1. The Use of Global Assays to Monitor Emicizumab Prophylactic Therapy in Patients with Hemophilia A with Inhibitors
Mid-Atlantic Region III HTCs Annual Meeting
Alexandria, VA
March 15, 2019
Janice G. Kuhn, RN, MPH
Virginia Commonwealth University

2. Disclosures
None

3. Donald F. Brophy, Pharm.D., M.Sc., FCCP, BCPS
Nancy L. and Ronald H. McFarlane Professor of Pharmacy
Chairman, Department of Pharmacotherapy & Outcomes Science
Professor of Medicine
Virginia Commonwealth University School of Pharmacy
Erika Martin, MT Research Professor
DOI: /hae.13689

4. Emicizumab
Humanized bi-specific antibody directed against activated factor IX (FIXa) and factor X (FX).
Functions as a bridge between FIXa and FX in the tenase complex, thereby mimicking the co-factor function of activated factor VIII.

5. Emicizumab: Problems with laboratory monitoring
Emicizumab therapy interferes with any coagulation test that measures the intrinsic coagulation pathway, including:
Activated clotting time
Bethesda FVIII inhibitor titer assay
Single factor assays
Traditional coagulation tests to quantify response to therapy are unreliable.
Additionally, significant inter-patient variance in emicizumab metabolism and/or the potential for antibody development to the drug underscore the need for accurate laboratory monitoring

6. Can we use global assays to measure response to Emicizumab: a Case Study

7. Thromboelastography (TEG) What does it do?
Demonstrates the contributions and interactions of hemostatic components during clotting, especially the role of the platelet
Measures the hemostatic potential of the blood at a given point in time.
Is not a “clotting assay” which depends upon comparison to a “standard” dilutional response to the presence of factor between a control and the sample

8. TEG® Data Related to Pathways

9. TEG® R and K Time
R–time
The “waiting period” until a the fibrin formation
K–time
The time it takes to achieve a certain level of clot strength (amplitude 20 mm)

10. What influences R and K time?
Factor deficiency
Anti-coagulation
Residual heparin
Severe hypofibrinogenemia
Severe thrombocytopenia
R and K time 
Hypercoagulable state

11. TEG® Pattern Recognition

12. Caveats of interpretation of TEG®
In the clinical setting, TEGs are often used to monitor hypo or hypercoagulable states
Cardiac bypass surgery
Echo
High-risk OB
Trauma
Therefore, target values may vary.

13. Thrombin Generation Assay Thrombin burst: the penultimate event in hemostasis
Thrombosis
time
thrombin
Normal
Bleeding
Tripodi A. The long-awaited whole-blood thrombin generation test. Clin Chem 2012; 58:

14. Thrombin Generation Assay What are we measuring?
Clot forms
Clotting Time
Calibrated Automated Thrombogram (CAT) system measurement parameters:
Lag Time- Time to initial thrombin generation
Peak- Maximum amount of thrombin generated
Time to peak-Time to generate maximum amount of thrombin
ETP- ---Area under the curve; overall potential to generate thrombin
VI- Velocity index/ rate of thrombin formation

15. Thrombin Generation Assay
Factor VIII or Factor IX Deficiency
Normal Thrombin Generation
Emicizumab Action on FVIII Deficiency
Emicizumab

16. Patient 1 Severe Factor VIII Deficiency with Inhibitor Titer of 1.9 BU
Prior to emicizumab:
ABR: bleeds/year
On-demand therapy: rFVIII 100U/kg every 12hr, typically for 48hr to treat bleeds
Surgical prophylaxis: rFVIIa
Received emicizumab 3 mg/kg subcutaneously initially, followed by 1.5 mg/kg subcutaneously 1 month later

17. Patient 1: TEG results TEG Normal Range: R-time: 3-8 min
k-time: 1-3 min
Angle: degrees
MA: mm

18. TEG results pre/post in comparison to mild Factor VIII Deficiency and control

19. Patient 1: TGA Results

20. TGA results TGA Normal Range: Lag-time: 0.5-5 min
ETP: nM/min
Thrombin Peak: nM

21. Patient 2 Severe Factor VIII Deficiency with Inhibitor of 7.1 BU
Prior to emicizumab:
ABR: 4 bleeds/year
On-demand therapy: FEIBA 75 mg/kg every 12hr
Received emicizumab 3 mg/kg subcutaneously initially, followed by 1.5 mg/kg subcutaneously 1 month later

22. Patient 2: TEG results

24. Patient 2: TGA TGA Normal Range: Lag-time: 0.5-5 min
ETP: nM/min
Thrombin Peak: nM

26. Conclusions
Global coagulation assays successfully monitored the pharmacodynamic response to emicizumab.
Normalization of TEG viscoelastic parameters and marked improvements in thrombin generation at 1 and 2 months post‐dose, compared to baseline, consistent with a mild HA phenotype was observed.
Clinicians should be aware of the potential pitfalls with using routine coagulation monitoring for emicizumab and should consider using other global coagulation measures to assess emicizumab activity.
Larger studies are needed

27. Further considerations
Can you use TEG or TGA for pre-surgical assessment of bleeding risk?
All labs were in a non-bleeding state. Would results change in a bleeding state?
Would the TEG predict response to BPA from in-vitro response to spiking studies with TGA? Would TEG give you additional information (would it push the R value too low?)
Why is there a difference in lag times between TEG and TGA?