-
Anaesthesiology Intensive Therapy 2015Blood loss and subsequent transfusions are associated with major morbidity and mortality. The use of antifibrinolytics can reduce blood loss in cardiac surgery, trauma,... (Review)
Review
Blood loss and subsequent transfusions are associated with major morbidity and mortality. The use of antifibrinolytics can reduce blood loss in cardiac surgery, trauma, orthopedic surgery, liver surgery and solid organ transplantation, obstetrics and gynecology, neurosurgery and non-surgical diseases. The evidence of their efficacy has been mounting for years. Tranexamic acid (TXA), a synthetic lysine-analogue antifibrinolytic, was first patented in 1957 and its use has been increasing in contrast to aprotinin, a serine protease inhibitor antifibrinolytic. This review aims to help acute care physicians navigate through the clinical evidence available for TXA therapy, develop appropriate dose regimens whilst minimizing harm, as well as understand its broadening scope of applications. Many questions remain unanswered regarding other clinical effects of TXA such as anti-inflammatory response to cardiopulmonary bypass, the risk of thromboembolic events, adverse neurological effects such as seizures, and its morbidity and mortality, all of which necessitate further clinical trials on its usage and safety in various clinical settings.
Topics: Antifibrinolytic Agents; Blood Loss, Surgical; General Surgery; Humans; Tranexamic Acid
PubMed: 25797505
DOI: 10.5603/AIT.a2015.0011 -
Anaesthesia Jan 2022Globally, approximately 70 million people sustain traumatic brain injury each year and this can have significant physical, psychosocial and economic consequences for... (Review)
Review
Globally, approximately 70 million people sustain traumatic brain injury each year and this can have significant physical, psychosocial and economic consequences for patients, their families and society. The aim of this review is to provide clinicians with a summary of recent studies of direct relevance to the management of traumatic brain injury in order to promote best clinical practice. The use of tranexamic acid in the management of traumatic brain injury has been the focus of several studies, with one large randomised controlled trial suggesting a reduction in all-cause mortality within 24 h of injury. The use of therapeutic hypothermia does not improve neurological outcomes and maintenance of normothermia remains the optimal management strategy. For seizure management, levetiracetam appears to be as effective as phenytoin, but the optimal dose remains unclear. There has been a lack of clear outcome benefit for any individual osmotherapy agent, with no difference in mortality or neurological recovery. Early tracheostomy (< 7 days from injury) for patients with traumatic brain injury is associated with a reduction in the incidence of ventilator-associated pneumonia and duration of mechanical ventilation, critical care and hospital stay. Further research is needed in order to determine the optimal package of care and interventions. There is a need for research studies to focus on patient-centred outcome measures such as long-term neurological recovery and quality of life.
Topics: Anticonvulsants; Antifibrinolytic Agents; Brain Injuries, Traumatic; Disease Management; Evidence-Based Medicine; Humans; Randomized Controlled Trials as Topic
PubMed: 35001375
DOI: 10.1111/anae.15608 -
Neurotherapeutics : the Journal of the... Oct 2020Spontaneous intracerebral hemorrhage (ICH) results in high rates of morbidity and mortality, with intraventricular hemorrhage (IVH) being associated with even worse... (Review)
Review
Spontaneous intracerebral hemorrhage (ICH) results in high rates of morbidity and mortality, with intraventricular hemorrhage (IVH) being associated with even worse outcomes. Therapeutic interventions in acute ICH have continued to emerge with focus on arresting hemorrhage expansion, clot volume reduction of both intraventricular and parenchymal hematomas, and targeting perihematomal edema and inflammation. Large randomized controlled trials addressing the effectiveness of rapid blood pressure lowering, hemostatic therapy with platelet transfusion, and other clotting complexes and hematoma volume reduction using minimally invasive techniques have impacted clinical guidelines. We review the recent evolution in the management of acute spontaneous ICH, discussing which interventions have been shown to be safe and which may potentially improve outcomes.
Topics: Antifibrinolytic Agents; Antihypertensive Agents; Blood Pressure; Cerebral Hemorrhage; Hemostasis; Humans; Minimally Invasive Surgical Procedures
PubMed: 32720246
DOI: 10.1007/s13311-020-00902-w -
Seminars in Perinatology Feb 2019Blood product transfusion capabilities are crucial for appropriate response to postpartum hemorrhage. Novel treatments are continually being sought to improve maternal... (Review)
Review
Blood product transfusion capabilities are crucial for appropriate response to postpartum hemorrhage. Novel treatments are continually being sought to improve maternal morbidity and mortality associated with massive hemorrhage.
