Abstract TMP117: Hyper-Acute Platelet-VWF Interactions Drive No-Reflow In Stroke
Bibliographic record
Abstract
Introduction: Despite timely recanalization, some ischemic stroke patients treated with endovascular thrombectomy experience persistent neurological deterioration. This has been partly attributed to no-reflow. Experimental stroke models have indicated a critical role for platelets in this process. However, the mechanism and timing of platelet involvement remain unknown. Methods: Transient middle cerebral artery occlusion was performed in C57Bl/6J mice. Intra-arterial blood was sampled directly from the brain immediately after reperfusion. In a different cohort, intra-venous blood was sampled immediately after reperfusion. A LEGENDplex assay was used to measure 23 inflammatory cytokines. Endothelial cell activation (von Willebrand factor, VWF) was measured through ELISA. We generated mice with endogenously fluorescent platelets and imaged the penumbra with 2-photon intravital microscopy at different times after stroke onset. Results: Immediately after reperfusion, intra-arterial blood sampled from the brain exhibited a distinct inflammatory cytokine profile compared to intravenous systemic blood samples. IL-1alpha, IL-1beta, and IL-6 were significantly elevated in the intra-arterial blood samples compared to the intravenous blood samples. These cytokines have been reported to influence the release and activity of VWF, a hemostatic protein secreted by activated endothelial cells. VWF levels increased both locally (3-fold) and systemically (2-fold) at the onset of reperfusion compared to baseline. The thrombogenicity of VWF is limited by ADAMTS13. Interestingly, ADAMTS13 activity was strongly reduced (2-fold) locally in the reperfused brain, while it remained normal systemically. These results suggest a prothrombotic imbalance of VWF localized in the reperfused ischemic stroke brain. VWF traps platelets, and excessive VWF activation leads to thrombosis. Therefore, we imaged the reperfused brain in mice using 2-photon intravital microscopy. Immediately after the onset of reperfusion, we observed VWF capturing platelets, resulting in the formation of platelet-rich thrombi that disrupted blood flow in the penumbra. Inhibition of platelet binding to VWF using a monoclonal antibody prevented this and resulted in greatly improved stroke outcomes. Conclusions: We found that ischemic stroke causes a local cytokine storm which potentiates VWF-mediated platelet accumulation in the reperfused brain contributing to no-reflow and exacerbated stroke outcomes.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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".