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1.
Am J Hematol ; 2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34748664

RESUMO

Thrombosomes are trehalose-stabilized, freeze-dried group O platelets with a 3-year shelf life. They can be stockpiled, rapidly reconstituted, and infused regardless of the recipient's blood type. Thrombosomes thus represent a potential alternative platelet transfusion strategy. The present study assessed the safety and potential early signals of efficacy of Thrombosomes in bleeding thrombocytopenic patients. We performed an open-label, phase 1 study of single doses of allogeneic Thrombosomes at 3 dose levels in 3 cohorts, each consisting of 8 patients who had hematologic malignancies, thrombocytopenia, and bleeding. Adverse events, dose-limiting toxicities (DLTs), World Health Organization (WHO) bleeding scores, and hematology values were assessed. No DLTs were reported. The median age was 59 years (24-71). Most patients had AML (58%) or ALL (29%), followed by MDS (8%) and myeloproliferative neoplasm (4%). The WHO scores of 22 patients who were actively bleeding at a total of 27 sites at baseline either improved (n=17 [63%]) or stabilized (n=10 [37%]) through day 6. Twenty-four hours after infusion, 12 patients (50%) had a clinically significant platelet count increase. Of 8 patients who received no platelet transfusions for 6 days after Thrombosomes infusion, 5 had a clinically significant increase in platelet count of ≥5000 platelets/µL and 2 had platelet count normalization. Thrombosomes doses up to 3.78 x 108 particles/kg demonstrated safety in 24 bleeding, thrombocytopenic patients with hematological malignancies. Thrombosomes may represent an alternative to conventional platelets to treat bleeding. A phase 2 clinical trial in a similar patient population is underway. This article is protected by copyright. All rights reserved.

2.
Blood Adv ; 5(20): 4031-4043, 2021 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-34474478

RESUMO

Donor-specific anti-HLA antibodies (DSAs) are a major cause of engraftment failure in patients receiving haploidentical stem cell transplantation (HaploSCT). Effective treatments are needed for these patients, who often have no other donor options and/or are in need to proceed urgently to transplantation. We studied a multimodality treatment with alternate-day plasma exchange (PE), rituximab, intravenous γ globulin (IVIg) and an irradiated donor buffy coat for patients with DSAs at 2 institutions. Thirty-seven patients with a median age of 51 years were treated with this desensitization protocol. Treatment outcomes were compared with a control group of HaploSCT patients without DSAs (n = 345). The majority of patients in the DSA group were female (83.8% vs 37.1% in controls, P < .001) and received stem cells from a child as the donor (67.6% vs 44.1%, P = .002). Mean DSA level before and after desensitization was 10 198 and 5937 mean fluorescence intensity (MFI), respectively, with mean differences of 4030 MFI. Fourteen of 30 tested patients (46.7%) had C1q positivity, while 8 of 29 tested patients (27.6%) remained positive after desensitization. In multivariable analysis, patients with initial DSA > 20 000 MFI and persistent positive C1q after desensitization had a significantly lower engraftment rate, which resulted in significantly higher non-relapse mortality and worse overall survival (OS) than controls, whereas graft outcome and survival of patients with initial DSA < 20 000 MFI and those with negative C1q after treatment were comparable with controls. In conclusion, treatment with PE, rituximab, IVIg, and donor buffy coat is effective in promoting engraftment in patients with DSAs ≤20 000 MFI.


Assuntos
Antígenos HLA , Transplante de Células-Tronco Hematopoéticas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Rituximab/uso terapêutico , Doadores de Tecidos , Transplante Homólogo
3.
Cell Rep ; 36(3): 109432, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34270918

