Robert W. Maitta

Sickle cell disease (SCD) represents one of the most complex hematological diseases leading to a lifetime of physiological crises characterized by chronic hemolysis, inflammation, hypoxia, and anemia with changes to body systems that result in patients having shorter lifespans. Transfusions, either simple or as part of red cell exchanges, are often needed to lower the hemoglobin S levels to minimize the possibility of sickling of red blood cells (RBCs) and provide patients with greater oxygen carrying capacity. However, hemolysis in SCD patients is a common finding/presentation of the disease, especially during acute crises. One of the ensuing complications of a life of transfusions is the development of alloantibodies to RBC antigens despite partial or extended matching. This is further complicated by formation of autoantibodies even in the setting of RBC matching, suggesting that a hyperactive immune response in these patients is primed to respond with formation of antibodies. In a sub-cohort of patients, no antibodies are detected despite extensive investigation, and the ensuing hemolysis requires minimizing exposure to RBC transfusions to avoid developing a greater hemolytic process. Instead, immunosuppression or monoclonals that target complement or cytokines shown to be involved in this type of hemolysis are necessary. In this context, this narrative review will present antibody-dependent and antibody-independent mechanisms of hemolysis in SCD, including therapeutic approaches that target specific areas of the immune response that are possibly involved in the destruction of RBCs.

Acute kidney failure from light chain cast nephropathy is a serious complication of multiple myeloma. Plasma exchange (PLEX) has been used to remove circulating free light chains (FLCs), but its benefit in the modern treatment era remains uncertain. We performed a retrospective multicenter cohort study using the TriNetX Research Network to identify newly diagnosed multiple myeloma cases presenting between 2014 and 2024 with acute kidney failure and FLC levels > 1500 mg/L. Patients were classified by receipt of PLEX within 7 days. Propensity score matching incorporated demographics, comorbidities, laboratory values, and initial myeloma‐directed therapies. The primary outcome was dialysis dependence at 90 days. Secondary outcomes included dialysis dependence at 180 days, mortality, renal recovery (creatinine < 2.0 mg/dL), ICU admission within 7 days, and dialysis‐free survival. Among 5454 eligible patients, 251 (4.6%) received PLEX. After matching, 248 patients were included in each group. PLEX was not associated with reduced dialysis dependence at 90 (16.1% vs. 18.1%; OR 0.87, 95% CI 0.54–1.39) or 180 days (18.5% vs. 20.2%; OR 0.90, 95% CI 0.58–1.41). Mortality, ICU admission, and dialysis‐free survival were also similar. PLEX was not associated with improved dialysis independence or survival, supporting rapid initiation of effective anti‐myeloma therapy.

Platelets are anucleated cell fragments representing the second most abundant blood element in circulation, with approximately 100 billion new platelets released from the bone marrow daily in a healthy individual. For over a century, their hemostatic role was considered their primary function; however, the past few decades of research have revealed significant immunological functions in both innate and adaptive immunity. Through the release of mediators stored in platelet granules and the expression and realignment of a diverse array of surface receptors, platelets influence immune cells while simultaneously recognizing, reacting to, and phagocytosing offending pathogens such as viruses and bacteria. Their activation initiates signaling cascades that either amplify platelet responses or drive the activation, recruitment, migration, and maturation of immune cells to sites of infection. This narrative review synthesizes platelet biology, receptor signaling, granule physiology, and platelet interactions with innate and adaptive immune cells to provide an integrated perspective on platelet immunologic function. We examine platelets as frontline immune sentinels and evaluate their capacity to regulate both innate and adaptive immune responses, detailing specific receptors and granule contents as the mechanistic foundation for their immunologic roles. We further explore the molecular mechanisms by which platelets interact with pathogens and immune cells to drive pathogen clearance, inflammation modulation, and the interplay between thrombosis and immunity, including their contributions to chronic inflammatory disease and tumorigenesis.

Background and Clinical Significance: Extracorporeal therapies such as hemodialysis, continuous renal replacement therapy (CRRT) or therapeutic plasma exchange (TPE) are mainstay treatments for acute toxins, venoms and poisonings. Ibuprofen is a common drug implicated in acute toxicity, with a major complication being acute kidney injury (AKI). As such, these patients often receive hemodialysis or CRRT, which do not remove substances with high protein binding (>80%) and low volumes of distribution (Vd) (<0.2 L/kg). The pharmacokinetics of ibuprofen have these characteristics. While hemodialysis or CRRT can clear the accumulated toxic metabolites, they do not remove the ibuprofen that causes renal injury. In contrast, TPE can remove protein-bound drugs such as ibuprofen. Case Presentation: We describe the case of a previously healthy young male who presented with AKI due to ibuprofen toxicity requiring concurrent continuous renal replacement therapy and plasma exchange. Conclusions: TPE in conjunction with hemodialysis or CRRT is an effective treatment modality for ibuprofen toxicity.

