Letter: The Anticoagulation Dilemma in Atrial Fibrillation Complicating Chronic Mountain Sickness

Dear Editor,

Chronic mountain sickness (CMS) is relatively common in long-term high-altitude residents, manifested by excessive erythrocytosis, severe chronic hypoxemia, and progressive cardiopulmonary complications (Gatterer et al., 2024). Atrial fibrillation (AF) is an emerging but neglected complication in this group. CMS combined with AF forms a unique “double risk”: there is a higher risk of stroke during arrhythmia and in a complex blood environment, and there are pharmacological risks in traditional anticoagulant therapy.

The pathological substrate linking CMS to AF is multidimensional. Hyperviscosity of blood caused by polycythemia can increase pulmonary vascular resistance and facilitate right atrial dilation and structural remodeling. Chronic hypoxia can stabilize hypoxia-inducible factor, trigger a cascade reaction of pro-fibrotic cytokines, resulting in atrial electrical heterogeneity. At the same time, sympathetic overactivity and the prevalence of sleep—disordered breathing (more than 91% of high-altitude cardiovascular patients have it) have increased sharply, jointly aggravating the susceptibility to arrhythmia (Otero et al., 2016). Despite this elevated risk, standard stroke risk stratification tools, such as the CHA₂DS₂-VASc score, lack validation in CMS. They do not consider pro-thrombotic factors related to altitude, including extreme hyperviscosity, platelet aggregation caused by secondary polycythemia, and coagulation activity conditions because of hypoxia (Chaudhry et al., 2024).

Prescribing anticoagulants for CMS patients with AF subsequently presents a profound pharmacological dilemma. According to current international guidelines, direct oral anticoagulants (DOACs) are unequivocally the first-line therapy for non-valvular AF. Given their fixed dosing and lack of routine international normalized ratio monitoring, clinicians increasingly favor DOACs for high-altitude populations to circumvent logistical challenges. However, blindly extrapolating these low-altitude guidelines to CMS patients represents a leap into a pharmacological terra incognita. Major DOAC registration trials were conducted exclusively at low altitudes and systematically excluded patients with severe erythrocytosis. In the special pathological condition of CMS, severe polycythemia (hematocrit often exceeds 60%) makes the plasma volume smaller, changes the distribution of plasma drugs, and may lead to toxic peaks at fixed doses. Additionally, hypoxia-induced inhibition of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) could unpredictably impair drug clearance.

Conversely, relying on traditional warfarin is also dangerous. Clinical data show that for patients with AF, along with the rise in altitude, the INR increases by 5.6 times (Van Patot et al., 2006), mechanistically driven by altitude-induced suppression of hepatic cytochrome P450 2C9 (Zhang et al., 2024). More critically, the extreme hematocrit associated with CMS not only impairs primary hemostasis but also alters the citrate-to-plasma ratio in standard blood collection tubes. This leads to serious pre-analytical errors in conventional plasma INR testing, rendering routine monitoring unreliable without custom volume correction. Interestingly, animal studies suggest that factor Xa inhibitors may attenuate hypoxia-induced cardiac remodeling (Imano et al., 2018), a cardioprotective potential warranting rigorous investigation. Thus, clinicians are trapped in a true dilemma: forced to choose between an unmonitorable traditional drug and unvalidated novel agents whose safety profiles ignore the severe physiological extremes of CMS.

To conclude, AF complicating CMS is a specialized clinical challenge lacking evidence-based solutions. We urge the high-altitude medicine community to prioritize prospective cohort studies quantifying AF burden and thromboembolic risk in CMS. There is an urgent need to carry out pharmacokinetic analysis of DOACs in high-altitude areas, evaluation of drug genomics of enzymes, and research on the INR algorithm corrected by hematocrit. Until such definitive evidence emerges, clinicians must navigate this complex anticoagulation dilemma with caution, relying on individualized risk assessments and meticulous clinical monitoring.