RESUMO
Acquired bleeding disorders because of an autoimmune phenomenon are rare events. Acquired von Willebrand disease (aVWD) has been estimated as having a prevalence of 400 per million in the general population. Acquired hemophilia A (AHA), the most common of the acquired hemophilias, has an estimated incidence of 1.3-1.5 cases per million per year. Immune checkpoint inhibitors (ICI) targeting PD-1, PD-L1, and CTLA-4 are being used with increasing frequency for hematologic and oncologic disorders. Acquired hemophilias and aVWD have been reported with the use of ICI therapy. We performed a systematic review of the literature to identify cases of acquired bleeding disorders with ICI therapy and contribute our own institution's experience with a case of AHA after pembrolizumab therapy. Six cases of AHA, one case of aVWD, and one case of factor V inhibitor were identified in the literature. Inhibitors were successfully eradicated in five of the eight cases identified. We propose that a centralized registry, possibly through the Scientific and Standardization Subcommittee on Plasma Coagulation Inhibitors through the International Society on Thrombosis and Hemostasis (ISTH), be developed to record treatment and outcomes of this rare ICI complication in order to prognosticate risk and better understand optimal treatment strategies.
Assuntos
Hemofilia A , Doenças de von Willebrand , Humanos , Inibidores de Checkpoint Imunológico , Doenças de von Willebrand/complicações , Hemostasia , Hemofilia A/complicaçõesRESUMO
Restoration of the international normalized ratio (INR) to values <1.5 is commonly targeted to achieve hemostasis in patients with major bleeding or undergoing urgent surgery who are treated using vitamin K antagonists (VKAs). However, the relationship between corrected INR and vitamin K-dependent factor (VKDF) levels for hemostasis is uncertain. We aim to examine the impact of 4-factor prothrombin complex concentrate (4F-PCC) or plasma on INR correction and VKDF restoration and evaluate the relationship between INR values and VKDF levels in patients with acute major bleeding or patients requiring an urgent surgical procedure. Adult patients treated with VKA with an elevated INR (≥2.0 within 3 hours before study treatment) who received 4F-PCC or plasma after major bleeding or before an urgent surgery or invasive procedure were included in this retrospective analysis of data from 2 prospective phase 3b randomized controlled trials. Of the 370 patients included in this analysis, 185 received 4F-PCC, and 185 received plasma. In the 4F-PCC group, 159 of 185 (85.9%) had an INR ≤1.5 at 30 minutes after the end of infusion compared with only 72 of 184 (39.1%) in the plasma group. After 4F-PCC treatment, all VKDF levels exceeded 50% activity regardless of the postinfusion INR value. However, after plasma administration, mean activity levels for factors II and X were <50% at all time points assessed within 3 hours after starting the infusion, regardless of the postinfusion INR value. This retrospective analysis demonstrated that treatment with 4F-PCC among patients treated with VKA rapidly restores VKDFs to hemostatic levels irrespective of the postinfusion INR value, whereas treatment with plasma does not.
Assuntos
Fator IX , Vitamina K , Adulto , Humanos , Coeficiente Internacional Normatizado , Estudos Prospectivos , Estudos Retrospectivos , Anticoagulantes/efeitos adversos , Hemorragia/induzido quimicamente , Fibrinolíticos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Cell saver blood is typically washed with normal saline (NS); however, recent studies have reported decreased red blood cell hemolysis and increased platelet function when a more physiologic washing solution, such as Plasma-Lyte A (PL-A) is used. We evaluated the in vitro and in vivo effects of NS compared to PL-A as washing solutions for cell saver blood in pediatric cardiac surgery. Cell saver blood was re-infused for up to 24 hours post-collection. Laboratory and clinical data were collected from infants receiving cell saver washed with either NS (n = 20) or PL-A (n = 21). Compositions of the cell saver blood were compared between groups at 5 in vitro time points and in vivo patient blood at 24 hours post-bypass. Although there were differences in in vitro laboratory values between groups; 24 hours post-bypass, in vivo results were similar. Our data supports 24-hour reinfusion of cell saver washed with either NS versus PL-A in pediatric cardiac surgery patients, and provides data on the differences in cell saver composition to guide future studies.
