Impaired mitochondrial activity explains platelet dysfunction in thrombocytopenic cancer patients undergoing chemotherapy

Constance C. F. M. J. Baaten, Floor C. J. I. Moenen, Yvonne M. C. Henskens, Frauke Swieringa, Rick J. H. Wetzels, Rene van Oerle, Harry F. G. Heijnen, Hugo ten Cate, Graham P. Holloway, Erik A. M. Beckers, Johan W. M. Heemskerk, Paola E. J. van der Meijden*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Severe thrombocytopenia (<= 50x10(9) 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 independent of disease or treatment type - were to a variable extent compromised in Ca2+ flux, integrin alpha(IIb)beta(3) activation and P-selectin expression 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 phosphatidylserine exposure, which was not due to apoptotic caspase activity Interestingly, mitochondria' function was markedly reduced in platelets from a representative subset of patients, as evidenced by a low mitochondria' membrane potential (P<0.001) and low oxygen consumption (P<0.05), while the mitochondria' content was normal. Moreover, the mitochondria' impairments coincided with elevated levels of reactive oxygen species (Spearman's rho=-0.459, P=0.012). Markedly, the impairment 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 mitochondria' bioenergetics, independent of apoptosis, in platelets from cancer patients treated with chemotherapy, explaining the low hemostatic potential of these patients.
Original languageEnglish
Pages (from-to)1557-1567
Number of pages11
JournalHaematologica-the Hematology Journal
Volume103
Issue number9
DOIs
Publication statusPublished - 31 Aug 2018

Keywords

  • ACUTE MYELOID-LEUKEMIA
  • SKELETAL-MUSCLE
  • IN-VIVO
  • ACTIVATION
  • METABOLISM
  • DEFECT
  • CYCLOPHOSPHAMIDE
  • TRANSFUSION
  • DOXORUBICIN
  • HEMOSTASIS

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