RESUMO

Adoptive cell therapy with virus-specific T cells has been used successfully to treat life-threatening viral infections, supporting application of this approach to coronavirus disease 2019 (COVID-19). We expand severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) T cells from the peripheral blood of COVID-19-recovered donors and non-exposed controls using different culture conditions. We observe that the choice of cytokines modulates the expansion, phenotype, and hierarchy of antigenic recognition by SARS-CoV-2 T cells. Culture with interleukin (IL)-2/4/7, but not under other cytokine-driven conditions, results in more than 1,000-fold expansion in SARS-CoV-2 T cells with a retained phenotype, function, and hierarchy of antigenic recognition compared with baseline (pre-expansion) samples. Expanded cytotoxic T lymphocytes (CTLs) are directed against structural SARS-CoV-2 proteins, including the receptor-binding domain of Spike. SARS-CoV-2 T cells cannot be expanded efficiently from the peripheral blood of non-exposed controls. Because corticosteroids are used for management of severe COVID-19, we propose an efficient strategy to inactivate the glucocorticoid receptor gene (NR3C1) in SARS-CoV-2 CTLs using CRISPR-Cas9 gene editing.

4.
Front Immunol ; 12: 675679, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995420

RESUMO

Background: COVID-19 Convalescent plasma (CCP) is safe and effective, particularly if given at an early stage of the disease. Our study aimed to identify an association between survival and specific antibodies found in CCP. Patients and Methods: Patients ≥18 years of age who were hospitalized with moderate to severe COVID-19 infection and received CCP at the MD Anderson Cancer Center between 4/30/2020 and 8/20/2020 were included in the study. We quantified the levels of anti-SARS-CoV-2 antibodies, as well as antibodies against antigens of other coronavirus strains, in the CCP units and compared antibody levels with patient outcomes. For each antibody, a Bayesian exponential survival time regression model including prognostic variables was fit, and the posterior probability of a beneficial effect (PBE) of higher antibody level on survival time was computed. Results: CCP was administered to 44 cancer patients. The median age was 60 years (range 37-84) and 19 (43%) were female. Twelve patients (27%) died of COVID-19-related complications. Higher levels of two non-SARS-CoV-2-specific antibodies, anti-HCoV-OC43 spike IgG and anti-HCoV-HKU1 spike IgG, had PBE = 1.00, and 4 SARS-CoV-2-specific antibodies had PBEs between 0.90 and 0.95. Other factors associated with better survival were shorter time to CCP administration, younger age, and female sex. Conclusions: Common cold coronavirus spike IgG antibodies anti-HCoV-OC43 and anti-HCoV-HKU1 may target a common domain for SARS-CoV-2 and other coronaviruses. They provide a promising therapeutic target for monoclonal antibody production.


Assuntos
Anticorpos Antivirais , Betacoronavirus/imunologia , COVID-19/terapia , Resfriado Comum/imunologia , Convalescença , Coronavirus Humano OC43/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/administração & dosagem , Anticorpos Antivirais/imunologia , COVID-19/imunologia , COVID-19/mortalidade , Reações Cruzadas , Feminino , Humanos , Imunização Passiva , Masculino , Pessoa de Meia-Idade
5.
J Clin Oncol ; 39(24): 2710-2719, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-33929874

RESUMO

PURPOSE: BK virus-associated hemorrhagic cystitis (BKV-HC) is a common complication of allogenic hematopoietic stem cell transplantation (AHSCT), particularly in recipients of alternative donor transplants, which are being performed in increasing numbers. BKV-HC typically results in painful hematuria, urinary obstruction, and renal dysfunction, without a definitive therapeutic option. METHODS: We performed a clinical trial (ClinicalTrials.gov identifier: NCT02479698) to assess the feasibility, safety, and efficacy of administering most closely HLA-matched third-party BKV-specific cytotoxic T lymphocytes (CTLs), generated from 26 healthy donors and banked for off-the-shelf use. The cells were infused into 59 patients who developed BKV-HC following AHSCT. Comprehensive clinical assessments and correlative studies were performed. RESULTS: Response to BKV-CTL infusion was rapid; the day 14 overall response rate was 67.7% (40 of 59 evaluable patients), which increased to 81.6% among evaluable patients at day 45 (40 of 49 evaluable patients). No patient lost a previously achieved response. There were no cases of de novo grade 3 or 4 graft-versus-host disease, graft failure, or infusion-related toxicities. BKV-CTLs were identified in patient blood samples up to 3 months postinfusion and their in vivo expansion predicted for clinical response. A matched-pair analysis revealed that, compared with standard of care, after accounting for prognostic covariate effects, treatment with BKV-CTLs resulted in higher probabilities of response at all follow-up timepoints as well as significantly lower transfusion requirement. CONCLUSION: Off-the-shelf BKV-CTLs are a safe and effective therapy for the management of patients with BKV-HC after AHSCT.


