Effects of Multimerin 1 on Platelet and Plasma FV as Determined by Calibrated Automated Thrombography.
Bibliographic record
Abstract
Abstract Multimerin 1 (MMRN1) is a protein that is not found in plasma and that is complexed with factor V (FV) in platelet α-granules. Following thrombin activation, platelet FV and MMRN1 are released, and FV is converted to Va, promoting its dissociation from MMRN1. Recent studies identifying functional overlap between FV/Va binding sites for phospholipids and MMRN1, and unanswered questions about the functional consequences of MMRN1 on platelet FV function, led us to compare how MMRN1 modulates platelet and plasma FV procoagulant functions using calibrated automated thrombograms (CAT). The effects of platelet and exogenous MMRN1 on FV activity were evaluated using samples of platelet poor human plasma or platelet extracts resuspended in FV deficient plasma to equivalent final FV antigen concentrations. Reactions were triggered with a commercial reagent containing saturating concentrations of tissue factor and phospholipids (60:20:20 phosphatidylcholine: phosphatidylserine: phosphatidylethanolamine). These assays were also used to compare the functional properties of FV in MMRN1-immunodepleted and sham-depleted fractions of a soluble platelet protein extract (prepared with calpain inhibitors). The effects of exogenous MMRN1 on platelet-dependent thrombin generation were also evaluated using normal platelets resuspended in FV deficient plasma. In contrast to plasma, platelet fractions (with an equivalent FV antigen content) consistently showed lower peak and total endogenous thrombin potential. Addition of 17 fold molar excess of exogenous MMRN1 (which represents the physiologic ratio of MMRN1 to FV in platelets) to plasma, or to MMRN1 depleted platelet protein extracts, induced similar reductions in thrombin generation, manifested by increases in lag times (p<0.05), and reductions in peak (p<0.05), and total thrombin generation (p<0.05). Higher concentrations of exogenous MMRN1 caused further attenuation. Analogous, dose-dependent, inhibitory effects of MMRN1 were observed on thrombin generation by normal platelets in FV deficient plasma. Further investigations of the thrombin generating potential of platelet FV were done using sham and MMRN1-depleted platelet extracts. While exogenous MMRN1 inhibited platelet FV dependent thrombin generation, sham-depleted platelet FV (containing MMRN1) consistently showed higher thrombin generation than the same quantity of FV in MMRN1-depleted platelet extracts, characterized by shorter lag times (p<0.05), higher peak thrombin generation (p<0.05), and increased endogenous thrombin potential (p<0.05). Although the sham-depleted fraction had a similar reduced mobility to the MMRN1 depleted platelet FV, it contained very large forms of platelet FV, linked to MMRN1 via the human FV B-domain cysteine. These data indicate that the pool of platelet FV associated with MMRN1 in vivo has procoagulant function and that MMRN1 has inhibitory effects on thrombin generation. The observed differences in the procoagulant properties of platelet and plasma FV in CAT assays likely result from a partial inhibition of platelet FV by MMRN1 that may be counterbalanced by partial platelet FV activation. The paradoxical effects of MMRN1 depletion on the procoagulant function of platelet FV suggests MMRN1 may have other influences that help preserve platelet FV function in vitro, and possibly also in vivo. The MMRN1 liberated by activated platelets and endothelium in vivo could have local modulating effects on thrombin generation.
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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 | 0.001 |
| 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) | 0.001 | 0.000 |
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".