RESUMO
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by recurring episodes of thrombotic microangiopathy, causing ischemic organ impairment. Black patients are overrepresented in iTTP cohorts in the United States, but racial disparities in iTTP outcome and response to therapy have not been studied. Using the United States Thrombotic Microangiopathies Consortium iTTP Registry, we evaluated the impact of race on mortality and relapse-free survival (RFS) in confirmed iTTP in the United States from 1995 to 2020. We separately examined the impact of rituximab therapy and presentation with newly diagnosed (de novo) or relapsed iTTP on RFS by race. A total of 645 participants with 1308 iTTP episodes were available for analysis. Acute iTTP mortality did not differ by race. When all episodes of iTTP were included, Black race was associated with shorter RFS (hazard ratio [HR], 1.60; 95% CI, 1.16-2.21); the addition of rituximab to corticosteroids improved RFS in White (HR, 0.37; 95% CI, 0.18-0.73) but not Black patients (HR, 0.96; 95% CI, 0.71-1.31). In de novo iTTP, rituximab delayed relapse, but Black patients had shorter RFS than White patients, regardless of treatment. In relapsed iTTP, rituximab significantly improved RFS in White but not Black patients. Race affects overall relapse risk and response to rituximab in iTTP. Black patients may require closer monitoring, earlier retreatment, and alternative immunosuppression after rituximab treatment. How race, racism, and social determinants of health contribute to the disparity in relapse risk in iTTP deserves further study.
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Púrpura Trombocitopênica Trombótica , Proteína ADAMTS13 , Corticosteroides , Humanos , Púrpura Trombocitopênica Trombótica/terapia , Recidiva , Rituximab/uso terapêuticoRESUMO
BACKGROUND: Patients hospitalized with COVID-19 have an increased incidence of thromboembolism. The role of extended thromboprophylaxis after hospital discharge is unclear. OBJECTIVE: To determine whether anticoagulation is superior to placebo in reducing death and thromboembolic complications among patients discharged after COVID-19 hospitalization. DESIGN: Prospective, randomized, double-blind, placebo-controlled clinical trial. (ClinicalTrials.gov: NCT04650087). SETTING: Done during 2021 to 2022 among 127 U.S. hospitals. PARTICIPANTS: Adults aged 18 years or older hospitalized with COVID-19 for 48 hours or more and ready for discharge, excluding those with a requirement for, or contraindication to, anticoagulation. INTERVENTION: 2.5 mg of apixaban versus placebo twice daily for 30 days. MEASUREMENTS: The primary efficacy end point was a 30-day composite of death, arterial thromboembolism, and venous thromboembolism. The primary safety end points were 30-day major bleeding and clinically relevant nonmajor bleeding. RESULTS: Enrollment was terminated early, after 1217 participants were randomly assigned, because of a lower than anticipated event rate and a declining rate of COVID-19 hospitalizations. Median age was 54 years, 50.4% were women, 26.5% were Black, and 16.7% were Hispanic; 30.7% had a World Health Organization severity score of 5 or greater, and 11.0% had an International Medical Prevention Registry on Venous Thromboembolism risk prediction score of greater than 4. Incidence of the primary end point was 2.13% (95% CI, 1.14 to 3.62) in the apixaban group and 2.31% (CI, 1.27 to 3.84) in the placebo group. Major bleeding occurred in 2 (0.4%) and 1 (0.2%) and clinically relevant nonmajor bleeding occurred in 3 (0.6%) and 6 (1.1%) apixaban-treated and placebo-treated participants, respectively. By day 30, thirty-six (3.0%) participants were lost to follow-up, and 8.5% of apixaban and 11.9% of placebo participants permanently discontinued the study drug treatment. LIMITATIONS: The introduction of SARS-CoV-2 vaccines decreased the risk for hospitalization and death. Study enrollment spanned the peaks of the Delta and Omicron variants in the United States, which influenced illness severity. CONCLUSION: The incidence of death or thromboembolism was low in this cohort of patients discharged after hospitalization with COVID-19. Because of early enrollment termination, the results were imprecise and the study was inconclusive. PRIMARY FUNDING SOURCE: National Institutes of Health.
