Anticoagulation Monitoring and Targets: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE Consensus Conference.

OBJECTIVES: To derive systematic-review informed, modified Delphi consensus regarding anticoagulation monitoring assays and target levels in pediatric extracorporeal membrane oxygenation (ECMO) for the Pediatric ECMO Anticoagulation CollaborativE. DATA SOURCES: A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021. STUDY SELECTION: Anticoagulation monitoring of pediatric patients on ECMO. DATA EXTRACTION: Two authors reviewed all citations independently, with a third independent reviewer resolving any conflicts. Evidence tables were constructed using a standardized data extraction form. DATA SYNTHESIS: Risk of bias was assessed using the Quality in Prognosis Studies tool or the revised Cochrane risk of bias for randomized trials, as appropriate and the evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation system. Forty-eight experts met over 2 years to develop evidence-based recommendations and, when evidence was lacking, expert-based consensus statements for clinical recommendations focused on anticoagulation monitoring and targets, using a web-based modified Delphi process to build consensus (defined as > 80% agreement). One weak recommendation, two consensus statements, and three good practice statements were developed and, in all, agreement greater than 80% was reached. We also derived some resources for anticoagulation monitoring for ECMO clinician use at the bedside. CONCLUSIONS: There is insufficient evidence to formulate optimal anticoagulation monitoring during pediatric ECMO, but we propose one recommendation, two consensus and three good practice statements. Overall, the available pediatric evidence is poor and significant gaps exist in the literature.

Executive Summary: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE (PEACE) Consensus Conference.

OBJECTIVES: To present recommendations and consensus statements with supporting literature for the clinical management of neonates and children supported with extracorporeal membrane oxygenation (ECMO) from the Pediatric ECMO Anticoagulation CollaborativE (PEACE) consensus conference. DATA SOURCES: Systematic review was performed using PubMed, Embase, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021, followed by serial meetings of international, interprofessional experts in the management ECMO for critically ill children. STUDY SELECTION: The management of ECMO anticoagulation for critically ill children. DATA EXTRACTION: Within each of eight subgroup, two authors reviewed all citations independently, with a third independent reviewer resolving any conflicts. DATA SYNTHESIS: A systematic review was conducted using MEDLINE, Embase, and Cochrane Library databases, from January 1988 to May 2021. Each panel developed evidence-based and, when evidence was insufficient, expert-based statements for the clinical management of anticoagulation for children supported with ECMO. These statements were reviewed and ratified by 48 PEACE experts. Consensus was obtained using the Research and Development/UCLA Appropriateness Method. Results were summarized using the Grading of Recommendations Assessment, Development, and Evaluation method. We developed 23 recommendations, 52 expert consensus statements, and 16 good practice statements covering the management of ECMO anticoagulation in three broad categories: general care and monitoring; perioperative care; and nonprocedural bleeding or thrombosis. Gaps in knowledge and research priorities were identified, along with three research focused good practice statements. CONCLUSIONS: The 91 statements focused on clinical care will form the basis for standardization and future clinical trials.

Causes of red blood cell loss during extracorporeal membrane oxygenation.

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.

Causes of platelet loss during extracorporeal life support.

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.

Conversion From Activated Clotting Time to Anti-Xa Heparin Activity Assay for Heparin Monitoring During Extracorporeal Membrane Oxygenation.

