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  • 1
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 5246-5246
    Abstract: Introduction We have evaluated Antithrombin (AT) values and Whole Blood Rotation Thromboelastometry (ROTEM) profiles in children affected by acute lymphoblastic leukemia (ALL), followed at the Clinic of Pediatric Hematology Oncology of Padua. L-Asparaginase, used in protocols for pediatric ALL, is an inhibitor of protein synthesis. Typical collateral effects are coagulation disturbances. Guidelines for identification of patients at risk of thrombosis and hemorrhages are not yet established. AT levels are the only reliable parameter for thrombotic risk. Very low levels of fibrinogen are not correctly detected by classical Clauss method; ROTEM test using FIBTEM is considered a valid tool to identify hypofibrinogenemia and hemorrhagic risk in surgical patients. The aim of the study was to analyze coagulation patterns during treatment with Pegilated L-Asparaginase (Peg-Asp). Methods Forty-two children (25 males, 17 females; 31 pB-ALL; 11 T-ALL; 23 at standard/medium risk; 19 at high risk) were consecutively diagnosed and treated with AIEOP BFM ALL 2009 protocol from June 2012 to March 2014. They received 3 (standard/medium risk) or 8 (high risk) doses of Peg-Asp (2500UI/mq/dose). ROTEM and AT determinations were performed at 5 fixed time-points before and after each Peg-Asp administration. Prothrombin time (PT), fibrinogen plasma levels and platelets counts were recorded. Maximum Clot Firmness (MCF; normal value 9-25 mm), measuring the maximum amplitude reached in FIBTEM thromboelastogram, assessed the specific role of fibrinogen in the whole blood clot formation following platelets inhibition by Cytocalasin D. Results: 798 AT and 706 FIBTEM tests were performed; details are reported in Table. We divided abnormal MCF in 3 grade levels. Only values of MCF 〉 9 mm had a linear correlation with fibrinogen levels. Plasma fibrinogen values 〈 1 g/l were seen only in 45/286 (15%) cases with low MCF, without the possibility to discriminate the 3 MCF groups. Hemorrhagic risk was not suggested by PT, which was highly prolonged only in 5 cases (MCF 4-8 mm). Supplementation with AT or fibrinogen concentrates was suggested for patients with AT 〈 50% or MCF 〈 2 and decided on clinical basis. Twenty six children had a complete set of tests available during Induction phase (2 doses of Peg-Asp). They showed two different patterns of AT and MCF behavior. In 13 patients, mean AT levels decreased until 12-14 days after Peg-Asp, never being 〈 50% and increased thereafter. The other thirteen patients had low AT levels from day 12 after Peg-Asp, required supplementation even before the second dose of Peg-Asp and did not show recovery until the forth week after treatment (figure 1). In 11 patients , MCF were never 〈 9mm , without any trend to reduction. In 15 patients, who had at least 2 tests of MCF 〈 9mm, mean MCF decreased regularly from first Peg-Asp dose until day 21, showing a trend to recovery at day 28 (figure 2). One child had a cerebral sinus thrombosis at the end of induction; one child had extensive thrombosis, strongly related to the central line used for dialysis. Thromboses were not related to fibrinogen concentrates administration or low AT levels. No bleedings were observed. Conclusions: Extensive analysis of coagulation parameters in children undergoing chemotherapy for ALL containing PEG Asp showed abnormalities of AT in 88% of patients and of MCF in 30%. These tests identified patients with significant abnormalities more closely than classical methods. Careful use of AT dosage and FIBTEM can help in managing coagulation disturbances, by identifying patients at risk and suggesting prevention measures. Table: AT and FIBTEM analysis in ALL patients Total N. pts / total N. tests AT 42/798 MCF 42/706 Pts with pathological tests AT 〈 50% 37 (88%) MCF 〈 9mm 13 (30%) N. of Pathological tests AT 〈 50% 158 (19%) MCF 〈 9 mm 286 (40%) MCF 5-9 mm 212 (30.5%) MCF 3-4 mm 56 (7%) MCF 〈 2 mm 18 (2.5%) Supplementation with AT or FC AT 〈 50% 58 units in 24 pts MCF 〈 2 mm 18 units in 11 pts Figure 1: Mean AT levels in ALL patients during induction (according to AT supplementation) Figure 1:. Mean AT levels in ALL patients during induction (according to AT supplementation) Figure 2: Mean MCF levels in ALL patients during induction (MCF 〉 9 and MCF 〈 9mm) Figure 2:. Mean MCF levels in ALL patients during induction (MCF 〉 9 and MCF 〈 9mm) Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 2
