Vitronectin promotes immunothrombotic dysregulation in the venular microvasculature.

Microvascular immunothrombotic dysregulation is a critical process in the pathogenesis of severe systemic inflammatory diseases. The mechanisms controlling immunothrombosis in inflamed microvessels, however, remain poorly understood. Here, we report that under systemic inflammatory conditions the matricellular glycoproteinvitronectin (VN) establishes an intravascular scaffold, supporting interactions of aggregating platelets with immune cells and the venular endothelium. Blockade of the VN receptor glycoprotein (GP)IIb/IIIa interfered with this multicellular interplay and effectively prevented microvascular clot formation. In line with these experimental data, particularly VN was found to be enriched in the pulmonary microvasculature of patients with non-infectious (pancreatitis-associated) or infectious (coronavirus disease 2019 (COVID-19)-associated) severe systemic inflammatory responses. Targeting the VN-GPIIb/IIIa axis hence appears as a promising, already feasible strategy to counteract microvascular immunothrombotic dysregulation in systemic inflammatory pathologies.

Microvascular Thrombosis as a Critical Factor in Severe COVID-19.

Platelet-endothelial interactions have a critical role in microcirculatory function, which maintains tissue homeostasis. The subtle equilibrium between platelets and the vessel wall is disturbed by the coronavirus disease 2019 (COVID-19), which affects all three components of Virchow's triad (endothelial injury, stasis and a hypercoagulable state). Endotheliitis, vasculitis, glycocalyx degradation, alterations in blood flow and viscosity, neutrophil extracellular trap formation and microparticle shedding are only few pathomechanisms contributing to endothelial damage and microthrombosis resulting in capillary plugging and tissue ischemia. In the following opinion paper, we discuss major pathological processes leading to microvascular endothelial activation and thrombosis formation as a possible major adverse factor driving the deterioration of patient disease course in severe COVID-19.

Immune-Mediated Platelet Activation in COVID-19 and Vaccine-Induced Immune Thrombotic Thrombocytopenia.

Both qualitative and quantitative platelet abnormalities are common in patients with coronavirus disease 2019 (COVID-19) and they correlate with clinical severity and mortality. Activated platelets contribute to the prothrombotic state in COVID-19 patients. Several groups have shown immune-mediated activation of platelets in critically ill COVID-19 patients. Vaccine-induced immune thrombotic thrombocytopenia is an autoimmune condition characterized by thrombocytopenia and life-threatening thrombotic events in the arterial and venous circulation. Although the initial trigger has yet to be determined, activation of platelets by immune complexes through Fc gamma RIIA results in platelet consumption and thrombosis. A better understanding of platelet activation in COVID-19 as well as in vaccine-induced thrombotic complications will have therapeutic implications. In this review, we focused on the role of immune-mediated platelet activation in thrombotic complications during COVID-19 infection and vaccine-induced immune thrombotic thrombocytopenia.

An Insight into Recent Advances on Platelet Function in Health and Disease.

Platelets play a variety of roles in vascular biology and are best recognized as primary hemostasis and thrombosis mediators. Platelets have a large number of receptors and secretory molecules that are required for platelet functionality. Upon activation, platelets release multiple substances that have the ability to influence both physiological and pathophysiological processes including inflammation, tissue regeneration and repair, cancer progression, and spreading. The involvement of platelets in the progression and seriousness of a variety of disorders other than thrombosis is still being discovered, especially in the areas of inflammation and the immunological response. This review represents an integrated summary of recent advances on the function of platelets in pathophysiology that connects hemostasis, inflammation, and immunological response in health and disease and suggests that antiplatelet treatment might be used for more than only thrombosis.

The Use of Total Thrombus Formation Analysis System as a Tool to Assess Platelet Function in Bleeding and Thrombosis Risk-A Systematic Review.

BACKGROUND: Today there are many devices that can be used to study blood clotting disorders by identifying abnormalities in blood platelets. The Total Thrombus Formation Analysis System is an automated microchip flow chamber system that is used for the quantitative analysis of clot formation under blood flow conditions. For several years, researchers have been using a tool to analyse various clinical situations of patients to identify the properties and biochemical processes occurring within platelets and their microenvironment. METHODS: An investigation of recent published literature was conducted based on PRISMA. This review includes 52 science papers directly related to the use of the Total Clot Formation Analysis System in relation to bleeding, surgery, platelet function assessment, anticoagulation monitoring, von Willebrand factor and others. CONCLUSION: Most available studies indicate that The Total Thrombus Formation Analysis System may be useful in diagnostic issues, with devices used to monitor therapy or as a significant tool for predicting bleeding events. However, T-TAS not that has the potential for diagnostic indications, but allows the direct observation of the flow and the interactions between blood cells, including the intensity and dynamics of clot formation. The device is expected to be of significant value for basic research to observe the interactions and changes within platelets and their microenvironment.

