Hemostatic laboratory derangements in COVID-19 with a focus on platelet count

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease in 2019 (COVID-19) which rapidly evolved from an outbreak in Wuhan, China into a pandemic that has resulted in over millions of infections and over hundreds of thousands of mortalities worldwide. Various coagulopathies have been reported in association with COVID-19, including disseminated intravascular coagulation (DIC), sepsis-induced coagulopathy (SIC), local microthrombi, venous thromboembolism (VTE), arterial thrombotic complications, and thrombo-inflammation. There is a plethora of publications and conflicting data on hematological and hemostatic derangements in COVID-19 with some data suggesting the link to disease progress, severity and/or mortality. There is also growing evidence of potentially useful clinical biomarkers to predict COVID-19 progression and disease outcomes. Of those, a link between thrombocytopenia and COVID-19 severity or mortality was suggested. In this opinion report, we examine the published evidence of hematological and hemostatic laboratory derangements in COVID-19 and the interrelated SARS-CoV-2 induced inflammation, with a focussed discussion on platelet count alterations. We explore whether thrombocytopenia could be a potential disease biomarker and we provide recommendations for future studies in this regard.     

Dangerous liaisons: complement,coagulation, and kallikrein/kinin cross-talk act as a linchpin in the events leading to thromboinflammation

Innate immunity is fundamental to our defense against microorganisms. Physiologically, the intravascular innate immune system acts as a purging system that identifies and removes foreign substances leading to thromboinflammatory responses, tissue remodeling, and repair. It is also a key contributor to the adverse effects observed in many diseases and therapies involving biomaterials and therapeutic cells/organs. The intravascular innate immune system consists of the cascade systems of the blood (the complement, contact, coagulation, and fibrinolytic systems), the blood cells (polymorphonuclear cells, monocytes, platelets), and the endothelial cell lining of the vessels. Activation of the intravascular innate immune system in vivo leads to thromboinflammation that can be activated by several of the system's pathways and that initiates repair after tissue damage and leads to adverse reactions in several disorders and treatment modalities. In this review, we summarize the current knowledge in the field and discuss the obstacles that exist in order to study the cross-talk between the components of the intravascular innate immune system. These include the use of purified in vitro systems, animal models and various types of anticoagulants. In order to avoid some of these obstacles we have developed specialized human whole blood models that allow investigation of the cross-talk between the various cascade systems and the blood cells. We in particular stress that platelets are involved in these interactions and that the lectin pathway of the complement system is an emerging part of innate immunity that interacts with the contact/coagulation system. Understanding the resulting thromboinflammation will allow development of new therapeutic modalities.     

Platelets: "multiple choice" effectors in the immune response and their implication in COVID-19 thromboinflammatory process

Although platelets are traditionally recognized for their central role in hemostasis, the presence of chemotactic factors, chemokines, adhesion molecules, and costimulatory molecules in their granules and membranes indicates that they may play an immunomodulatory role in the immune response, flanking their capacity to trigger blood coagulation and inflammation. Indeed, platelets play a role not only in the innate immune response, through the expression of Toll-like receptors (TLRs) and release of inflammatory cytokines, but also in the adaptive immune response, through expression of key costimulatory molecules and major histocompatibility complex (MHC) molecules capable to activate T cells. Moreover, platelets release huge amounts of extracellular vesicles capable to interact with multiple immune players. The function of platelets thus extends beyond aggregation and implies a multifaceted interplay between hemostasis, inflammation, and the immune response, leading to the amplification of the body's defense processes on one hand, but also potentially degenerating into life-threatening pathological processes on the other. This narrative review summarizes the current knowledge and the most recent updates on platelet immune functions and interactions with infectious agents, with a particular focus on their involvement in COVID-19, whose pathogenesis involves a dysregulation of hemostatic and immune processes in which platelets may be determinant causative agents.     