Assuntos
Eletrólitos , Hemoglobinas , Solução Salina , Eritrócitos/química , Hemoglobinas/análise , Humanos , LactenteRESUMO
BACKGROUND: Anemia is an independent risk factor for hospitalization, readmission, prolonged length of stay (LOS), diminished quality of life, and mortality. A multidisciplinary program was implemented to manage anemia preoperatively as a patient blood management (PBM) initiative. METHODS AND MATERIALS: From March 2016 to August 2018, 240 patients were screened for anemia during their preoperative cardiovascular visit. About 52/240 (22%) were found to be anemic and met out inclusion criteria. Also, 45/52 (87%) had iron deficiency anemia and 7 (13%) had anemia without iron deficiency. A similar historical cohort of patients undergoing elective cardiovascular surgery with hemoglobin (Hb) < 12 g/dl from September 2014 to February /2016 (n = 52) served as control group. The primary outcome was perioperative red blood cell (RBC) transfusion. Secondary outcomes were date-of-surgery Hb, intensive care unit (ICU) and hospital LOS, complication rates, and transfusion cost. RESULTS: The two most common treatments were IV iron ± folate (n = 36/45; 80%) and oral iron (n = 9/45; 20%). As compared to historical patients, study patients had significantly higher day-of-surgery Hb (10.6 ± 1.4 vs. 9.8 ± 1.3 g/dl, p < .001), lower utilization of RBC transfusion (0.86 ± 1.4 vs. 2.78 ± 2.4, p < .001), fewer days in the ICU (2.1 ± 2.0 vs. 4.0 ± 3.5, p = .002), and shorter total LOS (6.9 ± 4.8 vs. 12.9 ± 6.8, p < .0001). Study patients also showed lower overall complication rates (p < .0001). Analysis of RBC acquisition cost and transfusion cost also showed significant saving of 69% ($293 vs. $945 and $656 vs. $2116, respectively). CONCLUSION: When corrected for type of procedures and surgeon, our pilot anemia program in elective cardiovascular surgeries showed higher day-of-surgery Hb and significant reduction in RBC transfusion rates, ICU and hospital LOS, and overall complication rates.
Assuntos
Anemia/terapia , Transfusão de Sangue , Procedimentos Cirúrgicos Eletivos , Cuidados Pré-Operatórios , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Tempo de Internação , Masculino , Projetos Piloto , Cuidados Pré-Operatórios/métodosAssuntos
Anticorpos Antifosfolipídeos/sangue , Artefatos , Autoantígenos/imunologia , Heparina/imunologia , Inibidor de Coagulação do Lúpus/sangue , Nefelometria e Turbidimetria/métodos , Fator Plaquetário 4/imunologia , Trombocitopenia/sangue , Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/diagnóstico , Síndrome Antifosfolipídica/imunologia , Automação , Biópsia , Medula Óssea/patologia , Dexametasona/farmacologia , Diagnóstico Diferencial , Relação Dose-Resposta Imunológica , Reações Falso-Positivas , Heparina/efeitos adversos , Humanos , AVC Isquêmico/etiologia , Masculino , Pessoa de Meia-Idade , Estado Epiléptico/etiologia , Trombocitopenia/induzido quimicamente , Trombocitopenia/diagnóstico , Trombocitopenia/imunologiaRESUMO
Platelet-transfusion refractoriness (PTR) is common in patients with hematological malignancies. The etiology of immune PTR is typically human leukocyte antigen (HLA) antibodies (Abs) from pregnancy or previous transfusion. Herein, we report PTR in the setting of induction chemotherapy for acute myelogenous leukemia (AML) from Abs against CD36/glycoprotein (GP)IV. A 66-year-old African American woman presented with anemia and thrombocytopenia. She was found to have transfusion-dependent AML, and a 7 + 3 regimen (7 days of standard-dose cytarabine and 3 days of an anthracycline antibiotic or an anthracenedione, most often daunorubicin) was initiated. The patient developed profound thrombocytopenia, with platelet nadir of 0 by day 13. The results of HLA antibody screening were negative. However, the results of a screening test for platelet-specific antibodies screen showed Abs against cluster of differentiation (CD)36. The platelets of the patient lacked expression of CD36, and DNA analysis showed mutations in the CD36 gene. HLA Ab-mediated PTR is common in patients with hematological malignancies. However, once HLA Abs are excluded, other less-frequent Abs should be considered, particularly in patient populations of Asian, African, or Middle Eastern descent.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Transtornos Plaquetários/imunologia , Decitabina/administração & dosagem , Doenças Genéticas Inatas/imunologia , Leucemia Mieloide Aguda/tratamento farmacológico , Transfusão de Plaquetas , Idoso , Transtornos Plaquetários/complicações , Transtornos Plaquetários/genética , Evolução Fatal , Feminino , Doenças Genéticas Inatas/complicações , Doenças Genéticas Inatas/genética , Humanos , Quimioterapia de Indução , Leucemia Mieloide Aguda/sangueRESUMO
