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. Methods: We performed a post hoc analysis of outcomes of patients randomized to receive either TXA or placebo in the double-blinded, multicenter American Trial to Evaluate Tranexamic Acid Therapy in Thrombocytopenia (Clinicaltrials.gov identifier: NCT02578901). Results: TXA did not change the overall rate of infections, but the rate of severe infections (Common Toxicology Criteria for Adverse Events grade 3+) was lower in patients who received TXA compared with the placebo group. Patients who experienced grade 3+ infections had higher rates of World Health Organization grade 2+ bleeding and red blood cell transfusion requirements than patients who did not experience a grade 3+ infection, irrespective of treatment group. TXA did not impact other inflammatory outcomes such as mucositis, rash, or graft vs host disease. Conclusion: Patients with hematologic malignancies who received TXA had less severe infections than those who received placebo with no difference in overall rate of infection or other inflammatory outcomes. Further investigation is needed on the impact of TXA on infections in this population.

Management of coagulopathy among patients with cirrhosis undergoing upper endoscopy and paracentesis: Persistent gaps and areas of consensus in a multispecialty Delphi.

Patients with cirrhosis have abnormal coagulation indices such as a high international normalized ratio and low platelet count, but these do not correlate well with periprocedural bleeding risk. We sought to develop a consensus among the multiple stakeholders in cirrhosis care to inform process measures that can help improve the quality of the periprocedural management of coagulopathy in cirrhosis. We identified candidate process measures for periprocedural coagulopathy management in multiple contexts relating to the performance of paracentesis and upper endoscopy. An 11-member panel with content expertise was convened. It included nominees from professional societies for interventional radiology, transfusion medicine, and anesthesia as well as representatives from hematology, emergency medicine, transplant surgery, and community practice. Each measure was evaluated for agreement using a modified Delphi approach (3 rounds of rating) to define the final set of measures. Out of 286 possible measures, 33 measures made the final set. International normalized ratio testing was not required for diagnostic or therapeutic paracentesis as well as diagnostic endoscopy. Plasma transfusion should be avoided for all paracenteses and diagnostic endoscopy. No consensus was achieved for these items in therapeutic intent or emergent endoscopy. The risks of prophylactic platelet transfusions exceed their benefits for outpatient diagnostic paracentesis and diagnostic endosopies. For the other procedures examined, the risks outweigh benefits when platelet count is >20,000/mm 3 . It is uncertain whether risks outweigh benefits below 20,000/mm 3 in other contexts. No consensus was achieved on whether it was permissible to continue or stop systemic anticoagulation. Continuous aspirin was permissible for each procedure. Clopidogrel was permissible for diagnostic and therapeutic paracentesis and diagnostic endoscopy. We found many areas of consensus that may serve as a foundation for a common set of practice metrics for the periprocedural management of coagulopathy in cirrhosis.

How I treat von Willebrand disorders in older adults.

ABSTRACT: von Willebrand disease (VWD) is the most common bleeding disorder and especially milder type 1 VWD might not be cared for in specialty clinics. VW factor levels rise with age, but the rise of these levels does not necessarily correlate with bleeding risk. A recent bleeding history combined with recent labs are important for hemostatic management decision during surgical interventions. Antifibrinolytics appear safe in the population of older adults, whereas desmopressin (DDAVP) should be used cautiously. Where needed, factor concentrates present a great treatment option. Acquired von Willebrand syndrome is vastly underrecognized, but likely to surface in the aging, especially in the setting of comorbidities, such as plasma-cell dyscrasias. Intravenous immunoglobulin can be an effective treatment in this scenario, but potentially increases thrombotic risk.

The role of emicizumab in acquired hemophilia A.

Acquired hemophilia is a rare bleeding disorder that predominantly affects older people with potential underlying comorbidities, including cardiovascular and thrombotic risk factors. The current standard therapies with hemostatic agents for acute bleeding and immunosuppression often require inpatient management, are not approved for routine bleeding prophylaxis, and contribute to the high mortality in this population. Emicizumab is a factor VIII (FVIII) mimetic approved for bleeding prophylaxis in congenital hemophilia A with and without FVIII inhibitors. Given subcutaneously, it may allow easier outpatient bleeding prophylaxis and reduce intensity of immunosuppression. This article summarizes the currently available data on the efficacy and safety of emicizumab in acquired hemophilia A.

Current advances in 2022: A critical review of selected topics by the Association for the Advancement of Blood and Biotherapies (AABB) Clinical Transfusion Medicine Committee.

