ONTraC: A 20-Year History of a Successfully Coordinated Provincewide Patient Blood Management Program: Lessons Learned and Goals Achieved.

Our understanding of the risks associated with perioperative anemia and transfusion, in terms of increased morbidity and mortality, has evolved over the past 2 decades. By contrast, our understanding of the potential mechanisms of injury and optimal treatment strategies remains incomplete. As such, the important role of effective patient blood management (PBM) programs, which address both the effective treatment of anemia and minimizes the need for red blood cell (RBC) transfusion, is of central importance to optimizing patient care and improving patient outcomes. We report on important clinical outcomes of the Ontario Transfusion Coordinator (ONTraC Program), a network of 25 hospital sites, working in coordination over the past 20 years. Transfusion nurse coordinators were assigned to apply multimodal best practice in PBM (including recommended changes in surgical approach; diagnosis, assessment, and treatment of anemia; and adherence to more restrictive RBC transfusion thresholds). Data were collected on various clinical parameters. We further described lessons learned and difficulties encountered in this multisite PBM initiative. A significant reduction in RBC transfusions was observed for numerous indexed surgeries. For example, RBC transfusion rates for knee arthroplasty decreased from 25% in 2002 to 0.4% in 2020. For coronary artery bypass graft (CABG) surgery, transfusion rates decreased from 60% in 2002 to 27% in 2020. We also observed a decrease in RBC units utilized per transfused patient for knee (2.1 ± 0.5 [2002] vs 1.0 ± 0.6 [2020] units per patient) and CABG surgery (3.3 ± 0.6 [2002] vs 2.3 ± 1.9 [2020] units per patient). These reductions were associated with favorable clinical outcomes, including reduced length of hospital stay (P = .00003) and a reduced rate of perioperative infections (P < .001) for nontransfused versus transfused patients. These advances have been achieved with estimated savings in the tens of millions of dollars annually. Our experience and data support the hypothesis that instituting an integrated network of transfusion nurse coordinators can provide an effective provincewide PBM program, reduce RBC transfusions, improve some patient outcomes, and reduce health care costs, as an example of a "win-win-win" medical program.

Preclinical Evaluation of a Modified Herpes Simplex Virus Type 1 Vector Encoding Human TGM1 for the Treatment of Autosomal Recessive Congenital Ichthyosis.

Autosomal recessive congenital ichthyosis (ARCI) is a diverse group of cornification diseases associated with severe clinical complications and decreased quality of life. Germline mutations in the TGM1 gene, which encodes the enzyme TGM1, are the predominant cause of ARCI. These TGM1 mutations trigger the abnormal epidermal differentiation and impaired cutaneous barrier function observed in patients with ARCI. Unfortunately, current ARCI therapies focus solely on symptomatic relief. Thus, there is a significant unmet need for therapeutic strategies aimed at correcting the TGM1 deficiency underlying ARCI. In this study, we investigated the ability of KB105, a gene therapy vector encoding full-length human TGM1, to deliver functional human TGM1 to keratinocytes. In vitro, KB105 efficiently infected TGM1-deficient human keratinocytes, produced TGM1 protein, and rescued transglutaminase enzyme function. In vivo studies demonstrated that both single and repeated topical KB105 administration induced TGM1 protein expression in the target epidermal layer without triggering fibrosis, necrosis, or acute inflammation. Toxicity and biodistribution assessments on repeat dosing indicated that KB105 was well-tolerated and restricted to the dose site. Overall, our results demonstrate that rescuing TGM1 deficiency in patients with ARCI through topical KB105 application represents a promising strategy for safely and noninvasively treating this debilitating disease.

Platelet Apoptosis Can Be Triggered Bypassing the Death Receptors.

In nucleated cells, the extrinsic pathway of the programmed cell death (apoptosis) is triggered by interaction of death ligands of the tumor necrosis factor superfamily with the death receptors on external cell surface membrane. In this review, we present evidence that, in contrast to nucleated cells, apoptosis in anucleate platelets can be induced through bypassing the death receptors, using instead specific receptors on the platelet surface mediating platelet activation, aggregation, and blood coagulation. These platelet surface receptors include the protease-activated receptor 1 of thrombin and glycoproteins IIbIIIa and Ibα, receptors of fibrinogen, and von Willebrand factor. The pro-apoptotic BH3 mimetic ABT-737 and calcium ionophore A23187 also trigger platelet apoptosis without using death receptors. These agents induce the intrinsic pathway of platelet apoptosis by direct targeting mitochondrial and extra-mitochondrial apoptotic responses.