Assuntos
Cistite/tratamento farmacológico , Transtornos Hemorrágicos/tratamento farmacológico , Linfócitos T Citotóxicos/metabolismo , Alotransplante de Tecidos Compostos Vascularizados/efeitos adversos , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
6.
medRxiv ; 2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33758890

RESUMO

Background: COVID-19 Convalescent plasma (CCP) is safe and effective, particularly if given at an early stage of the disease. Our study aimed to identify an association between survival and specific antibodies found in CCP. Patients and Methods: Patients ≥18 years of age who were hospitalized with moderate to severe COVID-19 infection and received CCP at the MD Anderson Cancer Center between 4/30/2020 and 8/20/2020 were included in the study. We quantified the levels of anti-SARS-CoV-2 antibodies, as well as antibodies against antigens of other coronavirus strains, in the CCP units and compared antibody levels with patient outcomes. For each antibody, a Bayesian exponential survival time regression model including prognostic variables was fit, and the posterior probability of a beneficial effect (PBE) of higher antibody level on survival time was computed. Results: CCP was administered to 44 cancer patients. The median age was 60 years (range 37-84) and 19 (43%) were female. Twelve patients (27%) died of COVID-19-related complications. Higher levels of two non-SARS-CoV-2-specific antibodies, anti-HCoV-OC43 spike IgG and anti-HCoV-HKU1 spike IgG, had PBE = 1.00, and 4 SARS-CoV-2-specific antibodies had PBEs between 0.90 and 0.95. Other factors associated with better survival were shorter time to CCP administration, younger age, and female sex. Conclusions: Common cold coronavirus spike IgG antibodies anti-HCoV-OC43 and anti-HCoV-HKU1 may target a common domain for SARS-CoV-2 and other coronaviruses. They provide a promising therapeutic target for monoclonal antibody production.

7.
Transfus Apher Sci ; 60(3): 103096, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33612449

RESUMO

BACKGROUND: Platelet transfusion refractoriness (PTR) secondary to human leukocyte antigen (HLA) alloimmunization is a challenge in the treatment of hematology-oncologypatients and increases the risk of morbidity and mortality from bleeding events. Guidelines for treating PTR have not been clearly described in literature. We aim to describe the practice patterns for the management of PTR secondary to HLA alloimmunization, and to assess the mortality, thrombosis and bleeding-related clinical outcomes at 30 days from diagnosis. METHODS: A retrospective review of 51 cases of PTR secondary to HLA alloimmunization were analyzed. RESULTS: The majority of patients (98 %) had a diagnosis of hematological malignancy of which 88.2 % were undergoing active chemotherapy. Clinically relevant bleeding, by ISTH criteria, was observed in 33.3 %; hemorrhagic shock was diagnosed in 7%. The rate of bleeding-related mortality was estimated at 7.8 %. The use of antifibrinolytics and plasma products (including intravenous immunoglobulin) was more common in cases with major versus non-major bleeding. Grade A or B1U HLA matched products were available in less than half of cases. CONCLUSIONS: There is heterogeneity in the management of the bleeding risk and bleeding events during PTR, with antifibrinolytics more commonly used in patients who suffered severe bleeding. Grade A and B1U HLA-matched platelets are not always readily available, and HLA-typing and HLA-antibody testing are not always performed prior to PTR. Prospective randomized control trials may help to determine the safety and efficacy of antifibrinolytics and other supportive measures in the management of PTR.

