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Biomedical subjects

Neil Blumberg

Publications and source records attributed to Neil Blumberg.

18 recordsLinked to original sources
PubMed2006

The platelet as a therapeutic target for treating vascular diseases and the role of eicosanoid and synthetic PPARgamma ligands.

The platelet was traditionally thought only to serve as the instigator of thrombus formation, but now is emerging as a pivotal player in cardiovascular disease and diabetes by inciting and maintaining inflammation. Upon activation, platelets synthesize eicosanoids such as thromboxane A2 (TXA2) and PGE2 and release pro-inflammatory mediators including CD40 ligand (CD40L). These mediators activate not only platelets, but also stimulate vascular endothelial cells and leukocytes. These autocrine and paracrine activation processes make platelets an important target for attenuating inflammation. The growing interest and recent discoveries in platelet biology has lead to the search for therapeutic platelet targets. Recently, platelets, although anucleate, were discovered to possess the transcription factor PPARgamma. Treatment with eicosanoid and synthetic PPARgamma ligands blunts platelet release of the bioactive mediators, soluble (s) CD40L and TXA2, in thrombin-activated platelets. PPARgamma ligand treatment may prove useful for dampening unwanted platelet activation and chronic inflammatory diseases such as cardiovascular disease.

Blood Platelets↗
PubMed2006

Soluble CD40 ligand accumulates in stored blood components, primes neutrophils through CD40, and is a potential cofactor in the development of transfusion-related acute lung injury.

Transfusion-related acute lung injury (TRALI) is a form of posttransfusion acute pulmonary insufficiency that has been linked to the infusion of biologic response modifiers (BRMs), including antileukocyte antibodies and lipids. Soluble CD40 ligand (sCD40L) is a platelet-derived proinflammatory mediator that accumulates during platelet storage. We hypothesized that human polymorpho-nuclear leukocytes (PMNs) express CD40, CD40 ligation rapidly primes PMNs, and sCD40L induces PMN-mediated cytotoxicity of human pulmonary microvascular endothelial cells (HMVECs). Levels of sCD40L were measured in blood components and in platelet concentrates (PCs) implicated in TRALI or control PCs that did not elicit a transfusion reaction. All blood components contained higher levels of sCD40L than fresh plasma, with apheresis PCs evidencing the highest concentration of sCD40L followed by PCs from whole blood, whole blood, and packed red blood cells (PRBCs). PCs implicated in TRALI reactions contained significantly higher sCD40L levels than control PCs. PMNs express functional CD40 on the plasma membrane, and recombinant sCD40L (10 ng/mL-1 mug/mL) rapidly (5 minutes) primed the PMN oxidase. Soluble CD40L promoted PMN-mediated cytotoxicity of HMVECs as the second event in a 2-event in vitro model of TRALI. We concluded that sCD40L, which accumulates during blood component storage, has the capacity to activate adherent PMNs, causing endothelial damage and possibly TRALI in predisposed patients.

CD40 Antigens↗
PubMed2006

Allogeneic blood transfusions explain increased mortality in women after coronary artery bypass graft surgery.

BACKGROUND: Postoperative mortality is greater in women than men after coronary artery bypass graft surgery. Because allogeneic blood transfusions are more common in women and have been associated with immunomodulation, the impact of transfusion on sex differences in infection and mortality was examined. METHODS: A cohort study was conducted using Michigan Medicare beneficiaries who had undergone coronary artery bypass graft surgery. Information was used regarding allogeneic blood transfusion, infection, and mortality within the 100-day period after surgery. RESULTS: Blood transfusions were more common in women than in men (88.2%, 95% CI 87.1%-89.2% vs 66.7%, 95% CI 65.5%-67.9%). Patients who received transfused blood were more likely to have an infection than patients who did not (14.6%, 95% CI 13.8%-15.5% vs 4.9%, 95% CI 4.1%-5.9%). There was a dose-response relationship between the number of units of whole blood or packed red cells received and the prevalence of infection (P = .035). The unadjusted risk of mortality attributable to female sex was 13.9% (95% CI 8.1%-19.6%), but was no longer statistically significant when adjusted for blood transfusion (population attributable risk 0.6%, 95% CI -6.0% to 6.6%). Patients who received a transfusion were 5.6 times as likely to die within 100 days after surgery as those who did not receive a transfusion (95% CI 3.7-8.6). CONCLUSION: The increased risk of mortality in women after bypass surgery may be explained by transfusion-related immunosuppression.

Blood Transfusion↗
PubMed2006

An association of soluble CD40 ligand (CD154) with adverse reactions to platelet transfusions.