Prothrombotic Phenotype in COVID-19: Focus on Platelets.

COVID-19 infection is associated with a broad spectrum of presentations, but alveolar capillary microthrombi have been described as a common finding in COVID-19 patients, appearing as a consequence of a severe endothelial injury with endothelial cell membrane disruption. These observations clearly point to the identification of a COVID-19-associated coagulopathy, which may contribute to thrombosis, multi-organ damage, and cause of severity and fatality. One significant finding that emerges in prothrombotic abnormalities observed in COVID-19 patients is that the coagulation alterations are mainly mediated by the activation of platelets and intrinsically related to viral-mediated endothelial inflammation. Beyond the well-known role in hemostasis, the ability of platelets to also release various potent cytokines and chemokines has elevated these small cells from simple cell fragments to crucial modulators in the blood, including their inflammatory functions, that have a large influence on the immune response during infectious disease. Indeed, platelets are involved in the pathogenesis of acute lung injury also by promoting NET formation and affecting vascular permeability. Specifically, the deposition by activated platelets of the chemokine platelet factor 4 at sites of inflammation promotes adhesion of neutrophils on endothelial cells and thrombogenesis, and it seems deeply involved in the phenomenon of vaccine-induced thrombocytopenia and thrombosis. Importantly, the hyperactivated platelet phenotype along with evidence of cytokine storm, high levels of P-selectin, D-dimer, and, on the other hand, decreased levels of fibrinogen, von Willebrand factor, and thrombocytopenia may be considered suitable biomarkers that distinguish the late stage of COVID-19 progression in critically ill patients.

Platelets and COVID-19.

In 2019 first reports about a new human coronavirus emerged, which causes common cold symptoms as well as acute respiratory distress syndrome. The virus was identified as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and severe thrombotic events including deep vein thrombosis, pulmonary embolism, and microthrombi emerged as additional symptoms. Heart failure, myocardial infarction, myocarditis, and stroke have also been observed. As main mediator of thrombus formation, platelets became one of the key aspects in SARS-CoV-2 research. Platelets may also directly interact with SARS-CoV-2 and have been shown to carry the SARS-CoV-2 virus. Platelets can also facilitate the virus uptake by secretion of the subtilisin-like proprotein convertase furin. Cleavage of the SARS-CoV-2 spike protein by furin enhances binding capabilities and virus entry into various cell types. In COVID-19 patients, platelet count differs between mild and serious infections. Patients with mild symptoms have a slightly increased platelet count, whereas thrombocytopenia is a hallmark of severe COVID-19 infections. Low platelet count can be attributed to platelet apoptosis and the incorporation of platelets into microthrombi (peripheral consumption) and severe thrombotic events. The observed excessive formation of thrombi is due to hyperactivation of platelets caused by the infection. Various factors have been suggested in the activation of platelets in COVID-19, such as hypoxia, vessel damage, inflammatory factors, NETosis, SARS-CoV-2 interaction, autoimmune reactions, and autocrine activation. COVID-19 does alter chemokine and cytokine plasma concentrations. Platelet chemokine profiles are altered in COVID-19 and contribute to the described chemokine storms observed in severely ill COVID-19 patients.

COVID-19 in Pregnancy: Implication on Platelets and Blood Indices.

OBJECTIVE: To describe the hematological changes, the platelet indices in particular, in pregnant women with coronavirus disease 2019 (COVID-19) compared to healthy pregnant women. METHODS: A retrospective case-control study conducted at the Al Yarmouk Teaching Hospital, in Baghdad, Iraq, involving 100 pregnant women, 50 with positive viral DNA for COVID-19 (case group), and 50 with negative results (control group); both groups were subjected to a thorough hematological evaluation. RESULTS: Among the main hematological variables analyzed, the platelet indices, namely the mean platelet volume (MPV) and the platelet distribution width (PDW), showed statistically significant differences (MPV: 10.87 ± 66.92 fL for the case group versus 9.84 ± 1.2 fL for the control group; PDW: 14.82 ± 3.18 fL for the case group versus 13.3 ± 2.16 fL for the controls). The criterion value of the receiver operating characteristic (ROC) curve for PDW at a cutoff point of > 11.8 fL showed a weak diagnostic marker, while the MPV at a cutoff value of > 10.17 fL showed a good diagnostic marker. CONCLUSION: The MPV and PDW are significantly affected by the this viral infection, even in asymptomatic confirmed cases, and we recommend that both parameters be included in the diagnostic panel of this infection.