8.
Artigo em Inglês | MEDLINE | ID: mdl-33625094

RESUMO

While advancements in cellular therapy have improved outcomes for patients with refractory leukemia, severe infections may hinder access. Granulocyte transfusions, in combination with anti-microbial therapy, may be a safe option to facilitate candidacy for chimeric antigen receptor T-cell therapy in patients with leukemia and prolonged immune-compromised status.

9.
bioRxiv ; 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32995792

RESUMO

Adoptive cell therapy with viral-specific T cells has been successfully used to treat life-threatening viral infections, supporting the application of this approach against COVID-19. We expanded SARS-CoV-2 T-cells from the peripheral blood of COVID-19-recovered donors and non-exposed controls using different culture conditions. We observed that the choice of cytokines modulates the expansion, phenotype and hierarchy of antigenic recognition by SARS-CoV-2 T-cells. Culture with IL-2/4/7 but not other cytokine-driven conditions resulted in >1000 fold expansion in SARS-CoV-2 T-cells with a retained phenotype, function and hierarchy of antigenic recognition when compared to baseline (pre-expansion) samples. Expanded CTLs were directed against structural SARS-CoV-2 proteins, including the receptor-binding domain of Spike. SARS-CoV-2 T-cells could not be efficiently expanded from the peripheral blood of non-exposed controls. Since corticosteroids are used for the management of severe COVID-19, we developed an efficient strategy to inactivate the glucocorticoid receptor gene ( NR3C1 ) in SARS-CoV-2 CTLs using CRISPR-Cas9 gene editing.

10.
Transfusion ; 59(11): 3519-3524, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31587288

RESUMO

BACKGROUND: In the past, conventional treatment strategies for transplant-associated thrombotic microangiopathy (TA-TMA) have not proven to be very effective. Recently, eculizumab which is a humanized monoclonal antibody that works as a terminal complement inhibitor has demonstrated promise in the treatment landscape of TA-TMA. METHODS AND MATERIALS: This was a single-center retrospective analysis of 20 consecutive adult patients with TA-TMA: 10 patients who received conventional therapy and 10 patients who received eculizumab-based therapy. These patients had undergone allogeneic HSCT at MD Anderson Cancer Center between August 2011 and September 2016. RESULTS: When comparing the treatment outcomes in the two cohorts, none of the patients in the conventional therapy group obtained a hematologic or complete response according to our response criteria whereas seven patients in the eculizumab group achieved a hematologic response with one patient achieving a complete response with organ recovery. In addition, overall survival at the end of assessment was 60% in the eculizumab cohort and 30% in the conventional cohort. One major difference in practice at our institution versus previously published studies is the management of immunosuppression. In a majority of patients, tacrolimus was continued or transitioned to sirolimus for GVHD prophylaxis. CONCLUSION: Response rates and survival were improved for patients who were transitioned to sirolimus, so a two-pronged approach of inhibiting complement along with providing an alternative effective immunosuppressive agent may be beneficial in the treatment of early onset TA-TMA.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Inativadores do Complemento/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunossupressores/uso terapêutico , Sirolimo/uso terapêutico , Tacrolimo/uso terapêutico , Microangiopatias Trombóticas/tratamento farmacológico , Adolescente , Adulto , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Microangiopatias Trombóticas/etiologia , Microangiopatias Trombóticas/mortalidade , Resultado do Tratamento , Adulto Jovem
11.
Cancer ; 125(18): 3219-3224, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31150121

