Complement Factor H in Human Platelets: Implications for Atypical HUS.
Notice bibliographique
Résumé
Abstract Atypical hemolytic uremic syndrome (aHUS) is a severe kidney disease that mainly affects children, where risks of progression to renal failure and death remain significant. aHUS pathology is associated with hyperactivity of the complement system and activation of platelet-dependent clotting leading to the formation of platelet-rich thromboemboli that occlude the glomerular microvasculature. These events have been linked to defects in the regulation of the alternative complement pathway, with >25% of pediatric aHUS cases being associated with mutations in the soluble complement activation inhibitor Factor H (CFH), or inhibitory autoantibodies. There is also evidence that interactions between platelets and the complement system are important in the progression of aHUS (Stahl AL et al., Blood. 2008;111:5307–5315). Immunoblot analysis detected the presence of CFH in washed cell lysates from serumfree cultured megakaryocytes, normal circulating platelets and platelets from an ARC syndrome patient lacking a-granules. CFH was also detected in supernatants recovered after in vitro activation of normal platelets with thrombin and other agonists. The location of CFH in resting platelets was determined via immunostaining of fixed cells followed by laser fluorescence confocal microscopic (LFCM) imaging. CFH staining was observed inside and on the surface of platelets and microparticles, and was not confined to granules or other secretory vesicles. Deconvolved LFCM images were used for colocalization analysis (Volocity software) with known platelet proteins. CFH showed significant colocalization (p<0.05; Pearson correlation coefficient) with actin (cytoplasmic), tubulin (cytoskeletal) and GPIIIa (CD61, cell surface receptor), but not with α-granule proteins Von Willebrand Factor and fibrinogen, or dense granule/lysosomal proteins CD63 (tetraspanin) and LAMP-1. CFH surface staining was observed to intensify uniformly during the early stages of platelet activation and then subside and disperse to patches on fully-activated platelets. Blood samples were taken from an aHUS patient lacking CFH due to mutation before and after therapeutic fresh frozen plasma (FFP) infusion, and over the following 14 days. Immunoblot analysis of plasma and lysates from washed circulating platelets showed rapid platelet uptake of CFH in vivo after FFP treatment, with the level of platelet CFH declining in parallel with plasma CFH levels. Laboratory assays of blood clotting via thromboelastography showed blood samples from pediatric aHUS patients to have a consistent hypercoagulable tendency. Thrombin generation assays via calibrated automated thrombography of aHUS patient plasmas revealed an elevated level of platelet-dependent, but not platelet-independent, thrombin generation compared to normal. We conclude that CFH in circulating platelets is likely derived from both megakaryocyte synthesis and plasma uptake. CFH uptake and secretion by platelets does not appear to be granule-dependent and may be surface-mediated, with platelets developing a transient increase in CFH affinity early in activation. Pediatric aHUS patients have a tendency towards hypercoagulability, which may be associated with constitutively elevated platelet-dependent thrombin generation. These observations support the hypothesis that loss of CFH-mediated complement inhibition contributes to increased platelet procoagulant activity, which may contribute to the progression of aHUS, and possibly other thrombosis-associated diseases.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 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 | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
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 tête enseignante, 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 ».