Multimodal Patient Blood Management Program Based on a Three-pillar Strategy: A Systematic Review and Meta-analysis.

OBJECTIVES: To determine whether a multidisciplinary, multimodal Patient Blood Management (PBM) program for patients undergoing surgery is effective in reducing perioperative complication rate, and thereby is effective in improving clinical outcome. BACKGROUND: PBM is a medical concept with the focus on a comprehensive anemia management, to minimize iatrogenic (unnecessary) blood loss, and to harness and optimize patient-specific physiological tolerance of anemia. METHODS: A systematic review and meta-analysis was performed. Eligible studies had to address each of the 3 PBM pillars with at least 1 measure per pillar, for example, preoperative anemia management plus cell salvage plus rational transfusion strategy. The study protocol has been registered with PROSPERO (CRD42017079217). RESULTS: Seventeen studies comprising 235,779 surgical patients were included in this meta-analysis (100,886 pre-PBM group and 134,893 PBM group). Implementation of PBM significantly reduced transfusion rates by 39% [risk ratio (RR) 0.61, 95% confidence interval (CI) 0.55-0.68, P < 0.00001], 0.43 red blood cell units per patient (mean difference -0.43, 95% CI -0.54 to -0.31, P < 0.00001), hospital length of stay (mean difference -0.45, 95% CI -0.65 to -0.25, P < 0,00001), total number of complications (RR 0.80, 95% CI 0.74-0.88, P <0.00001), and mortality rate (RR 0.89, 95% CI 0.80-0.98, P = 0.02). CONCLUSIONS: Overall, a comprehensive PBM program addressing all 3 PBM pillars is associated with reduced transfusion need of red blood cell units, lower complication and mortality rate, and thereby improving clinical outcome. Thus, this first meta-analysis investigating a multimodal approach should motivate all executives and health care providers to support further PBM activities.

Hemoglobin Optimization for Coronary Bypass: A 10-Year Canadian Multicenter Experience.

BACKGROUND: We report our 10-year experience of a multicenter hemoglobin optimization program with the aim to reduce red blood cell transfusion in patients undergoing coronary artery bypass grafting (CABG). METHODS: From 2006 to 2016, patients undergoing CABG at 10 centers in Ontario were referred to the Ontario Transfusion Coordinators (ONTraC) program. Of these, we present data on the first 60 consecutive patients per center, per year (n = 6,145). RESULTS: Overall, 45.7% patients were assessed <14 days preoperatively, 16.4% were assessed ≥14 days preoperatively, and 37.9% were not assessed by ONTraC preoperatively. Transfusion rates fell from 40.1% in 2006 to 26.2% in 2016 (p < 0.01). Patients undergoing assessment were more likely to be older (p < 0.01), female (p < 0.01), and anemic (p < 0.01) versus nonassessed patients. Those patients assessed were more likely to be treated with iron (p < 0.01) and erythropoietin (p < 0.01) preoperatively versus nonassessed patients. Transfusion rates were 26%, 28%, and 28% for patients undergoing assessment ≥14 days prior to operation, <14 days prior to operation, or not at all. After baseline covariate adjustment, patients assessed ≥14 days preoperatively had shorter length of stay (effect -0.83, 95% confidence interval [CI] -1.41 to -0.25; p < 0.01) and a trend towards lower risk of red blood cell transfusion (odds ratio [OR] 0.83, 95% CI 0.68 to 1.00; p = 0.06). Blood transfusion was independently associated with an increased risk of death (OR 1.49, 95% CI 1.37 to 1.60; p < 0.01), infection (OR 1.24, 95% CI 1.18 to 1.30; p < 0.01), and longer hospital length of stay (effect 1.49, 95% CI 1.35 to 1.62; p < 0.01). CONCLUSIONS: The results of this study suggest that preoperative hemoglobin optimization may be effective in reducing red blood cell transfusion after CABG, particularly for patients assessed ≥14 days preoperatively.

GPIbα is required for platelet-mediated hepatic thrombopoietin generation.

