RESUMEN
During extracorporeal membrane oxygenation (ECMO) support, the high shear stress in the ECMO circuit results in increased proteolysis of von Willebrand factor (VWF), loss of VWF high-molecular-weight multimers, and impaired ability to bind to platelets and collagen. These structural changes in VWF are consistent with acquired von Willebrand syndrome (AVWS) type 2A and may contribute to the bleeding diathesis frequently observed in ECMO patients. We performed a systematic review of all clinical studies evaluating the prevalence and associated outcomes of AVWS in ECMO patients. Our findings suggest that almost all ECMO patients develop partial or complete loss of VWF high-molecular-weight multimers within a few hours of device implantation. The AVWS persists as long as the patient is supported by ECMO. Weaning from ECMO rapidly and completely resolves the AVWS. Nevertheless, few studies have reported bleeding outcomes in ECMO patients with AVWS, and the extent to which AVWS contributes to the bleeding diathesis during ECMO support cannot be determined by current evidence. Data supporting the use of VWF concentrates to prevent bleeding complications in ECMO patients remain limited.
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Coagulación Intravascular Diseminada , Fibrinólisis , Hemostasis , Humanos , Fibrinólisis/fisiología , Fibrinólisis/efectos de los fármacos , Coagulación Intravascular Diseminada/sangre , Coagulación Intravascular Diseminada/diagnóstico , Coagulación Intravascular Diseminada/fisiopatología , Hemostasis/fisiologíaRESUMEN
BACKGROUND: The activity of von Willebrand factor (VWF) in facilitating platelet adhesion and aggregation correlates with its multimer size. Traditional ristocetin-dependent functional assays lack sensitivity to multimer sizes. Recently, nanobodies targeting the autoinhibitory module and activating VWF were identified. OBJECTIVES: To develop an assay that can differentiate the platelet-binding activity of VWF multimers. METHODS: A novel enzyme-linked immunosorbent assay (nanobody-triggered glycoprotein Ib binding assay [VWF:GPIbNab]) utilizing a VWF-activating nanobody was developed. Recombinant VWF, plasma-derived VWF (pdVWF), and selected gel-filtrated fractions of pdVWF were evaluated for VWF antigen and activity levels. A linear regression model was developed to estimate the specific activity of VWF multimers. RESULTS: Of the 3 activating nanobodies tested, 6C11 with the lowest activation effect exhibited the highest sensitivity for high-molecular-weight multimers (HMWMs) of VWF. VWF:GPIbNab utilizing 6C11 (VWF:GPIbNab6C11) produced significantly higher activity/antigen ratios for recombinant VWF (>2.0) and HMWM-enriched pdVWF fractions (>2.0) than for pdVWF (â¼1.0) or fractions enriched with shorter multimers (<1.0). The differences were much larger than those produced by VWF:GPIbNab utilizing other nanobodies, VWF:GPIbM, VWF:GPIbR, or VWF:CB assays. Linear regression analysis of 5 pdVWF fractions of various multimer sizes produced an estimated specific activity of 2.7 for HMWMs. The analysis attributed >90% of the VWF activity measured by VWF:GPIbNab6C11 to that of HMWMs, which is significantly higher than all other activity assays tested. CONCLUSION: The VWF:GPIbNab6C11 assay exhibits higher sensitivity to HMWMs than ristocetin-based and collagen-binding assays. Future studies examining the application of this assay in clinical settings and any associated therapeutic benefit of doing so are warranted.
