Is it time to switch to bivalirudin for ECMO anticoagulation?

For decades, unfractionated heparin (hereafter, heparin) has been the primary anticoagulant used for extracorporeal membrane oxygenation (ECMO) support. More recently, however, bivalirudin, a direct thrombin inhibitor, has emerged as an alternative. This systematic review based on PRISMA guidelines, aims to summarize 16 comparative studies and 8 meta-analysis and review articles published from January, 2011 till May, 2023 which directly compares ECMO courses using heparin versus bivalirudin as the anticoagulant. While this comparison is complicated by the lack of a standardized definition of major bleeding or thrombosis, our overall findings suggest there is no statistical difference between heparin and bivalirudin in incidence of bleeding and thrombosis. That said, some studies found a statistical significance favoring bivalirudin in reducing major bleeding, thrombosis, and the need for transfusions. We also offer essential guidance for appropriately selecting an anticoagulant and monitoring its effect in ECMO settings.

Pediatric Swine Model of Methicillin-Resistant Staphylococcus aureus Sepsis-Induced Coagulopathy, Disseminated Microvascular Thrombosis, and Organ Injuries.

Sepsis-induced coagulopathy leading to disseminated microvascular thrombosis is associated with high mortality and has no existing therapy. Despite the high prevalence of Gram-positive bacterial sepsis, especially methicillin-resistant Staphylococcus aureus (MRSA), there is a paucity of published Gram-positive pediatric sepsis models. Large animal models replicating sepsis-induced coagulopathy are needed to test new therapeutics before human clinical trials. HYPOTHESIS: Our objective is to develop a pediatric sepsis-induced coagulopathy swine model that last 70 hours. METHODS AND MODELS: Ten 3 weeks old piglets, implanted with telemetry devices for continuous hemodynamic monitoring, were IV injected with MRSA (n = 6) (USA300, Texas Children's Hospital 1516 strain) at 1 × 109 colony forming units/kg or saline (n = 4). Fluid resuscitation was given for heart rate greater than 50% or mean arterial blood pressure less than 30% from baseline. Acetaminophen and dextrose were provided as indicated. Point-of-care complete blood count, prothrombin time (PT), activated thromboplastin time, d-dimer, fibrinogen, and specialized coagulation assays were performed at pre- and post-injection, at 0, 24, 48, 60, and 70 hours. Piglets were euthanized and necropsies performed. RESULTS: Compared with the saline treated piglets (control), the septic piglets within 24 hours had significantly lower neurologic and respiratory scores. Over time, PT, d-dimer, and fibrinogen increased, while platelet counts and activities of factors V, VII, protein C, antithrombin, and a disintegrin and metalloproteinase with thrombospondin-1 motifs (13th member of the family) (ADAMTS-13) decreased significantly in septic piglets compared with control. Histopathologic examination showed minor focal organ injuries including microvascular thrombi and necrosis in the kidney and liver of septic piglets. INTERPRETATIONS AND CONCLUSIONS: We established a 70-hour swine model of MRSA sepsis-induced coagulopathy with signs of consumptive coagulopathy, disseminated microvascular thrombosis, and early organ injuries with histological minor focal organ injuries. This model is clinically relevant to pediatric sepsis and can be used to study dysregulated host immune response and coagulopathy to infection, identify potential early biomarkers, and to test new therapeutics.

Novel Coagulation Test Detects Anticoagulation Resistance and Is Associated With Thrombotic Events in Pediatric Patients Requiring Extracorporeal Membrane Oxygenation.

Bivalirudin, an IV direct thrombin inhibitor, and unfractionated heparin (UFH) are frequently used anticoagulants in the pediatric critical care setting. An accurate, specific, point-of-care test to quantify and detect anticoagulation resistance is not currently available. This study evaluates the ability of a rapid (< 10 min), micro-volume (< 50 uL) coagulation test to detect and quantify the anticoagulation effect of bivalirudin and UFH using a functional, clot time endpoint in pediatric critical care patients. DESIGN: Single-site retrospective laboratory sample analysis and chart review. SETTING: A 105-bed pediatric and cardiac ICUs delivering extracorporeal membrane oxygenation. SUBJECTS: Forty-one citrated, frozen, biobanked plasma specimens comprising 21 with bivalirudin and 20 with UFH from 15 anticoagulated pediatric patients were analyzed. Thirteen patients were on extracorporeal membrane oxygenation, one had a submassive pulmonary embolism, and one was on a left ventricular assist device. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: A Clotting Time Score (CTS) was derived on each sample. The CTS detected patients that had developed a pathologic clotting event with 100% sensitivity and 82% specificity compared with prothrombin time with 25% sensitivity/76% specificity and activated partial thromboplastin time with 0% sensitivity/0% specificity. Additionally, the CTS detected subtherapeutic anticoagulation in response to UFH in patients that were clinically determined to be UFH resistant requiring alternative anticoagulation with bivalirudin. CONCLUSIONS: The CTS appears to be a clinically valuable indicator of coagulation status in patients treated with either UFH or bivalirudin. Results outside of the therapeutic range due to inadequate dosing or anticoagulation resistance appeared to be associated with clot formation. CTS testing may reduce the risk of anticoagulation-related complications via the rapid identification of patients at high risk for pathologic thrombotic events.