Thrombopoietin (TPO), a hematopoietic growth factor produced predominantly by the liver, is essential for thrombopoiesis. Prevailing theory posits that circulating TPO levels are maintained through its clearance by platelets and megakaryocytes via surface c-Mpl receptor internalization. Interestingly, we found a two- to threefold decrease in circulating TPO in GPIbα-/- mice compared with wild-type (WT) controls, which was consistent in GPIbα-deficient human Bernard-Soulier syndrome (BSS) patients. We showed that lower TPO levels in GPIbα-deficient conditions were not due to increased TPO clearance by GPIbα-/- platelets but rather to decreased hepatic TPO mRNA transcription and production. We found that WT, but not GPIbα-/-, platelet transfusions rescued hepatic TPO mRNA and circulating TPO levels in GPIbα-/- mice. In vitro hepatocyte cocultures with platelets or GPIbα-coupled beads further confirm the disruption of platelet-mediated hepatic TPO generation in the absence of GPIbα. Treatment of GPIbα-/- platelets with neuraminidase caused significant desialylation; however, strikingly, desialylated GPIbα-/- platelets could not rescue impaired hepatic TPO production in vivo or in vitro, suggesting that GPIbα, independent of platelet desialylation, is a prerequisite for hepatic TPO generation. Additionally, impaired hepatic TPO production was recapitulated in interleukin-4/GPIbα-transgenic mice, as well as with antibodies targeting the extracellular portion of GPIbα, demonstrating that the N terminus of GPIbα is required for platelet-mediated hepatic TPO generation. These findings reveal a novel nonredundant regulatory role for platelets in hepatic TPO homeostasis, which improves our understanding of constitutive TPO regulation and has important implications in diseases related to GPIbα, such as BSS and auto- and alloimmune-mediated thrombocytopenias.

The integrin PSI domain has an endogenous thiol isomerase function and is a novel target for antiplatelet therapy.

Integrins are a large family of heterodimeric transmembrane receptors differentially expressed on almost all metazoan cells. Integrin ß subunits contain a highly conserved plexin-semaphorin-integrin (PSI) domain. The CXXC motif, the active site of the protein-disulfide-isomerase (PDI) family, is expressed twice in this domain of all integrins across species. However, the role of the PSI domain in integrins and whether it contains thiol-isomerase activity have not been explored. Here, recombinant PSI domains of murine ß3, and human ß1 and ß2 integrins were generated and their PDI-like activity was demonstrated by refolding of reduced/denatured RNase. We identified that both CXXC motifs of ß3 integrin PSI domain are required to maintain its optimal PDI-like activity. Cysteine substitutions (C13A and C26A) of the CXXC motifs also significantly decreased the PDI-like activity of full-length human recombinant ß3 subunit. We further developed mouse anti-mouse ß3 PSI domain monoclonal antibodies (mAbs) that cross-react with human and other species. These mAbs inhibited αIIbß3 PDI-like activity and its fibrinogen binding. Using single-molecular Biomembrane-Force-Probe assays, we demonstrated that inhibition of αIIbß3 endogenous PDI-like activity reduced αIIbß3-fibrinogen interaction, and these anti-PSI mAbs inhibited fibrinogen binding via different levels of both PDI-like activity-dependent and -independent mechanisms. Importantly, these mAbs inhibited murine/human platelet aggregation in vitro and ex vivo, and murine thrombus formation in vivo, without significantly affecting bleeding time or platelet count. Thus, the PSI domain is a potential regulator of integrin activation and a novel target for antithrombotic therapies. These findings may have broad implications for all integrin functions, and cell-cell and cell-matrix interactions.

Clostridium perfringens Enterotoxin: Action, Genetics, and Translational Applications.

Clostridium perfringens enterotoxin (CPE) is responsible for causing the gastrointestinal symptoms of several C. perfringens food- and nonfood-borne human gastrointestinal diseases. The enterotoxin gene (cpe) is located on either the chromosome (for most C. perfringens type A food poisoning strains) or large conjugative plasmids (for the remaining type A food poisoning and most, if not all, other CPE-producing strains). In all CPE-positive strains, the cpe gene is strongly associated with insertion sequences that may help to assist its mobilization and spread. During disease, CPE is produced when C. perfringens sporulates in the intestines, a process involving several sporulation-specific alternative sigma factors. The action of CPE starts with its binding to claudin receptors to form a small complex; those small complexes then oligomerize to create a hexameric prepore on the membrane surface. Beta hairpin loops from the CPE molecules in the prepore assemble into a beta barrel that inserts into the membrane to form an active pore that enhances calcium influx, causing cell death. This cell death results in intestinal damage that causes fluid and electrolyte loss. CPE is now being explored for translational applications including cancer therapy/diagnosis, drug delivery, and vaccination.

CD8+ T cells are predominantly protective and required for effective steroid therapy in murine models of immune thrombocytopenia.

