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Thrombosis Journal Sep 2023Tranexamic acid (TXA) is a widely used antifibrinolytic agent that has been used since the 1960's to reduce blood loss in various conditions. TXA is a lysine analogue... (Review)
Review
Tranexamic acid (TXA) is a widely used antifibrinolytic agent that has been used since the 1960's to reduce blood loss in various conditions. TXA is a lysine analogue that competes for the lysine binding sites in plasminogen and tissue-type plasminogen activator impairing its interaction with the exposed lysine residues on the fibrin surface. The presence of TXA therefore, impairs the plasminogen and tPA engagement and subsequent plasmin generation on the fibrin surface, protecting fibrin clot from proteolytic degradation. However, critical lysine binding sites for plasmin(ogen) also exist on other proteins and on various cell-surface receptors allowing plasmin to exert potent effects on other targets that are unrelated to classical fibrinolysis, notably in relation to immunity and inflammation. Indeed, TXA was reported to significantly reduce post-surgical infection rates in patients after cardiac surgery unrelated to its haemostatic effects. This has provided an impetus to consider TXA in other indications beyond inhibition of fibrinolysis. While there is extensive literature on the optimal dosage of TXA to reduce bleeding rates and transfusion needs, it remains to be determined if these dosages also apply to blocking the non-canonical effects of plasmin.
PubMed: 37700271
DOI: 10.1186/s12959-023-00540-0 -
Annals of Medicine and Surgery (2012) Oct 2023Intraoperative and postoperative bleeding is considered one of the most common risks in rhytidectomy. Recently, the use of antifibrinolytic agents in facial plastic and... (Review)
Review
BACKGROUND
Intraoperative and postoperative bleeding is considered one of the most common risks in rhytidectomy. Recently, the use of antifibrinolytic agents in facial plastic and reconstructive surgeries has been evaluated, but their use in rhytidectomy remains a topic of ongoing discussion. Tranexamic acid (TXA) is an antifibrinolytic agent that prevents enzymatic degradation of the fibrin clot by blocking the conversion of plasminogen to plasmin, improves platelet function, and has a direct anti-inflammatory effect. This review covers pertinent literature to elucidate whether the use of TXA in rhytidectomy confers intraoperative and postoperative benefits.
METHODS
A systematic literature search was conducted in online databases: PubMed, Google Scholar, Cochrane, Scopus, and Web of Science for all articles on the topic of TXA in facelift published up to and including June, 2023 using the following terms: "TXA," "tranexamic acid," "plastic surgery," "aesthetic surgery," "facelift," "rhytidectomy". They were either searched individually or in combination. All relevant original research articles, of any study design were included and narratively discussed in this review. Studies not carried out in humans and studies centred on the use of TXA in other specialties were excluded. English Language was included.
RESULTS
Eight articles were reviewed in this paper. Through these articles, the authors provided in detail the possible beneficial effects of TXA in facelift patients in evaluating several clinical outcomes: intraoperative blood loss, postoperative drain output, postoperative oedema, ecchymosis, operative time, and surgical field quality.
CONCLUSION
Although there is still a lack of information on TXA in facelift patients, we are not able to deny the beneficial effects of TXA on this topic. Therefore, further investigations including prospective, case-controlled multi-institutional studies comparing routes of delivery should be performed until reaching, at the end, an evidence-based guideline providing a clear protocol in terms of the administration and dosage of TXA in facelift.
PubMed: 37811108
DOI: 10.1097/MS9.0000000000001224 -
Polish Archives of Internal Medicine Nov 2023D‑Dimers derive from degradation of cross‑linked fibrin by plasmin, and thus their level is a marker of coagulation and fibrinolytic system activation. Guidelines...
D‑Dimers derive from degradation of cross‑linked fibrin by plasmin, and thus their level is a marker of coagulation and fibrinolytic system activation. Guidelines recommend that D‑dimers are determined if the pretest probability (PTP) is low or intermediate, to exclude venous thromboembolism (VTE), either deep vein thrombosis or pulmonary embolism, and to avoid imaging tests. If the PTP is high or D‑dimer level is above the suggested thresholds, imaging is recommended. D‑Dimer assays offer high sensitivity and low specificity, as D‑dimer levels can be above the threshold in several other conditions than thrombosis, and they increase with age. As a result, there have been several proposals to improve the diagnostic accuracy of D‑dimer levels by adjusting the cutoffs according to patient characteristics, such as age, PTP, pregnancy, renal function, or cancer. D‑Dimer levels can also predict clinical severity of COVID‑19, and escalated anticoagulation based on D‑dimer levels can be associated with a lower risk of mortality in patients with severe COVID‑19. Finally, D‑dimer levels have been incorporated in prediction models for recurrent VTE to help identify patients who may benefit from prolonged anticoagulation.
