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Biomedical subjects

M A Blajchman

Publications and source records attributed to M A Blajchman.

At least 19 recordsLinked to original sources
PubMed2006

The clinical benefits of the leukoreduction of blood products.

Many adverse events associated with the transfusion of allogeneic blood products have been shown to be related to the presence of allogeneic leukocytes in the blood product transfused. Until recently little attention has been paid to the leukocytes present in various blood components, however, over the past two decades it has been shown that the removal of such "passenger" leukocytes is associated with improved clinical outcomes. These include: the reduction in the incidence and severity of febrile transfusion reactions; reducing the CMV transfusion transmission risk; reducing the risk of alloimmune platelet refractoriness; the possible avoidance of vCJD transmission; as well as reducing the risk of mortality and organ dysfunction in cardiac surgery patients, and possibly in other categories of patients.

Animals↗
PubMed2005

Interspecies exchange mutagenesis of the first epidermal growth factor-like domain of human factor VII.

The first epidermal growth factor-like (EGF1) domain of human factor VII (FVII) is essential for binding to tissue factor (TF). We hypothesized that the previously observed increased coagulant activity of rabbit plasma (i.e. FVII) with human TF might be explained by the five non-conserved amino acids in the rabbit vs. the human FVII EGF1 domain. Accordingly, we 'rabbitized' the human FVII EGF1 domain either by exchanging the entire EGF1 domain creating human FVII(rabEGF1) or by the single amino acid substitutions S53N, K62E, P74A, A75D and T83K. After transient expression in HEK293 cells, the recombinant FVII (rFVII) mutant proteins were analyzed for biological activity and binding affinity to human TF by competitive enzyme-linked immunosorbent assay (ELISA). Biological activity of the unpurified rFVII mutant proteins was either depressed or statistically unchanged vs. rFVII(WT). However, three of six rFVII mutant proteins had increased affinity for human TF in the rank order rFVII(rabEGF1) (3.3-fold) > rFVII(K62E) (2.9-fold) > rFVII(A75D) (1.7-fold). The mutant protein rFVII(K62E) was then permanently expressed and purified. Fully activated, purified rFVIIa(K62E) had a twofold greater clotting activity and 2.8-fold greater direct FVIIa amidolytic activity when compared with rFVIIa(WT). Quantitation of the affinity of TF binding by surface plasmon resonance indicated that the KD of purified rFVII(K62E) for human soluble TF (sTF) was 1.5 nM compared with 7.5 nM for rFVII(WT), i.e. fivefold greater affinity. We conclude that substitution of selected amino acid residues of the FVII EGF1 domain facilitated the creation of human rFVII chimeric proteins with both enhanced biological activity and increased affinity for TF.

Amino Acid Substitution↗
PubMed2005

Transfusion immunomodulation or TRIM: what does it mean clinically?

Evidence from a variety of sources indicate that allogeneic blood transfusions can induce clinically significant immunosuppression, as well as other effects, in recipients. This clinical syndrome is generally referred to in the Transfusion Medicine literature as transfusion-associated immunomodulation, or TRIM. TRIM has been linked to an improved clinical outcome in the setting of renal allograft transplantation. Possible deleterious TRIM-associated effects include an increased rate of cancer recurrence and of post-operative bacterial infection. The recognition that TRIM can increase morbidity and mortality in allogeneically transfused individuals has become a major concern for those involved in Transfusion Medicine. However, based on available randomized controlled trials, whether TRIM predisposes recipients to increased risk for cancer recurrence and/or bacterial infection is still unproven. In contrast, data from experimental animal studies suggest that TRIM is an immunologically mediated biological effect, associated with the transfusion of allogeneic leukocytes; an effect, which can be completely ameliorated by the pre-storage leukoreduction of blood products. Relevantly, several (n = 5) recent large observational trials have provided important evidence for the existence of deleterious TRIM and related effects (mortality and organ dysfunction) of leukocyte-containing allogeneic cellular blood products. These latter data suggest that allogeneic blood product transfusions, containing leukocytes, are associated with an increased risk both for mortality, and organ dysfunction in recipients.

