Coumadin Therapy: Molecular Screens?

Coumadin Therapy: Molecular Screens?
Feb 15, 2020 2:17pm

George is preparing updates for several of our Educational Modules and is currently revising the Coumadin (Warfarin) module of the Antithrombotic Therapy series. While DOAC therapy is rapidly replacing Coumadin as the mainstay for stroke prevention in non-valvular atrial fibrillation and for prophylaxis following total hip and knee replacement surgery, Coumadin is still in everyday use.

In 2008 several studies (not referenced here) demonstrated that two prevalent polymorphisms in the cytochrome oxidase metabolic pathway, namely CYP2C9*2 and CYP2C9*3, along with a common VCORKC1 G&gt ;A mutation were associated with "Coumadin sensitivity." The FDA responded with a "black box" recommendation to screen for these three polymorphisms prior to Coumadin therapy initiation and reducing the starting dosage if any were present. Several molecular diagnostic manufactureres scrambled to develop rapid turnaround assays. However, George spoke with a hematologist in 2009 who suggested the variables of age, diet, and comorbidity created more profound effects on patient's Coumadin response and that molecular testing would take a back seat. Since then, it seems relatively few facilities instituted a policy of routine mutation screening.


The most recent guidelines for Coumadin management appear in Johnson JA, Caudle KE, Gong L, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for pharmacogenetics-guided warfarin dosing: 2017 Update. Clin Pharmacol Ther. 2017; 102: 397–404. doi:10.1002/cpt.668. Among many authoritative recommendations, the authors demonstrate that the CYP2C9*2, CYP2C9*3, and VCORKC1 G&gt ;A are not prevalent in people of Asian or African parentage and that alternative mutations should be applied and targeted to people groups. Further, the 2019 Coumadin, while it provides dosage recommendations, also includes the statement, "If the patient’s CYP2C9 and VKORC1 genotypes are not known, the initial dose of COUMADIN is usually 2 to 5 mg once daily. Determine each patient’s dosing needs by close monitoring of the INR response and consideration of the indication being treated. Typical maintenance doses are 2 to 10 mg once daily."

Sowe are looking for recommendations from clinicians. To prime the pump, George contacted colleague and friend Lance Williams, MD, Senior Associate Consultant. Transfusion Medicine and Apheresis, Department of Laboratory Medicine and Pathology. Mayo Clinic College of Medicine and Science in Scottsdale. Hie comments, with permission, are:

At the Mayo Clinic in Arizona, this is not common practice.  The most likely reason are...

  • I’m not sure how many insurance companies are reimbursing for the testing.
  • It is not an automatic part of our order set.
  • Things like this are often only considered when the patient isn’t responding as expected.

Dr. Williams referenced two facilities that he knows are performing molecular screens, one of which is being done on a research protocol. So, please comment on your facilitiy's Coumadin therapy policy by clicking on comments below or emailing George at george@fritsmafactor.com. Thanks in advance for your contributions.

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George is preparing updates for several of our Educational Modules and is currently revising the Coumadin (Warfarin) module of the Antithrombotic Therapy series. While DOAC therapy is rapidly replacing Coumadin as the mainstay for stroke prevention in non-valvular atrial fibrillation and for prophylaxis following total hip and knee replacement surgery, Coumadin is still in everyday use.

In 2008 several studies (not referenced here) demonstrated that two prevalent polymorphisms in the cytochrome oxidase metabolic pathway, namely CYP2C9*2 and CYP2C9*3, along with a common VCORKC1 G&gt ;A mutation were associated with "Coumadin sensitivity." The FDA responded with a "black box" recommendation to screen for these three polymorphisms prior to Coumadin therapy initiation and reducing the starting dosage if any were present. Several molecular diagnostic manufactureres scrambled to develop rapid turnaround assays. However, George spoke with a hematologist in 2009 who suggested the variables of age, diet, and comorbidity created more profound effects on patient's Coumadin response and that molecular testing would take a back seat. Since then, it seems relatively few facilities instituted a policy of routine mutation screening.


The most recent guidelines for Coumadin management appear in Johnson JA, Caudle KE, Gong L, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for pharmacogenetics-guided warfarin dosing: 2017 Update. Clin Pharmacol Ther. 2017; 102: 397–404. doi:10.1002/cpt.668. Among many authoritative recommendations, the authors demonstrate that the CYP2C9*2, CYP2C9*3, and VCORKC1 G&gt ;A are not prevalent in people of Asian or African parentage and that alternative mutations should be applied and targeted to people groups. Further, the 2019 Coumadin, while it provides dosage recommendations, also includes the statement, "If the patient’s CYP2C9 and VKORC1 genotypes are not known, the initial dose of COUMADIN is usually 2 to 5 mg once daily. Determine each patient’s dosing needs by close monitoring of the INR response and consideration of the indication being treated. Typical maintenance doses are 2 to 10 mg once daily."

Sowe are looking for recommendations from clinicians. To prime the pump, George contacted colleague and friend Lance Williams, MD, Senior Associate Consultant. Transfusion Medicine and Apheresis, Department of Laboratory Medicine and Pathology. Mayo Clinic College of Medicine and Science in Scottsdale. Hie comments, with permission, are:

At the Mayo Clinic in Arizona, this is not common practice.  The most likely reason are...

  • I’m not sure how many insurance companies are reimbursing for the testing.
  • It is not an automatic part of our order set.
  • Things like this are often only considered when the patient isn’t responding as expected.

Dr. Williams referenced two facilities that he knows are performing molecular screens, one of which is being done on a research protocol. So, please comment on your facilitiy's Coumadin therapy policy by clicking on comments below or emailing George at george@fritsmafactor.com. Thanks in advance for your contributions.

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