BACKGROUND: Removal of stored supernatant abrogates most transfusion reactions to leukoreduced platelets (PLTs), suggesting that PLT-derived soluble mediators are involved. PLTs are the primary source of soluble CD40 ligand (sCD40L). Engagement of the receptor for CD40L induces synthesis of proinflammatory mediators including interleukin (IL)-6, IL-8, and monocyte chemotactic protein-1 (MCP-1). STUDY DESIGN AND METHODS: Supernatants from poststorage leukoreduced PLT concentrates were assayed for white cell- (IL-6, IL-8, MCP-1) and PLT-derived (sCD40L, RANTES) inflammatory mediators. These levels were correlated with clinical outcomes. RESULTS: Of 534 transfusions, there were 12 reported (2.2%) and 2 unreported reactions (0.4%)--10 febrile and 4 allergic. Transfusions with reactions had significantly higher levels of IL-6 (2.3-fold higher; p = 0.005), IL-8 (2.2-fold higher; p = 0.001), MCP-1 (2.6-fold higher; p = 0.002), and sCD40L (1.24-fold higher; p = 0.015), but not RANTES. (1.14-fold higher; p = 0.22). The vast majority (>93%) of patients transfused with mediator levels in the highest quintile had no reactions. When levels of all five mediators were summed, the reaction rates in the first through fifth quintiles increased from 1 to 7 percent (p = 0.027). All but one reaction occurred in patients with hematologic malignancies (13 reactions/380 transfusions; 3.4%; p = 0.04 vs. other diagnoses). CONCLUSIONS: These are the first data demonstrating that a PLT-derived mediator, sCD40L, is associated with adverse transfusion events. Existing clinical factors, for example, inflammation or leukopenia, may influence whether infused mediators cause reactions.

Adult↗
PubMed2006

Platelets as a novel target for PPARgamma ligands : implications for inflammation, diabetes, and cardiovascular disease.

Peroxisome proliferator-activated receptor gamma (PPARgamma) is an important transcription factor for lipid and glucose metabolism. Currently, the PPARgamma ligands rosiglitazone and pioglitazone are used for the treatment of type 2 diabetes mellitus because they are potent insulin sensitizers. Recently, PPARgamma has emerged as an important anti-inflammatory factor. Platelets, anucleate cells involved in hemostasis, have also been implicated as key contributors to inflammation, because they produce many pro-inflammatory and pro-atherogenic mediators when activated. Surprisingly, it was discovered recently that platelets contain PPARgamma and that PPARgamma ligands, both natural and synthetic, inhibit platelet activation and release of bioactive mediators. In particular, release of soluble CD40 ligand (sCD40L) and thromboxane (TXA(2)) was inhibited by PPARgamma ligands in thrombin-activated platelets. CD40L signaling induces pro-inflammatory processes in many cell types, and increased blood levels of sCD40L are closely associated with inflammation, diabetes, and cardiovascular disease. Targeting platelet PPARgamma will, therefore, be an important treatment strategy for the attenuation of chronic inflammatory processes and prevention of thrombus formation.

Animals↗
PubMed2005

Decreased sepsis related to indwelling venous access devices coincident with implementation of universal leukoreduction of blood transfusions.

BACKGROUND: Randomized trials and animal models demonstrate that leukoreduction of transfusions can reduce the risk of post-operative infections. We performed a retrospective study of sepsis related to indwelling venous access devices (line related infections) before and after the July 2000 implementation of universal leukoreduction. METHODS: Line related infection data were collected from hospital infection control records for an 18-month period before and after July 2000. Transfusion histories were obtained from transfusion service records. RESULTS: Line related infections decreased in number from 150 to 98 (-35%) in transfused patients after implementation of universal leukoreduction, whereas line related infections increased from 41 to 45 (+10%) in nontransfused patients (p = 0.04). This corresponded to a decrease from 5.3 to 3.3 infections/10,000 patient days in transfused patients (p = 0.002). The infection rate remained stable in nontransfused patients at 1.5 infections/10,000 patient days both pre- and postimplementation of universal leukoreduction. Quantitatively similar decreases (33-45%) were seen in transfused surgical, medical and pediatric patients. CONCLUSIONS: A substantial and statistically significant decrease in line related infections occurred coincident with implementation of universal leukoreduction. These improved outcomes were observed in transfused but not nontransfused patients, across all clinical services, suggesting a causal relationship with universal leukoreduction.

Adolescent↗
PubMed2004

A randomized trial of washed red blood cell and platelet transfusions in adult acute leukemia [ISRCTN76536440].