Thrombosis and thromboembolism: Brighton collaboration case definition and guidelines for data collection, analysis, and presentation of immunization safety data.

This is a Brighton Collaboration case definition of thrombosis and thromboembolism to be used in the evaluation of adverse events following immunization, and for epidemiologic studies for the assessment of background incidence or hypothesis testing. The case definition was developed by a group of experts convened by the Coalition for Epidemic Preparedness Innovations (CEPI) in the context of active development of SARS-CoV-2 vaccines. The case definition format of the Brighton Collaboration was followed to develop a consensus definition and defined levels of certainty, after an exhaustive review of the literature and expert consultation. The document underwent peer review by the Brighton Collaboration Network and by selected expert reviewers prior to submission.

Derangement of Arginine and Related Amino Acids in Children Undergoing Surgery for Congenital Heart Disease With Cardiopulmonary Bypass.

Arginine is a conditionally essential amino acid, the precursor for nitric oxide and a key factor in cell proliferation, protein synthesis, and energy metabolism. When there is increased demand in the setting of inflammation, ischemia-reperfusion injury, and organ dysfunction, endogenous arginine production falls short, and external supplementation may be necessary. The goal of this study was to assess changes in concentrations of plasma arginine, citrulline, ornithine, glutamine, and plasma arginase in infants and children undergoing surgery for congenital heart disease with cardiopulmonary bypass. DESIGN: Prospective observational study. SETTING: The study was conducted in the Heart Center at Texas Children's Hospital. SUBJECTS: Children undergoing surgery for congenital heart disease with cardiopulmonary bypass. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Serial perioperative blood samples were collected for quantification of amino acids, arginase, nitric oxide metabolites, and markers of organ function (lactate, Pao2/Fio2 ratio, and creatinine clearance). Thirty children (18 males) were included in the study; median (interquartile range) age 0.5 years (0.3-0.9 yr). The mean ± sd for plasma amino acid concentrations before cardiopulmonary bypass: arginine 62 ± 20 µmol/L, citrulline 24 ± 6 µmol/L, ornithine 53 ± 32 µmol/L, and glutamine 591 ± 126 µmol/L. Arginine concentration was decreased within the first 24 hours (43 ± 15 µmol/L; p = 0.004), citrulline and glutamine concentrations decreased over the first 48 hours (11 ± 4 µmol/L; p < 0.001 and 493 ± 131 µmol/L; p = 0.019, respectively) and were associated with an increase in arginase (3.8 ± 3 µg/mL; p < 0.05). There was an increase in Vasoactive-Inotropic Score (5.9 ± 19 vs 0.5 ± 2; p < 0.001), decrease in creatinine clearance (76 ± 24 vs 93 ± 31; p = 0.002), and Pao2/Fio2 ratio (243 ± 138 vs 374 ± 200; p = 0.007) comparing to baseline. CONCLUSIONS: A widely variable degree of arginine, citrulline, and glutamine depletion occurs in children after surgery for congenital heart disease. These findings were associated with increased arginase and coincide with some of the markers of organ perfusion.

Hemostatic Management of Extracorporeal Circuits Including Cardiopulmonary Bypass and Extracorporeal Membrane Oxygenation.

Cardiopulmonary bypass and extracorporeal membrane oxygenation (ECMO) cause hemostatic derangements that can predispose patients to both bleeding and thrombotic complications. Often, patients present for urgent surgery while taking medications including antiplatelet agents, vitamin K antagonists, and direct oral anticoagulants, which must be recognized, monitored, and managed. During extracorporeal circulation, appropriate anticoagulation, most commonly with heparin, is required to maintain blood flow and avoid thrombotic complications. However, anticoagulation and other effects of extracorporeal circuits can also have an undesired consequence of bleeding. Extracorporeal circulation leads to coagulopathy that may require therapy with blood products such as platelets, cryoprecipitate, and plasma in case a patient bleeds. Platelet dysfunction related to exposure to a foreign circuit is a primary concern, as is the development of acquired von Willebrand syndrome, which frequently remains undetected on routine testing. Hemorrhagic complications in ECMO, such as intracranial hemorrhage, pulmonary hemorrhage, and hemithorax, can occur. Hemostatic agents including antifibrinolytics, desmopressin, fibrinogen concentrates, and other factor concentrates may be needed to achieve hemostasis in these often-challenging patients. Managing bleeding on extracorporeal support requires careful monitoring and a thoughtful approach.