Immune thrombocytopenia (ITP) is a common autoimmune bleeding disorder characterized by autoantibodies targeting platelet surface proteins, most commonly GPIIbIIIa (αIIbß3 integrin), leading to platelet destruction. Recently, CD8(+) cytotoxic T-lymphocytes (CTLs) targeting platelets and megakaryocytes have also been implicated in thrombocytopenia. Because steroids are the most commonly administered therapy for ITP worldwide, we established both active (immunized splenocyte engraftment) and passive (antibody injection) murine models of steroid treatment. Surprisingly, we found that, in both models, CD8(+) T cells limited the severity of the thrombocytopenia and were required for an efficacious response to steroid therapy. Conversely, CD8(+) T-cell depletion led to more severe thrombocytopenia, whereas CD8(+) T-cell transfusion ameliorated thrombocytopenia. CD8(+) T-regulatory cell (Treg) subsets were detected, and interestingly, dexamethasone (DEX) treatment selectively expanded CD8(+) Tregs while decreasing CTLs. In vitro coculture studies revealed CD8(+) Tregs suppressed CD4(+) and CD19(+) proliferation, platelet-associated immunoglobulin G generation, CTL cytotoxicity, platelet apoptosis, and clearance. Furthermore, we found increased production of anti-inflammatory interleukin-10 in coculture studies and in vivo after steroid treatment. Thus, we uncovered subsets of CD8(+) Tregs and demonstrated their potent immunosuppressive and protective roles in experimentally induced thrombocytopenia. The data further elucidate mechanisms of steroid treatment and suggest therapeutic potential for CD8(+) Tregs in immune thrombocytopenia.

Maternal anti-platelet ß3 integrins impair angiogenesis and cause intracranial hemorrhage.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening disease in which intracranial hemorrhage (ICH) is the major risk. Although thrombocytopenia, which is caused by maternal antibodies against ß3 integrin and occasionally by maternal antibodies against other platelet antigens, such as glycoprotein GPIbα, has long been assumed to be the cause of bleeding, the mechanism of ICH has not been adequately explored. Utilizing murine models of FNAIT and a high-frequency ultrasound imaging system, we found that ICH only occurred in fetuses and neonates with anti-ß3 integrin-mediated, but not anti-GPIbα-mediated, FNAIT, despite similar thrombocytopenia in both groups. Only anti-ß3 integrin-mediated FNAIT reduced brain and retina vessel density, impaired angiogenic signaling, and increased endothelial cell apoptosis, all of which were abrogated by maternal administration of intravenous immunoglobulin (IVIG). ICH and impairment of retinal angiogenesis were further reproduced in neonates by injection of anti-ß3 integrin, but not anti-GPIbα antisera. Utilizing cultured human endothelial cells, we found that cell proliferation, network formation, and AKT phosphorylation were inhibited only by murine anti-ß3 integrin antisera and human anti-HPA-1a IgG purified from mothers with FNAIT children. Our data suggest that fetal hemostasis is distinct and that impairment of angiogenesis rather than thrombocytopenia likely causes FNAIT-associated ICH. Additionally, our results indicate that maternal IVIG therapy can effectively prevent this devastating disorder.

Evaluation of a novel transfusion algorithm employing point-of-care coagulation assays in cardiac surgery: a retrospective cohort study with interrupted time-series analysis.

BACKGROUND: Cardiac surgery requiring the use of cardiopulmonary bypass is frequently complicated by coagulopathic bleeding that, largely due to the shortcomings of conventional coagulation tests, is difficult to manage. This study evaluated a novel transfusion algorithm that uses point-of-care coagulation testing. METHODS: Consecutive patients who underwent cardiac surgery with bypass at one hospital before (January 1, 2012 to January 6, 2013) and after (January 7, 2013 to December 13, 2013) institution of an algorithm that used the results of point-of-care testing (ROTEM; Tem International GmBH, Munich, Germany; Plateletworks; Helena Laboratories, Beaumont, TX) during bypass to guide management of coagulopathy were included. Pre- and postalgorithm outcomes were compared using interrupted time-series analysis to control for secular time trends and other confounders. RESULTS: Pre- and postalgorithm groups included 1,311 and 1,170 patients, respectively. Transfusion rates for all blood products (except for cryoprecipitate, which did not change) were decreased after algorithm institution. After controlling for secular pre- and postalgorithm time trends and potential confounders, the posttransfusion odds ratios (95% CIs) for erythrocytes, platelets, and plasma were 0.50 (0.32 to 0.77), 0.22 (0.13 to 0.37), and 0.20 (0.12 to 0.34), respectively. There were no indications that the algorithm worsened any of the measured processes of care or outcomes. CONCLUSIONS: Institution of a transfusion algorithm based on point-of-care testing was associated with reduced transfusions. This suggests that the algorithm could improve the management of the many patients who develop coagulopathic bleeding after cardiac surgery. The generalizability of the findings needs to be confirmed.