OBJECTIVES: To provide an overview of the clot viscoelastic testing technology and to describe its utility in guiding blood product transfusions. METHODS: A case scenario will be discussed as well as interpretation of thromboelastography (TEG) tracings. In addition, literature examining the utility of viscoelastic testing in guiding patient management and blood product transfusions will be reviewed. RESULTS: TEG/rotational thromboelastometry (ROTEM) is useful in evaluating clot kinetics in trauma and acutely bleeding patients. TEG/ROTEM parameters are reflective of values measured using standard coagulation assays; however, TEG/ROTEM parameters are more rapidly available and more costly. TEG and ROTEM are used in three main settings: cardiac surgery, liver transplantation, and trauma to assess global hemostasis and administration of blood products. CONCLUSIONS: TEG/ROTEM can be helpful in guiding resuscitation and blood product transfusion. Several studies have demonstrated a reduction in transfusion of blood components with TEG/ROTEM; however, other studies have suggested that TEG/ROTEM is not clinically effective in guiding transfusion.
Assuntos
Transtornos da Coagulação Sanguínea/terapia , Coagulação Sanguínea , Transfusão de Sangue/métodos , Hemorragia/terapia , Tromboelastografia , Procedimentos Cirúrgicos Cardíacos , Humanos , Transplante de FígadoRESUMO
BACKGROUND: Normal saline has been the fluid of choice for resuscitation, rehydration and fluid replacement during plasma or red cell exchange/cytapheresis. There are increased concerns about its clinical effects and data showing it causes more haemolysis in vitro than buffered solutions such as Plasma-Lyte A. METHODS: We investigated whether normal saline or Plasma-Lyte A was associated with greater haemolysis during hours of in vitro incubation with both normal red cells and samples from patients with sickle cell anaemia. RESULTS: Sickle red cells haemolysed more than normal red cells did in both crystalloid solutions. The results of 24-hour exposure to saline were particularly striking (median of 163 mg/dl (IQ range 105-247) for sickle red cells vs. 53 (48-92) for normal red cells (P < 0·0001). In patient samples containing variable quantities of haemoglobin S red cells, increased haemoglobin S was associated with increased haemolysis. This effect was greater for normal saline than Plasma-Lyte A (P = 0·12). CONCLUSIONS: These in vitro models demonstrate that short-term ex vivo exposure of sickle red cells to normal saline leads to greater haemolysis than short-term exposure of normal red cells, and this effect is exacerbated by normal saline. Whether use of normal saline causes increased haemolysis in vivo is unknown. Given recent evidence that normal saline increases renal failure and mortality in critically ill patients, further studies are urgently needed.
Assuntos
Eletrólitos/química , Eritrócitos/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Solução Salina/química , Anemia Falciforme/tratamento farmacológico , Anticoagulantes , Transfusão de Sangue , Estado Terminal , Contagem de Eritrócitos , Hidratação , Testes Hematológicos , Hemoglobina Falciforme/análise , Humanos , Segurança do Paciente , Plasma , Ressuscitação , Cloreto de Sódio/químicaRESUMO
INTRODUCTION: Chorionic cysts of the chorion laeve, fetal chorionic plate, septum, and free membranes have been associated with placental hypoxia, but they have no clear clinical significance. Although immunohistochemistry has identified fibronectin and collagen IV in cyst fluid, the contents have yet to be fully characterized. METHODS: Placental chorionic cysts (N = 10) were sampled by fluid extraction and hemotoxylin and eosin-stained sections. Amniotic fluid samples (N = 8) were obtained from pregnant women who had cytogenetic evaluation. The content of the cysts was tested for thrombogenicity using thromboelastography. The cyst content was tested by Luminex multiplex and ELISA assays and for known prothrombotic and proinflammatory factors. RESULTS: We identified cysts, especially those in the chorionic plate, adjacent to intervillous thrombi with apparent cyst rupture. Thromboelastography revealed a significantly shorter R time compared to whole blood control samples. Concentration of creatinine, α-fetoprotein, and surfactant D in the cyst fluid differed significantly from amniotic fluid. Cyst fluids had a significantly higher expression of all prothrombotic and some proinflammatory factors. DISCUSSION: Our data provide the first evidence that chorionic cyst fluid is prothrombotic and different from amniotic fluid. The association of ruptured cysts with adjacent thrombi and the prothrombotic properties of cyst fluid suggest a causal relationship; however, further studies are needed.