RESUMO

BACKGROUND: The combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has proven to be the most effective therapy for patients with acute promyelocytic leukemia (APL). The majority of the morbidity and mortality from APL therapy occur during the induction phase. The objective of the current study was to identify the risk factors associated with transfer to the intensive care unit (ICU) and endotracheal intubation during induction therapy in patients with APL. METHODS: The authors analyzed the clinical characteristics of 187 patients with newly diagnosed APL who were treated with ATRA and ATO with or without gemtuzumab ozogamicin. The authors documented the percentage change in body weight from baseline to the maximum recorded weight during induction or to the day of ICU transfer. RESULTS: A total of 18 patients (10%) who initiated therapy with ATRA and ATO on a regular hospital floor required transfer to the ICU after a median of 12 days of induction therapy. The median volume of transfusions was 4350 mL (range, 60-30,750 mL). The volume of transfusions was the main factor associated with the risk of ICU transfer (odds ratio, 4.1; P < .001). Of the 18 patients transferred to the ICU, 10 patients (5%) required intubation. An increase in the total volume of transfusions, increase in weight ≥10% during induction therapy, and a plasma albumin level ≤3.2 g/dL at the time of diagnosis were found to be associated with an increased risk of endotracheal intubation. CONCLUSIONS: Large volumes of blood product transfusions and unrecognized fluid overload during induction are associated with ICU transfer and endotracheal intubation in patients with APL. These can be prevented by limiting the amount of transfusions, careful monitoring for subtle signs of fluid overload, and early intervention with aggressive diuretic therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transfusão de Componentes Sanguíneos/estatística & dados numéricos , Unidades de Terapia Intensiva/estatística & dados numéricos , Intubação Intratraqueal/estatística & dados numéricos , Leucemia Promielocítica Aguda/tratamento farmacológico , Desequilíbrio Hidroeletrolítico/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Trióxido de Arsênio/administração & dosagem , Transfusão de Componentes Sanguíneos/efeitos adversos , Feminino , Gemtuzumab/administração & dosagem , Humanos , Quimioterapia de Indução , Masculino , Pessoa de Meia-Idade , Transferência de Pacientes/estatística & dados numéricos , Estudos Retrospectivos , Fatores de Risco , Albumina Sérica/metabolismo , Tretinoína/administração & dosagem , Desequilíbrio Hidroeletrolítico/etiologia , Adulto Jovem
12.
Am J Hematol ; 93(10): 1245-1253, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30051599

RESUMO

The International Prognostic Scoring System-Revised (IPSS-R) is one standard for myelodysplastic syndrome (MDS) risk stratification. It divides patients into five categories including an intermediate subset (IPSS-R int-risk). Outcomes and clinical interventions for patients with IPSS-R int-risk are not well defined. We performed an analysis of outcomes of this group of patients. Out of 3167 patients, a total of 298 were identified with IPSS-R int-risk MDS and retrospectively analyzed to assess characteristics affecting outcomes. Cox proportional hazard models for overall survival (OS) were performed to identify statistically significant clinical factors that influence survival. Age of 66 years or greater, peripheral blood blasts of 2% or more, and history of red blood cell (RBC) transfusion were significantly associated with inferior survival. Based on these features, MDS patients with IPSS-R int-risk were classified into two prognostic risk groups for analysis, an int-favorable group and an int-adverse group, and had significantly divergent outcomes. Sequential prognostication was validated using two independent datasets comprising over 700 IPSS-R int-risk patients. The difference in median survival between int-favorable and int-adverse patients was 3.7 years in the test cohort, and 1.8 and 2.0 years in the two validation cohorts. These results confirm significantly variable outcomes of patients with IPSS-R int-risk and need for different prognostic systems.


Assuntos
Síndromes Mielodisplásicas/mortalidade , Índice de Gravidade de Doença , Adulto , Fatores Etários , Idoso , Transfusão de Eritrócitos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapia , Células-Tronco Neoplásicas , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Risco , Análise de Sobrevida , Resultado do Tratamento
13.
Eur J Haematol ; 101(3): 389-398, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29920784

