The Glycoprotein (GP)Ib-IX-V Complex on Platelets: GPIbα Protein Expression Is Reduced in HeartMate 3 Patients with Bleeding Complications Within the First 3 Months

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2023 Mar 29

PMID 36982712

Authors

Kristin Klaeske

Anneke Brade

Sandra Eifert

Khalil Jawad

Diyar Saeed

Josephina Haunschild

Franz Sieg

Michael A Borger

Maja-Theresa Dieterlen

Affiliations

Soon will be listed here.

Abstract

Non-surgical bleeding (NSB) remains the most critical complication in patients under left ventricular assist device (LVAD) support. It is well known that blood exposed to high shear stress results in platelet dysfunction. Compared to patients without NSB, decreased surface expression of platelet receptor GPIbα was observed in LVAD patients with NSB. In this study, we aimed to compare the expression level of glycoprotein (GP)Ib-IX-V platelet receptor complex in HeartMate 3 (HM 3) patients with and without bleeding complications to investigate the alterations of the platelet transcriptomic profile on platelet damage and increased bleeding risk. Blood samples were obtained from HM 3 patients with NSB (bleeder group, = 27) and without NSB (non-bleeder group, = 55). The bleeder group was further divided into patients with early NSB (bleeder ≤ 3 mo, = 19) and patients with late NSB (bleeder > 3 mo, = 8). The mRNA and protein expression of GPIbα, GPIX and GPV were quantified for each patient. Non-bleeder, bleeder ≤ 3 mo and bleeder > 3 mo were comparable regarding the mRNA expression of GPIbα, GPIX and GPV ( > 0.05). The protein analysis revealed a significantly reduced expression level of the main receptor subunit GPIbα in bleeders ≤ 3 mo ( = 0.04). We suggest that the observed reduction of platelet receptor GPIbα protein expression in patients who experienced their first bleeding event within 3 months after LVAD implantation may influence platelet physiology. The alterations of functional GPIbα potentially reduce the platelet adhesion capacities, which may lead to an impaired hemostatic process and the elevated propensity of bleeding in HM 3 patients.

References

Gardiner E, Karunakaran D, Shen Y, Arthur J, Andrews R, Berndt M . Controlled shedding of platelet glycoprotein (GP)VI and GPIb-IX-V by ADAM family metalloproteinases. J Thromb Haemost. 2007; 5(7):1530-7. DOI: 10.1111/j.1538-7836.2007.02590.x. View

Chen Z, Mondal N, Ding J, Koenig S, Slaughter M, Griffith B . Activation and shedding of platelet glycoprotein IIb/IIIa under non-physiological shear stress. Mol Cell Biochem. 2015; 409(1-2):93-101. PMC: 4763943. DOI: 10.1007/s11010-015-2515-y. View

Potapov E, Ignatenko S, Nasseri B, Loebe M, Harke C, Bettmann M . Clinical significance of PlA polymorphism of platelet GP IIb/IIIa receptors during long-term VAD support. Ann Thorac Surg. 2004; 77(3):869-74. DOI: 10.1016/j.athoracsur.2003.08.013. View

Klaeske K, Dieterlen M, Eifert S, Scholz U, Garbade J, Jawad K . Device-induced platelet dysfunction in patients after left ventricular assist device implantation. J Thromb Haemost. 2021; 19(5):1331-1341. DOI: 10.1111/jth.15279. View

Hu J, Mondal N, Sorensen E, Cai L, Fang H, Griffith B . Platelet glycoprotein Ibα ectodomain shedding and non-surgical bleeding in heart failure patients supported by continuous-flow left ventricular assist devices. J Heart Lung Transplant. 2013; 33(1):71-9. PMC: 3947169. DOI: 10.1016/j.healun.2013.08.013. View

Roka-Moiia Y, Miller-Gutierrez S, Palomares D, Italiano J, Sheriff J, Bluestein D . Platelet Dysfunction During Mechanical Circulatory Support: Elevated Shear Stress Promotes Downregulation of αβ and GPIb via Microparticle Shedding Decreasing Platelet Aggregability. Arterioscler Thromb Vasc Biol. 2021; 41(4):1319-1336. PMC: 8179715. DOI: 10.1161/ATVBAHA.120.315583. View