BACKGROUND: Platelet transfusion is universally employed in acute leukemia. Platelet concentrate supernatants contain high concentrations of biologic mediators that might impair immunity. We investigated whether washed platelet and red cell transfusions could improve clinical outcomes in adult patients with acute leukemia. METHODS: A pilot randomized trial of washed, leukoreduced ABO identical transfusions versus leukoreduced ABO identical transfusions was conducted in 43 adult patients with acute myeloid or lymphoid leukemia during 1991-94. Primary endpoints to be evaluated were platelet transfusion refractoriness, infectious and bleeding complications and overall survival. RESULTS: There were no significant differences in infectious or major bleeding complications and only one patient required HLA matched platelet transfusions. Minor bleeding was more frequent in the washed, leukoreduced arm of the study. Confirmed transfusion reactions were more frequent in the leukoreduced arm of the study. Overall survival was superior in the washed arm of the study (40% versus 22% at 5 years), but this difference was not statistically significant (p = 0.36). A planned subset analysis of those </=50 years of age found that those in the washed, leukoreduced arm (n = 12) had a 75% survival at five years compared with 30% in the leukoreduced arm (n = 10) (p = 0.037) CONCLUSION: This study provides the first evidence concerning the safety and efficacy of washed platelets, and also raises the possibility of improved survival. We speculate that transfusion of stored red cell and platelet supernatant may compromise treatment, particularly in younger patients with curable disease. Larger trials will be needed to assess this hypothesis.

Journal Article↗
PubMed2004

Human bone marrow megakaryocytes and platelets express PPARgamma, and PPARgamma agonists blunt platelet release of CD40 ligand and thromboxanes.

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-activated transcription factor important in lipid metabolism, diabetes, and inflammation. We evaluated whether human platelets and megakaryocytes express PPARgamma and whether PPARgamma agonists influence platelet release of bioactive mediators. Although PPARgamma is mainly considered a nuclear receptor, we show that enucleate platelets highly express PPARgamma protein as shown by Western blotting, flow cytometry, and immunocytochemistry. Meg-01 megakaryocyte cells and human bone marrow megakaryocytes also express PPARgamma. Platelet and Meg-01 PPARgamma bound the PPARgamma DNA consensus sequence, and this was enhanced by PPARgamma agonists. Platelets are essential not only for clotting, but have an emerging role in inflammation in part due to their release or production of the proinflammatory and proatherogenic mediators CD40 ligand (CD40L) and thromboxanes (TXs). Platelet incubation with a natural PPARgamma agonist, 15d-PGJ(2), or with a potent synthetic PPARgamma ligand, rosiglitazone, prevented thrombin-induced CD40L surface expression and release of CD40L and thromboxane B(2) (TXB(2)). 15d-PGJ(2) also inhibited platelet aggregation and adenosine triphosphate (ATP) release. Our results show that human platelets express PPARgamma and that PPARgamma agonists such as the thiazolidinedione class of antidiabetic drugs have a new target cell, the platelet. This may represent a novel mechanism for treatment of inflammation, thrombosis, and vascular disease in high-risk patients.

Adenosine Triphosphate↗
PubMed2004

Optimizing platelet transfusion therapy.

Platelet transfusions are widely used. Prophylactic transfusions are employed in severely thrombocytopenic patients without evidence of bleeding, but no randomized trial data prove the safety or efficacy of this approach. Randomized trials have demonstrated the equivalence of transfusion triggers of 10,000 and 20,000/microl for prophylactic transfusions. The former threshold is potentially safer for the patient, conservative of donor resources and leads to lower costs, with perhaps a slightly greater risk of minor hemorrhage. Randomized trials have demonstrated the equivalence of pheresis or whole blood-derived platelet transfusions. The former present a lower risk for infectious agents, and the latter are less expensive and a more efficient use of limited donor resources. Randomized trials prove that leukoreduced and ABO identical platelet transfusions reduce the risks of HLA alloimmunization and platelet transfusion refractoriness (both leukoreduction and ABO matching), transfusion reactions (leukoreduction) and CMV transmission (leukoreduction). Leukoreduction and ABO matching of platelet transfusions also have been associated in preliminary observational studies with reduced morbidity and mortality in surgical patients and reduced infections in patients with leukemia. These results require further investigation. Future challenges include (1) determining the best approach to bacterial contamination of platelets, whether by detection methods or pathogen inactivation and (2) determining the threshold for prophylactic platelet transfusions in thrombocytopenic patients undergoing surgery or invasive procedures.

ABO Blood-Group System↗
PubMed2003

Thy-1 expression in human fibroblast subsets defines myofibroblastic or lipofibroblastic phenotypes.