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Vacinas contra COVID-19 , COVID-19 , Hemorragia , Tromboembolia Venosa , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Anticoagulantes/efeitos adversos , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Método Duplo-Cego , Hemorragia/induzido quimicamente , Hospitalização , Estudos Prospectivos , SARS-CoV-2 , Resultado do Tratamento , Tromboembolia Venosa/tratamento farmacológicoRESUMO
[Figure: see text].
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Antineoplásicos/efeitos adversos , Arteriopatias Oclusivas/induzido quimicamente , Coagulação Sanguínea/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Trombose/induzido quimicamente , Trombose Venosa/induzido quimicamente , Animais , Arteriopatias Oclusivas/sangue , Arteriopatias Oclusivas/prevenção & controle , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Humanos , Terapia de Alvo Molecular/efeitos adversos , Neoplasias/sangue , Ativação Plaquetária/efeitos dos fármacos , Medição de Risco , Fatores de Risco , Transdução de Sinais , Trombose/sangue , Trombose/prevenção & controle , Trombose Venosa/sangue , Trombose Venosa/prevenção & controleRESUMO
Hereditary hemorrhagic telangiectasia (HHT, Osler-Weber-Rendu disease) is a rare multisystem vascular disorder causing chronic gastrointestinal bleeding, epistaxis, and severe anemia. Bevacizumab, an anti-vascular endothelial growth factor antibody, may be effective to treat bleeding in HHT. This international, multicenter, retrospective study evaluated the use of systemic bevacizumab to treat HHT-associated bleeding and anemia at 12 HHT treatment centers. Hemoglobin, epistaxis severity score, red cell units transfused, and intravenous iron infusions before and after treatment were evaluated using paired means testing and mixed-effects linear models. 238 HHT patients received bevacizumab for a median of 12 (range, 1-96) months. Compared with pretreatment, bevacizumab increased mean hemoglobin by 3.2 g/dL (95% CI, 2.9-3.5 g/dL) [mean hemoglobin 8.6 (8.5, 8.8) g/dL versus 11.8 (11.5, 12.1) g/dL, p<0.0001)] and decreased the epistaxis severity score (ESS) by 3.4 (3.2-3.7) points [mean ESS 6.8 (6.6-7.1) versus 3.4 (3.2-3.7), P<0.0001] during the first year of treatment. Compared with 6 months pretreatment, RBC units transfused decreased by 82% [median of 6.0 (IQR 0.0-13.0) units versus 0 (IQR, 0.0-1.0) units, P<0.0001] and iron infusions decreased by 70% [median of 6.0 (1.0-18.0) infusions versus 1.0 (0.0-4.0) infusions, P<0.0001] during the first 6 months of bevacizumab treatment. Outcomes were similar regardless of underlying pathogenic mutation. Following initial induction infusions, continuous/scheduled bevacizumab maintenance achieved higher hemoglobin and lower ESS than intermittent/as needed maintenance but with more drug exposure. Bevacizumab was well tolerated: hypertension, fatigue, and proteinuria were the most common adverse events. Venous thromboembolism occurred in 2% of patients. In conclusion, systemic bevacizumab was safe and effective to manage chronic bleeding and anemia in HHT.
Assuntos
Telangiectasia Hemorrágica Hereditária , Administração Intravenosa , Bevacizumab/uso terapêutico , Hemorragia/tratamento farmacológico , Humanos , Estudos Retrospectivos , Telangiectasia Hemorrágica Hereditária/complicações , Telangiectasia Hemorrágica Hereditária/tratamento farmacológicoRESUMO
The world is amid a pandemic caused by severe acute respiratory syndrome-coronavirus 2. Severe acute respiratory syndrome-coronavirus causes serious respiratory tract infections that can lead to viral pneumonia, acute respiratory distress syndrome, and death. Some patients with coronavirus disease 2019 (COVID-19) have an activated coagulation system characterized by elevated plasma levels of d-dimer-a biomarker of fibrin degradation. Importantly, high levels of D-dimer on hospital admission are associated with increased risk of mortality. Venous thromboembolism is more common than arterial thromboembolism in hospitalized COVID-19 patients. Pulmonary thrombosis and microvascular thrombosis are observed in autopsy studies, and this may contribute to the severe hypoxia observed in COVID-19 patients. It is likely that multiple systems contribute to thrombosis in COVID-19 patients, such as activation of coagulation, platelet activation, hypofibrinolysis, endothelial cell dysfunction, inflammation, neutrophil extracellular traps, and complement. Targeting these different pathways may reduce thrombosis and improve lung function in COVID-19 patients.
