Baaten 2018 Haematologica
|Baaten CCFMJ, Moenen FCJI, Henskens YMC, Swieringa F, Wetzels RJH, van Oerle R, Heijnen HFG, Ten Cate H, Holloway GP, Beckers EAM, Heemskerk JWM, van der Meijden PEJ (2018) Impaired mitochondrial activity explains platelet dysfunction in thrombocytopenic cancer patients undergoing chemotherapy. Haematologica [Epub ahead of print].|
» PMID: 29880611 »
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. In 77 patients with acute leukemia, multiple myeloma or malignant lymphoma, who experienced chemotherapy-induced thrombocytopenia, we studied platelet function. Platelets from all patients - independent of disease or treatment type - were to a variable extent compromised in Ca2+ flux, integrin αIIbβ3 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 (PS) exposure, which was not due to apoptotic caspase activity. 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 consumption (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 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 mitochondrial bioenergetics, independent of apoptosis, in platelets from cancer patients treated with chemotherapy, explaining the low hemostatic potential of these patients.
Labels: MiParea: Respiration, mt-Membrane, Patients Pathology: Cancer
Organism: Human Tissue;cell: Blood cells, Platelet Preparation: Intact cells
Coupling state: OXPHOS Pathway: N, NS HRR: Oxygraph-2k