scholarly journals A dry immersion model of microgravity modulates platelet phenotype, miRNA signature, and circulating plasma protein biomarker profile

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Laura Twomey ◽  
Nastassia Navasiolava ◽  
Adrien Robin ◽  
Marie-Pierre Bareille ◽  
Guillemette Gauquelin-Koch ◽  
...  
Keyword(s):  
Platelet Count ◽  
Physical Inactivity ◽  
Platelet Reactivity ◽  
Reactivity Index ◽  
Mirna Signature ◽  
Protein Biomarkers ◽  
Protein Biomarker ◽  
Dry Immersion ◽  
Age Related ◽  
Biomarker Signature

AbstractGround based research modalities of microgravity have been proposed as innovative methods to investigate the aetiology of chronic age-related conditions such as cardiovascular disease. Dry Immersion (DI), has been effectively used to interrogate the sequelae of physical inactivity (PI) and microgravity on multiple physiological systems. Herein we look at the causa et effectus of 3-day DI on platelet phenotype, and correlate with both miRomic and circulating biomarker expression. The miRomic profile of platelets is reflective of phenotype, which itself is sensitive and malleable to the exposome, undergoing responsive transitions in order to fulfil platelets role in thrombosis and haemostasis. Heterogeneous platelet subpopulations circulate at any given time, with varying degrees of sensitivity to activation. Employing a DI model, we investigate the effect of acute PI on platelet function in 12 healthy males. 3-day DI resulted in a significant increase in platelet count, plateletcrit, platelet adhesion, aggregation, and a modest elevation of platelet reactivity index (PRI). We identified 15 protein biomarkers and 22 miRNA whose expression levels were altered after DI. A 3-day DI model of microgravity/physical inactivity induced a prothrombotic platelet phenotype with an unique platelet miRNA signature, increased platelet count and plateletcrit. This correlated with a unique circulating protein biomarker signature. Taken together, these findings highlight platelets as sensitive adaptive sentinels and functional biomarkers of epigenetic drift within the cardiovascular compartment.

scholarly journals Function, Proteomic and miRomic Study of a Dry Immersion Model of Microgravity implicates the Wnt/Dkk1/AXIN1 axis in Prothrombotic Platelet Phenotype

2021 ◽  
Author(s):  
Laura Twomey ◽  
Nastassia Navasiolava ◽  
Adrien Robin ◽  
Marie-Pierre Bareille ◽  
Guillemette Gauquelin-Koch ◽  
...  
Keyword(s):  
Physical Inactivity ◽  
Platelet Adhesion ◽  
Platelet Reactivity ◽  
Reactivity Index ◽  
Mirna Regulation ◽  
Protein Biomarkers ◽  
Dry Immersion ◽  
Innovative Methods ◽  
Age Related ◽  
And Function

Abstract Objective: Ground based research modalities of microgravity have been proposed as innovative methods to investigate the aetiology of chronic age-related conditions such as cardiovascular disease. Dry Immersion (DI), has been effectively used to interrogate the sequelae of physical inactivity (PI) and microgravity on multiple physiological systems. Herein we look at the causa et effectus of 3-day DI on platelet phenotype, and correlate with both miRomic and biomarker expression.Approach and Results: The miRomic profile of platelets is reflective of phenotype, which itself is sensitive and malleable to the exposome, undergoing responsive transitions in order to fulfil platelets role in thrombosis and haemostasis. Heterogeneous platelet subpopulations circulate at any given time, with varying degrees of sensitivity to activation. Employing a DI model, we investigate the effect of acute PI on platelet function in 12 healthy males. 3-day DI resulted in a significant increase in platelet count, plateletcrit, platelet adhesion, aggregation, and a modest elevation of platelet reactivity index (PRI). We identified 15 protein biomarkers whose expression levels were altered after DI. 22 “DI/PI” related miRNA were identified, of which five have potential targets in the Wnt pathway associated with platelet biogenesis and function. These findings are supported by increased circulating Axin1 and DKK1.Conclusions: Circulating biomarker and miRomic analysis implicates miRNA regulation of Wnt/Dkk1/AXIN1 axis in DI/PI induced primed platelet phenotype. Taken together, these findings highlight platelets as sensitive adaptive sentinels and functional biomarkers of epigenetic drift within the cardiovascular compartment.