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Betacoronavirus , Transtornos da Coagulação Sanguínea/complicações , Coagulação Sanguínea , Infecções por Coronavirus/complicações , Pandemias , Pneumonia Viral/complicações , Trombose/etiologia , Transtornos da Coagulação Sanguínea/sangue , COVID-19 , Infecções por Coronavirus/epidemiologia , Humanos , Pneumonia Viral/epidemiologia , SARS-CoV-2 , Trombose/sangueRESUMO
DESCRIPTION: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease with an estimated prevalence of 1 in 5000 that is characterized by the presence of vascular malformations (VMs). These result in chronic bleeding, acute hemorrhage, and complications from shunting through VMs. The goal of the Second International HHT Guidelines process was to develop evidence-based consensus guidelines for the management and prevention of HHT-related symptoms and complications. METHODS: The guidelines were developed using the AGREE II (Appraisal of Guidelines for Research and Evaluation II) framework and GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. The guidelines expert panel included expert physicians (clinical and genetic) in HHT from 15 countries, guidelines methodologists, health care workers, health care administrators, patient advocacy representatives, and persons with HHT. During the preconference process, the expert panel generated clinically relevant questions in 6 priority topic areas. A systematic literature search was done in June 2019, and articles meeting a priori criteria were included to generate evidence tables, which were used as the basis for recommendation development. The expert panel subsequently convened during a guidelines conference to conduct a structured consensus process, during which recommendations reaching at least 80% consensus were discussed and approved. RECOMMENDATIONS: The expert panel generated and approved 6 new recommendations for each of the following 6 priority topic areas: epistaxis, gastrointestinal bleeding, anemia and iron deficiency, liver VMs, pediatric care, and pregnancy and delivery (36 total). The recommendations highlight new evidence in existing topics from the first International HHT Guidelines and provide guidance in 3 new areas: anemia, pediatrics, and pregnancy and delivery. These recommendations should facilitate implementation of key components of HHT care into clinical practice.
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Telangiectasia Hemorrágica Hereditária/diagnóstico , Telangiectasia Hemorrágica Hereditária/terapia , Anemia/etiologia , Anemia/terapia , Malformações Arteriovenosas/etiologia , Malformações Arteriovenosas/terapia , Criança , Epistaxe/etiologia , Epistaxe/terapia , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/terapia , Doenças Genéticas Inatas/etiologia , Doenças Genéticas Inatas/terapia , Humanos , Fígado/irrigação sanguínea , Telangiectasia Hemorrágica Hereditária/complicaçõesRESUMO
PURPOSE OF REVIEW: In this review, we discuss current clinical guidelines and potential underlying mechanisms regarding platelet transfusion therapy in patients at risk of bleeding, comparing management of patients with thrombocytopenia versus those with qualitative platelet disorders. RECENT FINDINGS: Platelet transfusion therapy is highly effective in managing bleeding in patients with hypoproliferative thrombocytopenia. Clinical trials have demonstrated that platelet transfusion can be used at a lower trigger threshold and reduced platelet doses, and may be used therapeutically rather than prophylactically in some situations, although additional data are needed. In patients with inherited platelet disorders such as Glanzmann's Thrombasthenia or those with RASGRP2 mutations, platelet transfusion may be ineffective because of competition between transfused and endogenous platelets at the site of vascular injury. Successful management of these patients may require transfusion of additional platelet units, or mechanism-driven combination therapy with other pro-hemostatic agents. In patients on antiplatelet therapy, timing of transfusion and inhibitor mechanism-of-action are key in determining therapeutic success. SUMMARY: Expanding our understanding of the mechanisms by which transfused platelets exert their pro-hemostatic function in various bleeding disorders will improve the appropriate use of platelet transfusion.
