Abstract
Abstract 3485
Poster Board III-422
The clinical response of hemophilia patients with inhibitors to bypassing agent therapy can be unexpectedly poor. Indeed, there are reports of “poor responders” who either require alternative treatment or dose escalation. The lack of correlation between routine coagulation assays or factor antigen/activity levels with clinical efficacy contributes to the problem in these patients. Analysis of the clotting characteristics of “poor responders” is limited. In a recent study of rFVIIa PK in 10 non-bleeding hemophilia A and B patients, we noted that four of the ten had a remarkable attenuated response as seen in whole blood assays. We report here a comparison of clotting parameters in the “poor responders” versus robust responders to rFVIIa infusion, and attempt to define what might be the source of the altered response.
Ten severe FVIII or FIX deficient patients in a non-bleeding state were infused with a single-dose of rFVIIa (90 μg/kg). Platelet contractile force (PCF), clot structure (CEM,MA,MCF), and clot formation time (FOT,R,CT) were analyzed in whole blood by Hemodyne HAS, Thromboelastography, and Rotation Thromboelastography before, and at 0.5,1,2,4 and 6 hours following rFVIIa dosing. Thrombin generation parameters (Tlag, Cmax) were measured in PRP by the Calibrated Automated Thrombogram. Plasma concentrations of FVII:C and FVII:Ag were measured at each time point. Patients with a clot formation time (FOT, R, CT) ≥ 15 minutes following rFVIIa dosing were termed “Poor Responders”.
There were few inter-group differences in baseline clotting characteristics. The values for all parameters are provided in Table 1. FVII PK were not different between the Responders and Poor-Responders. This can be appreciated from the PK parameters listed in the table as well as from relative lack of variability for the composite rFVIIa levels seen for the entire group of 10 patients (Figure 1, panels 1 and 2). Both groups had similar FVIIa Cmax and total body clearance values. However, the responders made significantly stronger clots (PCF, CEM) as can be appreciated in table 1 and even more dramatically in panels 3 and 4 of figure 1. In these panels, the responders and poor responders are plotted as separate groups. Even though the groups are small (n=6 vs 4) the minimal response (both in magnitude and duration) to rFVIIa in terms of platelet function (PCF) and clot structure (CEM) is grossly apparent. All three whole blood assays revealed significantly shorter time to clot formation (R, FOT, CT) in the responders. However, the MA (TEG) and MCF (ROTEG), and thrombin generation parameters (Tlag, max) failed to show significant inter-group differences following rFVIIa dosing.
| Parameter | Responders (N=6) | Poor-Responders (N=4) | P-Value |
|---|---|---|---|
| FVII:C (IU/mL) Cmax | 44.1 (13.9) | 34.0 (4.2) | NS |
| FVII:Ag (ng/mL) Cmax | 984.2 (194.4) | 865.3 (67.0) | NS |
| FVII:C Clearance (mL/h*kg) | 43.1 (17.1) | 62.2 (5.3) | NS |
| FVII:Ag Clearance (mL/h*kg) | 23.6 (6.3) | 26.9 (2.7) | NS |
| PCF (Kdynes) | 6.6 (1.5) | 1.5 (1.0) | <0.001 |
| CEM (Kdyne/cm2) | 20.0 (4.7) | 3.4 (2.6) | <0.001 |
| FOT (minutes) | 8.6 (1.0) | 17.5 (2.4) | <0.001 |
| CT (seconds) | 513.2 (68.3) | 1128.0 (228.9) | 0.001 |
| MCF (mm) | 61.6 (4.2) | 58.3 (2.3) | NS |
| R (minutes) | 7.9 (0.7) | 14.5 (2.8) | 0.002 |
| MA (mm) | 62.7 (3.3) | 59.2 (3.0) | NS |
| Thrombin Tlag (minutes) | 10.2 (0.9) | 11.4 (1.1) | NS |
| Thrombin Cmax(nM) | 2039.5 (541.1) | 1508.3 (152.4) | NS |
| Parameter | Responders (N=6) | Poor-Responders (N=4) | P-Value |
|---|---|---|---|
| FVII:C (IU/mL) Cmax | 44.1 (13.9) | 34.0 (4.2) | NS |
| FVII:Ag (ng/mL) Cmax | 984.2 (194.4) | 865.3 (67.0) | NS |
| FVII:C Clearance (mL/h*kg) | 43.1 (17.1) | 62.2 (5.3) | NS |
| FVII:Ag Clearance (mL/h*kg) | 23.6 (6.3) | 26.9 (2.7) | NS |
| PCF (Kdynes) | 6.6 (1.5) | 1.5 (1.0) | <0.001 |
| CEM (Kdyne/cm2) | 20.0 (4.7) | 3.4 (2.6) | <0.001 |
| FOT (minutes) | 8.6 (1.0) | 17.5 (2.4) | <0.001 |
| CT (seconds) | 513.2 (68.3) | 1128.0 (228.9) | 0.001 |
| MCF (mm) | 61.6 (4.2) | 58.3 (2.3) | NS |
| R (minutes) | 7.9 (0.7) | 14.5 (2.8) | 0.002 |
| MA (mm) | 62.7 (3.3) | 59.2 (3.0) | NS |
| Thrombin Tlag (minutes) | 10.2 (0.9) | 11.4 (1.1) | NS |
| Thrombin Cmax(nM) | 2039.5 (541.1) | 1508.3 (152.4) | NS |
These data suggest that the differences observed between Responders and Poor Responders are not due to PK influences, but may be related to differences in the effects of thrombin on platelet function. It is possible that whole blood assays may serve as a tool to monitor the clinical effects of rFVIIa. Changes in clot stiffness were better characterized by CEM compared to MA and MCF. There was good correlation between FOT, R and CT parameters to detect onset of clot formation. The thrombin parameters were highly dependent on sample type and triggering agent and did not significantly vary between the two groups. Further studies are needed to clarify the clinical significance of these findings.
Ezban:NovoNordisk A/S: Employment. Hedner:NovoNordisk A/S: Employment.