OBJECTIVES: Anticoagulation with unfractionated heparin remains the most common therapy used to prevent circuit thrombosis during extracorporeal membrane oxygenation, but no consensus exists on the optimal method or targets for heparin monitoring. From 2015 to 2018, we switched from monitoring heparin during extracorporeal membrane oxygenation using activated clotting times to anti-Xa heparin activity assays. This study describes the transition from activated clotting time to anti-Xa heparin activity assay monitoring and the associated clinical changes. DESIGN: Retrospective analysis at single institution. SETTING: Referral Children's Hospital. PATIENTS: A total of 145 pediatric patients over 152 extracorporeal membrane oxygenation runs using 206 extracorporeal membrane oxygenation circuits. INTERVENTIONS: Anticoagulation protocol quality improvement. MEASUREMENTS AND MAIN RESULTS: From 2015 to 2018, heparin monitoring during extracorporeal membrane oxygenation changed from hourly activated clotting time to anti-Xa heparin activity assay every 6 hours with an associated 75% reduction in the circuit changes per extracorporeal membrane oxygenation day. Over the 4 years, patients with an average anti-Xa heparin activity assay of at least 0.25 U/mL showed a 59% reduction in circuit changes per extracorporeal membrane oxygenation day compared with less than 0.15 U/mL. In addition to its association with reduced circuit changes, anti-Xa heparin activity assay monitoring was also associated with reduced heparin dose changes per day from 11 ± 4 to 2 ± 1 (p < 0.001), smaller heparin dose changes (less variation in dose), and reduced diagnostic phlebotomy volumes from 41 ± 6 to 25 ± 11 mL/day (p < 0.001). The number of patients with reported bleeding decreased from 69% using activated clotting time to 51% (p = 0.03). Transfusion rates did not change. CONCLUSIONS: Over 4 years, we replaced the activated clotting time assay with the anti-Xa heparin activity assay for heparin monitoring during extracorporeal membrane oxygenation. Minimum anti-Xa heparin activity assay levels of 0.25 U/mL were associated with reduced circuit changes. Further studies are needed to determine the optimum anti-Xa heparin activity assay therapeutic range during extracorporeal membrane oxygenation.

Interference in the anti-Xa heparin activity assay due to hemolysis and icterus during pediatric extracorporeal life support.

Chromogenic anti-Xa assays for unfractionated heparin monitoring (heparin activity) are susceptible to interference from hemolysis and icterus. The purpose of this study was to better understand the effect of hemolysis and icterus on anti-Xa heparin activity and to predict the magnitude of the error. Increasing levels of hemoglobin and unconjugated bilirubin were added to pooled normal plasma or buffer containing known levels of heparin. Increased plasma hemoglobin or bilirubin produced falsely increased residual factor Xa activity as measured by the absorbance change (OD/min) in the Stago heparin activity assay. This increased absorbance change slope resulted in falsely lower estimates of heparin activity. The falsely lower heparin activity measurement occurred even when heparin was not present, indicating it was not due to heparin neutralization. In a sample containing 0.62 ± 0.06 U/mL heparin and 228 mg/dL hemoglobin, the measured heparin activity was 0.41 ± 0.03 U/mL, underestimating heparin activity by 0.21 ± 0.07 U/mL. Interference occurred if plasma hemoglobin was above 70 mg/dL or bilirubin was above 16 mg/dL, which happened in 16%-26% of samples from pediatric patients on extracorporeal life support (ECLS). In conclusion, hemolysis and icterus were common in ECLS patients, leading to underestimates of unfractionated heparin activity and potentially higher doses of heparin than intended. The magnitude of the heparin activity measurement error could be predicted based on plasma hemoglobin and bilirubin levels until these levels exceeded the technical limits of the assay, ~230 mg/dL hemoglobin and 55 mg/dL bilirubin.

In-vitro thrombogenicity assessment of flow diversion and aneurysm bridging devices.

Endoluminal devices such as metallic flow diversion (FD) and aneurysm bridging (AB) stents are used for treatment of intracranial aneurysms. Treatments are associated with thrombogenic events mandating the use of dual antiplatelet therapy in all cases. In the current in vitro study, we utilize a slow binding fluorogenic thrombin specific substrate to measure the thrombin generation potential of six devices: four FD devices (Pipeline™ Flex embolization device, Pipeline™ Flex embolization device with Shield Technology™, SILK+, FRED™) and two AB devices (Solitaire™ AB, LEO+). We show that the Pipeline™ Flex embolization device with Shield Technology™ has significantly lower peak thrombin and takes significantly longer time to achieve peak thrombin (time to peak) compared to the other three FD devices (p < 0.05), with statistically similar results to the less thrombogenic AB devices. We conclude that surface modification of endoluminal stents could be an effective method to mitigate thrombogenic complications.

Analytical performance of QMS everolimus assay on ortho Vitros 5,1 FS fusion analyzer: measuring everolimus trough levels for solid organ transplant recipients.