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Transtornos Plaquetários/terapia , Transfusão de Plaquetas/métodos , Animais , Transtornos Plaquetários/sangue , Hemorragia/sangue , Hemorragia/terapia , Hemostasia/efeitos dos fármacos , Hemostáticos/uso terapêutico , Humanos , Inibidores da Agregação Plaquetária/uso terapêuticoRESUMO
BACKGROUND: Despite rapid and intensive treatments with therapeutic plasma exchange (TPE) and immunosuppression, immune thrombotic thrombocytopenic purpura (TTP) patients are at risk of disease exacerbation, i.e., early recurrence of TTP within 30 days of achieving treatment response. TPE taper, a practice of performing additional TPE procedures after achieving treatment response, is commonly performed for decreasing exacerbations, although no evidence supports this practice. STUDY DESIGN AND METHODS: In this prospective observational investigation over four years, our center switched its standard of care for treating all TTP patients from not performing TPE taper after achieving treatment response (i.e., no-taper cohort) to performance of TPE taper (i.e., yes-taper cohort) to characterize impacts on exacerbations. Continuous and categorical data were analyzed by Mann-Whitney, Fisher's exact, and log-rank tests; significance was defined as p < 0.05. RESULTS: The two cohorts were well matched and had no significant differences in demographics, presentation laboratory values, or TTP history (p > 0.05 for all). The yes-taper cohort of 26 patients with 29 consecutive episodes did not have a significantly different exacerbation rate from the no-taper cohort of 24 patients with 27 consecutive episodes (exacerbation rates of 37.9% vs. 33.3%, respectively; p = 0.78); however, treatment-related complications directly attributed to the TPE procedures, blood products, or central venous catheters were significantly greater in the yes-taper cohort (nine vs. one events, respectively; p = 0.01). CONCLUSION: Since TPE taper did not reduce exacerbations in our TTP patients, we no longer advocate for TPE taper and have reverted to our original standard of care.
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Progressão da Doença , Troca Plasmática , Púrpura Trombocitopênica Idiopática/terapia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Púrpura Trombocitopênica Idiopática/sangue , RecidivaRESUMO
Pazopanib (Votrient) is an orally administered tyrosine kinase inhibitor that blocks VEGF receptors potentially serving as anti-angiogenic treatment for hereditary hemorrhagic telangiectasia (HHT). We report a prospective, multi-center, open-label, dose-escalating study [50 mg, 100 mg, 200 mg, and 400 mg], designed as a proof-of-concept study to demonstrate efficacy of pazopanib on HHT-related bleeding, and to measure safety. Patients, recruited at 5 HHT Centers, required ≥ 2 Curacao criteria AND [anemia OR severe epistaxis with iron deficiency]. Co-primary outcomes, hemoglobin (Hgb) and epistaxis severity, were measured during and after treatment, and compared to baseline. Safety monitoring occurred every 1.5 weeks. Seven patients were treated with 50 mg pazopanib daily. Six/seven showed at least 50% decrease in epistaxis duration relative to baseline at some point during study; 3 showed at least 50% decrease in duration during Weeks 11 and 12. Six patients showed a decrease in ESS of > 0.71 (MID) relative to baseline at some point during study; 3/6 showed a sustained improvement. Four patients showed > 2 gm improvement in Hgb relative to baseline at one or more points during study. Health-related QOL scores improved on all SF-36 domains at Week 6 and/or Week 12, except general health (unchanged). There were 19 adverse events (AE) including one severe AE (elevated LFTs, withdrawn from dosing at 43 days); with no serious AE. In conclusion, we observed an improvement in Hgb and/or epistaxis in all treated patients. This occurred at a dose much lower than typically used for oncologic indications, with no serious AE. Further studies of pazopanib efficacy are warranted.
