Microparticles and cardiovascular diseases

Figures & data

Figure 1. Extracellular vesicles. (1): Production of microparticles after stimulation of paternal cell. Microparticles are released from activated cell after outwards rearrangement of the cellular membrane. (2): Production of microparticles during apoptotic process. Microparticles are released before the formation of apoptotic bodies. (3): Endosomes in multivesicular body. After exocytosis of the endosomes into the extracellular environment may be called exosomes.

Figure 2. Mechanisms involved in the generation of the microparticles. (1): After activation of the cell an increased Ca⁺² influx follows. (2): Externalisation of phosphatidylserine mediated by ATP-dependent floppases, scramblases and membrane pores. (3): Cytoskeleton Protein reconfiguration in order to produce outward membrane blebs. Capsases, caplains and Rho kinases are involved in the process.

Table 1. Stimuli causing generation of microparticles in vitro or in vivo [20,21].

Type of cell	Endothelial cell	Platelet	Neutrophil	T-cell	Monocyte and macrophage	Smooth cell
Stimuli
	Modified LDL	Flow conditions	Pro-inflammatory cytokines	Pro-inflammatory cytokines	Cigarette extract	Modified LDL
	HDL cholesterol	Thrombin		Phytohemagglutinin	Pro-inflammatory cytokines	HDL cholesterol
	Uremic toxin	Collagen	Phorbol myristate acetate	Staurosporin	Calcimycin
	Flow conditions	Homocysteine		Etoposide		Flow conditions
	Thrombin	Pro-inflammatory cytokines	Anti-neutrophil cytoplasmic antibodies	Actinomycin D	Lipopolysaccharides	Activated protein C
	Homocysteine	Calcimycin	Bacterial infection	Phorbol myristate acetate	Etoposide	Pro-inflammatory cytokines
	Activated protein C	collagen	N-formyl-methionyl-leucyl-phenylalanine		Fas Ligand	Fas-ligand
	Plasminogen activator inhibitor	Lipopolysaccharides	–	–	–	Platelet derived growth factor
	Pro-inflammatory cytokines^a	Shiga toxin	–	–	–
	Oxidative stress	sCD40 Ligand	–	–	–	–
	High glucose	Erythropoietin	–	–	–	–
	Uremic toxins	Noradrenaline	–	–	–	–
	Lipopolysaccharides	acid phosphatase 5	–	–	–	–
	Camptothecin	Reactive oxygen species	–	–	–	–
	Angiotensin II	–	–	–	–	–
	Plasminogen Activator Inhibitor 1	–	–	–	–	–
	C Reactive Protein	–	–	–	–	–

^a Tumour necrosis factor a, interleukin 1b, interleukin 6.

Figure 3. Microparticle content. External surface of plasma membrane in general contains negatively charged phosphatidylserine along with membrane proteins like major histocompatibility complex molecules, integrins and tissue factor. In the cytosol, there is no organised nucleus but apart from cytoskeleton proteins and enzymes, nucleic acid remnants (DNA or RNA) are present.

Table 2. Main antigen markers used for MP cell origin determination.

Cell	Cluster of differentiation (CD)
Endothelial	CD31 [53]
–	CD51[54]
–	CD105 [55]
–	CD62E [55]
–	CD144 [56]
–	CD34 [57]
Platelet	CD41 [58]
–	CD42a [59]
–	CD42b [60]
–	CD61 [57]
Red cell	CD235 [61]
Leukocyte	CD45 [61]
Monocyte	CD14 [62]
Neutrophil	CD66b [58]
T cell	CD4 [63]
–	CD8 [64]

CD31, CD51, CD105 are not specific for endothelial cells. CD31 is also expressed on platelets, CD51 on platelets and macrophages and CD105 in activated monocytes/macrophages. For MP detection, markers are usually combined to discriminate this population from other MPs. For example, platelet MPs are CD31 positive/CD42b positive whereas endothelial MPs are CD31 positive/CD42b negative.

Table 3. Bioactive molecules of microparticles.