BACKGROUND: Everolimus has recently been approved by Food and Drug Administration for graft maintenance in liver transplant recipients. This drug has a narrow therapeutic index and benefits from close blood level monitoring. Currently, in the United States, the Thermo Fisher Scientific Quantitative Microsphere System (QMS) Everolimus Immunoassay is the only Food and Drug Administration-cleared immunoassay for monitoring everolimus in renal transplant recipients. However, studies on this assay adapted to the Ortho Vitros 5,1 FS chemistry analyzer have not been published, and data of this assay applied to monitoring drug levels in liver transplant recipients are limited. Here, the authors evaluated and validated the QMS everolimus assay on the Vitros analyzer and its application to supporting the immunosuppressant management of mainly liver transplant recipients. METHODS: The analysis was performed according to the QMS assay package insert. The method was compared with a liquid chromatography-tandem mass spectrometry method from a reference laboratory using a total of 34 samples from 1 double lung and liver, 8 liver, and 3 kidney recipients. The method comparison was assessed by Deming regression. Proficiency test materials issued by Everolimus TDM Proficiency Support Program were tested and compared with the peer group results of using the QMS kits. RESULTS: The assay was linear in the range of 0.75-20.0 ng/mL. Limit of detection was 0.70 ng/mL and lower limit of quantitation was 0.75 ng/mL. Within-day and between-day (20 days) coefficients of variation were between 3.1% and 16.5% at mean levels of 5.3, 12.0, and 17.2 ng/mL, respectively. We obtained a Deming regression of y = 1.271 - 0.666 (r = 0.880) when comparing with the liquid chromatography-tandem mass spectrometry method. CONCLUSIONS: The authors concluded that the analytical performance of the QMS everolimus immunoassay by the Vitros 5,1 FS analyzer was satisfactory for monitoring drug levels of solid organ transplant patients.

Red Cell Damage During Extracorporeal Life Support.

Sublethal damage to red blood cells (RBCs) during extracorporeal life support (ECLS) may lead to RBC loss. Using flow cytometry, phosphatidylserine-positive (PhS+) RBCs and RBC extracellular vesicles were quantified as measures of sublethal RBC injury in 41 pediatric ECLS runs, stored RBC units, and normal adult subjects. We estimated the clearance half-life of PhS+ RBCs and compared the rates of RBC loss during pediatric ECLS due to phlebotomy, intravascular hemolysis, and extravascular clearance of PhS+ RBCs. Extracorporeal life support patients had 0.9% PhS+ RBCs, sixfold higher than normal subjects (p < 0.0001). Phosphatidylserine-positive RBCs were increased in stored RBC units (twofold in whole blood derived units, p = 0.0013; 12-fold in apheresis RBC units, p < 0.0001). Phosphatidylserine-positive RBCs were cleared with an average half-life of 15 hours. During ECLS, PhS+ RBC clearance accounted for 7% of RBC loss (1-60%), phlebotomy 12%, and intravascular hemolysis 12%. Increasing PhS+ RBCs occurred in 40% of patients that died on ECLS. Red blood cell extracellular vesicles, another marker of red cell injury/activation, were elevated fivefold during ECLS. Phosphatidylserine exposure on RBCs is increased during ECLS, marking these cells for extravascular clearance with a half-life of ~15 hours and accounting for ~7% of RBC loss.

Alternative monitoring of argatroban using plasma-diluted thrombin time.

