Procoagulant platelets: generation, function, and therapeutic targeting in thrombosis

Agbani, Ejaife O.; Poole, Alastair W.

doi:10.1182/blood-2017-05-787259

Cited by 146 publications

(176 citation statements)

References 86 publications

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“…Further studies should be addressed to explore whether platelets per se or non-platelet sources are responsible for this phenomenon. Therefore, as a future perspective, the role of thrombo-inflammatory molecules related to platelet-leukocyte interaction and microparticles should be extensively studied [16,17]. Importantly, the mechanism of 'on treatment' residual platelet reactivity can be very complex as platelets are not only regulators of inflammation contributing to vascular damage in acute or chronic inflammation such as atherosclerosis, but also play an important role in the resolution of inflammation, vascular protection and repair [18].…”

Section: Discussionmentioning

confidence: 99%

A novel approach of platelet function test for prediction of attenuated response to clopidogrel

Ezer

Schrick

Tökés-Füzesi

et al. 2019

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BACKGROUND: Elevated mean platelet volume (MPV) and immature platelet fraction (IPF) are predictive for vascular risk. Both can be associated with residual platelet reactivity. We aimed to explore associations among platelet characteristics and responder status in stroke patients on clopidogrel. METHODS: Blood samples from 46 patients and 15 healthy subjects were analyzed for platelet count, MPV, IPF, large cell ratio (LCR) and high-fluorsecent immature platelet fraction (H-IPF). As a novelty, not only whole blood, but upper and lower half blood samples after 1-hour gravity sedimentation were analyzed. Platelet aggregometry was used for the whole blood and separated samples to explore area under the curve (AUC) in patients and controls. RESULTS: The AUC of the whole blood showed significant differences compared to the upper and lower samples separated after 1-hour sedimentation in patients and controls (p < 0.001 and p = 0.005 respectively). Remarkably, AUC measured in the upper samples in 59% of patients on clopidogrel were exceeding the therapeutic range suggesting that ascending platelets exert aggregation in the presence of ADP. This observation was associated with increased MPV and LCR in the upper samples (both p = 0.04). Patients on clopidogrel were characterized as responders and non-responders and the percentage of H-IPF was significantly higher among non-responders compared to controls in the upper samples (p = 0.04). CONCLUSIONS:The modified platelet function test may help to stratify patients with high residual platelet reactivity.

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Section: Discussionmentioning

confidence: 99%

A novel approach of platelet function test for prediction of attenuated response to clopidogrel

Ezer

Schrick

Tökés-Füzesi

et al. 2019

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“…Recent literature shows that AZA is a potent antithrombotic in vivo, although the signaling pathway involved might include the regulation of reactive oxygen species; however, at the moment, there is no evidence in the literature of this effect. 39 More studies and long-term design protocols are needed to confirm and explain the improvement of some coagulation factors during AZA treatment.…”

Section: Discussionmentioning

confidence: 99%

AZATAX: Acetazolamide safety and efficacy in cerebellar syndrome in PMM2 congenital disorder of glycosylation (PMM2‐CDG)

Martinez‐Monseny¹,

Bolasell²,

Callejón‐Póo³

et al. 2019

Annals of Neurology

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Objective: Phosphomannomutase deficiency (PMM2 congenital disorder of glycosylation [PMM2-CDG]) causes cerebellar syndrome and strokelike episodes (SLEs). SLEs are also described in patients with gain-of-function mutations in the CaV2.1 channel, for which acetazolamide therapy is suggested. Impairment in N-glycosylation of CaV2.1 promotes gain-of-function effects and may participate in cerebellar syndrome in PMM2-CDG. AZATAX was designed to establish whether acetazolamide is safe and improves cerebellar syndrome in PMM2-CDG. Methods: A clinical trial included PMM2-CDG patients, with a 6-month first-phase single acetazolamide therapy group, followed by a randomized 5-week withdrawal phase. Safety was assessed. The primary outcome measure was improvement in the International Cooperative Ataxia Rating Scale (ICARS). Other measures were the Nijmegen Pediatric CDG Rating Scale (NPCRS), a syllable repetition test (PATA test), and cognitive scores. Results: Twenty-four patients (mean age = 12.3 AE 4.5 years) were included, showing no serious adverse events. Thirteen patients required dose adjustment due to low bicarbonate or asthenia. There were improvements on ICARS (34.9 AE 23.2 vs 40.7 AE 24.8, effect size = 1.48, 95% confidence interval [CI] = 4.0-7.6, p < 0.001), detected at 6 weeks in 18 patients among the 20 responders, on NPCRS (95% CI = 0.3-1.6, p = 0.013) and on the PATA test (95% CI = 0.5-3.0, p = 0.006). Acetazolamide improved prothrombin time, factor X, and antithrombin. Clinical severity, epilepsy, and lipodystrophy predicted greater response. The randomized withdrawal phase showed ICARS worsening in the withdrawal group (effect size = 1.46, 95% CI = 2.65-7.52, p = 0.001). Interpretation: AZATAX is the first clinical trial of PMM2-CDG. Acetazolamide is well tolerated and effective for motor cerebellar syndrome. Its ability to prevent SLEs and its long-term effects on kidney function should be addressed in future studies. ANN NEUROL 2019;85:740-751 View this article online at wileyonlinelibrary.com.

