scholarly journals The Central Role of Extracellular Vesicles in the Mechanisms of Thrombosis in COVID-19 Patients With Cancer and Therapeutic Strategies

2022 ◽  
Vol 9 ◽  
Author(s):  
Haijiao Jing ◽  
Nan Zuo ◽  
Valerie A. Novakovic ◽  
Jialan Shi
Keyword(s):  
Blood Cells ◽  
Antithrombotic Therapy ◽  
Feedback Loop ◽  
Early Stage ◽  
Thrombus Formation ◽  
Clinical Manifestations ◽  
Blood Perfusion ◽  
Coagulation Cascade ◽  
Patients With Cancer

Cancer patients have increased SARS-CoV-2 susceptibility and are prone to developing severe COVID-19 infections. The incidence of venous thrombosis is approximately 20% in COVID-19 patients with cancer. It has been suggested that thrombus formation has been suggested to correlate with severe clinical manifestations, mortality, and sequelae. In this review, we primarily elaborate on the pathophysiological mechanisms of thrombosis in COVID-19 patients with cancer, emphasize the role of microparticles (MPs) and phosphatidylserine (PS) in coagulation, and propose an antithrombotic strategy. The coagulation mechanisms of COVID-19 and cancer synergistically amplify the coagulation cascade, and collectively promotes pulmonary microvascular occlusion. During systemic coagulation, the virus activates immune cells to release abundant proinflammatory cytokines, referred to as cytokine storm, resulting in the apoptosis of tumor and blood cells and subsequent MPs release. Additionally, we highlight that tumor cells contribute to MPs and coagulation by apoptosis owing to insufficient blood supply. A positive feedback loop of cytokines storm and MPs storm promotes microvascular coagulation storm, leading to microthrombi formation and inadequate blood perfusion. Microthrombi-damaged endothelial cells (ECs), tumor, and blood cells further aggravate the apoptosis of the cells and facilitate MPs storm. PS, especially on MPs, plays a pivotal role in the blood coagulation process, contributing to clot initiation, amplification, and propagation. Since coagulation is a common pathway of COVID-19 and cancer, and associated with mortality, patients would benefit from antithrombotic therapy. The above results lead us to assert that early stage antithrombotic therapy is optimal. This strategy is likely to maintain blood flow patency contributing to viral clearance, attenuating the formation of cytokines and MPs storm, maintaining oxygen saturation, and avoiding the progress of the disease.

Disseminated intravascular coagulation syndrome

2020 ◽  
pp. 22-40
Author(s):  
A. Kulikov
Keyword(s):  
Clinical Practice ◽  
Disseminated Intravascular Coagulation ◽  
Blood Cells ◽  
Physical State ◽  
Clinical Manifestations ◽  
Vascular Wall ◽  
Stages Of Development ◽  
Intravascular Coagulation ◽  
Hemostatic Disorder

Presented material reveals main links in the pathogenesis of hemostatic disorder. In particular, attention is paid to the role of the lungs, liver and other organs in the development of this process. Role of vascular wall and blood cells in regulation of the physical state of blood is described in detail. The most frequent factors leading to hypercoagulation are indicated. Difference between hypercoagulation and thrombophilia is shown. The latter is found in clinical practice quite often, but at the same time, it is poorly diagnosed. Such a terrible complication of hemostatic disorder as disseminated intravascular coagulation is described. Its classification, stages of development, clinical manifestations are offered to the readers.

scholarly journals Distinct Mechanism between Arterial and Venous Thrombosis: Impact for Clinical Manifestations

2019 ◽  
Vol 5 (1 (P)) ◽  
pp. 47
Author(s):  
M. Taufik Ismail
Keyword(s):  
Clinical Manifestations ◽  
Circulatory System ◽  
Adenosine Diphosphate ◽  
Surface Glycoprotein ◽  
Coagulation Cascade ◽  
Wall Injury ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Adhesion Of Platelets

Hemostasis is a complex physiological process aiming to keep the integrity of a closed circulatory system after an occurrence of vessel wall injury. Hemostasis involving the role of circulating platelets and coagulation cascade.1 There are two major pathways that act independently to activate the platelet. The first pathway is mediated by collagen and the other by tissue factor. After intimal layer injury, platelets are recruited through the interaction between platelet’s surface glycoprotein (GPVI and GPIb/V/IX) with collagen and von Willebrand factor. This process results in adhesion of platelets in the site of injury. Further recruitment of platelets is achieved by secretion of aggregatory mediators such as thromboxane A2 and adenosine diphosphate.

