Journal of Thrombosis and Thrombolysis

, Volume 37, Issue 4, pp 499–506 | Cite as

Comparative efficacy of in vitro and in vivo metabolized aspirin in the DeBakey ventricular assist device

  • Jawaad Sheriff
  • Gaurav Girdhar
  • Wei-Che Chiu
  • Jolyon Jesty
  • Marvin J. Slepian
  • Danny Bluestein


Ventricular assist devices (VADs) are implanted in patients with end-stage heart failure to provide both short- and long-term hemodynamic support. Unfortunately, bleeding and thromboembolic complications due to the severely disturbed, dynamic flow conditions generated within these devices require complex, long-term antiplatelet and anticoagulant therapy. While several studies have examined the effectiveness of one such agent, aspirin, under flow conditions, data comparing the efficacy of in vitro and in vivo metabolized aspirin is lacking. Two sets of studies were conducted in vitro with purified human platelets circulating for 30 min in a flow loop containing the DeBakey VAD (MicroMed Cardiovascular, Houston, TX, USA): (a) 20 μM aspirin was added exogenously in vitro to platelets isolated from aspirin-free subjects, and (b) platelets were obtained from donors 2 h (n = 14) and 20 h (n = 13) after ingestion of 1,000 mg aspirin. Near real-time platelet activation state (PAS) was measured with a modified prothrombinase-based assay. Platelets exposed to aspirin in vitro and in vivo (metabolized) showed 28.2 and 25.3 % reduction in platelet activation rate, respectively, compared to untreated controls. Our results demonstrate that in vitro treatment with antiplatelet drugs such as aspirin is as effective as in vivo metabolized aspirin in testing the effect of reducing shear-induced platelet activation in the VAD. Using the PAS assay provides a practical in vitro alternative to in vivo testing of antiplatelet efficacy, as well as for testing the thrombogenic performance of devices during their research and development.


Aspirin Ventricular assist devices Platelets Thrombin 



The authors thank Dr. Sheela George for her assistance with experiments and the Stony Brook University Medical Center Chemistry Lab for salicylate measurements. This work was supported by the National Institute of Biomedical Imaging and Bioengineering Quantum Grant (Award No. 5U01EB012487-00, Dr. Bluestein).


Drs. Bluestein and Slepian were members of the Scientific Advisory Board of MicroMed Cardiovascular, Inc at the time of conduct of this investigation. The other authors report no conflicts of interest.