BACKGROUND: The Association for the Advancement of Blood and Biotherapies Clinical Transfusion Medicine Committee (CTMC) composes a summary of new and important advances in transfusion medicine (TM) on an annual basis. Since 2018, this has been assembled into a manuscript and published in Transfusion. STUDY DESIGN AND METHODS: CTMC members selected original manuscripts relevant to TM that were published electronically and/or in print during calendar year 2022. Papers were selected based on perceived importance and/or originality. References for selected papers were made available to CTMC members to provide feedback. Members were also encouraged to identify papers that may have been omitted initially. They then worked in groups of two to three to write a summary for each new publication within their broader topic. Each topic summary was then reviewed and edited by two separate committee members. The final manuscript was assembled by the first and senior authors. While this review is extensive, it is not a systematic review and some publications considered important by readers may have been excluded. RESULTS: For calendar year 2022, summaries of key publications were assembled for the following broader topics within TM: blood component therapy; infectious diseases, blood donor testing, and collections; patient blood management; immunohematology and genomics; hemostasis; hemoglobinopathies; apheresis and cell therapy; pediatrics; and health care disparities, diversity, equity, and inclusion. DISCUSSION: This Committee Report reviews and summarizes important publications and advances in TM published during calendar year 2022, and maybe a useful educational tool.

Advances in Acquired Hemophilia A.

Acquired Hemophilia A (AHA) is a rare, life-threatening bleeding disorder from autoantibodies against clotting factor VIII. These autoantibodies occur with increasing incidence with advanced age and are often associated with other medical conditions such as autoimmune diseases and malignancy. Not uncommonly, AHA presents as a new bleeding disorder in a person with prior thrombosis or thrombotic risk. Treatment of AHA focuses on managing and preventing bleeding, as well as immunosuppression with the goal to eradicate the autoantibody. Despite current treatment approaches, morbidity, and mortality are high due to complications from bleeding, immunosuppression, and underlying comorbidities. The most pressing needs to improved outcome for this disease are better bleeding prophylaxis in the outpatient setting and reduction of the need for intense immunosuppression. Because of the rare nature of this disease, there is limited prospective data and most treatment standards have been based on case series. The field has recently focused on improved diagnostics and advanced risk stratification, with a potential of tailoring the need and intensity of immunosuppression. Case reports of off label use of emicizumab, a factor FVIII mimetic approved for congenital hemophilia A, suggest emicizumab may provide effective and safe bleeding prophylaxis in the outpatient setting; this could permit reducing immunosuppression and decreasing the risk of treatment related infections. Two ongoing prospective clinical trials of emicizumab will help clarify the safety and efficacy in AHA.

Prevalence of comorbid conditions among older males with haemophilia receiving care in haemophilia treatment centers in the United States.

INTRODUCTION: Increased survival among men with haemophilia has brought with it an increased risk of age-related comorbidities that may be challenging to treat in the presence of a bleeding disorder. AIM: Estimate the prevalence of several age-related comorbidities among older males with haemophilia receiving care in the U.S. haemophilia treatment center (HTC) network compared to that among the general population. METHODS: People with bleeding disorders who receive care in network HTCs can volunteer to participate in a surveillance registry that collects detailed clinical information including the presence of comorbid conditions at annual visits. We used registry data collected on males with haemophilia age 45 years and older to calculate lifetime prevalence of obesity, diabetes, hypertension, cardiovascular disease, renal disease, cancer, anxiety and depression. Comparable data on the U.S. general male population was obtained from the National Health Interview Survey. RESULTS: During the surveillance period, 1592 middle-aged (45-64 years) and 645 older (≥65 years) patients with haemophilia had comorbidity data collected during 6435 HTC visits. Most haemophilia patients in both age groups had a higher prevalence of anxiety, depression and diabetes, but a lower prevalence of hypertension, coronary heart disease, stroke and myocardial infarction compared to the general U.S. male population. In addition, middle-aged patients had lower rates of leukemia, whereas older patients had higher rates of obesity than the general population. CONCLUSION: These findings highlight the mental stress associated with this chronic condition and support continued public health obesity prevention efforts in the haemophilia community.

Current advances in transfusion medicine 2021: A critical review of selected topics by the AABB Clinical Transfusion Medicine Committee.

