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Measuring Factor Inhibitors: Bethesda Titer

Here is a delightful message from my colleague Betty Ciesla at Morgan State University in Baltimore.

Hi George, I am trying to explain the Bethesda titer, which I find difficult. My students do too. I understand you make a 1:1 mix of patient plasma and control plasma, incubate, test using the PTT then you make a control mix? What is that and how does it fit in? And then what?

Also, how do we decide who is a low responder and high responder and how does that affect their treatment?

I have re-read your explanation in Rodak’s 2nd edition millions of time but it is just not doing it for me. Please help. Betty Ciesla

Betty, please see my discussion below…
Hi, Betty. I hate to admit it, but you are right. The discussion on page 692 of the third edition of Rodak is about the same as the second, and you really can’t translate it into action. Bethesda titer is a difficult concept to explain, and in a teaching environment you usually don’t have the resources and time to enable students to perform the titer.

I went back to a procedure I wrote with Flo Newlin, Rebecca Jensen, Lynn Quarles and Gordon Ens for our 1998 Coagulation Handbook, published by Clinical Hemostasis Review, and I’ll paraphrase it here. It uses factor VIII inhibitor as its example:

Prepare two-fold serial dilutions of patient plasma in buffered saline. To each dilution add an equal volume of reagent normal plasma that contains 100% factor VIII, and incubate the series 2 hours at 37 degrees centigrade. Simultaneously incubate an aliquot of the same reagent normal plasma.

Perform a factor VIII activity assay on all incubated dilutions and on the control plasma. The dilution that yields a factor VIII activity that is 50% of the control activity is the endpoint, and the reciprocal of the dilution is the result in Bethesda units.

So if the control result came to 100% factor VIII activity and the 1:16 dilution gave you a result of 50% factor VIII activity, the result would be 16 Bethesda units.

Hemophilia patients who have inhibitors maintain a relatively consistent titer over the years. According to Boggio LN and Kessler CM, who wrote Chapter 4, Hemophilia A and B, in Kitchens, Alving, and Kessler, Consultative Hemostasis and Thrombosis, if the inhibitor titer is less than 5 BU, treat with high doses of factor VIII concentrate, but if it is greater than 5 BU, use a factor VIII bypassing therapeutic like prothrombin complex concentrate, FEIBA, or NovoSeven.

I hope this discussion is clear. I think I will use it if we write another edition of Rodak. Please show it to your students and get their opinions. Geo

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