Allogeneic platelet transfusions prevent murine T-cell-mediated immune thrombocytopenia.

Platelet transfusions are life-saving treatments for many patients with thrombocytopenia; however, their use is generally discouraged in the autoimmune disorder known as immune thrombocytopenia (ITP). We examined whether allogeneic platelet major histocompatibility complex (MHC) class I transfusions affected antiplatelet CD61-induced ITP. BALB/c CD61 knockout mice (CD61(-)/H-2(d)) were immunized against platelets from wild-type syngeneic BALB/c (CD61(+)/H-2(d)), allogeneic C57BL/6 (CD61(+)/H-2(b)), or C57BL/6 CD61 KO (CD61(-)/H-2(b)) mice, and their splenocytes were transferred into severe combined immunodeficient (SCID) mice to induce ITP. When nondepleted splenocytes were transferred to induce antibody-mediated ITP, both CD61(+) platelet immunizations generated immunity that caused thrombocytopenia independently of allogeneic MHC molecules. In contrast, when B-cell-depleted splenocytes were transferred to induce T-cell-mediated ITP, transfer of allogeneic MHC-immunized splenocytes completely prevented CD61-induced ITP development. In addition, allogeneic platelet transfusions into SCID mice with established CD61-induced ITP rescued the thrombocytopenia. Compared with thrombocytopenic mice, bone marrow histology in the rescued mice showed normalized megakaryocyte morphology, and in vitro CD61-specific T-cell cytotoxicity was significantly suppressed. These results indicate that antibody-mediated ITP is resistant to allogeneic platelet transfusions, while the T-cell-mediated form of the disease is susceptible, suggesting that transfusion therapy may be beneficial in antibody-negative ITP.

Review article: risks of anemia and related management strategies: can perioperative blood management improve patient safety?

PURPOSE: Anemia in both acute and chronic conditions is associated with an increased risk of organ injury (brain, heart, kidney) and mortality. Thus, anemia is not "safe". Impairment of tissue oxygen delivery likely contributes as a central mechanism; however, the existing treatments for anemia (i.e., transfusion, erythropoiesis stimulating agents, blood substitutes) have not produced a demonstrable improvement in patient outcomes despite their efficacy to increase blood oxygen content. Indeed, transfusion of red blood cells (RBCs) has been attributed to increase mortality in non-bleeding patients. Thus, the pathophysiology of anemia-induced morbidity and mortality and its treatments are complex and incompletely understood. New knowledge continues to emerge regarding the cellular mechanisms that maintain oxygen homeostasis during anemia. Nevertheless, the application of this knowledge has not yet led to improvements in patient outcomes. As both anemia and transfusion are associated with increased mortality, utilization of multimodal patient blood management strategies may be effective in avoiding both of these predictors of adverse outcomes. We propose to review new strategies to avoid both anemia and transfusion with the goal of improving patient outcomes and safety. PRINCIPAL FINDINGS: We reviewed several approaches that utilize patient blood management to improve patient outcomes, including 1) characterization of biomarkers of anemia-induced tissue hypoxia to identify appropriate patient-specific treatment thresholds or hemoglobin (Hb) triggers; 2) development of adequately powered clinical trials that will help to define appropriate guidelines for the perioperative treatment of anemia and optimal Hb thresholds for transfusion of RBCs in specific patient populations; and 3) demonstration that an established blood conservation program (ONTraC) can reduce RBC transfusion and its associated adverse outcomes. CONCLUSIONS: Anemia is associated with increased morbidity and mortality. Ongoing initiatives to treat anemia and optimize patient blood management may improve patient outcomes. A broader application of these approaches may improve the overall safety of anesthesia and surgery for patients with anemia.

Drug, devices, technologies, and techniques for blood management in minimally invasive and conventional cardiothoracic surgery: a consensus statement from the International Society for Minimally Invasive Cardiothoracic Surgery (ISMICS) 2011.

