Until recently, it was widely accepted that megakaryocytes mainly reside in the bone marrow, and thus, the bone marrow is the site of platelet production. However, in 2017, Lefrançais et al. [1] published a groundbreaking study demonstrating blood formation in the lungs of mice. Using lung microcirculation imaging, they showed that a large number of megakaryocytes circulate through the lungs, where they dynamically release platelets. Their observation that megakaryocytes produce more than 10 million platelets per hour in the blood vessels of the lungs suggests that more than half of the mouse’s platelet production occurs in the lungs, instead of the bone marrow. Together, their results provided strong evidence that the lungs play a key role in blood formation in mice.

Megakaryocytes are a special type of hematopoietic cell, the grandmother cell that produces platelets [2, 3, 4]. Ionizing radiation causes a decrease in megakaryocytes and platelets [5, 6]. In a previous study, megakaryocyte progenitors were found to be more sensitive to X-rays than other hematopoietic cells [7]. In vitro studies revealed that platelets exposed to gamma rays are ultimately damaged under storage conditions, leading to shortened life after transfusion; this is due to increased clearance of the reticuloendothelial system, resulting in decreased survival after 24-hour commodity channel index (CCI) and platelet transfusion [8, 9, 10]. When a lesion of a lung cancer patient is treated with radiation, the rest of the normal lung tissue is also exposed to radiation. Here, we investigated the consequence of radiation exposure of the lung tissues to platelets in the human body. Specifically, we investigated the relationships between dose-volume histogram (DVH) parameters and the incidence of thrombocytopenia in lung cancer patients treated with radiotherapy (RT).

In observing the platelet changes in patients with lung radiation exposure, we found that 18.3% of patients developed thrombocytopenia during lung cancer radiation therapy, and increased lung radiation dose was closely associated with decreased platelet count. In vitro studies have also found that when human megakaryocytes are exposed to radiation, the DNA structure inside the cells is damaged, resulting in decreased numbers of megakaryocytes and platelets produced.

From the logistic regression analysis in the present study, the MLD, V${}_5$, V${}_{10}$, and V${}_{20}$ were associated with thrombocytopenia (all p 0.05). Presently in our hospital, the maximum limit dose for the normal part of both lung organs for patients with chest radiotherapy is MLD $\le$20 Gy, V${}_5$ $\le$65%, V${}_{20}$ $\le$35%. However, we determined the threshold values for these DVH parameters that best predict thrombocytopenia: MLD $\le$10.6 Gy, V${}_5$ $\le$44.5%, V${}_{10}$ $\le$27.5%, and V${}_{20}$ $\le$14.5%. For each parameter, the incidence of thrombocytopenia was greater when the radiation doses to the lung exceeded the threshold value. Clinically, severe thrombocytopenia can require RT treatment interruptions and/or a reduction in radiation dose and even lead to shortened survival time. Unscheduled interruptions in potentially curative treatments have been related to a reduced probability of local control of lung cancer [11, 12]. In addition, severe thrombocytopenia can cause bleeding problems and reduce the quality of life for patients. Therefore, in clinical practice, the ability to protect the lungs by controlling the value of DVH parameters and thereby reducing the risk of thrombocytopenia could offer great benefits to lung cancer patients receiving RT.

Our study shows that chemotherapy is associated with thrombocytopenia. Simultaneously, DVH parameters also have an association with thrombocytopenia. This indicates that the increase in lung radiation dosage was an important factor causing platelet reduction, in the context of chemotherapy-induced myelosuppression (p 0.05). However, some studies also found that the number of megakaryocytes in the peripheral blood of patients increased after chemotherapy and growth factory-induced mobilization [13, 14]. Because the patients in this study were treated based on chemotherapy, they could not be analyzed separately. Nonetheless, regardless of the increase or decrease of megakaryocytes after chemotherapy, we analyzed the decrease of platelets in the peripheral blood after receiving radiation in human lungs based on chemotherapy.

The association between thrombocytopenia and radiation dose to thoracic bone marrow (sternum, ribs, scapula) was not analyzed in this study, because these patients adopted the precise radiotherapy technology in our hospital. The radiotherapy dose is mainly concentrated on the lung tumor tissue and the surrounding lung tissue, and the irradiation dose to the chest bone marrow is very small. And previous studies have also shown that there is no significant correlation between radiation dose to thoracic bone marrow (sternum, ribs, scapula) and thrombocytopenia [15]. In addition, more than one-half of the body’s bone marrow is located in the pelvic bone marrow (os coxae, sacrum, proximal femora, and lower lumbar spine) [16], however, there is no significant correlation between dosimetric parameters and platelet count nadirs [17]. Furthermore, only 25% of the bone marrow in the human body is located in the thoracic bone marrow (sternum, ribs, scapula), thus thoracic bone marrow irradiation does not affect platelets. The treatments that patients received before RT were not homogeneous due to the retrospective study design. In the future, a well-designed prospective study is needed to overcome the limitations of the present study and to confirm the correlation between radiation dose to the lung and thrombocytopenia, as well as provide insight into the underlying mechanisms, particularly the production of platelets within the human.

Higher doses of radiation to the lung are associated with an increased risk of thrombocytopenia. Moreover, optimization of treatment plans via the control of DVH parameters may reduce the risk of bleeding and improve the quality of life in lung cancer patients treated with RT.

RT, radiotherapy; DVH, dose-volume histogram; MLD, mean lung dose; GTVs, gross tumor volumes; CTV, clinical target volume; PTV, planning target volume; RTOG, Radiation Therapy Oncology Group; TNM, tumor node metastasis; CT, computed tomography; MRI, magnetic resonance imaging; KPS, Karnofsky Perormance Scale; ROC, Receiver operating characteristic; PLT, platelet.

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SHY designed the study; SST collected the patients’ clinical data and SST, LL analyzed the data, SST wrote the paper. All authors read and approved the final manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

This study has been approved by the Ethics Committee of Shandong Cancer Research Institute (SDTHEC2020004042). The patients enrolled all presented written informed consent.

The authors would like to thank Ms. Laney Weber for excellent assistance.

This study was supported in part by National Natural Science Foundation of China (grant No. NSFC82073345), Natural Science Innovation and Development Joint Foundation of Shandong (ZR202209010002), the Taishan Scholars Program and Jinan Clinical Medicine Science and Technology Innovation Plan (202019060) to Shuanghu Yuan, and the Major Basic Research Program of National Natural Science Foundation of Shandong (ZR2022ZD16) and Natural Science Youth Foundation of Shandong Province (ZR2023QH155) to Li Li.

The authors declare no conflict of interest.