Elevated Inflammatory Markers and Arterial Stiffening Exacerbate Tau but Not Amyloid Pathology in Older Adults with Mild Cognitive Impairment

2021 ◽  
pp. 1-13
Author(s):  
Alexandra L. Clark ◽  
Alexandra J. Weigand ◽  
Kelsey R. Thomas ◽  
Seraphina K. Solders ◽  
Lisa Delano-Wood ◽  
...  
Keyword(s):  
Older Adults ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Inflammatory Markers ◽  
Memory Performance ◽  
Cognitive Testing ◽  
Interactive Effects ◽  
Protein Biomarkers ◽  
Age Related ◽  
T Tau

Background: Age-related cerebrovascular and neuroinflammatory processes have been independently identified as key mechanisms of Alzheimer’s disease (AD), although their interactive effects have yet to be fully examined. Objective: The current study examined 1) the influence of pulse pressure (PP) and inflammatory markers on AD protein levels and 2) links between protein biomarkers and cognitive function in older adults with and without mild cognitive impairment (MCI). Methods: This study included 218 ADNI (81 cognitively normal [CN], 137 MCI) participants who underwent lumbar punctures, apolipoprotein E (APOE) genotyping, and cognitive testing. Cerebrospinal (CSF) levels of eight pro-inflammatory markers were used to create an inflammation composite, and amyloid-beta 1–42 (Aβ 42), phosphorylated tau (p-tau), and total tau (t-tau) were quantified. Results: Multiple regression analyses controlling for age, education, and APOE ɛ4 genotype revealed significant PP x inflammation interactions for t-tau (B = 0.88, p = 0.01) and p-tau (B = 0.84, p = 0.02); higher inflammation was associated with higher levels of tau within the MCI group. However, within the CN group, analyses revealed a significant PP x inflammation interaction for Aβ 42 (B = –1.01, p = 0.02); greater inflammation was associated with higher levels of Aβ 42 (indicative of lower cerebral amyloid burden) in those with lower PP. Finally, higher levels of tau were associated with poorer memory performance within the MCI group only (p s <  0.05). Conclusion: PP and inflammation exert differential effects on AD CSF proteins and provide evidence that vascular risk is associated with greater AD pathology across our sample of CN and MCI older adults.

Combined effects of plasma von Willebrand factor and platelet measures on the risk of incident venous thromboembolism

Blood ◽  
2021 ◽  
Author(s):  
Magnus Sandvik Edvardsen ◽  
Ellen-Sofie Hansen ◽  
Kristian Hindberg ◽  
Vânia Maris Morelli ◽  
Thor Ueland ◽  
...  
Keyword(s):  
Platelet Count ◽  
Venous Thromboembolism ◽  
Von Willebrand Factor ◽  
Platelet Reactivity ◽  
High Plasma ◽  
Combined Effects ◽  
Exposure Group ◽  
Increased Risk ◽  
Von Willebrand ◽  
Willebrand Factor

Plasma von Willebrand factor (VWF) and platelet reactivity are both risk factors for venous thromboembolism (VTE), and VWF can promote hemostasis by interaction with platelets. In this study, we explored the combined effects of plasma VWF and platelet measures on the risk of incident VTE. A population-based nested case-control study with 403 cases and 816 controls was derived from the Tromsø Study. VWF, platelet count and mean platelet volume (MPV) were measured in blood samples drawn at baseline. Odds ratios (ORs) with 95% confidence intervals (CIs) for VTE were estimated across VWF tertiles, within predefined MPV (&lt;8.5, 8.5-9.5, ≥9.5 fL) and platelet count (&lt;230, 230-299, ≥300·109 L-1) strata. Here, participants with VWF levels in the highest tertile and MPV ≥9.5 fL had an OR of 1.98 (95% CI 1.17-3.36) for VTE compared with those in the lowest VWF tertile and with MPV &lt;8.5 fL in the age- and sex-adjusted model. In the joint exposure group, 48% (95% CI 15% to 96%) of VTEs were attributable to the biological interaction between VWF and MPV. Similarly, individuals with VWF in the highest tertile and platelet count ≥300·109 L-1 had an OR of 2.91 (95% CI 1.49-5.67) compared with those with VWF in the lowest tertile and platelet count &lt;230, and 39% (95% CI -2% to 97%) of VTEs in the joint exposure group were explained by the interaction. Our results suggest that both platelet reactivity and platelet count interact biologically with high plasma VWF, resulting in an increased risk of incident VTE.

