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Platelet Biology & its Disorders
Impaired mitochondrial activity explains platelet dysfunction in thrombocytopenic cancer patients undergoing chemotherapy
Constance C. F. M. J. Baaten,1 Floor C. J. I. Moenen,2* Yvonne M. C. Henskens,3* Frauke Swieringa,1,4 Rick J. H. Wetzels,3 René van Oerle,3,5 Harry F. G. Heijnen,6 Hugo ten Cate,1,5 Graham P. Holloway,7 Erik A. M. Beckers,2
Johan W. M. Heemskerk1 and Paola E. J. van der Meijden1
1Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, the Netherlands; 2Department of Hematology, Maastricht University Medical Centre, the Netherlands; 3Central Diagnostic Laboratory, Maastricht University Medical Centre, the Netherlands; 4Department of Protein Dynamics, Leibniz Institute for Analytical Sciences - ISAS-e.V., Dortmund, Germany; 5Laboratory for Clinical Thrombosis and Hemostasis, Department of Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, the Netherlands; 6Department of Cell Biology and Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, the Netherlands and 7Department of Human Health and Nutritional Sciences, University of Guelph, Ontario, Canada
ABSTRACT
Severe thrombocytopenia (≤50x109 platelets/L) due to hematological
malignancy and intensive chemotherapy is associated with an
increased risk of clinically significant bleeding. Since the bleeding
risk is not linked to the platelet count only, other hemostatic factors must
be involved. We studied platelet function in 77 patients with acute
leukemia, multiple myeloma or malignant lymphoma, who experienced
chemotherapy-induced thrombocytopenia. Platelets from all patients -
Ferrata Storti Foundation
Haematologica 2018 Volume 103(9):1557-1567
*FCJIM and YMCH contributed equally to this work.
independent of disease or treatment type - were to a variable extent
compromised in Ca2+ flux, integrin a β activation and P-selectin expres- IIb 3
sion when stimulated with a panel of agonists. The patients' platelets were also impaired in spreading on fibrinogen. Whereas the Ca2+ store content was unaffected, the patients’ platelets showed ongoing phos- phatidylserine exposure, which was not due to apoptotic caspase activ- ity. Interestingly, mitochondrial function was markedly reduced in platelets from a representative subset of patients, as evidenced by a low mitochondrial membrane potential (P<0.001) and low oxygen consump- tion (P<0.05), while the mitochondrial content was normal. Moreover, the mitochondrial impairments coincided with elevated levels of reactive oxygen species (Spearman’s rho=-0.459, P=0.012). Markedly, the impair- ment of platelet function only appeared after two days of chemotherapy, suggesting origination in the megakaryocytes. In patients with bone marrow recovery, platelet function improved. In conclusion, our findings disclose defective receptor signaling related to impaired mitochondrial bioenergetics, independent of apoptosis, in platelets from cancer patients treated with chemotherapy, explaining the low hemostatic potential of these patients.
Introduction
Platelets are indispensable for maintaining vascular integrity and accomplishing hemostatic plug formation.1 A sufficient platelet count as well as an adequate platelet function is required for prevention of bleeding. Patients with hematological malignancies, such as leukemia, multiple myeloma or malignant lymphoma, are commonly treated with combination chemotherapy, frequently followed by bone marrow transplantation. This treatment impairs the proliferation of megakary- ocytes and the production of proplatelets. As a consequence, severe thrombocy-
Correspondence:
p.vandermeijden@maastrichtuniversity.nl
Received: November 22, 2017. Accepted: June 5, 2018. Pre-published: June 7, 2018.
doi:10.3324/haematol.2017.185165
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/9/1557
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