Clinical characteristics of venous thromboembolism onset from severe high altitude pulmonary edema in plateau regions

This study explored the prevalence and clinical characteristics of venous thromboembolism from severe high altitude pulmonary edema in plateau regions. We performed a single-institution retrospective study of patients with confirmed severe HAPE and found a high prevalence of VTE and an association between VTE and longer time in hospital, respiratory failure, the shortened APTT and the higher level of D-dimer in hospitalized patients with severe HAPE. In our current study of the largest sample size to date, little is known about the occurrence rate and the association of VTE in severe HAPE.

We observed that the occurrence rate of VTE in our study population was 38.9% (7/18 studied), 26.9% (7/26 of all severe HAPE studied) and 2.65% (7/264 of all patients in our center). This prevalence appears to be higher than that reported in the literature [7,8,9,10], which reported that the rates of objectively confirmed VTE in 4 prospective studies ranged from 13 to 31% and suggested a potential role for thromboprophylaxis in patients requiring critical care. This rate was also higher than that reported for many other hospitalized patients [11, 12] and series of patients in ICUs reported from China [13].

Several reasons probably account for the high prevalence of DVT in severe HAPE patients. First, most of the previously mentioned studies focused on critically ill patients who were in the ICU for different diseases. HAPE is an abnormally high pulmonary artery pressures due to multiple factors. Most studies suggest that HAPE is associated with damaged endothelium and alveolar epithelium caused by inflammatory responses under hypoxic conditions, which involve several pathways and mediators, including hypoxia-inducible factor, vascular endothelial growth factor, endothelin-1, and inducible nitric oxide synthase, and also involving sodium channels that regulate water transport, Na-K-ATPase, and aquaporin, pulmonary hemodynamic changes and higher hydrostatic pressure play a vital role in the acute and rapid progression of HAPE [14,15,16]. Second, there are aspects of altitude excursions that increase blood viscosity, for example, dehydration causing hemoconcentration, and polycythemia, in addition to the compensatory rise in hematocrit with acclimatization, which are likely to increase VTE risk. Furthermore, Studies have shown hypoxia and low temperature at high altitude can induce hypercoagulabilitys to increase thromboembolic events at high-altitude [17].

Outcome analyses clinical characteristics of venous thromboembolism onset from severe high altitude pulmonary edema in plateau regions, including longer time in hospital, respiratory failure, the shortened APTT and the higher level of D-dimer. Therefore, we speculate that the inflammatory state may promote venous thrombosis under hypoxic conditions. Coagulation activation could also be associated with a sustained infammatory response [18]. D-dimer is an important indicator for diagnosing of patients with VTE, and its increase is important significance for the differential diagnosis of patients with symptomatic VTE. Le Roux et al. demonstrated that the levels of D-dimer levels increased significantly at 6542 m after 1 week and at 3 weeks compared to those observed at sea level in seven climbers [19]. Analogously, Pichler Hefti et al. found that D-dimer levels increased with increasing altitude in Muztagh Ata, China [20]. Our data showed that serum D-dimer levels in patients with VTE in severe high altitude pulmonary edema were higher than non-VTE groups. This suggests that D-dimer, as an important differential index for VTE diagnosis, still has diagnostic efficacy in plateau regions. A transcriptomic and proteomic analysis of platelets demonstrated that plateau regions were associated with the upregulation of proteins with thrombosis and platelet activation without thrombosis in plateau regions -residing patients compared to subjects residing at low-altitude [21]. Moreover, a novel genome-wide expression analysis performed by Jha et al. showed that genes associated with the coagulation cascade and platelet activation were significantly upregulated in patients with VTE at plateau regions [22]. These studies indicate that platelet activation may induce thrombosis.

Prophylaxis for VTE [23, 24] and for extended-duration VTE [25, 26] has been investigated in clinical trials to improve clinical outcomes in severely or critically ill patients. Regrettably, the proportion of thromboprophylaxis is too low in our cohort which 2 of 18 (11.1%) patients were given VTE prophylaxis. There was no statistically significant difference between the VTE and non-VTE groups (0 [0.0%] versus 2 [18.2%]; P = 0.497). Our data suggest that there is a possible protective effect of prophylaxis for VTE in the higher risk in this cohort. This also suggests that for HAPE, thromboprophylaxis strategies should fully be recognized and strengthened, including moderately increasing the dose of anticoagulant drugs. Because our sample size is limited, the effect of VTE prophylaxis on hospitalized patients with COVID-19 warrants further investigation.

Although these findings are not surprising, given that our patient population represented severely ill patients at high risk for VTE, our data raised the question of screening for VTE, risk stratification, and potential VTE prophylaxis to improve outcomes in hospitalized patients with HAPE. Meanwhile, since VTE has no specific clinical manifestations, it can be easily diagnosed as other respiratory diseases at the initial stage, and a combination of these diseases cannot be ruled out. These results make it difficult to diagnose VTE. Therefore, more attention should be paid to the high-risk VTE groups in HAPE groups and VTE prophylaxis.

This study has some limitations. First, this is a single center retrospective study, as the sample size is small, and it is difficult to exclude accidental errors. Second, due to the critical condition of patients with severe HAPE, CTPA examinations were restricted, which significantly underestimated the prevalence of VTE. Thus, Prospective multi-center large sample studies might be needed in the future to further confirm the findings in our current study.

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