Apoptosis as a Determinant of Atherothrombosis

2001 ◽  
Vol 86 (07) ◽  
pp. 420-426 ◽  
Author(s):  
Ziad Mallat ◽  
Alain Tedgui
Keyword(s):  
Atherosclerotic Plaque ◽  
Cell Apoptosis ◽  
Plaque Rupture ◽  
Apoptotic Cell ◽  
Thrombus Formation ◽  
Clinical Manifestations ◽  
Procoagulant Activity ◽  
Coagulation Cascade ◽  
Anionic Phospholipid ◽  
Plaque Disruption

SummaryClinical manifestations of atherosclerosis are the consequences of atherosclerotic plaque rupture that triggers thrombus formation. Tissue factor (TF) is a key element in the initiation of the coagulation cascade and is crucial in thrombus formation following plaque disruption. TF activity is highly dependent on the presence of phosphatidylserine (PS), an anionic phospholipid that is redistributed on the cell surface during apoptotic death conferring a potent procoagulant activity to the apoptotic cell. Apoptosis occurs in the human atherosclerotic plaque and shed membrane apoptotic microparticles rich in PS are produced in considerable amounts within the lipid core. These microparticles carry almost all TF activity and are responsible for the procoagulant activity of the plaque. Moreover, luminal endothelial cell apoptosis might be responsible for thrombus formation on eroded plaques without rupture. Apoptosis might also play a major role in blood thrombogenicity via circulating procoagulant microparticles that are found at high levels in patients with acute coronary syndromes.

scholarly journals NADPH Oxidases Are Required for Full Platelet Activation In Vitro and Thrombosis In Vivo but Dispensable for Plasma Coagulation and Hemostasis

2020 ◽  
Author(s):  
Dina Vara ◽  
Reiner K. Mailer ◽  
Anuradha Tarafdar ◽  
Nina Wolska ◽  
Marco Heestermans ◽  
...  
Keyword(s):  
Thrombus Formation ◽  
Single Gene ◽  
Coagulation Cascade ◽  
Intracellular Cgmp ◽  
Antithrombotic Effects ◽  
Tail Tip ◽  
Synthase Inhibitor

Objective: Using 3KO (triple NOX [NADPH oxidase] knockout) mice (ie, NOX1 −/− /NOX2 −/− /NOX4 −/− ), we aimed to clarify the role of this family of enzymes in the regulation of platelets in vitro and hemostasis in vivo. Approach and Results: 3KO mice displayed significantly reduced platelet superoxide radical generation, which was associated with impaired platelet aggregation, adhesion, and thrombus formation in response to the key agonists collagen and thrombin. A comparison with single-gene knockouts suggested that the phenotype of 3KO platelets is the combination of the effects of the genetic deletion of NOX1 and NOX2, while NOX4 does not show any significant function in platelet regulation. 3KO platelets displayed significantly higher levels of cGMP—a negative platelet regulator that activates PKG (protein kinase G). The inhibition of PKG substantially but only partially rescued the defective phenotype of 3KO platelets, which are responsive to both collagen and thrombin in the presence of the PKG inhibitors KT5823 or Rp-8-pCPT-cGMPs, but not in the presence of the NOS (NO synthase) inhibitor L-NG-monomethyl arginine. In vivo, triple NOX deficiency protected against ferric chloride–driven carotid artery thrombosis and experimental pulmonary embolism, while hemostasis tested in a tail-tip transection assay was not affected. Procoagulatory activity of platelets (ie, phosphatidylserine surface exposure) and the coagulation cascade in platelet-free plasma were normal. Conclusions: This study indicates that inhibiting NOXs has strong antithrombotic effects partially caused by increased intracellular cGMP but spares hemostasis. NOXs are, therefore, pharmacotherapeutic targets to develop new antithrombotic drugs without bleeding side effects.

scholarly journals Atherothrombosis and Thromboembolism: Position Paper from the Second Maastricht Consensus Conference on Thrombosis

