Fewer severe infections with tranexamic acid in patients with hematologic malignancies.

Background: Tranexamic acid (TXA) is an antifibrinolytic agent that reduces bleeding in a multitude of clinical settings from postpartum hemorrhage to trauma. TXA may have clinical effects unrelated to bleeding; plasminogen, the target of TXA, alters immune responses, and TXA appears to decrease the risk of infection in patients undergoing cardiac surgery, as well as joint arthroplasty.

Objectives: To address whether TXA alters rates of infection and inflammatory outcomes in patients with hematologic malignancies.

COVID-19 convalescent plasma boosts early antibody titer and does not influence the adaptive immune response.

Multiple randomized, controlled clinical trials have yielded discordant results regarding the efficacy of convalescent plasma in outpatients, with some showing an approximately 2-fold reduction in risk and others showing no effect. We quantified binding and neutralizing antibody levels in 492 of the 511 participants from the Clinical Trial of COVID-19 Convalescent Plasma in Outpatients (C3PO) of a single unit of COVID-19 convalescent plasma (CCP) versus saline infusion. In a subset of 70 participants, peripheral blood mononuclear cells were obtained to define the evolution of B and T cell responses through day 30.

Absence of hyperfibrinolysis may explain lack of efficacy of tranexamic acid in hypoproliferative thrombocytopenia.

The American Trial Using Tranexamic Acid (TXA) in Thrombocytopenia (A-TREAT, NCT02578901) demonstrated no superiority of TXA over placebo in preventing World Health Organization (WHO) grade 2 or higher bleeding in patients with severe thrombocytopenia requiring supportive platelet transfusion following myeloablative therapy for hematologic disorders. In this ancillary study, we sought to determine whether this clinical outcome could be explained on the basis of correlative assays of fibrinolysis. Plasma was collected from A-TREAT participants (n = 115) before the initiation of study drug (baseline) and when TXA was at steady-state trough concentration (follow-up).

Prophylactic tranexamic acid in patients with hematologic malignancy: a placebo-controlled, randomized clinical trial.

Evidence of the effectiveness of prophylactic use of tranexamic acid (TXA) in thrombocytopenia is lacking. To determine whether TXA safely reduces bleeding incidence in patients undergoing treatment for hematologic malignancies, a randomized, double-blind clinical trial was conducted from June 2016 through June 2020. Of 3120 screened adults, 356 patients were eligible and enrolled, and 337 patients (mean age, 53.

Early Convalescent Plasma for High-Risk Outpatients with Covid-19.

Background: Early administration of convalescent plasma obtained from blood donors who have recovered from coronavirus disease 2019 (Covid-19) may prevent disease progression in acutely ill, high-risk patients with Covid-19.

Methods: In this randomized, multicenter, single-blind trial, we assigned patients who were being treated in an emergency department for Covid-19 symptoms to receive either one unit of convalescent plasma with a high titer of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or placebo. All the patients were either 50 years of age or older or had one or more risk factors for disease progression.

Recommended primary outcomes for clinical trials evaluating hemostatic blood products and agents in patients with bleeding: Proceedings of a National Heart Lung and Blood Institute and US Department of Defense Consensus Conference.

High-quality evidence guiding optimal transfusion and other supportive therapies to reduce bleeding is needed to improve outcomes for patients with either severe bleeding or hemostatic disorders that are associated with poor outcomes. Alongside challenges in performing high-quality clinical trials in patient populations who are at risk of bleeding or who are actively bleeding, the interpretation of research evaluating hemostatic agents has been limited by inconsistency in the choice of primary trial outcomes. This lack of standardization of primary endpoints or outcomes decreases the ability of clinicians to assess the validity of endpoints and compare research results across studies, impairs meta-analytic efforts, and, ultimately, delays the translation of research results into clinical practice.

Pulmonary Complications of Pediatric Hematopoietic Cell Transplantation. A National Institutes of Health Workshop Summary.