β2 glycoprotein I participates in phagocytosis of apoptotic neurons and in vascular injury in experimental brain stroke

Beta-2 Glycoprotein I (β2-GPI) is the main target of anti-phospholipid antibodies (aPL) in the autoimmune anti-phospholipid syndrome, characterized by increased risk of stroke. We here investigated the antibody independent role of β2-GPI after ischemia/reperfusion, modeled in vivo by transient middle cerebral artery occlusion (tMCAo) in male C57Bl/6J mice; in vitro by subjecting immortalized human brain microvascular endothelial cells (ihBMEC) to 16 h hypoxia and 4 h re-oxygenation. ApoH (coding for β2-GPI) was upregulated selectively in the liver at 48 h after tMCAo. At the same time β2-GPI circulating levels increased. β2-GPI was detectable in brain parenchyma and endothelium at all time points after tMCAo. Parenchymal β2-GPI recognized apoptotic neurons (positive for annexin V, C3 and TUNEL) cleared by CD68+ brain macrophages. Hypoxic ihBMEC showed increased release of IL-6, over-expression of thrombomodulin and IL-1α after re-oxygenation with β2-GPI alone. β2-GPI interacted with mannose-binding lectin in mouse plasma and ihBMEC medium, potentially involved in formation of thrombi. We show for the first time that brain ischemia triggers the hepatic production of β2-GPI. β2-GPI is present in the ischemic endothelium, enhancing vascular inflammation, and extravasates binding stressed neurons before their clearance by phagocytosis. Thus β2-GPI may be a new mediator of brain injury following ischemic stroke.     

Platelet lipidome: Dismantling the “Trojan horse” in the bloodstream

The platelet‐lipid chapter in the story of atherothrombosis is an old one, recapitulated and revised in many contexts. For decades several stimulating facets have been added to it, both unraveling and increasing the perplexity of platelet‐lipid interplay and its pathophysiological consequences. The recent paradigm shift in our perspective has evolved with lipidomic analysis of the intraplatelet compartment and platelet releasate. These investigations have disclosed that platelets are in constant interaction with circulatory lipids, often reflected in their lipid repertoire. In addition, they offer a shielded intracellular space for oxidative lipid metabolism generating “toxic” metabolites that escape degradation by plasma lipases and antioxidant defense, circulate undetected by conventional plasma lipid profile, and deposited at atherosclerotic lesions or thrombus. Lipidomics divulges this silent invader in platelet vehicles, thereby providing potential biomarkers of pathologic manifestations and therapeutic targets to be exploited, which is surmised in this review.     

Neutrophil “plucking” on megakaryocytes drives platelet production and boosts cardiovascular disease

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The complex functioning of the complement system in xenotransplantation

The role of complement in xenotransplantation is well‐known and is a topic that has been reviewed previously. However, our understanding of the immense complexity of its interaction with other constituents of the innate immune response and of the coagulation, adaptive immune, and inflammatory responses to a xenograft is steadily increasing. In addition, the complement system plays a function in metabolism and homeostasis. New reviews at intervals are therefore clearly warranted. The pathways of complement activation, the function of the complement system, and the interaction between complement and coagulation, inflammation, and the adaptive immune system in relation to xenotransplantation are reviewed. Through several different mechanisms, complement activation is a major factor in contributing to xenograft failure. In the organ‐source pig, the detrimental influence of the complement system is seen during organ harvest and preservation, for example, in ischemia‐reperfusion injury. In the recipient, the effect of complement can be seen through its interaction with the immune, coagulation, and inflammatory responses. Genetic‐engineering and other therapeutic methods by which the xenograft can be protected from the effects of complement activation are discussed. The review provides an updated source of reference to this increasingly complex subject.     

A historical review of experimental imaging of the beating heart coronary microcirculation in vivo

Following a myocardial infarction (MI), the prognosis of patients is highly dependent upon the re-establishment of perfusion not only in the occluded coronary artery, but also within the coronary microcirculation. However, our fundamental understanding of the pathophysiology of the tiniest blood vessels of the heart is limited primarily because no current clinical imaging tools can directly visualise them. Moreover, in vivo experimental studies of the beating heart using intravital imaging have also been hampered due to obvious difficulties related to significant inherent contractile motion, movement of the heart brought about by nearby lungs and its location in an anatomically challenging position for microscopy. However, recent advances in microscopy techniques, and the development of fluorescent reporter mice and fluorescently conjugated antibodies allowing visualisation of vascular structures, thromboinflammatory cells and blood flow, have allowed us to overcome some of these challenges and increase our basic understanding of cardiac microvascular pathophysiology. In this review, the elegant attempts of the pioneers in intravital imaging of the beating heart will be discussed, which focussed on providing new insights into the anatomy and physiology of the healthy heart microvessels. The reviews end with the more recent studies that focussed on disease pathology and increasing our understanding of myocardial thromboinflammatory cell recruitment and flow disturbances, particularly in the setting of diseases such as MI.