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Blood Reviews Mar 2021Haemostasis stops bleeding at the site of vascular injury and maintains the integrity of blood vessels through clot formation. This regulated physiological process... (Review)
Review
Haemostasis stops bleeding at the site of vascular injury and maintains the integrity of blood vessels through clot formation. This regulated physiological process consists of complex interactions between endothelial cells, platelets, von Willebrand factor and coagulation factors. Haemostasis is initiated by a damaged vessel wall, followed with a rapid adhesion, activation and aggregation of platelets to the exposed subendothelial extracellular matrix. At the same time, coagulation factors aggregate on the procoagulant surface of activated platelets to consolidate the platelet plug by forming a mesh of cross-linked fibrin. Platelets and coagulation mutually influence each other and there are strong indications that, thanks to the interplay between platelets and coagulation, haemostasis is far more effective than the two processes separately. Clinically this is relevant because impaired interaction between platelets and coagulation may result in bleeding complications, while excessive platelet-coagulation interaction induces a high thrombotic risk. In this review, platelets, coagulation factors and the complex interaction between them will be discussed in detail.
Topics: Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Blood Platelets; Disease Susceptibility; Hemostasis; Humans; Platelet Activation; Platelet Aggregation; Platelet Membrane Glycoproteins; Protein Binding
PubMed: 32682574
DOI: 10.1016/j.blre.2020.100733 -
International Journal of Molecular... May 2022In the present decade, we are seeing a rapid increase in available genetics and multiomics information on blood and vascular components of the human and mammalian...
In the present decade, we are seeing a rapid increase in available genetics and multiomics information on blood and vascular components of the human and mammalian circulation, involved in haemostasis, athero- and venous thrombosis, and thrombo-inflammation [...].
Topics: Animals; Hemostasis; Humans; Inflammation; Mammals; Thrombosis; Venous Thrombosis
PubMed: 35628635
DOI: 10.3390/ijms23105825 -
Cell and Tissue Research Mar 2022Endothelial cells form a monolayer, which lines blood vessels. They are crucially involved in maintaining blood fluidity and providing controlled vascular hemostasis at... (Review)
Review
Endothelial cells form a monolayer, which lines blood vessels. They are crucially involved in maintaining blood fluidity and providing controlled vascular hemostasis at sites of injury. Thereby endothelial cells facilitate multiple mechanisms, including both procoagulant and anticoagulant, which must be kept in balance. Under physiological conditions, endothelial cells constitute a nonadhesive surface preventing activation of platelets and the coagulation cascade. Multiple fibrinolytic and antithrombotic properties act on their cell surface contributing to the maintenance of blood fluidity. These include platelet inhibition, the heparin-antithrombin III system, tissue factor pathway inhibition, thrombomodulin/protein C system, and fibrinolytic qualities. At sites of vascular damage, platelets react immediately by adhering to the exposed extracellular matrix, followed by platelet-platelet interactions to form a clot that effectively seals the injured vessel wall to prevent excessive blood loss. For solid thrombus formation, functional platelets are essential. In this process, endothelial cells serve as a support surface for formation of procoagulant complexes and clotting. This review gives an overview about the central role of the endothelium as a dynamic lining which controls the complex interplay of the coagulation system with the surrounding cells.
Topics: Blood Platelets; Endothelial Cells; Endothelium; Hemostasis; Humans; Thrombosis
PubMed: 34014399
DOI: 10.1007/s00441-021-03471-2 -
Hematology/oncology Clinics of North... Dec 2021Fibrinogen plays a fundamental role in coagulation through its support for platelet aggregation and its conversion to fibrin. Fibrin stabilizes clots and serves as a... (Review)
Review
Fibrinogen plays a fundamental role in coagulation through its support for platelet aggregation and its conversion to fibrin. Fibrin stabilizes clots and serves as a scaffold and immune effector before being broken down by the fibrinolytic system. Given its importance, abnormalities in fibrin(ogen) and fibrinolysis result in a variety of disorders with hemorrhagic and thrombotic manifestations. This review summarizes (i) the basic elements of fibrin(ogen) and its role in coagulation and the fibrinolytic system; (ii) the laboratory evaluation for fibrin(ogen) disorders, including the use of global fibrinolysis assays; and (iii) the management of congenital and acquired disorders of fibrinogen and fibrinolysis.