Assuntos
Doenças Placentárias/patologia , Placenta/patologia , Trombose/patologia , Líquido Amniótico/metabolismo , Córion/patologia , Líquido Cístico/metabolismo , Cistos/patologia , Feminino , Humanos , Gravidez , TromboelastografiaRESUMO
The main clinical distinction between post-transfusion purpura (PTP) and idiopathic thrombocytopenic purpura (ITP) is the sudden development of severe thrombocytopenia in the days after transfusion. Herein, we report the case of a 53-year-old Caucasian woman who developed multiple myeloma (MM) after peripheral blood-stem-cell transplant (PBSCT), along with severe thrombocytopenia (with a nadir of 1 × 109/L); she also experienced severe adverse events after each platelet transfusion, including the first one. These reactions were absent with any other transfused blood products. The results of an human leukocyte antigen (HLA) class-1 panel reactive antibody assay were 0%, and the results of a platelet-antibody screening assay were positive for HLA class-1 antibodies and glycoprotein (Gp)IIb/IIIa antibodies. Her platelet count reached 42 × 109 per L on day 50, after rituximab on day 22 and daratumumab on day 29. Her clinical scenario was most consistent with the course of PTP.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Púrpura Trombocitopênica Idiopática/patologia , Transplante de Células-Tronco/efeitos adversos , Reação Transfusional/diagnóstico , Reação Transfusional/patologia , Autoanticorpos/sangue , Diagnóstico Diferencial , Feminino , Humanos , Pessoa de Meia-Idade , Contagem de PlaquetasRESUMO
INTRODUCTION: Fibrin monomer (FM) concentrations reflect pro-thrombin activity and have the potential to predict thrombotic events relatively earlier than other haemostatic markers. Most often, FM are compared with D-dimer (DD) as increased DD have been documented in disseminated intravascular coagulation (DIC), deep vein thrombosis (DVT) and pulmonary embolism. Although DD have a high sensitivity and negative predictive value, their specificity is much lower depending on the assay chosen, clinical pre-test probability and patient condition. There are limited reports investigating the utility of FM in hyper-coagulable patients. METHODS: We performed a literature search of FM concentrations in hyper-coagulable patients including those with DIC, acute ischaemic stroke, atrial fibrillation, acute myocardial infarction, venous thromboembolism (VTE) and cancer, as well as those who are pregnant or undergoing surgery. RESULTS: FM were increased in patients with DIC and those with malignancy. In contrast, detection of VTE or post-operative DVT development is likely enhanced using both FM and DD concentrations. Similarly, measuring FM concentrations with other biomarker levels may be more beneficial in patients suffering an acute myocardial infarction or acute ischaemic stroke. Lastly, FM concentrations vary substantially throughout pregnancy with no definitive role of FM as of yet. CONCLUSION: Utilizing FM concentrations to assess hyper-coagulable patients seems promising; however, there are limitations including variations in FM cut-off values, the effect of patient medications and the timing of FM measurement relative to an acute event. Thus, further investigation is required before a true advantage for FM as a haemostatic marker can be established.
Assuntos
Biomarcadores/metabolismo , Coagulação Sanguínea , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Tromboembolia Venosa/diagnóstico , Animais , Feminino , Hemostasia , Humanos , Gravidez , Prognóstico , Tromboembolia Venosa/sangueRESUMO
BACKGROUND: There are data suggesting that free hemoglobin (Hb), heme, and iron contribute to infection, thrombosis, multiorgan failure, and death in critically ill patients. These outcomes may be mitigated by haptoglobin. STUDY DESIGN AND METHODS: 164 consecutively treated children undergoing surgery for congenital heart disease were evaluated for associations between free Hb and haptoglobin and clinical outcomes, physiologic metrics, and biomarkers of inflammation RESULTS: Higher perioperative free Hb levels (and lower haptoglobin levels) were associated with mortality, nosocomial infection, thrombosis, hours of intubation and inotropes, increased interleukin-6, peak serum lactate levels, and lower nadir mean arterial pressures. The median free Hb in patients without infection (30 mg/dL; 29 interquartile range [IQR], 24-52 mg/dL) was lower than in those who became infected (39 mg/dL; IQR, 33-88 mg/ 31 dL; p = 0.0046). The median mechanical ventilation requirements were 19 (IQR, 7-72) hours in patients with higher levels of haptoglobin versus 48 (IQR, 18-144) hours in patients with lower levels (p =â0.0047). Transfusion dose, bypass duration, and complexity of surgery were all significantly correlated with Hb levels and haptoglobin levels. Multivariate analyses demonstrated that these variables were independently and significantly associated with outcomes. CONCLUSIONS: Elevated pre- and postoperative levels of free Hb and decreased levels of haptoglobin were associated with adverse clinical outcomes, inflammation, and unfavorable physiologic metrics. Transfusion, RACHS score, and duration of bypass were associated with increased free Hb and decreased haptoglobin. Further investigation of the role of hemolysis and haptoglobin as potential mediators or markers of outcomes is warranted.
