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The Rational Basis of Thrombosis Models
Published in Josef Hladovec, Antithrombotic Drugs in Thrombosis Models, 2020
If the clinical experience is taken into account in only a portion of thrombosis patients, between 10 and 20%, a hereditary defect of a known blood clotting factor or inhibitor may be of such an important influence, or may have substantially contributed to the development of thrombosis.3–6 Antithrombin III deficiency, caused either by the lack of or a qualitative defect in the molecule, was found in about 2% of thrombosis cases. Deficiency of protein S was estimated in 10% of cases up to 40 years of age. The frequency of factor C defects is still difficult to assess. Other hereditary defects such as dysfibrinogenemias, factor XII deficiency, and sickle cell anemia are infrequently connected with the occurrence of thrombosis. Another portion of thrombosis patients may have inherited defects of the fibrinolytic system such as deficient or defective plasminogen, deficient tissue plasminogen activator (tPA) synthesis or release, as well as increased plasminogen activator inhibitor (PAI). This particularly concerns patients with recurrent attacks of deep vein thrombosis. Of course, not all possibly important factors and their hereditary defects have been properly identified as yet. Some factors inhibiting endothelial synthesis, accumulation or release of blood clotting or fibrinolytic factors or endothelial viability may exist as well, such as in homocysteinemia.7, 8 A special kind of a hereditary predisposition in thrombosis patients is suggested by the high freqency of some HLA antigens (Cw 4)9 and the prevalence of blood group A.10–14
Pregnancy-Related Proteins Detected by Their Biological Activities
Published in Gábor N. Than, Hans Bohn, Dénes G. Szabó, Advances in Pregnancy-Related Protein Research, 2020
Plasminogen activators (PAs) are serine proteases that catalyze the conversion of the serine protease zymogen, plasminogen, to the active protease, plasmin. Primarily, this fibrinolytic system is responsible for the dissolution of blood clots but its components also function in a variety of other biological processes, including ovulation and embryo implantation. Sherman et al.124 have shown that, in the mouse, plasminogen activator is secreted by the blastocyst during invasion of the uterus.
Fibrinolytic Defects in the Cutaneous Vasculitis Atrophie Blanche
Published in Pia Glas-Greenwalt, Fibrinolysis in Disease Molecular and Hemovascular Aspects of Fibrinolysis, 2019
Michael G. Hitchcock, Salvatore V. Pizzo
First described by Milian in 1929,1 “atrophie blanche” describes the clinical appearance of porcelain-white, often stellate, cutaneous scars found most frequently on the legs of adult women.2 Reflecting the lack of knowledge about the etiology and pathogenesis of atrophie blanche, several names have been applied to various stages of its development. Livedoid reticularis refers to alterations in vascular markings observed in the skin. Livedo vasculitis, a term used by Bard and Winkelmann, emphasizes the microscopic features that are seen.3 Modern terminology often combines two descriptions into a syndrome name “livedo vasculitis-atrophie blanche”.4,5 The condition may occur alone, or in association with a number of systemic diseases.2 Examples include the connective tissue diseases rheumatoid arthritis, lupus erythematosus, scleroderma, and Sjogren’s syndrome. Underlying infections, cardiovascular disease, or malignancy have also been implicated. In many patients no predisposing disease is identified. Over the past 60 years a unifying concept of the pathogenesis of the syndrome atrophie blanche has developed. An essential role of the fibrinolytic system is the main focus of discussion in this chapter. A summary of the clinical and microscopic appearances of the lesion, and its differential diagnosis, is provided to orient the reader.
Testing strategies used in the diagnosis of rare inherited bleeding disorders
Published in Expert Review of Hematology, 2023
The key pro-enzyme plasminogen is proteolytically activated by plasminogen activators (tissue type (tPA) and urokinase (uPA)) to plasmin, which in turn degrades fibrin to soluble fibrin degradation products. tPA is produced by the vascular endothelium and binds to fibrin, and uPA is extravascular and primarily responsible for cell migration and tissue remodeling. Plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor (SERPIN), inhibits the generation of plasmin; plasmin action is inhibited by α2-antiplasmin (α2-plasmin inhibitor), and α2-macroglobulin. Original assays evaluating fibrinolysis consisted of global assays of clot lysis performed on whole blood, plasma, or the euglobulin fraction of plasma [80]. Many of these assays lack standardization and are affected by fibrinogen and FXIII levels; hence, interlaboratory comparison is likely not possible. However, commercial assays for specific components of the fibrinolytic system are available [81]. Currently, the assessment of the fibrinolytic system consists of measurements of PAI-1 activity and antigen and α2-plasmin inhibitor activity.
Circadian rhythms of risk factors and management in atherosclerotic and hypertensive vascular disease: Modern chronobiological perspectives of an ancient disease
Published in Chronobiology International, 2023
Yong-Jian Geng, Michael H. Smolensky, Oliver Sum-Ping, Ramon Hermida, Richard J. Castriotta
The fibrinolytic system, which is composed of plasmin, plasminogen activators and their inhibitors, constitutes an important defense against intravascular thrombosis by complementing the effects of the various anticoagulant moieties, including Protein C, Protein S, antithrombin III, heparin cofactor II and endothelial-derived platelet inhibitors NO and prostacyclin. Plasminogen is activated primarily by t-PA, and it is inhibited by plasminogen activator inhibitors (PAIs), the most important one being PAI-1 produced by endothelial cells of the vascular wall, liver, adipose tissue and platelets (Haus 2007). The antigen concentration and activity of t-Pa and PAI-1 each exhibit a high-amplitude circadian rhythm (Andreotti et al. 1988; Andreotti and Kluft 1991; Angleton et al. 1989; Haus 2007). The highest t-Pa antigen concentration occurs around the commencement of wakefulness and the lowest antigen t-Pa concentration occurs around bedtime or early sleep. However, the circadian rhythm in the activity of t-PA is differently phased; t-Pa activity is lowest during sleep and highest around the commencement of the wake span. The circadian rhythms in PAI-1 antigen concentration and activity, which are characterized by peak between mid-sleep and awakening and absolute nadir around the mid-to-late span of wakefulness, override the circadian rhythm in t-Pa activity and, therefore, are deterministic of the 24 h temporal variation in overall fibrinolytic activity (Andreotti et al. 1988; Andreotti and Kluft 1991; Angleton et al. 1989; Haus 2007; Scheer and Shea 2014).
TSG-6 Inhibits the Growth of Keloid Fibroblasts Via Mediating the TGF-β1/Smad Signaling Pathway
Published in Journal of Investigative Surgery, 2021
Xin-Yi Li, Xiao-Juan Weng, Xiao-Jing Li, Xiao-Yu Tian
Plasminogen activator inhibitor‐1 (PAI‐1), an inhibitor of the fibrinolytic system, is a serine protease inhibitor [5]. PAI‐1 exerts various bioactivities, including the regulation of ECM degradation, cell proliferation, migration and apoptosis through fibrinolysis‐dependent or independent effects [6,7]. PAI-1 had been demonstrated to play a role in the regulation of wound healing by disrupting the normal balance between the deposition of ECM by myofibroblasts and clearance by MMPs, thus orienting the process in a profibrotic direction [8,9]. It had been shown that the normal downregulation of myofibroblasts seen in wound healing did not take place in fibrotic states due to the impeded control of mediators, e.g., TGF-β1 [10], possibly through epigenetic changed that affect apoptosis [11].