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Journal of Thrombosis and Haemostasis :... Dec 2023Fibrinolysis is the system primarily responsible for removal of fibrin deposits and blood clots in the vasculature. The terminal enzyme in the pathway, plasmin, is... (Review)
Review
Fibrinolysis is the system primarily responsible for removal of fibrin deposits and blood clots in the vasculature. The terminal enzyme in the pathway, plasmin, is formed from its circulating precursor, plasminogen. Fibrin is by far the most legendary substrate, but plasmin is notoriously prolific and is known to cleave many other proteins and participate in the activation of other proteolytic systems. Fibrinolysis is often overshadowed by the coagulation system and viewed as a simplistic poorer relation. However, the primordial plasminogen activators evolved alongside the complement system, approximately 70 million years before coagulation saw the light of day. It is highly likely that the plasminogen activation system evolved with its roots in primordial immunity. Almost all immune cells harbor at least one of a dozen plasminogen receptors that allow plasmin formation on the cell surface that in turn modulates immune cell behavior. Similarly, numerous pathogens express their own plasminogen activators or contain surface proteins that provide binding sites for host plasminogen. The fibrinolytic system has been harnessed for clinical medicine for many decades with the development of thrombolytic drugs and antifibrinolytic agents. Our refined understanding and appreciation of the fibrinolytic system and its alliance with infection and immunity and beyond are paving the way for new developments and interest in novel therapeutics and applications. One must ponder as to whether the nomenclature of the system hampered our understanding, by focusing on fibrin, rather than the complex myriad of interactions and substrates of the plasminogen activation system.
Topics: Humans; Fibrinolysis; Fibrinolysin; Plasminogen Activators; Plasminogen; Fibrin; Serine Proteases
PubMed: 38000850
DOI: 10.1016/j.jtha.2023.09.012 -
Haematologica Apr 2024D-dimer, a soluble fibrin degradation product that originates from plasmin-induced degradation of cross-linked fibrin, is an important biomarker of coagulation... (Review)
Review
D-dimer, a soluble fibrin degradation product that originates from plasmin-induced degradation of cross-linked fibrin, is an important biomarker of coagulation activation and secondary fibrinolysis that is routinely used to rule out venous thromboembolism (VTE), and to evaluate the risk of VTE recurrence, as well as the optimal duration of anticoagulant therapy. Besides VTE, D-dimer may be high due to physiologic conditions, including aging, pregnancy, and strenuous physical activity. In addition, several disorders have been associated with increased D-dimer levels, ranging from disseminated intravascular coagulation to infectious diseases and cancers. Thus, it is far from unusual for hematologists to have to deal with ambulatory individuals with increased D-dimer without signs or symptoms of thrombus formation. This narrative review is dedicated to the management of these cases by the hematologist.
Topics: Female; Pregnancy; Humans; Venous Thromboembolism; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Disseminated Intravascular Coagulation
PubMed: 37881856
DOI: 10.3324/haematol.2023.283966 -
Frontiers in Immunology 2024Excessive activation of immune cells by environmental factors, such as infection or individual genetic risk, causes various autoimmune diseases. species are... (Review)
Review
Excessive activation of immune cells by environmental factors, such as infection or individual genetic risk, causes various autoimmune diseases. species are gram-positive bacteria that colonize the nasopharynx, respiratory tract, gastrointestinal tract, genitourinary tract, and skin. Group A (GAS) species cause various symptoms, ranging from mild infections, such as tonsillitis and pharyngitis, to serious infections, such as necrotizing fasciitis and streptococcal toxic shock syndrome. The contribution of GAS infections to several autoimmune diseases, including acute rheumatic fever, vasculitis, and neuropsychiatric disorders, has been studied. In this review, we focus on the association between streptococcal infections and autoimmune diseases, and discuss current research on the mechanisms underlying the initiation and progression of autoimmune diseases.
Topics: Humans; Streptococcal Infections; Rheumatic Fever; Streptococcus pyogenes; Pharyngitis; Autoimmune Diseases
PubMed: 38464518
DOI: 10.3389/fimmu.2024.1361123 -
International Journal of Molecular... Sep 2023Newborns are the most vulnerable patients for thrombosis development among all children, with critically ill and premature infants being in the highest risk group. The... (Review)
Review
Newborns are the most vulnerable patients for thrombosis development among all children, with critically ill and premature infants being in the highest risk group. The upward trend in the rate of neonatal thrombosis could be attributed to progress in the treatment of severe neonatal conditions and the increased survival in premature babies. There are physiological differences in the hemostatic system between neonates and adults. Neonates differ in concentrations and rate of synthesis of most coagulation factors, turnover rates, the ability to regulate thrombin and plasmin, and in greater variability compared to adults. Natural inhibitors of coagulation (protein C, protein S, antithrombin, heparin cofactor II) and vitamin K-dependent coagulation factors (factors II, VII, IX, X) are low, but factor VIII and von Willebrand factor are elevated. Newborns have decreased fibrinolytic activity. In the healthy neonate, the balance is maintained but appears more easily converted into thrombosis. Neonatal hemostasis has less buffer capacity, and almost 95% of thrombosis is provoked. Different triggering risk factors are responsible for thrombosis in neonates, but the most important risk factors for thrombosis are central catheters, fluid fluctuations, liver dysfunction, and septic and inflammatory conditions. Low-molecular-weight heparins are the agents of choice for anticoagulation.