Controlled Trial to Compare Therapeutic Efficacy of Endoscopic Third Ventriculostomy Plus Choroid Plexus Cauterization with Ventriculoperitoneal Shunt in Infants with Obstructive Hydrocephalus.

CONTEXT: Ventriculoperitoneal (VP) shunt and endoscopic third ventriculostomy (ETV) are the established surgical treatments for obstructive hydrocephalus (HCP). Powerful evidence regarding the best therapeutic approach for infants with obstructive HCP is lacked. AIMS: Comparison of the therapeutic efficacy of VP shunt and ETV/choroid plexus cauterization (CPC) in infants with obstructive HCP. SETTINGS AND DESIGN: This was a randomized, active control, unblind, single-center, clinical trial. METHODS: Infants with obstructive HCP were randomly allocated to each intervention group (ETV/CPC or VP shunt). They were monitored for at least 6 months for any sign of raised intracranial pressure (rICP). The recurrence of rICP signs requiring surgical intervention was considered as intervention failure. STATISTICAL ANALYSIS: The association between intervention group and outcome was tested with Chi-square test, and P = 0.05 or less was considered statistically significant. RESULTS: Of the total fifty patients entering the study, 49 were included in the final analysis, 27 of them were in VP shunt and 22 in ETV/CPC group. Seventeen patients (34%) were female and 33 (66%) were male with mean age of 3.74 ± 3.1 months (range = 10 days - 11 months). Thirty-nine (79.6%) were under 6 months of age and the remaining were 6 months or older. The overall success rate in 36-month follow-up was 88.5% and 68.2% for VP shunt and ETV/CPC, respectively, with the difference being not statistically significant. CONCLUSION: The current study determined no inferiority of ETV/CPC compared to VP shunt, and therefore, it may become an efficient treatment for obstructive HCP in infants.

Correlation between ERG Fusion Protein and Androgen Receptor Expression by Immunohistochemistry in Prostate, Possible Role in Diagnosis and Therapy.

Background: Recent discovery of gene rearrangements have brought a new look to the molecular pathogenesis of cancer. Gene fusions occur in nearly 60% of prostate adenocarcinoma, being the TMPRSS2-ERG one of the most common. Evidence supports the role of ERG fusion in tumorigenesis, progression and invasion via effecting pathways such as WNT, MYC, uPA, PI3K/AKT/PTEN, RAS/RAF/MAPF, NKX3.1, GST-pi and androgen receptor (AR) mediated signaling. Most of the ERG fusions involve 5'-partners androgen responsive. Therefore, we aimed to evaluate AR and ERG fusion protein expression on prostate tissue to find clinicopathological applications and possible role in therapy. Methods: One hundred three samples, including prostate core biopsies and radical prostatectomy specimens, were evaluated for ERG and AR expression by immunohistochemistry (IHC). ERG rearrangement was done by fluorescence in situ hybridization (FISH) on 11 randomly selected cases and correlated with IHC results. Results: From the total of 103 samples, eight (8/103) were benign, fourteen (14/103) had atypical glands, two (2/103) had prostatic intraepithelial neoplasia (PIN), and seventy nine (79/103) showed prostate adenocarcinoma. Forty four (44/79) tumor cases were Gleason score (GS) 6-7 (lower GS), and thirty five (35/79) were GS of 8-10 (higher GS). ERG immunoreaction was observed in 27.8% (22/79) of the tumor cases, showing higher expression in those with lower GS (68.2%, 15/22) compared to higher GS (31.8%, 7/22). Neither benign glands nor PIN stained with ERG. AR expression was observed in 75% of benign samples, 78.5% of atypical glands, 100% of PIN, and in 87.3% of tumor cases with no significant difference based on GS. Co-expression of ERG and AR was evaluated on all the tumor samples. ERG+/AR+ was seen in 77.3% (17/22) of the ERG+ tumor cases, with higher frequency in lower GS (64.7%, 11/17) compared to those with higher GS (35.3%, 6/17). All but five corresponding ERG+ tumor samples were negative for AR. Only 5 samples were ERG-/AR- corresponding to adenocarcinoma GS of 6. Presence or absence of ERG rearrangement was confirmed by FISH and correlated with IHC results. Conclusions: Characterization of ERG status by IHC in prostate tissue has an excellent correlation with FISH. It may also assist in diagnosis since none of the benign glands stained with ERG. Co-expression of ERG+/AR+ in prostate tumor by IHC may suggest gene fusion between ERG and a 5'-partner driven by androgen signaling such as TMPRSS2, which it could represent an important ancillary test for clinical management and development of new therapeutic targets.