Topics: Antifibrinolytic Agents; Blood Transfusion; Clinical Protocols; Delivery, Obstetric; Female; Humans; Postpartum Hemorrhage; Pregnancy; Tranexamic Acid
PubMed: 30527516
DOI: 10.1053/j.semperi.2018.11.008 -
Anesthesiology Mar 2018Fibrinolysis is a physiologic component of hemostasis that functions to limit clot formation. However, after trauma or surgery, excessive fibrinolysis may contribute to... (Review)
Review
Fibrinolysis is a physiologic component of hemostasis that functions to limit clot formation. However, after trauma or surgery, excessive fibrinolysis may contribute to coagulopathy, bleeding, and inflammatory responses. Antifibrinolytic agents are increasingly used to reduce bleeding, allogeneic blood administration, and adverse clinical outcomes. Tranexamic acid is the agent most extensively studied and used in most countries. This review will explore the role of fibrinolysis as a pathologic mechanism, review the different pharmacologic agents used to inhibit fibrinolysis, and focus on the role of tranexamic acid as a therapeutic agent to reduce bleeding in patients after surgery and trauma.
Topics: Antifibrinolytic Agents; Blood Coagulation Disorders; Blood Loss, Surgical; Fibrinolysis; Humans; Perioperative Care; Tranexamic Acid
PubMed: 29200009
DOI: 10.1097/ALN.0000000000001997 -
Blood May 2021Plasminogen is an abundant plasma protein that exists in various zymogenic forms. Plasmin, the proteolytically active form of plasminogen, is known for its essential... (Review)
Review
Plasminogen is an abundant plasma protein that exists in various zymogenic forms. Plasmin, the proteolytically active form of plasminogen, is known for its essential role in fibrinolysis. To date, therapeutic targeting of the fibrinolytic system has been for 2 purposes: to promote plasmin generation for thromboembolic conditions or to stop plasmin to reduce bleeding. However, plasmin and plasminogen serve other important functions, some of which are unrelated to fibrin removal. Indeed, for >40 years, the antifibrinolytic agent tranexamic acid has been administered for its serendipitously discovered skin-whitening properties. Plasmin also plays an important role in the removal of misfolded/aggregated proteins and can trigger other enzymatic cascades, including complement. In addition, plasminogen, via binding to one of its dozen cell surface receptors, can modulate cell behavior and further influence immune and inflammatory processes. Plasminogen administration itself has been reported to improve thrombolysis and to accelerate wound repair. Although many of these more recent findings have been derived from in vitro or animal studies, the use of antifibrinolytic agents to reduce bleeding in humans has revealed additional clinically relevant consequences, particularly in relation to reducing infection risk that is independent of its hemostatic effects. The finding that many viruses harness the host plasminogen to aid infectivity has suggested that antifibrinolytic agents may have antiviral benefits. Here, we review the broadening role of the plasminogen-activating system in physiology and pathophysiology and how manipulation of this system may be harnessed for benefits unrelated to its conventional application in thrombosis and hemostasis.
Topics: Animals; Antifibrinolytic Agents; Brain; Conjunctivitis; Enzyme Activation; Fibrin; Fibrinolysin; Fibrinolysis; Fibrinolytic Agents; Humans; Immunity; Infections; Inflammation; Mice; Plasminogen; Radiodermatitis; Receptors, Cell Surface; Skin Diseases, Genetic; Thrombosis; Tranexamic Acid; Wound Healing; Wounds and Injuries
PubMed: 33735914
DOI: 10.1182/blood.2020008951 -
Circulation Research Aug 2019Activated fibroblasts are the major cell type that secretes excessive extracellular matrix in response to injury, contributing to pathological fibrosis and leading to...
RATIONALE
Activated fibroblasts are the major cell type that secretes excessive extracellular matrix in response to injury, contributing to pathological fibrosis and leading to organ failure. Effective anti-fibrotic therapeutic solutions, however, are not available due to the poorly defined characteristics and unavailability of tissue-specific fibroblasts. Recent advances in single-cell RNA-sequencing fill such gaps of knowledge by enabling delineation of the developmental trajectories and identification of regulatory pathways of tissue-specific fibroblasts among different organs.
OBJECTIVE
This study aims to define the transcriptome profiles of tissue-specific fibroblasts using recently reported mouse single-cell RNA-sequencing atlas and to develop a robust chemically defined protocol to derive cardiac fibroblasts (CFs) from human induced pluripotent stem cells for in vitro modeling of cardiac fibrosis and drug screening.
