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C.C.F.M.J. Baaten et al.
The impaired platelet responsiveness after myeloabla- tive chemotherapy (median of eight days) was only weak- ly correlated to the whole blood platelet count, thus indi- cating that the extent of thrombocytopenia was not a main factor in the dysfunction. In agreement with this conclusion, in patients with a recovering platelet count after transplantation, the functionality of the platelets was enhanced. Detailed analysis indicated that neither disease type nor chemotherapy regimen could explain the inter- patient variation in platelet responsiveness. This points to other factors determining the severity of dysfunction, such as a different sensitivity of megakaryocytes in the bone marrow to the previous chemotherapy treatment.
As the sensitivity of megakaryocytic precursor cells to chemotherapeutics is known to vary,31 the extent of platelet dysfunction might be a combined result of the sensitivity of the precise drugs administered and their dosage.
The dysfunction of platelets identified in this patient group differs markedly from the so-called ‘exhausted’ platelets, which have been described for patients with solid tumors.32 Exhausted platelets were characterized by a high integrin activation and P-selectin expression in the absence of stimulating agents, and a reduced increase in the parameters after agonist stimulation. These changes might point to platelet activation in vivo, resulting in a sec-
A
B
C
P=0.054
P=0.071
Figure 5. Impaired mitochondrial bioenergetics in patient platelets. A) Initial screening of TMRE staining of washed platelets from patients. To assess the mitochondrial membrane potential, platelets were stained with TMRE and subsequently analyzed by flow cytometry. Shown are mean fluorescence intensities of TMRE ((n=39: treatment classes: A+B: n=10; A+B+C: n=5; B+C: n=7; C: n=13) and healthy controls (n=27)). B) High resolution respirometry to measure mitochondrial respiration in washed platelets from additionally included patients (n=7) and controls (n=9). Depicted is oxygen consumption due to sequential addition of saturating amounts of pyruvate (P), malate (M), ADP, glutamate (G), suc- cinate (S) and cytochrome C (Cyto C). C) Citrate synthase activity in washed platelets from patients (n=6) and controls (n=7) to assess mito- chondrial content. Medians with IQR, *P<0.05, ***P<0.001. Overall platelet responsiveness of the patients was 28.7– 46.9% (IQR). ADP: adenosine diphosphate.
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haematologica | 2018; 103(9)