RESUMO

OBJECTIVE: To evaluate response rates and survival in adults with transplant-associated thrombotic microangiopathy (TA-TMA) after allogeneic hematopoietic stem cell transplantation (HSCT) who were treated with eculizumab (ECU). METHODS: Patients were identified retrospectively and data collected through HSCT and pharmacy databases. RESULTS: Ten patients with TA-TMA after allogeneic HSCT were treated with ECU between 2013 and 2016. TA-TMA was diagnosed at a median of 93 days post-HSCT. Organ-specific injury was documented in all ten patients at time of TA-TMA diagnosis, the most common being renal dysfunction (90%). Acute GVHD (70%) and active infection (80%) were common at time of diagnosis. The median time to ECU initiation from TA-TMA diagnosis was 4 days. Seven patients received ECU as first-line therapy in combination with other treatment modalities, while three patients were treated with ECU as second-line therapy. ECU was well tolerated with the exception of one case of severe skin rash leading to discontinuation. ECU achieved an overall hematologic response rate of 70% and an overall survival rate of 60%. One patient achieved a complete response with corresponding organ recovery. CONCLUSION: Early initiation of ECU may not alter the disease process enough to restore organ function, but it may prolong survival.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Microangiopatias Trombóticas/tratamento farmacológico , Microangiopatias Trombóticas/etiologia , Adolescente , Adulto , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Microangiopatias Trombóticas/diagnóstico , Condicionamento Pré-Transplante , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
14.
J Thromb Thrombolysis ; 45(3): 377-385, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29417408

RESUMO

Patients with hematological malignancies often have severe thrombocytopenia, which poses problems when making thrombosis management decisions. A retrospective study was conducted to analyze the clinical outcomes associated with different management options in acute leukemic patients with thrombocytopenia (≤ 50 × 109/L) following an acute venous thromboembolic event. A total of 74 patients were divided into three treatment groups: observation only (n = 30); anticoagulation (n = 23); or inferior vena cava placement (n = 21). Multivariate analysis showed that anticoagulant administration was significantly associated with improved overall survival without an increased rate of clinical relevant bleeding events when compared to other thrombosis management modalities. This study notes that dose adjusted-anticoagulant therapy may offer a safe and clinical advantageous strategy for the treatment and secondary prevention of recurrent venous thrombosis in thrombocytopenic patients with hematologic malignancies.


Assuntos
Anticoagulantes/farmacologia , Leucemia/complicações , Trombocitopenia/complicações , Tromboembolia Venosa/prevenção & controle , Doença Aguda , Idoso , Anticoagulantes/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
15.
PLoS One ; 13(1): e0190827, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29346441

RESUMO

BACKGROUND: The use of centrifugation-based approaches for processing donated blood into components is routine in the industrialized world, as disparate storage conditions require the rapid separation of 'whole blood' into distinct red blood cell (RBC), platelet, and plasma products. However, the logistical complications and potential cellular damage associated with centrifugation/apheresis manufacturing of blood products are well documented. The objective of this study was to evaluate a proof-of-concept system for whole blood processing, which does not employ electromechanical parts, is easily portable, and can be operated immediately after donation with minimal human labor. METHODS AND FINDINGS: In a split-unit study (n = 6), full (~500mL) units of freshly-donated whole blood were divided, with one half processed by conventional centrifugation techniques and the other with the new blood separation system. Each of these processes took 2-3 hours to complete and were performed in parallel. Blood products generated by the two approaches were compared using an extensive panel of cellular and plasma quality metrics. Comparison of nearly all RBC parameters showed no significant differences between the two approaches, although the portable system generated RBC units with a slight but statistically significant improvement in 2,3-diphosphoglyceric acid concentration (p < 0.05). More notably, several markers of platelet damage were significantly and meaningfully higher in products generated with conventional centrifugation: the increase in platelet activation (assessed via P-selectin expression in platelets before and after blood processing) was nearly 4-fold higher for platelet units produced via centrifugation, and the release of pro-inflammatory mediators (soluble CD40-ligand, thromboxane B2) was significantly higher for centrifuged platelets as well (p < 0.01). CONCLUSION: This study demonstrated that a simple, passive system for separating donated blood into components may be a viable alternative to centrifugation-particularly for applications in remote or resource-limited settings, or for patients requiring highly functional platelet product.