Grote Beverborg N, Van Veldhuisen D, van der Meer P . Anemia in Heart Failure: Still Relevant?. JACC Heart Fail. 2017; 6(3):201-208. DOI: 10.1016/j.jchf.2017.08.023. View

Leebeek F, Muslem R . Bleeding in critical care associated with left ventricular assist devices: pathophysiology, symptoms, and management. Hematology Am Soc Hematol Educ Program. 2019; 2019(1):88-96. PMC: 6913502. DOI: 10.1182/hematology.2019000067. View

Mehra M, Goldstein D, Cleveland J, Cowger J, Hall S, Salerno C . Five-Year Outcomes in Patients With Fully Magnetically Levitated vs Axial-Flow Left Ventricular Assist Devices in the MOMENTUM 3 Randomized Trial. JAMA. 2022; 328(12):1233-1242. PMC: 9459909. DOI: 10.1001/jama.2022.16197. View

10.

Bendas G, Schlesinger M . The GPIb-IX complex on platelets: insight into its novel physiological functions affecting immune surveillance, hepatic thrombopoietin generation, platelet clearance and its relevance for cancer development and metastasis. Exp Hematol Oncol. 2022; 11(1):19. PMC: 8976409. DOI: 10.1186/s40164-022-00273-2. View

11.

Sun S, Qiao B, Han Y, Wang B, Wei S, Chen Y . Posttranslational modifications of platelet adhesion receptors. Pharmacol Res. 2022; 183:106413. DOI: 10.1016/j.phrs.2022.106413. View

12.

Hennessy-Strahs S, Kang J, Krause E, Dowling R, Rame J, Bartoli C . Patient-specific severity of von Willebrand factor degradation identifies patients with a left ventricular assist device at high risk for bleeding. J Thorac Cardiovasc Surg. 2022; 167(1):196-204. DOI: 10.1016/j.jtcvs.2022.03.018. View

13.

Mondal N, Li T, Chen Z, Chen H, Sorensen E, Pham S . Mechanistic insight of platelet apoptosis leading to non-surgical bleeding among heart failure patients supported by continuous-flow left ventricular assist devices. Mol Cell Biochem. 2017; 433(1-2):125-137. PMC: 5612884. DOI: 10.1007/s11010-017-3021-1. View

14.

Chen Z, Mondal N, Ding J, Koenig S, Slaughter M, Wu Z . Paradoxical Effect of Nonphysiological Shear Stress on Platelets and von Willebrand Factor. Artif Organs. 2015; 40(7):659-68. PMC: 4871771. DOI: 10.1111/aor.12606. View

15.

Hanke J, Dogan G, Zoch A, Ricklefs M, Wert L, Feldmann C . One-year outcomes with the HeartMate 3 left ventricular assist device. J Thorac Cardiovasc Surg. 2018; 156(2):662-669. DOI: 10.1016/j.jtcvs.2018.01.083. View

16.

Koliopoulou A, McKellar S, Rondina M, Selzman C . Bleeding and thrombosis in chronic ventricular assist device therapy: focus on platelets. Curr Opin Cardiol. 2016; 31(3):299-307. PMC: 4982370. DOI: 10.1097/HCO.0000000000000284. View

17.

Arias K, Sun W, Wang S, Sorensen E, Feller E, Kaczorowski D . Acquired platelet defects are responsible for nonsurgical bleeding in left ventricular assist device recipients. Artif Organs. 2022; 46(11):2244-2256. PMC: 11382350. DOI: 10.1111/aor.14319. View

18.

Bergmeier W, Piffath C, Cheng G, Dole V, Zhang Y, von Andrian U . Tumor necrosis factor-alpha-converting enzyme (ADAM17) mediates GPIbalpha shedding from platelets in vitro and in vivo. Circ Res. 2004; 95(7):677-83. DOI: 10.1161/01.RES.0000143899.73453.11. View

19.

Huizinga E, Tsuji S, Romijn R, Schiphorst M, de Groot P, Sixma J . Structures of glycoprotein Ibalpha and its complex with von Willebrand factor A1 domain. Science. 2002; 297(5584):1176-9. DOI: 10.1126/science.107355. View

20.

Lukito P, Wong A, Jing J, Arthur J, Marasco S, Murphy D . Mechanical circulatory support is associated with loss of platelet receptors glycoprotein Ibα and glycoprotein VI. J Thromb Haemost. 2016; 14(11):2253-2260. DOI: 10.1111/jth.13497. View