Assuntos
Haptoglobinas/metabolismo , Hemoglobinas/metabolismo , Cirurgia Torácica , Adolescente , Transfusão de Sangue/métodos , Proteína C-Reativa/metabolismo , Ligante de CD40/metabolismo , Criança , Pré-Escolar , Feminino , Hemólise , Humanos , Lactente , Recém-Nascido , Interleucina-6/metabolismo , Masculino , Período Pós-Operatório , Trombose/terapiaRESUMO
Oxidation reduction potential (ORP) or Redox is the ratio of activity between oxidizers and reducers. Oxidative stress (OS) can cause cellular injury and death, and is important in the regulation of immune response to injury or disease. In the present study, we investigated changes in the redox system as a function of cardiopulmonary bypass (CPB) in pediatric patients. 664 plasma samples were collected from 162 pediatric patients having cardiac surgery of various CPB times. Lower ORP values at 12 h post-CPB were associated with poor survival rate (mean ± SD 167 ± 20 vs. 138 ± 19, p = 0.005) and higher rate of thrombotic complications (153 ± 21 vs. 168 ± 20, p < 0.008). Similarly, patients who developed infections had lower ORP values at 6 h (149 ± 19 vs. 160 ± 22, p = 0.02) and 12 h (156 ± 17 vs. 168 ± 21, p = 0.004) post-CPB. Patients that developed any post-operative complication also had lower 6 h (149 ± 17 vs. 161 ± 23, p = 0.002) and 12 h (157 ± 18 vs. 170 ± 21, p = 0.0007) post-CPB ORP values. Free hemoglobin and IL-6, IL-10, and CRP were not associated with ORP levels. However, higher haptoglobin levels preoperatively were protective against decreases in ORP. Decreased ORP is a marker for poor outcome and predictive of post-operative thrombosis, infection, and other complications in critically ill pediatric cardiac surgery patients. These results suggest that redox imbalance and OS may contribute to the risk of complications and poor outcome in pediatric CBP patients. Haptoglobin may be a marker for increased resilience to OS in this population.
Assuntos
Biomarcadores/sangue , Ponte Cardiopulmonar/efeitos adversos , Estresse Oxidativo , Complicações Pós-Operatórias/etiologia , Adolescente , Proteína C-Reativa/análise , Criança , Pré-Escolar , Citocinas/sangue , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Complicações Pós-Operatórias/epidemiologia , RiscoRESUMO
BACKGROUND: Extracorporeal membrane oxygenation supplies oxygenated blood to the body supporting the heart and lungs. Survival rates of 20% to 50% are reported among patients receiving ECMO for cardiac arrest, severe cardiogenic shock, or failure to wean from cardiopulmonary bypass following cardiac surgery. Bleeding is one of the most common complications in ECMO patients due to coagulopathy, systemic anticoagulation, and the presence of large bore cannulas at systemic pressure. Absence of a standardized transfusion protocol in this population leads to inconsistent transfusion practices. Here, we assess a newly developed dedicated transfusion protocol in this clinical setting. METHODS: Data were retrospectively reviewed for the first 30 consecutive cardiac ECMO patients prior and post implementation of the ECMO transfusion protocol. Diagnoses, laboratory results, blood component utilization, and outcomes were collected and analyzed. RESULTS: Comorbidities were similar between the 2 eras, as well as the pre-ECMO ejection fraction (P = .568) and duration on ECMO (P = .278). Transfusion utilization data revealed statistically significant decreases in almost all blood components and a savings in blood component acquisition costs of 51% ($175, 970). In addition, an almost 2-fold increase in survival rate was observed in the post-ECMO transfusion protocol era (63% vs 33%; relative risk = 1.82; 95% confidence interval, 1.07-3.10; P = .028). CONCLUSIONS: Our data indicate that implementation of a standardized transfusion protocol, using more restrictive transfusion indications in cardiac ECMO patients, was associated with reduced blood product utilization, decreased complications, and improved survival. This multidepartmental approach facilitates better communication and adherence to consensus clinical decision making between intensive care unit, surgery, and transfusion service and optimizes care of complicated and acutely ill patients.
