A Novel Marker for Blood Platelet Storage Lesion: Newly Synthesized Rap1 in Integrin Signaling.
Bibliographic record
Abstract
Abstract Platelet transfusion is a standard live-saving medical procedure for patients with platelet-deficient diseases like leukemia. Platelets have a limited shelf-life of 5–7 days for transfusion purposes. This is in part due to a storage-related deterioration typified by altered morphology features and platelet metabolism as well as increased platelet activation. While the manifestations of the platelet storage lesion (PSL) are well known, the precise biochemical pathways involved in the initiation or exacerbation of this process have yet to be identified. Recently, we analyzed protein changes in the platelet proteome at day 1 and day 7 of storage by using a comprehensive proteomic approach. Out of 503 proteins, twelve were identified as significantly and consistently changing in relative concentration across all proteomic probes, including glycoprotein (GP) IIb/IIIa, Rap1 and talin, which showed an increase in their concentration paralleled with an increase in surface expression of GPIIb/IIIa. Synthesis of Rap1 in stored platelets could be demonstrated after incubation with the translational inhibitor rapamycin at a final concentration of 10 nM for twelve hours and subsequent activation with thrombin. Flow cytometry revealed that storage lead to a moderate level of platelet activation (10.5 ± 1.4% at day1 and 28.8 ± 1.3% at day 7 of storage) compared to ADP-treated controls (73.7 ± 1.2%) monitored by CD62P surface expression, in a rapamycin-independent manner. Microscopic analyses revealed similar re-localization patterns for GPIIIa, Rap1 and talin comparing changes during platelet storage and agonist induced activation. A significant correlation (p=0.007) between Rap1 activation and CD62P surface expression was seen. This observation is in strong agreement with a model for platelet GP IIb/IIIa activation [Han et al., Current Biology, 16, 1796–1806, 2007] also suggesting a calcium-dependent initiation of signal transduction. To analyze this hypothesis in more detail, treatment of platelets sampled at days 1, 4 and 7 of storage with 1 mM EDTA for 2 hours resulted in decreased Rap1 activation, in reduced surface expression of CD41 (GPIIb) and CD61 (GPIIIa) as well as in a lower level of platelet activation compared to untreated controls, respectively. This study unravels one aspect of the PSL, showing involvement of integrin signaling and identifying Rap1 as a novel marker for PSL. Therefore, this pathway offers potential targets for intervention which might lead to a reduction in platelet activation during storage, and may enable platelets to be stored for longer periods of time. From a transfusion point of view, however, extending the shelf-life of platelet units will ultimately need to be balanced with maintaining the quality of transfused platelets, their functionality, and efficacy in the patient.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".