Immature platelets represent the youngest platelets in circulation. They are also present in all platelet units given to patients. However, there is limited knowledge of what occurs to these platelets during routine blood manipulation at transfusion facilities. We aimed to establish quantitative changes in immature platelets during routine volume reduction procedures. Platelet units were centrifuged followed by volume reduction and resuspension in a smaller volume. Centrifugation and hemoconcentration resulted in a significant increase per milliliter in platelets and immature platelets. Analysis of total counts of platelets and immature platelets after manipulation showed that these were conserved without significant changes. Furthermore, the ratio of platelets to immature platelets after manipulation also remained unchanged. Importantly manipulation did not seem to affect viability of immature platelets. These results indicate that centrifugation and hemoconcentration preserved immature platelets in platelet units.

Blood transfusion is one of the most frequently used medical interventions in modern healthcare, without which many treatments, including surgery, would be impossible. Unlike other medical products, blood supply is supported by voluntary blood donations, which have been on a steady decline due to an aging donor population as well as reduced interest in donation despite increased outreach efforts, both of which were exacerbated by the COVID19 pandemic (1). To mitigate these supply challenges and ensure sufficient inventory in the future, a dual strategy is being developed by optimizing utilization of blood components using evidence-based guidelines and by advancing methods to extend components shelf-life.Blood stewardship emphasizes the judicious and evidence-based use of blood components. The need for robust blood stewardship is illustrated in the study by Velasco et al in this special issue, which looked at transfusion appropriateness through a multicenter approach of perioperative transfusion practices in 43 Spanish hospitals (2). Transfusion appropriateness was evaluated based on patient's hemoglobin (Hgb) and clinical conditions using the restrictive transfusion threshold of <7g/dL with higher thresholds for patients with existing comorbidities. They found that the overall perioperative transfusion rate was about 9.7% half of which constituted transfusion to patients undergoing cardiac surgery, with a smaller but significant percentage represented vascular and orthopedic surgeries. Higher transfusion rates were associated with older patients, presence of comorbidities, lower perioperative Hgb, higher American Society of Anesthesiology physical status (ASA score), and worse postsurgical outcomes. Interestingly, despite having an overall perioperative transfusion rate lower than the international figure, about 43% of transfusions in the study were found to be inappropriate. The authors found that advanced patient age was the factor most strongly associated with inappropriate transfusion. These data highlight an opportunity for potential practice biases that could be remedied by implementation of decision support tools. This represents the first study of its kind from Spain.Despite the substantial proportion of inappropriate transfusion, the overall decreased rate of perioperative transfusions was attributed to the presence of a patient blood management (PBM) system. A PBM system supports blood stewardship by providing a patient-centered and evidencebased approach to improve a patient's outcome by managing and preserving their own blood so that less blood would be needed perioperatively. To this end, PBM seeks to optimize pre-operative blood cell mass, minimize intra-operative blood loss, and properly manage signs of anemia in the post-operative phase. PBM is explored in the paper by Zhu et al in this special issue, which studied the perioperative management of Factor VII (FVII) deficiency (3). FVII is a vitamin Kdependent protein belonging to the extrinsic coagulation pathway that activates almost immediately in response to tissue damage. Perioperative bleeding is a major concern in patients with FVII deficiency which has heterogeneous presentation. Consequently, there is neither clear consistent correlation between bleeding symptoms and FVII levels, nor clear guidelines in FVII replacement in the perioperative setting. In this study, the authors conducted a retrospective review of the perioperative management of FVII deficiency in 20 patients at a single institution. The authors were unable to find a significant correlation between perioperative hemostasis complications and FVII activity levels. Conversely, the authors noted that replacement of FVII along with anti-fibrinolytic treatment should be considered in the management of severe FVII deficiency especially if there is a history of bleeding. By optimizing FVII levels in the perioperative settings, the authors argue that the risk of hemorrhage can be reduced, thus abrogating the need for extraneous blood component transfusion.Addressing the complementary challenge of the blood supply shortage, there have been studies into processes that can extend the shelf-life of blood components. Because of their biological nature, bacterial contamination during storage is a major limitation of shelf-life and is especially important in platelet storage, which is normally stored at room temperature. Traditionally, platelet units have a shelf-life of 5 days, 2 of which are reserved for bacterial testing, meaning that at best, blood banks and transfusion services have only 3 days in which to use these units; alternatively, platelet units can have a shelf-life of 7 days they undergo cultures using large-volume-delayed sampling. With the advent of pathogen-reduction technologies (PRT) there is improved safety of the blood supply. Common PRT technologies include INTERCEPT Blood System (Cerus) and MIRASOL-Pathogen Reduction technology (Terumo BCT). INTERCEPT uses a psoralen compound which selectively binds to nucleic acids and forms strong cross-linkages after UV light exposure, preventing nucleic acid replication of pathogens. By contrast, MIRASOL is based on riboflavin that intercalates with DNA and RNA and causes single strand breaks following UV light exposure. Both technologies inactivate most pathogen contamination and enhance safety of platelets during storage. Some of the challenges of PRT include being implicated in platelet refractoriness and alloimmunization, platelet responsiveness to agonists, and possible diminished platelet viability. These challenges contribute to storage lesions, which are a series of negative structural and functional alterations during storage. The study by Barham et al in this issue seeks to explore the ultrastructural effect of PRT-treated platelets under electron microscopy (4). Resting platelets have high mitochondrial activity to meet the adenosine triphosphate (ATP) necessary to maintain cellular...

