Abstract Number: PB0933
Meeting: ISTH 2020 Congress
Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia - Clinical
Background: Inhibitor formation is currently the greatest treatment related complication in severe hemophilia A. Inhibitor risk factors are genetic and environmental. Prediction of individuals at risk of developing inhibitors may optimize care.
Aims: To prospectively evaluate changes in blood transcriptome expression prior to and following first FVIII concentrate treatment.
Methods: Severe hemophilia A previously untreated patients (PUPs) were treated using a B-domain deleted FVIII concentrate, simoctocog alfa (ClinicalTrials.gov identifier: NCT01712438). Study cumulative inhibitor incidence (105 PUPs) was: high-titre=17.6% (95%CI:10.0-25.3%); all inhibitors=27.9% (95%CI:19.1-36.7%). Whole blood mRNA was collected prior to treatment and every 3-4 exposure days (EDs) until inhibitor detection or 20ED, with 84 patients (449 samples) recruited. Case-control matching (3:1) was performed, based on ED1 age and timing of subsequent samples. Next-generation RNA sequencing (RNA-Seq) was performed using the Illumina HiSeq.
Results: 16 patients (controls=12, inhibitors=4) with median age (ED1) of 11.5 months on prophylaxis were included. Inhibitors occurred at a median 10ED (7-14ED), with peak titre of 27.4BU (2.3-137.6BU). Serial transcriptome analysis was performed on baseline, early (3-4ED) and inhibitor/matched samples. Greatest variation in transcriptome profiles was seen on principal component analysis (PCA) relating to individual and age, with apparent grouping of inhibitor patients on Kernel PCA. Differential expression was seen comparing baseline profiles in inhibitor to non-inhibitor patients. Adjusting for potential false discovery, upregulation of HLA-DMB and downregulation of LENG8 was seen at all timepoints in inhibitor patients. Comparing baseline to early samples in inhibitor patients, a number of genes were differentially regulated: the most prominent being upregulation of TGM4.
Conclusions: Differential transcriptome profiles were seen in this pilot cohort comparing inhibitor patients to matched controls. Upregulation of the HLA Class II beta chain paralogue, HLA-DMB, involved in MHC Class II peptide loading appeared discriminatory to inhibitor risk. Extension of this analysis within the whole cohort may provide additional insights into inhibitor formation.
To cite this abstract in AMA style:
Batty P, Watson D, Wozniak E, Savage E, Mein CA, Barnes MR, Hart DP. Dynamic Changes in Peripheral Blood Transcriptome Profiles May Predict Inhibitor Formation in Previously Untreated Patients with Severe Hemophilia A [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/dynamic-changes-in-peripheral-blood-transcriptome-profiles-may-predict-inhibitor-formation-in-previously-untreated-patients-with-severe-hemophilia-a/. Accessed March 21, 2024.« Back to ISTH 2020 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/dynamic-changes-in-peripheral-blood-transcriptome-profiles-may-predict-inhibitor-formation-in-previously-untreated-patients-with-severe-hemophilia-a/