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Multiparameter platelet function analysis of bleeding patients with a prolonged platelet function analyser closure time.

ABSTRACT: Patients referred for evaluation of bleeding symptoms occasionally have a prolonged platelet function analyser (PFA) closure time, without evidence for von Willebrand disease or impaired platelet aggregation. The aim of this study was to establish a shear-dependent platelet function defect in these patients. Patients were included based on high bleeding score and prior PFA prolongation. Common tests of von Willebrand factor (VWF) and platelet function and exome sequencing were performed. Microfluidic analysis of shear-dependent collagen-induced whole-blood thrombus formation was performed. In 14 PFA-only patients, compared to healthy volunteers, microfluidic tests showed significantly lower platelet adhesion and thrombus formation parameters. This was accompanied by lower integrin activation, phosphatidylserine exposure and P-selectin expression. Principal components analysis indicated VWF as primary explaining variable of PFA prolongation, whereas conventional platelet aggregation primarily explained the reduced thrombus parameters under shear. In five patients with severe microfluidic abnormalities, conventional platelet aggregation was in the lowest range of normal. No causal variants in Mendelian genes known to cause bleeding or platelet disorders were identified. Multiparameter assessment of whole-blood thrombus formation under shear indicates single or combined effects of low-normal VWF and low-normal platelet aggregation in these patients, suggesting a shear-dependent platelet function defect, not detected by static conventional haemostatic tests.

SUBMITTER: Heubel-Moenen FCJI

PROVIDER: S-EPMC9303561 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Aim: To assess platelet (PLT) function and bleeding risks in patients with acute coronary syndrome after tirofiban infusion. Methods: Patients diagnosed with acute coronary syndrome from May 2016 to February 2018 in the Department of Cardiac Intensive Care Unit, Zhongshan Hospital, were enrolled. They were symmetrically allocated into two groups: tirofiban treatment group or control group (without tirofiban treatment). Blood samples were collected 24 h postoperation for the evaluation of antiplatelet effect of tirofiban. We applied thromboelastography to detect on-treatment PLT reactivity and conducted laboratory tests to assess the risk of bleeding following tirofiban treatment. After discharge, telephone follow-up and outpatient interview were carried out. The primary clinical endpoint was major adverse cardiovascular events, including cardiovascular death, cardiovascular mortality, myocardial infarction, and revascularization for the targeted vascular lesion. Results: There were a total of 196 patients with acute coronary syndrome after screening with the inclusion criteria and the exclusion criteria. Ninety-eight patients were assigned to receive either tirofiban treatment or control treatment. Patients treated with tirofiban had more coronary lesions and stents implanted compared with the control group (P = 0.000). After tirofiban infusion, inhibition of platelet aggregation induced by thromboxane A2 and adenosine diphosphate was significantly higher compared to patients without tirofiban infusion (80.3% ± 19.6% vs. 72.6% ± 13.0%, P = 0.002; and 81.0% ± 19.8% vs. 75.4% ± 12.4%, P = 0.020, respectively). There was no significant difference in the reduction of hemoglobin (Hb), hematocrit (Hct), and PLT after administration of tirofiban, compared with baseline (P > 0.05). In addition, no significant differences were identified between the two groups with respect to Hb, Hct, and PLT after tirofiban infusion. However, C-reactive protein level, referred to as an inflammation marker, was significantly lowered after infusion tirofiban compared with the control group (11.9 ± 14.2 vs. 17.9 ± 21.2, P = 0.020). During the 1-year follow-up, the incidence rate of major adverse cardiovascular events remains indiscriminate between the two groups (P = 0.208). The assessments of cardiac biomarkers showed that tirofiban could decrease incidence of procedural myocardial infarction (odds ratio [OR] = 0.250, 95% confidence interval [CI] = 0.067-0.925, P = 0.027). At follow-up, the morbidity of left atrial dilation in tirofiban-treated patients, defined as enlargement of left atrial diameter >40mm, was lower compared to the control group (OR = 0.533, 95% CI = 0.301-0.945, P = 0.031). Conclusion: Tirofiban infusion could decrease PLT activation in patients with acute coronary syndrome without increasing the risk of bleeding. As a concomitant medication, tirofiban shows no benefit in reducing the occurrence of major adverse cardiovascular events.

Project description:BackgroundSevere leptospirosis is frequently complicated by a hemorrhagic diathesis, of which the pathogenesis is still largely unknown. Thrombocytopenia is common, but often not to the degree that spontaneous bleeding is expected. We hypothesized that the hemorrhagic complications are not only related to thrombocytopenia, but also to platelet dysfunction, and that increased binding of von Willebrand factor (VWF) to platelets is involved in both platelet dysfunction and increased platelet clearance.Methodology/principal findingsA prospective study was carried out in Semarang, Indonesia, enrolling 33 hospitalized patients with probable leptospirosis, of whom 15 developed clinical bleeding, and 25 healthy controls. Platelet activation and reactivity were determined using flow cytometry by measuring the expression of P-selectin and activation of the αIIbβ3 integrin by the binding of fibrinogen in unstimulated samples and after ex vivo stimulation by the platelet agonists adenosine-diphosphate (ADP) and thrombin-receptor activating peptide (TRAP). Platelet-VWF binding, before and after VWF stimulation by ristocetin, as well as plasma levels of VWF, active VWF, the VWF-inactivating enzyme ADAMTS13, thrombin-antithrombin complexes (TAT) and P-selectin were also measured. Bleeding complications were graded using the WHO bleeding scale. Our study revealed that platelet activation, with a secondary platelet dysfunction, is a feature of patients with probable leptospirosis, especially in those with bleeding manifestations. There was a significant inverse correlation of bleeding score with TRAP-stimulated P-selectin and platelet-fibrinogen binding (R = -0.72, P = 0.003 and R = -0.66, P = 0.01, respectively) but not with platelet count. Patients with bleeding also had a significantly higher platelet-VWF binding. Platelet counts were inversely correlated with platelet-VWF binding (R = -0.74; P = 0.0009. There were no correlations between platelet-VWF binding and the degree of platelet dysfunction, suggesting that increased platelet-VWF binding does not directly interfere with the platelet αIIbβ3 signaling pathway in patients with probable leptospirosis.Conclusion/significancePlatelet dysfunction is common in probable leptospirosis patients with manifest bleeding. Increased VWF-platelet binding may contribute to the activation and clearance of platelets.

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Multiparameter platelet function analysis of bleeding patients with a prolonged platelet function analyser closure time.

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