OBJETIVO: Descrever as alterações hematológicas, em particular os índices plaquetários em gestantes com doença coronavírus 2019 (COVID-19) em comparação com gestantes saudáveis. MéTODOS: Estudo caso-controle retrospectivo realizado no Hospital Universitário Al Yarmouk, em Bagdá, Iraque envolvendo 100 gestantes, 50 com DNA viral positivo para COVID-19 (grupo caso) e 50 com resultados negativos (grupo controle); ambos os grupos foram submetidos a uma avaliação hematológica completa. RESULTADOS: Entre as principais variáveis hematológicas analisadas, os índices plaquetários, nomeadamente o volume plaquetário médio (VPM) e a largura de distribuição plaquetária (PDW), apresentaram diferenças estatisticamente significativas (VPM: 10,87 ± 66,92 fL para o grupo caso versus 9,84 ± 1.2 fL para o o grupo controle; PDW: 14,82 ± 3,18 fL para o grupo caso versus 13,3 ± 2,16 fL para os controles). O valor de critério da curva de característica de operação do receptor (ROC) para PDW em um ponto de corte de> 11,8 fL mostrou um marcador diagnóstico fraco, enquanto o do VPM em um valor de corte de> 10,17 fL mostrou um bom marcador de diagnóstico. CONCLUSãO: O MPV e PDW são significativamente afetados por esta infecção viral, mesmo em casos confirmados assintomáticos, e recomendamos que ambos os parâmetros sejam incluídos no painel de diagnóstico desta infecção.

Platelets in the perspective of COVID-19; pathophysiology of thrombocytopenia and its implication as prognostic and therapeutic opportunity.

Despite endorsed and exponential research to improve diagnostic and therapeutic strategies, efforts have not yet converted into a better prospect for patients infected with the novel coronavirus (2019nCoV), and still, the name of SARS-CoV-2 is coupled with numerous unanswered questions. One of these questions is concerning how this respiratory virus reduces the number of platelets (PLTs)? The results of laboratory examinations showed that about a quarter of COVID-19 cases experience thrombocytopenia, and more remarkably, about half of these patients succumb to the infection due to coagulopathy. These findings have positioned PLTs as a pillar in the management as well as stratifying COVID-19 patients; however, not all the physicians came into a consensus about the prognostic value of these cells. The current review aims to unravel the contributory role of PLTs s in COVID-19; and alsoto summarize the original data obtained from international research laboratories on the association between COVID-19 and PLT production, activation, and clearance. In addition, we provide a special focus on the prognostic value of PLTs and their related parameters in COVID-19. Questions on how SARS-CoV-2 induces thrombocytopenia are also responded to. The last section provides a general overview of the most recent PLT- or thrombocytopenia-related therapeutic approaches. In conclusion, since SARS-CoV-2 reduces the number of PLTs by eliciting different mechanisms, treatment of thrombocytopenia in COVID-19 patients is not as simple as it appears and serious cautions should be considered to deal with the problem through scrutiny awareness of the causal mechanisms.

Is COVID-19-Induced Platelet Activation a Cause of Concern for Patients with Cancer?

Patients with cancer are more susceptible to be infected by SARS-CoV-2 and develop severe outcomes including ICU admittance, mechanical ventilator support, and a high rate of mortality. Like mid-to late-stage cancer, SARS-CoV-2 infection is associated with platelet hyperactivity, systemic inflammation, thrombotic complications, and coagulopathy. Platelets also promote cancer cell growth, survival in circulation, and angiogenesis at sites of metastases. In this article, we will discuss the potential for platelets in the development of systemic inflammation and thrombosis in SARS-CoV-2-infected patients with cancer, with the concern that the platelet-induced pathogenic events are likely magnified in cancer patients with COVID-19.

Preventing the development of severe COVID-19 by modifying immunothrombosis.

