Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Cardiovascular Diabetology
Published in: Cardiovascular Diabetology 1/2003

Open Access 01-12-2003 | Original investigation

Platelet-neutrophil conjugate formation is increased in diabetic women with cardiovascular disease

Authors: Hillary A Tuttle, Grace Davis-Gorman, Steven Goldman, Jack G Copeland, Paul F McDonagh

Published in: Cardiovascular Diabetology | Issue 1/2003

Login to get access

Abstract

Background

More than seventeen million Americans are afflicted with diabetes and these people have four times the rate of coronary heart disease (CHD) as non-diabetics. Furthermore, diabetic women have a 3.8 fold greater risk for CHD compared to diabetic men. Little is known why diabetic women are at an increased risk for CHD. It is possible that diabetic women with cardiovascular disease (CVD) have a greater inflammatory response resulting in an increased platelet neutrophil conjugate formation than diabetic men with CVD or non-diabetic women with CVD. This study tested the hypothesis that platelet-neutrophil conjugates, which are associated with several cardiovascular diseases, are increased in diabetic women with CVD compared to diabetic men with CVD and non-diabetic women with CVD.

Methods

Platelet-neutrophil conjugates were quantified by flow cytometry. The primary method is through direct binding of the neutrophil PSGL-1 receptor with P-selectin expressed on the platelet.

Results

In this study, we found when the blood was stimulated with PAF (platelet activating factor), diabetic women without CVD demonstrated an increase in platelet-neutrophil conjugates compared to diabetic women with CVD and non-diabetic women with CVD (% conjugates: 63.3 ± 5.2 vs 46.8 ± 4.3 vs 48.6 ± 3.4, p < 0.05). The stimulation ratio was significantly increased in diabetic and non-diabetic women with CVD in comparison to diabetic men with CVD (ratio: 3.3 ± 0.4 vs 3.3 ± 0.3 vs 2.1 ± 0.3, p < 0.05).

