Background
Platelets are critical for hemostasis and thrombosis [
1]. It is a classic view that megakaryocytes (MKs) produce platelets in the bone marrow. Interestingly, several studies have shown that a large mass of MKs exist in lungs, which indicates that the lungs may be a specific organ for platelet biogenesis [
2‐
4]. The latest discovery strongly indicated that a large number of MKs circulated through the lungs, where they dynamically released platelets, and an animal model showed that the lungs contributed approximately 50% of total platelet production in mice [
3]. It is often observed that thrombocytopenia appears in patients with pulmonary diseases, such as pneumonia, chronic obstructive pulmonary disease (COPD) or respiratory failure (RF), which leads to major bleeding events and death [
4‐
7]. However, whether pathophysiological state of lung affects platelets is unclear from both clinical and basic research information. The present study, firstly, aims to explore whether the risk of thrombocytopenia varies among different organ infection, and we found that the incidence of thrombocytopenia in pulmonary infection (PIN) was the highest and low oxygen partial pressure (PaO
2) was a key risk factor for thrombocytopenia in PIN. Secondly, mice hypoxia model were used to uncover the potential mechanism of thrombocytopenia associated with the lung.
Discussion
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, suggesting that thrombocytopenia was 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 PaO
2 were more likely to have thrombocytopenia. These results indicated that low PaO
2 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 PaO
2 might induce thrombocytopenia by impairing platelet production in 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 PaO
2 indeed induced thrombocytopenia. In keeping with the fact that MKs circulate through the pulmonary capillaries where they release platelets[
19], the PLT
post representing the postpulmonary(left ventricle) blood platelet, was increased compared with the PLT
pre indicating the prepulmonary(right ventricle) blood platelet in normoxic mice. Hence, the △PLT
post-pre index represented the generation of platelets in lungs [
20,
21]. Our results showed that △PLT
post-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 △PLT
post-pre in hypoxic mice confirmed the speculation that low PaO
2 could reduce MKs and impair the thrombocytopoiesis in 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 [
23], we speculate that lower PaO
2 might cause pulmonary thrombocytopenia.
The correlation between low PaO
2 and thrombocytopenia had been previously described. A clinical observation showed that thrombocytopenia occurred in 31% of neonates with asphyxia versus 5% of matched controls without asphyxia [
25]. Another study found that thrombocytopenia was a predictive factor for the progression of pneumonia to RF [
26]. We confirmed in clinical cases that low PaO
2 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 was a relatively high incidence of thrombocytopenia ranging from 20 to 50% in critical patients [
27]. Both the CPIS and the APACHE II score were positively associated with the risk of thrombocytopenia. It was worth mentioning that low PaO
2 was 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 [
28] and inhibit the differentiation of bone marrow MKs[
29], 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 [
30]. 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 PaO
2 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 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 [
21], but thrombocytopenia occurs in patients with congenital heart diseases because a right-to-left shunt bypasses the lung where thrombocytopoiesis occurs [
31]. A large number of MKs dynamically circulate through the lungs, where they release platelets [
19]. Consistent with these findings, we observed a large number of CD41-positive MKs in the mouse lungs and found that the PLT
post was higher than the PLT
pre, 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 lung.
The conclusion from the present study could be helpful for patients with respiratory diseases. We discovered an interesting relationship between thrombocytopenia and pulmonary infections, as well as the corresponding hypoxemia. We found that megakaryocytes decreased in lung of hypoxia mice who produce only few platelets, suggesting that hypoxemia could result in reduced platelets and increased the risk of bleeding. Hypoxemia was common in patients suffering from COPD or bronchiectasis, or living in high altitude, so the clinicians should be aware of the risk of pulmonary thrombocytopenia. According to these reasons, we suggest that patients with severe lung diseases, especially those with hypoxemia complications should dynamically monitor the platelet and take circumspect application of antiplatelet drugs.
It is important to note that there are several limitations in our study. First, a larger-scale, multicenter, prospective investigation based on the relationship between thrombocytopenia and respiratory failure is needed to provide more convinced evidence. Second, the detailed molecular mechanisms underlying the process of platelet generation in lungs and how low PaO2 affected 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. We anticipate that future studies will focus on identification of mechanisms underlying pulmonary thrombocytopenia through mouse models of lung injury.
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