Topics: Blood Coagulation; Fibrin; Fibrinogen; Fibrinolysis; Hemostatics; Humans; Thrombosis
PubMed: 34404562
DOI: 10.1016/j.hoc.2021.07.011 -
Critical Reviews in Biochemistry and... 2015The plasma coagulation system in mammalian blood consists of a cascade of enzyme activation events in which serine proteases activate the proteins (proenzymes and... (Review)
Review
The plasma coagulation system in mammalian blood consists of a cascade of enzyme activation events in which serine proteases activate the proteins (proenzymes and procofactors) in the next step of the cascade via limited proteolysis. The ultimate outcome is the polymerization of fibrin and the activation of platelets, leading to a blood clot. This process is protective, as it prevents excessive blood loss following injury (normal hemostasis). Unfortunately, the blood clotting system can also lead to unwanted blood clots inside blood vessels (pathologic thrombosis), which is a leading cause of disability and death in the developed world. There are two main mechanisms for triggering the blood clotting, termed the tissue factor pathway and the contact pathway. Only one of these pathways (the tissue factor pathway) functions in normal hemostasis. Both pathways, however, are thought to contribute to thrombosis. An emerging concept is that the contact pathway functions in host pathogen defenses. This review focuses on how the initiation phase of the blood clotting cascade is regulated in both pathways, with a discussion of the contributions of these pathways to hemostasis versus thrombosis.
Topics: Animals; Blood Coagulation; Hemostasis; Humans; Models, Biological; Platelet Activation; Proteolysis; Thromboplastin; Thrombosis
PubMed: 26018600
DOI: 10.3109/10409238.2015.1050550 -
Journal of the American College of... Aug 2021Hemostasis and thrombosis are believed to be so intricately linked that any strategies that reduce thrombosis will have an inevitable impact on hemostasis. Consequently,... (Review)
Review
Hemostasis and thrombosis are believed to be so intricately linked that any strategies that reduce thrombosis will have an inevitable impact on hemostasis. Consequently, bleeding is viewed as an unavoidable side effect of anticoagulant therapy. Emerging evidence suggests that factor XI is important for thrombosis but has a minor role in hemostasis. This information raises the possibility that anticoagulants that target factor XI will be safer than currently available agents. The authors provide a visual representation of the coagulation pathways that distinguishes between the steps involved in thrombosis and hemostasis to explain why factor XI inhibitors may serve as hemostasis-sparing anticoagulants. A safer class of anticoagulants would provide opportunities for treatment of a wider range of patients, including those at high risk for bleeding. Ongoing clinical studies will determine the extent to which factor XI inhibitors attenuate thrombosis without disruption of hemostasis.
Topics: Blood Coagulation; Factor Xa Inhibitors; Hemostasis; Humans; Thrombosis
PubMed: 34353538
DOI: 10.1016/j.jacc.2021.06.010 -
Blood Reviews May 2015Upon activation, platelets secrete more than 300 active substances from their intracellular granules. Platelet dense granule components, such as ADP and polyphosphates,... (Review)
Review
Upon activation, platelets secrete more than 300 active substances from their intracellular granules. Platelet dense granule components, such as ADP and polyphosphates, contribute to haemostasis and coagulation, but also play a role in cancer metastasis. α-Granules contain multiple cytokines, mitogens, pro- and anti-inflammatory factors and other bioactive molecules that are essential regulators in the complex microenvironment of the growing thrombus but also contribute to a number of disease processes. Our understanding of the molecular mechanisms of secretion and the genetic regulation of granule biogenesis still remains incomplete. In this review we summarise our current understanding of the roles of platelet secretion in health and disease, and discuss some of the hypotheses that may explain how platelets may control the release of its many secreted components in a context-specific manner, to allow platelets to play multiple roles in health and disease.
Topics: Animals; Blood Platelets; Hemostasis; Humans; Inflammation; Neoplasms; Platelet Activation; Wound Healing
PubMed: 25468720
DOI: 10.1016/j.blre.2014.10.003 -
Blood Mar 2022Disseminated intravascular coagulation (DIC) is a syndrome triggered by infectious and noninfectious pathologies characterized by excessive generation of thrombin within...
Disseminated intravascular coagulation (DIC) is a syndrome triggered by infectious and noninfectious pathologies characterized by excessive generation of thrombin within the vasculature and widespread proteolytic conversion of fibrinogen. Despite diverse clinical manifestations ranging from thrombo-occlusive damage to bleeding diathesis, DIC etiology commonly involves excessive activation of blood coagulation and overlapping dysregulation of anticoagulants and fibrinolysis. Initiation of blood coagulation follows intravascular expression of tissue factor or activation of the contact pathway in response to pathogen-associated or host-derived, damage-associated molecular patterns. The process is further amplified through inflammatory and immunothrombotic mechanisms. Consumption of anticoagulants and disruption of endothelial homeostasis lower the regulatory control and disseminate microvascular thrombosis. Clinical DIC development in patients is associated with worsening morbidities and increased mortality, regardless of the underlying pathology; therefore, timely recognition of DIC is critical for reducing the pathologic burden. Due to the diversity of triggers and pathogenic mechanisms leading to DIC, diagnosis is based on algorithms that quantify hemostatic imbalance, thrombocytopenia, and fibrinogen conversion. Because current diagnosis primarily assesses overt consumptive coagulopathies, there is a critical need for better recognition of nonovert DIC and/or pre-DIC states. Therapeutic strategies for patients with DIC involve resolution of the eliciting triggers and supportive care for the hemostatic imbalance. Despite medical care, mortality in patients with DIC remains high, and new strategies, tailored to the underlying pathologic mechanisms, are needed.