Comparison of VASP-phosphorylation assay to light-transmission aggregometry in assessing inhibition of the platelet ADP P2Y12 receptor

2006 ◽  
Vol 96 (12) ◽  
pp. 767-773 ◽  
Author(s):  
Agnieszka Pampuch ◽  
Giovanni de Gaetano ◽  
Chiara Cerletti
Keyword(s):  
Light Transmission ◽  
Platelet Reactivity ◽  
Flow Cytometric Analysis ◽  
Individual Variability ◽  
P2y12 Receptor ◽  
Reactivity Index ◽  
Drug Induced ◽  
Light Transmission Aggregometry ◽  
Adp Receptor

SummaryThere is need to improve platelet function testing to monitor the response to antiplatelet drugs. We compared flow-cytometric analysis of intraplatelet vasodilator-stimulated phosphoprotein phosphorylation (VASP-P) to light-transmission aggregometry for the detection of drug-induced in-vitro inhibition of the platelet P2Y12 ADP receptor on 22 healthy subjects (10 males, 12 females, 28.5 ± 6.6 years). The platelet reactivity index (PRI) of VASP was calculated both from mean fluorescence intensity (MFI) and percent of fluorescence-positive platelets in the presence of PGE1 with or without ADP (10 µM). Platelet aggregation was induced by ADP (1.25, 2.5 and 5 µM). Cangrelor, a competitive inhibitor of the P2Y12 receptor, preincubated 5 minutes, induced a concentration-dependent inhibition of platelet ADP-receptor function in both tests. Indeed PRI (%) based on either MFI or percent platelets gated were highly correlated with each other (r = 0.97, p<0.0001) and with aggregation in- duced by ADP. The IC50 of cangrelor against each of the three ADP concentrations used in aggregometry increased from 5.8 ± 3.4 nM to 23.1 ± 4.0 nM and to 98 ± 25 nM, respectively. The IC50 of cangrelor based on VASP-P was within the same range (25.5 ± 7.7 nM). No correlation was observed between IC50 values of cangrelor and ADP concentrations giving 50% effect (EC50) in the absence of the drug. However, at 10 nM cangrelor seven subjects could be identified by the VASP-P assay as “low responders” to the drug (PRI> 50%), and six of them also had an aggregation response to 5 µM ADP > 50%. These six subjects showed the lowest ADP EC50 values in the absence of the drug, possibly reflecting high sensitivity of their platelet P2Y12 receptors to ADP. In conclusion, both the VASP-P assay and light-transmission aggregometry detect in a comparable way in-vitro pharmacological inhibition of the platelet P2Y12 ADP receptor and its individual variability.

Abstract 14004: Pharmacodynamic Profiles of Ticagrelor in Patients With ST-Elevation Myocardial Infarction: A Prospective Randomized Comparison of Escalating Loading Dose Regimens

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Francesco Franchi ◽  
Fabiana Rollini ◽  
Jung Rae Cho ◽  
Mona Bhatti ◽  
Christopher DeGroat ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Time Course ◽  
Peak Plasma ◽  
Platelet Reactivity ◽  
Randomized Study ◽  
Plasma Concentrations ◽  
St Elevation Myocardial Infarction ◽  
Reactivity Index ◽  
Loading Dose ◽  
St Elevation