Assuntos
Transfusão de Sangue/normas , Protocolos Clínicos/normas , Oxigenação por Membrana Extracorpórea/normas , Cardiopatias/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Transfusão de Sangue/economia , Transfusão de Sangue/mortalidade , Redução de Custos , Análise Custo-Benefício , Oxigenação por Membrana Extracorpórea/efeitos adversos , Oxigenação por Membrana Extracorpórea/economia , Oxigenação por Membrana Extracorpórea/mortalidade , Feminino , Cardiopatias/economia , Cardiopatias/mortalidade , Cardiopatias/fisiopatologia , Custos Hospitalares , Humanos , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
Thrombocytopenia or receipt of antiplatelet drugs, with or without bleeding, is a common indication for platelet transfusions in the ICU. However, there is almost no evidence base for these practices other than expert opinion. Also common is use of platelet transfusions prior to invasive procedures or surgery in patients with thrombocytopenia. Likewise, there is no high-quality evidence that such practices are efficacious or safe. Recently, it has become clear that, whether causal or not, patients receiving prophylactic platelet transfusions experience high rates of nosocomial infection, thrombosis, organ failure, and mortality, which increase the urgency and need for randomized trials to assess these practices. Investigational methods of improving the safety and efficacy of platelet transfusions include use of alternate strategies such as antifibrinolytics; use of ABO-identical, leukoreduced, and washed platelet transfusions; and improved storage solutions.
Assuntos
Transtornos Plaquetários/terapia , Unidades de Terapia Intensiva , Transfusão de Plaquetas , Antifibrinolíticos/uso terapêutico , Transtornos Plaquetários/sangue , Humanos , Transfusão de Plaquetas/métodos , Transfusão de Plaquetas/estatística & dados numéricos , Trombocitopenia/sangue , Trombocitopenia/terapiaRESUMO
Obesity and associated type 2 diabetes (T2D) are important risk factors for infection following orthopedic implant surgery. Staphylococcus aureus, the most common pathogen in bone infections, adapts to multiple environments to survive and evade host immune responses. Whether adaptation of S. aureus to the unique environment of the obese/T2D host accounts for its increased virulence and persistence in this population is unknown. Thus, we assessed implant-associated osteomyelitis in normal versus high-fat-diet obese/T2D mice and found that S. aureus infection was more severe, including increases in bone abscesses relative to nondiabetic controls. S. aureus isolated from bone of obese/T2D mice displayed marked upregulation of four adhesion genes (clfA, clfB, bbp, and sdrC), all with binding affinity for fibrin(ogen). Immunostaining of infected bone revealed increased fibrin deposition surrounding bacterial abscesses in obese/T2D mice. In vitro coagulation assays demonstrated a hypercoagulable state in obese/T2D mice that was comparable to that of diabetic patients. S. aureus with an inactivating mutation in clumping factor A (clfA) showed a reduction in bone infection severity that eliminated the effect of obesity/T2D, while infections in control mice were unchanged. In infected mice that overexpress plasminogen activator inhibitor-1 (PAI-1), S. aureusclfA expression and fibrin-encapsulated abscess communities in bone were also increased, further linking fibrin deposition to S. aureus expression of clfA and infection severity. Together, these results demonstrate an adaptation by S. aureus to obesity/T2D with increased expression of clfA that is associated with the hypercoagulable state of the host and increased virulence of S. aureus.