BACKGROUND: Each year the AABB Clinical Transfusion Medicine Committee (CTMC) procures a synopsis highlighting new, important, and clinically relevant studies in the field of transfusion medicine (TM). This has been made available as a publication in Transfusion since 2018. METHODS: CTMC members reviewed and identified original manuscripts covering TM-related topics published electronically (ahead-of-print) or in print from December 2020 to December 2021. Selection of publications was discussed at committee meetings and chosen based on perceived relevance and originality. Next, committee members worked in pairs to create a synopsis of each topic, which was then reviewed by additional committee members. The first and senior authors assembled the final manuscript. Although this synopsis is extensive, it is not exhaustive, and some articles may have been excluded or missed. RESULTS: The following topics are included: blood products; convalescent plasma; donor collections and testing; hemoglobinopathies; immunohematology and genomics; hemostasis; patient blood management; pediatrics; therapeutic apheresis; and cell therapy. CONCLUSIONS: This synopsis highlights and summarizes recent key developments in TM and may be useful for educational purposes.

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, 53.9; 141 [41.8%] women), randomized to 1300 mg TXA orally or 1000 mg TXA through IV (n = 168) vs placebo (n = 169) thrice daily for maximum 30 days. Three hundred thirty patients were activated when their platelet counts fell below 30 000 per µL; 279 (83%) had complete outcome ascertainment. World Health Organization (WHO) grade ≥2 bleeding was observed in the 30 days following activation in 50.3% (73/145) and 54.2% (78/144) of patients in the TXA and placebo groups, with an adjusted odds ratio of 0.83 (95% confidence interval [CI], 0.50-1.34; P = .44). There was no statistically significant difference in the mean number of platelet transfusions (mean difference, 0.1; 95% CI, -1.9 to 2.0), mean days alive without grade ≥2 bleeding (mean difference, 0.8; 95% CI, -0.4 to 2.0), thrombotic events (6/163 [3.7%] TXA, 9/163 [5.5%] placebo), or deaths due to serious bleeding. Most common adverse events were: diarrhea (116/164 [70.7%] TXA and 114/163 [69.9%] placebo); febrile neutropenia (111/164 [67.7%] TXA, 105/163 [64.4%] placebo); fatigue (106/164 [64.6%] TXA, 109/163 [66.9%] placebo); and nausea (104/164 [63.4%] TXA, 97/163 [59.5%] placebo). Among patients with hematologic malignancy undergoing chemotherapy or hematopoietic stem cell transplantation, prophylactic treatment with TXA compared with placebo did not significantly reduce the risk of WHO grade ≥2 bleeding.

Adaptation of a Modified Diet Quality Index to Quantify Healthfulness of Food-Related Toy Sets.

The objective of this cross-sectional study was to examine the construct validity of an adapted modified Diet Quality Index (aDQI) as a measure of the healthfulness of food-related toy sets for young children (3-8 years). A standardized online search was used to identify toy sets (n = 50) from 10 retailers. An aDQI score (aDQI score, range 0-50) was determined for each toy set, mean (standard deviation) = 28.7 (6.1). Regression analyses demonstrated a positive association between aDQI score and percentage of dairy, refined grains, protein, vegetables, and fruit and inverse association with percentage of desserts, sugar-sweetened beverages, and total number of servings. Sets contained more protein and fewer fruits than recommended. The aDQI score demonstrates construct validity to objectively assess the healthfulness of food-related toy sets. There is opportunity for toy manufacturers to make changes to improve the healthfulness in toy sets for young children, and future research can explore the impact of food-related toy sets on nutrition behaviors.

In utero exposure to alloantigens primes alloimmunization to platelet transfusion in mice.

BACKGROUND: Platelet transfusions remain a mainstay of treatment for many patients with thrombocytopenia, but can lead to alloantibodies to Human Leukocyte Antigens (anti-HLA) resulting in inadequate responses to subsequent platelet transfusions (refractoriness), as well as complicate transplantation. Despite substantial decreases in alloimmunization with the implementation of leukoreduction, a significant percentage of patients still become alloimmunized following platelet transfusions. It remains unclear why some patients make anti-HLA antibodies, but others do not make anti-HLA antibodies even with chronic transfusion. Antecedent pregnancy correlates with risk of alloimmunization due to platelet transfusion in humans - however, isolation of pregnancy as a single variable is not possible in human populations. STUDY DESIGN AND METHODS: A tractable murine model of pregnancy and transfusion was engineered by breeding C57BL/6 (H-2b ) dames with BALB/c (H-2d ) sires. After pregnancy, female mice were transfused with leukoreduced platelets from F1 (H-2b/d ) donors that expressed the same paternal major histocompatibility complex (MHC) H-2d alloantigens as the sires. Control groups allowed isolation of pregnancy or transfusion alone as independent variables. Alloimmunization was determined by testing serum for antibodies to H-2d MHC alloantigens. RESULTS: No alloantibodies were detected after pregnancy alone, or in response to transfusion of platelets alone; however, significant levels of alloantibodies were detected when pregnancy was followed by transfusion. CONCLUSIONS: These findings isolate antecedent pregnancy as a causal contribution to increased frequencies of alloimmunization by subsequent platelet transfusion in mice and provide a platform for ongoing mechanistic investigation.