OBJECTIVE: The objectives of this consensus conference were to evaluate the evidence for the efficacy and safety of perioperative drugs, technologies, and techniques in reducing allogeneic blood transfusion for adults undergoing cardiac surgery and to develop evidence-based recommendations for comprehensive perioperative blood management in cardiac surgery, with emphasis on minimally invasive cardiac surgery. METHODS: The consensus panel short-listed the potential topics for review from a comprehensive list of potential drugs, devices, technologies, and techniques. The process of short-listing was based on the need to prioritize and focus on the areas of highest importance to surgeons, anesthesiologists, perfusionists, hematologists, and allied health care involved in the management of patients who undergo cardiac surgery whether through the conventional or minimally invasive approach. MEDLINE, Cochrane Library, and Embase databases were searched from their date of inception to May 2011, and supplemental hand searches were also performed. Detailed methodology and search strategies are outlined in each of the subsequently published systematic reviews. In general, all relevant synonyms for drugs (antifibrinolytic, aprotinin, [Latin Small Letter Open E]-aminocaproic acid, tranexamic acid [TA], desmopressin, anticoagulants, heparin, antiplatelets, anti-Xa agents, adenosine diphosphate inhibitors, acetylsalicylic acid [ASA], factor VIIa [FVIIa]), technologies (cell salvage, miniaturized cardiopulmonary bypass (CPB) circuits, biocompatible circuits, ultrafiltration), and techniques (transfusion thresholds, minimally invasive cardiac or aortic surgery) were searched and combined with terms for blood, red blood cells, fresh-frozen plasma, platelets, transfusion, and allogeneic exposure. The American Heart Association/American College of Cardiology system was used to label the level of evidence and class of each recommendation. RESULTS AND RECOMMENDATIONS: Database search identified more than 6900 articles, with 4423 full-text randomized controlled trials assessed for eligibility, and the final 125 systematic reviews and meta-analyses were used in the consensus conference. The results of the consensus conference, including the evidence-based statements and the recommendations, are outlined in the text, with references given for the relevant evidence that formed the basis for the statements and recommendations. RECOMMENDATIONS FOR ANTIFIBRINOLYTICS: The lysine analogs ?-aminocaproic acid (Amicar) and tranexamic acid (TA) reduce exposure to allogeneic blood inpatients undergoing on-pump cardiac surgery. These agents are recommended to be used routinely as part of a blood conservation strategy especially in patients at risk of undergoing onpump cardiac surgery (Class I, Level A). It is important not to exceed maximum TA total dosages (50Y100mg/kg) because of potential neurotoxicity in the elderly and open-heart procedures (Class IIb, Level C). Aprotinin is not recommended in adult cardiac surgery until further studies on its safety profile have been performed (Class III, Level A). RECOMMENDATIONS FOR TA IN OFF-PUMP CORONARY ARTERY BYPASS: Tranexamic acid may be recommended as part of a blood conservation strategy in high risk patients undergoing off-pump coronary artery bypass (OPCAB) surgery (Class I, Level A).Tranexamic acid dosing in OPCAB surgery needs further study particularly with regard to possible neurotoxicity such as seizures.In addition, the benefit-risk ratio in OPCAB needs further eludication because of the lower inherent risk for bleeding in this group (Class IIb, Level C). RECOMMENDATIONS FOR DDAVP: DDAVP can be considered for prophylaxis in coronary artery bypass grafting (CABG) surgery, in particular, for patients onASA within 7 days or prolonged CPB more than 140 minutes (Class IIa, Level A). Caution should be used with the DDAVP infusion rate to avoid significant systemic hypotension (Class I, Level A). RECOMMENDATIONS FOR TOPICAL HEMOSTATICS: The routine use of topical antifibrinolytics in cardiac surgery isnot recommended (Class IIa, Level A). Topical fibrin sealants may be considered in clinical situations where conventional approaches of surgical and medical improvement of hemostasis are not effective, that is, with bleeding problems more local than generalized, bearing in mind the blackbox warning of bovine thrombin by the US Food and Drug Administration (Class IIb, Level C).Recommendations for FVIIa:Prophylactic use of FVIIa cannot be recommended because of a significant increase in the risk of thromboembolic events and stroke (Class IIa, Level A).Factor VIIa may be considered in clinical situations where conventional approaches of surgical and pharmacologic hemostasis have failed and uncontrollable hemorrhage poses a high risk of severe and life-threatening outcomes (Class IIb, Level B). RECOMMENDATIONS FOR ERYTHROPOIETIN PLUS IRON: It is reasonable to administer erythropoietin preoperatively to increase red blood cell mass in patients who are anemic or refuse blood products (such as for Jehovah's Witness faith) or who are likely to have postoperative anemia (Class IIa, Level A). RECOMMENDATIONS FOR ANTIPLATELETS BEFORE CARDIAC SURGERY: Acetylsalicylic acid may be continued until surgery (Class IIa,Level B) For stable elective CABG procedures with no drug-elutingstent, stop clopidogrel 5 days before surgery (Class I, Level A).h For stable elective CABG procedures with drug-eluting stents less than 1 year old, consider continuing clopidogrel or heparin as abridge to surgery (Class IIb, Level C).h Direct-acting P2Y12 receptor antagonists may be a better alternative than clopidogrel in acute coronary syndrome patients undergoing CABG surgery (Class IIa, Level B). RECOMMENDATIONS FOR ANTIPLATELETS AFTER CARDIAC SURGERY: In stable CABG surgery (nonYacute coronary syndrome patients), the routine use of postoperative clopidogrel with ASAis not warranted (Class IIb, Level B). RECOMMENDATIONS FOR ACUTE NORMOVOLEMIC HEMODILUTION: Acute normovolemic hemodilution can be considered in selected patients with adequate preoperative hemoglobin to reduce post-CPB bleeding (Class IIa, Level A).The routine use of acute normovolemic hemodilution is not recommended (Class IIb, Level B). RECOMMENDATIONS FOR RETROGRADE AUTOLOGOUS PRIMING: Retrograde autologous priming is recommended as a blood conservation modality to reduce allogeneic blood transfusion for onpump cardiac surgery (Class I, Level A). RECOMMENDATIONS FOR CELL SALVAGE: Routine use of cell salvage is recommended in operations where an increased blood loss is expected (Class 1, Level A). Cell salvage should be used throughout the entire operation and not merely as a replacement for CPB cardiotomy suction (Class IIa, Level A). RECOMMENDATIONS: BIOCOMPATIBLE CPB CIRCUITS: The routine use of biocompatible coated CPB circuitry may be considered as part of a multimodal blood conservation program. However, the heterogeneity of surface-modified products, anticoagulation management, and CPB technique does not significantly impact surgical blood loss and transfusion needs (Class IIb,Level A). RECOMMENDATIONS FOR MINIATURIZED EXTRACORPOREAL CARDIOPULMONARY CIRCUIT VERSUS CONVENTIONAL EXTRACORPOREAL CARDIOPULMONARY CIRCUIT: Miniaturized extracorporeal cardiopulmonary circuit can be considered as a blood conservation technique to reduce allogeneic blood exposure (Class IIa, Level A); however, issues related to heparinization management and biocompatible coatings remain to be clarified. RECOMMENDATIONS FOR ULTRAFILTRATION (CONTINUOUS OR MODIFIED):h Ultrafiltration may be considered for blood conservation (Class IIb, Level A); however, the impact on clinically relevant outcomes remains unknown. RECOMMENDATIONS FOR PLATELET PLASMAPHERESIS:It is reasonable to recommend platelet plasmapheresis for blood management in cardiac surgery (Class IIa, Level A), although the impact on clinically relevant outcomes remains unknown. RECOMMENDATIONS FOR POINT-OF-CARE MONITORING:The evidence is too premature to recommend point-of-caretechnology for routine use because its use has not been shown to impact clinical outcome (Class IIb, Level A). RECOMMENDATIONS FOR SURGICAL TECHNIQUES FOR OPCAB, MINIMALLY INVASIVE STERNOTOMY FOR AORTIC VALVE SURGERY, MINIMALLY INVASIVE STERNOTOMY FOR MITRAL VALVE SURGERY, AND TRANSCATHETHER AORTIC VALVE IMPLANTATION: Although these minimally invasive procedures are not primarily selected for the purpose of blood management, the reduced allogeneic blood exposure should be considered in the balance of benefits and risks when selecting the appropriate surgery for patients.

