Abstract 410: Lipoprotein(a) And Apolipoprotein(a) Inhibit Lysis Of Human Thrombi Formed From Whole Blood Under Conditions Of Flow
Bibliographic record
Abstract
The apolipoprotein(a) (apo(a)) component of Lp(a) is homologous to the proenzyme plasminogen, containing domains which are highly similar to plasminogen kringle (K) 4, followed by sequences that closely resemble the K5 and protease domains of plasminogen. Due to key amino acid substitutions/deletions, the protease (P) domain of apo(a) is catalytically inactive. It has been hypothesized that by competing for binding to fibrin, apo(a) can inhibit plasminogen activation and hence fibrinolysis, thereby leading to a prothrombotic role for Lp(a) in the vasculature. Although previous studies have shown inhibition by apo(a), but not Lp(a), of fibrinolysis in an ex vivo clot lysis assay, the ability of Lp(a) to inhibit lysis of clots formed from whole blood under conditions of flow that more closely resemble arterial thrombi in vivo has not been assessed. In the current study, whole blood was collected from a human donor with low Lp(a) levels, recalcified, and rotated in a Chandler loop device at 30 rpm for 90 minutes. Blood in the closed loops was supplemented with fluorescently labelled fibrinogen, and 0 or 250 nmol/L of purified plasma-derived Lp(a), 17-kringle (17K) recombinant apo(a) or a 17KΔP apo(a) variant lacking the protease-like domain. Interestingly, this protease-like domain has been shown to mediate lysine-dependent binding of apo(a) to plasminogen. Resultant thrombi were exposed to tPA and clot lysis was measured as release of fluorescent fibrinogen over time in a fluorescent plate reader. The addition of 250 nmol/L Lp(a) significantly decreased clot lysis by up to 15% compared to control (p<0.05). On the other hand, 250 nmol/L 17K apo(a) markedly reduced clot lysis by up to 48% relative to control (p<0.01). 17KΔP apo(a), however, did not affect clot lysis in this system. Our findings show that Lp(a) impedes lysis of human clots formed from whole blood under flow conditions, albeit with a much lower potency than 17K apo(a). Interestingly, our results indicate that the antifibrinolytic effect of apo(a) is dependent on the presence of the inactive protease domain, revealing the importance of the apo(a)-plasminogen interaction. These findings suggest that markedly elevated plasma Lp(a) levels might predispose thrombotic events in vivo .
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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 | 0.000 |
| 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".