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 2305-2305
    Abstract: Introduction. Hypofibrinogenemia and its correlation with hemorrhagic risk is usually detected by serum fibrinogen level with Clauss test. Recently the role FIBTEM test of rotational thromboelastometry (ROTEM) has been evaluated for prevention and management of acute bleeding in intesive care and surgical settings. We applied it for monitoring fibrinogen deficiency for the first time in children affected by acute lymphoblastic leukemia (ALL) treated with Peg-asparaginase (PEG-Asp). Antithrombin levels (AT) were measured as parameter for thrombotic risk. This drug impairs protein synthesis and causes severe coagulative deficiencies, with both hemorrhagic and thrombotic complications. Guidelines for the management of coagulation abnormalities being missing, we tried to identify parameters for management and prevention. Methods. Eightytwo children (age 1-17 years, mean 6 year) affected by ALL treated with AIEOP BFM ALL 2009 protocol at our Institution were studied. Platelet count and coagulation tests (protrombin time PT/INR, activated partial tromboplastin time aPTT, AT, serum fibrinogen level (SF) at Clauss test and fibrinogen function at MCF) were performed before and after each PEG-Asp administration. We previously found linear correlation with SF levels only for MCF 〉 9 mm. We then tried to identify clinically significant deficiency of SF. Severe hypofibrinogenemia was considered when Clauss test showed SF levels 〈 1g/L. MCF limit for severe fuctional hypofibrinogenemia was considered 〈 = 5mm according to our experience in congenital and acquired hypofibrinogemia (cardiac surgery, liver transplant and intensive care settings). Severe AT deficiency was considered at 〈 50%. Results. Severe hypofibrinogenemia was found in 240 Clauss test (24.3%), but only in 44 (4.5%) of MCF at FIBTEM. Only 28% of SF at Clauss test 〈 1 g/L had an MCF value 〈 = 4mm. Thirty-five percent of children presented MCF 〈 =4mm with a prolonged alteration in 5.3% of them, mostly observed during Induction phase, when steroid therapy was concomitant. Prolonged administration of Peg-Asp (10 doses in 20 weeks) did not cause a prologed hypofribrinogenemia. Fibrinogen concentrates was supplemented only at MCF 〉 = 2mm or at 3-4 mm in association with INR 〉 2.8. Fresh frozen plasma administration was avoided. No significant bleeding was observed. Severe AT deficiency was found in 287 measurements (23%) and in 57% of patients. AT deficiency was more frequent according to the number of PEG-Asp doses, in particular the percentage of affected patients increased in the different phases of chemotherapy (Table 1), being observed in all patients receiving prologed PEG-Asp therapy. AT was suggested at level of 〈 50%, but it was performed only in 54% of cases. Three thrombotic events were registered (3.6%) all in presence of AT levels 〈 50%. Conclusions. The frequency of fibrinogen functional deficiency as detected by MCF level at FIBTEM was inferior than hypofibrinogenemia at Clauss test. The MCF level chosen in our study to identify a parameter for hemorrhagic risk was helpful to select patients for coagulant therapy with fibrinogen concentrates. AT deficiency was more frequent than fibrinogen deficiency and was related to the numer of PEG-Asp doses. These tests can help in the management of patients with coagulative disturbancies in order to prevent seriuos adverse events. Table 1. Frequency of MCF and AT deficiencies according to number of PEG-Asp doses N° of doses 1 2 4 10 MCF 〈 =4mm 25% 42% 43% 40% AT 〈 50% 19% 65% 86% 100% N° of patients 67 59 7 10 Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