Mitigation strategies for anti-D alloimmunization by platelet transfusion in haematopoietic stem cell transplant patients: a survey of NCCN® centres.

BACKGROUND AND OBJECTIVES: D-negative patients are at risk of developing an alloantibody to D (anti-D) if exposed to D during transfusion. The presence of anti-D can lead to haemolytic transfusion reactions and haemolytic disease of the newborn. Anti-D alloimmunization can also complicate allogeneic haematopoietic stem cell transplantation (HSCT) with haemolysis and increased transfusion requirements. The goal of this study was to determine whether cancer centres have transfusion practices intended to prevent anti-D alloimmunization with special attention in patients considered for HSCT. METHODS AND MATERIALS: To understand transfusion practices regarding D-positive platelets in D-negative patients with large transfusion needs, we surveyed the 28 cancer centres that are members of the National Comprehensive Cancer Network® (NCCN® ). RESULTS: Nineteen centres responded (68%). Most centres (79%) avoid transfusing D-positive platelets to RhD-negative patients when possible. Four centres (21%) avoid D-positive platelets only in D-negative women of childbearing age. If a D-negative patient receives a D-positive platelet transfusion, 53% of centres would consider treating with Rh immune globulin (RhIg) to prevent alloimmunization in women of childbearing age. Only one centre also gives RhIg to all D-negative patients who are HSCT candidates including adult men and women of no childbearing age. CONCLUSION: There is wide variation in platelet transfusion practices for supporting D-negative patients. The majority of centres do not have D-positive platelet transfusion policies focused on preventing anti-D alloimmunization specifically in patients undergoing HSCT. Multicentre, longitudinal studies are needed to understand the clinical implications of anti-D alloimmunization in HSCT patients.

Glucocorticoids promote response to thrombopoietin-receptor agonists in refractory ITP: a case series.

A proportion of patients with immune thrombocytopenic purpura are refractory to multiple therapies including thrombopoietin-receptor agonists (TPO-RA). We report 10 patients who did not respond to a TPO-RA until the addition of a glucocorticoid. These patients were previously treated with a median of 6 therapies. One patient elected to discontinue both medications despite persistent thrombocytopenia. The remaining 9 patients continued on the combination of prednisone (doses 5 mg every other day to 10 mg daily) and a TPO-RA. Combination therapy with low dose glucocorticoid and a TPO-RA may be an option for patients unresponsive to a TPO-RA alone.

The Diving Bell and the Butterfly Revisited: A Fatal Case of Locked-in Syndrome in a Man With Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma, Not Otherwise Specified.

Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) is a rare variant of DLBCL. The natural history of this subtype is poorly understood. Incomplete literature in the era of rituximab suggests that patients with EBV-positive DLBCL have similar outcomes to patients with EBV-negative DLBCL when treated with rituximab and anthracycline-based chemotherapy regimens; however, there are few prospective studies on this subtype and little is known about the risk of central nervous system (CNS) relapse with EBV-positive DLBCL. Herein, we describe the case of a 64-year-old man who presented with stage IIA EBV-positive DLBCL. His international age-adjusted International Prognostic Index (IPI) was 2. He achieved a complete response to 6 cycles of rituximab combined with chemotherapy consisting of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin. After 10 days of completion of chemotherapy, he had a fulminant neurologic decline manifested by diffuse weakness followed by a locked-in syndrome; he could only communicate by moving his eyes. He had been deemed at low risk for CNS relapse based on the application of the recently developed CNS-IPI score of 2 (1 point for age >60 years and 1 point for lactate dehydrogenase higher than normal) and consequently did not receive therapy for CNS prophylaxis. A limited postmortem autopsy revealed extensive lymphoma throughout the brain, particularly in the deep basal nuclei, midbrain, pons, centrum semiovale, and corpus callosum. This presentation of CNS relapse is rare and has not yet been described in EBV-positive DLBCL. We discuss some of the unique aspects of this case including the clinical manifestations of locked-in syndrome and its differential diagnosis and the uncertain benefits of CNS prophylaxis in this clinical context.