Assuntos
Coagulase/metabolismo , Diabetes Mellitus Tipo 2/complicações , Obesidade/complicações , Osteomielite/patologia , Infecções Estafilocócicas/microbiologia , Abscesso/patologia , Animais , Anticorpos Antibacterianos/genética , Anticorpos Antibacterianos/metabolismo , Coagulase/genética , Diabetes Mellitus Tipo 2/microbiologia , Modelos Animais de Doenças , Fibrinogênio/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/microbiologia , Osteomielite/microbiologia , Análise de Sequência de RNA , Ativação Transcricional , Regulação para Cima , VirulênciaRESUMO
OBJECTIVES: Clinicians often need to rapidly reverse vitamin K antagonists (VKAs) in the setting of major hemorrhage or urgent need for surgery. Little is known about the safety profile of the traditional reversal agent, plasma, or the newly approved agent, four-factor prothrombin complex concentrate (4F-PCC), in a randomized setting. This is an integrated analysis of safety data from two clinical trials that evaluated 4F-PCC versus plasma for the treatment of patients requiring rapid VKA reversal for acute major bleeding or prior to an urgent surgical/invasive procedure. METHODS: This descriptive analysis comprised adverse event (AE) data from two phase IIIb, randomized, controlled trials. The bleeding and surgical studies were performed across 36 and 33 sites, respectively, in nine countries, with the integrated analysis comprising 388 patients (4F-PCC, n = 191; plasma, n = 197) aged ≥ 18 years, who required VKA reversal due to major bleeding or prior to an urgent surgical/invasive procedure. Patients received either 4F-PCC, containing nonactivated factors II, VII, IX, and X and proteins C and S (Beriplex/Kcentra, CSL Behring) or plasma, both dosed according to baseline international normalized ratio and body weight. Patients were also to receive vitamin K1. AEs and serious AEs (SAEs) were assessed up to days 10 and 45, respectively. RESULTS: The proportion of patients with AEs (4F-PCC, 115/191 [60.2%]; plasma, 124/197 [62.9%]) and SAEs (4F-PCC, 54/191 [28.3%]; plasma, 49/197 [24.9%]) was similar between groups. The proportion of patients with thromboembolic events was also similar between groups (4F-PCC, 14/191 [7.3%]; plasma, 14/197 [7.1%]). There were 13 (6.8%) deaths in the 4F-PCC group and 13 (6.6%) in the plasma group. Fluid overload events occurred in more patients in the plasma group than the 4F-PCC group (25 [12.7%] and 9 [4.7%], respectively). CONCLUSIONS: These safety data represent the largest controlled assessment of a 4F-PCC to date. For patients requiring urgent VKA reversal, 4F-PCC had a safety profile similar to that of plasma (AEs, SAEs, thromboembolic events, and deaths), but was associated with fewer fluid overload events.
Assuntos
Fatores de Coagulação Sanguínea/uso terapêutico , Hemorragia/tratamento farmacológico , Plasma , Vitamina K/antagonistas & inibidores , Idoso , Fatores de Coagulação Sanguínea/efeitos adversos , Feminino , Humanos , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Tromboembolia/induzido quimicamenteRESUMO
Platelet transfusion has been a vital therapeutic approach in patients with hematologic malignancies for close to half a century. Randomized trials show that prophylactic platelet transfusions mitigate bleeding in patients with acute myeloid leukemia. However, even with prophylactic transfusions, as many as 75% of patients, experience hemorrhage. While platelet transfusion efficacy is modest, questions and concerns have arisen about the risks of platelet transfusion therapy. The acknowledged serious risks of platelet transfusion include viral transmission, bacterial sepsis, and acute lung injury. Less serious adverse effects include allergic and non-hemolytic febrile reactions. Rare hemolytic reactions have occurred due to a common policy of transfusing without regard to ABO type. In the last decade or so, new concerns have arisen; platelet-derived lipids are implicated in transfusion-related acute lung injury after transfusion. With the recognition that platelets are immune cells came the discoveries that supernatant IL-6, IL-27 sCD40L, and OX40L are closely linked to febrile reactions and sCD40L with acute lung injury. Platelet transfusions are pro-inflammatory, and may be pro-thrombotic. Anti-A and anti-B can bind to incompatible recipient or donor platelets and soluble antigens, impair hemostasis and thus increase bleeding. Finally, stored platelet supernatants contain biological mediators such as VEGF and TGF-ß1 that may compromise the host versus tumor response. This is particularly of concern in patients receiving many platelet transfusions, as for acute leukemia. New evidence suggests that removing stored supernatant will improve clinical outcomes. This new view of platelets as pro-inflammatory and immunomodulatory agents suggests that innovative approaches to improving platelet storage and pre-transfusion manipulations to reduce toxicity could substantially improve the efficacy and safety of this long-employed therapy.