2018 ◽  
Vol 118 (02) ◽  
pp. 229-250 ◽  
Author(s):  
H. Spronk ◽  
T. Padro ◽  
J. Siland ◽  
J. Prochaska ◽  
J. Winters ◽  
...  
Keyword(s):  
Risk Factors ◽  
Antithrombotic Therapy ◽  
Thrombus Formation ◽  
Consensus Conference ◽  
Risk Scores ◽  
Dependent Manner ◽  
Metabolomics Data ◽  
Circulating Cells ◽  
The Impact

AbstractAtherothrombosis is a leading cause of cardiovascular mortality and long-term morbidity. Platelets and coagulation proteases, interacting with circulating cells and in different vascular beds, modify several complex pathologies including atherosclerosis. In the second Maastricht Consensus Conference on Thrombosis, this theme was addressed by diverse scientists from bench to bedside. All presentations were discussed with audience members and the results of these discussions were incorporated in the final document that presents a state-of-the-art reflection of expert opinions and consensus recommendations regarding the following five topics: 1. Risk factors, biomarkers and plaque instability: In atherothrombosis research, more focus on the contribution of specific risk factors like ectopic fat needs to be considered; definitions of atherothrombosis are important distinguishing different phases of disease, including plaque (in)stability; proteomic and metabolomics data are to be added to genetic information. 2. Circulating cells including platelets and atherothrombosis: Mechanisms of leukocyte and macrophage plasticity, migration, and transformation in murine atherosclerosis need to be considered; disease mechanism-based biomarkers need to be identified; experimental systems are needed that incorporate whole-blood flow to understand how red blood cells influence thrombus formation and stability; knowledge on platelet heterogeneity and priming conditions needs to be translated toward the in vivo situation. 3. Coagulation proteases, fibrin(ogen) and thrombus formation: The role of factor (F) XI in thrombosis including the lower margins of this factor related to safe and effective antithrombotic therapy needs to be established; FXI is a key regulator in linking platelets, thrombin generation, and inflammatory mechanisms in a renin–angiotensin dependent manner; however, the impact on thrombin-dependent PAR signaling needs further study; the fundamental mechanisms in FXIII biology and biochemistry and its impact on thrombus biophysical characteristics need to be explored; the interactions of red cells and fibrin formation and its consequences for thrombus formation and lysis need to be addressed. Platelet–fibrin interactions are pivotal determinants of clot formation and stability with potential therapeutic consequences. 4. Preventive and acute treatment of atherothrombosis and arterial embolism; novel ways and tailoring? The role of protease-activated receptor (PAR)-4 vis à vis PAR-1 as target for antithrombotic therapy merits study; ongoing trials on platelet function test-based antiplatelet therapy adjustment support development of practically feasible tests; risk scores for patients with atrial fibrillation need refinement, taking new biomarkers including coagulation into account; risk scores that consider organ system differences in bleeding may have added value; all forms of oral anticoagulant treatment require better organization, including education and emergency access; laboratory testing still needs rapidly available sensitive tests with short turnaround time. 5. Pleiotropy of coagulation proteases, thrombus resolution and ischaemia–reperfusion: Biobanks specifically for thrombus storage and analysis are needed; further studies on novel modified activated protein C–based agents are required including its cytoprotective properties; new avenues for optimizing treatment of patients with ischaemic stroke are needed, also including novel agents that modify fibrinolytic activity (aimed at plasminogen activator inhibitor-1 and thrombin activatable fibrinolysis inhibitor.

Platelet JNK1 is involved in secretion and thrombus formation

Blood ◽  
2010 ◽  
Vol 115 (20) ◽  
pp. 4083-4092 ◽  
Author(s):  
Frédéric Adam ◽  
Alexandre Kauskot ◽  
Paquita Nurden ◽  
Eric Sulpice ◽  
Marc F. Hoylaerts ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Thrombus Formation ◽  
Blood Perfusion ◽  
Collagen Matrix ◽  
In Vivo Model ◽  
Wild Type ◽  
Platelet Secretion

