Can chronic lung disease, smoking, or carbon-monoxide exposure cause secondary erythrocytosis?

Chronic hypoxic lung disease, cigarette smoking, and carbon-monoxide (CO) exposure are established causes of secondary erythrocytosis through impaired oxygen delivery and compensatory erythropoiesis.

Clinical and mechanistic evidence

• Hypoxic pulmonary disease, including COPD, can cause sustained hypoxemia and secondary erythrocytosis. In moderate-to-very-severe COPD, severe hypoxemia is associated with greater secondary-polycythemia risk, whereas continuous or nocturnal supplemental oxygen is associated with lower risk.
• Smoking directly contributes to CO exposure. CO binds hemoglobin to form carboxyhemoglobin, reducing blood oxygen content and impairing oxygen release to tissues—functional hypoxia even when oxygen saturation measurements appear relatively reassuring.
• Sustained hypoxia activates compensatory erythropoietin (EPO)-driven erythroid production, producing secondary erythrocytosis. A normal or elevated serum EPO level supports a secondary process, whereas low EPO is more consistent with primary erythrocytosis.

Diagnostic and clinical implications

• In a 77-year-old man with elevated hemoglobin or hematocrit, assessment should include cardiopulmonary oxygenation and carboxyhemoglobin testing when smoking or other CO exposure is plausible. Pulse oximetry alone may not adequately characterize CO-related impairment in oxygen delivery.
• EPO results should be interpreted with JAK2 testing and evaluation for pulmonary and other secondary causes. Smoking-related erythrocytosis is not uniformly accompanied by high circulating EPO: prospective evidence found higher hematocrit but lower median EPO among current smokers, consistent with possible hemoconcentration or altered erythroid responsiveness alongside CO-related hypoxia.

Bottom line

• The overall causal pathway is well supported: chronic lung disease can produce sustained hypoxia, while smoking and CO produce functional hypoxia; hypoxia-associated EPO signaling can lead to secondary erythrocytosis. Correcting hypoxemia and eliminating CO exposure address the underlying drivers while primary erythrocytosis must be excluded.