    In: JAMA, American Medical Association (AMA), Vol. 327, No. 18 ( 2022-05-10), p. 1782-
    Abstract: In nonurban areas with limited access to thrombectomy-capable centers, optimal prehospital transport strategies in patients with suspected large-vessel occlusion stroke are unknown. Objective To determine whether, in nonurban areas, direct transport to a thrombectomy-capable center is beneficial compared with transport to the closest local stroke center. Design, Setting, and Participants Multicenter, population-based, cluster-randomized trial including 1401 patients with suspected acute large-vessel occlusion stroke attended by emergency medical services in areas where the closest local stroke center was not capable of performing thrombectomy in Catalonia, Spain, between March 2017 and June 2020. The date of final follow-up was September 2020. Interventions Transportation to a thrombectomy-capable center (n = 688) or the closest local stroke center (n = 713). Main Outcomes and Measures The primary outcome was disability at 90 days based on the modified Rankin Scale (mRS; scores range from 0 [no symptoms] to 6 [death] ) in the target population of patients with ischemic stroke. There were 11 secondary outcomes, including rate of intravenous tissue plasminogen activator administration and thrombectomy in the target population and 90-day mortality in the safety population of all randomized patients. Results Enrollment was halted for futility following a second interim analysis. The 1401 enrolled patients were included in the safety analysis, of whom 1369 (98%) consented to participate and were included in the as-randomized analysis (56% men; median age, 75 [IQR, 65-83] years; median National Institutes of Health Stroke Scale score, 17 [IQR, 11-21] ); 949 (69%) comprised the target ischemic stroke population included in the primary analysis. For the primary outcome in the target population, median mRS score was 3 (IQR, 2-5) vs 3 (IQR, 2-5) (adjusted common odds ratio [OR], 1.03; 95% CI, 0.82-1.29). Of 11 reported secondary outcomes, 8 showed no significant difference. Compared with patients first transported to local stroke centers, patients directly transported to thrombectomy-capable centers had significantly lower odds of receiving intravenous tissue plasminogen activator (in the target population, 229/482 [47.5%] vs 282/467 [60.4%]; OR, 0.59; 95% CI, 0.45-0.76) and significantly higher odds of receiving thrombectomy (in the target population, 235/482 [48.8%] vs 184/467 [39.4%]; OR, 1.46; 95% CI, 1.13-1.89). Mortality at 90 days in the safety population was not significantly different between groups (188/688 [27.3%] vs 194/713 [27.2%]; adjusted hazard ratio, 0.97; 95% CI, 0.79-1.18). Conclusions and Relevance In nonurban areas in Catalonia, Spain, there was no significant difference in 90-day neurological outcomes between transportation to a local stroke center vs a thrombectomy-capable referral center in patients with suspected large-vessel occlusion stroke. These findings require replication in other settings. Trial Registration ClinicalTrials.gov Identifier: NCT02795962
    Type of Medium: Online Resource
    ISSN: 0098-7484
    RVK:
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2022
    detail.hit.zdb_id: 2958-0
    detail.hit.zdb_id: 2018410-4
    SSG: 5,21
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  • 4
    In: Bulletin of the World Health Organization, WHO Press, Vol. 100, No. 03 ( 2022-03-01), p. 187-195
    Type of Medium: Online Resource
    ISSN: 0042-9686 , 0042-9686
    URL: Issue
    RVK:
    Language: Unknown
    Publisher: WHO Press
    Publication Date: 2022
    detail.hit.zdb_id: 2030027-X
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