Background: Pharmacodynamic (PD) studies have shown that in ST-elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PPCI), ticagrelor is associated with suboptimal platelet inhibition and elevated rates of high on-treatment platelet reactivity (HPR) in the early hours after loading dose (LD) administration. Impaired absorption affecting drug pharmacokinetics (PK) has been hypothesized as a contributing factor suggesting increasing LD regimens to improve PK/PD profiles. To date there are no randomized studies which have investigated the PK/PD effects of escalating ticagrelor LD regimens in patients undergoing PPCI. Methods: In this prospective, randomized study, STEMI patients undergoing PPCI (n=52) were randomized 1:1:1 to receive 180mg, 270mg or 360mg LD of ticagrelor. PK and PD analysis were performed before and at 6 time points after LD. PD assessments included P2Y 12 reaction units (PRU) measured by VerifyNow P2Y12 and platelet reactivity index (PRI) measured by VASP. PK assessments included plasma concentrations of ticagrelor and its metabolite AR-C124910XX. Results: At baseline there were no differences in platelet reactivity between groups. At 2 hrs (primary endpoint), there were no differences in PRU between groups (p=0.54). There were no differences in PRU between groups during the overall study time course (p=0.17; Figure). Accordingly, HPR (PRU>208) at 2 hrs was observed in 30% of patients and was not reduced by escalating ticagrelor LD regimens. Consistent PD findings were observed with VASP-PRI. PK data tracked PD results, with a non-dose related delay in peak plasma concentrations of both ticagrelor and AR-C124910XX, particularly in HPR patients. Conclusions: In STEMI patients undergoing PPCI, increasing the LD regimen of ticagrelor did not translate into more prompt or potent P2Y 12 inhibition, which is attributed to impaired absorption in the early hours after drug administration.

Abstract 2041: Low P2Y 12 -Specific Platelet Inhibition in Clopidogrel-Treated Patients with Coronary Artery Disease is Common and not Reliably Detected by Conventional Aggregation Tests

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Andreas Schaefer ◽  
Sarah Weinberger ◽  
Martin Eigenthaler ◽  
Georg Ertl ◽  
Johann Bauersachs
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Real World ◽  
Platelet Reactivity ◽  
Reactivity Index ◽  
Individual Response ◽  
Specific Assay ◽  
Cardiovascular Morbidity And Mortality ◽  
Increased Risk ◽  
Artery Disease

Background: Incomplete inhibition of P2Y 12 -mediated platelet activation during clopidogrel treatment has been associated with increased cardiovascular morbidity and mortality after percutaneous coronary intervention. This study aimed to investigate the incidence of impaired individual clopidogrel-responsiveness using a P2Y 12 -specific and pre-treatment-independent assay in a real world situation. Methods: 100 consecutive patients with coronary artery disease on clopidogrel treatment (> 5 days including a loading dose of at least 300 mg) were screened for response to ADP-induced platelet signalling. We assessed the vasodilator-stimulated phosphoprotein-based platelet reactivity index (PRI) as the only P2Y 12 -specific assay to determine clopidogrel responsiveness. Insufficient inhibition of P2Y 12 by clopidogrel was defined as a PRI >50% based on previous studies indicating increased risk of stent thrombosis under this condition. The results were compared with conventional assays to assess ADP-induced P-selectin surface-expression and conventional turbinometric platelet aggregation to several concentrations of ADP. Results: Clopidogrel significantly lowered functional platelet reactivity in patients with coronary artery disease compared to untreated patients. However, insufficient individual response to treatment predisposing for adverse events and therefore previously described as “non-response” was diagnosed in 69% of clopidogrel-treated patients using PRI. Conventional aggregation failed to detect insufficient P2Y 12 -inhibition in 1/3of patients with a PRI>50%. Conclusion: Using the PRI as the only P2Y 12 -specific assay to evaluate the treatment effect of clopidogrel in patients with coronary artery disease, insufficient P2Y 12 -inhibition was present in the majority of patients in a real-world scenario. Insufficient P2Y12-inhibition could not be reliably detected by conventional aggregation More prospective studies are needed to evaluate the influence of the high prevalence of incomplete clopidogrel responsiveness to major adverse cardiac events.

