To Clot or Not to Clot? Ad is the Question - Insights on Mechanisms Related to Vaccine Induced Thrombotic Thrombocytopenia
Bibliographic record
Abstract
Vaccine-induced immune thrombotic thrombocytopenia (VITT), or thrombotic thrombocytopenic syndrome (TTS), has caused global concern. VITT is characterized by thrombosis and thrombocytopenia following COVID-19 vaccinations with the AstraZeneca ChAdOx1 nCov-19 and the Janssen Ad26.COV2.S vaccines. The clinical features of VITT include thrombosis, typically cerebral venous thrombosis, and severe thrombocytopenia developing 5 to 24 days following first dose of vaccine, with elevated D-dimer, and antibodies specific to platelet factor 4 (PF4), signifying platelet activation. As of June 1, 2021, over 1.93 billion COVID-19 vaccine doses had been administered worldwide. Currently, 467 VITT cases (0.000024%) have been reported across the UK, Europe, Canada and Australia. Clinically, VITT presents similarly to a rare autoimmune condition called “spontaneous/autoimmune heparin Induced Thrombocytopenia” (HIT) without prior heparin exposure. Guidance on diagnosis and management of VITT has been reported but the pathogenic mechanism of VITT is not fully elucidated. A definite causal relationship with the vaccine material is yet to be confirmed. To date, it is established that IgG antibodies recognizing PF4 activate platelets through FcγRIIA, however it remains unclear what triggers production of these antibodies. The fact that VITT, has only been described in association with adenoviral vector-based DNA virus vaccines, but not mRNA/lipid-based vaccines, raises the likelihood that the syndrome is somehow linked to the vector or other constituents in the vaccine preparation. Here, we propose and discuss potential mechanisms in relation to adenovirus induction of VITT. We discuss adenovirus immunogenicity and interactions with platelets and other host proteins, the role of PF4 and platelet activation. Whilst confirming a single mechanism underpinning VITT is challenging, we provide insights and clues into areas warranting investigation into the mechanistic basis of VITT, highlighting the unanswered questions. Further research is required to help solidify a pathogenic model for this condition.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.004 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.002 |
| Scholarly communication | 0.004 | 0.003 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.003 | 0.003 |
| Insufficient payload (model declined to judge) | 0.015 | 0.006 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".