  1. 1.
    Christiansen S, Klocke A, Autschbach R (2008) Past, present, and future of long-term mechanical cardiac support in adults. J Card Surg 23(6):664–676. doi:10.1111/j.1540-8191.2008.00696.x PubMedGoogle Scholar
  2. 2.
    Bellumkonda L, Bonde P (2012) Ventricular assist device therapy for heart failure–past, present, and future. Int Anesthesiol Clin 50(3):123–145. doi:10.1097/AIA.0b013e31826233a9 PubMedCrossRefGoogle Scholar
  3. 3.
    Eckman PM, John R (2012) Bleeding and thrombosis in patients with continuous-flow ventricular assist devices. Circulation 125(24):3038–3047. doi:10.1161/CIRCULATIONAHA.111.040246 PubMedCrossRefGoogle Scholar
  4. 4.
    Ensor CR, Paciullo CA, Cahoon WD Jr, Nolan PE Jr (2011) Pharmacotherapy for mechanical circulatory support: a comprehensive review. Ann Pharmacother 45(1):60–77. doi:10.1345/aph.1P459 PubMedCrossRefGoogle Scholar
  5. 5.
    Harrison P, Frelinger AL 3rd, Furman MI, Michelson AD (2007) Measuring antiplatelet drug effects in the laboratory. Thromb Res 120(3):323–336. doi:10.1016/j.thromres.2006.11.012 PubMedCrossRefGoogle Scholar
  6. 6.
    Braunwald E, Angiolillo D, Bates E, Berger PB, Bhatt D, Cannon CP, Furman MI, Gurbel P, Michelson AD, Peterson E, Wiviott S (2008) Assessing the current role of platelet function testing. Clin Cardiol 31(3 Suppl 1):I10–I16. doi:10.1002/clc.20361 PubMedCrossRefGoogle Scholar
  7. 7.
    Wever-Pinzon O, Stehlik J, Kfoury AG, Terrovitis JV, Diakos NA, Charitos C, Li DY, Drakos SG (2012) Ventricular assist devices: pharmacological aspects of a mechanical therapy. Pharmacol Ther 134(2):189–199. doi:10.1016/j.pharmthera.2012.01.003 PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Majeed F, Kop WJ, Poston RS, Kallam S, Mehra MR (2009) Prospective, observational study of antiplatelet and coagulation biomarkers as predictors of thromboembolic events after implantation of ventricular assist devices. Nat Clin Pract Cardiovasc Med 6(2):147–157. doi:10.1038/ncpcardio1441 PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Slaughter MS, Sobieski MA 2nd, Graham JD, Pappas PS, Tatooles AJ, Koenig SC (2011) Platelet activation in heart failure patients supported by the HeartMate II ventricular assist device. Int J Artif Organs 34(6):461–468. doi:10.5301/IJAO.2011.8459 PubMedCrossRefGoogle Scholar
  10. 10.
    Kundu SK, Heilmann EJ, Sio R, Garcia C, Davidson RM, Ostgaard RA (1995) Description of an in vitro platelet function analyzer–PFA-100. Semin Thromb Hemost 21(Suppl 2):106–112PubMedGoogle Scholar
  11. 11.
    Mammen EF, Comp PC, Gosselin R, Greenberg C, Hoots WK, Kessler CM, Larkin EC, Liles D, Nugent DJ (1998) PFA-100 system: a new method for assessment of platelet dysfunction. Semin Thromb Hemost 24(2):195–202. doi:10.1055/s-2007-995840 PubMedCrossRefGoogle Scholar
  12. 12.
    Varon D, Dardik R, Shenkman B, Kotev-Emeth S, Farzame N, Tamarin I, Savion N (1997) A new method for quantitative analysis of whole blood platelet interaction with extracellular matrix under flow conditions. Thromb Res 85(4):283–294PubMedCrossRefGoogle Scholar
  13. 13.
    Varon D, Lashevski I, Brenner B, Beyar R, Lanir N, Tamarin I, Savion N (1998) Cone and plate(let) analyzer: monitoring glycoprotein IIb/IIIa antagonists and von Willebrand disease replacement therapy by testing platelet deposition under flow conditions. Am Heart J 135(5 Pt 2 Su):S187–S193PubMedCrossRefGoogle Scholar
  14. 14.
