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C.C.F.M.J. Baaten et al.
sible strategy to improve mitochondrial function after chemotherapy are the administration of antioxidants to reduce ROS, considering that patients with hematological malignancies have low levels of vitamin C.30,43 Alternatively, treatment with metformin to improve the mitochondrial energy metabolism could be beneficial.30
Due to ethical limitations, we could not assess whether the platelet dysfunction after chemotherapeutic treatment was linked to abnormal (pro)platelet formation from megakaryocytes in the bone marrow. The available litera- ture suggests that the progenitor cells are more vulnerable towards chemotherapy than matured megakaryocytes.31 In patients who received chemotherapy and had not yet developed thrombocytopenia, we observed a normal platelet activity comparable to that before treatment had started. Furthermore, in vitro treatment of whole blood from healthy controls with cytarabine and/or melphalan affected neither platelet reactivity nor mitochondrial func- tion. This agrees with an indirect drug effect via the megakaryocytes or precursor cells, rather than a direct effect on the circulating platelets.
With regard to the coagulant state, the reduced level of factor VII found in combination with high circulating D- dimers in the patients' plasmas is suggestive for a mild ongoing state of tissue factor-triggered coagulation.44 However, the data do not provide evidence for apprecia- ble consumption of other coagulation factors. Given that factor VII has a short half-life in blood,45 it will be the first coagulation factor to decline upon ongoing coagulation. Chemotherapy can induce endothelial cell activation and upregulate tissue factor levels,46 which also can explain the elevated VWF levels in patients. The increased bleeding tendency is most likely the result of the impaired platelet function, without compensation by a higher coagulant
activity. Moreover, although the relative number of PS positive platelets is high, given their fast clearance from circulation it is unlikely that this platelet population would significantly compensate for primary hemostasis.
The study herein has several limitations. Given that the number of isolated platelets was limited due to severe thrombocytopenia, only a restricted subset of measure- ments could be performed per patient blood sample, with the consequence that different patient samples needed to be used for some of the measurements. Furthermore, platelet samples were analyzed from patients with differ- ent disease types (AML/ALL, multiple myeloma and malignant lymphoma) after receiving chemotherapy in distinct treatment regimens. Herein, we wish to stress the fact that a reduced platelet function was detected in all patient groups and all therapeutic regimens.
Current guidelines for prophylactic transfusion during myelosuppression are based on platelet count only. Our novel findings indicate that, along with the platelet count, the activity of circulating platelets also needs to be consid- ered for an optimal control of hemostasis. Hence, this work encourages an inclusion of platelet function assays for the prediction of bleeding in this patient group.
Acknowledgments
We thank all medical students involved for assisting in patient inclusion.
Funding
Funding for this project was provided by the EHA-ISTH Research Fellowship granted by the European Hematology Association and the International Society of Thrombosis and Haemostasis to PvdM. FS is supported by the Alexander von Humboldt Foundation.
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