CO ‐Rebreathing in Essential Thrombocythemia and Polycythemia Vera. A Revival of an Old Methodology to Improve Diagnosis and Phlebotomy Decisions

ABSTRACT The diagnostic landscape for the Philadelphia‐negative myeloproliferative neoplasms (MPNs), particularly in distinguishing Essential Thrombocythemia (ET) from Polycythemia Vera (PV), is compromised. The gold standard for diagnosing PV—measurement of red cell mass (RCM) by radioisotope dilution—has been largely abandoned, leading to widespread misclassification. Thus, an estimated 30%–50% (varying by diagnostic center and testing practice) of JAK2V617F ‐positive ET patients may, in fact, have “hidden” PV, depriving them of the cornerstone PV therapy: phlebotomy. This diagnostic inaccuracy exposes a sizable patient population to an unfortunate high risk of life‐threatening thrombotic events. Concurrently, the management of established PV is suboptimal, often relying solely on hematocrit, a flawed parameter especially in iron‐deficient or hydroxyurea‐treated patients. This perspective calls for the revival and clinical implementation of the Carbon Monoxide (CO)‐rebreathing technique as a promising, rapid, and nonradioactive alternative for RCM assessment. Herein, we review the history of this methodology and discuss its potential to improve MPN care by ensuring precise diagnosis, guiding rational phlebotomy, and ultimately reducing thrombotic morbidity and mortality, while also candidly addressing the current evidentiary and practical limitations that must be resolved before clinical adoption, while also offering potential health‐economic benefits.