Platelet Adhesion to Insolubilized Aggregating Agents

1975 ◽  
Author(s):  
D. L. Heene ◽  
G. Grotemeyer ◽  
F. R. Matthias ◽  
H. G. Lasch
Keyword(s):  
Platelet Count ◽  
Reaction Time ◽  
Venous Thrombosis ◽  
Platelet Adhesion ◽  
Platelet Reactivity ◽  
Platelet Rich Plasma ◽  
Arterial Occlusive Disease ◽  
Chemical Fixation ◽  
Thromboembolic Complications ◽  
Healthy Donors

Platelet aggregating substances, such as bovine fibrinogen (FG) and collagen (Col), were insolubilized by means of chemical fixation to CNBr-activated agarose. Platelets exposed to bovine FG-ag or Col-ag readily adhere and “aggregate” to these insolubilized agents. An assay system was designed which indicates the platelet reactivity towards FG-ag and Col-ag by means of the decrease of platelet count in platelet rich plasma after exposure to the agarose bound aggregating substance. After evaluation of the standard conditions concerning reaction time, amount of substrate and degree of disappearance of platelets for PRP from healthy donors (arbitrarily set to 100% ) the procedure was applied to clinical cases and revealed significant (p < 0.001) increase of platelet reactivity in patients with venous thrombosis (n = 11), arterial occlusive disease (n = 12), hyperlipemia (n = 26) and storke (n = 6). Mainly the FG-ag test was found to be suitable to detect hyperactivity (up to 300%) in cases with thromboembolic complications and to control the effect of ASA.

Early determination of clopidogrel responsiveness by platelet reactivity index identifies patients at risk for cardiovascular events after myocardial infarction

2011 ◽  
Vol 106 (07) ◽  
pp. 141-148 ◽  
Author(s):  
Andreas Schäfer ◽  
Ulrike Flierl ◽  
Jürgen Kössler ◽  
Nora Seydelmann ◽  
Anna Kobsar ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Platelet Reactivity ◽  
Density Lipoprotein ◽  
Coronary Intervention ◽  
Platelet Inhibition ◽  
Systematic Evaluation ◽  
Reactivity Index ◽  
Operating Characteristics ◽  
Patients At Risk ◽  
Acute Mi

SummaryWhile acute myocardial infarction (MI) is associated with impaired clopidogrel responsiveness, systematic evaluation is lacking due to the inability of functional aggregation-based assays to analyse clopidogrel responsiveness in the presence of glycoprotein IIb/IIIa inhibitors. Using the P2Y12-specific, non-aggregation-based platelet-reactivity-index (PRI) we assessed clopidogrel responsiveness in patients with acute MI. Clopidogrel responsiveness was determined 24 hours (h) after loading with 600 mg clopidogrel in 54 patients with acute MI admitted for coronary intervention. A PRI > 50% was considered as suboptimal inhibition. Overall response in MI patients was suboptimal with a median PRI of 58%. Diabetes, low high-density lipoprotein and pre-hospital clopidogrel loading were associated with impaired clopidogrel responsiveness. Patients loaded at first medical contact had a significantly weaker platelet inhibition by clopidogrel after 24 h (PRI 63%) compared to those loaded peri-interventionally (PRI 54%, p=0.014). Clinical outcome was assessed as a combination of cardiac death, non-fatal MI, stent thrombosis, ischaemic stroke, and urgent target vessel revascularisation after 12 months. The pre-selected cut-off of PRI ≤ 50% yielded a sensitivity of 87% at a specificity of 26%, whereas a PRI ≤ 57% determined by receiver-operating characteristics (ROC)-analysis yielded a sensitivity of 80% at a specificity of 56% (event rate: PRI ≤ 57%: 12.0%; PRI > 57%: 41.4%, p=0.0136). In conclusion, PRI detects clopidogrel responsiveness in acute MI patients requiring glycoprotein IIb/IIIa antagonism; and impaired clopidogrel responsiveness predisposes to clinical events. Pre-hospital clopidogrel loading was associated with impaired response and more adverse events challenging the concept of earliest oral clopidogrel loading in MI patients.