Assuntos
Hemorragia , Pirimidinas , Sulfonamidas , Telangiectasia Hemorrágica Hereditária , Adulto , Feminino , Hemorragia/sangue , Hemorragia/tratamento farmacológico , Humanos , Indazóis , Masculino , Pessoa de Meia-Idade , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Telangiectasia Hemorrágica Hereditária/sangue , Telangiectasia Hemorrágica Hereditária/tratamento farmacológicoRESUMO
OBJECTIVE: To evaluate the accuracy of the clinical Curaçao criteria in the diagnosis of hereditary hemorrhagic telangiectasia (HHT) in children and adolescents. STUDY DESIGN: This was a retrospective, multicenter chart review of 673 patients evaluated between 2002 and 2016; 290 were eligible for the study. Genetic testing for a pathogenic mutation was considered the gold standard against which the clinical Curaçao criteria were compared. Patients were divided into 4 age categories: 0-5, 6-10, 11-15, and 16-21-years. Sensitivity and specificity were calculated for each age group, and for the overall population. RESULTS: Overall the Curaçao criteria had a sensitivity of 68% (95% CI 60%-76%) and a specificity of 98% (95% CI 91%-100%). Sensitivity was lowest in the 0- to 5-year group, and increased with advancing age. The Curaçao criteria had the highest sensitivity in the 16- to 21-year-olds. Specificity was 100% in all age groups except for the 11- to 15-year-olds. CONCLUSIONS: This study evaluated the use of the Curaçao criteria for the diagnosis of HHT in the pediatric population with a family history of HHT. In those between the age of 0 and 21 years who meet 1 criterion (unlikely HHT) or 2 criteria (possible HHT), genetic testing is preferred for diagnosis. The Curaçao criteria appear to reliably diagnose HHT in children and adolescents who meet 3 or 4 criteria (definite HHT).
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Testes Genéticos/métodos , Telangiectasia Hemorrágica Hereditária/diagnóstico , Receptores de Activinas Tipo II/genética , Adolescente , Adulto , Criança , Pré-Escolar , Curaçao , Endoglina/genética , Feminino , Genótipo , Humanos , Lactente , Masculino , Mutação , Estudos Retrospectivos , Sensibilidade e Especificidade , Proteína Smad4/genética , Telangiectasia Hemorrágica Hereditária/genética , Adulto JovemRESUMO
Thrombophilias are hereditary and/or acquired conditions that predispose patients to thrombosis. Testing for thrombophilia is commonly performed in patients with venous thrombosis and their relatives; however such testing usually does not provide information that impacts management and may result in harm. This manuscript, initiated by the Anticoagulation Forum, provides clinical guidance for thrombophilia testing in five clinical situations: following 1) provoked venous thromboembolism, 2) unprovoked venous thromboembolism; 3) in relatives of patients with thrombosis, 4) in female relatives of patients with thrombosis considering estrogen use; and 5) in female relatives of patients with thrombosis who are considering pregnancy. Additionally, guidance is provided regarding the timing of thrombophilia testing. The role of thrombophilia testing in arterial thrombosis and for evaluation of recurrent pregnancy loss is not addressed. Statements are based on existing guidelines and consensus expert opinion where guidelines are lacking. We recommend that thrombophilia testing not be performed in most situations. When performed, it should be used in a highly selective manner, and only in circumstances where the information obtained will influence a decision important to the patient, and outweigh the potential risks of testing. Testing should not be performed during acute thrombosis or during the initial (3-month) period of anticoagulation.
