Immune thrombocytopenia (ITP) is a complex autoimmune disease characterized by low platelet counts. The pathogenesis of ITP remains unclear although both antibody‐mediated and/or T cell‐mediated platelet destruction are key processes. In addition, impairment of T cells, cytokine imbalances, and the contribution of the bone marrow niche have now been recognized to be important. Treatment strategies are aimed at the restoration of platelet counts compatible with adequate hemostasis rather than achieving physiological platelet counts. The first line treatments focus on the inhibition of autoantibody production and platelet degradation, whereas second‐line treatments include immunosuppressive drugs, such as Rituximab, and splenectomy. Finally, thirdline treatments aim to stimulate platelet production by megakaryocytes. This review discusses the pathophysiology of ITP and how the different treatment modalities affect the pathogenic mechanisms.

Transfusion-associated circulatory overload (TACO) and transfusion-related acute lung injury (TRALI) are syndromes of acute respiratory distress that occur within 6 hours of blood transfusion. TACO and TRALI are the leading causes of transfusion-related fatalities, and specific therapies are unavailable. Diagnostically, it remains very challenging to distinguish TACO and TRALI from underlying causes of lung injury and/or fluid overload as well as from each other. TACO is characterized by pulmonary hydrostatic (cardiogenic) edema, whereas TRALI presents as pulmonary permeability edema (noncardiogenic). The pathophysiology of both syndromes is complex and incompletely understood. A 2-hit model is generally assumed to underlie TACO and TRALI disease pathology, where the first hit represents the clinical condition of the patient and the second hit is conveyed by the transfusion product. In TACO, cardiac or renal impairment and positive fluid balance appear first hits, whereas suboptimal fluid management or other components in the transfused product may enable the second hit. Remarkably, other factors beyond volume play a role in TACO. In TRALI, the first hit can, for example, be represented by inflammation, whereas the second hit is assumed to be caused by antileukocyte antibodies or biological response modifiers (eg, lipids). In this review, we provide an up-to-date overview of TACO and TRALI regarding clinical definitions, diagnostic strategies, pathophysiological mechanisms, and potential therapies. More research is required to better understand TACO and TRALI pathophysiology, and more biomarker studies are warranted. Collectively, this may result in improved diagnostics and development of therapeutic approaches for these life-threatening transfusion reactions.

Primary immune thrombocytopenia is an autoimmune disease associated with a reduced peripheral blood platelet count. The phenotype is variable with some patients suffering no bleeding whilst others have severe bleeding which may be fatal. Variability in clinical behaviour and treatment responses reflects its complex underlying pathophysiology. Historically the management has relied heavily on immune suppression. Recent studies have shown that the older empirical immune suppressants fail to alter the natural history of the disease and are associated with a poor quality of life for patients. Newer treatments, such as the thrombopoietin receptor agonists, have transformed ITP care. They have high efficacy, are well tolerated and improve patients’ quality of life. A greater understanding of the underlying pathophysiology of this disorder has helped develop a number of new targeted therapies. These include inhibitors of the neonatal Fc receptor inhibitors, Bruton tyrosine kinase and complement pathway. Here we discuss the mechanisms underlying ITP and the new approach to ITP care.

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder mediated by antiplatelet autoantibodies and antigen-specific T cells that either destroy platelets peripherally in the spleen or impair platelet production in the bone marrow. There have been a plethora of publications relating to the pathophysiology of ITP and since January of 2019, at least 50 papers have been published on ITP pathophysiology.Purpose of review: To summarize the literature relating to the pathophysiology of ITP including the working mechanisms of therapies, T-cell and B-cell physiology, protein/RNA/DNA biochemistry, and animal models in an attempt to unify the perceived abnormal immune processes.Recent findings: The most recent pathophysiologic irregularities associated with ITP relate to abnormal T-cell responses, particularly, defective T regulatory cell activity and how therapeutics can restore these responses. The robust literature on T cells in ITP points to the notion that ITP is a disease initiated by faulty self-tolerance mechanisms very much like that of other organ-specific autoimmune diseases. There is also a large literature on new and existing animal models of ITP and these will be discussed. It appears that understanding how to specifically modulate T cells in patients with ITP will undoubtedly lead to effective antigen-specific therapeutics.Conclusions: ITP is predominately a T cell disorder which leads to a breakdown in self tolerance mechanisms and allows for the generation of anti-platelet autoantibodies and T cells. Novel therapeutics that target T cells may be the most effective way to perhaps cure this disorder.

Key Points: CD4+CD25+FoxP3+ T regulatory cells and CD11c+ dendritic cells protect against antibody-mediated murine TRALI. Murine TRALI is associated with reduced IL-10 levels, and IL-10 administration prevents and rescues TRALI development.

In addition to their hemostatic role, platelets play a significant role in immunity. Once activated, platelets release extracellular vesicles (EVs) formed by the budding of their cytoplasmic membranes. Because of their heterogeneity, platelet EVs (PEVs) are thought to perform diverse functions. It is unknown, however, whether the proteasome is transferred from platelets to PEVs or whether its function is retained. We hypothesized that functional protein processing and antigen presentation machinery are transferred to PEVs by activated platelets. Using molecular and functional assays, we found that the active 20S proteasome was enriched in PEVs, along with major histocompatibility complex class I (MHC-I) and lymphocyte costimulatory molecules (CD40L and OX40L). Proteasome-containing PEVs were identified in healthy donor blood, but did not increase in platelet concentrates that caused adverse transfusion reactions. They were augmented, however, after immune complex injections in mice. The complete biodistribution of murine PEVs after injection into mice revealed that they principally reached lymphoid organs, such as spleen and lymph nodes, in addition to the bone marrow, and to a lesser extent, liver and lungs. The PEV proteasome processed exogenous ovalbumin (OVA) and loaded its antigenic peptide onto MHC-I molecules, which promoted OVA-specific CD8+ T-lymphocyte proliferation. These results suggest that PEVs contribute to adaptive immunity through cross-presentation of antigens and have privileged access to immune cells through the lymphatic system, a tissue location that is inaccessible to platelets.