The emerging value of P-selectin as a disease marker

AbstractActivated platelets are key components in many arterial disorders. P-selectin is an activation-dependent platelet receptor, which is also identified in endothelial cells. Together with E-and L-selectin it constitutes the selectin family. These transmembrane proteins have continued to attract great interest as they support rapid and reversible cell adhesion in flow systems and thus play an essential role in multicellular interactions during thrombosis and inflammation. Similarly to other lectins, selectins bind to different glycoconjugates with varying affinities. Protein ligands, equipped with the appropriate carbohydrate and sulfate moieties for P-selectin binding, have been identified in normal peripheral blood leukocytes and several non-hematopoietic organs, as well as on cancer cells. For diagnostic purposes, P-selectin can readily be detected on the platelet surface by flow cytometry and by ELISA as a soluble ligand in the plasma. Along with other markers, these data can be used in the assessment of platelet activation status. Such results bear clinical significance since P-selectin has been implicated in the pathogenesis of widespread disorders including coronary artery disease, stroke, diabetes and malignancy.

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High retinoic acid receptor-related orphan receptor A gene expression in peripheral blood leukocytes may be related to acute myocardial infarction

Journal of International Medical Research ◽

10.1177/03000605211019663 ◽

2021 ◽

Vol 49 (6) ◽

pp. 030006052110196

Author(s):

Heyu Meng ◽

Jianjun Ruan ◽

Xiaomin Tian ◽

Lihong Li ◽

Weiwei Chen ◽

...

Keyword(s):

Myocardial Infarction ◽

Coronary Artery Disease ◽

Acute Myocardial Infarction ◽

Coronary Artery ◽

Peripheral Blood ◽

Retinoic Acid Receptor ◽

Stable Coronary Artery Disease ◽

Orphan Receptor ◽

Blood Leukocytes ◽

Artery Disease

Objective This study aimed to investigate whether differential expression of the retinoic acid receptor-related orphan receptor A ( RORA) gene is related to occurrence of acute myocardial infarction (AMI). Methods This was a retrospective study. White blood cells of 93 patients with acute myocardial infarction and 74 patients with stable coronary artery disease were collected. Reverse transcription quantitative polymerase chain reaction and western blotting were used to measure RORA mRNA and protein expression, respectively. Results RORA mRNA expression levels in peripheral blood leukocytes in patients with AMI were 1.57 times higher than those in patients with stable coronary artery disease. Protein RORA levels in peripheral blood of patients with AMI were increased. Binary logistic regression analysis showed that high expression of RORA was an independent risk factor for AMI, and it increased the risk of AMI by 2.990 times. Conclusion RORA expression levels in patients with AMI is significantly higher than that in patients with stable coronary artery disease. High expression of RORA is related to AMI and it may be an independent risk factor for AMI.

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The Stromelysin-1 5A/6A Promoter Polymorphism Is a Disease Marker for the Extent of Coronary Heart Disease

Disease Markers ◽

10.1155/2002/418383 ◽

2002 ◽

Vol 18 (3) ◽

pp. 121-128 ◽

Cited By ~ 21

Author(s):

Adelheid Schwarz ◽

Werner Haberbosch ◽

Harald Tillmanns ◽

Andreas Gardemann

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Total Sample ◽

Promoter Polymorphism ◽

Mean Values ◽

Glucose Levels ◽

Disease Marker ◽

Triple Vessel Disease ◽

Artery Disease ◽

Glucose Plasma

Background.Matrix metalloproteinases, such as stromelysin-1, are implicated in the pathogenesis of coronary artery disease (CAD) and acute myocardial infarction (MI). A 5A/6A promoter polymorphism can regulate the transcription of the stromelysin-1 gene in an allele-specific manner. Evidence has been presented that the 6A allele is associated with the progression of coronary heart disease (CHD). In contrast, the 5A allele may be linked to the risk of MI.Results.To analyse the relation of the 5A/6A polymorphism with the risk and severity of CHD and the risk of MI, a case-control study of 515 healthy controls and 1848 participants who underwent coronary angiography for diagnostic purposes was conducted. In the total sample, the mean CHD scores—according to Gensini—were different between 5A/6A genotypes: 5A5A homozygotes had the lowest, 6A6A genotypes the highest and 5A6A heterozygotes intermediate scores. These differences were even more pronounced when the participants were restricted to individuals with a high coronary risk profile (high apoB levels, high Lp(a) levels, high glucose levels, combinations of either high apoB and Lp(a) levels or high apoB, Lp(a) and glucose plasma levels). Mean values were used as cut points for high-risk populations, respectively. In contrast, the 5A allele was not associated with the risk of CHD or MI. Even when angiographically controlled individuals without MI were compared with MI patients in subpopulations of participants with no, single, double and triple vessel disease, the frequencies of the 5A/6A and/or the 5A5A genotypes were not higher in each subgroup, respectively.Conclusions.The present results do not confirm an association of the 5A allele with the risk of MI, observed in another investigation, but strengthen the hypothesis of earlier studies that the 6A allele is a disease marker for progression of coronary heart disease. Further investigations should evaluate whether 6A allele carriers and especially 6A homozygotes might benefit from a more aggressive therapy against CHD progression.

