Zane Kaplan

The Role of Platelets in Atherothrombosis

Platelets have evolved highly specialized adhesion mechanisms that enable cell-matrix and cell-cell interactions throughout the entire vasculature irrespective of the prevailing hemodynamic conditions. This unique property of platelets is critical for their ability to arrest bleeding and promote vessel repair. Platelet adhesion under conditions of high shear stress, as occurs in stenotic atherosclerotic arteries, is central to the development of arterial thrombosis; therefore, precise control of platelet adhesion must occur to maintain blood fluidity and to prevent thrombotic or hemorrhagic complications. Whereas the central role of platelets in hemostasis and thrombosis has long been recognized and well defined, there is now a major body of evidence supporting an important proinflammatory function for platelets that is linked to host defense and a variety of autoimmune and inflammatory diseases. In the context of the vasculature, experimental evidence indicates that the proinflammatory function of platelets can regulate various aspects of the atherosclerotic process, including its initiation and propagation. The mechanisms underlying the proatherogenic function of platelets are increasingly well defined and involve specific adhesive interactions between platelets and endothelial cells at atherosclerotic-prone sites, leading to the enhanced recruitment and activation of leukocytes. Through the release of chemokines, proinflammatory molecules, and other biological response modulators, the interaction among platelets, endothelial cells, and leukocytes establishes a localized inflammatory response that accelerates atherosclerosis. These inflammatory processes typically occur in regions of the vasculature experiencing low shear and perturbed blood flow, a permissive environment for leukocyte-platelet and leukocyte-endothelial interactions. Therefore, the concept has emerged that platelets are a central element of the atherothrombotic process and that future therapeutic strategies to combat this disease need to take into consideration both the prothrombotic and proinflammatory function of platelets.

Platelets are not just for clots

Although the role of platelets as central mediators of hemostasis and thrombosis has been the primary focus of research into platelet biology for more than a century, over the last decade, nonhemostatic functions of platelets have been increasingly defined. As such, a large body of experimental evidence now exists, which places the platelet as a key player in mediating a diverse range of immune, inflammatory, and malignant disease processes. This review outlines the central mechanisms that underpin the nonhemostatic role of platelets and provides a summary of evidence demonstrating a role for platelets in mediating selected inflammatory, immune, and malignant disease processes.

Low adhesion receptor levels on circulating platelets in patients with lymphoproliferative diseases before receiving Navitoclax (ABT-263)

To the editor: Leukemia cells express high levels of Bcl-2[1][1] and BH3 mimetics that antagonize the prosurvival function of Bcl-2 and related proteins, thereby inducing apoptosis, are useful treatments for patients with chemotherapy-refractory leukemia.[2][2] BH3 mimetics such as ABT-737 and ABT-

Neutrophil macroaggregates promote widespread pulmonary thrombosis after gut ischemia

Neutrophil macroaggregates induce a distinct arterial-venous thrombotic response in the lung after gut ischemia. Rip n’ roll Ischemia in critically ill patients can result in thrombosis of unrelated organs, which is partially due to neutrophil recruitment. Yuan et al. combined intravital microscopy of thrombosis after gut ischemia-reperfusion injury with samples from acute respiratory distress syndrome patients. They observed that rolling neutrophils grab and rip fragments from phosphatidylserine-expressing dying platelets, which leads to macroaggregates. These macroaggregates, in turn, induce thrombosis and were not able to be targeted by conventional therapies such as aspirin. Conversely, targeting the necrotic factor cyclophilin D did have beneficial effects. These studies reveal new thrombotic biology and suggest the development of alternatively targeted therapies to prevent distant organ injury. Gut ischemia is common in critically ill patients, promoting thrombosis and inflammation in distant organs. The mechanisms linking hemodynamic changes in the gut to remote organ thrombosis remain ill-defined. We demonstrate that gut ischemia in the mouse induces a distinct pulmonary thrombotic disorder triggered by neutrophil macroaggregates. These neutrophil aggregates lead to widespread occlusion of pulmonary arteries, veins, and the microvasculature. A similar pulmonary neutrophil-rich thrombotic response occurred in humans with the acute respiratory distress syndrome. Intravital microscopy during gut ischemia-reperfusion injury revealed that rolling neutrophils extract large membrane fragments from remnant dying platelets in multiple organs. These platelet fragments bridge adjacent neutrophils to facilitate macroaggregation. Platelet-specific deletion of cyclophilin D, a mitochondrial regulator of cell necrosis, prevented neutrophil macroaggregation and pulmonary thrombosis. Our studies demonstrate the existence of a distinct pulmonary thrombotic disorder triggered by dying platelets and neutrophil macroaggregates. Therapeutic targeting of platelet death pathways may reduce pulmonary thrombosis in critically ill patients.

