Circulating Blasts Are Associated with High Levels of vWF and Thrombin Activation in Children with Newly Diagnosed ALL.
Notice bibliographique
Résumé
Abstract Background: Children with acute lymphoblastic leukemia (ALL) are known to have thrombin activation at diagnosis. However, the pathophysiology of thrombin generation and the impact of therapy on thrombin activation are so far unknown. Steroids are shown to induce prothrombotic state by increasing prothrombotic factors and reducing fibrinolytic potential. The investigational window on DFCI 05-01 protocol offered an unique opportunity to study the haemostatic effects of prednisone, independent of previous or concurrent therapy, in children with newly diagnosed ALL. Aims: In children with newly diagnosed ALL, To evaluate the effects of methyleprednisone monotherapy (PMT) (32 mg/m2/day IV for 3 days) on the parameters of thrombin generation [prothrombin fragments 1.2 (F1.2), thrombin-antithrombin complex (TAT), and D-Dimer], fibrinolytic potential [plasminogen, tissue plasminogen activator (tPA), alpha-2 antiplasmin, alpha-2 macroglobulin, plasminogen activator inhibitor-1 (PAI-1), ratio of tPA/PAI-1], and coagulation factors [FVIII:C, von Willebrand factor (vWF) and fibrinogen] To study the effect age at diagnosis (< 10 Vs ³ 10 years), gender, risk categorization of ALL [standard (SR) Vs high risk (HR)], presence or absence of circulating blasts, presenting white cell and platelet count on the above hemostatic factors pre and post steroid therapy Methods: Children (> 1 to £ 18 years of age) enrolled on DFCI ALL 05-01 protocol, without prior steroid therapy or presence of clot, were eligible for study. Overnight fasting blood samples was collected prior to and after PMT, and analyzed for hemostatic factors. The change in the level of each of the hemostatic parameters following PMT was expressed as percent increase or decrease from the baseline. The effect of steroids was tested using “paired t test”. To assess the effects of patient and disease variable student’s t-test was used. Results: Of 30 patients (13 females) enrolled, 8 (27%) had HR ALL. The mean age was 6.33 years (SD 4.35); 24 patients were < 10 years. At baseline the levels of F1.2 (mean 1.54 nmol/L; SD 0.90), TAT (mean 10.90 microgram/L; SD 14.93) and D-dimers (2,766.03ng/mL; SD 2385.82) were increased indicating endogenous thrombin activation. Patients with circulating blasts (n=17) had significantly higher mean levels of vWF [1.89 (0.61) vs. 1.14 (0.48) p=0.001], TAT [15.39 (18.62) vs. 5.02 (3.29) p=0.038] and D-dimer [3640 (2499) vs. 1623 (1711) p=0.019] compared to those without circulating blasts. For children with circulating blasts at diagnosis, following steroid therapy the blast count decreased significantly from 24.2% to 3.5% (P<0.001)) with reduction in level of vWF, TAT and D-dimer (Table1). Conclusions: Patients with circulating blasts had significantly higher baseline level of vWF, TAT, and D-dimer compared to those without circulating blasts. Following steroid therapy there was reduction in circulating blast count and significant reduction in vWF (despite increase in VIII:C levels), TAT and D-dimer whereas children without circulating blasts had increased levels of vWF, FVIII:C, TAT and D-dimer. We postulate that circulating blasts lead to endothelial activation (with vWF production) which in turn activates the coagulation system with resultant thrombin generation. In children with newly diagnosed ALL, PMT has two-fold hemostatic effects, a direct effect inducing procoagulant state and an indirect effect through reduction of blasts. Table 1. Effect of PMT on hemostatic factors in patients with and without circulating blasts Parameters Blasts Presents (n=17) Blasts absent (n=13) Pre-PMT Post-PMT % change from baseline (95% CI) P value Pre-PMT Post-PMT % change from baseline (95% CI) P value VWF 1.89 1.5 −19.5 (−27.9, −11.1) <0.001 1.14 1.25 15.6 (−6.0, 37.2) 0.142 F VIII:C 1.45 1.8 31.2 (11.2, 51.3) 0.005 1.3 1.63 27.5 (13, 42) 0.002 TAT 15.4 8.9 − 41.9 (−65.1, 148.9) 0.417 5.02 6.4 50.0 (−6.6, 106.7) 0.078 D-dimer 3640 2509 − 23.8 (−43, −4.6) 0.018 1622.6 2137.2 120.4 (−75.8, 316.6) 0.206
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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 | 0,001 |
| 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 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 ».