    Alstrom U, Granath F, Oldgren J, Stahle E, Tyden H, Siegbahn A (2009) Platelet inhibition assessed with VerifyNow, flow cytometry and PlateletMapping in patients undergoing heart surgery. Thromb Res 124(5):572–577. doi:10.1016/j.thromres.2009.06.024 PubMedCrossRefGoogle Scholar
  15. 15.
    Michelson AD, Frelinger AL 3rd, Furman MI (2006) Current options in platelet function testing. Am J Cardiol 98(10A):4N–10N. doi:10.1016/j.amjcard.2006.09.008 PubMedCrossRefGoogle Scholar
  16. 16.
    Michelson AD (2009) Methods for the measurement of platelet function. Am J Cardiol 103(3 Suppl):20A–26A. doi:10.1016/j.amjcard.2008.11.019 PubMedCrossRefGoogle Scholar
  17. 17.
    Von Ruden SA, Murray MA, Grice JL, Proebstle AK, Kopacek KJ (2012) The pharmacotherapy implications of ventricular assist device in the patient with end-stage heart failure. J Pharm Pract 25(2):232–249. doi:10.1177/0897190011431635 CrossRefGoogle Scholar
  18. 18.
    Rossi M, Serraino GF, Jiritano F, Renzulli A (2012) What is the optimal anticoagulation in patients with a left ventricular assist device? Interact Cardiovasc Thorac Surg. doi:10.1093/icvts/ivs297 Google Scholar
  19. 19.
    Antithrombotic Trialists’ Collaboration (2002) Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 324(7329):71–86CrossRefGoogle Scholar
  20. 20.
    Armstrong PC, Truss NJ, Ali FY, Dhanji AA, Vojnovic I, Zain ZN, Bishop-Bailey D, Paul-Clark MJ, Tucker AT, Mitchell JA, Warner TD (2008) Aspirin and the in vitro linear relationship between thromboxane A2-mediated platelet aggregation and platelet production of thromboxane A2. J Thromb Haemost 6(11):1933–1943PubMedCrossRefGoogle Scholar
  21. 21.
    Szczeklik A, Krzanowski M, Gora P, Radwan J (1992) Antiplatelet drugs and generation of thrombin in clotting blood. Blood 80(8):2006–2011PubMedGoogle Scholar
  22. 22.
    Massel D, Little SH (2001) Risks and benefits of adding anti-platelet therapy to warfarin among patients with prosthetic heart valves: a meta-analysis. J Am Coll Cardiol 37(2):569–578PubMedCrossRefGoogle Scholar
  23. 23.
    Houel R, Mazoyer E, Boval B, Kirsch M, Vermes E, Drouet L, Loisance DY (2004) Platelet activation and aggregation profile in prolonged external ventricular support. J Thorac Cardiovasc Surg 128(2):197–202. doi:10.1016/j.jtcvs.2003.11.059 PubMedCrossRefGoogle Scholar
  24. 24.
    Boyle AJ, Russell SD, Teuteberg JJ, Slaughter MS, Moazami N, Pagani FD, Frazier OH, Heatley G, Farrar DJ, John R (2009) Low thromboembolism and pump thrombosis with the HeartMate II left ventricular assist device: analysis of outpatient anti-coagulation. J Heart Lung Transplant 28(9):881–887. doi:10.1016/j.healun.2009.05.018 PubMedCrossRefGoogle Scholar
  25. 25.
    Miller LW, Pagani FD, Russell SD, John R, Boyle AJ, Aaronson KD, Conte JV, Naka Y, Mancini D, Delgado RM, MacGillivray TE, Farrar DJ, Frazier OH (2007) Use of a continuous-flow device in patients awaiting heart transplantation. N Engl J Med 357(9):885–896. doi:10.1056/NEJMoa067758 PubMedCrossRefGoogle Scholar
  26. 26.
    Goldstein DJ (2003) Worldwide experience with the MicroMed DeBakey Ventricular Assist Device as a bridge to transplantation. Circulation 108(Suppl 1):II272–II277. doi:10.1161/01.cir.0000087387.02218.7e PubMedGoogle Scholar
  27. 27.
    Goldstein DJ, Zucker M, Arroyo L, Baran D, McCarthy PM, Loebe M, Noon GP (2005) Safety and feasibility trial of the MicroMed DeBakey ventricular assist device as a bridge to transplantation. J Am Coll Cardiol 45(6):962–963. doi:10.1016/j.jacc.2004.12.020 PubMedCrossRefGoogle Scholar
  28. 28.
    Nakamura T, Uchiyama S, Yamazaki M, Iwata M (2002) Effects of dipyridamole and aspirin on shear-induced platelet aggregation in whole blood and platelet-rich plasma. Cerebrovasc Dis 14(3–4):234–238PubMedCrossRefGoogle Scholar
  29. 29.
    Yamamoto J, Taka T, Nakajima S, Ueda M, Sugimoto E, Sasaki Y, Muraki T, Seki J, Watanabe S (1999) A shear-induced in vitro platelet function test can assess clinically relevant anti-thrombotic effects. Platelets 10(2–3):178–184. doi:10.1080/09537109976266 PubMedCrossRefGoogle Scholar
  30. 30.
    Tschopp M, Reinhart WH (2008) Platelet aggregation under high shear conditions during and after a 28-day administration of 100 mg acetylsalicylic acid in healthy volunteers. Clin Hemorheol Microcirc 38(1):45–50PubMedGoogle Scholar
  31. 31.
    Turner NA, Moake JL, Kamat SG, Schafer AI, Kleiman NS, Jordan R, McIntire LV (1995) Comparative real-time effects on platelet adhesion and aggregation under flowing conditions of in vivo aspirin, heparin, and monoclonal antibody fragment against glycoprotein IIb-IIIa. Circulation 91(5):1354–1362PubMedCrossRefGoogle Scholar
  32. 32.
    Jesty J, Bluestein D (1999) Acetylated prothrombin as a substrate in the measurement of the procoagulant activity of platelets: elimination of the feedback activation of platelets by thrombin. Anal Biochem 272(1):64–70PubMedCrossRefGoogle Scholar
  33. 33.
    Claiborne TE, Girdhar G, Gallocher-Lowe S, Sheriff J, Kato YP, Pinchuk L, Schoephoerster RT, Jesty J, Bluestein D (2011) Thrombogenic potential of Innovia polymer valves versus Carpentier-Edwards Perimount Magna aortic bioprosthetic valves. ASAIO J 57(1):26–31. doi:10.1097/MAT.0b013e3181fcbd86 PubMedCrossRefGoogle Scholar
  34. 34.
    Girdhar G, Xenos M, Alemu Y, Chiu WC, Lynch BE, Jesty J, Einav S, Slepian MJ, Bluestein D (2012) Device thrombogenicity emulation: a novel method for optimizing mechanical circulatory support device thromboresistance. PLoS One 7(3):e32463. doi:10.1371/journal.pone.0032463 PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Slepian MJ, Alemu Y, Soares JS, Smith RG, Einav S, Bluestein D (2013) The Syncardia(™) total artificial heart: in vivo, in vitro, and computational modeling studies. J Biomech 46(2):266–275. doi:10.1016/j.jbiomech.2012.11.032 PubMedCrossRefGoogle Scholar
  36. 36.
    Schulz-Heik K, Ramachandran J, Bluestein D, Jesty J (2005) The extent of platelet activation under shear depends on platelet count: differential expression of anionic phospholipid and factor Va. Pathophysiol Haemost Thromb 34(6):255–262PubMedCrossRefGoogle Scholar
  37. 37.
    Jesty J, Yin W, Perrotta P, Bluestein D (2003) Platelet activation in a circulating flow loop: combined effects of shear stress and exposure time. Platelets 14(3):143–149PubMedCrossRefGoogle Scholar
  38. 38.
    Buerke M, Pittroff W, Meyer J, Darius H (1995) Aspirin therapy: optimized platelet inhibition with different loading and maintenance doses. Am Heart J 130(3 Pt 1):465–472PubMedCrossRefGoogle Scholar
  39. 39.
    Houel R, Mazoyer E, Kirsch M, Boval B, Drouet L, Loisance DY (2003) Resistance to aspirin after external ventricular assist device implantation. J Thorac Cardiovasc Surg 126(5):1636–1637. doi:10.1016/S0022 PubMedCrossRefGoogle Scholar
  40. 40.
    Zimmermann N, Kienzle P, Weber AA, Winter J, Gams E, Schror K, Hohlfeld T (2001) Aspirin resistance after coronary artery bypass grafting. J Thorac Cardiovasc Surg 121(5):982–984. doi:10.1067/mtc.2001.111416 PubMedCrossRefGoogle Scholar
  41. 41.