Asunto(s)
Ensayo de Inmunoadsorción Enzimática , Multimerización de Proteína , Anticuerpos de Dominio Único , Factor de von Willebrand , Factor de von Willebrand/metabolismo , Factor de von Willebrand/análisis , Humanos , Anticuerpos de Dominio Único/inmunología , Anticuerpos de Dominio Único/química , Modelos Lineales , Proteínas Recombinantes , Plaquetas/metabolismo , Agregación Plaquetaria/efectos de los fármacos , Complejo GPIb-IX de Glicoproteína Plaquetaria/metabolismo , Unión Proteica , Adhesividad Plaquetaria , Peso MolecularRESUMEN
Maintaining tissue perfusion in sepsis depends on vascular integrity provided by the endothelial glycocalyx, the critical layer covering the luminal surface of blood vessels. The glycocalyx is composed of proteoglycans, glycosaminoglycans, and functional plasma proteins that are critical for antithrombogenicity, regulating tone, controlling permeability, and reducing endothelial interactions with leukocytes and platelets. Degradation of the glycocalyx in sepsis is substantial due to thromboinflammation, and treatments for sepsis and septic shock may exacerbate endotheliopathy via additional glycocalyx injury. As a result, therapeutic strategies aimed at preserving glycocalyx integrity should be considered, including modifications in fluid volume resuscitation, minimizing catecholamine use, controlling hyperglycemia, and potential use of corticosteroids and anticoagulants. In this review, we explore treatment strategies aligned with the recommendations outlined in the Surviving Sepsis Campaign Guidelines 2021 with a special emphasis on evidence regarding glycocalyx protection.
RESUMEN
Coagulopathy alongside micro- and macrovascular thrombotic events were frequent characteristics of patients presenting with acute COVID-19 during the initial stages of the pandemic. However, over the past 4 years, the incidence and manifestations of COVID-19-associated coagulopathy have changed due to immunity from natural infection and vaccination and the appearance of new SARS-CoV-2 variants. Diagnostic criteria and management strategies based on early experience and studies for COVID-19-associated coagulopathy thus require reevaluation. As many other infectious disease states are also associated with hemostatic dysfunction, the coagulopathy associated with COVID-19 may be compounded, especially throughout the winter months, in patients with diverse etiologies of COVID-19 and other infections. This commentary examines what we have learned about COVID-19-associated coagulopathy throughout the pandemic and how we might best prepare to mitigate the hemostatic consequences of emerging infection agents.
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Trastornos de la Coagulación Sanguínea , COVID-19 , SARS-CoV-2 , Humanos , COVID-19/complicaciones , COVID-19/sangre , COVID-19/terapia , COVID-19/epidemiología , Trastornos de la Coagulación Sanguínea/diagnóstico , Trastornos de la Coagulación Sanguínea/etiología , Trastornos de la Coagulación Sanguínea/terapia , Coagulación Sanguínea/efectos de los fármacos , Factores de Riesgo , Hemostasis , Anticoagulantes/uso terapéutico , Enfermedad AgudaRESUMEN
Inflammation and coagulation are critical self-defense mechanisms for mitigating infection that can nonetheless induce tissue injury and organ dysfunction. In severe cases, like sepsis, a dysregulated thromboinflammatory response may result in multiorgan dysfunction. Sepsis-associated acute kidney injury (AKI) is a significant contributor to patient morbidity and mortality. The connection between AKI and thromboinflammation is largely due to unique aspects of the renal vasculature. Specifically, the interaction between blood cells with the endothelial, glomerular, and peritubular capillary systems during thromboinflammation reduces oxygen supply to tubular epithelial cells. Previous studies have focused on tubular epithelial cell damage due to hypoxia, oxidative stress, and nephrotoxins. Although these factors are pivotal in acute tubular injury or necrosis, recent studies have demonstrated that AKI in sepsis encompasses a mixture of tubular and glomerular damage subtypes. In cases of sepsis-induced coagulopathy, thromboinflammation within the glomerulus and peritubular capillaries is an important pathogenic mechanism for AKI. Unfortunately, and despite the use of renal replacement therapy, the development of AKI in sepsis continues to be associated with high morbidity, mortality, and clinical challenges requiring alternative approaches. This review introduces the important role of thromboinflammation in AKI pathogenesis and details innovative vascular-targeting therapeutic strategies.