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An intronic polymorphism in the PAR-1 gene is associated with platelet receptor density and the response to SFLLRN

Blood ◽

10.1182/blood-2002-07-2149 ◽

2003 ◽

Vol 101 (5) ◽

pp. 1833-1840 ◽

Cited By ~ 79

Author(s):

Annabelle Dupont ◽

Pierre Fontana ◽

Christilla Bachelot-Loza ◽

Jean-Luc Reny ◽

Ivan Bièche ◽

...

Keyword(s):

Allelic Frequency ◽

Interindividual Variation ◽

Expression Data ◽

Receptor Density ◽

Platelet Response ◽

Platelet Surface ◽

Mrna Expression Data ◽

Intronic Polymorphism ◽

Platelet Receptor ◽

Protease Activated Receptor 1

Protease-activated receptor 1 (PAR-1), the main thrombin receptor on vascular cells, plays a key role in platelet activation. We examined the range of PAR-1 expression on platelets, obtained twice, 1 week apart, from 100 healthy subjects and found a 2-fold interindividual variation in receptor numbers (95% CI = 858-1700). Because PAR-1 density was stable with time (r2 = 76%,P < .001), we sought a genetic explanation for the observed variability. To validate this approach, we also analyzed the α2β1 genotype according to receptor density and platelet mRNA expression data. We found that the number of PAR-1 receptors on the platelet surface is associated with the intervening sequence IVSn−14 A/T intronic variation. The number of receptors was also found to govern the platelet response to the SFLLRN agonist, in terms of aggregation and P-selectin expression. The T allele (allelic frequency, 0.14) can be considered as an allele with decreased expression, because it was associated with lower PAR-1 expression on the platelet surface and with a lower response to SFLLRN. The IVSn−14 A/T intronic variation may therefore be clinically relevant.

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Dynamic Debonding Force Measurements of Ligand (RGD)-Platelet Receptor (GP Ilb/IIIa) System under Physiological Conditions

Microscopy and Microanalysis ◽

10.1017/s1431927600037363 ◽

2000 ◽

Vol 6 (S2) ◽

pp. 974-975

Author(s):

ImShik Lee ◽

Roger E. Marchant

Keyword(s):

Thrombus Formation ◽

Peptide Sequence ◽

Chain Extension ◽

Force Measurements ◽

Platelet Surface ◽

Force Microscopy ◽

Atomic Force ◽

Direct Measurements ◽

Platelet Receptor ◽

Physical Absorption

ABSTRACTBinding formation between a peptide sequence (GSSSGRGDSPA) which contains the cell adhesion sequence –RGD-found in fibrinogen, vWF, fibrinonectin, and vitronectin and human platelet intergrin GP Ilb/IIIa plays an important role in thrombus formation. Using atomic force microscopy (AFM), we visualized the detailed structures of membrane and submembrane of the cell, and measured the interaction forces between a peptide modified cantilever probe tip and platelet surface from pN to nN levels under physiological buffer. Direct measurements of the debonding force for the RGD ligand - GP Ilb/IIIa system are presented. To eliminate the possible measurement of the hgand-receptor pair, or of the ligand and AFM tip, following desorption of the ligand; the cantilever tip surface was modified with covalent coupling chemistry rather than physical absorption. Our results showed that the single molecular rupturing force was 93.3 ± 10.41 pN with considerable chain extension in the receptor. The rupturing forces showed a logarithmic dependence of the rate of loading

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Influence of platelet count on the expression of platelet collagen receptor glycoprotein VI (GPVI) in patients with acute coronary syndrome

Thrombosis and Haemostasis ◽

10.1160/th08-06-0399 ◽

2009 ◽

Vol 101 (05) ◽

pp. 911-915 ◽

Cited By ~ 25

Author(s):

Boris Bigalke ◽

Konstantinos Stellos ◽

Dimitrios Stakos ◽

Thomas Joos ◽

Oliver Pötz ◽

...

