More on Mixing Studies and the RVVT

Hi George,

I have a further question about “Interpreting a prolonged PT and PTT,” posted April 16. My question is, “what if the PT and PTT are prolonged and correct upon mixing with normal reagent plasma, but the Russell viper venom time (RVVT) is normal?”

This question is part of a coagulation project I’m doing for the University of Cincinnati Clinical Laboratory Science Distance Learning program. I enjoyed your lectures during the hematology/coagulation quarter, fall of 2008.

Anyway, I was wondering if I’m on the right track.  All I need to do is discover the most likely factor affected in this scenario. The normal RVVT test indicates that factor X was activated and therefore the common pathway is functional, right? So, I can rule out X, V, II, and I. In this case the factors in question would be VII, XI, IX, VIII. Factors XI, IX and VIII are only involved in the intrinsic pathway while VII is involved in the extrinsic. I am completely stumped. Could you let me know if my thinking so far is reasonable?  Any help is appreciated.

Thank you, Jenny Van Orsow, University of Cincinnati CLSDL student.

Hi, Jenny. Thank you for your question, and you are justified in being stumped. I’m slow in answering because I am now busy coordinating the University of Cincinnati Distance Learning Molecular Diagnostics course. Teaching online for Cincinnati is just too much fun for one man to enjoy in his man-cave.

From your message, you are attempting to identify a congenital single factor deficiency that causes prolonged PT and PTT results which correct when mixed with normal reagent plasma. There is a normal RVVT and all other screening results are normal.

I may be missing some piece of information because this combination doesn’t lead to a congenital single factor deficiency. Let’s work through the sequence.

The PT, which tests the extrinsic system beginning at the level of factor VII is prolonged by deficiencies ofVII, X, V, prothrombin (II), and fibrinogen (I) when fibrinogen is profoundly low at <100 mg/dL. The PTT, which tests the intrinsic system beginning at the level of factor XII is prolonged by deficiencies of XII, PK, HMWK, XI, IX, VIII, X, V, prothrombin (II), and fibrinogen (I) at <100 mg/dL. We usually ignore XII, PK and HMWK because their absence is not associated with bleeding. The phrase “all other screening tests are normal” indicates a fibrinogen level or thrombin time was performed, and that the fibrinogen concentration is normal. This narrows the answer to a deficiency of X, V, or prothrombin (II).

The RVVT activates the extrinsic system at the level of factor X, so it is prolonged by deficiency of V, prothrombin (II) or fibrinogen (which we ruled out), but not factor VII. So the combination of a prolonged PT and normal RVVT narrows the deficiency to factor VII. But factor VII is not part of our conclusion because the PTT was prolonged.

So either there is something missing from the question, or the writer is looking for an acquired multiple factor deficiency. I can think of one possibility, but it is going to sound contrived. As you know, vitamin K deficiency is common and reduces the production of functional prothrombin (II), VII, IX and X. Let’s say someone is in early vitamin K deficiency, or is just starting coumadin (vitamin K antagonist) therapy, and the only factors that are reduced are VII and IX. It could happen because the half-life of VII is 6 hours and IX is 24 hours, whereas prothrombin and X have longer half-lives. You can look up their half-lives on page 702 of the Rodak Hematology textbook. Thus, the combination of VII and IX deficiency could prolong the PT and PTT but not the RVVT. Remember, I warned you this would sound contrived, and I’d love to learn of other scenarios from our participants.

A further comment on RVVT: as you can see from our discussion, the RVVT adds little to routine coagulation screening and has been off the market for years. The dilute RVVT (DRVVT), however, is a mainstay of lupus anticoagulant screening and confirmation, and is used in every lab that runs the lupus anticoagulant profile. I hope this helps, and feel free to follow up with additional information. Geo.