Abstract The role of c-Jun NH2-terminal kinase 1 (JNK1) in hemostasis and thrombosis remains unclear. We show here, with JNK1-deficient (JNK1−/−) mice, that JNK1 plays an important role in platelet biology and thrombus formation. In tail-bleeding assays, JNK1−/− mice exhibited longer bleeding times than wild-type mice (396 ± 39 seconds vs 245 ± 32 seconds). We also carried out in vitro whole-blood perfusion assays on a collagen matrix under arterial shear conditions. Thrombus formation was significantly reduced for JNK1−/− platelets (51%). In an in vivo model of thrombosis induced by photochemical injury to cecum vessels, occlusion times were 4.3 times longer in JNK1−/− arterioles than in wild-type arterioles. Moreover, in vitro studies carried out in platelet aggregation conditions demonstrated that, at low doses of agonists, platelet secretion was impaired in JNK1−/− platelets, leading to altered integrin αIIbβ3 activation and reduced platelet aggregation, via a mechanism involving protein kinase C. JNK1 thus appears to be essential for platelet secretion in vitro, consistent with its role in thrombus growth in vivo. Finally, we showed that ERK2 and another isoform of JNK affect platelet aggregation through 2 pathways, one dependent and another independent of JNK1.

Decreased lymphocyte dopamine transporter in romantic lovers

CNS Spectrums ◽  
2016 ◽  
Vol 22 (3) ◽  
pp. 290-294 ◽  
Author(s):  
Donatella Marazziti ◽  
Stefano Baroni ◽  
Gino Giannaccini ◽  
Armando Piccinni ◽  
Federico Mucci ◽  
...  
Keyword(s):  
Blood Cells ◽  
Healthy Subjects ◽  
Psychiatric Illness ◽  
Early Stage ◽  
Romantic Love ◽  
Synaptic Cleft ◽  
Imaging Studies ◽  
Resting Lymphocytes ◽  
The Brain

ObjectiveThe role of dopamine (DA) in romantic love is suggested by different evidence and is supported by the findings of some brain imaging studies. The DA transporter (DAT) is a key structure in regulating the concentration of the neurotransmitter in the synaptic cleft. Given the presence of DAT in blood cells, the present study aimed to explore it in resting lymphocytes of 30 healthy subjects of both sexes in the early stage of romantic love (no longer than 6 months), as compared with 30 subjects involved in a long-lasting relationship.MethodsAll subjects had no physical or psychiatric illness. The DAT was measured by means of the [3H]-WIN 35,428 binding and the [3H]-DA reuptake to resting lymphocytes membranes. Romantic love was assessed by a specific questionnaire developed by us.ResultsThe results showed that the subjects in the early phase of romantic love had a global alteration of the lymphocyte DAT involving both a decreased number of proteins (Bmax) and a reduced functionality (Vmax).ConclusionsTaken together, these findings would indicate the presence of increased levels of DA in romantic love that, if paralleled by similar concentrations in the brain, would explain some peculiar features of this human feeling.

scholarly journals Chronically Elevated Interleukin-6 Disturbs the Coagulation Cascade in Mice

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2065-2065
Author(s):  
Tanja Knopp ◽  
Jeremy Lagrange ◽  
Rebecca Jung ◽  
Johannes Wild ◽  
Heidi Rossmann ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Interleukin 6 ◽  
Thrombus Formation ◽  
Vena Cava ◽  
Coagulation Cascade ◽  
Bleeding Complications ◽  
Thrombin Inhibitor ◽  
Advisory Committees ◽  
Hemostatic System

