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* Context.--Assessing direct oral anticoagulant (DOAC) drug levels by reliable laboratory assays is necessary in a number of clinical scenarios. Objective.--To evaluate the performance of DOACspecific assays for various concentrations [...]

Context.--The College of American Pathologists (CAP) developed proficiency testing for platelet function assays by using blood collected by the participant added to challenge tubes containing either saline (normal) or tirofiban (abnormal). Objective.--To analyze platelet function proficiency testing for Platelet Function Analyzer PFA-100, platelet aggregation, PlateletWorks, and PlateletMapping. Design.--Proficiency testing data from 2012-2016 were analyzed. Results.--For PFA-100, a total of 1200 laboratories participated; the coefficient variation (CV) of cartridge closure times was 22% (saline); 44,952 of 45,616 survey responses (99%) provided an interpretation, and 42,934 of 44,952 (96%) were correct. For optical platelet aggregation, 190 laboratories participated; the CV was 17% (saline), 7444 of 7813 survey responses (95%) provided an interpretation, and 7015 of 7444 (94%) were correct. For PlateletWorks, 60 laboratories participated; the CV was 3% to 11% (saline); 2412 of 2454 survey responses (98%) provided an interpretation, and 1207 of 1276 (95%) were correct for adenosine diphosphate (ADP) and 936 of 1136 (82%) for collagen. For PlateletMapping, 200 laboratories participated. For ADP, 1128 of 2697 survey responses (42%) provided an interpretation, but only 927 of 1128 (82%) were correct. For arachidonic acid, 1139 of 2604 survey responses (44%) provided an interpretation and 964 of 1139 (85%) were correct. Conclusions.--CAP is the first to provide proficiency testing for platelet aggregation, PlateletWorks, and PlateletMapping. Platelet aggregation, PFA-100, and PlateletWorks using ADP as an agonist performed well with more than 90% of laboratories providing an interpretation and a similar number providing correct results. PlateletWorks using collagen and PlateletMapping showed worse interpretive accuracy than the other methods. (Arch Pathol Lab Med. 2019;143:472-482; doi: 10.5858/arpa.2017-0556-CP), Platelets perform multiple functions related to hemostasis and can be activated by multiple pathways; thus, no single platelet function test can assess all aspects of platelet function or diagnose all [...]

Background: Pediatric patients on extracorporeal membrane oxygenation (ECMO) often receive repeated red blood cell (RBC) transfusions. This study aims to quantify and characterize causes of RBC loss on ECMO. Methods: This retrospective, single‐center, observational study includes 91 ECMO patients (age 1 day–20 years). An RBC loss index (RLI), equal to ml RBCs lost per liter of patient + circuit volume per hour, was calculated from the changes in hematocrit and transfused RBCs. To measure the contribution of RBC injury/activation, RBC extracellular vesicle (REV) generation was measured by flow cytometry. Results: Median RLI on ECMO was 1.9 ml/L/h, 13‐fold higher than normal RBC production rate (0.15 ml/L/h) and equivalent to a 4.6 drop in hematocrit/day. Median RBC loss was higher in patients who died (2.95 ml/L/h) versus survived (1.70 ml/L/h, p =.0008). RLI correlated with transfusion rate (r2 = 0.71); however, transfusion rate (ml/kg) underestimated RBC loss in patients with large changes in hematocrit and over‐estimated RBC loss in neonates where the circuit volume is greater than the patient blood volume. In non‐bleeding patients, intravascular hemolysis represented 16% of total RBC loss and diagnostic phlebotomy 24%, suggesting that ~60% of RBC loss was due to other causes. REV generation was increased sevenfold to ninefold during ECMO. Discussion: RLI (ml/L/h) is a more reliable quantitative indicator of RBC loss than transfusion rate (ml/kg) for pediatric patients on ECMO. Phlebotomy and intravascular hemolysis only account for 40% of RBC loss in non‐bleeding ECMO patients. High REV generation suggests sublethal damage and extravascular clearance may be a cause of RBC loss on ECMO. See editorial on page 899–902, in this issue [ABSTRACT FROM AUTHOR]