OBJECTIVE: To report a case of heparin-induced thrombocytopenia (HIT) in a patient with concurrent liver dysfunction and a prolonged baseline activated partial thromboplastin time (aPTT) in whom argatroban therapy was monitored with aPTT and a novel plasma-diluted thrombin assay. CASE SUMMARY: An 80-year-old man with HIT and liver dysfunction was treated with argatroban, which was initiated at a dose of 0.5 µg/kg/min and gradually decreased to 0.09 µg/kg/min. The patient had a mildly prolonged aPTT at baseline (37.5 seconds). He was concurrently monitored with aPTT, per institution protocol, and plasma-diluted thrombin time. Plasma-diluted thrombin times were consistently lower than aPTTs, but mirrored the trend of the aPTTs. Eleven hours after argatroban was stopped, the aPTT remained elevated (53.9 seconds), while the plasma-diluted thrombin time returned to normal range (26.4 seconds). The patient's therapy was transitioned to warfarin and he had a hospital course with no thrombotic or bleeding complications. DISCUSSION: Plasma-diluted thrombin time is a novel laboratory test consisting of 1 part patient plasma diluted with 3 parts normal plasma. Plasma-diluted thrombin time has been shown to blunt the sensitivity of the thrombin time and may be more accurate for drug monitoring. A MEDLINE search revealed 2 studies using the plasma-diluted thrombin time assay. The first study compared aPTT and plasma-diluted thrombin times in blood samples mixed with argatroban, bivalirudin, or lepirudin at 3 different concentrations. Blood samples contained lupus inhibitors, vitamin k deficiency, or normal baseline aPTTs. The aPTT overestimated drug concentrations in all samples with lupus anticoagulant and vitamin k deficiency, while the plasma-diluted thrombin time correctly estimated drug concentrations in nearly all samples. The second study looked at monitoring dabigatran with plasma-diluted thrombin time and found a linear relationship between the plasma-diluted thrombin time and the dabigatran dose-response curve. CONCLUSIONS: Plasma-diluted thrombin time may be an alternative for direct thrombin inhibitor monitoring in patients with elevated aPTT values at baseline. Further randomized control trials are needed to determine its applicability in clinical practice.

Monitoring Direct Thrombin Inhibitors With Calibrated Diluted Thrombin Time vs Activated Partial Thromboplastin Time in Pediatric Patients.

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.

Coagulation activation during extracorporeal membrane oxygenation (ECMO).

INTRODUCTION: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Thrombosis in Extracorporeal Membrane Oxygenation (ECMO) Circuits.

Thrombosis in extracorporeal membrane oxygenation (ECMO) circuits remains a frequent complication. We characterize the location, extent, structure, and clinical implications of thrombi in 53 ECMO circuits from 46 pediatric patients. The tubing, pump, and oxygenator were examined for visible thrombi. Representative samples of thrombi were collected for histologic, immunofluorescence, and immunohistochemical analysis. Thrombi were found in 81% of ECMO circuits. The most clinically significant were inflow oxygenator membrane surface thrombi (11% of circuits), arterial tubing thrombi (30%), and venous tubing (26%) or connector thrombi (26%). Oxygenator membrane surface thrombi resulted in rapidly increasing delta pressure across the oxygenator over 1-2 days, oxygenator failure, and circuit replacement. Oxygenator membrane surface thrombi were associated with intravascular venous thrombosis and bacterial infection before starting ECMO. Arterial cannula/tubing thrombi led in one case to aortic and mesenteric artery thrombosis followed by bowel infarction. In 11% of cases, venous tubing thrombi grew large enough to break off and embolize to the pump, resulting in increased hemolysis. Antifibrinolytic therapy during ECMO was associated with an increased risk of pump thromboembolism. Other less clinically significant thrombi included pump axle thrombi with thrombus fragments trapped in the oxygenator (45%), and deep oxygenator membrane thrombi (15%). Examination of ECMO circuits after removal is a useful quality improvement tool that can elucidate the cause of circuit problems, indicate patients at increased risk of thrombosis, and suggest areas for possible improvements.

Recurrent Gastrointestinal Bleeding in a Middle-Aged Man.

Acquired von Willebrand disease (avWD) arises because of mechanisms that destroy, decrease, absorb, or clear von Willebrand factor (vWF). A 59-year-old man presented with a 3-year history of recurrent gastrointestinal bleeding. Laboratory workup revealed a prolonged platelet function assay-100. The vWF antigen was decreased, and a low vWF immunofunctional activity/antigen ratio, low collagen binding/antigen ratio, and decreased intermediate and high molecular weight multimers were noted. The patient had no high-shear stress conditions, and an antibody-mediated process was suspected. A vWF mixing study showed complete correction of vWF activity, suggesting no direct functional inhibitor. The patient was given a bolus of vWF concentrate with serial measurements of vWF; the vWF half-life was 2.5 hours. The vWF propeptide/antigen ratio was 4:1, supporting a diagnosis of aVWD resulting from increased antibody-mediated vWF clearance. This case study emphasizes the laboratory's role in the diagnosis and treatment of rare, overlooked acquired bleeding disorders.