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Lesión Renal Aguda , Sepsis , Humanos , Lesión Renal Aguda/etiología , Sepsis/complicaciones , Sepsis/sangre , Tromboinflamación , Trastornos de la Coagulación Sanguínea/etiología , Trastornos de la Coagulación Sanguínea/sangre , Animales , Coagulación Sanguínea , Riñón/patologíaRESUMEN
Haemorrhagic shock is frequent in critical care settings and responsible for a high mortality rate due to multiple organ dysfunction and coagulopathy. The management of critically ill patients with bleeding and shock is complex, and treatment of these patients must be rapid and definitive. The administration of large volumes of blood components leads to major physiological alterations which must be mitigated during and after bleeding. Early recognition of bleeding and coagulopathy, understanding the underlying pathophysiology related to specific disease states, and the development of individualised management protocols are important for optimal outcomes. This review describes the contemporary understanding of the pathophysiology of various types of coagulopathic bleeding; the diagnosis and management of critically ill bleeding patients, including major haemorrhage protocols and post-transfusion management; and finally highlights recent areas of opportunity to better understand optimal management strategies for managing bleeding in the intensive care unit (ICU).
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Trastornos de la Coagulación Sanguínea , Enfermedad Crítica , Humanos , Enfermedad Crítica/terapia , Hemorragia/etiología , Hemorragia/terapia , Trastornos de la Coagulación Sanguínea/diagnóstico , Trastornos de la Coagulación Sanguínea/etiología , Trastornos de la Coagulación Sanguínea/terapia , Transfusión de Componentes Sanguíneos , Cuidados CríticosRESUMEN
Ensuring adequate anticoagulation for patients requiring cardiac surgery and cardiopulmonary bypass (CPB) is important due to the adverse consequences of inadequate anticoagulation with respect to bleeding and thrombosis. When target anticoagulation is not achieved with typical doses, the term heparin resistance is routinely used despite the lack of uniform diagnostic criteria. Prior reports and guidance documents that define heparin resistance in patients requiring CPB and guidance documents remain variable based on the lack of standardized criteria. As a result, we conducted a review of clinical trials and reports to evaluate the various heparin resistance definitions employed in this clinical setting and to identify potential standards for future clinical trials and clinical management. In addition, we also aimed to characterize the differences in the reported incidence of heparin resistance in the adult cardiac surgical literature based on the variability of both target-activated clotting (ACT) values and unfractionated heparin doses. Our findings suggest that the most extensively reported ACT target for CPB is 480 seconds or higher. Although most publications define heparin resistance as a failure to achieve this target after a weight-based dose of either 400 U/kg or 500 U/kg of heparin, a standardized definition would be useful to guide future clinical trials and help improve clinical management. We propose the inability to obtain an ACT target for CPB of 480 seconds or more after 500 U/kg as a standardized definition for heparin resistance in this setting.
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Procedimientos Quirúrgicos Cardíacos , Trombosis , Adulto , Humanos , Heparina/efectos adversos , Anticoagulantes/efectos adversos , Tiempo de Coagulación de la Sangre Total , Coagulación Sanguínea , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Puente Cardiopulmonar/efectos adversos , Cuidados Críticos , Trombosis/etiología , Trombosis/prevención & control , Trombosis/tratamiento farmacológico , ComunicaciónRESUMEN
Rising temperatures associated with climate change have significantly increased the risk of heatstroke. Unfortunately, the trend is anticipated to persist and increasingly threaten vulnerable populations, particularly older adults. According to Japan's environment ministry, over 1000 people died from heatstroke in 2021, and 86% of deaths occurred in those above 65. Since the precise mechanism of heatstroke is not fully understood, we examined the pathophysiology by focusing on the microcirculatory derangement. Online search of published medical literature through MEDLINE and Web of Science using the term "heatstroke," "heat-related illness," "inflammation," "thrombosis," "coagulation," "fibrinolysis," "endothelial cell," and "circulation." Articles were chosen for inclusion based on their relevance to heatstroke, inflammation, and thrombosis. Reference lists were reviewed to identify additional relevant articles. Other than preexisting conditions (genetic background, age, etc.), factors such as hydration status, acclimatization, dysregulated coagulation, and inflammation are the additional major factors that promote tissue malcirculation in heatstroke. The fundamental pathophysiologic mechanisms significantly overlap with those seen in the systemic inflammatory response to sepsis, and as a result, coagulation-predominant coagulopathy develops during heat stress. Although a bleeding tendency is not common, bleeding frequently occurs in the microcirculation, causing additional injury. Sterile inflammation is mediated by proinflammatory cytokines, chemokines, and other humoral mediators in concert with cellular factors, including monocytes, neutrophils, platelets, and endothelial cells. Excess inflammation results in inflammatory cell death, including pyroptosis and necroptosis, and the release of danger signals that further propagate systemic inflammation and coagulopathy. Consequently, thromboinflammation is the critical factor that induces microcirculatory disturbance in heatstroke.