Molecule	Type of cell producing microparticles	Target cell or environment
Receptor/membrane molecule
Chemokine receptor CCR5 [72]	Peripheral blood mononuclear cells	Various cells
CXCR4 receptor [73,74]	Platelets	Various cells
Glycoprotein IIb/IIIa receptors [75]	Platelets	Neutrophils
Oncogenic receptor EGFRvIII (epidermal growth factor receptor variant III) [76]	Tumour cells	Various cells
Major histocompatibility complex (MHC) class II [77]	Immune cells	Immune cells
Tissue factor [48]	Monocytes	Platelets
Peroxisome proliferator-activated receptor gamma [78]	Platelets	Monocytes
Cytokines
Interleukin-1beta [79–82]	Various cells	Various cells
Chemokine (C-C motif) ligand 5[83]	Platelets	Endothelial cells
Growth factors
Vascular endothelial growth factor [84–85]	Platelets/tumour cells	Endothelial cells
Basic fibroblast growth factor [84,86]	Platelets/tumour cells	Endothelial cells
Platelet-derived growth factor [86]	Platelets	Endothelial cells
Lysis enzymes
Matrix metalloproteinases [85]	Tumour cells	Extracellular matrix
Extracellular matrix metalloproteinase inducer [87]	Tumour cells	Extracellular matrix
Caspase 1 [88]	Monocyte	Smooth muscle cell
Lipids
Arachidonic acid [89–91]	Platelets	Various cells
Platelet activated factor [92,93]	Various cells	Platelets
Ribonucleic acid (RNA)
Messenger RNA [38,94]	Stem cells	Various cells
Micro RNA [95–97]	Stem cells	Various cells

Figure 4. Mechanisms and molecules related with Microparticle induced coagulation. Abbreviations: PS: phospatildylserine; GLA: γ-carboxyglutamic acid; clotting proteins factors VII, IX, X and prothrombin. Negatively charged PS electrostatically attract the positively charged segment of clotting proteins/GLA complex and induce thrombogenesis. Tissue factor may also activate the coagulation cascade via the FVII/VIIa complex. Additionally, inhibition of fibrinolysis by microparticle membrane proteins such as plasminogen activator inhibitor-1 and protein S may augment thrombogenesis.

Table 4. Inflammation and microparticles (MPs).

Type of cell producing MPs	Target cell	Molecules involved in the pathogenesis of inflammation mediated by MPs
		Cytokines
Endothelial	Various inflammatory cells	IL-1β and TNF-α [113]
Leucocytes	Endothelial	IL-6 and MCP-1 [114]
T cells	Monocytes	IL-8, TNF-a and IL-1β [43,115]
		Adhesion molecules
Monocytes Platelet	Endothelial	Intercellular adhesion molecule-1, vascular cell adhesion molecule-1 E-selectin [91,116]
–	–	Lipids
Platelet	Endothelial	Thromboxane A2 and cyclooxygenase [89]
		Other
Polymorphonuclear	Macrophage	transforming growth factor beta1 [117]
–	–	Annexin V [118]
Monocytes	Macrophage	peroxisome proliferator-activated receptor gamma protein [119]
Polymorphonuclear	Various cells	complement proteins (C1q) [51]

IL: interleukin; TNF: tumour necrosis factor; MCP-1: monocyte chemoattractant protein-1.

Table 5. Angiogenesis and microparticles (MPs).

Type of cell producing MPs	Target cell or environment	Molecules involved in the angiogenesis mediated by MPs
Promotion of neovascularisation
Platelets	Human umbilical vein endothelial cells	Bioactive lipids [84,121]
Platelets	Ischaemic myocardium	Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (BFGF), inhibition of platelet factor-4 [86]
Various cells expressing membrane tissue factor	Endothelial	beta1-integrin, extracellular signal regulated kinase [122]
T-cells	Endothelial	Activation of morphogen Sonic Hedgehog (Shh) pathway which promotes synthesis of adhesion molecules and proangiogenic factors [123,124]
Endothelial	Endothelial	Plasmin activating factors [125]
Endothelial	Matrix	Metalloproteinases [126]
Endothelial	endothelial	Messenger RNA [127]
Adipose cells	Human umbilical vein endothelial cells	Leptin, fibroblast growth factor alpha (FGFa), Tumour necrosis factor a, matrix metalloprotease (MMP)-2 and MMP-9 mediated activation [128]
Inhibition of neovascularisation
Lymphocyte	Endothelial	CD36 antiangiogenic receptor [129]

CD: cluster of differentiation; RNA: ribonucleic acid.

Table 6. Studies with microparticles (MPs) in diabetic populations or high glucose concentration conditions.