Keyword(s):

Acute Coronary Syndrome ◽

Platelet Count ◽

Thrombus Formation ◽

Surface Expression ◽

Platelet Surface ◽

Glycoprotein Vi ◽

Coronary Syndrome ◽

Symptomatic Coronary Artery Disease ◽

Artery Disease ◽

Collagen Receptor

SummaryPlatelets play a key role in the development of an acute coronary syndrome (ACS) and contribute to cardiovascular events. Platelet collagen receptor glycoprotein VI (GPVI) contributes significantly to platelet adhesion and thrombus formation in ACS. We consecutively investigated both the platelet count and the platelet surface expression of GPVI in 843 patients with a symptomatic coronary artery disease verified by coronary angiography. Four hundred fourteen patients presented with stable angina pectoris and 429 patients with ACS. Platelet surface expression of GPVI and CD62P was determined by flow cytometry and platelet count with a coulter counter, plasmatic soluble GPVI was measured by ELISA. Platelet GPVI expression in patients with ACS was compared to platelet count. Patients with ACS showed significantly elevated GPVI expression levels in the first and second quartiles of platelet count compared to patients with higher platelet count [mean fluorescence intensity (MFI) ± standard deviation): 1st vs. 4th: 20.44 ± 6.1 vs. 18.62 ± 3.7; p=0.012; 2ndvs.3rd:21.2±8.5vs.18.76±3.7;P=0.03; 2ndvs.4th: 21.2±8.5vs.18.62±3.7;P=0.004], which was paralleled in trend for the CD62P expression [MFI: 1st vs. 4th: 11.2 ± 6.8 vs. 12.3 ± 9; p=0.057; 2nd vs. 3rd: 16.3 ± 16 vs.12.7 ± 5.3; p=0.138; 2nd vs. 4th: 16.3 ± 16 vs.11 ± 4.4; p=0.043]. In a subgroup of 48 patients with ACS, determination of soluble GPVI showed similar results [plasma GPVI (ng/ml): 1stvs.4th: 1.6 ± 0.6 vs. 1.2 ± 0.4; p=0.046; 1st vs. 3rd: 1.6 ± 0.6 vs. 1.1 ± 0.5; p=0.038; 2nd vs. 3rd: 1.9 ± 0.8 vs. 1.1 ± 0.5; p=0.04; 2nd vs. 4th: 1.9 ± 0.8 vs. 1.2 ± 0.4; p=0.056]. Thus, a lower platelet count comes along with a higher GPVI surface expression and plasma concentration in patients with ACS, which potentially reflects increased activation and enhanced recruitment of platelets to the site of vascular injury.

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Soluble CD40L in peripheral artery disease

Thrombosis and Haemostasis ◽

10.1160/th04-09-0586 ◽

2005 ◽

Vol 93 (03) ◽

pp. 578-583 ◽

Cited By ~ 31

Author(s):

Kiat Tan ◽

Muzahir Tayebjee ◽

Indran Davagnanam ◽

Mark Moss ◽

Gregory Lip ◽

...

Keyword(s):