Background: Most pediatric patients show a decline in platelet counts while on extracorporeal life support (ECLS) and require multiple platelet transfusions. To better understand platelet loss during ECLS, this study estimated platelet loss rates due to diagnostic phlebotomy, platelet activation, bleeding and other causes. Methods: We collected data on 91 patients (1d‐20y, 50 M, 41F). Platelet losses were estimated based on changes in platelet count, patient+circuit blood volume, and transfused platelet volumes. Platelet extracellular vesicles were measured by flow cytometry. Results: Median platelet loss was 2.8 × 109/L/hr, more than twice the normal rate of platelet removal and equivalent to a 67 000/μl decrease in platelet count per day. While platelet loss was correlated with platelet transfusion (r2 = 0.51), transfusion underestimated platelet loss in patients with large decreases in platelet count and over‐estimated platelet loss in neonates where the circuit volume > patient blood volume. Patients with disseminated intravascular coagulation before or significant bleeding during ECLS have double the rate of platelet loss. Platelet activation accounted for ~32% of total platelet loss, bleeding ~36% and phlebotomy 4%, with the remaining one‐third due to other causes. Annexin‐negative platelet extracellular vesicle release, a measure of platelet damage, was increased 9‐fold during ECLS. Conclusion: Our study is the first to quantitate total, phlebotomy and activation related platelet loss during ECLS. Platelet activation accounts for ~32% of total platelet loss, while bleeding doubles the platelet loss rate. The etiology of the remaining platelet loss is unknown. [ABSTRACT FROM AUTHOR]

Objectives: Activated partial thromboplastin time (aPTT) is the primary test used to monitor intravenous (IV) direct thrombin inhibitors (DTIs) but has many limitations. The plasma diluted thrombin time (dTT) has shown better correlation with DTI levels than aPTT. This study compared dose-response curves for dTT and aPTT in pediatric patients receiving argatroban and bivalirudin.Methods: A retrospective review of pediatric patients treated with argatroban (n = 45) or bivalirudin (n = 14) monitored with dTT and aPTT.Results: The dTT assay was calibrated to report DTI concentrations in µg/mL for argatroban and bivalirudin with good analytic sensitivity and specificity. The dTT was fivefold more likely to show a stable dose-response slope than the aPTT (P < .0002; odds ratio, 4.9). For patients in whom both dTT and aPTT showed a significant correlation between dose and assay results, dTT had a higher average correlation factor compared with aPTT (P = .007). Argatroban dose-response slopes showed more inter- and intrapatient variation than bivalirudin (dose-response slope coefficient of variation, 132% vs 52%).Conclusions: The dTT assay was more likely to show a stable dose response and have a stronger correlation with DTI dose than aPTT. Argatroban shows more variation in dose response than bivalirudin. [ABSTRACT FROM AUTHOR]

Extracorporeal membrane oxygenation (ECMO) can be life-saving, but suffers from thrombus formation in the circuit with associated risks of oxygenator occlusion, hemolysis and arterial embolism. The formation of thrombin is the key step to thrombus formation and two factors are needed for sustained thrombin generation, a coagulation activator to initiate the process and a procoagulant phospholipid surface for the coagulation system to assemble on. The purpose of this study was to use thrombin generation potential (TGP) and other assays to determine the specific coagulation activators and sources of procoagulant phospholipid that are present in ECMO patient plasma. Samples were collected from 60 patients on ECMO (age 1d-19y) followed evaluation of native and stimulated TGP, measurement of factor II levels and determination of procoagulant extracellular vesicle levels by flow cytometry. During ECMO, native (unstimulated) TGP was increased, followed by a decrease back towards normal after ECMO ended. The main activator of TGP in ECMO plasma was increased FXIa (100% of samples tested), while increased tissue factor activity was present in 7%. Procoagulant phospholipids were present in plasma from ECMO patients in the form of circulating platelet and red cell extracellular vesicles, which were increased 2 to 7-fold compared to normal. Procoagulant extracellular vesicle levels correlated with increased plasma native TGP activity. ECMO activates coagulation in plasma primarily through activation of the contact system and formation of activated factor XIa and generation of circulating procoagulant extracellular vesicles through platelet and red cell activation. • In pediatric patients, ECMO stimulates increased thrombin generation potential. • ECMO activates the contact system generating activated factor IXa. • ECMO increases procoagulant phospholipids through extracellular vesicle release. • Maquet circuits showed higher TGP and platelet activation than Cardiohelp circuits. [ABSTRACT FROM AUTHOR]