Controversies Regarding Use of Myeloid Growth Factors in Leukemia.

This review focuses on the data supporting the use of myeloid growth factors (MGFs) in patients being treated for acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and hairy cell leukemia, for which neutropenia is a common complication of treatment. However, due to the lack of randomized trial data or conflicting results of clinical studies, comprehensive guidelines have been difficult to formulate. Moreover, to date, these diagnoses have not been addressed in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for MGFs. However, in most cases, the general principles have been included in the applicable NCCN Guidelines for each individual cancer site.

Bone-marrow mesenchymal stem-cell administration significantly improves outcome after retinal ischemia in rats.

PURPOSE: Ischemia-associated retinal degeneration is one of the leading causes of vision loss, and to date, there are no effective treatment options. We hypothesized that delayed injection of bone-marrow stem cells (BMSCs) 24 h after the onset of ischemia could effectively rescue ischemic retina from its consequences, including apoptosis, inflammation, and increased vascular permeability, thereby preventing retinal cell loss. METHODS: Retinal ischemia was induced in adult Wistar rats by increasing intraocular pressure (IOP) to 130-135 mmHg for 55 min. BMSCs harvested from rat femur were injected into the vitreous 24 h post-ischemia. Functional recovery was assessed 7 days later using electroretinography (ERG) measurements of the a-wave, b-wave, P2, scotopic threshold response (STR), and oscillatory potentials (OP). The retinal injury and anti-ischemic effects of BMSCs were quantitated by measuring apoptosis, autophagy, inflammatory markers, and retinal-blood barrier permeability. The distribution and fate of BMSC were qualitatively examined using real-time fundus imaging, and retinal flat mounts. RESULTS: Intravitreal delivery of BMSCs significantly improved recovery of the ERG a- and b-waves, OP, negative STR, and P2, and attenuated apoptosis as evidenced by decreased TUNEL and caspase-3 protein levels. BMSCs significantly increased autophagy, decreased inflammatory mediators (TNF-α, IL-1ß, IL-6), and diminished retinal vascular permeability. BMSCs persisted in the vitreous and were also found within ischemic retina. CONCLUSIONS: Taken together, our results indicate that intravitreal injection of BMSCs rescued the retina from ischemic damage in a rat model. The mechanisms include suppression of apoptosis, attenuation of inflammation and vascular permeability, and preservation of autophagy.

De novo CD5+ diffuse large B-cell lymphoma: Adverse outcomes with and without stem cell transplantation in a large, multicenter, rituximab treated cohort.

De novo CD5+ diffuse large B-cell lymphomas (DLBCL) are a distinct subgroup of DLBCL with poor prognosis. However the role of rituximab-containing therapy and salvage stem cell transplantation in this patients' population remain to be defined. We retrospectively reviewed clinical features and outcomes of 102 patients with de novo CD5+ DLBCL treated with rituximab-containing therapy at nine different institutions. By Hans' criteria, 64 patients had activated B-cell (ABC) subtype, 24 germinal center B-cell (GCB) subtype, and 14 were not evaluated. No patients had a myc translocation. Eighty-three patients were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP), 7 with rituximab, etoposide, cyclophosphamide, doxorubicin, vincristine, prednisone (R-EPOCH), and 6 with R-CHOP with methotrexate, 3 g/m(2) . The overall response rate to front-line therapy was 85%. The 3-year progression free survival (PFS) and overall survival (OS) for all patients were 40 and 65%, respectively. The 3-year PFS for ABC- and GCB-subtypes was 34 and 45%, respectively. The 3-year OS for ABC- and GCB-subtypes was 62 and 67%, respectively. The median time to second treatment failure was 3 months and 1 month for ABC- and GCB-subtypes, respectively. Twenty of 28 (71%) transplanted patients with autologous, allogeneic, or both, relapsed. This study confirms the poor prognosis of de novo CD5+ DLBCL in a large multi-center cohort despite initial rituximab-containing chemotherapy and suggests that stem cell transplantation fails to salvage the majority of these patients. Approaches to prevent recurrence and/or novel therapies for relapsed disease are needed for this subgroup of DLBCL patients.