Peripheral Artery Disease ◽

Sole Source ◽

Clinical Severity ◽

Healthy Controls ◽

Peripheral Artery ◽

Platelet Surface ◽

Soluble Cd40l ◽

Soluble P ◽

Artery Disease

SummaryAlthough soluble CD40L (sCD40L, possibly derived from platelets and pro-inflammatory in vitro) may be implicated in thrombosis and haemostasis, there are little data in peripheral artery disease (PAD). We hypothesised the following: (a) that sCD40L relates to the clinical severity of PAD; and (b) that peripheral artery angioplasty acutely raises sCD40L levels. sCD40L was compared to established platelet markers soluble P selectin, platelet microparticles and platelet surface expression of CD62 and CD63. We recruited 36 healthy controls, 33 patients with intermittent claudication (IC), and 33 with symptomatically more severe critical limb is chaemia (CLI), measuring plasma markers by ELISA and membrane markers by flow cytometry. Eleven patients with CLI subsequently underwent peripheral artery angioplasty: blood was taken before and 10 minutes after the intervention. Results show that sCD40L was raised in IC at median 68 (IQR 28–333) pg/ml and in CLI at 64 (34–282) pg/mL compared to 35 (IQR 28–55) pg/ml in the healthy controls (p=0.009). Levels were no different between IC and CLI. The same distribution pattern was present for soluble P selectin, %platelets CD62+ve and CD63+ve. sCD40L failed to correlate significantly with ABPI (p=0.264), unlike %platelets CD62+ve (p=0.0032) and CD63+ve (p=0.009). Pre-angioplasty sCD40L level of 72 (35–610) ng/ml rose to 100 ng/ml (IQR=60–237)(p=0.018) post–angioplasty. Plasma sCD40L, in addition to other platelet indices, is raised in peripheral atherosclerosis and is increased by peripheral artery angioplasty, although levels seem unrelated to clinical severity. Failure to correlate with other markers suggest the platelet may not be the sole source of sCD40L, and that other cells may contribute to plasma levels.

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c-Fos protooncogene expression in human normal peripheral blood leukocytes

Cytotechnology ◽

10.1007/bf00351124 ◽

1987 ◽

Vol 1 (1) ◽

pp. 61-64

Author(s):

Francesco Colotta ◽

Nadia Polentarutti ◽

Ji Ming Wang ◽

Alberto Mantovani

Keyword(s):

Peripheral Blood ◽

Peripheral Blood Leukocytes ◽

Blood Leukocytes ◽

Normal Peripheral Blood

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Analysis of Platelet Receptor Expression in ITP,

Blood ◽

10.1182/blood.v118.21.3289.3289 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3289-3289

Author(s):

Jianlin Qiao ◽

Huy Tran ◽

Fi-Tjen Mu ◽

Robert K Andrews ◽

Elizabeth E Gardiner

Keyword(s):

Platelet Count ◽

Conflicts Of Interest ◽

Surface Expression ◽

Experimental Models ◽

Receptor Expression ◽

Response To Treatment ◽

Platelet Surface ◽

Healthy Donors ◽

Platelet Receptor ◽

Von Willebrand

Abstract Abstract 3289 In this study we assess platelet receptor expression and shedding in patients with immune thrombocytopenia (ITP) before and during treatment. The aim is to evaluate the potential value of quantitative measurement of platelet receptors for diagnosis and/or monitoring treatment in thrombocytopenia due to immune or other causes. The platelet-specific collagen receptor, glycoprotein (GP)VI, is associated with the Fc receptor γ-chain (FcRγ). GPVI/FcRγ is coassociated on platelet surface with the GPIb-IX-V complex; GPIbα of GPIb-IX-V binds von Willebrand factor and other ligands. Our previous studies showed engagement of platelet FcγRIIa by antiplatelet antibodies induced ectodomain shedding of GPVI, generating soluble ectodomain (sGPVI) in plasma. However, apart from one individual with an anti-GPVI antibody, whether anti-platelet antibodies associated with ITP affect GPVI/GPIb expression/shedding has not been addressed. In this study we used flow cytometry and a sGPVI ELISA to assess 1) whether patients with ITP had dysregulated expression/shedding of GPVI or GPIbα, and 2) whether platelet receptor expression changes prior to recovery of platelet count in individuals undergoing treatment for ITP. In 9 ITP patients (mean age=48.6, range 29–79; 6 female) with platelet count 61±9 × 109/L (range, 33–122 × 109/L), GPVI surface expression (GeoMean±SE, 137±17) was lower than healthy controls (274±26; n=17; platelet count 247±13), and sGPVI in patient plasma was significantly higher (39±4 ng/mL) compared to 17 healthy donors (19±3 ng/mL) (P=0.0006). In longitudinal samples analysed at weekly intervals during 2-month treatment with steroids, decreased GPVI surface expression and increased sGPVI in plasma remained essentially unchanged as the platelet count normalized, consistent with persistent anti-platelet antibody. However, while levels of intact platelet GPIbα were significantly reduced in ITP compared to healthy donors (P=0.0053), they approached healthy levels within 1 week of treatment, preceding improvement in platelet count or other measures. GPIbα expression/cleavage has been previously implicated in platelet clearance in experimental models, and our analysis suggests the proteolytic status of human GPIbα may be a novel early marker for evaluating response to treatment in ITP. Disclosures: No relevant conflicts of interest to declare.

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