Fibroblasts represent a dynamic population of cells, exhibiting functional heterogeneity within and among tissues. Fibroblast heterogeneity also results from phenotypic differences and may arise from activation or differentiation processes taking place in the cells. We previously reported that human fibroblasts were heterogeneous with respect to surface Thy-1 expression and that separation into Thy-1(+) and Thy-1(-) subsets resulted in functionally distinct subpopulations, leading to the concept of fibroblast subset specialization. In this report we investigated whether Thy-1(+) and/or Thy-1(-) fibroblasts were capable of differentiating into myofibroblasts or lipofibroblasts. Fibroblast subsets were used from human myometrium and orbit to test this hypothesis. Only Thy-1(+) human myometrial and orbital fibroblasts were capable of myofibroblast differentiation after treatment with TGFbeta or platelet concentrate supernatant, assessed by alpha smooth muscle actin expression. Interestingly, only Thy-1(-), but not Thy-1(+) subsets differentiated to lipofibroblasts, as determined by the accumulation of cytoplasmic lipid droplets after treatment with 15-deoxy-Delta(12, 14)-PGJ(2) or ciglitazone. We propose that fibroblast Thy-1 display pre-determines lineage to a contractile or lipid-like phenotype in the human myometrium and orbit. This additional distinction between Thy-1(+) and Thy-1(-) human fibroblast subtypes has important consequences in normal tissue homeostasis and in pathogenesis of orbital and myometrial diseases characterized by persistent myofibroblasts or fat accumulation, such as occurs in Graves' ophthalmopathy, tissue fibrosis, abnormal wound healing, and scarring.

Actins↗
PubMed2003

ABO incompatibility between donor and recipient and clinical outcomes in allogeneic stem cell transplantation.

We performed a retrospective, cohort study to evaluate the impact on recipient survival of ABO incompatibility between recipient and donor after allogeneic stem cell transplantation, primarily involving marrow-derived cells. No statistically significant difference was noted in survival for 153 patients with acute or chronic leukemia or myelodysplastic syndrome receiving ABO identical or ABO mismatched allografts. Five patients who had allografts that were bidirectionally incompatible (both donor cells and plasma incompatible) did have significantly poorer survival than the other recipients, similar to the experience reported in one other cohort study. However, these patients had other risks for mortality, including being older and receiving transplants from matched, unrelated donors. Our data do not support a significant role for ABO donor-recipient matching in allogeneic stem cell transplantation.

ABO Blood-Group System↗
PubMed2003

WBC reduction of RBC transfusions is associated with a decreased incidence of RBC alloimmunization.

BACKGROUND: Allogeneic transfusion stimulates Th2 (humoral) immunity. A hypothesis was developed that WBC reduction, by reducing the Th2 stimulus associated with transfusions, might reduce RBC alloimmunization. STUDY DESIGN AND METHODS: The first retrospective cohort study involved determining the prevalence of newly detected alloimmunization in transfused patients with acute myeloid leukemia (AML) in our hospital in the period before WBC reduction and after its introduction for this particular group of patients. The second study involved determining the incidence of newly detected RBC alloimmunization in all transfused hospital patients during three annual periods with WBC-reduction prevalences ranging from 0 to 100 percent. RESULTS: The alloimmunization prevalence rate in AML patients was 8.2 percent in those receiving non-WBC-reduced RBCs and platelets (n=195) and 2.8 percent in those receiving only WBC-reduced components (n=215) (p=0.016). In all patients, the alloimmunization incidence rate decreased from 3.47 per 1000 antibody screens in 1987 (no WBC reduction) to 2.97 per 1000 in 1999 (40% of transfusions WBC-reduced) to 2.38 per 1000 in 2001 (100% of transfusions WBC-reduced) (p=0.0298). A decrease in alloimmunization was observed in both males and females, with the decrease more clearly evident in males. CONCLUSION: These preliminary data support the hypothesis that WBC reduction may be associated with a reduced frequency of RBC alloimmunization. These findings require confirmation and further investigation.

Blood Component Removal↗
PubMed2002

Leukocyte-reduced transfusions in cardiac surgery results of an implementation trial.

An implementation trial of leukocyte-reduced transfusions in cardiac surgery (primary coronary artery bypass graft and valve replacement) was performed from July to December 1998; comparisons were made with data from the same period in 1997. Patients from both periods were similar in important preoperative and intraoperative variables (age, sex, weight, number of units of RBCs transfused, ejection fraction). The mean total number of complications was statistically significantly decreasedfrom 0.26 complications per patient in the non-leukocyte-reduced to 0.19 in the leukocyte-reduced recipients. Overall, the mean +/- ISD costs of care per patient decreasedfrom 1997 ($27,615 +/- $33,973) to 1998 ($27,038 +/- $24,107). Mean costs decreased $1,700 per patient for recipients of leukocyte-reduced blood in 1998 compared with recipients of non-leukocyte-reduced blood in 1997 Mean costs increased $4,000 per patient in patients who did not receive transfusions in 1998 compared with 1997. Hospitalization costs decreased when leukocyte-reduced transfusions were implemented for patients undergoing cardiac surgery in our institution. Implementation of leukocyte reduction may be cost neutral or cost saving in at least some settings.

Adjuvants, Immunologic↗