Could the Increased Prevalence of Thrombotic Complications at High Altitude In Polycythemia Vera (PV) Be Contributed by Hypoxia?

# Both authors contributed equally.

Thrombotic complications are a major cause of morbidity and mortality in polycythemia vera (PV). While the risk of PV thrombotic complications is significantly higher in patients with a previous history of thrombosis or transient ischemic attacks, advanced age (> 60 years), leukocytosis and possibly a high JAK2 V617F allelic burden, other contributing etiologies have not been excluded. It is unclear whether environmental variations including hypoxia could modify thrombosis risk. Chronic hypoxia induces many phenotypic changes, including increased erythropoietin production resulting in secondary erythrocytosis and pulmonary hypertension. Moreover, a congenital disorder of augmented hypoxia sensing at ambient oxygen tension, Chuvash polycythemia, is associated with a marked, yet unexplained, increased rate of thrombotic complications.

Salt Lake City, UT is located in a valley at ~5,000 feet of altitude and the surrounding areas from which PV patients are referred ranges from 4,300 to 6,900 feet in altitude. In this area, the average hemoglobin concentration is 0.6–1.3 gm/dL higher than the average US value, indicating a physiological response to this level of hypoxia.

To analyze the possible effect of moderate hypoxia on PV thrombotic complications, we retrospectively compared the history of thrombotic complications in PV patients from Salt Lake City and Baltimore, MD, a city with a referral area in which the elevation is <500 feet. A total of 237 PV patients were analyzed in this study; 166 were treated in Baltimore and 71 were treated in Salt Lake City, Their demographics are presented in the Table.

Patients from Salt Lake City were older than the Baltimore patients, more often male, and had longer disease duration. A history of thrombosis was present in 58% of the Salt Lake City patients compared to 27% of the Baltimore patients (P <0.0001). After adjusting for age, sex and disease duration, Salt Lake City patients had an estimated 3.9-fold increase in the odds of history of thrombosis compared to Baltimore patients (95% confidence interval of 1.9 to 7.8; P = 0.0002).

The analysis suggests that hypoxia may modify the PV phenotype. The degree of HIF-1 and HIF-2 augmentation and altered regulation of their target genes, and the potential for increased thrombotic risk due to environmental hypoxia should be evaluated prospectively in PV patients living at different altitudes.

No relevant conflicts of interest to declare.