Conclusion

These results suggest that platelets and neutrophils in diabetic women have a greater potential for activation compared to diabetic men and may contribute to thrombosis/inflammation and the greater severity of coronary heart disease observed in diabetic women as compared to diabetic men.
Appendix
Available only for authorised users
Literature
1.
Howard BV, Cowan LD, Go O, Welty TK, Robbins DC, Lee ET: Adverse effects of diabetes on multiple cardiovascular disease risk factors in women. Diabetes Care. 1998, 21: 1258-1265.CrossRefPubMed
2.
Phillips P: Diabetes and the menopause. Special considerations. Aust Fam Physician. 1998, 27: 59-63.PubMed
3.
Libby P, Ridker PM, Maseri A: Inflammation and atherosclerosis. Circulation. 2002, 105: 1135-1143. 10.1161/hc0902.104353.CrossRefPubMed
4.
Hokama JY, Mullarkey PJ, Logan JJ, Cimetta AD, Leprince P, Goldman S, Copeland JG, McDonagh PF: Platelet-leukocyte interactions are increased in patients with type II diabetes. FASEB J. 1999, 13: A660.
5.
McDonagh PF, Hokama JY, Copeland JG, Reynolds JM: The blood contribution to early myocardial reperfusion injury is amplified in diabetes. Diabetes. 1997, 46: 1859-1867.CrossRefPubMed
6.
Hokama JY, Ritter LS, Davis-Gorman G, McDonagh PF: Leukocyte accumulation is enhanced in the diabetic heart early in reperfusion following ischemia. Microcirculation. 1997, 4: 173.
7.
McDonagh PF, Hokama J: Microvascular perfusion and transport and exchange in the diabetic heart. Microcirculation. 2000, 7: 163-181. 10.1038/sj.mn.7300106.CrossRefPubMed
8.
Mosca L, Manson JE, Suthterland SE, Langer RD, Manolio T, Barrett-Connor E: Cardiovascular disease in women: a statement for healthcare professionals from the american heart association. Circulation. 1997, 96: 2468-2482.CrossRefPubMed
9.
American Heart Association: Heart Disease and Stroke statistics – 2003 update. 2003
10.
Libby P: Atherosclerosis: the new view. Sci Am. 2002, 47-55.
11.
Peters MJ, Heyderman RS, Hatch DJ, Klein NJ: Investigation of platelet-neutrophil interactions in whole blood by flow cytometry. J Immunol Methods. 1997, 209: 125-135. 10.1016/S0022-1759(97)00139-7.CrossRefPubMed
12.
Montrucchio G, Alloatti G, Tetta C, De Luca R, Saunders RN, Emanuelli G, Camussi G: Release of platelet-activating factor from ischemic-reperfused rabbit heart. Am J Physiol. 1989, 256: H1236-H1246.PubMed
13.
Arabía FA, Copeland JG, Smith RG, Banchy M, Sethi GK, Foy B, Kormos R, Tector A, Long J, Dembitsky W: Infections with the CardioWest total artificial heart. ASAIO J. 1998, 44: M336-M339.CrossRefPubMed
14.
Rinder HM, Bonan JL, Rinder CS, Ault KA, Smith BR: Dynamics of leukocyte-platelet adhesion in whole blood. Blood. 1991, 78: 1730-1737.PubMed
15.
Rinder HM, Bonan JL, Rinder CS, Ault KA, Smith BR: Activated and unactivated platelet adhesion to monocytes and neutrophils. Blood. 1991, 78: 1760-1769.PubMed
16.
Hamburger SA, McEver RP: GMP-140 mediates adhesion of stimulated platelets to neutrophils. Blood. 1990, 75: 550-554.PubMed
17.
Diacovo TG, Roth SJ, Buccola JM, Bainton DF, Springer TA: Neutrophil rolling, arrest, and transmigration across activated, surface-adherent platelets via sequential action of P-selectin and the β2-integrin CD11b/CD18. Blood. 1996, 1: 146-157.
18.
Konstantopoulos K, Neelamegham S, Burns AR, Hentzen E, Kansas GS, Snapp KR, Berg EL, Hellums JD, Smith CW, McIntre LV: Venous levels of shear support neutrophil-platelet adhesion and neutrophil aggregation in blood via P-selectin and β2-integrin. Circulation. 1998, 98: 873-882.CrossRefPubMed
19.
Sako D, Chang X-J, Barone KM, Vachino G, White HM, Shaw G, Veldman GM, Bean KM, Ahern TJ, Furie B: Expression cloning of a functional glycoprotein ligand for P-selectin. Cell. 1993, 75: 1179-1186.CrossRefPubMed
20.