Approximately 2,500 pediatric hematopoietic cell transplants (HCTs), most of which are allogeneic, are performed annually in the United States for life-threatening malignant and nonmalignant conditions. Although HCT is undertaken with curative intent, post-HCT complications limit successful outcomes, with pulmonary dysfunction representing the leading cause of nonrelapse mortality. To better understand, predict, prevent, and/or treat pulmonary complications after HCT, a multidisciplinary group of 33 experts met in a 2-day National Institutes of Health Workshop to identify knowledge gaps and research strategies most likely to improve outcomes.

National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Immune Dysregulation and Pathobiology Working Group Report.

Immune reconstitution after hematopoietic stem cell transplantation (HCT) beyond 1 year is not completely understood. Many transplant recipients who are free of graft-versus-host disease (GVHD) and not receiving any immunosuppression more than 1 year after transplantation seem to be able to mount appropriate immune responses to common pathogens and respond adequately to immunizations. However, 2 large registry studies over the last 2 decades seem to indicate that infection is a significant cause of late mortality in some patients, even in the absence of concomitant GVHD.

High levels of IL-7 cause dysregulation of thymocyte development.

IL-7 signaling is required for thymocyte development and its loss has a severe deleterious effect on thymus function. Thymocyte-stromal cell interactions and other mechanisms tightly regulate IL-7 expression. We show that disruption of that regulation by over-expression of IL-7 inhibits T-cell development and promotes extensive B-cell lymphopoiesis in the thymus.

Tbata modulates thymic stromal cell proliferation and thymus function.

Niche availability provided by stromal cells is critical to thymus function. Thymi with diminished function contain fewer stromal cells, whereas thymi with robust function contain proliferating stromal cell populations. Here, we show that the thymus, brain, and testes-associated gene (Tbata; also known as SPATIAL) regulates thymic epithelial cell (TEC) proliferation and thymus size.

An overview of IL-7 biology and its use in immunotherapy.

Interleukin (IL)-7 is required for T-cell development as well as for the survival and homeostasis of mature T-cells. In the thymus, the double negative (DN) CD4(-) CD8(-) thymocyte progenitor transition into double positive CD4+ CD8+ cells requires Notch and IL-7 signaling. Importantly, IL-7 seems to have a dose effect on T-cell development and, at high doses, DN progression is blocked.

Dynamic regulation of IL-7 receptor expression is required for normal thymopoiesis.

Interleukin-7 receptor (IL-7R) levels are tightly controlled during ontogeny: high on double-negative (DN) cells, absent on double-positive (DP) cells, and high once again on thymocytes undergoing positive selection. To determine if loss of IL-7-mediated survival signals in DP cells is necessary for normal antigen-specific selection, we created T-lineage-specific IL-7R alpha chain (IL-7Ralpha) transgenic (Tg) mice in which IL-7R is expressed throughout ontogeny. There was no effect of the IL-7Ralpha Tg on negative selection.

A dose effect of IL-7 on thymocyte development.

To study interleukin-7 (IL-7) in early thymocyte development, we generated mice transgenic (Tg) for the IL-7 gene under control of the lck proximal promoter. Founder line TgA, with the lowest level of IL-7 overexpression, showed enhanced alphabeta T-cell development. In contrast, in the highest overexpressing founder line, TgB, alphabeta T-cell development was disturbed with a block at the earliest intrathymic precursor stage.

Long-term kidney graft survival across a positive historic but negative current sensitized cross-match.

Background: The sensitive cross-match (XM) techniques that have been introduced for clinical transplantation can detect anti-donor immune reactivity despite a negative standard National Institute of Health (NIH) cross-match. One of them uses anti-kappa human light chain globulins (AHG). But there is some discussion about the clinical consequences of a positive AHG-XM in the historical sera that became negative in the sera collected just before the transplantation (pretransplant sera).

High resolution HLA class I and II typing and CTLp frequency in unrelated donor transplantation: a single-institution retrospective study of 69 BMTs.