METHODS AND RESULTS
By analyzing the single-cell transcriptome profiles of fibroblasts from 10 selected mouse tissues, we identified distinct tissue-specific signature genes, including transcription factors that define the identities of fibroblasts in the heart, lungs, trachea, and bladder. We also determined that CFs in large are of the epicardial lineage. We thus developed a robust chemically defined protocol that generates CFs from human induced pluripotent stem cells. Functional studies confirmed that iPSC-derived CFs preserved a quiescent phenotype and highly resembled primary CFs at the transcriptional, cellular, and functional levels. We demonstrated that this cell-based platform is sensitive to both pro- and anti-fibrosis drugs. Finally, we showed that crosstalk between human induced pluripotent stem cell-derived cardiomyocytes and CFs via the atrial/brain natriuretic peptide-natriuretic peptide receptor-1 pathway is implicated in suppressing fibrogenesis.
CONCLUSIONS
This study uncovers unique gene signatures that define tissue-specific identities of fibroblasts. The bona fide quiescent CFs derived from human induced pluripotent stem cells can serve as a faithful in vitro platform to better understand the underlying mechanisms of cardiac fibrosis and to screen anti-fibrotic drugs.
Topics: Animals; Antifibrinolytic Agents; Cells, Cultured; Fibroblasts; Fibrosis; Humans; Induced Pluripotent Stem Cells; Mice; Myocytes, Cardiac
PubMed: 31288631
DOI: 10.1161/CIRCRESAHA.119.315491 -
Pediatric Neurology Dec 2020
Topics: Antifibrinolytic Agents; Child Abuse; Humans; Infant, Newborn; Physician's Role; Treatment Refusal; Vitamin K
PubMed: 33190689
DOI: 10.1016/j.pediatrneurol.2020.09.006 -
Brazilian Journal of Anesthesiology... 2021The role of the anesthesiologist in the perioperative management of hemostasis has attracted increasing attention. The fibrinolytic system participates in hemostasis,... (Review)
Review
INTRODUCTION AND OBJECTIVES
The role of the anesthesiologist in the perioperative management of hemostasis has attracted increasing attention. The fibrinolytic system participates in hemostasis, removing clots after repair of the vascular injury. Over the past two decades, several studies have assessed the efficacy and safety of antifibrinolytic agents in reducing perioperative bleeding and transfusion requirements. Some of the conditions that seem to benefit from antifibrinolytic drugs involve trauma, postpartum hemorrhage, cardiac surgery, spine surgery, knee or hip arthroplasty, urological and gynecological surgery, among others. However, there are currently few publications focusing on the perioperative features of fibrinolytic system, which will be the subject of the present review.
CONTENT AND CONCLUSIONS
Fibrinolytic physiology, its relationship with the clot structure and its perioperative behavior are described. Pathophysiological mechanisms related to anesthesiology clinical practice and their possible perioperative scenarios are addressed according to a suggested classification. This article aims to provide anesthesiologists with a broader understanding of the normal functioning of fibrinolysis, the mechanisms of possible deviations from normality in the perioperative period, the pathophysiological rationale supporting the current indications of antifibrinolytics, and some recent outcomes obtained with their use.
Topics: Antifibrinolytic Agents; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Blood Coagulation Disorders; Fibrinolysis; Humans
PubMed: 33712256
DOI: 10.1016/j.bjane.2020.12.007 -
Seminars in Hematology Jan 2004Factor XI (FXI) deficiency leads to an injury-related bleeding diathesis, which is notable for the variability in the bleeding tendency and the lack of a clear... (Review)
Review
Factor XI (FXI) deficiency leads to an injury-related bleeding diathesis, which is notable for the variability in the bleeding tendency and the lack of a clear relationship between bleeding and FXI coagulant activity. Bleeding in this disorder occurs especially in areas of high fibrinolytic activity. Although a rare disorder, the frequency of FXI deficiency is high in certain populations, notably persons of Ashkenazi descent and the Basque population of Southern France. In these populations, five mutations of the FXI gene have been identified and a founder effect has been confirmed for three of these. This paper reviews the role of FXI in coagulation and documents factors known to modify the bleeding tendency. Treatment of surgical bleeding in patients with FXI deficiency is reviewed with emphasis on the combined use of recombinant activated factor VII (rFVIIa; NovoSeven(R), Novo Nordisk, Bagsvaerd, Denmark) and the antifibrinolytic agent, tranexamic acid.
Topics: Antifibrinolytic Agents; Blood Coagulation Factors; Factor VII; Factor VIIa; Factor XI Deficiency; Female; Fibrinolysis; Hemophilia A; Hemorrhage; Humans; Male; Recombinant Proteins; von Willebrand Diseases
PubMed: 14872426
DOI: 10.1053/j.seminhematol.2003.11.015