Inherited Thrombophilia Testing as Observed at a Reference Laboratory

1. Inherited Thrombophilia Testing as Observed at a Reference Laboratory Brian Jackson, MD, MS Medical Director of Informatics

2. Introduction • Pathologic thrombosis is common • Many patients are worked up for inherited thrombophilia • Testing for inherited thrombophilia is a complex and changing area of the laboratory • Some evidence exists that physicians have not kept on changes in this area

3. CAP Consensus Conference XXXVI: Diagnostic Issues in Thrombophilia • 2nd generation APC resistance assays are equivalent to V Leiden direct mutation detection. • For AT and Protein C and S, functional assays (and Protein S free Ag) are the appropriate primary tests. • Total AT, Protein C and S may have limited role • Overall, inherited thrombophilia tests may be useful in determining etiology and family counseling, but have a limited role in influencing treatment.

4. Suggested Ordering Algorithm Test for most common defect (V Leiden by functional assay) Positive Result? Test for next most common (Prothrombin) No Yes Stop Etc.

5. Key Questions • To what extent is ordering consistent with: • Recommendations of the CAP Consensus Conference? • ARUP’s suggested ordering algorithm?

6. ARUP Overview • Reference laboratory • Owned by University of Utah • Several hundred hospital clients nationwide • Data warehouse going back to 1997 • Test orders and results • Age and sex of patients • No other clinical information

7. Datamining: Potential Biases • ARUP client base modestly skewed toward academic medical centers • Only have data on tests performed at ARUP, not those performed by our clients in-house • Volumes are biased toward the most esoteric tests

8. Test orders analyzed Dec 03-Nov04 • V Leiden • Direct mutation and APC resistance • Prothrombin mutation detection • Antithrombin • Functional and total antigen • Protein C • Functional and total antigen • Protein S • Functional, free Ag and total Ag

9. If these tests were used optimally, what ordering patterns would we expect to see? • Volume distributions would reflect prevalence • V Leiden orders > Prothrombin orders > etc. • Functional V Leiden orders >> DNA test • Functional AT orders >> Total AT Ag • Functional Prot. C orders >> Total C Ag • Function Prot S + Free Ag >> Total S Ag

10. Test Volumes by Category

11. Test Volume Ratios by Category

12. Antithrombin Orders by Specimen

13. Protein C Orders by Specimen

14. Protein S Orders by Specimen

15. Specific Conclusions • Order volumes do not follow disease prevalence • Protein C and Protein S ordered too much relative to V Leiden • Prothrombin not ordered often enough relative to Prot C, S, AT • Second-line tests for Protein S, Protein C and Antithrombin are ordered about as often as first-line tests

16. General Conclusions • On average, diagnosis process for hereditary thrombophilia is inefficient and possibly unreliable • Laboratories need better mechanisms to support appropriate test ordering