Topics: Humans; Venous Thromboembolism; Venous Thrombosis; Fibrin Fibrinogen Degradation Products; Pulmonary Embolism; Anticoagulants; COVID-19; COVID-19 Testing
PubMed: 37965939
DOI: 10.20452/pamw.16604 -
Thrombosis and Haemostasis Mar 2024Two phenotypes of disseminated intravascular coagulation (DIC) are systematically reviewed. DIC is classified into thrombotic and fibrinolytic phenotypes characterized...
Two phenotypes of disseminated intravascular coagulation (DIC) are systematically reviewed. DIC is classified into thrombotic and fibrinolytic phenotypes characterized by thrombosis and hemorrhage, respectively. Major pathology of DIC with thrombotic phenotype is the activation of coagulation, insufficient anticoagulation with endothelial injury, and plasminogen activator inhibitor-1-mediated inhibition of fibrinolysis, leading to microvascular fibrin thrombosis and organ dysfunction. DIC with fibrinolytic phenotype is defined as massive thrombin generation commonly observed in any type of DIC, combined with systemic pathologic hyperfibrinogenolysis caused by underlying disorder that results in severe bleeding due to excessive plasmin formation. Three major pathomechanisms of systemic hyperfibrinogenolysis have been considered: (1) acceleration of tissue-type plasminogen activator (t-PA) release from hypoxic endothelial cells and t-PA-rich storage pools, (2) enhancement of the conversion of plasminogen to plasmin due to specific proteins and receptors that are expressed on cancer cells and endothelial cells, and (3) alternative pathways of fibrinolysis. DIC with fibrinolytic phenotype can be diagnosed by DIC diagnosis followed by the recognition of systemic pathologic hyperfibrin(ogen)olysis. Low fibrinogen levels, high fibrinogen and fibrin degradation products (FDPs), and the FDP/D-dimer ratio are important for the diagnosis of systemic pathologic hyperfibrin(ogen)olysis. Currently, evidence-based treatment strategies for DIC with fibrinolytic phenotypes are lacking. Tranexamic acid appears to be one of the few methods to be effective in the treatment of systemic pathologic hyperfibrin(ogen)olysis. International cooperation for the elucidation of pathomechanisms, establishment of diagnostic criteria, and treatment strategies for DIC with fibrinolytic phenotype are urgent issues in the field of thrombosis and hemostasis.
Topics: Humans; Disseminated Intravascular Coagulation; Fibrinolysin; Endothelial Cells; Fibrinolysis; Phenotype; Thrombosis; Fibrinogen; Fibrin Fibrinogen Degradation Products
PubMed: 37657485
DOI: 10.1055/a-2165-1142 -
MedRxiv : the Preprint Server For... Oct 2023Coagulopathy and associated bleeding and venous thromboembolism (VTE) are major causes of morbidity and mortality in patients with acute leukemia. The underlying...
BACKGROUND
Coagulopathy and associated bleeding and venous thromboembolism (VTE) are major causes of morbidity and mortality in patients with acute leukemia. The underlying mechanisms of these complications have not been fully elucidated.
OBJECTIVES
To evaluate the associations between biomarker levels and bleeding and VTE in acute leukemia patients.
PATIENTS/METHOD
We examined plasma levels of activators, inhibitors and biomarkers of the coagulation and fibrinolytic pathways in patients ≥18 years with newly diagnosed acute leukemia compared to healthy controls. Multivariable regression models were used to examine the association of biomarkers with bleeding and VTE in acute leukemia patients. The study included 358 patients with acute leukemia (29 acute promyelocytic leukemia [APL], 253 non-APL acute myeloid leukemia [AML] and 76 acute lymphoblastic leukemia [ALL]), and 30 healthy controls.
RESULTS
Patients with acute leukemia had higher levels of extracellular vesicle (EV) tissue factor (TF) activity, phosphatidylserine-positive EVs, plasminogen activator inhibitor-1 (PAI-1), plasmin-antiplasmin complexes, cell-free DNA and lower levels of citrullinated histone H3-DNA complexes compared to healthy controls. APL patients had the highest levels of EVTF activity and the lowest levels of tissue plasminogen activator among the acute leukemia patients. There were 41 bleeding and 37 VTE events in acute leukemia patients. High EVTF activity was associated with increased risk of bleeding (sHR 2.30, 95%CI 0.99-5.31) whereas high PAI-1 was associated with increased risk of VTE (sHR 3.79, 95%CI 1.40-10.28) in these patients.
CONCLUSIONS
Our study shows alterations in several biomarkers in acute leukemia and identifies biomarkers associated with risk of bleeding and VTE.