Topics: Infant, Newborn; Adult; Infant; Child; Humans; Hemostatics; Thrombosis; Blood Coagulation; von Willebrand Factor; Thrombin
PubMed: 37762167
DOI: 10.3390/ijms241813864 -
Journal of Thrombosis and Haemostasis :... Dec 2023Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a rare syndrome associated with adenoviral vector vaccines for COVID-19. The syndrome is characterized...
BACKGROUND
Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a rare syndrome associated with adenoviral vector vaccines for COVID-19. The syndrome is characterized by thrombosis, anti-platelet factor 4 (PF4) antibodies, thrombocytopenia, high D-dimer, and hypofibrinogenemia.
OBJECTIVES
To investigate abnormalities in fibrinolysis that contribute to the clinical features of VITT.
METHODS
Plasma samples from 18 suspected VITT cases were tested for anti-PF4 by ELISA and characterized as meeting criteria for VITT (11/18) or deemed unlikely (7/18; non-VITT). Antigen levels of PAI-1, factor XIII (FXIII), plasmin-αantiplasmin (PAP), and inflammatory markers were quantified. Plasmin generation was quantified by chromogenic substrate. Western blotting was performed with antibodies to fibrinogen, FXIII-A, and plasminogen.
RESULTS
VITT patients 10/11 had scores indicative of overt disseminated intravascular coagulation, while 0/7 non-VITT patients met the criteria. VITT patients had significantly higher levels of inflammatory markers, IL-1β, IL-6, IL-8, TNFα, and C-reactive protein. In VITT patients, both fibrinogen and FXIII levels were significantly lower, while PAP and tPA-mediated plasmin generation were higher compared to non-VITT patients. Evidence of fibrinogenolysis was observed in 9/11 VITT patients but not in non-VITT patients or healthy controls. Fibrinogen degradation products were apparent, with obvious cleavage of the fibrinogen α-chain. PAP complex was evident in those VITT patients with fibrinogenolysis, but not in non-VITT patients or healthy donors.
CONCLUSION
VITT patients show evidence of overt disseminated intravascular coagulation and fibrinogenolysis, mediated by dysregulated plasmin generation, as evidenced by increased PAP and plasmin generation. These observations are consistent with the clinical presentation of both thrombosis and bleeding in VITT.
Topics: Humans; Fibrinolysis; Purpura, Thrombocytopenic, Idiopathic; Fibrinolysin; Disseminated Intravascular Coagulation; COVID-19 Vaccines; Thrombocytopenia; Thrombosis; Vaccines; Fibrinogen
PubMed: 37734715
DOI: 10.1016/j.jtha.2023.09.007 -
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 -
Advanced Science (Weinheim,... Aug 2023The circadian clock in animals and humans plays crucial roles in multiple physiological processes. Disruption of circadian homeostasis causes detrimental effects. Here,...
The circadian clock in animals and humans plays crucial roles in multiple physiological processes. Disruption of circadian homeostasis causes detrimental effects. Here, it is demonstrated that the disruption of the circadian rhythm by genetic deletion of mouse brain and muscle ARNT-like 1 (Bmal1) gene, coding for the key clock transcription factor, augments an exacerbated fibrotic phenotype in various tumors. Accretion of cancer-associated fibroblasts (CAFs), especially the alpha smooth muscle actin positive myoCAFs, accelerates tumor growth rates and metastatic potentials. Mechanistically, deletion of Bmal1 abrogates expression of its transcriptionally targeted plasminogen activator inhibitor-1 (PAI-1). Consequently, decreased levels of PAI-1 in the tumor microenvironment instigate plasmin activation through upregulation of tissue plasminogen activator and urokinase plasminogen activator. The activated plasmin converts latent TGF-β into its activated form, which potently induces tumor fibrosis and the transition of CAFs into myoCAFs, the latter promoting cancer metastasis. Pharmacological inhibition of the TGF-β signaling largely ablates the metastatic potentials of colorectal cancer, pancreatic ductal adenocarcinoma, and hepatocellular carcinoma. Together, these data provide novel mechanistic insights into disruption of the circadian clock in tumor growth and metastasis. It is reasonably speculated that normalization of the circadian rhythm in patients provides a novel paradigm for cancer therapy.
Topics: Mice; Humans; Animals; Transforming Growth Factor beta; Tissue Plasminogen Activator; Fibrinolysin; Plasminogen Activator Inhibitor 1; Liver Neoplasms; Muscles; Brain; Tumor Microenvironment
PubMed: 37330661
DOI: 10.1002/advs.202301505