Abstract Number: OC 49.2
Meeting: ISTH 2021 Congress
Theme: Hemophilia and Rare Bleeding Disorders » Novel Biotherapeutics in Hemophilia
Background: Emicizumab, a factor VIII (FVIII) mimetic, is being widely adopted by persons with hemophilia A (PwHA) due to excellent efficacy and convenient administration. It is unclear whether emicizumab will support normal bone metabolism, as evidence suggests that FVIII is required and it unknown whether the FVIII effect on bones is mediated by thrombin, factor Xa or FVIII itself.
Aims: To investigate bone biomarkers in PwHA.
Methods: Biobank samples from an approved consented cohort study of PwHA, including on emicizumab, and healthy controls were assayed. Samples from PwHA on FVIII prophylaxis were troughs. Bone biomarkers measured by ELISA included osteocalcin uncarboxylated (OC, Biolegend, Legend Max™); osteoprotegerin (OPG, R&D Systems, TNFRSF IIB/OCIF); and carboxy terminal collagen crosslinks (CTX-1, IDS Serum CrossLaps). Thrombin generation was determined by calibrated automated thrombogram (CAT, Diagnostica Stago). Group values were compared using ANOVA and post-hoc paired comparisons. Paired sample [WB1] [TD2] t-tests compared values pre and on emicizumab.
Results: Table 1 shows bone biomarkers in controls and PwHA. Within age groups, there were no differences in OC or CTX-1 comparing hemophilia groups to controls. OPG differed for PwHA vs controls, with child PwHA lower and adult PwHA higher than controls (p=0.03, p=0.007, respectively). OPG in PwHA on emicizumab trended towards normal, but differed marginally from controls (p=0.1 children, p=0.09 adults). Only OC increased in children on emicizumab (p=0.05); all other changes in bone biomarkers on emicizumab vs pre-emicizumab failed to reach significance (Table 2). Compared with the minimal change in bone biomarkers on emicizumab, there was significant improvement in thrombin generation (p<0.001).
| Table 1 | Children (median 10 Range 0.33- <18 yrs) | Adults (median 34, Range 18-86 yrs) | |||||
| Mean (standard deviation) | CTX-1 (ng/mL) | OPG (pg/mL) | OC (ng/mL) | CTX-1 (ng/mL) | OPG (pg/mL) | OC (ng/mL) | |
| Healthy Controls (n=36 children, 76 adults) |
1.55 (0.42) | 1121 (282) | 17.6 (10.9) | 0.58 (0.43) | 1039 (354) | 3.0 (1.7) | |
| Mild Hemophilia (n=29 children, 53 adults) |
1.53 (0.54) | 917 (201) | 25.1 (22.8) | 0.48 (0.36) | 1119 (462) | 4.2 (2.7) | |
| Moderate Hemophilia (n=18 children, 20 adults) |
1.56 (0.57) | 941 (183) | 31.6 (23.0) | 0.38 (0.22) | 1454 (497) | 2.69 (1.7) | |
| Severe Hemophilia (n=48 children, 63 adults) |
1.64 (0.49) | 992 (244) | 21.4 (19.9) | 0.59 (0.47) | 1367 (578) | 6.7 (12.5) | |
Bone biomarkers in Children and Adults not on Emicizumab
| Table 2 | Pre-Emicizumab | On Emicizumab | ||
| mean (stdev) | Children | Adults | Children | Adults |
| CTX-1 (ng/mL) | 1.71 (0.44) | 0.75 (0.37) | 1.70 (0.57) | 0.62 (0.37) |
| OPG (pg/mL) | 1028 (280) | 1101 (548) | 1024 (230) | 1325 (458) |
| OC (ng/mL) | 18.4 (11.3) | 6.8 (7.7) | 22.1 (15.4) | 5.1 (4.2) |
| Endogenous thrombin potential, ETP (% normal) | 29.2% (18.5%) | 57.7% (17.7%) | ||
| Peak Thrombin (% normal) | 17.3% (15.6%) | 38.2% (17.1%) | ||
| Velocity Index (% normal) | 9.9% (13%) | 20.0% (18.1%) | ||
Bone biomarkers and thrombin generation parameters for paired samples for 31 child (21 severe, 13 inhibitors) and 10 adult (6 severe, 2 inhibitors) PwHA
Conclusions: These data are reassuring that bone biomarkers on emicizumab are at least no worse than with factor VIII prophylaxis and may be slightly better. Future research must address long term bone and joint health in PwHA using novel factor and non-factor therapeutics.
To cite this abstract in AMA style:
Manco-Johnson M, Briones N, Tran A, Thornhill D, Baird C, Jacobson L, Warren B, Kuldanek S, Ambruso D, Karsenty G. Emicizumab: Will it Suffice for Bone Metabolism? [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/emicizumab-will-it-suffice-for-bone-metabolism/. Accessed November 29, 2023.« Back to ISTH 2021 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/emicizumab-will-it-suffice-for-bone-metabolism/