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Activation and shedding of platelet glycoprotein IIb/IIIa under non-physiological shear stress

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Abstract

The purpose of this study was to investigate the influence of non-physiological high shear stress on activation and shedding of platelet GP IIb/IIIa receptors. The healthy donor blood was exposed to three levels of high shear stresses (25, 75, 125 Pa) from the physiological to non-physiological status with three short exposure time (0.05, 0.5, 1.5 s), created by a specific blood shearing system. The activation and shedding of the platelet GPIIb/IIIa were analyzed using flow cytometry and enzyme-linked immunosorbent assay. In addition, platelet P-selectin expression of sheared blood, which is a marker for activated platelets, was also analyzed. The results from the present study showed that the number of activated platelets, as indicated by the surface GPIIb/IIIa activation and P-selectin expression, increased with increasing the shear stress level and exposure time. However, the mean fluorescence of GPIIb/IIIa on the platelet surface, decreased with increasing the shear stress level and exposure time. The reduction of GPIIb/IIIa on the platelet surface was further proved by the reduction of further activated platelet GPIIb/IIIa surface expression induced by ADP and the increase in GPIIb/IIIa concentration in microparticle-free plasma with increasing the applied shear stress and exposure time. It is clear that non-physiological shear stress induce a paradoxical phenomenon, in which both activation and shedding of the GPIIb/IIIa on the platelet surface occur simultaneously. This study may offer a new perspective to explain the reason of both increased thrombosis and bleeding events in patients implanted with high shear blood-contacting medical devices.

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References

  1. Go AS, Mozaffarian D, Roger VL et al (2014) Heart disease and stroke statistics–2014 update: a report from the American Heart Association. Circulation 129:28–292

    Article  Google Scholar 

  2. National Kidney Foundation (2012) The facts about chronic kidney disease. National Kidney Foundation, New York

    Google Scholar 

  3. Eckman PM, John R (2012) Bleeding and thrombosis in patients with continuous-flow ventricular assist devices. Circulation 125:3038–3047

    Article  PubMed  Google Scholar 

  4. Boyle AJ, Russell SD, Teuteberg JJ et al (2009) Low thromboembolism and pump thrombosis with the HeartMate II left ventricular assist device: analysis of outpatient anti-coagulation. J Heart Lung Transpl 28:881–887

    Article  Google Scholar 

  5. Bruckner BA, DiBardino DJ, Ning Q, Adeboygeun A, Mahmoud K, Valdes J et al (2009) High incidence of thromboembolic events in left ventricular assist device patients treated with recombinant activated factor VII. J Heart Lung Transpl 28:785–790

    Article  Google Scholar 

  6. John R, Kamdar F, Liao K et al (2008) Low thromboembolic risk for patients with the Heartmate II left ventricular assist device. J Thorac Cardiovasc Surg 136:1318–1323

    Article  PubMed  Google Scholar 

  7. Fraser KH, Zhang T, Taskin ME, Griffith BP, Wu ZJ (2012) A quantitative comparison of mechanical blood damage parameters in rotary ventricular assist devices: shear stress, exposure time and hemolysis index. J Biomech Eng 134(8):081002

    Article  PubMed  Google Scholar 

  8. Alemu Y, Bluestein D (2007) Flow-induced platelet activation and damage accumulation in a mechanical heart valve: numerical studies. Artif Organs 31(9):677–688

    Article  PubMed  Google Scholar 

  9. Morbiducci U, Ponzini R, Nobili M, Massai D, Montevecchi FM, Bluestein D, Redaelli A (2009) Blood damage safety of prosthetic heart valves: shear-induced platelet activation and local flow dynamics: a fluid-structure interaction approach. J Biomech 42(12):1952–1960

    Article  PubMed  Google Scholar 

  10. Nobili M, Sheriff J, Morbiducci U, Redaelli A, Bluestein D (2008) Platelet activation due to hemodynamic shear stresses: damage accumulation model and comparison to in vitro measurements. ASAIO J 54(1):64–72

