On the Trail of Microparticles
2009; Lippincott Williams & Wilkins; Volume: 104; Issue: 8 Linguagem: Inglês
10.1161/circresaha.109.196840
ISSN1524-4571
Autores Tópico(s)Pregnancy and preeclampsia studies
ResumoHomeCirculation ResearchVol. 104, No. 8On the Trail of Microparticles Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBOn the Trail of Microparticles Nigel Mackman Nigel MackmanNigel Mackman From the Division of Hematology and Oncology, Department of Medicine, University of North Carolina at Chapel Hill. Originally published24 Apr 2009https://doi.org/10.1161/CIRCRESAHA.109.196840Circulation Research. 2009;104:925–927Stimulation of a variety of cell types leads to the release of submicron vesicles that bud off from the plasma membrane. These so-called microparticles (MPs) or microvesicles are defined by their small size (0.1 to 1 μm) and the presence of surface antigens from the parental cells.1,2 MPs contribute to a variety of physiological and pathological processes. For instance, they appear to play a role in both hemostasis and thrombosis. MPs released into the bloodstream can act as messengers delivering a variety of cargos, such as cell surface receptors, proinflammatory cytokines, signaling molecules, and even mRNA, to distal cells.1,2 They may also contribute to disease by transporting viruses and prions.1,2 In addition, in vitro studies have shown that binding of MPs to endothelial cells and monocytes induces the expression of proinflammatory and procoagulant molecules (Figure 1). In this issue of Circulation Research, Simoncini et al explore the inflammatory pathways that trigger the release of MPs from endothelial cells.3Download figureDownload PowerPointFigure 1. MPs derived from different cell types induce the expression of proinflammatory and procoagulant molecules in endothelial cells, monocytes, and epithelial cells. Monocyte-derived MPs also bind to activated platelets. MPs derived from endothelial precursor cells (EPC) bind to endothelial cells and enhance angiogenesis. TF indicates tissue factor.MPs are generated from a variety of different vascular cell types, including endothelial cells, monocytes, and platelets. Early studies on MPs focused on platelets because these cells readily generated MPs on activation. Indeed, the original term for MPs was "platelet dust" and platelets are the major source of MPs in the blood of healthy individuals.4 Importantly, the procoagulant activity of MPs can be significantly increased by altering the phospholipid composition of the membrane surface. Under normal conditions the distribution of phospholipids moieties in the plasma membrane of cells is asymmetrical due to the activity of several enzymes whose net effect is to maintain phosphatidylcholine and sphingomyelin in the outer layer and phosphatidylserine (PS) and phosphatidylethanolamine in the inner layer. During formation of MPs, membrane asymmetry may be lost, resulting in the exposure of PS on the surface of the MPs. PS is an anionic phospholipid that binds the positively charged "Gla" domain of coagulation proteins. This means that PS-positive MPs are more procoagulant than PS-negative MPs. Interestingly, patients with Scott's syndrome have a defect in platelet prothrombinase activity and a bleeding phenotype that appears to be attributable to a defect in PS translocation to the surface of platelets and presumably platelet MPs.2 These data suggest that platelet MPs may play a role in hemostasis in healthy individuals. Another study showed that stimulation of monocytes with a P-selectin and immunoglobulin chimera increased the number of circulating monocyte MPs and restored hemostasis in hemophilia A mice,5 leading the authors to propose that MPs could be used to treat patients with hemophilia.Elevated numbers of MPs have been reported in a variety of diseases, including patients with acute coronary syndromes, cancer, anti-phospholipid antibody syndrome, sickle cell