Assuntos
Doadores de Sangue , Sangue , Manejo de Espécimes , Centrifugação , Humanos
16.
Platelets ; 28(1): 99-102, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27534811

RESUMO

Cyclooxygenase (COX) is the rate-limiting enzyme in conversion of arachidonic acid to prostanoids, and has two isoforms, COX1 and COX2, which share ~65% amino acid homology. COX1 is universally expressed in many cell types including platelets; however, expression of COX2 is known to be more limited. We examined expression of COX2 mRNA and protein in platelets and platelet-derived microparticles (MPs); using quantitative RT-PCR, immunostaining, and Western blotting. We have detected a significant amount of COX2 in platelets, both at mRNA and protein levels. We found that COX1/COX2 mRNA and protein ratios in platelets were 370:1 and 17:1, respectively. Expression level of COX2 in platelets was less than COX1, but comparable to the expression of COX2 in malignant epithelial cells. Considering the important role of COX2 in tumorigenesis and thrombosis, and the large number of circulating platelets, we propose that platelet COX2 may play an important role in physiologic and pathologic conditions.


Assuntos
Plaquetas/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Expressão Gênica , Micropartículas Derivadas de Células/metabolismo , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 1/metabolismo , Humanos , Imuno-Histoquímica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
17.
BBA Clin ; 6: 76-81, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27453821

RESUMO

BACKGROUND: Ovarian cancer patients have a high risk of developing venous thrombosis. The membrane lipid bilayer of platelets and platelet-derived microparticles (PMP) provides a platform for assembly of coagulation proteins and generation of blood clots. METHODS: We compared the lipid composition of platelets and PMPs in patients with ovarian cancer to those in healthy subjects. We used shotgun lipidomics to quantify 12 classes and 177 species of lipids. RESULTS: We found a significant change in 2 classes of lipids in platelets and PMPs isolated from ovarian cancer patients: higher phosphatidylinositol and lower lyso-phosphatidylcholine. The level of 28 species of lipids was also significantly altered in the direction of an increase in the pro-coagulant and a reduction in the anticoagulant lipids. We found that cancer platelets expressed less lipid phosphate phosphatase 1 (LPP1), a key enzyme in phospholipid biosynthesis pathways, than normal platelets. The reduction in LPP1 might contribute to the changes in the lipid profile of cancer platelets. CONCLUSION: Our results support a procoagulant lipid profile of platelets in ovarian cancer patients that can play a role in the increased risk of venous thrombosis in these patients. GENERAL SIGNIFICANCE: As far as we are aware, our study is the first study on platelet lipidomics in ovarian cancer. The importance of our findings for the future studies are: 1) a similar change in lipid profile of platelets and PMP may be responsible for hypercoagulability in other cancers, and 2) plasma level of high-risk lipids for venous thrombosis may be useful biomarkers.

18.
Biol Blood Marrow Transplant ; 22(5): 961-5, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26921820

RESUMO

In major ABO-mismatched allogeneic hematopoietic stem cell transplantation (HSCT) persistence of antidonor isohemagglutinins leads to pure red cell aplasia (PRCA). To investigate severe pancytopenia noted in a previous study of PRCA, we analyzed all major ABO-mismatched HSCT between January 2003 and December 2012. Of 83 PRCA patients, 13 (16%) had severe pancytopenia. Severe pancytopenia was defined as an absolute neutrophil count (ANC) < 1.5 K/µL or requiring granulocyte colony-stimulating factor, platelets < 50 K/µL or transfusion dependent, and PRCA with RBC transfusion dependence at post-transplant day 90. In 6 patients (46%) severe pancytopenia resolved after PRCA resolution. Two patients (15%) received a second transplant because of persistent pancytopenia/secondary graft failure, 1 (8%) died from secondary graft failure despite a stem cell boost, 1 (8%) did not recover his platelet counts despite RBC/ANC recovery, and 3 patients (23%) died from disease relapse. We found that severe pancytopenia is frequently associated with PRCA in 16% of major ABO-incompatible HSCT with a higher incidence in males and pancytopenia resolved with resolution of PRCA in 46% of patients.