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“…More recently, the discovery that dual stimulation with collagen and thrombin 16,17 polarises platelets into distinct pro-coagulant and pro-aggregatory phenotypes 8,18-24 has renewed interest on the topic of platelet diversity. In particular, the pro-coagulant platelets have been further characterised 25-30 , revealing diverse functions that either represent multiple pro-coagulant subpopulations or a unified, yet versatile pro-coagulant subpopulation 21 . The bifurcation of the platelet population into the two phenotypes further creates debate regarding intrinsic versus extrinsic functional programming 8 .…”

Section: Introductionmentioning

confidence: 99%

Single platelet variability governs population sensitivity and initiates intrinsic heterotypic behaviours

Jongen

MacArthur

Englyst

et al. 2020

Preprint

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9Droplet microfluidics combined with flow cytometry was used for high throughput single platelet function 10 analysis. A large-scale sensitivity continuum was shown to be a general feature of human platelets from 11 individual donors, with hypersensitive platelets coordinating significant sensitivity gains in bulk platelet 12 populations and shown to direct aggregation in droplet-confined minimal platelet systems. Sensitivity gains 13 scaled with agonist potency (convulxin>TRAP-14>ADP) and reduced the collagen and thrombin activation 14 threshold required for platelet population polarization into pro-aggregatory and pro-coagulant states. The 15 heterotypic platelet response results from an intrinsic behavioural program. The method and findings invite 16 future discoveries into the nature of hypersensitive platelets and how community effects produce population 17 level behaviours in health and disease. 18 19 30 platelet activation represents an ideal system for investigating cellular diversity and consequences for 31 homeostatic system control. Indeed, the nature and functional consequences of platelet diversity has been a 32 matter of enquiry for almost half a century 8,10,11 . More recently, the discovery that dual stimulation with 33 collagen and thrombin 16,17 polarises platelets into distinct pro-coagulant and pro-aggregatory phenotypes 8,18-24 34 has renewed interest on the topic of platelet diversity. In particular, the pro-coagulant platelets have been 35 further characterised 25-30 , revealing diverse functions that either represent multiple pro-coagulant 36 subpopulations or a unified, yet versatile pro-coagulant subpopulation 21 . The bifurcation of the platelet 37 population into the two phenotypes further creates debate regarding intrinsic versus extrinsic functional 38 programming 8 . Allied to this, subjects with reduced GPVI levels showed reduced thrombus formation 31 , 39 implicating platelet heterogeneity with increased activity by platelets with elevated GPVI levels 32 . Overall, a 40 complex picture is emerging, with precision methods required to accurately delineate subpopulations and their 41 functional roles to inform our understanding of platelet interactions governing thrombus formation. 2The paracrine signalling inherent to platelet activation represents a technical challenge for measuring 43 single platelet behaviour without interference by the secretion products of activated platelets in the vicinity. 44This implies the requirement for confinement, discretising the analysis into single platelet measurements. The 45 other requirement is throughput to effectively resolve the functional structure of the platelet population. 46Droplet microfluidics allows the reliable production of monodisperse droplets in the nanolitre to femtolitre 4 aggregation responses to be investigated. Dual fluorescent imaging (P-selectin and CD63) with brightfield overlay of minimal 100 platelet collectives stimulated with 1 ng/mL convulxin (H) and dose response violin plots of minimal platelet collectives 101 comp...

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Procoagulant platelets: generation, function, and therapeutic targeting in thrombosis

Cited by 146 publications

References 86 publications

A novel approach of platelet function test for prediction of attenuated response to clopidogrel

A novel approach of platelet function test for prediction of attenuated response to clopidogrel

AZATAX: Acetazolamide safety and efficacy in cerebellar syndrome in PMM2 congenital disorder of glycosylation (PMM2‐CDG)

Single platelet variability governs population sensitivity and initiates intrinsic heterotypic behaviours

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