Evangelista V, Manarini S, Sideri R, Rotondo S, Martelli N, Piccoli A, Totani L, Piccardoni P, Vestweber D, de Gaetano G: Platelet/polymorphonuclear leukocyte interaction: P-selectin triggers protein-tyrosine phosphorylation-dependent CD11b/CD18 adhesion: role of PSGL-1 as a signaling molecule. Blood. 1999, 93: 876-885.PubMed
21.
Evangelista V, Manarini S, Rotondo S, Martelli N, Polischuk R, McGregor JL, de Gaetano G, Cerletti C: Platelet/polymorphonuclear leukocyte interaction in dynamic conditions: evidence of adhesion cascade and cross talk between P-selectin and the β 2 integrin CD11b/CD18. Blood. 1996, 88: 4183-4194.PubMed
22.
Jwa Hidari KIP, Weyrich AS, Zimmerman GA, McEver RP: Engagement of P-selectin glycoprotein ligand-1 enhances tyrosine phosphorylation and activates mitogen-activated protein kinases in human neutrophils. J Biol Chem. 1997, 272: 28750-28756. 10.1074/jbc.272.45.28750.CrossRef
23.
Lehr H-A, Olofsson AM, Carew TE, Vajkoczy P, Von Andrian UH, Hubner C, Berndt MC, Steinberg D, Messmer K, Arfors KE: P-selectin mediates the interaction of circulating leukocytes with platelets and microvascular endothelium in response to oxidized lipoprotein in vivo. Laboratory Investigation. 1994, 71: 380-386.PubMed
24.
McEver RP, Martin MN: A monocolonal antibody to a membrane glycoprotein binds only to activated platelets. J Biol Chem. 1984, 259: 9799-9804.PubMed
25.
McEver RP, Beckstead JH, Moore KL, Marshall-Carlson L, Bainton DF: GMP-140, a platelet alpha-granule membrane protein, is also synthesized by vascular endothelial cells and is localized in Weibel-Palade bodies. J Clin Invest. 1989, 84: 92-99.PubMedCentralCrossRefPubMed
26.
Patel KD, Zimmerman GA, Prescott SM, McEver RP, McIntyre TM: Oxygen radicals induce human endothelial cells to express GMP-140 and bind neutrophils. J Cell Biology. 1991, 112: 749-759.CrossRef
27.
Kogaki S, Sawa Y, Sano T, Matsushita T, Ohata T, Kurotobi S, Tojo SJ, Matsuda H, Okada S: Selectin on activated platelets enhances neutrophil endothelial adherence in myocardial reperfusion injury. Cardiovasc Res. 1999, 43: 968-973. 10.1016/S0008-6363(99)00140-6.CrossRefPubMed
28.
Sheikh S, Nash GB: Continuous activation and deactivation of integrin CD11b/CD18 during de novo expression enables rolling neutrophils to immoboilize on platelets. Blood. 1996, 12: 5040-5050.
29.
Neumann F-J, Marx N, Gawaz M, Brand K, Ott I, Rokitta C, Sticherling C, Meinl C, May A, Schömig A: Induction of cytokine expression in leukocytes by binding of thrombin-stimulated platelets. Circulation. 1997, 95: 2387-2394.CrossRefPubMed
30.
Simon DI, Chen Z, Xu H, Li CQ, Dong J, McIntire LV, Ballantyne CM, Zhang L, Furman MI, Berndt MC: Platelet glycoprotein Ibα is a counterreceptor for the leukocyte integrin Mac-1 (CD11b/CD18). J Exp Med. 2000, 192: 193-204. 10.1084/jem.192.2.193.PubMedCentralCrossRefPubMed
31.
Rinder C, Fitch J: Amplification of the inflammatroy response: adhesion molecuels associated with platelet/white cell responses. J Cardiovasc Pharmacol. 1996, 27: 6-12. 10.1097/00005344-199600001-00005.CrossRef
32.
Nagata K, Tsuji T, Todoroki N, Katagiri Y, Tanoue K, Yamazaki H, Hanai N, Irimura T: Activated platelets induce superoxide anion release by monocytes and neutrophils through P-selectin (CD62). J Immunol. 1993, 151: 3267-3273.PubMed
33.
Ott I, Neumann F-J, Gawaz M, Schmitt M, Schomig A: Coronary heart disease/myocardial infarction/bypass grafts/endothelial function: increased neutrophil-platelet adhesion in patients with unstable angina. Circulation. 1996, 94: 1239-1246.CrossRefPubMed
34.
Rinder CS, Bonan JL, Rinder HM, Mathew J, Hines R, Smith BR: Cardiopulmonary bypass induces leukocyte-platelet adhesion. Blood. 1992, 79: 1201-1205.PubMed
35.
Morse DS, Adams D, Magnani B: Platelet and neutrophil activation during cardiac surgical procedures: impact of cardiopulmonary bypass. Ann Thorac Surg. 1998, 65: 691-695. 10.1016/S0003-4975(97)01425-2.CrossRefPubMed
