Platelet count and mean platelet volume predict outcome in adults with Eisenmenger syndrome

Martín-García, Agustín; Arachchillage, Deepa Rj; Kempny, Aleksander; Alonso‐Gonzalez, Rafael; Martin-García, Ana; Uebing, Anselm; Swan, Lorna; Wort, Stephen J.; Price, Laura; McCabe, Colm; Sánchez, Pedro L.; Dimopoulos, Konstantinos; Gatzoulis, Michael Α.

doi:10.1136/heartjnl-2016-311144

Cited by 31 publications

(21 citation statements)

References 30 publications

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“…MPO also showed a positive, nominally significant (p = 0.03), association with PLT in FHS data ( Supplementary Table 2); furthermore, MPO knockdown MK clones showed a statistically significant decrease in MK derived platelet count, demonstrating a positive correlation between the protein and platelet production (Figure 3). MPO's positive correlation with both MPV and PLT is not concordant with the inverse relationship between MPV and PLT shown in prior literature 32 MCAM was negatively correlated with CHD risk in a prior MR study 18 . The MCAM instrumental variable SNP (rs11217234) in our study was nominally associated with (p = 0.027) with decreased risk of a second myocardial infarction event ( Supplementary Table 5).…”

Section: Discussioncontrasting

confidence: 40%

“…Seven proteins showed significant association with both PLT and MPV: soluble CD40 ligand (sCD40L), stromal cell-derived factor 1 (SDF1), pro-platelet basic protein (PPBP), translocation associated notch homolog (Notch1), adrenomedullin (ADM), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and cadherin-13 (CDH13). All seven proteins' direction of effect for MPV was the opposite of their direction of effect for PLT (Pearson's correlation: -0.90, 95% CI: (-0.99, -0.48)), reflecting the inverse correlation of MPV and PLT 32 .…”

Section: Fhs Protein-mpv/plt Association Analysesmentioning

confidence: 94%

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Integrative Genomic Analysis and Functional Studies Reveal GP5, GRN, MPO and MCAM as Causal Protein Biomarkers for Platelet Traits

Lee

Yao

Bhan

et al. 2019

Preprint

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Rationale Mean platelet volume (MPV) and platelet count (PLT) are platelet measures that have been linked to cardiovascular disease (CVD) and mortality risk. Identifying protein biomarkers for these measures may yield insights into CVD mechanisms.Objective We aimed to identify causal protein biomarkers for MPV and PLT among 71 CVDrelated plasma proteins measured in Framingham Heart Study (FHS) participants. Methods and ResultsWe conducted integrative analyses of genetic variants associated with PLT and MPV with protein quantitative trait locus (pQTL) variants associated with plasma proteins followed by Mendelian randomization (MR) to infer causal relations of proteins for PLT/MPV, and tested protein-PLT/MPV association in FHS participants. Utilizing induced pluripotent stem cell (iPSC)-derived megakaryocyte (MK) clones that produce functional platelets, we conducted RNA-sequencing and analyzed transcriptome-wide differences between low-and high-platelet producing clones. We then performed small interfering RNA (siRNA) gene knockdown experiments targeting genes encoding proteins with putatively causal platelet effects in MK clones to examine effects on platelet production.2 Protein-trait association analyses were conducted for MPV (n = 4,348) and PLT (n = 4,272).Eleven proteins were associated with MPV and 31 with PLT. MR identified four putatively causal proteins for MPV and four for PLT. Glycoprotein V (GP5), granulin (GRN), and melanoma cell adhesion molecule (MCAM) were associated with PLT in both protein-trait and MR analyses. Myeloperoxidase (MPO) showed significant association with MPV in both analyses. MK RNA-sequencing analysis results were directionally concordant with observed and MR-inferred associations for GP5, GRN, and MCAM.In siRNA gene knockdown experiments, silencing GP5, GRN, and MPO decreased platelet counts.Conclusions By integrating population genomics data, epidemiological data, and iPSC-derived MK experiments, we identified four proteins that are causally linked to platelet counts. These proteins and genes may be further explored for their utility in increasing platelet production in bioreactors for transfusion medicine purposes as well as their roles in the pathogenesis of CVD via a platelet/blood coagulation-based mechanism.