Animals↗
PubMed2005

Assessing the effectiveness of whole blood-derived platelets stored as a pool: a randomized block noninferiority trial.

BACKGROUND: Prestorage pooling of whole blood-derived platelets (PLTs) would simplify bacterial detection. This study evaluated the in vivo effect of the prestorage pooling of PLTs stored for up to 5 days, by assessing the corrected count increment (CCI) 18 to 24 hours after transfusion of the product. STUDY DESIGN AND METHODS: A randomized block noninferiority design was used. Eligible patients had chemotherapy-induced thrombocytopenia and were considered likely to need at least six PLT transfusions. For every block of two transfusion events, one consisted of PLTs stored individually and then pooled before transfusion, and the other was a product pooled before storage. The primary outcome was categorized as a successful (>4.5) or unsuccessful (<or=4.5) 18- to 24-hour posttransfusion CCI analyzed with a matched pair score test. A mixed-effect linear model estimated the mean difference in CCI between the two types of storage. RESULTS: Twenty-three eligible patients received a total of 189 PLT transfusions. The median number of PLT transfusions was 7 (range, 0-27). Eighty-five complete transfusion pairs were used in the primary analysis. The proportions of transfusions leading to a CCI of greater than 4.5 was identical for both routine and PLTs pooled before storage (45/85=52.9%; relative risk, 1.00; lower limit of the one-sided 95% confidence interval [CI], 0.83). The estimate of the mean difference in CCI between pooled and routine storage (pooled-routine) was -0.45 (95% CI, -2.23 to 1.33; p=0.63). CONCLUSION: These results provide evidence that storage of PLTs as a pool for up to 5 days results in posttransfusion CCIs that are not inferior to PLTs stored individually.

Adult↗
PubMed2005

In vitro evaluation of prestorage pooled leukoreduced whole blood-derived platelets stored for up to 7 days.

BACKGROUND: Advantages to storing whole blood-derived platelets (PLTs) as a pool for 7 days would include operational efficiencies and facilitation of bacterial testing and pathogen inactivation. The in vitro quality of pre-storage pooled PLTs stored for up to 7 days was assessed. STUDY DESIGN AND METHODS: Leukoreduced PLTs were pooled before storage (5 units/pool) and stored for either 5 or 7 days. Samples were collected at the time of pooling and either on Day 5 (n=16-29) or on Day 7 (n=4-30) and tested for biochemical and activation markers and morphology and/or shape change. Control PLTs were stored individually for 5 or 7 days and then tested as indicated above. RESULTS: The mean PLT counts (x10(9)/L) were similar: control PLTs, 1344 (464 SD); and prestorage pooled PLTs, 1327 (220 SD; p=0.93). On Day 5, the pH value was significantly lower (p<or=0.0001) for the prestorage pooled PLTs. Lactate and partial pressure of O2 (pO2) were significantly higher (p<or=0.003). On Day 7 of storage, significant differences were noted with pH, pCO2, and hypotonic shock all being lower with the prestorage pooled product, whereas pO2, lactate, and morphology scores were higher (p values all <0.03). Although significant differences were found, the magnitude of the difference would not be expected to impact on transfusion outcomes. CONCLUSION: These results suggest that prestorage pooled PLTs can be stored for up to 7 days; however, studies are needed to ensure that the clinical benefit of PLTs stored as a pool is not inferior to those stored individually.

Biomarkers↗
PubMed2003

Substitutes and alternatives to platelet transfusions in thrombocytopenic patients.