Unlabelled: The results of unrelated donor transplantation (URD-BMT) are difficult to analyze since the continuous advances in HLA typing technology allow the detection of new mismatches unknown at the time of transplantation. We sought to confirm that matched recipient-donor pairs are in fact often mismatched when advanced HLA typing techniques are used. We retrospectively studied the impact of the results of high resolution HLA typing for HLA class I (-A, -B, -C) and HLA class II (-DR, -DQ, -DP) loci, and cytotoxic T lymphocyte precursor (CTLp) frequency, on the outcome of 69 URD-BMT procedures.

A novel HLA-B*39 allele (HLA-B*3916) due to a rare mutation causing cryptic splice site activation.

A novel HLA-B*39 variant, found in an African patient with sickle cell anemia undergoing bone marrow transplantation is described. Initially suspected by inconsistent serological typing (B-blank, Bw6), then recognized by PCR-SSP, and finally characterized by nucleotide sequencing, this novel allele is designated HLA-B*3916. It differs from HLA-B*3910 by a point mutation (G to C) at position 17 of exon 3 causing glutamine to histidine change at codon 96 of alpha(2) domain, a conserved position among HLA class I alleles.

Clonality markers in polycythaemia and primary thrombocythaemia.

Our current understanding of the pathogenesis of the myeloproliferative disorders is based on the assumption that they represent a clonal disorder resulting from transformation of a haematopoietic stem cell. Clonality assays exploit the fact that female cells have only one active X-chromosome. Methods for determining X chromosome inactivation have been devised at the protein (G6PD isoenzymes); DNA (HUMARA; phosphoglycerate kinase (PGK); hypoxanthine-phosphoribosyl transferase (HPRT) and RNA (G6PD; P55; IDS) levels.

Clonality analysis of hematopoiesis and thrombopoietin levels in patients with essential thrombocythemia.

Essential thrombocythemia (ET) is a myeloproliferative disorder, characterized by sustained thrombocytosis. Diagnosis requires the elimination of all known causes of thrombocytosis. ET is believed to be a clonal disorder, and we investigated the frequency of a clonal hematopoiesis in this disease with the aim of using this as a positive diagnostic criterion.

X-chromosome inactivation in healthy females: incidence of excessive lyonization with age and comparison of assays involving DNA methylation and transcript polymorphisms.

Skewed lyonization in healthy females represents the major disadvantage of X-chromosome-based clonality assays. Because most techniques are based on the difference in DNA methylation between active and inactive X-chromosomes, incomplete DNA digestion may occur, giving an unreliable clonality result. Here, we compare two different techniques carried out in healthy females belonging to three age groups and in a group of patients with essential thrombocythemia.

Clonality analysis of hematopoiesis in essential thrombocythemia: advantages of studying T lymphocytes and platelets.

Essential thrombocythemia (ET) is a myeloproliferative disorder characterized by a sustained elevation of the platelet count in the absence of other causes of thrombocytosis. ET is difficult to diagnose, and the demonstration of clonal hematopoiesis may be of value. However, clonality analysis of hematopoietic cells based on the study of the X-chromosome inactivation pattern is complicated by the observation that some normal females present skewed lyonization.

Fusidic acid induced acute immunologic thrombocytopenia.

Fusidic acid is used in hospitals as second-line therapy for multidrug-resistant staphylococcal infections. We report the first fully documented case of fusidic acid induced thrombocytopenia, in a 48-year-old patient. The thrombocytopenia was abrupt and severe but resolved spontaneously 7 d after drug withdrawal.

Posttransfusion purpura-like syndrome associated with CD36 (Naka) isoimmunization.

Background: CD36 deficiency, which could lead to CD36 isoimmunization, has been reported in the Japanese population. CD36 isoantibody has been involved in platelet transfusion refractoriness.

Case Report: A 50-year-old woman originally from Corsica developed severe acute thrombocytopenia after massive transfusion.