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Golpe de Calor , Inflamación , Microcirculación , Trombosis , Humanos , Golpe de Calor/fisiopatología , Golpe de Calor/complicaciones , Inflamación/fisiopatología , Trombosis/etiología , Trombosis/fisiopatologíaRESUMEN
Disseminated intravascular coagulation (DIC) is a frequent complication in patients with sepsis and is associated with increased mortality. Anticoagulant therapy may be appropriate for certain patients with DIC, particularly those with increased disease severity and deficiency in the physiologic anticoagulant antithrombin. We retrospectively analyzed post-marketing survey data from 1562 patients with sepsis-associated DIC and antithrombin activity of 70% or less. All the patients were treated with antithrombin concentrates. Baseline sequential organ failure assessment (SOFA) score, DIC score, and antithrombin activity were assessed. Cox multivariate regression analysis, Kaplan-Meier curve analysis, and receiver operating characteristic (ROC) curve analysis were performed to evaluate the performance of variables used to assess mortality. Furthermore, a decision tree was constructed to classify the risk of 28-day mortality. COX multivariate regression analysis demonstrated a significant association of age, sex, baseline SOFA score, baseline antithrombin activity, and the presence of pneumonia or skin/soft tissue infection with increased mortality. The area under the curve of SOFA score or antithrombin activity for mortality was 0.700 and 0.614, respectively. Kaplan-Meier analysis demonstrated that mortality was significantly higher in patients with SOFA score ≥ 12 and antithrombin activity < 47%. The decision tree analysis accurately classified the risk of death into high (> 40%), medium (40%-20%), and low (< 20%) categories in 86.1% of the cohort. Twenty eight-day mortality can be strongly predicted using baseline SOFA score, antithrombin activity, infection site, age, and sex as variables in the clinical decision tree for patients with sepsis-associated disseminated intravascular coagulation (DIC).
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Coagulación Intravascular Diseminada , Sepsis , Humanos , Antitrombinas/uso terapéutico , Puntuaciones en la Disfunción de Órganos , Coagulación Intravascular Diseminada/etiología , Estudios Retrospectivos , Anticoagulantes/uso terapéutico , Antitrombina III , Medición de Riesgo , DemografíaRESUMEN
Red blood cell (RBC) transfusion is a common clinical intervention used to treat patients with acute and chronic anemia. The decision to transfuse RBCs in the acute setting is based on several factors but current clinical studies informing optimal RBC transfusion decision making (TDM) are largely based upon hemoglobin (Hb) level. In contrast to transfusion in acute settings, chronic RBC transfusion therapy has several different purposes and is associated with distinct transfusion risks such as iron overload and RBC alloimmunization. Consequently, RBC TDM in the chronic setting requires optimizing the survival of transfused RBCs in order to reduce transfusion exposure over the lifespan of an individual and the associated transfusion complications mentioned. This review summarizes the current medical literature addressing optimal RBC-TDM in the acute and chronic transfusion settings and discusses the current gaps in knowledge which need to be prioritized in future national and international research initiatives.
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Anemia Hemolítica Autoinmune , Transfusión Sanguínea , Humanos , Enfermedad Aguda , Transfusión de Eritrocitos , EritrocitosRESUMEN
The term heparin resistance (HR) is used by clinicians without specific criteria. We performed a literature search and surveyed our SSC membership to better define the term when applied to medical and intensive care unit patients. The most common heparin dosing strategy reported in the literature (53%) and by survey respondents (80.4%) was the use of weight-based dosing. Heparin monitoring results were similar based on the proportion of publications and respondents that reported the use of anti-Xa and activated partial thromboplastin time. The most common literature definition of HR was >35 000 U/d, but no consensus was reported among survey respondents regarding weight-based and the total dose of heparin when determining resistance. Respondent consensus on treating HR included antithrombin supplementation, direct thrombin inhibitors, or administering more heparin as the strategies available for treating HR. A range of definitions for HR exist. Given the common use of heparin weight-based dosing, future publications employing the term HR should include weight-based definitions, monitoring assay, and target level used. Further work is needed to develop a consensus for defining HR.
