Sacha Uljon, MD, PhD, Medical Director, Core Laboratory, Massachusetts General Hospital, sent this provocative question on 6-10-2026.
Hello–just an update. This has been frustrating–others also have issues distinguishing FXI deficiency from LAC. Here is one report available from your medical library: Rabichow L, Dinh J, Nguyen L, Qiao J. In vitro differential inhibition of the factor XI activity assay in the setting of a lupus anticoagulant. Blood Coagul Fibrinolysis. 2024;35:217–22. doi: 10.1097/MBC.0000000000001287.
Abstract
Acquired factor XI deficiencies due to factor-specific inhibitors are rare and may be associated with lupus anticoagulant. We report a 63-year-old male with suspected postsurgical bleeding, prior surgical site infection, an isolated prolonged activated partial thromboplastin time, and a positive lupus anticoagulant. Although the factor II assay was normal, factor VIII and IX assays initially demonstrated nonparallelism with factor activity that consistently increased to normal reference ranges with serial dilutions. A discrepancy in factor XI activity results was discovered when the in-house method demonstrated undetectable activity (<3%); send-out testing using different instrument/reagent combinations revealed the presence of factor XI activity between 70% and 76%. The patient received surgical follow-up and was subsequently discharged home. Given the differential in vitro inhibition of factor XI activity on our initial in-house testing, this case highlights the importance of recognizing factor assay interference in the presence of a known lupus anticoagulant inhibitor, with strategies to mitigate potentially erroneous results.
Dr. Uljon continues: It seems we have a patient population enriched for pts with LAC and a question of FXI deficiency. There is a direct-to-consumer genetic testing for pregnant women that looks at “carrier status” for FXI, so maybe that’s why I am seeing a lot of this. I can’t find a good reason to do higher dilutions for FXI and FXII, so when the CV is high, reporting the 1:10 is one solution. That way, the error is not propagated by multiplication. But I was thinking, has anyone tried substituting a different silica-phospholipid reagent for the PTT reagent in FXI and XII tests? As an alternative to purchasing an instrument or doing a send-out to Siemens whenever we encounter this? The SCT Confirm© in particular comes to mind. It looks like just a PTT with extra phospholipid, which is exactly what would help.
- From Geo: My question is, how many FXI deficiencies do you see? Are you caring for a population with a high FXI prevalence?
- From Dr. Emanuel Favaloro, June 11: What APTT reagent are they using, and what are their APTT and FXI reference ranges? Could be a simple case of using an LA-sensitive APTT reagent or a too-tight reference range.
- From Mr. Bob Gosselin, June 11, an “autoneutralization” approach. Gosselin RC. An acute need inspiration: sutoneutralization of lupus snticoagulants in sffected prothrombin times (PT) and activated partial yhromboplastin times (APTT). Methods Mol Biol. 2023;2663:289–95. doi: 10.1007/978-1-0716-3175-1_18. PMID: 37204718. In: Emmanuel J. Favaloro and Robert C. Gosselin (eds.), Hemostasis and Thrombosis: Methods and Protocols, Methods in Molecular Biology, vol. 2663, https://doi.org/10.1007/978-1-0716-3175-1_18, © The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature 2023
Abstract
Lupus anticoagulants are antibodies directed to phospholipids (PL) and in particular represent an in vitro phenomenon where these antibodies bind to PL in coagulation reagents creating an artificial prolongation of the activated partial thromboplastin time (APTT) and sometimes also prothrombin time (PT) clotting times. Prolongation of LA-induced clotting times is typically not associated with bleeding risk. However, the degree of prolongation may cause some trepidation for clinicians who will be performing delicate surgeries or those with high bleeding risks, so a mechanism to alleviate their anxiety may be prudent. As such, an autoneutralizing method to mitigate or eliminate the LA effect on the PT and APTT may be beneficial. In this document, the detailing of an autoneutralizing procedure to diminish the LA effect on the PT and APTT will be provided.
Mr. Gosselin adds: Taking our old historical observation and putting it to good clinical use…I’ve used it several times to edify clinicians about LAC effect prolonging PT/APTT, but with no underlying factor deficiency. I had one case where there was LAC and a weak underlying factor deficiency. I think this process could also work for monitoring warfarin in patients with prolonged baseline due to LAC instead of factor assays (chromo or chrono).
A 2012 article addressing PTT sensitivity to LAC (available from your library): Fritsma GA, Dembitzer FR, Randhawa A, Marques MB, Van Cott EM, Adcock-Funk D, Peerschke EI. Recommendations for appropriate activated partial thromboplastin time reagent selection and utilization. Am J Clin Pathol. 2012 Jun;137(6):904-8. doi: 10.1309/AJCP3J1ZKYBFQXJM. PMID: 22586049.
Abstract
The activated partial thromboplastin time (aPTT) is widely used as a screening coagulation test and for monitoring unfractionated heparin therapy. Various commercial reagents are available, with different performance characteristics, particularly responsiveness to the lupus anticoagulant (LA). Because aPTT reagent selection significantly affects the interpretation of results, we reviewed College of American Pathologists proficiency testing data involving approximately 4,000 coagulation laboratories, and conducted a survey of coagulation laboratories (n = 93) using The Fritsma Factor hemostasis Web site to determine the basis for aPTT reagent selection. The data demonstrate that for routine aPTT testing, most laboratories use reagents with high/moderate responsiveness to LA. Significant misunderstanding was apparent regarding the use of appropriate aPTT reagent for routine testing and LA identification. We recommend aPTT reagents with low LA responsiveness to screen for coagulation factor deficiencies and heparin monitoring, and suggest continued education of laboratory professionals and reagent manufacturers about appropriate aPTT reagent use.
Response from Dr. Uljon, 6-12-16: we resulted 400 low FXI patients during lookback, and I found 2 patients that displayed this behavior. Both had a known FXI mutation, and I resulted normal levels after 1:160 dilution and multiplication. I just learned that Werfen makes an ellagic acid-based reagent (SynthAFax)–so I think that is the best answer. Whenever I see FXI or FXII increasing with dilution, I will use the ellagic acid-based reagent to rule out deficiencies.
Now, can someone tell me why I need three dilutions for every FXI in the first place? It decreases precision, leaves room for error, and has not “found” some phantom inhibitor that can’t be detected using LAC tests or a FXI Bethesda?! I would not have gotten into any of these situations with FXI if we had just reported the 1:10.
From Geo: The multiple-dilution approach makes sense when measuring FVIII or FIX, given the prevalence of specific inhibitors, whereas the prevalence of naturally developing FXI inhibitors is low. Meanwhile, several researchers continue to work on FXI inhibitor antithrombotics, so we may soon have more reason to use FIX assays.
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