Over the past decade, there have been many improvements in both the safety profile and quality of liquid-stored allogeneic platelet concentrates. However, significant problems with the clinical use of such products remain. Efforts to overcome some of these have resulted in the development of an array of novel therapeutic strategies for the manufacture of platelet products and platelet substitutes, as well as other approaches using alternatives to platelet concentrates. These various products or procedures are at various stages of clinical development. This review summarizes some recent advancements in the preparation of liquid and frozen stored platelets, as well as approaches used for the pathogen inactivation of platelets. Thus, the status of lyophilized platelets, infusible platelet membranes, red blood cells (RBCs) bearing RGD ligands, fibrinogen-coated albumin microcapsules, and liposome-based agents are discussed. Pre-clinical studies and phase 1-3 clinical trials have been encouraging for several of these; however, to date, very few have been licensed for clinical use. Potential alternatives to allogeneic platelet transfusions including correction of anemia by RBC transfusions, recombinant activated factor VII and HLA-reduced platelets are also reviewed. With the ongoing technical and scientific development of such diverse products, those properties that may be necessary for such agents to have hemostatic efficacy will become apparent. However, safety and efficacy must be demonstrable in preclinical studies and clinical trials, before novel platelet concentrates, platelet substitutes and alternatives to platelets can be used in patients with thrombocytopenia.

Blood Platelets↗
PubMed2002

Incidence and significance of the bacterial contamination of blood components.

A septic reaction occurring during or following the transfusion of cellular blood components was one of the earliest recognized complications of allogeneic blood transfusions. The presence of bacteria in blood products has been a problem for many decades and currently it is probably the most common microbiological cause of transfusion-associated morbidity and mortality. Transfusion-associated sepsis due to contaminated platelet concentrates appears to be much more common than those due to red cells. The overall prevalence of contaminated cellular blood products (red cells and platelets) is approximately one in 3000; however, the transfusion to a recipient of a contaminated blood product may not necessarily be associated with clinically evident morbidity. This is because the majority of contaminated blood product units contain only few bacteria. In other instances, contaminated units may contain large numbers of virulent bacteria as well as endotoxins, and their transfusion may be associated with significant morbidity and even be lethal to the recipient. The prevalence of severe episodes of transfusion-associated sepsis has not been clearly established, but is probably of the order of one in 50,000 per platelet unit and one in 500,000 per red cell unit transfused. As a result of the increased recognition that such transfusion-associated episodes can occur, a variety of measures have been proposed to try to prevent and/or control the risk of transfusion-associated septic reactions.

Bacteremia↗
PubMed2001

Bacterial contamination of platelet concentrates: incidence, significance, and prevention.

Severe transfusion reactions associated with bacteria and/or their products, during or following a blood transfusion, were one of the earliest recognized complications of allogeneic blood transfusions. Bacterial contamination of blood products has thus been a problem for many decades and at present is likely the most common microbiological cause of transfusion-associated morbidity and mortality. Transfusion-associated sepsis due to contaminated platelet concentrates appears to be much more common than that due to contaminated red blood cells. The overall incidence of contaminated cellular blood products is approximately 1 in 3,000. However, transfusion to a recipient of a contaminated platelet unit may not necessarily be associated with clinically apparent morbidity, because the majority of contaminated platelet units contain relatively few organisms. In a minority of instances, contaminated units contain large numbers of potentially virulent bacteria, as well as endotoxins, and their transfusion is often associated with significant recipient morbidity and mortality. The incidence of severe septic episodes has not been clearly established, but is probably of the order of 1 per 50,000 platelet units transfused. With heightened awareness in recent years of the possibility that platelet transfusion-associated septic episodes can occur, a variety of measures have been proposed, and in some cases implemented, to try to prevent and control this transfusion risk.

Blood Platelets↗
PubMed2001

Novel platelet products, substitutes and alternatives.