BACKGROUND: COVID-19-associated acute respiratory distress syndrome (ARDS) is associated with significant morbidity and high levels of mortality. This paper describes the processes involved in the pathophysiology of COVID-19 from the initial infection and subsequent destruction of type II alveolar epithelial cells by SARS-CoV-2 and culminating in the development of ARDS. MAIN BODY: The activation of alveolar cells and alveolar macrophages leads to the release of large quantities of proinflammatory cytokines and chemokines and their translocation into the pulmonary vasculature. The presence of these inflammatory mediators in the vascular compartment leads to the activation of vascular endothelial cells platelets and neutrophils and the subsequent formation of platelet neutrophil complexes. These complexes in concert with activated endothelial cells interact to create a state of immunothrombosis. The consequence of immunothrombosis include hypercoagulation, accelerating inflammation, fibrin deposition, migration of neutrophil extracellular traps (NETs) producing neutrophils into the alveolar apace, activation of the NLRP3 inflammazome, increased alveolar macrophage destruction and massive tissue damage by pyroptosis and necroptosis Therapeutic combinations aimed at ameliorating immunothrombosis and preventing the development of severe COVID-19 are discussed in detail.

The protective rather than prothrombotic fibrinogen in COVID-19 and other inflammatory states.

Hypercoagulability has been recognized as a common complication of COVID-19. Exact mechanisms for this extreme coagulation activation have not yet been elucidated. However, one of the consistent laboratory finding is the increase in fibrinogen, in some cases, marked elevation. High circulating levels of fibrinogen have been linked to thrombosis for years and for this reason, hyperfibrinogenemia is considered one of the mechanisms for COVID-19 coagulopathy. In this forum article, instead of the prothrombotic role, a protective function for fibrinogen is discussed. Fibrinogen, like the other well-known acute phase reactants, is increased in COVID-19 possibly to protect the host.

Platelet functions and activities as potential hematologic parameters related to Coronavirus Disease 2019 (Covid-19).

Coronavirus disease 2019 (COVID-19) is a new infectious disease that currently lacks standardized and established laboratory markers to evaluate its severity. In COVID-19 patients, the number of platelets (PLTs) and dynamic changes of PLT-related parameters are currently a concern. The present paper discusses the potential link between PLT parameters and COVID-19. Several studies have identified a link between severe COVID-19 patients and specific coagulation index, in particular, high D-dimer level, prolonged prothrombin time, and low PLT count. These alterations reflect the hypercoagulable state present in severe COVID-19 patients, which could promote microthrombosis in the lungs, as well as in other organs. Further information and more advanced hematological parameters related to PLTs are needed to better estimate this link, also considering COVID-19 patients at different disease stages and stratified in different cohorts based on preexisting co-morbidity, age, and gender. Increasing the understanding of PLT functions in COVID-19 will undoubtedly improve our knowledge on disease pathogenesis, clinical management, and therapeutic options, but could also lead to the development of more precise therapeutic strategies for COVID-19 patients.

The diagnostic and predictive role of NLR, d-NLR and PLR in COVID-19 patients.

AIM: To accumulate evidence that indicated the key role played by virus-triggered inflammation in the 2019-novel coronavirus disease (COVID-19) which emerged in Wuhan City and rapidly spread throughout China. METHODS: Age, neutrophil(NEU)-to-lymphocyte (LYM) ratio (NLR), lymphocyte-to-monocyte (MON) ratio, platelet-to-lymphocyte ratio (PLR), and C-reactive protein (CRP) of 93 patients with laboratory confirmed COVID-19 were investigated and compared. The receiver operating characteristic curve was applied to determine the thresholds for five bio-markers, and their prognostic values were assessed via the Kaplan-Meier curve and multivariate COX regression models. RESULTS: The median age was 46.4 years old, and 37cases were females. A total of 27.8% of patients had been to Wuhan, and 73.1% had contacted with people from Wuhan. Fever (83.8%) and cough (70.9%) were the two most common symptoms. Elevated NLR and age were significantly associated with illness severity. The binary logistic analysis identified elevated NLR (hazard risk [HR] 2.46, 95% confidence interval [CI] 1.98-4.57) and age (HR 2.52, 95% CI 1.65-4.83) as independent factors for poor clinical outcome of COVID-19. NLR exhibited the largest area under the curve at 0.841, with the highest specificity (63.6%) and sensitivity (88%). CONCLUSIONS: Elevated age and NLR can be considered independent biomarkers for indicating poor clinical outcomes.