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Complicações Cardiovasculares na Gravidez/diagnóstico , Complicações Cardiovasculares na Gravidez/terapia , Trombofilia/diagnóstico , Trombofilia/terapia , Feminino , Humanos , Masculino , Guias de Prática Clínica como Assunto , GravidezRESUMO
An excess of free heme is present in the blood during many types of hemolytic anemia. This has been linked to organ damage caused by heme-mediated oxidative stress and vascular inflammation. We investigated the mechanism of heme-induced coagulation activation in vivo. Heme caused coagulation activation in wild-type mice that was attenuated by an anti-tissue factor antibody and in mice expressing low levels of tissue factor. In contrast, neither factor XI deletion nor inhibition of factor XIIa-mediated factor XI activation reduced heme-induced coagulation activation, suggesting that the intrinsic coagulation pathway is not involved. We investigated the source of tissue factor in heme-induced coagulation activation. Heme increased the procoagulant activity of mouse macrophages and human PBMCs. Tissue factor-positive staining was observed on leukocytes isolated from the blood of heme-treated mice but not on endothelial cells in the lungs. Furthermore, heme increased vascular permeability in the mouse lungs, kidney and heart. Deletion of tissue factor from either myeloid cells, hematopoietic or endothelial cells, or inhibition of tissue factor expressed by non-hematopoietic cells did not reduce heme-induced coagulation activation. However, heme-induced activation of coagulation was abolished when both non-hematopoietic and hematopoietic cell tissue factor was inhibited. Finally, we demonstrated that coagulation activation was partially attenuated in sickle cell mice treated with recombinant hemopexin to neutralize free heme. Our results indicate that heme promotes tissue factor-dependent coagulation activation and induces tissue factor expression on leukocytes in vivo. We also demonstrated that free heme may contribute to thrombin generation in a mouse model of sickle cell disease.
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Anemia Hemolítica/genética , Anemia Falciforme/genética , Coagulação Sanguínea/efeitos dos fármacos , Heme/administração & dosagem , Tromboplastina/genética , Anemia Hemolítica/sangue , Anemia Hemolítica/induzido quimicamente , Anemia Hemolítica/patologia , Anemia Falciforme/sangue , Anemia Falciforme/patologia , Animais , Anticorpos/farmacologia , Coagulação Sanguínea/genética , Permeabilidade Capilar/efeitos dos fármacos , Células Cultivadas , Fator XI/genética , Fator XI/metabolismo , Fator XIIa/antagonistas & inibidores , Fator XIIa/genética , Fator XIIa/metabolismo , Feminino , Deleção de Genes , Expressão Gênica , Hemopexina/farmacologia , Humanos , Injeções Intravenosas , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Suínos , Tromboplastina/antagonistas & inibidores , Tromboplastina/metabolismoRESUMO
Heparin-induced thrombocytopenia (HIT) is a potentially devastating form of drug-induced thrombocytopenia that occurs in patients receiving heparin for prevention or treatment of thrombosis. Patients with HIT develop autoantibodies to the platelet factor 4 (PF4)/heparin complex, which is termed the HIT Ab complex. Despite a decrease in the platelet count, the most feared complication of HIT is thrombosis. The mechanism of thrombosis in HIT remains poorly understood. We investigated the effects of the HIT Ab complex on tissue factor (TF) expression and release of TF-positive microparticles in peripheral blood mononuclear cells and monocytes. To model these effects ex vivo, we used a murine mAb specific for the PF4/heparin complex (KKO), as well as plasma from patients with HIT. We found that the HIT Ab complex induced TF expression in monocytes and the release of TF-positive microparticles. Further, we found that induction of TF is mediated via engagement of the FcγRI receptor and activation of the MEK1-ERK1/2 signaling pathway. Our data suggest that monocyte TF may contribute to the development of thrombosis in patients with HIT.