Topics: Blood Coagulation; Disseminated Intravascular Coagulation; Fibrinolysis; Hemostasis; Humans; Thrombosis
PubMed: 34428280
DOI: 10.1182/blood.2020007208 -
Seminars in Thrombosis and Hemostasis Sep 2020The liver is unique in its remarkable regenerative capacity, which enables the use of liver resection as a treatment for specific liver diseases, including removal of... (Review)
Review
The liver is unique in its remarkable regenerative capacity, which enables the use of liver resection as a treatment for specific liver diseases, including removal of neoplastic liver disease. After resection, the remaining liver tissue (i.e, liver remnant) regenerates to maintain normal hepatic function. In experimental settings as well as patients, removal of up to two-thirds of the liver mass stimulates a rapid and highly coordinated process resulting in the regeneration of the remaining liver. Mechanisms controlling the initiation and termination of regeneration continue to be discovered, and many of the fundamental signaling pathways controlling the proliferation of liver parenchymal cells (i.e., hepatocytes) have been uncovered. Interestingly, while hemostatic complications (i.e., bleeding and thrombosis) are primarily thought of as a complication of surgery itself, strong evidence suggests that components of the hemostatic system are, in fact, powerful drivers of liver regeneration. This review focuses on the clinical and translational evidence supporting a link between the hemostatic system and liver regeneration, and the mechanisms whereby the hemostatic system directs liver regeneration discovered using experimental settings.
Topics: Hemostasis; Humans; Liver Diseases; Liver Regeneration
PubMed: 32906177
DOI: 10.1055/s-0040-1715450 -
Journal of the American College of... Jun 2021Direct oral anticoagulants (DOACs) have shown a positive benefit-risk balance in both clinical trials and real-world data, but approximately 2% to 3.5% of patients... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Direct oral anticoagulants (DOACs) have shown a positive benefit-risk balance in both clinical trials and real-world data, but approximately 2% to 3.5% of patients experience major bleeding annually. Many of these patients require hospitalization, and the administration of reversal agents may be required to control bleeding.
OBJECTIVES
The aim of this study was to investigate clinical outcomes associated with the use of 4-factor prothrombin complex concentrates, idarucizumab, or andexanet for reversal of severe DOAC-associated bleeding.
METHODS
The investigators systematically searched for studies of reversal agents for the treatment of severe bleeding associated with DOAC. Mortality rates, thromboembolic events, and hemostatic efficacy were meta-analyzed using a random effects model.
RESULTS
The investigators evaluated 60 studies in 4,735 patients with severe DOAC-related bleeding who were treated with 4-factor prothrombin complex concentrates (n = 2,688), idarucizumab (n = 1,111), or andexanet (n = 936). The mortality rate was 17.7% (95% confidence interval [CI]: 15.1% to 20.4%), and it was higher in patients with intracranial bleedings (20.2%) than in patients with extracranial hemorrhages (15.4%). The thromboembolism rate was 4.6% (95% CI: 3.3% to 6.0%), being particularly high with andexanet (10.7%; 95% CI: 6.5% to 15.7%). The effective hemostasis rate was 78.5% (95% CI: 75.1% to 81.8%) and was similar regardless of the reversal agent considered. The rebleeding rate was 13.2% (95% CI: 5.5% to 23.1%) and 78% of rebleeds occurred after resumption of anticoagulation. The risk of death was markedly and significantly associated with failure to achieve effective hemostasis (relative risk: 3.63; 95% CI: 2.56 to 5.16). The results were robust regardless of the type of study or the hemostatic scale used.
CONCLUSIONS
The risk of death after severe DOAC-related bleeding remains significant despite a high rate of effective hemostasis with reversal agents. Failure to achieve effective hemostasis strongly correlated with a fatal outcome. Thromboembolism rates are particularly high with andexanet. Comparative clinical trials are needed.
Topics: Administration, Oral; Antibodies, Monoclonal, Humanized; Anticoagulants; Blood Coagulation; Blood Coagulation Factors; Factor Xa; Hemorrhage; Hemostasis; Humans; Recombinant Proteins; Retrospective Studies
PubMed: 34140101
DOI: 10.1016/j.jacc.2021.04.061