Bortezomib-based antibody depletion for refractory autoimmune hematological diseases

Certain patients with antibody-mediated autoimmune disease exhibit poor responses to conventional immunosuppression, including B-cell depletion with rituximab. Proteasome inhibitors such as bortezomib demonstrate pleiotropic immunomodulatory effects, including direct toxicity to antibody-producing cells. Here, we report preliminary evidence for the efficacy of bortezomib as salvage therapy for refractory autoimmune hematological disease. Thirteen treatment episodes in 10 patients with autoimmune hematological phenomena (autoimmune hemolytic anemia [AIHA; n = 8], acquired hemophilia (n = 1), immune thrombocytopenia (n = 1), and thrombotic thrombocytopenic purpura [TTP; n = 3]) and a median of 5 (range, 3-12) prior lines of therapy demonstrated an overall response rate of 77% (10 of 13) including 38% (5 of 13) complete remissions. The majority of clinical improvements were rapid, correlated with biomarkers of autoantibody reduction, and were associated with an acceptable safety profile. Responses appeared durable following treatment of TTP and acquired hemophilia; AIHA responses were more limited with a pattern of relapse following bortezomib cessation. These data provide proof of concept for the utility of proteasome inhibition as antibody depletion therapy in autoimmune disease.

Factor VIII inhibitor eradication with bortezomib in acquired haemophilia A

Philip M. Kluin Marieke Griffioen Marcelo A. Navarrete Hendrik Veelken Department of Hematology, Department of Medical Statistics and Bioinformatics, Department of Human Genetics, Leiden Genome Technology Centre, Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands, Department of Pathology, University Medical Centre Groningen, Groningen, The Netherlands and School of Medicine, University of Magallanes, Punta Arenas, Chile. E-mail: j.h.veelken@lumc.nl, and marcelo.navarrete@umag.cl

SR-BI and fatty platelets

Dysregulated cholesterol transport and metabolism are important risk factors for atherothrombosis and are commonly associated with enhanced platelet reactivity; however, the molecular mechanisms linking hypercholesterolemia with increased platelet function remain unclear. In this issue of Blood , Ma

Understanding of the significance and health implications of asplenia in a cohort of patients with haemaglobinopathy: possible benefits of a spleen registry

ABSTRACT Objectives: Asplenia and hyposplenism carry a significant risk of ongoing morbidity and mortality which can be reduced by education, vaccination and antibiotic use. We aimed to assess education and other methods of prevention in a cohort of patients with haemoglobinopathy in a tertiary referral centre, which also had access to a post-splenectomy registry created to reduce post-splenectomy infection risk. Methods: A standardized questionnaire was used on patients who attended the service for regular therapy. Patients were also asked about standard post-splenectomy preventive therapies including antibiotics and vaccinations. Results: There were 49 patients who had either had a splenectomy or knew their spleen to be non-functional. Of these, nearly half knew themselves to be on the Victorian Spleen Registry (51.0%). The median knowledge score was 12 (range 4–17) out of a possible 18. Most significantly the benefits of the registry were not seen in terms of knowledge but in delivery of recommended vaccines and the use of a medical alert card. Conclusion: This study examined knowledge and attitudes about splenectomy in a cohort of haemoglobinopathy patients in an Australian tertiary referral centre. The majority had good or fair knowledge with a strong association of some elements of post-splenectomy care with being placed on a spleen registry and having received targeted education. Implementation of systematic approaches by medical staff is likely to be the main benefit of a clinical registry approach in this setting.

High rates of potentially infectious exposures between immunocompromised patients and their companion animals: an unmet need for education

A cross‐sectional survey of 265 adult patients with haematological malignancy, haemoglobinopathy or human immunodeficiency virus was performed to determine the potential risk of infection from animal exposures. One hundred and thirty‐seven (52%) owned an animal; the majority were dogs (74%) and cats (39%), but 14% owned birds and 3% reptiles. Eighty percent engaged in behaviour with their animals that potentially put them at risk of zoonotic infections. The most frequent behaviours were picking up animal faeces 72 (52%), cleaning animal areas 69 (50%) and allowing animals to sleep in the same bed 51 (37%). Twenty‐eight percent allowed the animal to lick their face. Of all patients, 80 (30%) had been bitten or scratched by an animal. Only 16% of those who owned pets could recall receiving education regarding safe behaviours around animals. These immunocompromised patients are at risk of infection through exposure to pets. Our study highlights the need for increased education of patients regarding how to remain safe around their pets.

Antiplatelet therapy: present status and future prospects

The excessive accumulation of platelets at sites of vascular injury is a key event in the development of arterial thrombosis, the principal pathogenic mechanism underlying the acute coronary syndromes and ischaemic stroke. In combination, these disorders are the leading causes of morbidity and mortality in the industrialised world and, as a consequence, the platelet is a major therapeutic target in the management of cardiovascular disease. This perspective focuses on the present state of antiplatelet therapy and potential future strategies to improve the safety and efficacy of antiplatelet agents.