    Article  PubMed Central  PubMed  Google Scholar 

  11. Song X, Throckmorton AL, Wood HG, Antaki JF, Olsen DB (2004) Quantitative evaluation of blood damage in a centrifugal VAD by computational fluid dynamics. J Fluids Eng 126:410–418

    Article  Google Scholar 

  12. Bluestein D (2004) Research approaches for studying flow-induced thromboembolic complications in blood recirculating devices. Expert Rev Med Devices 1(1):65–80

    Article  PubMed  Google Scholar 

  13. Deutsch S, Tarbell JM, Manning KB, Rosenberg G, Fontaine AA (2006) Experimental fluid mechanics of pulsatile artificial blood pumps. Annu Rev Fluid Mech 38:65–86

    Article  Google Scholar 

  14. Rivera J, Lozano ML, Navarro-Núñez L, Vicente V (2009) Platelet receptors and signaling in the dynamics of thrombus formation. Haematologica 94(5):700–711

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Li Z, Delaney MK, O’Brien KA, Du X (2010) Signaling during platelet adhesion and activation. Arterioscler Thromb Vasc Biol 30(12):2341–2349

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. John R, Panch S, Hrabe J, Wei P, Solovey A, Joyce L, Hebbel R (2009) Activation of endothelial and coagulation systems in left ventricular assist device recipients. Ann Thorac Surg 88(4):1171–1179

    Article  PubMed  Google Scholar 

  17. Steinlechner B, Dworschak M, Birkenberg B, Duris M, Zeidler P, Fischer H, Milosevic L, Wieselthaler G, Wolner E, Quehenberger P, Jilma B (2009) Platelet dysfunction in outpatients with left ventricular assist devices. Ann Thorac Surg 87(1):131–137

    Article  PubMed  Google Scholar 

  18. Avrahami I, Rosenfeld M, Einav S (2006) The hemodynamics of the Berlin pulsatile VAD and the role of its MHV configuration. Ann Biomed Eng 34:1373–1388

    Article  PubMed  Google Scholar 

  19. Wagner CL, Mascelli MA, Neblock DS, Weisman HF, Coller BS, Jordan RE (1996) Analysis of GPIIb/IIIa receptor number by quantification of 7E3 binding to human platelets. Blood 88(3):907–914

    CAS  PubMed  Google Scholar 

  20. Phillips DR, Charo IF, Parise LV, Fitzgerald LA (1988) The platelet membrane glycoprotein IIb-IIIa complex. Blood 71(4):831–843

    CAS  PubMed  Google Scholar 

  21. Reddy KB, Smith DM, Plow EF (2008) Analysis of Fyn function in hemostasis and alphaIIbbeta3-integrin signaling. J Cell Sci 15:1211641–1211648

    Google Scholar 

  22. Canobbio I, Balduini C, Torti M (2004) Signalling through the platelet glycoprotein Ib-V-IX complex. Cell Signal 16(12):1329–1344

    Article  CAS  PubMed  Google Scholar 

  23. Cheng H, Yan R, Li S et al (2009) Shear-induced interaction of platelets with von Willebrand factor results in glycoprotein Ibα shedding. Am J Physiol Heart Circ Physiol 297:H2128–H2135

    Article  CAS  PubMed  Google Scholar 

  24. Hu J, Mondal NK, Sorensen EN et al (2014) Platelet glycoprotein Ibα ectodomain shedding and non-surgical bleeding in heart failure patients supported by continuous-flow left ventricular assist devices. J Heart Lung Transpl 33:71–79

    Article  Google Scholar 

  25. Al-Tamimi M, Tan CW, Qiao J et al (2012) Pathologic shear triggers shedding of vascular receptors: a novel mechanism for down-regulation of platelet glycoprotein VI in stenosed coronary vessels. Blood 119:4311–4320

    Article  CAS  PubMed  Google Scholar 

  26. Maxwell MJ, Westein E, Nesbitt WS, Giuliano S, Dopheide SM, Jackson SP (2007) Identification of a 2-stage platelet aggregation process mediating shear-dependent thrombus formation. Blood 109:566–776

