Genome-Wide Expression Analysis Suggests Hypoxia-Triggered Hyper-Coagulation Leading to Venous Thrombosis at High Altitude

Abstract

Venous thromboembolism (VTE), a multi-factorial disease, is the third most common cardiovascular disease. Established genetic and acquired risk factors are responsible for the onset of VTE. High altitude (HA) also poses as an additional risk factor, predisposing individuals to VTE; however, its molecular mechanism remains elusive. This study aimed to identify genes/pathways associated with the pathophysiology of deep vein thrombosis (DVT) at HA. Gene expression profiling of DVT patients, who developed the disease, either at sea level or at HA-DVT locations, resulted in differential expression of 378 and 875 genes, respectively. Gene expression profiles were subjected to bioinformatic analysis, followed by technical and biological validation of selected genes using quantitative reverse transcription-polymerase chain reaction. Both gene ontology and pathway analysis showed enrichment of genes involved in haemostasis and platelet activation in HA-DVT patients with the most relevant pathway being 'response to hypoxia'. Thus, given the environmental condition the differential expression of hypoxia-responsive genes (angiogenin, ribonuclease, RNase A family, 5; early growth response 1; lamin A; matrix metallopeptidase 14 [membrane-inserted]; neurofibromin 1; PDZ and LIM domain 1; procollagen-lysine 1, 2-oxoglutarate 5-dioxygenase 1; solute carrier family 6 [neurotransmitter transporter, serotonin], member 4; solute carrier family 9 [sodium/hydrogen exchanger], member 1; and TEK tyrosine kinase, endothelial) in HA-DVT could be a determining factor to understand the pathophysiology of DVT at HA.

High Incidence of Venous Thromboembolism in Patients with Coronavirus Disease 2019: A Call for Improved Awareness and Prevention

“…This con rms that VTE is an important complication in COVID-19 patients. Profound hypoxemia in the pulmonary capillaries may induce endothelial dysfunction and platelet dysfunction [24]. Endothelial cell injury activates a large number of pro-in ammatory cytokines, contributing to microvascular thrombosis including plugging of the pulmonary microvasculature and the occurrence of VTE [25,26].…”

Venous thrombosis at altitude presents with distinct biochemical profiles: a comparative study from the Himalayas to the plains

“…Although several clinical reports, including case reports and cohort studies, suggested the prothrombotic bent of hypoxia at HA, a few studies have instead supported its nonprothrombogenic nature. 10,18,19,21,25,26,[29][30][31][32][33][34] Thus, with the paucity of adequate information about any underlying connection between HA and a shift in coagulation mechanisms, we focused on the identification of factors that could ascertain the crucial role of HA in the aggravation of VTE events and, consequently, help to establish strategies to reduce these lifethreatening episodes at altitude. The present study evaluated 54 markers of parameters that have relevance to the development of thrombotic events under the influence of HA hypoxia as per our existing knowledge with support from the literature.…”

“…Next, we assessed the age distribution: 81.13% of the HAP population was #40 years of age, whereas only 62.22% of SLPs fell into this range. The median (IQR) age of 33 (29)(30)(31)(32)(33)(34)(35)(36)(37)(38) years in HAPs was significantly lower than in their corresponding SLPs, which was 36 (31-43.5) years ( Figure 1A). Likewise, patients with CVT, DVT, and PVT from HA were comparatively younger than their manifestation type-matched SLP counterparts ( Figure 1B).…”

Hypoxia Signaling in Cardiovascular Diseases

“…In another parallel study, aimed to investigate the role of hypoxia-induced platelet hyper-reactivity, platelet specific novel regulator protein 'calpain' was found to be involved in promoting prothrombotic tendency on ascension to high altitude [86]. A genome wide expression analysis of genes in patients of high altitude-induced venous thrombosis revealed that the progression of venous thrombus formation is attributed to the differential expression of hypoxia responsive genes in response to environmental hypoxia [87].…”