RESUMO
Background: Some COVID-19 vaccinated individuals develop anti-platelet factor 4 (PF4) antibodies that cause thrombocytopenia and thrombosis;a rare syndrome referred to as vaccine-induced immune thrombotic thrombocytopenia (VITT). Currently, information on the characteristics and persistence of anti-PF4 antibodies that cause VITT after Ad26.COV2.S vaccination is limited, and available PF4-polyanion enzyme-linked immunosorbent assays (ELISAs) and functional diagnostic assays fail to differentiate Ad26.COV2.S and ChAdOx1 nCoV-19-associated VITT from similar clinical disorders, namely heparin-induced thrombocytopenia (HIT) and spontaneous HIT. Aim(s): Evaluate the persistence of anti-PF4 antibodies in Ad26. COV2.S-associated VITT and correlate findings with clinical and laboratory variables such as thrombosis and platelet counts. Develop/ investigate laboratory tools that differentiate VITT antibodies from HIT and spontaneous HIT. Method(s): Blood samples from VITT and HIT patient cohorts were tested in antigen-based and functional assays and correlated with clinical and laboratory features. Result(s): While Ad26.COV2.S-associated VITT patients were strongly positive in PF4-polyanion ELISAs;they were frequently negative in the serotonin release assay (4 of 8 tested patients were negative). In contrast, the PF4-dependent p-selectin expression assay (PEA) that uses PF4-treated platelets consistently diagnosed Ad26.COV2.S-associated VITT. Most Ad26.COV2.S-associated VITT antibodies persisted for >5 months in PF4-polyanion ELISAs, while the PEA became negative earlier. Two patients had otherwise unexplained mild persistent thrombocytopenia (140-150,000/ mul) six months after acute presentation. No recurrence of thrombosis was noted. Additionally, a novel un-complexed PF4 ELISA specifically differentiated VITT secondary to Ad26.COV2.S and ChAdOx1 nCoV-19 vaccination, from spontaneous HIT and HIT (Fig 1A-PF4/ polyanion ELISA;Fig 1B-Un-complexed PF4 ELISA;closed black circles-Ad26. COV2.S-associated VITT;closed red circle-ChAdOx1 nCoV-19-associated VITT;***p < 0.001;****p < 0.0001). Its specificity was further confirmed by testing commonly-encountered HIT-suspected patient samples that are PF4/polyanion ELISA-positive but negative in functional assays (1A-1B). Conclusion(s): Ad26.COV2.S-associated VITT antibodies are persistent, and the un-complexed PF4 ELISA appears to be both sensitive and specific for VITT diagnosis.
RESUMO
Background : Damoctocog alfa pegol (BAY 94-9027) is an extended-half-life PEGylated recombinant factor VIII product, approved for use in previously-treated patients (PTPs) aged ≥12 years with hemophilia A. Aims : HEM-POWR (NCT03932201) is a multicenter, noninterventional, open-label, prospective phase IV trial investigating routine clinical use of damoctocog alfa pegol. Planned enrollment is ≥200 PTPs with mild, moderate, or severe hemophilia A. The 6-month interim safety analysis is presented. Methods : Eligible patients include all PTPs receiving damoctocog alfa pegol on-demand or as prophylaxis, according to local label who provided informed consent. Primary outcomes include total bleeding events and annualized bleeding rate. Secondary outcomes include long-term safety, joint health, and patient-reported outcomes. Analyses will be exploratory, stratified by prophylaxis regimen and hemophilia severity. Ethical approval was obtained for all sites. Results : At data cut-off (21 October), 39 PTPs were enrolled;38 patients comprised the safety analysis set (one patient withdrew consent), including 8 mild/moderate patients (Table 1). Most patients ( n = 32) had received damoctocog alfa pegol within 12 months of baseline for variable time periods (mean [SD]=354.6 [614.02] days). Median (Q1;Q3) dose was 3000 (2000;3650) IU/infusion;the most common dosing regimen being twice-weekly prophylaxis (44%). 26/32 patients provided information about Factor VIII treatment within 12 months prior to initiation of damoctocog alfa pegol. In this group, the most common dosing frequency was three times weekly (data available for 24 patients). A group of six damoctocog alfa pegol-naïve patients had a comparatively worse bleeding history (Table 2). There were no study-drug-related treatment-emergent adverse events, nor inhibitor development. Two patients discontinued. Remote follow-up visits were made due to Covid-19;initial visits may now be conducted remotely. Conclusions : This first interim analysis of the HEM-POWR study provides real-world evidence that damoctocog alfa pegol is welltolerated in routine clinical use in patients with mild, moderate, or severe disease.