A preliminary study of platelet activation after embolization of marrow contents.

OBJECTIVES: Intravasation of bone marrow contents into venous circulation and pulmonary embolization after intramedullary nailing may be coupled with the activation of coagulation and fibrinolytic cascades. The objective of this study was to assess hemostatic response to pulmonary extravasated marrow contents. We hypothesize that activation of platelet activity and the coagulation cascade may occur after embolization of marrow contents in an experimental animal model of intramedullary nailing. METHODS: Fifteen New Zealand white male rabbits were randomly assigned to control or fat embolism (FE) groups. In the FE group (n = 8), femurs were surgically instrumented with retrograde intramedullary nails and pressurized with bone cement. In the control group (n = 7), a sham knee incision was made that was immediately closed without drilling, reaming, or pressurization. Fibrinogen, D-dimer latex screen assay, 1 stage prothrombin time, and activated partial thromboplastin time were analyzed. RESULTS: As the main platelet activation indicators, the marker Annexin-V percent binding increased in the FE group at 2 hours (P = 0.04) and 4 hours (P = 0.04), and the marker CD62P percent expression increased in the FE group at 2 hours (P = 0.04). CONCLUSIONS: This preliminary study showed that pressurization of marrow and intravasation of fat and marrow products cause activation of platelets and the coagulation cascade, with or without tissue trauma. This may be relevant to the treatment of multiply injured patients with prior respiratory and coagulation abnormalities. A future larger study may be needed.