Despite the many advances in the safety, processing, and storage of conventional 22 degrees C liquid-stored allogeneic platelet concentrates, there still are significant drawbacks to the use of such products. Efforts to overcome these shortcomings have resulted in an array of novel platelet products, substitutes, and alternatives; which are currently at various stages of development. This review summarizes the recent developments in the frozen and cold storage of platelets; their pathogen inactivation; as well as the status of lyophilized platelets, infusible platelet membranes (IPMs), red cells bearing arginine-glycine-aspartic acid (RGD) ligands, fibrinogen-coated albumin microcapsules, and liposome-based agents; as potential alternatives to the use of conventional platelet transfusions. Pre-clinical studies have been encouraging for several of these novel products; however, to date, very few have entered human trials. Nonetheless, with the ongoing development of diverse products, those properties that may be necessary for their hemostatic effectiveness will become apparent. However, safety and efficacy must be demonstrated in pre-clinical and phase I to III clinical trials before these novel agents, substitutes and alternatives can be used clinically for patients with thrombocytopenia.

Animals↗
PubMed2001

Red blood cell transfusion strategies.

Although the hemoglobin level of 100 g/L has been used for many years as the allogeneic red blood cell (RBC) transfusion trigger, current evidence indicates that for most patients a more restrictive transfusion strategy is at least as effective as and possibly superior to a liberal transfusion strategy. Moreover, the available data indicate that the use of smaller volumes of allogeneic RBCs may be associated with decreased risk of morbidity and mortality. Thus several recent studies indicate that the use of more restrictive triggers than 100 g/L does not appear to adversely affect patient outcomes. Indeed, the majority of recently published RBC transfusion guidelines recommend a more conservative and cautious approach to allogeneic RBC transfusion practice, primarily to reduce the risk of transfusion-related adverse effects. However, the available transfusion trigger studies do not provide sufficient data to allow the claim that the improved outcomes observed are the sole result of the transfusion strategy used. It is possible that the results are the consequence of effects yet to be defined clearly. Additional studies will be necessary to determine the effects of RBC storage time and the presence of allogeneic leukocytes in allogeneic RBC transfusion practice. Nonetheless, the available data, together with detailed information about alternatives to blood product transfusions, will enable physicians to improve outcomes in transfused patients.

Anemia↗
PubMed2001

Rapid in vivo induction of leukocyte tissue factor mRNA and protein synthesis following low dose endotoxin administration to rabbits.

INTRODUCTION: Disseminated intravascular coagulation in humans is frequently associated with Gram-negative bacterial sepsis. Therefore, to examine the role and time frame of the in vivo induction of tissue factor (TF) by bacterial endotoxin, a reverse transcription polymerase chain reaction and a solid-phase ELISA assay were developed to monitor the in vivo production in rabbits, of TF mRNA and TF antigen by peripheral blood leukocytes (PBL). METHODS: : Healthy rabbits were injected intravenously with either 1, 10 or 50 microg/kg of Salmonella endotoxin. Blood samples were obtained both before endotoxin administration and at various time points thereafter, up to 24 h. Some experiments were also done to determine whether all-trans retinoic acid would ameliorate the signs of the endotoxin-induced disseminated intravascular coagulation. RESULTS: PBL counts dropped significantly within 2 h of rabbits receiving the endotoxin, recovering to baseline levels by 24 h. Platelet counts decreased gradually over this same time frame. Fibrin deposition was noted in renal glomerular capillaries at 24 h. An increase (P<0.001) in PBL-associated TF mRNA levels was observed 2 h post-endotoxin (10 microg/kg, n = 8), followed by a gradual decline over the subsequent 24 h. The average increase in TF mRNA at 2 h was approximately 4.6-fold (P<0.001) over that seen at time 0. The amount of mononuclear cell associated TF antigen demonstrated a peak at 2 h post-endotoxin (10 microg/kg, n = 13), with levels approximately 9.6-fold greater than (P<0.001) baseline. Pre-treatment of rabbits with all-trans retinoic acid significantly (P<0.001) ameliorated the PBL-associated increase in TF mRNA and TF antigen levels. CONCLUSION: These results suggest that low dose endotoxin (10 microg/kg) faithfully reproduces the non-overt activation of coagulation observed in primates and human volunteers, supporting the hypothesis that TF expression is involved in the in vivo initiation and propagation of disseminated intravascular coagulation. Moreover, all-trans retinoic acid may be effective in modulating in vivo the TF transcription induced by endotoxin.

Animals↗