36.
Gawaz M, Reininger A, Neumann F-J: Platelet function and platelet-leukocyte adhesion in symptomatic coronary heart disease. Effects of intravenous magnesium. Thromb Res. 1996, 83: 341-349. 10.1016/0049-3848(96)00144-2.CrossRefPubMed
37.
Lefer AM, Campbell B, Scalia R, Lefer DJ: Synergism between platelets and neutrophils in provoking cardiac dysfunction after ischemia and reperfusion. Role of selectins. Circulation. 1998, 98: 1322-1328.CrossRefPubMed
38.
Bazzoni G, Dejana E, Mashcio AD: Platelet-neutrophil interactions. possible relevance in the pathogenesis of thrombosis and inflammation. Haematologica. 1991, 76: 491-499.PubMed
39.
Weksler BB: Platelets. New York: Raven Press. 1988
40.
Sharpe RL, Maione TE, whitaker D, Murphy GF: Induction of intercullular adhesion molecule-1 (ICAM-1) in cultured endothelium by recombinant platelet factor 4 (PF-4). J Invest Dermatol. 1990, 94: 578.
41.
Deuel TF, Senior RM, Chang D, Griffin GL, Heinrikson RL, Kaiser ET: Platelet factor 4 is chemotactic for neutrophils and monocytes. Proc Natl Acad Sci USA. 1981, 78: 4584-4587.PubMedCentralCrossRefPubMed
42.
Deuel TF, Senior RM, Huang JS, Griffin GL: Chemotaxis of monocytes and neutrophils to platelet-derived growth factor. J Clin Invest. 1982, 69: 1046-1049.PubMedCentralCrossRefPubMed
43.
Morley DJ, Feuerstein IA: Adhesion of polymorphonuclear leukocytes to protein-coated and platelet adherent surfaces. Thrombosis and Haemostatis. 1989, 62: 1023-1028.
44.
45.
46.
Canoso RT, Rodvien R, Scoon K, Levine PH: Hydrogen peroxide and platelet function. Blood. 1974, 5: 645-656.
47.
Kornecki E, Ehrlich YH, Egbring R, Gramse M, Seitz R, Eckardt A, Lukasiewicz H, Niewiarowski S: Granulocyte-platelet interactions and platelet fibrinogen receptor exposure. Am J Physiol. 1988, 255: H651-H658.PubMed
48.
Aziz KA, Cawley JC, Treweeke AT, Zuzel M: Sequential potentiation and inhibition of PMN reactivity by maximally stimulated platelets. J Leukoc Biol. 1997, 61: 322-328.PubMed
49.
Kaplar M, Kappelmayer J, Veszpremi A, Szabo K, Udvardy M: The possible association of in vivo leukocyte-platelet heterophilic aggregate formation and the development of diabetic angiopathy. Platelets. 2001, 12: 419-422. 10.1080/09537100120078368.CrossRefPubMed
50.
Marso SP, Lincoff AM, Ellis SG, Bhatt DL, Tanguay J-F, Kleiman NS, Hammoud T, Booth JE, Sapp SK, Topol EJ: Optimizing the percutaneous interventional outcomes for patients with diabetes mellitus: results of the EPISTENT (Evaluation of platelet IIb/IIIa inhibitor for stenting trial) diabetic substudy. Circulation. 1999, 100: 2477-2484.CrossRefPubMed
51.
Vozarova B, Weyer C, Linsay RS, Pratley RE, Pratley RE, Bogardus C, Tataranni PA: High white blood cell count is associated with a worsening of insulin sensitivity and predicts the development of type 2 diabetes. Diabetes. 2002, 51: 455-461.CrossRefPubMed
52.
Thorand B, Löwel h, Schneider A, Kolb H, Meisinger C, Fröhlich M, Koenig W: C-reactive protein as a predictor for incident diabetes mellitus among middle-aged men. Arch Intern Med. 2003, 163: 93-99. 10.1001/archinte.163.1.93.CrossRefPubMed
53.
Barzilay JI, Abraham L, Heckbert SR, Cushman M, Kuller LH, Resnick HE, Tracy RP: The relation of markers of inflammation to the development of glucose disorders in the elderly: the cardiovascular health study. Diabetes. 2001, 50: 2384-2390.CrossRefPubMed
54.
Mehta JL, Nicolini FA, Donnelly WH, Nichols WW: Platelet-leukocyte-endothelial interactions in coronary artery disease. Am J Cardiol. 1992, 69: 8B-13B.CrossRefPubMed
55.
Lawson DL, Mehta JL, Nichols WW, Mehta P, Donnelly WH: Superoxide radical-mediated endothelial injury and vasoconstriction of rat thoracic aortic rings. J Lab Clin Med. 1990, 115: 541-548.PubMed
56.
