I (Geo) received these questions from Brenda Goforth on 12/19/24 and received assistance from colleague and coagulation expert David McGlasson in locating relevant research documents:
I have two questions regarding the interpretation of PFA-100 closure times (CTs):
1. If the CT results are below (shorter than) the normal reference range, would this still be considered a normal result or abnormal, indicating either an elevated platelet count or increased platelet function?
2. What would cause the combination of a normal collagen-EPI (CEPI) cartridge CT and an abnormal (prolonged) collagen-ADP (CADP) cartridge CT?
Thank you.
Dave steered me to a beautifully designed study recorded in Vázquez-Santiago M, Vilalta N, Cuevas B, et al. Short closure time values in PFA-100® are related to venous thrombotic risk. Results from the RETROVE Study. Thromb Res. 2018;169:57-63. doi: 10.1016/j.thromres.2018.07.012. The article is copyrighted, please obtain it from your facility’s library. Their study established reference intervals using specimens from 80 healthy individuals for CEPI cartridges, 72–191 CT seconds, and for CADP cartridges CT 58–123 CT seconds. These intervals are closely parallel to the intervals we apply in most facilities. The investigators documented 800 participants, stratified into percentiles by CEPI and CADP CT levels, and learned that participants whose CT values were in the shortest 10%, at a mean for CEPI CT at 110 seconds, and a mean for CADP CT at 77 seconds, experienced a higher risk of thromboembolic disease at an odds ratio of 4.0, which correlated with elevated VWF:Ag levels. They noted that the relationship of CT with thrombosis was not reflected in platelet aggregometry results.
Dr. Emmanuel Favaloro published a “Test of the Month” brief review, Favaloro EJ. Clinical utility of closure times using the platelet function analyzer-100/200. Am J Hematol. 2017;92:398-404. doi: 10.1002/ajh.24620 (also copyrighted). The PFA-100 was introduced in 1995 as a platelet function analyzer that was more reliable than the obsolete skin bleeding time. When the CEPI CT is prolonged and the CADP CT is within the reference interval, consider the aspirin effect, low hematocrit, thrombocytopenia, or mild VWD. When both are prolonged, consider severe VWD or platelet dysfunction, aspirin, severe thrombocytopenia, or markedly low hematocrit. The review indicates that a normal CEPI in association with a prolonged CADP is rare. When both cartridges exceed the upper limit, their results predict a VWF:Ag level of <25 IU/dL in 90% of cases, however, prolongation of one, the other, or both, also occurs in anemia or thrombocytopenia. Most authorities require the whole blood specimen to be tested within four hours of collection (some say 5), and must not be activated by agitation or centrifugation with resuspension.
Additionally, the PFA-200, which boasts enhanced features, produces CEPI and CADP reference intervals similar to the PFA-100. The PFA-200 is used in most countries except for the USA, where it has never earned FDA approval. Neither PFA is cleared for documenting aspirin or clopidogrel efficacy.
Dr. Favaloro responded on 12-21-24:
2. The causes of an elevated C/ADP but normal C/Epi CT can be multifactorial. I suspect the largest group of patients with this “epiphenomenon” is simply due to the incorrect establishment of normal reference ranges (NRR), where the C/Epi CT NRR is ‘accurate’ but where the C/ADP CT NRR is set too low. Indeed, we have reported many times that the manufacturer reported NRR for the C/ADP CT are set too low (upper limit 100s), so if a lab follows these ranges, they will often see the occurrence of this epiphenomenon. I suggest Favaloro EJ, Mohammed S, Vong R, et al. Harmonizing platelet function analyzer testing and reporting in a large laboratory network. Int J Lab Hematol. 2022;44:934–44. doi: 10.1111/ijlh.13907. PMID: 35754202; PMCID: PMC9545980 (attached below). as a good contemporary evaluation of manufacturer vs lab-established NRRs. For those labs that have established a proper NRR for both C/ADP (upper limit closer to 124sec) and C/Epi CT(upper limit close to 160s), the epiphenomenon is rare but may have multiple causes. We have seen this in pregnancy and in patients on P2Y12 inhibitors, but this is not to say all such patients will show this pattern, nor do we have any evidence these events are causal – could just be a chance event.
No comments here.