Impact of reticulated platelets on antiplatelet response to thienopyridines is independent of platelet turnover

2016 ◽  
Vol 116 (11) ◽  
pp. 941-948 ◽  
Author(s):  
Thomas Nührenberg ◽  
Michael Amann ◽  
Marco Cederqvist ◽  
Pascal Kleiner ◽  
Christian M. Valina ◽  
...  
Keyword(s):  
Platelet Count ◽  
Drug Exposure ◽  
Platelet Reactivity ◽  
Adenosine Diphosphate ◽  
Coronary Intervention ◽  
Underlying Mechanism ◽  
Entire Cohort ◽  
Reticulated Platelets ◽  
Impedance Aggregometry ◽  
The Impact

SummaryReticulated platelets are associated with impaired antiplatelet response to thienopyridines. It is uncertain whether this interaction is caused by a decreased drug exposure due to high platelet turnover reflected by elevated levels of reticulated platelets or by intrinsic properties of reticulated platelets. This study sought to investigate if the impact of reticulated platelets on early antiplatelet response to thienopyridines is mainly caused by platelet turnover as previously suggested. Elective patients undergoing coronary intervention were randomised to loading with clopidogrel 600 mg or prasugrel 60 mg (n=200). Adenosine diphosphate (ADP)-induced platelet reactivity was determined by impedance aggregometry before, at 30, 60, 90, and 120 minutes and at day 1 after loading. Immature platelet count was assessed as marker of reticulated platelets by flow cytometry. Platelet reactivity increased with rising levels of immature platelet count in both groups. This effect was more distinctive in patients on clopidogrel as compared to patients on prasugrel. Overall, immature platelet count correlated well with on-treatment platelet reactivity at all timepoints (p < 0.001). These correlations did not change over time in the entire cohort as well as in patients treated with clopidogrel or prasugrel indicating an effect independent of platelet turnover (comparison of correlations 120 minutes/day 1: p = 0.64). In conclusion, the association of immature platelet count with impaired antiplatelet response to thienopyridines is similar early and late after loading. This finding suggests as main underlying mechanism another effect of reticulated platelets on thienopyridines than platelet turnover.Supplementary Material to this article is available online at www.thrombosis-online.com.

scholarly journals RGS10 and RGS18 differentially limit platelet activation, promote platelet production, and prolong platelet survival

Blood ◽  
2020 ◽  
Vol 136 (15) ◽  
pp. 1773-1782 ◽  
Author(s):  
Daniel DeHelian ◽  
Shuchi Gupta ◽  
Jie Wu ◽  
Chelsea Thorsheim ◽  
Brian Estevez ◽  
...  
Keyword(s):  
Platelet Count ◽  
G Protein ◽  
Platelet Activation ◽  
Platelet Reactivity ◽  
Rgs Proteins ◽  
Platelet Recovery ◽  
Platelet Production ◽  
Platelet Survival

Abstract G protein–coupled receptors are critical mediators of platelet activation whose signaling can be modulated by members of the regulator of G protein signaling (RGS) family. The 2 most abundant RGS proteins in human and mouse platelets are RGS10 and RGS18. While each has been studied individually, critical questions remain about the overall impact of this mode of regulation in platelets. Here, we report that mice missing both proteins show reduced platelet survival and a 40% decrease in platelet count that can be partially reversed with aspirin and a P2Y12 antagonist. Their platelets have increased basal (TREM)-like transcript-1 expression, a leftward shift in the dose/response for a thrombin receptor–activating peptide, an increased maximum response to adenosine 5′-diphosphate and TxA2, and a greatly exaggerated response to penetrating injuries in vivo. Neither of the individual knockouts displays this constellation of findings. RGS10−/− platelets have an enhanced response to agonists in vitro, but platelet count and survival are normal. RGS18−/− mice have a 15% reduction in platelet count that is not affected by antiplatelet agents, nearly normal responses to platelet agonists, and normal platelet survival. Megakaryocyte number and ploidy are normal in all 3 mouse lines, but platelet recovery from severe acute thrombocytopenia is slower in RGS18−/− and RGS10−/−18−/− mice. Collectively, these results show that RGS10 and RGS18 have complementary roles in platelets. Removing both at the same time discloses the extent to which this regulatory mechanism normally controls platelet reactivity in vivo, modulates the hemostatic response to injury, promotes platelet production, and prolongs platelet survival.

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