Mehta JL, Nichols WW, Donnelly WH, Lawson DL, Thompson L, ter Riet M, Saldeen TGP: Protection by superoxide dismutase from myocardial dysfunction and attention of vasodilator reserve after coronary occlusion and reperfusion in dog. Circ Res. 1989, 65: 1283-1295.CrossRefPubMed
57.
Mehta JL, Lawson DL, Nichols WW: Attenuated coronary relaxation after reperfusion: effects of superoxide dismutase and TxA2 inhibitor U 63557A. Am J Physiol. 1989, 257: H1240-H1246.PubMed
58.
Siminiak T, Flores NA, Sheridan DJ: Neutrophil interactions with endothelium and platelets: possible role in the development of cardiovascular injury. European Heart Journal. 1995, 16: 160-170.PubMed
59.
Hokama JY, Ritter LS, Davis-Gorman G, Cimetta AD, Copeland JG, McDonagh PF: Diabetes enhances leukocyte accumulation in the coronary microcirculation early in reperfusion following ischemia. J Diabetes Complications. 2000, 14: 96-107. 10.1016/S1056-8727(00)00068-4.CrossRefPubMed
60.
Neumann F-J, Zohlnhöfer D, Fakhoury L, Ott I, Gawaz M, Schömig A: Effect of glycoprotein IIb/IIIa receptor blockade on platelet-leukocyte interaction and surface expression of the leukocyte integrin Mac-1 in acute myocardial infarction. J Am Coll Cardiol. 1999, 34: 1420-1426. 10.1016/S0735-1097(99)00350-2.CrossRefPubMed
61.
Todoroki N, Watanabe Y, Akaike T, Katagiri Y, Tanoue K, Yamazaki H, Tsuji T, Toyoshima S, Osawa T: Enhancement by IL-1β and IFN-γ of platelet activation: adhesion to leukocytes via GMP-140/padgem protein (CD62). Biochem Biophys Res Comm. 1991, 179: 756-761.CrossRefPubMed
62.
Weyrich AS, McIntyre TM, McEver RP, Prescott SM, Zimmerman GA: Monocyte tethering by P-selectin regulates monocyte chemotactic protein-1 and tumor necrosis factor-1 secretion. J Clin Invest. 1995, 95: 2297-2303.PubMedCentralCrossRefPubMed
63.
Brown KK, Henson PM, Maclouf J, Mayle M, Ely JA, Worthen GS: Neutrophil-platelet adhesion: relative roles of platelet p-selectin and neutrophil β2 (CD18) integrins. Am J Respir Cell Mol Biol. 1998, 18: 100-110.CrossRefPubMed
64.
Hayden RM, Tyagi SC: Is type 2 diabetes mellitus a vascular disease (ATHEROSCLEROPATHY) with hyperglycemia a late manifestation? The role of NOS, NO, and redox stress. Cardiovasc Diabetol. 2003, 2: 2-10.1186/1475-2840-2-2.PubMedCentralCrossRefPubMed
65.
Laufs U, La Fata V, Plutzky J, Liao JK: Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation. 1998, 97: 1129-1135.CrossRefPubMed
66.
Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E: Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation. 1999, 100: 230-235.CrossRefPubMed
Metadata
Title
Platelet-neutrophil conjugate formation is increased in diabetic women with cardiovascular disease
Authors
Hillary A Tuttle
Grace Davis-Gorman
Steven Goldman
Jack G Copeland
Paul F McDonagh
Publication date
01-12-2003
Publisher
BioMed Central
Published in
Cardiovascular Diabetology / Issue 1/2003
Electronic ISSN: 1475-2840
DOI
https://doi.org/10.1186/1475-2840-2-12

Other articles of this Issue 1/2003

Cardiovascular Diabetology 1/2003 Go to the issue

Original investigation

Brachial-ankle pulse wave velocity and symptomatic cerebral infarction in patients with type 2 diabetes: a cross-sectional study

Hypothesis

Cardiovascular diabetology in the core of a novel interleukins classification: the bad, the good and the aloof

Original investigation

Trimetazidine improves left ventricular function in diabetic patients with coronary artery disease: a double-blind placebo-controlled study

Original investigation

Silent myocardial infarction in women with impaired glucose tolerance: The Northern Sweden MONICA study

Hypothesis

Is type 2 diabetes mellitus a vascular disease (atheroscleropathy) with hyperglycemia a late manifestation? The role of NOS, NO, and redox stress.

Review

Influence of diabetes mellitus on heart failure risk and outcome

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits