Red Blood Cell Mechanical Fragility as a Potential Predictor of Long-Term Hemolysis from Ventricular Assist Devices

Main Article Content

M. Tarasev S. Chakraborty K. Alfano F.D. Pagani


Introduction: Recent improvement in design and performance of Left Ventricular Assist Devices facilitate their use for destination therapy. The shear stresses in such devices can damage patients’ red blood cells (RBC), leading to increased hemolysis, which has been associated with pump thrombosis and patient mortality. Here we report an investigation assessing RBC mechanical fragility as a potential metric of blood damage and its potential utility in monitoring LVAD performance.

Methods: Twenty subjects were recruited from the Center for Circulatory Support at the University of Michigan. Thirteen were implanted with the HeartWare HVAD (Medtronic, Inc.) and 7 with HeartMate 3® LVAD (HM3; Abbott Labs). Blood samples were obtained before surgery and at 1 hour, 24 hours, 1 week and 4 weeks after. Hemolysis biomarkers, total lactate dehydrogenase (LDH) and LDH isoenzymes, bilirubin, haptoglobin, and serum hemoglobin were determined through standard clinical tests. Mechanical fragility, as a metric of sub-hemolytic RBC damage, was determined using electromagnetically driven bead milling in a tube with a cylindrical bead, combined with non-invasive spectrophotometric analysis of induced hemolysis upon selected durations of the stress application. Certain variations of the stressing regime were employed for comparison.

Results: RBC mechanical fragility, as assessed through some of the stress application regimes, was correlated with certain hemolysis metrics like bilirubin, LDH, and LDH1. Specifically, a subset of pre-surgery RBC mechanical fragility markers were strongly correlated with bilirubin levels measured 1 day, 1 week, and 1 month (though not immediately) after the surgery. While such correlation with unconjugated bilirubin declined in significance over time, the correlation to conjugated bilirubin reached significance at 1 month. Mechanical fragility values determined in albumin-supplemented medium at 1-day post-surgery, showed strong correlation to total LDH and LDH1 at 1-month post-surgery (p < 0.01, R2 up to 0.45), with the correlation with LDH1 stronger than with total LDH.

Conclusions: These data demonstrate the potential for some RBC mechanical fragility metrics as predictive prognostic biomarkers for hemolysis induced by implantable circulatory support systems. With appropriate tailoring of testing parameters to best suit the application, mechanical fragility assays could help facilitate the transition to greater utilization of ventricular assist devices.

Article Details

How to Cite
TARASEV, M. et al. Red Blood Cell Mechanical Fragility as a Potential Predictor of Long-Term Hemolysis from Ventricular Assist Devices. Medical Research Archives, [S.l.], v. 10, n. 10, oct. 2022. ISSN 2375-1924. Available at: <>. Date accessed: 06 dec. 2022. doi:
Research Articles


1. Virani SS, Alonso A, Benjamin EJ, et al. Heart Disease and Stroke Statistics—2020 Update: A Report From the American Heart Association. Circulation. 2020;141(9):e139-e596. doi:doi:10.1161/CIR.0000000000000757
2. Taylor DO, Edwards LB, Mohacsi PJ, et al. The registry of the International Society for Heart and Lung Transplantation: twentieth official adult heart transplant report--2003. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. Jun 2003;22(6):616-24. doi:10.1016/s1053-2498(03)00186-4
3. Ammirati E, Oliva F, Cannata A, et al. Current indications for heart transplantation and left ventricular assist device: a practical point of view. European journal of internal medicine. Jun 2014;25(5):422-9. doi:10.1016/j.ejim.2014.02.006
4. Frazier OH, Rose EA, Oz MC, et al. Multicenter clinical evaluation of the HeartMate vented electric left ventricular assist system in patients awaiting heart transplantation. The Journal of thoracic and cardiovascular surgery. 2001/12/01/ 2001;122(6):1186-1195. doi:
5. Shah P, Yuzefpolskaya M, Hickey GW, et al. Twelfth Interagency Registry for Mechanically Assisted Circulatory Support Report: Readmissions After Left Ventricular Assist Device. The Annals of thoracic surgery. 2022/03/01/ 2022;113(3):722-737. doi:
6. Molina EJ, Shah P, Kiernan MS, et al. The Society of Thoracic Surgeons Intermacs 2020 Annual Report. The Annals of thoracic surgery. Mar 2021;111(3):778-792. doi:10.1016/j.athoracsur.2020.12.038
7. Kameneva MV, Burgreen GW, Kono K, Repko B, Antaki JF, Umezu M. Effects of turbulent stresses upon mechanical hemolysis: experimental and computational analysis. ASAIO journal (American Society for Artificial Internal Organs : 1992). Sep-Oct 2004;50(5):418-23. doi:10.1097/01.mat.0000136512.36370.b5
8. Ravichandran AK, Parker J, Novak E, et al. Hemolysis in left ventricular assist device: A retrospective analysis of outcomes. The Journal of Heart and Lung Transplantation. 2014;33(1):44-50. doi:10.1016/j.healun.2013.08.019
9. de Nattes T, Litzler PY, Gay A, Nafeh-Bizet C, François A, Guerrot D. Hemolysis induced by Left Ventricular Assist Device is associated with proximal tubulopathy. PloS one. 2020;15(11):e0242931. doi:10.1371/journal.pone.0242931
10. Shah P, Mehta VM, Cowger JA, Aaronson KD, Pagani FD. Diagnosis of hemolysis and device thrombosis with lactate dehydrogenase during left ventricular assist device support. The Journal of Heart and Lung Transplantation. 2014/01/01/ 2014;33(1):102-104. doi:
11. Cowger JA, Romano MA, Shah P, et al. Hemolysis: A harbinger of adverse outcome after left ventricular assist device implant. The Journal of Heart and Lung Transplantation. 2014/01/01/ 2014;33(1):35-43. doi:
12. Ravichandran A, Parker J, Joseph S, et al. Hemolysis Is Strongly Associated with Mortality in LVAD Patients. The Journal of Heart and Lung Transplantation. 2013/04/01/ 2013;32(4, Supplement):S56. doi:
13. Minneci PC, Deans KJ, Zhi H, et al. Hemolysis-associated endothelial dysfunction mediated by accelerated NO inactivation by decompartmentalized oxyhemoglobin. The Journal of clinical investigation. Dec 2005;115(12):3409-17. doi:10.1172/jci25040
14. Rother RP, Bell L, Hillmen P, Gladwin MT. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. Jama. Apr 6 2005;293(13):1653-62. doi:10.1001/jama.293.13.1653
15. Seiyama A, Suzuki Y, Maeda N. Increased viscosity of erythrocyte suspension upon hemolysis. Colloid and Polymer Science. 1993/01/01 1993;271(1):63-69. doi:10.1007/BF00652304
16. Vercaemst L. Hemolysis in cardiac surgery patients undergoing cardiopulmonary bypass: a review in search of a treatment algorithm. The journal of extra-corporeal technology. Dec 2008;40(4):257-67.
17. Brinsfield DE, Hopf MA, Geering RB, Galletti PM. Hematological changes in long-term perfusion. Journal of applied physiology. May 1962;17:531-4. doi:10.1152/jappl.1962.17.3.531
18. Baskurt OK, Meiselman HJ. Analyzing shear stress-elongation index curves: comparison of two approaches to simplify data presentation. Clinical hemorheology and microcirculation. 2004;31(1):23-30.
19. Vrtovec B, Radovancevic R, Delgado RM, et al. Significance of anaemia in patients with advanced heart failure receiving long-term mechanical circulatory support. European journal of heart failure. 2009;11(10):1000-1004. doi:
20. Pierce CN, Larson DF, Arabia FA, Copeland JG. Inflammatory mediated chronic anemia in patients supported with a mechanical circulatory assist device. The journal of extra-corporeal technology. Mar 2004;36(1):10-5.
21. Pierce CN, Larson DF. Inflammatory cytokine inhibition of erythropoiesis in patients implanted with a mechanical circulatory assist device. Perfusion. Mar 2005;20(2):83-90. doi:10.1191/0267659105pf793oa
22. Wiegmann L, Boës S, de Zélicourt D, et al. Blood Pump Design Variations and Their Influence on Hydraulic Performance and Indicators of Hemocompatibility. Annals of biomedical engineering. 2018/03/01 2018;46(3):417-428. doi:10.1007/s10439-017-1951-0
23. Liu GM, Jin DH, Zhou JY, et al. Numerical Investigation of the Influence of Blade Radial Gap Flow on Axial Blood Pump Performance. ASAIO journal (American Society for Artificial Internal Organs : 1992). Jan 2019;65(1):59-69. doi:10.1097/mat.0000000000000745
24. Chen Z, Jena SK, Giridharan GA, et al. Flow features and device-induced blood trauma in CF-VADs under a pulsatile blood flow condition: A CFD comparative study. International journal for numerical methods in biomedical engineering. Feb 2018;34(2)doi:10.1002/cnm.2924
25. Cheng A, Williamitis CA, Slaughter MS. Comparison of continuous-flow and pulsatile-flow left ventricular assist devices: is there an advantage to pulsatility? Ann Cardiothorac Surg. Nov 2014;3(6):573-81. doi:10.3978/j.issn.2225-319X.2014.08.24
26. Wiegmann L, Thamsen B, de Zélicourt D, et al. Fluid Dynamics in the HeartMate 3: Influence of the Artificial Pulse Feature and Residual Cardiac Pulsation. Artificial organs. Apr 2019;43(4):363-376. doi:10.1111/aor.13346
27. Boraschi A, Bozzi S, Thamsen B, et al. Thrombotic Risk of Rotor Speed Modulation Regimes of Contemporary Centrifugal Continuous-flow Left Ventricular Assist Devices. ASAIO journal (American Society for Artificial Internal Organs : 1992). Jul 1 2021;67(7):737-745. doi:10.1097/mat.0000000000001297
28. Olia SE, Maul TM, Antaki JF, Kameneva MV. Mechanical blood trauma in assisted circulation: sublethal RBC damage preceding hemolysis. The International journal of artificial organs. Jun 15 2016;39(4):150-9. doi:10.5301/ijao.5000478
29. Baskurt OK, Meiselman HJ. Red blood cell mechanical stability test. Clinical hemorheology and microcirculation. 2013;55(1):55-62. doi:10.3233/ch-131689
30. Raval JS, Waters JH, Seltsam A, et al. The use of the mechanical fragility test in evaluating sublethal RBC injury during storage. Vox sanguinis. Nov 2010;99(4):325-31. doi:10.1111/j.1423-0410.2010.01365.x
31. Gu L, Smith WA, Chatzimavroudis GP. Mechanical fragility calibration of red blood cells. ASAIO journal (American Society for Artificial Internal Organs : 1992). May-Jun 2005;51(3):194-201. doi:10.1097/01.mat.0000161940.30190.6d
32. Sutera SP. Flow-induced trauma to blood cells. Circulation research. Jul 1977;41(1):2-8. doi:10.1161/01.res.41.1.2
33. Yen JH, Chen SF, Chern MK, Lu PC. The effect of turbulent viscous shear stress on red blood cell hemolysis. Journal of artificial organs : the official journal of the Japanese Society for Artificial Organs. Jun 2014;17(2):178-85. doi:10.1007/s10047-014-0755-3
34. Tarasev M, Chakraborty S, Light L, Davenport R. Impact of environment on Red Blood Cell ability to withstand mechanical stress. Clinical hemorheology and microcirculation. Nov 4 2016;64(1):21-33. doi:10.3233/ch-152037
35. Tarasev M, Chakraborty S, Light L, Alfano K, Pagani FD. Red blood cell mechanical fragility as potential metric for assessing blood damage caused by implantable durable ventricular assist devices: Comparison of two types of centrifugal flow left ventricular assist devices. Progress in Pediatric Cardiology. 2020/03/01/ 2020;56:101198. doi:
36. Nadler SB, Hidalgo JH, Bloch T. Prediction of blood volume in normal human adults. Surgery. Feb 1962;51(2):224-32.
37. Alfano KM, Chakraborty S, Tarasev M. Differences in bead-milling-induced hemolysis of red blood cells due to shape and size of oscillating bead. Bio-medical materials and engineering. Sep 28 2016;27(4):405-412. doi:10.3233/bme-161594
38. Alfano KM, Tarasev M, Meines S, Parunak G. An approach to measuring RBC haemolysis and profiling RBC mechanical fragility. Journal of medical engineering & technology. 2016;40(4):162-71. doi:10.3109/03091902.2016.1153741
39. Tarasev M, Muchnik M, Chakraborti S. Impact of the Oscillating Bead Size and Shape on Induced Mechanical Stress on Red Blood Cells and Associated Hemolysis in Bead Milling. International journal of blood research and disorders. 2019;6(1):14. doi:10.23937/2469-5696/1410041
40. Sowemimo-Coker SO. Red blood cell hemolysis during processing. Transfusion medicine reviews. Jan 2002;16(1):46-60. doi:10.1053/tmrv.2002.29404
41. Kanias T, Lanteri MC, Page GP, et al. Ethnicity, sex, and age are determinants of red blood cell storage and stress hemolysis: results of the REDS-III RBC-Omics study. Blood advances. Jun 27 2017;1(15):1132-1141. doi:10.1182/bloodadvances.2017004820
42. Dumont LJ, AuBuchon JP. Evaluation of proposed FDA criteria for the evaluation of radiolabeled red cell recovery trials. Transfusion. Jun 2008;48(6):1053-60. doi:10.1111/j.1537-2995.2008.01642.x
43. Van 't Erve TJ, Wagner BA, Martin SM, et al. The heritability of hemolysis in stored human red blood cells. Transfusion. Jun 2015;55(6):1178-85. doi:10.1111/trf.12992
44. Tuzun E, Roberts K, Cohn WE, et al. In vivo evaluation of the HeartWare centrifugal ventricular assist device. Texas Heart Institute journal. 2007;34(4):406-11.
45. Larose JA, Tamez D, Ashenuga M, Reyes C. Design concepts and principle of operation of the HeartWare ventricular assist system. ASAIO journal (American Society for Artificial Internal Organs : 1992). Jul-Aug 2010;56(4):285-9. doi:10.1097/MAT.0b013e3181dfbab5
46. Bourque K, Cotter C, Dague C, et al. Design Rationale and Preclinical Evaluation of the HeartMate 3 Left Ventricular Assist System for Hemocompatibility. ASAIO journal (American Society for Artificial Internal Organs : 1992). Jul-Aug 2016;62(4):375-83. doi:10.1097/mat.0000000000000388
47. Netuka I, Sood P, Pya Y, et al. Fully Magnetically Levitated Left Ventricular Assist System for Treating Advanced HF: A Multicenter Study. Journal of the American College of Cardiology. Dec 15 2015;66(23):2579-2589. doi:10.1016/j.jacc.2015.09.083
48. Uriel N, Colombo PC, Cleveland JC, et al. Hemocompatibility-Related Outcomes in the MOMENTUM 3 Trial at 6 Months. Circulation. 2017;135(21):2003-2012. doi:doi:10.1161/CIRCULATIONAHA.117.028303
49. Kuck L, Simmonds MJ, Chan CHH, et al. Ex vivo assessment of erythrocyte tolerance to the HeartWare ventricular assist device operated in three discrete configurations. Artificial organs. Nov 24 2020;doi:10.1111/aor.13877
50. Radley G, Pieper IL, Robinson CR, et al. In Vitro Benchmarking Study of Ventricular Assist Devices in Current Clinical Use. Journal of cardiac failure. Jan 2020;26(1):70-79. doi:10.1016/j.cardfail.2019.09.013
51. Grinstein J, Torii R, Bourantas CV, Garcia-Garcia HM. Left Ventricular Assist Device Flow Pattern Analysis Using a Novel Model Incorporating Left Ventricular Pulsatility. ASAIO journal (American Society for Artificial Internal Organs : 1992). Jul 1 2021;67(7):724-732. doi:10.1097/mat.0000000000001341
52. Fraser KH, Zhang T, Taskin ME, Griffith BP, Wu ZJ. A quantitative comparison of mechanical blood damage parameters in rotary ventricular assist devices: shear stress, exposure time and hemolysis index. Journal of biomechanical engineering. Aug 2012;134(8):081002. doi:10.1115/1.4007092
53. Butt N, Grinstein J, Najjar SS, Sheikh FH. A Hemolytic Event in a Heartmate 3 Patient in the Setting of Polycythemia. The Journal of Heart and Lung Transplantation. 2021/04/01/ 2021;40(4, Supplement):S525-S526. doi:
54. Raskin A, Villa C, Morales DL, Lorts A. Hemolysis with a Ventricular Assist Device; Sometimes It is Not the Pump's Fault. The Journal of Heart and Lung Transplantation. 2022;41(4):S474-S475. doi:10.1016/j.healun.2022.01.1198
55. Madden JL, Drakos SG, Stehlik J, et al. Does Red Blood Cell Fragility Predict the Degree of Post-LVAD Hemolysis? The Journal of Heart and Lung Transplantation. 2013;32(4):S273. doi:10.1016/j.healun.2013.01.717
56. Potapov EV, Kaufmann F, Müller M, Mulzer J, Falk V. Longest Ongoing Support (13 Years) with Magnetically Levitated Left Ventricular Assist Device. ASAIO journal (American Society for Artificial Internal Organs : 1992). Sep/Oct 2020;66(9):e121-e122. doi:10.1097/mat.0000000000001131
57. Zimpfer D, Fiane AE, Larbalestier R, et al. Long-Term Survival of Patients With Advanced Heart Failure Receiving an Left Ventricular Assist Device Intended as a Bridge to Transplantation. Circulation: Heart Failure. 2020;13(3):e006252. doi:doi:10.1161/CIRCHEARTFAILURE.119.006252
58. Kormos RL, Antonides CFJ, Goldstein DJ, et al. Updated definitions of adverse events for trials and registries of mechanical circulatory support: A consensus statement of the mechanical circulatory support academic research consortium. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. Aug 2020;39(8):735-750. doi:10.1016/j.healun.2020.03.010
59. Papanastasiou CA, Kyriakoulis KG, Theochari CA, Kokkinidis DG, Karamitsos TD, Palaiodimos L. Comprehensive review of hemolysis in ventricular assist devices. World journal of cardiology. Jul 26 2020;12(7):334-341. doi:10.4330/wjc.v12.i7.334
60. Gladwin MT, Kim-Shapiro DB. Storage lesion in banked blood due to hemolysis-dependent disruption of nitric oxide homeostasis. Current opinion in hematology. Nov 2009;16(6):515-23. doi:10.1097/MOH.0b013e32833157f4
61. INTERMACS Adverse Event Definitions: Adult and Pediatric patients. Appendix A: INTERMACS Executive Committee; 2013. p. 1-13.