PubMed: 37905148
DOI: 10.1101/2023.10.18.23297216 -
Journal of Inflammation Research 2023Venous thromboembolism is a condition that includes deep vein thrombosis and pulmonary embolism. It is the third most common cardiovascular disease behind acute coronary... (Review)
Review
Venous thromboembolism is a condition that includes deep vein thrombosis and pulmonary embolism. It is the third most common cardiovascular disease behind acute coronary heart disease and stroke. Over the past few years, growing research suggests that venous thrombosis is also related to the immune system and inflammatory factors have been confirmed to be involved in venous thrombosis. The role of inflammation and inflammation-related biomarkers in cerebrovascular thrombotic disease is the subject of ongoing debate. P-selectin leads to platelet-monocyte aggregation and stimulates vascular inflammation and thrombosis. The dysregulation of miRNAs has also been reported in venous thrombosis, suggesting the involvement of miRNAs in the progression of venous thrombosis. Plasminogen activator inhibitor-1 (PAI-1) is a crucial component of the plasminogen-plasmin system, and elevated levels of PAI-1 in conjunction with advanced age are significant risk factors for thrombosis. In addition, it has been showed that one of the ways that neutrophils promote venous thrombosis is the formation of neutrophil extracellular traps (NETs). In recent years, the role of extracellular vesicles (EVs) in the occurrence and development of VTE has been continuously revealed. With the advancement of research technology, the complex regulatory role of EVs on the coagulation process has been gradually discovered. However, our understanding of the causes and consequences of these changes in venous thrombosis is still limited. Therefore, we review our current understanding the molecular mechanisms of venous thrombosis and the related clinical trials, which is crucial for the future treatment of venous thrombosis.
PubMed: 38111686
DOI: 10.2147/JIR.S439205 -
JCI Insight Mar 2024Joint injury is associated with risk for development of osteoarthritis (OA). Increasing evidence suggests that activation of fibrinolysis is involved in OA pathogenesis....
Joint injury is associated with risk for development of osteoarthritis (OA). Increasing evidence suggests that activation of fibrinolysis is involved in OA pathogenesis. However, the role of the fibrinolytic pathway is not well understood. Here, we showed that the fibrinolytic pathway, which includes plasminogen/plasmin, tissue plasminogen activator, urokinase plasminogen activator (uPA), and the uPA receptor (uPAR), was dysregulated in human OA joints. Pharmacological inhibition of plasmin attenuated OA progression after a destabilization of the medial meniscus in a mouse model whereas genetic deficiency of plasmin activator inhibitor, or injection of plasmin, exacerbated OA. We detected increased uptake of uPA/uPAR in mouse OA joints by microPET/CT imaging. In vitro studies identified that plasmin promotes OA development through multiple mechanisms, including the degradation of lubricin and cartilage proteoglycans and induction of inflammatory and degradative mediators. We showed that uPA and uPAR produced inflammatory and degradative mediators by activating the PI3K, 3'-phosphoinositide-dependent kinase-1, AKT, and ERK signaling cascades and activated matrix metalloproteinases to degrade proteoglycan. Together, we demonstrated that fibrinolysis contributes to the development of OA through multiple mechanisms and suggested that therapeutic targeting of the fibrinolysis pathway can prevent or slow development of OA.
Topics: Animals; Mice; Humans; Fibrinolysin; Osteoarthritis; Fibrinolysis; Urokinase-Type Plasminogen Activator; Receptors, Urokinase Plasminogen Activator; Disease Models, Animal; Male; Female; Mice, Inbred C57BL; Plasminogen; Signal Transduction; Mice, Knockout
PubMed: 38502232
DOI: 10.1172/jci.insight.173603 -
Natural Products and Bioprospecting Nov 2023L-Palmitoylcarnitine (L-PC) is an important endogenous fatty acid metabolite. Its classical biological functions are involved in the regulations of membrane molecular...
L-Palmitoylcarnitine (L-PC) is an important endogenous fatty acid metabolite. Its classical biological functions are involved in the regulations of membrane molecular dynamics and the β-oxidation of fatty acids. Decreased plasma long-chain acylcarnitines showed the association of venous thrombosis, implying anticoagulant activity of the metabolites and inspiring us to investigate if and how L-PC, a long-chain acylcarnitine, takes part in coagulation. Here we show that L-PC exerted anti-coagulant effects by potentiating the enzymatic activities of plasmin and tissue plasminogen activator (tPA). L-PC directly interacts with plasmin and tPA with an equilibrium dissociation constant (KD) of 6.47 × 10 and 4.46 × 10 M, respectively, showing high affinities. In mouse model, L-PC administration significantly inhibited FeCl-induced arterial thrombosis. It also mitigated intracerebral thrombosis and inflammation in a transient middle cerebral artery occlusion (tMCAO) mouse model. L-PC induced little bleeding complications. The results show that L-PC has anti-thrombotic function by potentiating plasmin and tPA.
PubMed: 37938456
DOI: 10.1007/s13659-023-00413-z