Type of MPs	Conclusion	References
Endothelial-derived microparticles CD62E positive, CD62P positive, CD142 positive, CD45 positive circulating MPs, their apoptotic (AnnexinV positive) fractions and miRNA-126 expression	CD62E positive MPs level and miR-126-3p content in MPs are abnormal in subjects with pre-diabetes	Giannella et al. [162]
CD3 positive T- Lymphocyte MPs, CD105 positive EMPs, Annexin V positive MPs, CD31 positive MPs, CD41a positive and Annexin V/CD31/ CD41a positive	Increased number of MPs in diabetic patients compared with healthy control group	Kurtzman et al. [163]
PMPs	Association with vascular changes in T2DM/ endothelial dysfunction and activated platelets/PMPs	Nomura et al. [164]
Μonocytes-derived MPs Annexin V/CD14 positive, PMPs GPI positive	higher in diabetic patients of with related vascular complications	Omoto et al. [165]
AnnexinV positive, PMP CD31/CD42 positive, LMP CD45positive , CD31positive/CD42negative EMP, CD51positive EMP	MPs increased in patients with T2DM. EMPs levels are associated with vascular dysfunction.	Feng et al. [55]
CD36 positive	CD 36 positive MPs in DM patients were from erythrocyte origin compare with healthy subjects, originated from endothelial cells.	Alkhatatbeh et al. [166]
PMPs CD41 positive, EMPs CD51 positive, leukocytes-derived MPs CD45 positive, neutrophil-derived MPs CD66b positive, monocyte-derived MPs CD14 positive and total Annexin V-positive MPs.	Different phenotypes identified between T1, T2 DM and healthy subjects. Differences in properties and particularly the procoagulant activities.	Sabatier et al. [59]
Annexin V positive, MPs from non- activated platelet (CD41positive), MPs from activated platelets (CD62p positive), EMPs (CD144 positive)	MPs properties and type (composition, content and cellular origin) are related with the type of vascular complications due to DM.	Tsimerman et al. [167]
MPs from Human umbilical vein endothelial cells	Raised glucose levels is a potent stimulus for MP formation that affects their molecular composition and may cause endothelial injury	Burger et al. [168]
PMPs CD41 positive, Annexin V MPs, MPs expressing tissue factor (CD142)	DM is associated with high levels circulating MPs with procoagulant features	Tripodi et al. [169]
EMPs CD144 positive, PMPs CD42b positive, monocyte-derived MPs CD14 positive	MPs from T1DM patients promoted platelet/endothelial cell interaction with an intensity correlated with the degree of the associated vascular complications	Terrisse et al. [61]
Lymphocyte and plasma MPs (Surface markers: CD3, CD11a, GP1b, CD31)	Lymphocyte-derived MPs from diabetic patients or in vivo circulating MPs from diabetic patients reduced endothelial NO synthase expression	Martin [138]
Surface markers: CD41a, CD64, CD144, CD144/CD31, Annexin V, CD144/annexin V and CD144/CD31/annexin V.	Apoptotic endothelial cell-derived were significantly increased in diabetic patients and associated with asymptomatic atherosclerosis	Berezin et al. [170]
Human coronary endothelial cells-derived MPs	High glucose environment increases NADPH oxidase activity in EMPs and promotes endothelial dysfunction	Jansen et al. [171]
EMPs (surface markers: CD31, CD42b, Annexin V, and CD62E)	EMP levels are associated with different risk of diabetic vascular complications	Jung et al. [54]
PMPs CD41 (GPIIb) positive, EMPs CD144 (VE-Cadherin) positive	Unstable coronary artery plaques in diabetics are associated with elevated EMPs	Bernard et al. [57]
PMPs (surface marker: antiplatelet GPIX monoclonal antibody)	Plasma PMPs are significantly higher in patient with DM compare with normal controls. Antiplatelet therapy reduces the level of PMPs.	Omoto et al. [172]
EMPs CD 144 positive, monocyte-derived MPs CD 14 positive, PMPs tissue factor and CD 41 positive	Normalisation of glycaemic control in DM patients after bariatric surgery leads to reduction of the MPs levels	Cheng et al. [63]
PMPs, T-lymphocytes-MPs and leukocyte-derived MPs (surface markers: quadruple-stained with Annexin V, CD61, anti-TF, and CD15 (ligand for P-selectin), CD66e (granulocytic marker), or CD62P (P-selectin), or with CD4 (T-lymphocytes), anti-TF, and CD11b (leukocyte marker)	TF on MPs from DM patients may be involved in processes other than coagulation such as angiogenesis	Diamant et al. [64]
TF bearing MPs from human renal mesangial cells and human dermal microvascular endothelial cells	MPs expressing TF might be a mediator to neovascularisation due to elevated glucose levels	Ettelaie et al. [173]
MPs from human umbilical vein endothelial cells	Reduction of miR-126 from plasma vesicles might explain the impaired neo-angiogenesis in DM patients	Zampetaki et al. [174]

CD: cluster of differentiation; EMP: endothelial-derived MP; PMP: platelet-derived MP; T2DM; Type 2 diabetes mellitus; GP: glycoprotein; LMP: leukocyte-derived MP; TF: tissue factor; miR: micro Ribonucleic acid; NADPH: nicotinamide adenine dinucleotide phosphate; NO: nitric monoxide.

