Several Mechanisms Contribute to the Basic Carboxypeptidase Mediated Downregulation of Fibrinolysis.
Notice bibliographique
Résumé
Abstract Activated thrombin-activatable fibrinolysis inhibitor (TAFIa) is an intrinsically unstable basic carboxypeptidase which removes C-terminal lysine residues from plasmin-degraded fibrin. This modification of the fibrin surface attenuates fibrinolysis via several mechanisms. First, plasminogen activation is downregulated due to the loss of high affinity plasminogen binding. Second, the rate of plasmin inhibition is increased due to the loss of the protection from inhibition that degraded fibrin confers on plasmin. Finally, fibrin degradation by plasmin becomes less efficient due to the loss of cleavage cooperativity. Although carboxypeptidase-mediated downregulation of the fibrinolytic process has been studied, the relative contribution of each mechanism to the aggregate antifibrinolytic process remains unclear. We, therefore, undertook the following study to measure the contribution of plasmin protection and fibrin cleavage cooperativity to the overall antifibrinolytic effect. To this end, we studied the lysis of clots formed from purified fibrinogen, thrombin and plasmin in the presence and absence of various concentrations of aprotinin, a tight-binding but reversible plasmin inhibitor, and pancreatic carboxypeptidase B (CPB), a stable carboxypeptidase highly homologous to TAFIa. To determine the overall antifibrinolytic effect, we studied the lysis of clots formed from the same components, but using plasminogen with various concentrations of tissue plasminogen activator (tPA) in place of plasmin. In the absence of the inhibitor, CPB saturably increased the plasmin-mediated lysis time by 1.2-fold of that seen in the absence of CPB, suggesting that the loss of cleavage cooperativity increases lysis time by ~20%. The effect of plasmin protection from aprotinin, mediated by recruitment of plasmin to the degraded fibrin surface, was demonstrated using a fixed concentration of plasmin (20nM) and various concentrations of aprotinin (5–20nM). When plasmin was equimolar with or in excess of aprotinin, CPB saturably prolonged lysis by a factor which increased as the concentration of aprotinin increased: saturating CPB (50nM) increased the lysis times by 1.3, 1.5, 1.9 and 2.3-fold at 5, 10, 15 and 20nM aprotinin. When an excess of aprotinin was included (30nM), CPB saturably increased the plasmin-mediated lysis time identically over a range of plasmin concentrations: saturating CPB (50nM) increased the lysis times 2.4, 2.4, 2.3 and 2.3-fold at plasmin concentrations of 10, 15, 20 and 25nM, respectively. Since the total increase (2.4-fold) results from the loss of plasmin protection in addition to the loss of cleavage cooperativity (1.2-fold), we conclude that the loss of plasmin protection increases lysis time ~ 2.4/1.2 = 2-fold. When plasminogen (200nM) and tPA (25–200pM) were used in place of plasmin, CPB also saturably increased lysis time: saturating CPB (50nM) increased lysis times by ~ 15-fold at 150nM aprotinin and by ~ 17-fold at 300nM aprotinin for 25, 50, 100 and 200pM tPA. Since the total increase in lysis time (~ 16-fold) in these experiments results from the downregulation of plasminogen activation in addition to the loss of cleavage cooperativity (1.2-fold) and the loss of plasmin protection (2-fold), we estimate that the downregulation of plasminogen activation resulting from sustained removal of C-terminal lysine residues by a basic carboxypeptidase during fibrinolysis increases clot lysis time by 16/(1.2 x 2) ~ 6.7-fold.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».