Assuntos
Anticoagulantes/efeitos adversos , Autoanticorpos/imunologia , Heparina/efeitos adversos , Fator Plaquetário 4/imunologia , Trombocitopenia/induzido quimicamente , Trombocitopenia/imunologia , Anticoagulantes/imunologia , Anticoagulantes/farmacocinética , Anticoagulantes/uso terapêutico , Autoanticorpos/sangue , Micropartículas Derivadas de Células/imunologia , Micropartículas Derivadas de Células/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/imunologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Heparina/imunologia , Heparina/farmacocinética , Heparina/uso terapêutico , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/imunologia , Masculino , Monócitos/imunologia , Monócitos/metabolismo , Fator Plaquetário 4/sangue , Receptores de IgG/imunologia , Receptores de IgG/metabolismo , Trombocitopenia/sangue , Tromboplastina/biossíntese , Tromboplastina/imunologia , Trombose/tratamento farmacológico , Trombose/imunologiaRESUMO
Background: The Accelerating COVID-19 Therapeutic Interventions and Vaccines-4c (ACTIV-4c) trial investigated prophylactic apixaban for 30 days following hospitalization for COVID-19. The overall incidence of early postdischarge death or thromboembolism was low, and the trial was closed early. Objectives: To identify a high-risk patient population who might benefit from postdischarge thromboprophylaxis through subgroup analyses stratified by age, race/ethnicity, obesity, D-dimer elevation, World Health Organization score, and modified International Medical Prevention Registry on Venous Thromboembolism score on 30-day composite outcome of all-cause death, arterial thromboembolism (ATE), and venous thromboembolism (VTE). Methods: Cumulative incidences of all-cause death, ATE, and VTE within 30 days were described for each subgroup. Time to death, ATE, or VTE by 30 days was analyzed using Cox proportional hazard models with interaction testing for each subgroup. Results: Among 1217 patients randomized to apixaban or placebo group, 32% were >60 years old. Modified International Medical Prevention Registry on Venous Thromboembolism score was ≥4 in 2% and 2 or 3 with an elevated D-dimer in an additional 9% of participants. The overall incidence of the primary endpoint was 2.13% in the apixaban group and 2.31% in the placebo group. At day 30, similar rates of the primary endpoint occurred within subgroups, except for participants aged >60 years. No benefit of thromboprophylaxis was seen in any subgroup. Conclusion: The combined incidence of 30-day death, ATE, and VTE was low in patients who survived COVID-19 hospitalization, except in patients over age 60 years. Due to the limited number of events, the findings remain inconclusive; nonetheless, the study did not identify a high-risk subgroup that would derive benefits from extended thromboprophylaxis.
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Background: Mortality due to immune-mediated thrombotic thrombocytopenic purpura (iTTP) remains significant. Predicting mortality risk may potentially help individualize treatment. The French Thrombotic Microangiopathy (TMA) Reference Score has not been externally validated in the United States. Recent advances in machine learning technology can help analyze large numbers of variables with complex interactions for the development of prediction models. Objectives: To validate the French TMA Reference Score in the United States Thrombotic Microangiopathy (USTMA) iTTP database and subsequently develop a novel mortality prediction tool, the USTMA TTP Mortality Index. Methods: We analyzed variables available at the time of initial presentation, including demographics, symptoms, and laboratory findings. We developed our model using gradient boosting machine, a machine learning ensemble method based on classification trees, implemented in the R package gbm. Results: In our cohort (n = 419), the French score predicted mortality with an area under the receiver operating characteristic curve of 0.63 (95% CI: 0.50-0.77), sensitivity of 0.35, and specificity of 0.84. Our gradient boosting machine model selected 8 variables to predict acute mortality with a cross-validated area under the receiver operating characteristic curve of 0.77 (95% CI: 0.71-0.82). The 2 cutoffs corresponded to sensitivities of 0.64 and 0.50 and specificities of 0.76 and 0.87, respectively. Conclusion: The USTMA Mortality Index was acceptable for predicting mortality due to acute iTTP in the USTMA registry, but not sensitive enough to rule out death. Identifying patients at high risk of iTTP-related mortality may help individualize care and ultimately improve iTTP survival outcomes. Further studies are needed to provide external validation. Our model is one of many recent examples where machine learning models may show promise in clinical prediction tools in healthcare.
