Activation of coagulation and proinflammatory pathways in thrombosis with thrombocytopenia syndrome and following COVID-19 vaccination

Thrombosis with thrombocytopenia syndrome (TTS) is a rare but potentially severe adverse event following immunization with adenovirus vector-based COVID-19 vaccines such as Ad26.COV2.S (Janssen) and ChAdOx1 (AstraZeneca). However, no case of TTS has been reported in over 1.5 million individuals who received a second immunization with Ad26.COV2.S in the United States. Here we utilize transcriptomic and proteomic profiling to compare individuals who receive two doses of Ad26.COV2.S with those vaccinated with BNT162b2 or mRNA-1273. Initial Ad26.COV2.S vaccination induces transient activation of platelet and coagulation and innate immune pathways that resolve by day 7; by contrast, patients with TTS show robust upregulation of these pathways on days 15–19 following initial Ad26.COV2.S vaccination. Meanwhile, a second immunization or a reduced initial dose of Ad26.COV2.S induces lower activation of these pathways than does the full initial dose. Our data suggest a role of coagulation and proinflammatory pathways in TTS pathogenesis, which may help optimize vaccination regimens to reduce TTS risk.

The color gradient indicates increased (in red gradient) or decreased (in blue gradient) proteins in serum.
Innate immune response

Platelet activation and coagulation cascade markers upregulated in TTS
Heatmaps showing the serum levels of markers of innate proinflammatory pathways (a, c) and coagulation cascade pathways (b, d) increased one day after initial immunization with 5x10 10 vp or 1x10 11 vp of Ad26.COV2.S and after the second immunization with Ad26.COV2.S, after mRNA-1273 and BNT162b2 boost immunization and in TTS patients.
Transient activation of innate proinflammatory pathways and coagulation cascades following Ad26.HIV.EnvA vaccination.a PCA of peripheral blood transcriptomics at baseline (D1) and on day 1 (D2) following Ad26.HIV.EnvA vaccination in healthy individuals.Ad26.HIV seronegative (n=7) and seronegative (n=5) are shown in green and blue, respectively.b and c, Heatmaps of SLEA scores of innate immune pathways and coagulation cascades increased after one day (D2) by transcriptomics (b) and proteomics (c) following vaccination with Ad26.HIV.EnvA.These pathways largely resolved by one week (D8) following vaccination.Color gradient ranging from dark for unchanged to dark pink for upregulated genes and proteins.Source data are provided as a Source data file.
a t e i m m u n e p a t h w a y s P l a t e l e t a c t i v a t i o n a n d c o a g u l a t i o n c a s c a d e Principal component analysis (PCA) of peripheral blood transcriptomic (a) and serum proteomics (b) of Ad26.COV2.S, shown in red and Ad26.HIV.EnvA seronegative and seropositive, shown in green and blue, respectively, vaccinated healthy individuals at baseline (D1) and on days 1 (D2) and 7 (D8) following vaccination.Each dot represents an individual.D1: circle; D2: triangle and D8: square.