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Prothrombin Time Mixing Studies

A colleague recently contacted George about prothrombin time mixing studies. Apparently, the College of American Pathologists provided a PT mixing study challenge in a recent survey. George discussed PT mixing studies with Fritsma Factor advisers Larry Brace, PhD and Dave McGlasson who helped list reasons for not doing them:

Reasons for not performing a PT mixing study are…

  • The combination of prolonged PT and normal PTT leads to a presumed diagnosis of rare congenital factor VII deficiency without need for a mixing study.
  • All coagulopathies except VII prolong the PTT, so a PTT mixing study would be the first choice.
  • There are few inhibitors that affect prothrombin, V, VII, and X, particularly since we no longer use bovine fibrin glue in surgery.
  • The most likely cause for prothrombin, V, VII, and X deficiency is liver disease, and the PT mix doesn’t add much to the diagnosis.

We were unable to find compelling reasons for performing the PT mixing study, so we are inviting you to share your experience.

Comments (2)
Mixing Studies
Dec 21, 2017 12:19pm

From George on behalf of Dr.
From George on behalf of Dr. Ravinda (Ravi) Sarode, University of Texas Southwestern Medical Center:
As you know I am totally opposed to routine mixing studies for PTT and definitely not for PT because these are old approaches when we did not know about or have better tests for lupus anticoagulant. These can lead in the wrong direction and to wrong treatment. I have ample examples that caused harm to the patient including a death. These mixing studies are not standardized and hence many ‘non-expert’ labs do them and they often don’t use proper normal pooled plasma, may not use platelet free plasma and of course don’t use a control and 2 hour incubation at 37oC. I have yet to find usefulness for PT mixing! I may do it only if we have ruled out common causes first–usually congenital FVII deficiency or liver disease.

Dec 20, 2017 1:55am

The combination of prolonged
The combination of prolonged PT and normal APTT may also reflect early onset VKA therapy, but in any case I would agree that this would not warrant a PT mixing study. Also agree that there is no obvious need to perform a stand alone PT mixing study. However, a PT mixing study might be useful when combined with an APTT mixing study, should both PT and APTT be abnormal. Might help point to next stage investigation for differential ‘diagnosis’ of several plausible events (e.g., FV inhibitor, EDTA contamination, combined FV/FVIII deficiency, heparin contamination, etc), although in some cases is just as easy to start testing factor levels. Probably also time to plug my favorite references here:
1. Kershaw G, Orellana D. Mixing tests: diagnostic aides in the investigation of prolonged prothrombin times and activated partial thromboplastin times. Semin Thromb Hemost. 2013;39:283–90.
2. Kershaw G. Performance and interpretation of mixing tests in coagulation. Methods Mol Biol. 2017;1646:85–90.

And don’t predict the future absence of FV inhibitors just yet. Yes, they have declined in number due to reduced surgical use of bovine products, but we had a very interesting case last year (unrelated to cows) that we are currently writing up.

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