Amplified inflammatory response to sequential hemorrhage, resuscitation, and pulmonary fat embolism: an animal study.

BACKGROUND: The objective of this study was to assess the role of pulmonary fat embolism caused by intramedullary pressurization of the femoral canal in the development of acute lung injury in the setting of acute hemorrhagic shock and resuscitation. METHODS: Thirty New Zealand White rabbits were randomly assigned to one of four groups: (1) nine animals in which hemorrhagic shock was induced by carotid bleeding, resuscitation was performed, and the femoral canal was reamed and pressurized with bone cement to induce fat embolism (hemorrhagic shock and resuscitation/fat embolism [HR/FE] group); (2) six animals in which shock was induced by carotid bleeding, resuscitation was performed, and a sham knee incision was made and closed without drilling, reaming, or pressurization (hemorrhagic shock and resuscitation [HR] group); (3) eight animals in which no hemorrhage or shock was induced but the femoral canal was reamed and pressurized with bone cement to induce fat embolism (fat embolism [FE] group); and (4) seven animals that had a three-hour ventilation period followed by a sham knee incision (control group). The animals were ventilated for four hours following closure. Flow cytometry with use of antibodies against CD45 and CD11b was performed to test neutrophil activation in whole blood. Histological examination of lung specimens was also performed. Plasma and bronchoalveolar lavage fluid were analyzed for monocyte chemotactic peptide-1 and interleukin-8 levels with use of the ELISA (enzyme-linked immunosorbent assay) method. RESULTS: Three animals in the HR/FE group died immediately after canal pressurization and were excluded. CD11b mean channel fluorescence was significantly elevated, as compared with baseline, only in the HR/FE group at two hours (p = 0.025) and four hours (p = 0.024) after knee closure. Histological analysis showed that only the HR/FE (p < 0.001) and HR (p = 0.010) groups had significantly greater infiltration of alveoli by polymorphonuclear leukocytes as compared with that in the controls. No significant differences in plasma cytokine levels were found between the groups. Only the HR/FE group had significantly higher interleukin-8 (p = 0.020) and monocyte chemotactic peptide-1 (p = 0.004) levels in the bronchoalveolar lavage fluid as compared with those in the controls. CONCLUSIONS: Fat embolism from canal pressurization alone did not activate a pulmonary inflammatory response. The combination of hemorrhagic shock, resuscitation, and fat embolism elicited neutrophil activation, infiltration of alveoli by polymorphonuclear leukocytes, and inflammatory cytokine expression in bronchoalveolar lavage fluid.

ABO-identical versus nonidentical platelet transfusion: a systematic review.

BACKGROUND: The significance of ABO matching for platelet (PLT) transfusion has not been clearly defined. The primary objective of this report is to assess whether ABO-identical PLT transfusion is associated with improved mortality and/or morbidity for patients with hematologic/oncologic disorders. STUDY DESIGN AND METHODS: A systematic review to January 2009 was conducted. Data on mortality, morbidity, PLT refractoriness, and PLT increment after transfusion were abstracted. RESULTS: A total of 100 citations were identified. Nineteen studies were included in the systematic review. A total of 1502 patients from three randomized controlled trials and 16 observational studies were included. Survival, bleeding events, and transfusion reactions were only considered as secondary outcomes in the reports reviewed. The PLT count increment was the primary outcome of several studies and was consistently higher with ABO-identical PLT transfusion. The largest difference in increment between ABO-identical and nonidentical PLT transfusion was 4 x 10(9)/L. No consistent benefit in clinical outcomes was noted. Survival was assessed in three reports with conflicting results. Although two studies described bleeding as an outcome, the assessment of hemorrhage was considered inadequate. In six studies, ABO-nonidentical PLT transfusion was not associated with transfusion reactions, and the results from four studies addressing the impact of ABO-identical PLT transfusion on PLT and red blood cell utilization were conflicting. CONCLUSION: ABO-identical PLT transfusion results in a higher PLT increment. Randomized controlled trials are required to definitely determine the effect of ABO-identical PLT transfusion on survival, bleeding events, or transfusion reactions.