The letter, authored by Barina Khan of Karachi Medical and Dental College and published on 3 September 2026 as Volume 29, article number 59 of the journal, is written in direct response to a pilot study by Tran and colleagues that documented dynamic platelet dysfunction in patients undergoing extracorporeal membrane oxygenation. That pilot work, which appeared in the same journal earlier in 2026, used platelet function testing to follow how platelet performance changed over the course of ECMO support and explored whether those changes tracked with clinically significant bleeding. The new letter does not dispute that platelet dysfunction is real and important in ECMO patients. Instead, it questions whether the specific instrument and protocol used can reliably detect it in this population.

The core of the concern lies in what laboratory scientists call a ceiling effect. The PFA-200 measures the time it takes for platelets, under controlled high shear conditions, to form a plug that occludes a microscopic aperture in a cartridge coated with platelet agonists such as collagen and epinephrine or collagen and adenosine diphosphate. When platelet function is severely impaired, the plug simply never forms, and the instrument reports a result at or above the maximum assay limit, typically a value greater than 300 seconds. In profoundly thrombocytopenic or platelet-exhausted patients, which many ECMO patients quickly become, large numbers of test results pile up at this artificial ceiling. Once a value has been censored at the upper limit, the assay can no longer distinguish between moderately severe and catastrophic platelet failure, compressing exactly the range of dysfunction that matters most for predicting bleeding.

Khan’s letter argues that this censoring problem is particularly acute during ECMO, where platelet counts fall progressively, platelets become activated and exhausted through continuous contact with the oxygenator membrane and circuit tubing, and acquired platelet defects accumulate over days of support. If a study correlates closure times with bleeding episodes in such a cohort, the relationship may be flattened or distorted by the many results that read simply as greater than 300 seconds. Statistical associations computed on censored data risk either underestimating the true strength of the link between platelet failure and hemorrhage or, depending on how the ceiling values are handled in the analysis, producing misleading conclusions about when platelet dysfunction begins to matter clinically.

The second confounder the letter highlights is hematocrit, the proportion of blood volume occupied by red blood cells. It is a long-standing observation in hematology that the PFA-100 and PFA-200 are exquisitely sensitive to the hematocrit of the sample. Red cells are not passive bystanders in primary hemostasis; they physically push platelets toward the vessel wall in flowing blood and contribute chemical signals, including adenosine diphosphate released from erythrocytes, that amplify platelet activation. When the hematocrit drops below roughly 30 percent, closure times lengthen even if platelets themselves are functioning normally, and severe anemia can push closure times beyond the assay limit on its own. Conversely, elevating the hematocrit can shorten closure times and mask genuine platelet defects, an effect documented decades ago in studies of uremic and cirrhotic patients evaluated on the platelet function analyzer.

This sensitivity is a serious problem in the ECMO population specifically. Patients on extracorporeal support are frequently anemic, whether from hemodilution caused by circuit priming, hemolysis within the circuit, repeated blood sampling, gastrointestinal bleeding, or the suppressed red cell production that accompanies critical illness. In such patients, a prolonged closure time may reflect the red cell deficit rather than intrinsic platelet failure, and the degree of prolongation may bear little relationship to the true functional capacity of the platelets. Khan’s letter suggests that unless hematocrit is either matched across study groups or formally adjusted for in the statistical model, the association reported between PFA-200 closure times and bleeding in ECMO patients may be confounded from the outset, with anemia masquerading as platelet dysfunction.

The letter places these concerns in a broader and somewhat sobering context. The clinical utility of closure times on the platelet function analyzer has been debated for more than two decades. Studies in cardiac surgery patients have repeatedly questioned whether the device predicts blood loss after cardiopulmonary bypass, another setting in which acquired platelet defects, hemodilution and anemia coexist. A comprehensive review in the American Journal of Hematology catalogued the assay’s utility across bleeding disorders while also documenting its susceptibility to hematologic variables, and a worldwide survey of platelet function testing practices conducted under the auspices of the International Society on Thrombosis and Haemostasis underscored how much variability exists in how platelet function is assessed even among expert laboratories. Against that backdrop, applying the PFA-200 to the uniquely harsh environment of extracorporeal circulation demands particular caution about the assay’s known limitations.

None of this means the assay should be abandoned in the ECMO setting, the letter’s argument implies, but rather that its results must be interpreted with an awareness of when the instrument can and cannot see. Practical strategies exist. Researchers can report the proportion of censored results explicitly and use statistical methods designed for data with detection limits rather than treating the ceiling value as a genuine number. Studies can stratify closure times by hematocrit, exclude samples with severe anemia from platelet-focused analyses, or measure closure times only after red cell transfusion has stabilized the hematocrit. Complementary tests that are less dependent on shear, hematocrit and sample handling, such as light transmission aggregometry, flow cytometric markers of platelet activation, or other point-of-care viscoelastic and platelet-mapping devices, can help triangulate the true state of platelet function. The pilot study’s central observation, that platelet dysfunction evolves dynamically during ECMO, remains valuable; the question is whether the PFA-200, as deployed, is measuring that dysfunction or partly measuring the anemia around it.

The stakes are far from academic. Bleeding remains one of the most feared complications of ECMO, occurring in a substantial fraction of patients and driving decisions about anticoagulation intensity, transfusion thresholds and circuit management. If closure times on the PFA-200 are adopted as a bedside guide without accounting for ceiling effects and hematocrit, clinicians risk both false reassurance, when an apparently normal result is actually capped by the assay limit in a patient with profound platelet exhaustion, and false alarm, when a prolonged result in an anemic patient triggers unnecessary platelet transfusion. Given that platelet transfusions carry their own risks, including allergic reactions, transfusion-associated circulatory overload and the theoretical promotion of thrombosis in a patient group already prone to circuit clotting, refining which patients truly need platelet support is a matter of real clinical consequence.

Khan’s letter is a compact methodological intervention, but it lands at a moment when interest in platelet function testing during extracorporeal support is growing rapidly. As devices for measuring closure times, aggregometry and platelet activation migrate from hematology laboratories to the intensive care unit bedside, the letter serves as a reminder that the validity of any such measurement depends on the biology of the sample as much as the precision of the instrument. In ECMO patients, where thrombocytopenia, platelet exhaustion and anemia march together, closure times must be read with both eyes open. Whether future studies can confirm a robust, hematocrit-independent association between PFA-200 results and bleeding in this population will determine whether the assay earns a genuine place in the ECMO management toolkit, or remains a test whose ceiling it cannot see above and whose red cell context it cannot escape.

Subject of Research: The reliability of PFA-200 platelet function closure times for assessing bleeding risk during extracorporeal membrane oxygenation

Article Title: PFA-200 closure times in ECMO: Are ceiling effects and hematocrit confounding the bleeding association?

Article References: Khan, B. (2026). PFA-200 closure times in ECMO: Are ceiling effects and hematocrit confounding the bleeding association?. Journal of Artificial Organs, 29(4), Article 59. https://doi.org/10.1007/s10047-026-01589-0

Image Credits: AI Generated

DOI: 10.1007/s10047-026-01589-0

Keywords: ECMO, PFA-200, platelet function, closure time, bleeding risk, hematocrit, coagulation, extracorporeal membrane oxygenation, platelet dysfunction, anemia, point-of-care testing, Journal of Artificial Organs