Assuntos
Sistema ABO de Grupos Sanguíneos , Transplante de Células-Tronco Hematopoéticas , Pancitopenia , Aplasia Pura de Série Vermelha , Índice de Gravidade de Doença , Adulto , Idoso , Aloenxertos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pancitopenia/sangue , Pancitopenia/etiologia , Pancitopenia/mortalidade , Aplasia Pura de Série Vermelha/sangue , Aplasia Pura de Série Vermelha/mortalidade , Aplasia Pura de Série Vermelha/terapia , Estudos Retrospectivos , Fatores de Tempo
19.
Biol Blood Marrow Transplant ; 21(8): 1392-8, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25985919

RESUMO

Detection of donor-specific anti-HLA antibodies (DSA) has been associated with graft rejection in all forms of transplantation. The mechanism by which DSA increase the risk of graft failure remains unclear. We hypothesized that complement-binding DSA are associated with engraftment failure in hematopoietic stem cell transplantation (HSCT) and analyzed 122 haploidentical transplant recipients tested prospectively for DSA. Retrospective analysis to detect C1q binding DSA (C1q+DSA) was performed on 22 allosensitized recipients. Twenty-two of 122 patients (18%) had DSA, 19 of which were women (86%). Seven patients with DSA (32%) rejected the graft. Median DSA level at transplant for patients who failed to engraft was 10,055 mean fluorescence intensity (MFI) versus 2065 MFI for those who engrafted (P = .007). Nine patients with DSA were C1q positive in the initial samples with median DSA levels of 15,279 MFI (range, 1554 to 28,615), compared with 7 C1q-negative patients with median DSA levels of 2471 MFI (range, 665 to 12,254) (P = .016). Of 9 patients who were C1q positive in the initial samples, 5 patients remained C1q positive at time of transplant (all with high DSA levels [median, 15,279; range, 6487 to 22,944]) and experienced engraftment failure, whereas 4 patients became C1q negative pretransplant and all engrafted the donor cells (P = .008). In conclusion, patients with high DSA levels (>5000 MFI) and complement-binding DSA antibodies (C1q positive) appear to be at much higher risk of primary graft failure. The presence of C1q+DSA should be assessed in allosensitized patients before HSCT. Reduction of C1q+DSA levels might prevent engraftment failure in HSCT.


Assuntos
Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Teste de Histocompatibilidade/métodos , Isoanticorpos/sangue , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
20.
Am J Clin Pathol ; 142(4): 524-32, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25239420

RESUMO

OBJECTIVES: To differentiate the leprosy agents Mycobacterium leprae and Mycobacterium lepromatosis and correlate them with geographic distribution and clinicopathologic features. METHODS: Species-specific polymerase chain reactions were used to detect each bacillus in archived skin biopsy specimens from patients with leprosy from Brazil (n = 52), Malaysia (n = 31), Myanmar (n = 9), and Uganda (n = 4). Findings were correlated with clinical and pathologic data. RESULTS: Etiologic species was detected in 46 of the 52 Brazilian patients, including 36 patients with M leprae, seven with M lepromatosis, and three with both bacilli. The seven patients with sole M lepromatosis all had tuberculoid leprosy, whereas only nine of the 36 patients infected with M leprae exhibited this type, and the rest were lepromatous (P < .001). All patients with dual infections had lepromatous leprosy. Of the nine patients from Myanmar, six were test positive: four with M leprae and two with M lepromatosis. Of the Malaysian and Ugandan patients, only M leprae was detected in 27 of the 31 Malaysians and two of the four Ugandans. CONCLUSIONS: The leprosy agents vary in geographic distribution. Finding M lepromatosis in Brazil and Myanmar suggests wide existence of this newly discovered species. The leprosy manifestations likely vary with the etiologic agents.


Assuntos
Hanseníase Virchowiana/microbiologia , Hanseníase Tuberculoide/microbiologia , Hanseníase/microbiologia , Mycobacterium leprae/isolamento & purificação , Mycobacterium/isolamento & purificação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil , Criança , Pré-Escolar , Coinfecção , Diagnóstico Diferencial , Feminino , Humanos , Malásia , Masculino , Pessoa de Meia-Idade , Mianmar , Especificidade da Espécie , Uganda , Adulto Jovem
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