain (CP). Results were compared with fifty normal controls. Both the total group of CP patients (n = 100) and the subset of patients (n = 36) with documented coronary artery disease (CAD) had significantly elevated PCF and CEM, and significantly decreased platelet aggregation relative to normal (p <0.001 for the total group, p

Platelet function in critically ill patients.

OBJECTIVE: The critically ill patient is at risk to develop coagulation abnormalities at different levels. Platelet dysfunction in these patients is of multifactorial origin, including drug interactions, hormonal response, and infection. The time course of platelet function in severely traumatized patients was studied. DESIGN: Prospective. SETTING: Clinical investigation, intensive care unit (ICU) of an university hospital. PATIENTS: Twenty-six consecutive, severely traumatized patients (injury severity score [ISS] > 30 points) were studied. The patients were divided into those who showed an uncomplicated course (n = 16) and those who developed sepsis during the investigation period ("complicated" trauma; n = 10). INTERVENTIONS: All therapy (parenteral feeding, antibiotics, volume therapy, ventilation) was comparable for all patients. MEASUREMENTS: Platelet function was assessed by aggregometry (inductors: adenosine diphosphate [ADP], 2.0 mumol/L; collagen, 4 micrograms/ml; epinephrine, 25 mumol/L; NaCl). Aggregometry was carried out from arterial blood samples within 24 h after admission to the ICU ("baseline") and the following 5 days. RESULTS: Standard coagulation variables (antithrombin III, fibrinogen, platelet count) showed no significant differences between the two groups. Platelet aggregation parameters were already reduced when the patients were admitted to ICU in all patients. In "uncomplicated" patients (without sepsis), aggregation increased during the following 5 days (maximal aggregation: ADP from 41 percent to 54 percent; collagen from 36 percent to 48 percent; epinephrine from 32 percent to 61 percent). Maximum gradient of platelet aggregation had a similar course. In the traumatized patients with sepsis, ADP- and collagen induced aggregation was significantly reduced within the investigation period. All patients with an ADP aggregation of less than 20 percent died. CONCLUSIONS: Platelet function in patients with isolated trauma recovered during the following 5 days. When sepsis complicated trauma, complex derangements in platelet function were present as seen by altered platelet aggregometry despite adequate platelet count.