There have been some cases of thrombocytopenia in PIN patients, but observational study of large samples is rare. We performed a retrospective study to observe the incidence of thrombocytopenia in patients with PIN, and patients with one of three other kinds of infections which was the most common in our hospital were chosen as controls. The results showed that the highest incidence of thrombocytopenia occurred in PIN patients among the four groups of infectious disease patients, which suggests that thrombocytopenia is likely associated with pulmonary infection. Subgroup analysis showed that PIN patients with RF had a higher risk of thrombocytopenia than those without RF. Furthermore, PIN with RF patients showing low PaO2 were more likely to have thrombocytopenia. These results indicated that low PaO2 might be a key risk factor for thrombocytopenia. In view of studies showing that the lungs can produce platelets[18, 19], it was reasonable to speculate that low PaO2 might induce thrombocytopenia by impairing platelet production in the lungs. To verify our hypothesis, we built a hypoxic mouse model, and the results showed that PLTs were decreased in hypoxic mice compared with normoxic mice, which demonstrated that low PaO2 indeed induced thrombocytopenia. In keeping with the fact that MKs circulate through the pulmonary capillaries where they release platelets, the PLTpost representing the postpulmonary(left ventricle) blood platelet was increased compared with the PLTpre indicating the prepulmonary(right ventricle) blood platelet in normoxic mice. Hence, the △PLTpost−pre index represented the generation of platelets in the lungs[20, 21]. Our results showed that △PLTpost−pre was significantly attenuated in hypoxic mice compared with normoxic mice. The lower proportion of CD41-positive MKs indicated by histology and flow cytometry, and the decreased △PLTpost−pre in hypoxic mice confirmed the speculation that low PaO2 could reduce MKs and impair the thrombocytopoiesis in the lungs.
Although infection is known to cause thrombocytopenia[22–24], cohort studies associated with different organ infections have not been reported. In the present study, the incidence of thrombocytopenia in PIN patients showed a significant increase, which suggested that the lungs could affect the physiological behavior of platelets in a particular way. Based on the conclusion that there were no associations between bacterial species and the incidence of thrombocytopenia in infectious diseases, we speculate that additional mechanisms might cause pulmonary thrombocytopenia.
Several previous studies described the link between low PaO2 and thrombocytopenia. A clinical observation showed that thrombocytopenia occurred in 31% of neonates with asphyxia versus 5% of matched controls without asphyxia. Another study found that thrombocytopenia was a predictive factor for the progression of pneumonia to RF. We confirmed in clinical cases that low PaO2 was a key risk factor for thrombocytopenia through a relatively large sample of PIN patients for the first time. Severity of disease was associated with the incidence of thrombocytopenia [22, 24]. There is a relatively high incidence of thrombocytopenia ranging from 20–50% in critical patients. Both the CPIS and the APACHE II score were positively associated with the risk of thrombocytopenia. It is worth mentioning that low PaO2 is an independent risk factor for thrombocytopenia after adjusting for the APACHE II score, which makes the results more convincing.
The influence of hypoxia on bone marrow MKs is well described. Chronic hypoxia impair bone marrow MKs  and inhibit the differentiation of bone marrow MKs. Or the erythroid system and the MK system share a common precursor in the bone marrow, and there is competition between erythroid and MK differentiation upon exposure to a hypoxic environment . However, the effect of hypoxia on pulmonary thrombocytopoiesis has not been investigated as the lung is another important site of platelet biogenesis. We constructed hypoxic mouse models and found that low PaO2 caused thrombocytopenia. P-selectin, an indicator of platelet activation, showed no significant difference between hypoxic and normoxic mice, which indicated that thrombocytopenia was not attributed to platelet activation. Researchers have paid close attention to the process of platelet generation in the lungs[3, 19]. There are abundant MKs in the pulmonary arterial blood but only a few MKs in the pulmonary venous blood under normal conditions, but thrombocytopenia occurs in patients with congenital heart diseases because a right-to-left shunt bypasses the lung where thrombocytopoiesis occurs . A large number of MKs dynamically circulate through the lungs, where they release platelets . Consistent with these findings, we observed a large number of CD41-positive MKs in the mouse lungs and found that the PLTpost was higher than the PLTpre, indicating that the mouse lungs indeed were a site of platelet production. Interestingly, we found that hypoxia could reduce lung MKs and impair efficacy of thrombocytopoiesis in the lung.
It is important to note that there are several limitations to our study. First, A large-scale, multicenter, prospective investigation based on the relationship between thrombocytopenia and respiratory is needed to provide more convinced evidence. Second, the detailed molecular mechanisms underlying the process of platelet generation in the lungs and how low PaO2 affects this process were not illuminated. In spite of these limitations, we believe that our results are the first to provide the correlation between lung diseases and thrombocytopenia with data from both clinical studies and mouse models, which would help to guide the management of patients with respiratory diseases, especially for those people with lung damage or chronic respiratory failure; but also optimize antiplatelet therapy in specific patients with respiratory comorbidities. We anticipate that future studies utilizing mouse models of chronic lung injury will focus on identification of mechanisms underlying pulmonary thrombocytopenia.