Thrombosis at High Altitude Is Not Associated with Increased Transferrin

Abstract

Bolivian Andean Aymara highlanders have been living at 4000 meters for 14,000 years, and have developed evolutionary genetic adaptations to hypoxia (PMID:28448578; PMID:29100088; PMID:36980912). These include EGLN1 encoding prolyl hydroxylase 2 (PHD2), a regulator of transferrin transcription. Transferrin increases in hypoxia and iron deficiency (PMID: 9242677); contrasting reports indicate that elevated transferrin associates with thrombosis in mice but decreased thrombosis in a congenital disorder of hypoxia-sensing (PMID: 36040436; PMID: 31310728; PMID: 8281634). We analyzed clinical and laboratory data of Andean Aymara patients with High-Altitude Anemia (n=137, mean age 45 years, female gender 79%,) or High-Altitude Erythrocytosis (n=149, mean age 56 years, female gender 30%) with transferrin results in their medical records. Iron deficiency was present in 57% of anemia and 23% of erythrocytosis patients. Mean (SD) transferrin concentration was 3.08 (1.25) g/L in anemia and 3.34 (0.84) g/L in erythrocytosis patients. Thrombosis history was present in 8% of anemia and 13% of erythrocytosis patients. In logistic regression analysis in High-Altitude Anemia patients with adjustment for age and gender, iron deficiency associated with increased thrombosis history (odds ratio [OR] 6.7, P=0.030) while higher serum transferrin associated with decreased thrombosis history (OR 0.4, P=0.013). In High-Altitude Erythrocytosis patients iron deficiency associated with increased thrombosis history (OR 5.0, P=0.005), but transferrin's association with thrombosis history was not statistically significant (OR 0.8, P=0.52). In anemia and erythrocytosis patients combined, iron deficiency associated with increased thrombosis history (OR 4.6, P=0.0006) while elevated transferrin associated with reduced thrombosis history (OR 0.62, P=0.038). In individuals with extreme environmental hypoxia, we found no evidence that increasing transferrin is associated with increased thrombosis history, but rather observed a trend to decreased thrombosis history.