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Heparina , Trombosis , Humanos , Heparina/efectos adversos , Anticoagulantes/efectos adversos , Antitrombinas/uso terapéutico , Tiempo de Tromboplastina Parcial , Trombosis/tratamiento farmacológico , Hemostasis , Cuidados Críticos , ComunicaciónRESUMEN
The optimal use of prophylactic platelet transfusion remains uncertain in a number of clinical scenarios. Platelet count thresholds have been established in patients with hematologic malignancies, yet thresholds backed by scientific data are limited or do not exist for many patient populations. Clinical scenarios involving transfusion thresholds for thrombocytopenic patients with critical illness, need for surgery or invasive procedures, or those involving specials populations like children and neonates, lack clear evidence for discerning favorable outcomes without undue risk related to platelet transfusion. In addition, while prophylactic platelet transfusions are administered with the goal of enhancing hemostasis, increasing evidence supports critical nonhemostatic roles for platelets related to innate and adaptive immunity, inflammation, and angiogenesis, which may impact patient responses and outcomes. Here we review several recent studies conducted in adult or pediatric patients that highlight the limitations in our current understanding of prophylactic platelet transfusion. Together, these studies underscore the need for additional research, especially in the form of robust randomized clinical trials and integrating additional parameters beyond the platelet count. Future research at the basic, translational, and clinical levels will best define the optimal role for prophylactic transfusion across the lifespan and its broader impact on health and disease.
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Transfusión de Plaquetas , Trombocitopenia , Recién Nacido , Adulto , Humanos , Niño , Transfusión de Plaquetas/métodos , Hemorragia/prevención & control , Trombocitopenia/terapia , Recuento de Plaquetas , Transfusión SanguíneaRESUMEN
Antibodies against fetal red blood cell (RBC) antigens can cause hemolytic disease of the fetus and newborn (HDFN). Reductions in HDFN due to anti-RhD antibodies have been achieved through use of Rh immune globulin (RhIg), a polyclonal antibody preparation that causes antibody-mediated immunosuppression (AMIS), thereby preventing maternal immune responses against fetal RBCs. Despite the success of RhIg, it is only effective against 1 alloantigen. The lack of similar interventions that mitigate immune responses toward other RBC alloantigens reflects an incomplete understanding of AMIS mechanisms. AMIS has been previously attributed to rapid antibody-mediated RBC removal, resulting in B-cell ignorance of the RBC alloantigen. However, our data demonstrate that antibody-mediated RBC removal can enhance de novo alloimmunization. In contrast, inclusion of antibodies that possess the ability to rapidly remove the target antigen in the absence of detectable RBC clearance can convert an augmented antibody response to AMIS. These results suggest that the ability of antibodies to remove target antigens from the RBC surface can trigger AMIS in situations in which enhanced immunity may otherwise occur. In doing so, these results hold promise in identifying key antibody characteristics that can drive AMIS, thereby facilitating the design of AMIS approaches toward other RBC antigens to eliminate all forms of HDFN.
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Eritroblastosis Fetal , Eritrocitos , Femenino , Recién Nacido , Humanos , Eritrocitos/metabolismo , Anticuerpos , Tolerancia Inmunológica , Terapia de Inmunosupresión , Globulina Inmune rho(D) , Isoantígenos , IsoanticuerposRESUMEN
The pathogenesis of multi-organ dysfunction associated with severe acute SARS-CoV-2 infection remains poorly understood. Endothelial damage and microvascular thrombosis have been identified as drivers of COVID-19 severity, yet the mechanisms underlying these processes remain elusive. Here we show alterations in fluid shear stress-responsive pathways in critically ill COVID-19 adults as compared to non-COVID critically ill adults using a multiomics approach. Mechanistic in-vitro studies, using microvasculature-on-chip devices, reveal that plasma from critically ill COVID-19 adults induces fibrinogen-dependent red blood cell aggregation that mechanically damages the microvascular glycocalyx. This mechanism appears unique to COVID-19, as plasma from non-COVID sepsis patients demonstrates greater red blood cell membrane stiffness but induces less significant alterations in overall blood rheology. Multiomics analyses in pediatric patients with acute COVID-19 or the post-infectious multi-inflammatory syndrome in children (MIS-C) demonstrate little overlap in plasma cytokine and metabolite changes compared to adult COVID-19 patients. Instead, pediatric acute COVID-19 and MIS-C patients show alterations strongly associated with cytokine upregulation. These findings link high fibrinogen and red blood cell aggregation with endotheliopathy in adult COVID-19 patients and highlight differences in the key mediators of pathogenesis between adult and pediatric populations.