Table 7. List of medications induced reduction of microparticle (MP) levels in diabetic populations.

Medication category	Pharmacological name	Type of MPs investigated	Other co-morbidities apart from DM
Antiplatelet	Cilostazol [182]	PMPs GPIX positive
–	Ticlopidine [183–185]	PMPs GPIX positive, Monocyte-derived MPs CD14 positive	Hyperlipidemia
–	Sarpogrelate [186]	PMPs	–
–	Aspirin & Clopidogrel [187]	PMPs CD151 positive, Monocyte-derived MPs CD14 positive	TIA
Antihypertensive	Efonidipine [188]	PMPs GPIX positive, Monocyte-derived MPs CD14 positive	HTN
–	Nifedipine [189,190]	PMPs GPIX positive, Monocyte-derived MPs CD14/Annexin V positive, EMPs CD51/Annexin V positive	HTN
–	Losartan [191,192]	PMPs GPIX positive, Monocyte-derived MPs CD14/ Annexin V positive, EMPs CD51/ Annexin V positive	HTN
–	Valsartan [193]	Monocyte-derived MPs CD14/ Annexin V positive	HTN
Anti-lipidaemic	Pitavastatin [194]	PMPs CD42b and CD42a (glycoprotein Ib and IX) positive	Hyperlipidemia
–	Pravastatin [71]	MPs derived from: platelets (CD61 positive), T-helper cells (CD4 positive), T-suppressor cells (CD8 positive), monocytes (CD14 positive), B cells (CD20 positive), endothelial cells (CD62e positive), erythrocytes (glyco-A positive) and granulocytes (CD66b positive), annexin V and TF positive MPs	Hyperlipidemia
–	Simvastatin [191,192]	PMPs GPIX positive, Monocyte-derived MPs CD14/ Annexin V positive, EMPs CD51/ Annexin V positive	Hyperlipidemia, HTN
–	Atorvastatin [195]	PMPs, surface markers CD42a (Glycoprotein IX), together with either CD61 (GPIIIa), CD62P (P-selectin) or CD142 (TF)	Hyperlipidemia
–	Bezafibrate [196]	PMPs CD42b positive	Hyperlipidemia
–	Probucol [183]	PMPs GPIX positive , Monocyte-derived MPs CD14 positive	Hyperlipidemia
–	Eicosapentaenoic acid [194,197,198]	PMPs CD42b and CD42a (glycoprotein Ib and IX) positive	Hyperlipidemia
–	Vitamin C [199]	EMPs CD31 positive, PMPs GPIb positive	Acute myocardial infarction
Antidiabetic	Acarbose [200]	PMPs CD42b and CD42a (glycoprotein Ib and IX) positive	–
–	Miglitol [201]	PMPs CD42b and CD42a (glycoprotein Ib and IX) positive	–
–	Pioglitazone [202]	EMPs CD31 positive	–

CD: cluster of differentiation; HTN: hypertension; EMP: endothelial-derived MP; PMP: platelet-derived MP; GP: glycoprotein; TF: tissue factor; DM: diabetes mellitus.

Figure 5. Mechanisms associated with initiation and progression of atherosclerosis mediated by Microparticles (MPs).

Table 8. Studies with microparticles (MPs) in acute coronary syndrome populations (ACS).