    Article  CAS  PubMed  Google Scholar 

  27. Kroll MH, Hellums JD, McIntire LV, Schafer AI, Moake JL (1996) Platelets and shear stress. Blood 88(5):1525–1541

    CAS  PubMed  Google Scholar 

  28. Miyazaki Y, Nomura S, Miyake T, Kagawa H, Kitada C, Taniguchi H, Komiyama Y, Fujimura Y, Ikeda Y, Fukuhara S (1996) High shear stress can initiate both platelet aggregation and shedding of procoagulant containing microparticles. Blood 88:3456–3464

    CAS  PubMed  Google Scholar 

  29. Nesbitt WS, Kulkarni S, Giuliano S, Goncalves I, Dopheide SM, Yap CL, Harper IS, Salem HH, Jackson SP (2002) Distinct glycoprotein Ib/V/IX and integrin alpha(IIb)beta(3)-dependent calcium signals cooperatively regulate platelet adhesion under flow. J Biol Chem 277:2965–2972

    Article  CAS  PubMed  Google Scholar 

  30. Kasirer-Friede A, Cozzi MR, Mazzucato M, De Marco L, Ruggeri ZM, Shattil SJ (2004) Signaling through GP Ib-IX-V activates alpha IIb beta 3 independently of other receptors. Blood 103:3403–3411

    Article  CAS  PubMed  Google Scholar 

  31. Wenger RK, Lukasiewicz H, Mikuta BS, Niewiarowski S, Edmunds LH Jr (1989) Loss of platelet fibrinogen receptors during clinical cardiopulmonary bypass. J Thorac Cardiovasc Surg 97(2):235–239

    CAS  PubMed  Google Scholar 

  32. Du X, Saido TC, Tsubuki S, Indig FE, Williams MJ, Ginsberg MH (1995) Calpain cleavage of the cytoplasmic domain of the integrin β3 subunit. J Biol Chem 270:26146–26151

    Article  CAS  PubMed  Google Scholar 

  33. Pfaff M, Du X, Ginsberg MH (1999) Calpain cleavage of integrin βa cytoplasmic domains. FEBS Lett 460:17–22

    Article  CAS  PubMed  Google Scholar 

  34. Zhang T, Taskin ME, Fang HB et al (2011) Study of flow-induced hemolysis using novel Couette-type blood-shearing devices. Artif Organs 35:1180–1186

    Article  PubMed  Google Scholar 

  35. Malek AM, Alper SL, Izumo S (1999) Hemodynamic shear stress and its role in atherosclerosis. JAMA 282(21):2035–2042

    Article  CAS  PubMed  Google Scholar 

  36. Taskin ME, Fraser KH, Zhang T, Wu C, Griffith BP, Wu ZJ (2012) Evaluation of Eulerian and Lagrangian models for hemolysis estimation. ASAIO J 58:363–372

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was partially supported by the National Institutes of Health (Grant numbers: R01 HL 088100, R01 HL124170) and the International Postdoctoral Exchange Fellowship Program (No. 20130028).

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    Authors and Affiliations

    1. Department of Cardiovascular and Thoracic Surgery, Cardiovascular Innovation Institute, University of Louisville School of Medicine, Room 410, 302 E. Muhammad Ali Blvd, Louisville, KY, 40202, USA

      Zengsheng Chen, Nandan K. Mondal, Jun Ding, Steven C. Koenig, Mark S. Slaughter & Zhongjun J. Wu

    2. Department of Engineering Mechanics, School of Aerospace, Tsinghua University, Beijing, 100084, China

      Zengsheng Chen

    3. Department of Mechanical Engineering, University of Maryland Baltimore County, Baltimore, MD, 21250, USA

      Jun Ding

    4. Department of Surgery, School of Medicine, University of Maryland, Baltimore, MD, 21201, USA

      Bartley P. Griffith

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    1. Zengsheng Chen
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    Correspondence to Zhongjun J. Wu.

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    Zengsheng Chen and Nandan K. Mondal have contributed equally to this work.

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    Chen, Z., Mondal, N.K., Ding, J. et al. Activation and shedding of platelet glycoprotein IIb/IIIa under non-physiological shear stress. Mol Cell Biochem 409, 93–101 (2015). https://doi.org/10.1007/s11010-015-2515-y

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