disease, sepsis, and diabetes.1 Although all MPs are procoagulant, those with the highest procoagulant activity are MPs derived from activated monocytes because of the presence of tissue factor. This transmembrane receptor is a potent activator of the coagulation cascade.6 Endothelial cells may also contribute to the pool of tissue factor–positive MPs in different diseases, such as sickle cell disease.7 Lipopolysaccharide stimulation of human monocytic cells induced the release of MPs from cholesterol-rich lipid rafts in the membrane.8 These MPs were selectively enriched for tissue factor and P-selectin glycoprotein ligand (PSGL)-1 and were deficient in CD45. These data indicate that MPs are not simply generated randomly from the plasma membrane but instead are formed in a selective and regulated manner. In a mouse thrombosis model, leukocyte-derived, tissue factor–positive MPs contributed to the growth of the thrombus.9 Accumulation of these monocyte MPs was mediated by the binding of PSGL-1 on the MPs to P-selectin exposed on the surface of activated platelets.10 These results suggest that elevated numbers of MPs in the blood, particularly monocyte MPs, may trigger thrombosis. Tumor-derived MPs also express tissue factor and may increase the risk of venous thrombosis in cancer patients.11,12 Tissue factor–positive MPs may ultimately prove to be a useful biomarker to identify patients at risk for thrombosis.Inflammation and coagulation are linked processes in many diseases and MPs may amplify the responses by activating the endothelium (Figure 1). In addition, proinflammatory mediators directly induce tissue factor expression in endothelial cells, and the coagulation protease thrombin directly induces the expression of proinflammatory mediators in endothelial cells. This results in elevated levels of endothelial cell–derived MPs, so-called EMPs, in many disease states. The presence of these EMPs in blood can be used as biomarkers of endothelial cell injury. In vitro studies have shown that a variety of proinflammatory agents, such as tumor necrosis factor (TNF)α, will activate endothelial cells and induce the release of MPs. Interestingly, MPs generated from apoptotic endothelial cells have higher levels of PS on their surface compared with MPs generated from activated endothelial cells, suggesting that there are distinct mechanisms for the formation of MPs in apoptotic and activated cells.13 A recent study showed that treatment of endothelial cells with the cancer chemotherapy drug cisplatin induced the release of tissue factor-negative MPs.14 Further studies are required to compare the protein and lipid composition of MPs formed by exposure of endothelial cells to different agents and those formed in vivo in different diseases.There are very few studies that have analyzed the mechanisms leading to the formation and release of MPs from endothelial cells. An early study showed that fluvastatin decreased the generation of MPs from TNFα-stimulated human coronary artery endothelial cells.15 Importantly, a Rho-kinase inhibitor produced a similar suppression of MPs, indicating a critical role for this kinase in the formation of MPs. Another study found that the Rho-kinase ROCK-II was required for the generation of MPs from thrombin stimulated human microvascular endothelial cell line 1.16 Inhibition of caspase 2 also inhibited the release of MPs, and it was proposed that the proteolytic activity of caspase 2 was involved in the release of MPs. In platelets, proteolytic cleavage of proteins that anchor the plasma membrane to the cytoskeleton is required for the release of MPs. It is possible that caspase 2 plays a similar role in the release of MPs from endothelial cells.In this present study, Simoncini et al3 analyzed the mechanism of MP formation in thrombin stimulated human endothelial cells. The authors found that thrombin induced the expression of both cell associated and soluble forms of TRAIL/Apo2L, a member of the TNFα superfamily. Soluble TRAIL (sTRAIL) was found to play a role in MP release because knockdown of TRAIL expression reduced the ability of supernatants from thrombin-stimulated cells to generate MPs. Moreover, exogenous sTRAIL induced MP release from cells. TRAIL binds to a number of different receptors, including DR4 (TRAIL-R1) and DR5 (TRAIL-R2). Both receptors were expressed by the endothelial cells, but only TRAIL-R2 was induced by thrombin. Knockdown of TRAIL-R2 reduced thrombin induction of MPs indicating that it participated in the pathway of MP formation. However, this experiment did not exclude a role for TRAIL-R1 in MP production. Binding of sTRAIL to TRAIL-R2 leads to activation of NF-κB and, as expected, inhibition of nuclear factor (NF)-κB also reduced the generation of MPs. The transcription factor NF-κB was required for both the early and late production of MPs in thrombin-stimulated cells (Figure 2). The early pathway involves direct activation of NF-κB and may involve the Rho kinase ROCK-II, whereas the late pathway indirectly activates NF-κB by binding of newly synthesized sTRAIL to TRAIL-R2. Importantly, both pathways were involved in the expression of proinflammatory mediators (interleukin [IL]-8 and intercellular adhesion molecule [ICAM]-1) and tissue factor. Thus, thrombin production of MP and the expression of inflammatory mediators and tissue factor appear to be coordinately regulated in endothelial cells. Download figureDownload PowerPointFigure 2. Thrombin stimulation of endothelial cells induces the expression of proinflammatory mediators and tissue factor (TF) and the release of procoagulant EMPs via direct and indirect activation of NF-κB.Further studies are needed to determine whether intracellular pathways regulating the release of MP from endothelial cells can be separated from the general inflammatory response that requires activation of NF-κB. Interestingly, a recent study demonstrated that inhibition of the p38 mitogen-activated protein kinase (MAPK) reduced MP production in TNFα-stimulated human aortic endothelial cells.17 In contrast, inhibition of the extracellular signal-regulated kinase and c-Jun N-terminal kinase MAPKs did not affect the generation of MPs. At present, the pathways downstream of p38 MAPK that regulate MPs formation have not been defined. Nevertheless, targeted inhibition of the generation and release of MPs may represent a novel therapeutic strategy for the treatment of inflammatory and thrombotic diseases.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Sources of FundingSupported by the NIH.DisclosuresNone.FootnotesCorrespondence to Nigel Mackman, Division of Hematology and Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599. E-mail [email protected] References 1 Morel O, Toti F, Hugel B, Bakouboula B, Camoin-Jau L, Dignat-George F, Freyssinet JM. Procoagulant microparticles: disrupting the vascular homeostasis equation? Arterioscler Thromb Vasc Biol. 2006; 26: 2594–2604.LinkGoogle Scholar2 Burnier L, Fontana P, Kwak BR, Angelillo-Scherrer A. Cell-derived microparticles in haemostasis and vascular medicine. Thromb Haemost. 2009; 101: 439–451.CrossrefMedlineGoogle Scholar3 Simoncini S, Njock MS, Robert S, Camoin-Jau L, Sampol J, Harle JR, Nguyen C, Dignat-George F, Anfosso F. TRAIL/Apo2l mediates the release of procoagulant endothelial microparticles induced by thrombin in vitro. A potential mechanism linking inflammation and coagulation. Circ Res. 2009; 104: 943–951.LinkGoogle Scholar4 Wolf P. The nature and significance of platelet products in human plasma. Br J Haematol. 1967; 13: 269–288.CrossrefMedlineGoogle Scholar5 Hrachovinova I, Cambien B, Hafezi-Moghadam A, Kappelmayer J, Camphausen RT, Widom A, Xia L, Kazazian HH Jr, Schaub RG, McEver RP, Wagner DD. Interaction of P-selectin and PSGL-1 generates microparticles that correct hemostasis in a mouse model of hemophilia A. Nat Med. 2003; 9: 1020–1025.CrossrefMedlineGoogle Scholar6 Mackman N, Tilley RE, Key NS. Role of the extrinsic pathway of blood coagulation in hemostasis and thrombosis. Arterioscl Thromb Vasc Biol. 2007; 27: 1687–1693.LinkGoogle Scholar7 Shet AS, Aras O, Gupta K, Hass MJ, Rausch DJ, Saba N, Koopmeiners L, Key NS, Hebbel RP. Sickle blood contains tissue factor-positive microparticles derived from endothelial cells and monocytes. Blood. 2003; 102: 2678–2683.CrossrefMedlineGoogle Scholar8 Del Conde I, Shrimpton CN, Thiagarajan P, Lopez JA. Tissue-factor-bearing microvesicles arise from lipid rafts and fuse with activated platelets to initiate coagulation. Blood. 2005; 106: 1604–1611.CrossrefMedlineGoogle Scholar9 Chou J, Mackman N, Merrill-Skoloff G, Pedersen B, Furie BC, Furie B. Hematopoietic cell-derived microparticle tissue factor contributes to fibrin formation during thrombus propagation. Blood. 2004; 104: 3190–3197.CrossrefMedlineGoogle Scholar10 Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med. 2008; 359: 938–949.CrossrefMedlineGoogle Scholar11 Tesselaar ME, Romijn FP, Van Der Linden IK, Prins FA, Bertina RM, Osanto S. Microparticle-associated tissue factor activity: a link between cancer and thrombosis? J Thromb Haemost. 2007; 5: 520–527.CrossrefMedlineGoogle Scholar12 Khorana AA, Francis CW, Menzies KE, Wang JG, Hyrien O, Hathcock J, Mackman N, Taubman MB. Plasma tissue factor may be predictive of venous thromboembolism in pancreatic cancer. J Thromb Haemost. 2008; 6: 1983–1985.CrossrefMedlineGoogle Scholar13 Jimenez JJ, Jy W, Mauro LM, Soderland C, Horstman LL, Ahn YS. Endothelial cells release phenotypically and quantitatively distinct microparticles in activation and apoptosis. Thromb Res. 2003; 109: 175–180.CrossrefMedlineGoogle Scholar14 Lechner D, Kollars M, Gleiss A, Kyrle PA, Weltermann A. Chemotherapy-induced thrombin generation via procoagulant endothelial microparticles is independent of tissue factor activity. J Thromb Haemost. 2007; 5: 2445–2452.CrossrefMedlineGoogle Scholar15 Tramontano AF, O'Leary J, Black AD, Muniyappa R, Cutaia MV, El-Sherif N. Statin decreases endothelial microparticle release from human coronary artery endothelial cells: implication for the Rho-kinase pathway. Biochem Biophys Res Commun. 2004; 320: 34–38.CrossrefMedlineGoogle Scholar16 Sapet C, Simoncini S, Loriod B, Puthier D, Sampol J, Nguyen C, Dignat-George F, Anfosso F. Thrombin-induced endothelial microparticle generation: identification of a novel pathway involving ROCK-II activation by caspase-2. Blood. 2006; 108: 1868–1876.CrossrefMedlineGoogle Scholar17 Curtis AM, Wilkinson PF, Gui M, Gales TL, Hu E, Edelberg JM. p38 MAPK targets the production of pro-inflammatory endothelial microparticles. J Thromb Haemost. 2009; 7: 701–709.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Guilherme R, Silva J, Waclawiack I, Fraga-Junior V, Nogueira T, Pecli C, Araújo-Silva C, Magalhães N, Lemos F, Bulant C, Blanco P, Serra R, Svensjö E, Scharfstein J, Moraes J, Canetti C and Benjamim C (2023) Pleiotropic antifibrotic actions of aspirin-triggered resolvin D1 in the lungs, Frontiers in Immunology, 10.3389/fimmu.2023.886601, 14 Liu T, Wang J, Li T, Cui P, Hou B, Zhuang C, Wei G, Zhang S, Li H and Hu Y (2021) Predicting disease progression in advanced non-small cell lung cancer with circulating neutrophil-derived and platelet-derived microparticles, BMC Cancer, 10.1186/s12885-021-08628-4, 21:1, Online publication date: 1-Dec-2021. Koganti S, Eleftheriou D, Gurung R, Hong Y, Brogan P and Rakhit R (2021) Persistent circulating platelet and endothelial derived microparticle signature may explain on-going pro-thrombogenicity after acute coronary syndrome, Thrombosis Research, 10.1016/j.thromres.2021.07.018, 206, (60-65), Online publication date: 1-Oct-2021. Zacharia E, Zacharias K, Papamikroulis G, Bertsias D, Miliou A, Pallantza Z, Papageorgiou N and Tousoulis D Cell-Derived Microparticles and Acute Coronary Syndromes: Is there a Predictive Role for Microparticles?, Current Medicinal Chemistry, 10.2174/0929867327666191213104841, 27:27, (4440-4468) Wang H, Song N, Li J, Wang Z, Ti Y, Li Y, Zhang W and Zhong M (2020) The microvesicle/CD36 complex triggers a prothrombotic phenotype in patients with non‐valvular atrial fibrillation, Journal of Cellular and Molecular Medicine, 10.1111/jcmm.15311, 24:13, (7331-7340), Online publication date: 1-Jul-2020. Yamaguchi R, Sakamoto A, Yamaguchi R, Haraguchi M, Narahara S, Sugiuchi H, Katoh T and Yamaguchi Y (2019) Di-(2-Ethylhexyl) Phthalate Promotes Release of Tissue Factor-Bearing Microparticles From Macrophages via the TGFβ1/Smad/PAI-1 Signaling Pathway, The American Journal of the Medical Sciences, 10.1016/j.amjms.2019.02.012, 357:6, (492-506), Online publication date: 1-Jun-2019. Hosseini-Beheshti E and Grau G (2018) Extracellular vesicles and microvascular pathology: Decoding the active dialogue, Microcirculation, 10.1111/micc.12485, 26:2, (e12485), Online publication date: 1-Feb-2019. Shamekhi Amiri F (2017) Microparticles in kidney diseases: focus on kidney transplantation, Renal Replacement Therapy, 10.1186/s41100-017-0104-0, 3:1, Online publication date: 1-Dec-2017. Koganti S, Eleftheriou D, Brogan P, Kotecha T, Hong Y and Rakhit R (2017) Microparticles and their role in coronary artery disease, International Journal of Cardiology, 10.1016/j.ijcard.2016.12.108, 230, (339-345), Online publication date: 1-Mar-2017. Kim H, Choi E, Lim Y and Kil H (2017) The Usefulness of Platelet-derived Microparticle as Biomarker of Antiplatelet Therapy in Kawasaki Disease, Journal of Korean Medical Science, 10.3346/jkms.2017.32.7.1147, 32:7, (1147), . Koliopoulou A, McKellar S, Rondina M and Selzman C (2016) Bleeding and thrombosis in chronic ventricular assist device therapy, Current Opinion in Cardiology, 10.1097/HCO.0000000000000284, 31:3, (299-307), Online publication date: 1-May-2016. Bohman L, Riley J, Milovanova T, Sanborn M, Thom S and Armstead W (2016) Microparticles Impair Hypotensive Cerebrovasodilation and Cause Hippocampal Neuronal Cell Injury after Traumatic Brain Injury, Journal of Neurotrauma, 10.1089/neu.2015.3885, 33:2, (168-174), Online publication date: 15-Jan-2016. Kidd L, Geddings J, Hisada Y, Sueda M, Concannon T, Nichols T, Merricks E and Mackman N (2015) Procoagulant Microparticles in Dogs with Immune-Mediated Hemolytic Anemia, Journal of Veterinary Internal Medicine, 10.1111/jvim.12583, 29:3, (908-916), Online publication date: 1-May-2015. Colvin K and Yeager M (2015) Proteomics of pulmonary hypertension: Could personalized profiles lead to personalized medicine?, PROTEOMICS - Clinical Applications, 10.1002/prca.201400157, 9:1-2, (111-120), Online publication date: 1-Feb-2015. Renner B, Klawitter J, Goldberg R, McCullough J, Ferreira V, Cooper J, Christians U and Thurman J (2013) Cyclosporine Induces Endothelial Cell Release of Complement-Activating Microparticles, Journal of the American Society of Nephrology, 10.1681/ASN.2012111064, 24:11, (1849-1862), Online publication date: 1-Nov-2013. Bharthuar A, Khorana A, Hutson A, Wang J, Key N, Mackman N and Iyer R (2013) Circulating microparticle tissue factor, thromboembolism and survival in pancreaticobiliary cancers, Thrombosis Research, 10.1016/j.thromres.2013.06.026, 132:2, (180-184), Online publication date: 1-Aug-2013. Weisshaar S, Gouya G, Nguyen D, Kapiotis S and Wolzt M (2013) The LPS-induced increase in circulating microparticles is not affected by vitamin C in humans, European Journal of Clinical Investigation, 10.1111/eci.12096, 43:7, (708-715), Online publication date: 1-Jul-2013. Camaioni C, Gustapane M, Cialdella P, Della Bona R and Biasucci L (2011) Microparticles and microRNAs: new players in the complex field of coagulation, Internal and Emergency Medicine, 10.1007/s11739-011-0705-5, 8:4, (291-296), Online publication date: 1-Jun-2013. Hargett L and Bauer N (2013) On the