Type of MPs	Conclusion	References
Surface markers: Anexin V, anti-CD3, anti-CD11a, anti-CD31, anti-CD146 and anti-GP Ib	Higher levels of procoagulant EMPs in Patients with ACS compare with patients with no CAD or SA	Mallat et al. [254]
Combination of CD31 (PECAM-1) or CD51 (aV□3, vitronectin receptor) with CD42. EMPs and PMPs (PMPs CD42 positive)	EMPs were elevated in patients with CAD compared with control subjects, CD31□EMPs higher in patients with ACS compare with SA, among patients with a first MI, CD31 EMPs released in ACS and CD51 released in SA.	Bernal-Mizrachi et al. [255]
Leukocyte-derived MP CD11a positive , EMPs CD31 positive, PMPs GPIb positive, Anexin V positive	Early decrease of procoagulant MPs in patients with STEMI treated with PPCI and abciximab compare with patients treated only with PPCI.	Morel et al. [256]
EMPs CD146 and CD 106 (VCAM-1) positive	High density of VCAM-1 expressed on EMPs from patients with ACS	Radecke et al. [257]
Annexin V-binding MPs, MPs CD42b positive, EMPs CD144 positive and monocyte-derived MPs CD14 positive	In NSTEMI, EMP and monocyte-derived MPs were independently predictive for future admissions related to heart failure and PMPs for major bleedings	Montoro-García et al. [258]
EMPs CD144 positive, PMPs CD41 positive and leukocyte-derived MPs CD45 positive	Variation of levels of different origin MPs associated with time in patients before and after PPCI	Zhou et al. [259]
Surface markers: anti- CD11a (leukocytes), anti-CD31 (endothelial cells), anti-CD42b (endothelial cells), and anti-CD146 (platelets), Anexin V for apoptotic MPs	Increased levels of MPs in culprit coronary arteries after STEMI and significant reduction after successful PCI	Min et al. [260]
Lymphocyte-derived MPs CD45/CD3 positive, monocyte-derived MPs CD14 positive, EMPs CD146 positive or CD62e positive, granulocytes-derived MPs CD66b positive, other surface markers: CD142 (TF), Anexin V, CD31	Increased levels of MPs in culprit coronary arteries after STEMI, levels of MPs positively correlated to time of revascularisation post STEMI	Suades et al. [261]
EMPs CD31 positive/CD42 negative, PMPs CD31 positive/CD42 positive, anexin V positive	ACS are associated with higher levels of circulating MPs compare with SA patients. In SA the degree of atherosclerotic plaque is not related with the levels of plasma MPs	Biasucci et al. [262]
TF positive MPs	Thrombolysis failure in acute MI is associated with higher levels of procoagulant MPs	Huisse et al. [263]
TF positive MPs	MPs were lower as the severity of the stable angina/ACS was increasing (stable CAD vs UA vs MI)	Maly et al. [264]
PMPs CD42 positive, Leukocyte-derived MPs CD45 positive, Monocyte-derived MPs CD14 positive, EMPs CD31, CD51/61, CD34 positive and activated tissue factor positive (TF) MPs	Increased levels of MPs in ACS and positive correlation of MP levels with platelet activation markers	Stępień et al. [58]
EMPs CD31 positive/ CD42negative and CD144 positive, PMPs CD31/CD42 positive	EMPs and PMPs reflect the size of myocardium at risk in patients with STEMI	Jung et al. [265]

CD: cluster of differentiation; EMP: endothelial MP: STEMI: ST elevation myocardial infarction: PPCI: primary percutaneous coronary intervention; TF: tissue factor; PMP: platelet-derived MP; CAD: coronary artery disease; NSTEMI: non-ST elevation myocardial infarction; SA: stable angina; VCAM-1: vascular cell adhesion protein 1; PECAM-1: platelet endothelial cell adhesion molecule-1.

Table 9. Studies with microparticles (MPs) in heart failure.