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Iron is a critical and tightly regulated nutrient for both the malaria parasite and its human host. The importance of the relationship between host iron and the parasite has been underscored recently by studies showing that host iron supplementation may increase the risk of falciparum malaria. It is unclear what host iron sources the parasite is able to access. We developed a flow cytometry-based method for measuring the labile iron pool (LIP) of parasitized erythrocytes using the nucleic acid dye STYO 61 and the iron sensitive dye, calcein acetoxymethyl ester (CA-AM). This new approach enabled us to measure the LIP of P. falciparum through the course of its erythrocytic life cycle and in response to the addition of host serum iron sources. We found that the LIP increases as the malaria parasite develops from early ring to late schizont stage, and that the addition of either transferrin or ferric citrate to culture media increases the LIP of trophozoites. Our method for detecting the LIP within malaria parasitized RBCs provides evidence that the parasite is able to access serum iron sources as part of the host vs. parasite arms race for iron.
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Eritrócitos/metabolismo , Interações Hospedeiro-Parasita , Ferro/metabolismo , Malária Falciparum/metabolismo , Plasmodium falciparum/fisiologia , Eritrócitos/parasitologia , Humanos , Esquizontes/metabolismoAssuntos
Deficiência do Fator XIII/diagnóstico , Fator XIII/metabolismo , Hemorragia/diagnóstico , Imunossupressores/uso terapêutico , Ácido Micofenólico/uso terapêutico , Idoso de 80 Anos ou mais , Animais , Anticorpos Neutralizantes/sangue , Autoanticorpos/sangue , Biomarcadores Farmacológicos/metabolismo , Coagulação Sanguínea , Fator XIII/imunologia , Deficiência do Fator XIII/terapia , Hemorragia/terapia , Humanos , Masculino , Prognóstico , RiscoRESUMO
GEHEP, established in 2009, is an independent, multi-institutional, international consortium of early career hematology specialists in the field of hemophilia and other inherited bleeding disorders. The main objective of the group, whose members practice at institutions in North America, Europe, and South Africa, is to advance hemophilia care by providing a forum for mentored collaborative research, developing programs for improving clinical care, and promoting academic career development of junior faculty. GEHEP members collect and document anonymized data on intra- and interinstitutional differences in patient populations, diagnosis, and treatment in the field of hemophilia and other bleeding disorders. To facilitate sharing of aggregated data among GEHEP members, a global protocol was developed and approved by most members' local institutional review board. Current GEHEP research initiatives are varied, encompassing work in pediatric and adult patients. GEHEP members have presented research at international meetings on the initiation of prophylaxis in children, use of immune tolerance induction in adults, and prevalence of acute coronary syndromes in older patients with hemophilia. The main goal of the continuing work of GEHEP is to advance the care of patients with hemophilia worldwide.
RESUMO
Background: Patients with suspected or newly diagnosed venous thromboembolism (VTE) are often referred to the emergency department (ED) for management, where anticoagulation is initiated. However, when the patient is judged to be suitable for outpatient management, counseling and follow-up specialty care are frequently suboptimal. Objectives: To establish an advanced practice provider (APP)-led rapid follow-up clinic to improve transitions of care for patients with newly diagnosed deep vein thrombosis or low-risk pulmonary embolism and to provide continued specialty care and support, including management of complications and medication access issues. Methods: In order to address this gap in transition of care, we developed an APP-led clinic with a mandate to improve quality and safety in the outpatient setting for patients with acute VTE. Results: In the first 2 years, a total of 234 patients were evaluated, of whom data were standardized and reviewed for 229. Utilization steadily increased over time, with at least 10% of patients requiring financial medication assistance over both years. Seventy-two percent of patients were referred from the ED in the first year and 59% in the second year, and referrals from non-ED outpatient specialties increased. Data on deviations from standard care identified in referred patients were collected in the second year and found in 19 (12.7%) of cases. These included unnecessarily prescribed or changed anticoagulants, dosing errors, misclassification of thrombosis, and other deviations. Patient demographic data also demonstrated increasing diversity of the patient population over time, with increased utilization by Hispanic and African American patients in the second year. This highlighted the need for better patient education material translations into Spanish, which is a future aim. Conclusion: In summary, the APP-led VTE Transition Clinic was feasible and grew quickly in utilization, diversity of referrals, and diversity of patients served.