Thrombocytopenia is a frequent complication of patients presenting emergently across the world for a wide array of etiologies. From patients who develop thrombocytopenia due to invasive neoplastic disease affecting the bone marrow to patients who develop immune complications secondary to the formation of auto-antibody responses that drive patients’ platelet counts lower or even cause infection, these patients stress the clearest need for prompt tests to discern the more likely thrombocytopenic-inducing cause. It is in this setting that looking at other platelet variables easily obtainable from modern hematology analyzers has gained traction. One of the elements found in extended platelet profiles are immature platelets (youngest and newly released platelets), also known as reticulated platelets, which are readily measurable from a complete blood count. One of the advantages of obtaining these counts is that they represent the immediate response of the bone marrow to the thrombocytopenia and, depending on etiology inducing the thrombocytopenia, they also provide information on the marrow’s response to therapeutic approaches. It is in this context that this review will present information of how these relatively novel platelet parameters can be used in clinical practice and how they can be a rapid gauge of the body’s response to disease processes leading to platelet losses. Thrombocytopenias resulting from infection (sepsis, viremia), autoantibody formation (immune thrombocytopenia and immune-mediated thrombotic thrombocytopenic purpura), immune dysregulation (systemic lupus erythematosus), and iatrogenic (drug-induced) will be discussed and used to explain how these young platelet measurements can provide valuable clinical information.

Thrombocytopenia is a frequent complication of patients presenting emergently across the world for a wide array of etiologies. From patients who develop thrombocytopenia due to invasive neoplastic disease affecting the bone marrow to patients who developed immune-complications secondary to formation of auto-antibody responses that drive patients’ platelets counts lower or even infection, stress the clearest need of prompt tests to discern the more likely thrombocytopenic-inducing cause. It is in this setting that looking at other platelet variables easily obtainable from modern hematology analyzers have gained traction. One of these elements found in extended platelet profiles are immature platelets (youngest and newly released platelets) also known as reticulated platelets depending upon the platform performing the measurement. Among the advantages of obtaining these counts is that it represents the immediate responses by the bone marrow to the thrombocytopenia and depending on etiology inducing the thrombocytopenia it also provides information of the marrow response to therapeutic approaches. It is in this context that this review will present information of how these relatively novel platelet parameters can be used in clinical practice and how they can be a rapid gauge of the body’s response to disease processes leading to thrombocytopenia. Thrombocytopenias resulting from infection (sepsis), autoantibody formation (immune thrombocytopenia and immune-mediated thrombotic thrombocytopenic purpura), immune dysregulation (systemic lupus erythematosus), and iatrogenic (drug-induced) will be discussed and be used to explain how these young platelet measurements can provide valuable clinical information.

Platelet transfusions represent a common life-saving intervention used in intensive critical settings to treat neonates with thrombocytopenia, at risk of or actively bleeding, or undergoing clinical complications that make transfusions part of the management. Even though it is intended to help restore hemostasis in patients, platelet transfusions can, under certain circumstances, lead to negative effects, greater inflammation, and rarely increased mortality. It is the occurrence of these unforeseen and yet to be defined transfusion-associated complications that are at the center of a renewed effort to identify those factors increasing risk or that make a subset of patients more likely to develop adverse events as a result of transfusions. Platelets are active members of the native immune system and, as such, express surface receptors that mediate directly cross-talk with immune cells or do so indirectly though secretion of cytokines and chemokines that activate immune cells. Together with inherent differences between donated adult platelets and platelets in neonates, the reasons for negative responses begin to come into focus.