Interlaboratory Performance in Measurement of Dabigatran and Rivaroxaban.

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 DOAC-specific assays for various concentrations of dabigatran and rivaroxaban, assess the interlaboratory variability in measurement of these DOACs, and investigate the responsiveness of the routine clotting assays to various concentrations of these oral anticoagulants. DESIGN.­: College of American Pathologists proficiency testing survey data from 2013 to 2016 were summarized and analyzed. RESULTS.­: For dabigatran, the interlaboratory coefficient of variation (CV) of ecarin chromogenic assay was broad (ranging from 7.5% to 29.1%, 6.3% to 15.5%, and 6.8% to 9.0% for 100-ng/mL, 200-ng/mL, and 400-ng/mL targeted drug concentrations, respectively). The CV for diluted thrombin time for dabigatran was better overall (ranging from 11.6% to 17.2%, 9.3% to 12.3, and 7.1% to 11.2% for 100 ng/mL, 200 ng/mL, and 400 ng/mL, respectively). The rivaroxaban-calibrated anti-Xa assay CVs also showed variability (ranging from 11.5% to 22.2%, 7.2% to 10.9%, and 6.4% to 8.1% for 50-ng/mL, 200-ng/mL, and 400-ng/mL targeted drug concentrations, respectively). The prothrombin time (PT) and activated partial thromboplastin time (aPTT) showed variable dose- and reagent-dependent responsiveness to DOACs: PT was more responsive to rivaroxaban and aPTT to dabigatran. The undiluted thrombin time showed maximum prolongation across all 3 dabigatran concentrations, making it too sensitive for drug-level monitoring, but supporting its use as a qualitative screening assay. CONCLUSIONS.­: DOAC-specific assays performed reasonably well. While PT and aPTT cannot be used safely to determine DOAC degree of anticoagulation, a normal thrombin time excludes the presence of dabigatran.

Pharmacoeconomic, Medication Access, and Patient-Satisfaction Analysis of a Pharmacist-Managed VTE Clinic Compared to Primary Care Physician Outpatient Therapy.

Venous thromboembolism (VTE) is a common medical condition often treated with direct oral anticoagulants (DOACs). Current literature supports outpatient treatment of select, low-risk VTE patients by a pharmacist with DOACs; however, no studies exist to demonstrate if a pharmacist-managed VTE clinic provides financial benefit compared to physician-managed outpatient care. To compare the financial implications and patient satisfaction of pharmacist-managed VTE care versus outpatient VTE care by a primary care physician. A single-center retrospective chart review was conducted on all patients seen at a pharmacist-managed VTE clinic for safety and reimbursement outcomes between August 1, 2018 and July 31, 2019. These data points were used to assess the primary endpoint of net gain per patient visit and secondary outcomes, including patient satisfaction score. The primary outcome median (IQR) for net gain per visit was $16.57 (16.57, 16.57) for the pharmacist-managed group and $64.37 (47.04, 64.37) in the physician-managed group with a 95% CI of 39.13-47.80. The median cost to the organization per visit was $4.96 (4.96, 4.96) for the pharmacist-managed group and $39.41 (23.65, 39.41) for the physician managed group with a 95% CI of 26.57-34.45. Statistical difference was also found for a secondary outcome of percentage of days covered for the pharmacist-managed group compared to the physician managed group, median (IQR) 100% (76,100) vs 92.2% (67.2, 98.9) respectfully, with a p-value of 0.043. The pharmacist-managed VTE clinic, although financially sustainable, provides significantly less net revenue per patient than physician managed clinics, demonstrating the need for increased payer recognition for pharmacists.

Activation of the hemostatic system during cardiopulmonary bypass.