Origin of Microparticles: From "Platelet Dust" to Mediators of Intercellular Communication, Pulmonary Circulation, 10.4103/2045-8932.114760, 3:2, (329-340), Online publication date: 1-Apr-2013. DeWalt R, Petkovich D, Zahrt A, Bruns H and McDowell S (2013) Host cell invasion by Staphylococcus aureus stimulates the shedding of microvesicles, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2013.01.122, 432:4, (695-700), Online publication date: 1-Mar-2013. Toraldo D, Peverini F, De Benedetto M and De Nuccio F (2012) Obstructive Sleep Apnea Syndrome: Blood Viscosity, Blood Coagulation Abnormalities, and Early Atherosclerosis, Lung, 10.1007/s00408-012-9427-3, 191:1, (1-7), Online publication date: 1-Feb-2013. Kidd L and Mackman N (2013) Prothrombotic mechanisms and anticoagulant therapy in dogs with immune-mediated hemolytic anemia, Journal of Veterinary Emergency and Critical Care, 10.1111/j.1476-4431.2012.00824.x, 23:1, (3-13), Online publication date: 1-Jan-2013. WELSH J, SMITH J, YATES K, GREENMAN J, MARAVEYAS A and MADDEN L (2012) Tissue factor expression determines tumour cell coagulation kinetics, International Journal of Laboratory Hematology, 10.1111/j.1751-553X.2012.01409.x, 34:4, (396-402), Online publication date: 1-Aug-2012. Watts J, Lee Y, Gellar M, Fulkerson M, Hwang S and Kline J (2012) Proteomics of microparticles after experimental pulmonary embolism, Thrombosis Research, 10.1016/j.thromres.2011.09.016, 130:1, (122-128), Online publication date: 1-Jul-2012. Maruyama K, Morishita E, Sekiya A, Omote M, Kadono T, Asakura H, Hashimoto M, Kobayashi M, Nakatsumi Y, Takada S and Ohtake S (2012) Plasma Levels of Platelet-Derived Microparticles in Patients with Obstructive Sleep Apnea Syndrome, Journal of Atherosclerosis and Thrombosis, 10.5551/jat.8565, 19:1, (98-104), . Ranghino A, Cantaluppi V, Grange C, Vitillo L, Fop F, Biancone L, Deregibus M, Tetta C, Segoloni G and Camussi G (2012) Endothelial Progenitor Cell-Derived Microvesicles Improve Neovascularization in a Murine Model of Hindlimb Ischemia, International Journal of Immunopathology and Pharmacology, 10.1177/039463201202500110, 25:1, (75-85), Online publication date: 1-Jan-2012. Yates K, Welsh J, Echrish H, Greenman J, Maraveyas A and Madden L (2011) Pancreatic cancer cell and microparticle procoagulant surface characterization, Blood Coagulation & Fibrinolysis, 10.1097/MBC.0b013e32834ad7bc, 22:8, (680-687), Online publication date: 1-Dec-2011. Meiliana A and Wijaya A (2011) Microparticles Novel Mechanisms of Intracellular Communication: Implication in Health and Disease, The Indonesian Biomedical Journal, 10.18585/inabj.v3i1.131, 3:1, (18) Tsimerman G, Roguin A, Bachar A, Melamed E, Brenner B and Aharon A (2017) Involvement of microparticles in diabetic vascular complications, Thrombosis and Haemostasis, 10.1160/TH10-11-0712, 106:08, (310-321), . Diehl P, Aleker M, Helbing T, Sossong V, Beyersdorf F, Olschewski M, Bode C and Moser M (2010) Enhanced microparticles in ventricular assist device patients predict platelet, leukocyte and endothelial cell activation, Interactive CardioVascular and Thoracic Surgery, 10.1510/icvts.2010.232603, 11:2, (133-137), Online publication date: 1-Aug-2010. Ramacciotti E, Hawley A, Wrobleski S, Myers D, Strahler J, Andrews P, Guire K, Henke P and Wakefield T (2010) Proteomics of microparticles after deep venous thrombosis, Thrombosis Research, 10.1016/j.thromres.2010.01.019, 125:6, (e269-e274), Online publication date: 1-Jun-2010. Diaz J, Ramacciotti E and Wakefield T (2010) Do galectins play a role in venous thrombosis? a review, Thrombosis Research, 10.1016/j.thromres.2009.11.011, 125:5, (373-376), Online publication date: 1-May-2010. April 24, 2009Vol 104, Issue 8 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCRESAHA.109.196840PMID: 19390059 Originally publishedApril 24, 2009 Keywordsendothelial cellscoagulationmicroparticlesinflammationPDF download Advertisement
Referência(s)