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COVID-19 , Humanos , Niño , Adulto , SARS-CoV-2 , Enfermedad Crítica , Citocinas , FibrinógenoRESUMEN
RBC alloimmunization remains a significant barrier to ongoing transfusion therapy leading to morbidity, and in extreme cases mortality, due to delayed or insufficient units of compatible RBCs. In addition, the monitoring and characterization of alloantibodies, often with multiple specificities in a single patient, consumes substantial health care resources. Extended phenotypic matching has mitigated, but not eliminated, RBC alloimmunization and is only logistically available for specialized populations. Thus, RBC alloimmunization remains a substantial problem. In recent decades it has become clear that mechanisms of RBC alloimmunization are distinct from other antigens and lack of mechanistic understanding likely contributes to the fact that there are no approved interventions to prevent RBC alloimmunization from transfusion. The combination of human studies and murine modeling have identified several key factors in RBC alloimmunization. In both humans and mice, immunogenicity is a function of alloantigen copy number on RBCs. Murine studies have further shown that copy number not only changes rates of immunization but the mechanisms of antibody formation. This review summarizes the current understanding of quantitative and qualitative effects of alloantigen copy number on RBC alloimmunization.
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Variaciones en el Número de Copia de ADN , Isoantígenos , Humanos , Ratones , Animales , Eritrocitos , Transfusión Sanguínea , IsoanticuerposRESUMEN
INTRODUCTION: The impact of blood storage on red blood cell (RBC) alloimmunization remains controversial, with some studies suggesting enhancement of RBC-induced alloantibody production and others failing to observe any impact of storage on alloantibody formation. Since evaluation of storage on RBC alloimmunization in patients has examined antibody formation against a broad range of alloantigens, it remains possible that different clinical outcomes reflect a variable impact of storage on alloimmunization to specific antigens. METHODS: RBCs expressing two distinct model antigens, HEL-OVA-Duffy (HOD) and KEL, separately or together (HOD × KEL), were stored for 0, 8, or 14 days, followed by detection of antigen levels prior to transfusion. Transfused donor RBC survival was assessed within 24 h of transfusion, while IgM and IgG antibody production were assessed 5 and 14 days after transfusion. RESULTS: Stored HOD or KEL RBCs retained similar HEL or KEL antigen levels, respectively, as fresh RBCs, but did exhibit enhanced RBC clearance with increased storage age. Storage enhanced IgG antibody formation against HOD, while the oppositive outcome occurred following transfusion of stored KEL RBCs. The distinct impact of storage on HOD or KEL alloimmunization did not appear to reflect intrinsic differences between HOD or KEL RBCs, as transfusion of stored HOD × KEL RBCs resulted in increased IgG anti-HOD antibody development and reduced IgG anti-KEL antibody formation. CONCLUSIONS: These data demonstrate a dichotomous impact of storage on immunization to distinct RBC antigens, offering a possible explanation for inconsistent clinical experience and the need for additional studies on the relationship between RBC storage and alloimmunization.
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Antígenos , Transfusión de Eritrocitos , Ratones , Animales , Transfusión de Eritrocitos/efectos adversos , Eritrocitos , Isoantígenos , Isoanticuerpos , Inmunoglobulina GRESUMEN
We describe severe acute respiratory coronavirus virus 2 (SARS-CoV-2) IgG seroprevalence and antigenemia among patients at a medical center in January-March 2021 using residual clinical blood samples. The overall seroprevalences were 17% by infection and 16% by vaccination. Spent or residual samples are a feasible alternative for rapidly estimating seroprevalence or monitoring trends in infection and vaccination.