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Section: Discussioncontrasting

confidence: 40%

Section: Fhs Protein-mpv/plt Association Analysesmentioning

confidence: 94%

Integrative Genomic Analysis and Functional Studies Reveal GP5, GRN, MPO and MCAM as Causal Protein Biomarkers for Platelet Traits

Lee

Yao

Bhan

et al. 2019

Preprint

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“…Routine assessment of ES patients should include risk stratification, either using the criteria recommended by current European Society of Cardiology guidelines, and/or ES-specific predictors or outcome including BNP, C-reactive protein, platelet count and 6MWD. 2 , 36 – 38 In a multicentre study of 1098 ES patients, five independent predictors of mortality were identified: age, pre-tricuspid shunt, lower systemic oxygen saturations (SaO 2 ), presence of pericardial effusion and absence of sinus rhythm. 39 Patients at increased risk of death should be considered for PAH therapies, independent of FC.…”

Section: Methodsmentioning

confidence: 99%

Management dilemmas in pulmonary arterial hypertension associated with congenital heart disease

et al. 2018

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“…Platelets mediate and initiate thrombotic occlusion of the whole coronary artery and accumulate in the circulation resulting in impaired microcirculation and provoking myocardial ischemia during reperfusion [ 19 ]. However, patients with AMI with low platelet counts are commonly older with several comorbidities in most cases [ 20 ]. Similarly, our study showed that the patients with low platelet counts were older and had a higher prevalence of diabetes mellitus, hypertension, and previous stroke which could lead to higher rates of ischemic events despite low platelet counts.…”

Section: Discussionmentioning

confidence: 99%

Ischemic and Bleeding Events Associated with Thrombocytopenia and Thrombocytosis after Percutaneous Coronary Intervention in Patients with Acute Myocardial Infarction

Roh

Lim

Hwang

et al. 2020

JCM

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The early and late ischemic and bleeding clinical outcomes according to baseline platelet count after percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI) remain unclear. Overall, 10,667 patients from the Cardiovascular Risk and identification of potential high-risk population in AMI (COREA-AMI) I and II registries were classified according to the following universal criteria on baseline platelet counts: (1) moderate to severe thrombocytopenia (platelet < 100 K/μL, n = 101), (2) mild thrombocytopenia (platelet = 100~149 K/μL, n = 631), (3) normal reference (platelet = 150~450 K/μL, n = 9832), and (4) thrombocytosis (platelet > 450 K/μL, n = 103). The primary endpoint was the occurrence of major adverse cardiovascular events (MACE). The secondary outcome was Bleeding Academic Research Consortium (BARC) 2, 3, and 5 bleeding. After adjusting for confounders, the moderate to severe thrombocytopenia (HR, 2.03; 95% CI, 1.49–2.78); p < 0.001), mild thrombocytopenia (HR, 1.15; 95% CI, 1.01–1.34; p = 0.045), and thrombocytosis groups (HR, 1.47; 95% CI, 1.07–2.03; p = 0.019) showed higher 5-year MACE rates than the normal reference. In BARC 2, 3, and 5 bleeding outcomes, the bleedings rates were higher than the normal range in the moderate to severe thrombocytopenia (HR, 2.18; 95% CI, 1.36–3.49; p = 0.001) and mild thrombocytopenia (HR, 1.41; 95% CI, 1.12–1.78; p = 0.004) groups. Patients with AMI had higher 5-year MACE rates after PCI if they had lower- or higher-than-normal platelet counts. Thrombocytopenia revealed higher early and late bleeding rates whereas thrombocytosis showed long-term bleeding trends, although these trends were not statistically significant.

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Platelet count and mean platelet volume predict outcome in adults with Eisenmenger syndrome

Abstract: Thrombocytopaenia significantly increased the risk of mortality in ES. Furthermore, raised MPV, severe secondary erythrocytosis and anaemia, but not platelet count, were associated with an increased risk of thrombotic events in our adult cohort.

Cited by 31 publications

References 30 publications

Integrative Genomic Analysis and Functional Studies Reveal GP5, GRN, MPO and MCAM as Causal Protein Biomarkers for Platelet Traits

Integrative Genomic Analysis and Functional Studies Reveal GP5, GRN, MPO and MCAM as Causal Protein Biomarkers for Platelet Traits

Management dilemmas in pulmonary arterial hypertension associated with congenital heart disease

Ischemic and Bleeding Events Associated with Thrombocytopenia and Thrombocytosis after Percutaneous Coronary Intervention in Patients with Acute Myocardial Infarction

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