    Guthikonda S, Lev EI, Patel R, DeLao T, Bergeron AL, Dong JF, Kleiman NS (2007) Reticulated platelets and uninhibited COX-1 and COX-2 decrease the antiplatelet effects of aspirin. J Thromb Haemost 5(3):490–496. doi:10.1111/j.1538-7836.2007.02387.x PubMedCrossRefGoogle Scholar
  42. 42.
    Eikelboom JW, Hirsh J, Weitz JI, Johnston M, Yi Q, Yusuf S (2002) Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation 105(14):1650–1655PubMedCrossRefGoogle Scholar
  43. 43.
    Boeer K, Reinhofer M, Losche W (2010) Validation of a procedure to assess ASA-response in patients with decreased, initial TRAP induced aggregation. Platelets 21(5):314–319. doi:10.3109/09537101003763442 PubMedCrossRefGoogle Scholar
  44. 44.
    Rajah SM, Penny AF, Crow MJ, Pepper MD, Watson DA (1979) The interaction of varying doses of dipyridamole and acetyl salicylic acid on the inhibition of platelet functions and their effect on bleeding time. Br J Clin Pharmacol 8(5):483–489PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Eisert WG (2012) Dipyridamole in antithrombotic treatment. Adv Cardiol 47:78–86. doi:10.1159/000338053 PubMedCrossRefGoogle Scholar
  46. 46.
    Bluestein D, Einav S, Slepian MJ (2013) Device thrombogenicity emulation: a novel methodology for optimizing the thromboresistance of cardiovascular devices. J Biomech 46(2):338–344. doi:10.1016/j.jbiomech.2012.11.033 PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Michelson AD (1996) Flow cytometry: a clinical test of platelet function. Blood 87(12):4925–4936PubMedGoogle Scholar
  48. 48.
    Loffler C, Straub A, Bassler N, Pernice K, Beyersdorf F, Bode C, Siegenthaler MP, Peter K (2009) Evaluation of platelet activation in patients supported by the Jarvik 2000* high-rotational speed impeller ventricular assist device. J Thorac Cardiovasc Surg 137(3):736–741. doi:10.1016/j.jtcvs.2008.09.019 PubMedCrossRefGoogle Scholar
  49. 49.
    Sheriff J, Bluestein D, Girdhar G, Jesty J (2010) High-shear stress sensitizes platelets to subsequent low-shear conditions. Ann Biomed Eng 38(4):1442–1450. doi:10.1007/s10439-010-9936-2 PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Lietz K (2010) Destination therapy: patient selection and current outcomes. J Card Surg 25(4):462–471. doi:10.1111/j.1540-8191.2010.01050.x PubMedCrossRefGoogle Scholar
  51. 51.
    Lietz K, Miller LW (2008) Destination therapy: current results and future promise. Semin Thorac Cardiovasc Surg 20(3):225–233. doi:10.1053/j.semtcvs.2008.08.004 PubMedCrossRefGoogle Scholar
  52. 52.
    Kurien S, Hughes KA (2012) Anticoagulation and bleeding in patients with ventricular assist devices: walking the tightrope. AACN Adv Crit Care 23(1):91–98. doi:10.1097/NCI.0b013e31824124d0 PubMedCrossRefGoogle Scholar
  53. 53.
    Xenos M, Girdhar G, Alemu Y, Jesty J, Slepian M, Einav S, Bluestein D (2010) Device Thrombogenicity Emulator (DTE)—design optimization methodology for cardiovascular devices: a study in two bileaflet MHV designs. J Biomech 43(12):2400–2409. doi:10.1016/j.jbiomech.2010.04.020 PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Jawaad Sheriff
    • 1
  • Gaurav Girdhar
    • 1
  • Wei-Che Chiu
    • 1
  • Jolyon Jesty
    • 1
  • Marvin J. Slepian
    • 1
    • 2
  • Danny Bluestein
    • 1
  1. 1.Department of Biomedical EngineeringStony Brook University, T15-090 Health Sciences CenterStony BrookUSA
  2. 2.Departments of Medicine and Biomedical Engineering, Sarver Heart CenterUniversity of ArizonaTucsonUSA

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