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November Quick Question: Thrombophilia

Here  are the results of our November, 2017 Quick Question, answered by 60 respondents:
Question: When should you perform an antithrombin, protein C, and protein S profile?

a. Soon after starting anticoagulant therapy: chosen by 0 respondents, 0%
b. Just after a thrombotic event but before starting anticoagulant: chosen by 10 respondents, 17%
c. Seven days after discontinuing anticoagulant therapy: chosen by 6 respondents, 10%
d. Ten days after discontinuing anticoagulant therapy: chosen by 4 respondents, 7%
e. Fourteen days after discontinuing anticoagulant therapy: chosen by 20 respondents, 33%
f. Six weeks after discontinuing anticoagulant therapy: chosen by 20 respondents, 33%

As predicted, we have little consensus. This question arose subsequent to the October 19, 2017 posting of an American Society for Clinical Pathology recommendation on the Choosing Wisely site, “Do not test for Protein C, Protein S, or Antithrombin (ATIII) levels during an active clotting event to diagnose a hereditary deficiency because these tests are not analytically accurate during an active clotting event.”

The Choosing Wisely recommendation authors cite three authorities, all of whom document that the antithrombin (AT), protein C (PC), and protein S (PS) values are not analytically accurate when collected during an acute thrombotic event, as they are acute phase reactants.

The same authorities conclude that PC and PS, both vitamin K dependent proteins, are reduced during Coumadin therapy, as Coumadin is a vitamin K antagonist, and that AT levels rise during Coumadin therapy, so laboratory scientists avoid testing during Coumadin therapy.

To those who selected answer B, we recommend you change your practice, as the results obtained during acute thrombosis cannot be used to plan subsequent therapy. As a generalization, we avoid collecting thrombosis risk testing profiles from inpatients, instead waiting for a period subsequent to resolution of the episode and subsequent to the time anticoagulant therapy is discontinued.

So when do we collect the thrombosis risk profile? We posted three possibilities in the Quick Question, but of course some of us may choose longer or shorter intervals. The answer relates to anticoagulant half-life and the time required for AT, PC, and PS levels to normalize subsequent to therapy. For instance, the INR returns to normal at approximately five days following discontinuance of Coumadin (warfarin) therapy, however, according to John A. Heit, MD, Thrombophilia: Clinical and Laboratory Assessment and Management, chapter 14 in Kitchens CS, Kessler, CM, and Konkle BA, “Consutative Hemostasis and Thrombosis, Third Edition, Elsiver, 2013, the effect of warfarin on PS may not resolve for up to six weeks.

Many clinicians favor direct oral anticoagulant (DOAC) therapy over Coumadin, as the DOACs are cleared for post-thrombotic therapy. DOACs affect clot-based testing, consequently, many of the thrombosis risk tests are unreliable during therapy. Assuming normal renal function, the DOACs boast half-lives between 12 and 18 hours, and we assume that plasma procoagulant levels subsequntly normalize within a few hours, so in theory, seven days after discontinuing a DOAC may be enough time.

In addition to AT, PC, and PS, thrombosis risk profiles include clot-base lupus anticoagulant (LAC) testing, anticariolipin antibody (ACA) and anti-ß-2-glycoprotein 1 assays, activated protein C resistance (APCR) ratios, confirmed by molecular factor V Leiden mutation testing, and the prothrombin G20210A molecular assay. The molecular tests and the enzyme immunoassays for ACA and anti-ß-2-glycoprotein 1 may be assayed during anticoagulant therapy, however the clot-based assays LAC and APCR must be avoided.

George thanks ASCLS President Deb Rodahl, ASCLS Executive Vice President, Jim Flanigan, Dr. Cathy Otto, Rutgers University, and Prof. Brianna Miller, University of Alabama at Birmingham for their heads-up regarding the Choosing Wisely recommendation.

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