Type of MPs	Conclusion	References
Annexin V-binding MPs, MPs CD42b positive, EMPs CD144 positive and monocyte-derived MPs CD14 positive	In NSTEMI, EMP and monocyte-derived MPs were independently predictive for future admissions related to heart failure	Montoro-García et al. [258]
Annexin V-binding MPs, MPs CD42b positive, EMPs CD144 positive	Annexin V-MPs levels appear to reflect accurately the acute decompensated phase in systolic heart failure	Montoro-García et al. [273]
CD 31/Annexin V positive	EMPs was increased in patients with LV dysfunction compared with those with normal or preserved LV function.	Bulut et al. [274]
Surface markers for EMPs: CD31 (platelet endothelial cell adhesion molecule [PECAM]-1), CD144 (vascular endothelial [VE]-cadherin), CD62E (E-selectin) and annexin V	EMPs levels are higher in patients with HFrEF and increased Body Mass Index (BMI > 25kg/m2) compare with other patients with lower BMI.	Berezin et al. [275]
Surface markers for EMPs: CD31, CD62E, CD105, Annexin V	Adding CD31/annexin V positive EMPs to CD14/ CD309 positive cell ratio to other variables predict the risk of HFpEF.	Berezin et al. [56]
EMPs CD31/CD62E positive	EMPs in post-transplant patients are consistent with increased apoptotic activity	Garcia et al. [276]
Red blood cell-derived MPs (CD235 positive), leukocyte MPs (CD45 positive), platelet (CD31/CD41positive) and EMPs (CD31 positive/CD41 negative, CD62e positive, CD144 positive)	All types of MPs were elevated in patients with LVAD compare with patients with CAD and healthy subjects due to haemolysis and disturbed endothelial integrity	Sansone et al. [62]
EMPs	LVAD do not cause vascular damage 3 months after implantation.	Ivak et al. [277]
Surface markers for EMPs: CD31, CD41a, CD64, CD105, CD144, CD62E and Annexin V. PMPs CD41a positive	Patients with HF and metabolic syndrome have higher levels of CD31/Annexin V positive EMPs in addition with lower levels of CD62E positive EMPs compare with healthy subjects.	Berezin et al. [60]
Surface markers: CD31, CD144, CD62E, CD14, CD45, Annexin V, CD62P, CD42b	Patients with PPCM appears to have elevated levels of activated EMPs (CD144 positive) and PMPs (CD42b positive) compare with patients with ischaemic cardiomyopathy	Walenta et al. [278]

CD: cluster of differentiation; EMP: endothelial-derived MP: NSTEMI: non-ST elevation myocardial infarction; PMP: platelet-derived MP; HFrEF; heart failure with reduced ejection fraction; HFpEF: heart failure with preserved ejection fraction; LV: left ventricle; LVAD: LV assisting device; CAD; coronary artery disease; BMI: body mass index; PPCM: postpartum cardiomyopathy.

Table 10. Studies where microparticle levels are associated with outcomes.

Type of MPs	Prognostic value	References
Annexin V-binding MPs, MPs CD42b positive, EMPs CD144 positive and monocyte-derived MPs CD14 positive	In NSTEMI, EMP and monocyte-derived MPs were independently predictive for future admissions related to heart failure	Montoro-García et al. [258]
EMPs apoptotic CD31/Annexin V positive	CD31/Annexin V positive MPs is an independent predictor of MACCE in stable CAD patients	Sinning et al. [289]
Monocyte-derived MPs (surface markers: CD14+, CD14/CD11b and CD14/CD142)	Monocyte-derived MPs levels assessed in the acute phase of STEMI are related to the prognosis of long term CV death	Chiva-Blanch et al. [290]
Annexin V positive, CD41 positive PMPs, CD235a positive erythrocyte derive MPs	CD235a positive erythrocyte derive MPs concentrations appear to be positively associated with MACCE in patients with STEMI and PPCI	Giannopoulos et al. [291]
Surface markers: Annexin V, TF , CD41, CD66b	In the plasma of patients with ACS, the TF activity is a consequence of circulating MPs and is an independent predictor for MACCE	Steppich et al. [292]
EMPs CD146, CD31	Higher EMP levels had a higher risk of MACCE in ACS patients.	Fan et al. [293]
EMPs CD31/Annexin V positive	EMPs levels were associated with increased mortality and recurrent hospitalization due to CHF	Berezin et al. [294]
Apoptotic MPs Annexin V positive	elevation of apoptotic MP levels in LVAD-supported patients are associated with increased risk for adverse events.	Nascimbene et al. [295]
EMPs CD62e positive, CD144 positive, CD31 positive (+)/CD41 negative leukocytes-derived MPs CD45 positive	Elevated levels of CD62e positive EMPs in PHTN patients prior to treatment are associated with adverse clinical events	Amabile et al. [296]

MACCE: major adverse cardiovascular and cerebral event; CD: cluster of differentiation; EMP: endothelial-derived MP; NSTEMI: non-ST elevation myocardial infarction; CAD: coronary artery disease; STEMI: ST elevation myocardial infarction; CV: cardiovascular; TF: tissue factor; ACS: acute coronary syndrome; LVAD: left ventricular assisting device; PHTN: pulmonary hypertension.

Figure 6. Cardiovascular diseases and microparticles. Flow chart which summarises the role of microparticles in the genesis (related with several risk factors) and manifestation of cardiovascular diseases. Utilisation as biomarkers to assess disease activity/severity, prognosis and treatment guidance is emerging as detection and enumeration methods for microparticles are improving.

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