Cardiopulmonary bypass (CPB) is a unique clinical scenario that results in widespread activation of the hemostatic system. However, surgery also results in normal increases in coagulation activation, platelet activation, and fibrinolysis that are associated with normal wound hemostasis. Conventional CPB interferes with normal hemostasis by diluting hemostatic cells and proteins, through reinfusion of shed blood, and through activation on the bypass circuit surface of multiple systems including platelets, the kallikrein-kinin system, and fibrinolysis. CPB activation of the kallikrein-kinin system increases activated factor XIIa, kallikrein, bradykinin, and tissue plasminogen activator levels, but has little effect on thrombin generation. Increased tissue plasminogen activator and circulating fibrin result in increased plasmin generation, which removes hemostatic fibrin. The nonendothelial surface of the bypass circuit, along with circulating thrombin and plasmin, lead to platelet activation, platelet receptor loss, and reduced platelet response to wounds. In this review, we highlight the major mechanisms responsible for CPB-induced activation of the hemostatic system and examine some of the markers described in the literature. Additionally, strategies used to reduce this activation are discussed, including limiting cardiotomy suction, increasing circuit biocompatibility, antithrombin supplementation, and antifibrinolytic use. Determining which patients will most benefit from specific therapies will ultimately require investigation into genetic phenotypes of coagulation protein expression. Until that time, however, a combination of approaches to reduce the hemostatic activation from CPB seems warranted.

Platelet, Red Cell, and Endothelial Activation and Injury During Extracorporeal Membrane Oxygenation.

Extracorporeal membrane oxygenation (ECMO) can be lifesaving but suffers from high rates of bleeding and repeated transfusions. Current monitoring of blood cell damage during ECMO is limited to platelet counts, hematocrit, and plasma hemoglobin levels. Extracelluar vesicles (EV) are small cell fragments released when cells are activated/injured. The objective was to evaluate flow cytometric measurements of EV during ECMO as an indication of platelet, red cell, and endothelial activation/injury. Samples were collected from 55 patients (1 day to 19 years) during 58 ECMO runs. ECMO activated or injured blood cells, but the extent was highly variable and patient dependent. On average platelet activation was increased sevenfold during ECMO with up to 60-fold increased activation during the first 24 hours in some patients. EV associated with platelet and red-cell injury were increased eightfold on average but up to 200-fold in patients with disseminated intravascular coagulation, severe hemolysis, or massive transfusion. Approximately 9% of ECMO patients showed a red-cell and endothelial activation pattern that was associated with poor prognosis. Extracellular vesicles with autofluorescence similar to bilirubin appeared to come from monocytes processing hemoglobin. ECMO is associated with a highly variable, sustained increase in platelet, red-cell, and endothelial activation and injury that is a combination of circuit and transfusion related events, the patients underlying condition and possibly genetic influences on blood cell activation and injury. Extracellular vesicle measurements may improve our understanding of cellular activation and injury during ECMO as we work to improve the biocompatibility of these systems.

Development of a rapid emergency hemorrhage panel.

BACKGROUND: Evaluation of hemostasis in bleeding patients requires both accuracy and speed. STUDY DESIGN AND METHODS: As an alternative to point-of-care testing, we developed an emergency hemorrhage panel (EHP: prothrombin time [PT], fibrinogen, platelet count, hematocrit) for use in making transfusion decisions on bleeding patients with a goal of less than 20-minute turnaround time (TAT) when performed in the clinical laboratory on automated instruments. Because point-of-care samples are not checked for clotting or hemolysis, we evaluated their effect on automated testing. RESULTS: TAT was reduced by moving the sample immediately to testing and shortening centrifugation times. Clotting in samples was rare (1.1%) and shortened the PT by only 0.7 seconds. It lowered fibrinogen on average 18%, but resulted in only one of 2300 samples changing from normal to low fibrinogen. Hemolysis had no clinically significant effect on the PT or fibrinogen. Therefore, hemolysis checks were eliminated and clot checks minimized. Initially TAT averaged 15±4 minutes (range, 8-30min), but 9% of samples exceeded the 20-minute goal due to low fibrinogens that slowed testing. A revised fibrinogen assay with expanded calibration range resulted in a TAT of 14±3 minutes (range, 6-28min) with only 2% of samples exceeding the 20-minute goal. By limiting EHPs to patients that were actively bleeding, EHPs accounted for only 8 of 243 coagulation samples per day. CONCLUSION: Limiting EHPs to bleeding patients and modifications to the process and assays used for hemostasis testing lead to TATs of less than 20 minutes for critical testing in the clinical laboratory.