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Autoanti-FVIII and the Bethesda Titer

From Kim Kinney. (Clarian gets the most interesting cases.)

Hi George.
We have a patient with an acquired factor VIII (FVIII) inhibitor.  He started out having <1% VIII, but he is now up to 33%.  He has had a Bethesda titer all along, but it is starting to go down.  One thing I noticed is that when his VIII level got above around 30% we started having issues with his Bethesda titer in that the lower dilutions did not make much sense.  We had a 1:2 dilution with residual FVIII of 50% but then it went down with more dilutions until we hit the 1:16 dilution and it was back up to 51%.  From there, the FVIII went up in order.  I know that acquired antibodies follow second order kinetics and are not always accurate.  What is the VIII level above which you really should not do a Bethesda titer?  I would like to be able to tell docs above  certain VIII we do not do titers. Thanks for the help.

Hi, Kim. Thank you for your question. Acquired factor inhibitors are IgG autoantibodies that usually bind the C2 domain of FVIII. Unlike alloanti-FVIII, autoanti-FVIII antibodies have complex second order kinetics. This means that in a Bethesda titer, some FVIII remains unbound following 37°C incubation, creating the situation in which as you make further dilutions the results, expressed as Bethesda units, rise. I’ve always found this hard to explain, and direct readers to Kasper CK, Laboratory diagnosis of factor VIII inhibitors in Kessler C, Garvey MB, Green D, Kasper CK, Lusher J. Acquired Hemophilia, 2nd edition 1995. Excerpta Medica, Inc. Princton, NJ. This is a great little book, by the way, and it may be out of print, so I guard mine carefully. I hope you have one on your shelf.

So, the Bethesda titer in acquired hemophilia is a rough approximation, and we would be well-served to find something new, such as an enzyme immunoassay. At the April 14-17 Mayo Medical Laboratories Coagulation Testing Quality Conference, during a presentation on Factor VIII Inhibitor Evaluation by Dr. Rajiv Pruthi I heard a participant describing a sort of “prozone” (receptor-filling) effect in a smaller Bethesda titer dilution. I’d not heard of this before, but it may explain why you had factitious 50% inhibition in the 1:2 dilution. Also during the presentation there was some discussion of a FVIII limit above which the Bethesda is not performed, but it was inconclusive, and Kasper does not address it in her chapter. This is strictly anecdotal, but I’ve seen either 30% or 40% used most often. I will post this as next week’s quick question as soon as this week’s platelet aggregation question has been up for enough time.

I hope this is helpful, and again I thank you for your question. We’ll have more information on a cutoff next week. Geo.

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