Abstract Introduction: Pro-inflammatory cytokines play an essential role as activators of the hemostatic system and in the regulation of physiological antithrombotic mechanisms. Interleukin-6 (IL-6) influences platelet production and platelet activation. It was associated with accelerated clotting and intravascular coagulation in tissue factor (TF)-driven murine thrombosis models. However, the precise role of myeloid cell-derived IL-6 on thrombosis formation and the hemostatic system is still unknown. Methods and Results: To better understand the role of IL-6 in thrombosis and the hemostatic system, we developed a new mouse strain with Cre-recombinase driven constitutive IL-6 expression specifically in myeloid cells (LysM-IL-6 OE, Control mice: IL-6 OE). LysM-IL-6 OE mice had a prolonged tail bleeding time and lacked venous thrombus formation induced by inferior vena cava (IVC) stenosis. There were no differences in D-Dimer levels in LysM-IL-6 OE mice neither on baseline level nor after IVC ligation. However, we found unstoppable post-operative bleedings in LysM-IL-6 OE. They showed a prolonged aPTT, a significantly increased INR and a prolonged thrombin converting time. The Factor V and IX expression were reduced, but von Willebrand factor, antithrombin and fibrinogen expression were up-regulated and could not explain the missing thrombus formation. We found significantly elevated erythrocyte sedimentation in line with erythrocytes aggregates, which seemed to be mediated by IL-6 and α2M. Most importantly, hepatic levels of thrombin inhibitor α2 macroglobulin (α2M) mRNA and protein were increased in LysM-IL-6 OE/+ mice compared to control mice. In parallel, Platelet erythrocyte interaction seemed to be essential in the development of the bleeding phenotype. Conclusions: These findings show the role of chronically elevated IL-6 in driving the accumulation of A2m on the surface of erythrocytes, thereby mediating a phenotype of increased bleeding complications. This work was supported by the DFG KA4035/1-1 and by the German Ministry for Education and Research (BMBF 01EO1503) Disclosures Lämmle: Takeda: Membership on an entity's Board of Directors or advisory committees; Ablynx: Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Baxter: Other: Travel Support, Speakers Bureau; Alexion: Other: Travel Support, Speakers Bureau; Siemens: Other: Travel Support, Speakers Bureau; Bayer: Other: Travel Support, Speakers Bureau; Roche: Other: Travel Support, Speakers Bureau; Sanofi: Other: Travel Support, Speakers Bureau. Ruf: ARCA bioscience: Consultancy, Patents & Royalties; ICONIC Therapeutics: Consultancy; MeruVasimmune: Current holder of individual stocks in a privately-held company.

scholarly journals Megakaryopoiesis and Platelet Biology: Roles of Transcription Factors and Emerging Clinical Implications

2021 ◽  
Vol 22 (17) ◽  
pp. 9615
Author(s):  
Ji-Yoon Noh
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Transcription Factors ◽  
Blood Cells ◽  
Thrombus Formation ◽  
Critical Role ◽  
Clinical Implications ◽  
Disease Development ◽  
Hematopoietic Stem

Platelets play a critical role in hemostasis and thrombus formation. Platelets are small, anucleate, and short-lived blood cells that are produced by the large, polyploid, and hematopoietic stem cell (HSC)-derived megakaryocytes in bone marrow. Approximately 3000 platelets are released from one megakaryocyte, and thus, it is important to understand the physiologically relevant mechanism of development of mature megakaryocytes. Many genes, including several key transcription factors, have been shown to be crucial for platelet biogenesis. Mutations in these genes can perturb megakaryopoiesis or thrombopoiesis, resulting in thrombocytopenia. Metabolic changes owing to inflammation, ageing, or diseases such as cancer, in which platelets play crucial roles in disease development, can also affect platelet biogenesis. In this review, I describe the characteristics of platelets and megakaryocytes in terms of their differentiation processes. The role of several critical transcription factors have been discussed to better understand the changes in platelet biogenesis that occur during disease or ageing.

scholarly journals The role of oral anticoagulant therapy in patients with acute coronary syndrome

2017 ◽  
Vol 8 (12) ◽  
pp. 353-366 ◽  
Author(s):  
Jae Youn Moon ◽  
Deepa Nagaraju ◽  
Francesco Franchi ◽  
Fabiana Rollini ◽  
Dominick J. Angiolillo
Keyword(s):  
Acute Coronary Syndrome ◽  
Anticoagulant Therapy ◽  
Oral Anticoagulant ◽  
Thrombus Formation ◽  
Oral Anticoagulant Therapy ◽  
Ease Of Use ◽  
Coagulation Cascade ◽  
Bleeding Complications ◽  
Coronary Syndrome

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor antagonist represents the current standard of care to prevent atherothrombotic recurrences in patients with acute coronary syndrome (ACS). However, despite the use of DAPT, the recurrence rate of cardiovascular ischemic events still remains high. This persistent risk may be in part attributed to the sustained activation of the coagulation cascade leading to generation of thrombin, which may continue to play a key role in thrombus formation. The use of vitamin K antagonists (VKAs) as a strategy to reduce atherothrombotic recurrences after an ACS has been previously tested, leading to overall unfavorable outcomes due to the high risk of bleeding complications. The recent introduction of non-VKA oral anticoagulants (NOACs), characterized by a better safety profile and ease of use compared with VKA, has led to a reappraisal of the use of oral anticoagulant therapy for secondary prevention in ACS patients. The present article provides an overview of the rationale and prognostic role of oral anticoagulant therapy in ACS patients as well as recent updated clinical data, in particular with NOACs, in the field and future perspectives on this topic.

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