Abstract Number: LPB0114
Meeting: ISTH 2021 Congress
Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia - Clinical
Background: Hemophilia A (HA) patients on emicizumab still experience breakthrough bleeding and may need treatment with activated prothrombin complex concentrate (aPCC). A concomitant drug reaction between emicizumab and aPCC resulting in thrombotic events was noted in the HAVEN 1 study which led to a reduction in the use of aPCC. Previous in vitro studies demonstrated excess thrombin generation (TG) when aPCC was spiked into simulated hemophilia inhibitor plasma with emicizumab.
Aims: To determine TG of in vitro spiking and in vivo administration of aPCC at escalating concentrations/doses in patients on emicizumab.
Methods: Patients with severe HA with inhibitors who are currently on emicizumab had TG performed at baseline and after spiking clinically relevant concentrations of aPCC in vitro into blood samples. Then, the same patients had TG performed at baseline and following an infusion of escalating doses of aPCC (5–75 U/kg) in the in vivo portion of the study. Once a patient’s endogenous thrombin potential (ETP) was ≥90% of the pooled normal plasma’s ETP, no further escalation was done.
Results: Nine patients with severe HA and inhibitors currently on emicizumab were enrolled in the study. The summary statistics are provided in Table 1.
| Patient number | Dose of aPCC at final visit | Lag time | ETP | Peak thrombin | Ratio of Patient’s ETP to Pooled Normal Plasma’s ETP | Adverse events |
| SAFE-01 | 50 U/kg | 4.17 | 724.62 | 47.7 | *71.85 % | No |
| SAFE-02 | 50 U/kg | 4.1 | 986.16 | 62.73 | *88.45 % | No |
| SAFE-03 | 75 U/kg | 4 | 1415.16 | 90.95 | 106.74 % | No |
| SAFE-04 | 50 U/kg | 4.94 | 1113.72 | 70.75 | 96.13 % | No |
| SAFE-05 | 25 U/kg | 3.64 | 1274.32 | 82.53 | 115.79 % | No |
| SAFE-06 | 10 U/kg | 5.00 | 1221.72 | 66.66 | 92.15 % | No |
| SAFE-07 | 75 U/kg | 4.1 | 897.43 | 60.28 | †80.49 % | No |
| SAFE-08 | 75 U/kg | 3.1 | 741.61 | 49.4 | †66.52 % | No |
| SAFE-09 | 75 U/kg | 3.1 | 623.95 | 47.89 | †55.96 % | No |
| *Patient moved out of state, was eligible for the last visit but could not be enrolled.†Patient reached maximum dose of 75 IU/kg of aPCC. | ||||||
Comparison of in vitro and in vivo administration of aPCC
Conclusions: This study demonstrates that spiking experiments of aPCC and emicizumab may be misleading. The in vitro portion of the study demonstrated that clinically relevant concentrations of aPCC resulted in excessive TG, however in vivo administration of aPCC to the same patients demonstrated significantly different results, with most of the patients (66%) having normal (not excessive) TG at the approved doses of aPCC (Figure 1). In conclusion, this data suggests that a single licensed dose of aPCC is safe for most patients on emicizumab and importantly calls into question the validity of in vitro spiking studies using TG in this setting.
The summary statistics
To cite this abstract in AMA style:
Kizilocak H, Marquez-Casas E, Malvar J, Young G. Safety of FEIBA and Emicizumab (SAFE): Dose Escalation Study Evaluating the Safety of in vivo Administration of Activated Prothrombin Complex Concentrate in Hemophilia A Patients with Inhibitors on Emicizumab [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/safety-of-feiba-and-emicizumab-safe-dose-escalation-study-evaluating-the-safety-of-in-vivo-administration-of-activated-prothrombin-complex-concentrate-in-hemophilia-a-patients-with-inhibitors/. Accessed December 10, 2023.« Back to ISTH 2021 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/safety-of-feiba-and-emicizumab-safe-dose-escalation-study-evaluating-the-safety-of-in-vivo-administration-of-activated-prothrombin-complex-concentrate-in-hemophilia-a-patients-with-inhibitors/