The Minimum Concentration of Fibrinogen Needed for Platelet Aggregation Using ADP
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Factor XIII and Fibrin Clot Properties in Acute Venous Thromboembolism
International Journal of Molecular Sciences Review Factor XIII and Fibrin Clot Properties in Acute Venous Thromboembolism Michał Z ˛abczyk 1,2 , Joanna Natorska 1,2 and Anetta Undas 1,2,* 1 John Paul II Hospital, 31-202 Kraków, Poland; [email protected] (M.Z.); [email protected] (J.N.) 2 Institute of Cardiology, Jagiellonian University Medical College, 31-202 Kraków, Poland * Correspondence: [email protected]; Tel.: +48-12-614-30-04; Fax: +48-12-614-21-20 Abstract: Coagulation factor XIII (FXIII) is converted by thrombin into its active form, FXIIIa, which crosslinks fibrin fibers, rendering clots more stable and resistant to degradation. FXIII affects fibrin clot structure and function leading to a more prothrombotic phenotype with denser networks, characterizing patients at risk of venous thromboembolism (VTE). Mechanisms regulating FXIII activation and its impact on fibrin structure in patients with acute VTE encompassing pulmonary embolism (PE) or deep vein thrombosis (DVT) are poorly elucidated. Reduced circulating FXIII levels in acute PE were reported over 20 years ago. Similar observations indicating decreased FXIII plasma activity and antigen levels have been made in acute PE and DVT with their subsequent increase after several weeks since the index event. Plasma fibrin clot proteome analysis confirms that clot-bound FXIII amounts associated with plasma FXIII activity are decreased in acute VTE. Reduced FXIII activity has been associated with impaired clot permeability and hypofibrinolysis in acute PE. The current review presents available studies on the role of FXIII in the modulation of fibrin clot properties during acute PE or DVT and following these events. -
Update on Antithrombin I (Fibrin)
©2007 Schattauer GmbH,Stuttgart AnniversaryIssueContribution Update on antithrombinI(fibrin) Michael W. Mosesson 1957–2007) The Blood Research Institute,BloodCenter of Wisconsin, Milwaukee,Wisconsin, USA y( Summary AntithrombinI(fibrin) is an important inhibitor of thrombin exosite 2.Thelatterreaction results in allostericchanges that generation that functions by sequestering thrombin in the form- down-regulate thrombin catalytic activity. AntithrombinIdefi- Anniversar ingfibrin clot,and also by reducing the catalytic activity of fibrin- ciency (afibrinogenemia), defectivethrombin binding to fibrin th boundthrombin.Thrombin binding to fibrin takesplace at two (antithrombin Idefect) found in certain dysfibrinogenemias (e.g. 50 classesofnon-substrate sites: 1) in thefibrin Edomain (two per fibrinogen Naples 1), or areduced plasma γ ’ chain content (re- molecule) throughinteractionwith thrombin exosite 1; 2) at a ducedantithrombin Iactivity),predispose to intravascular singlesite on each γ ’ chain through interaction with thrombin thrombosis. Keywords Fibrinogen,fibrin, thrombin, antithrombin I ThrombHaemost 2007; 98: 105–108 Introduction meric with respecttoits γ chains,and accounts for ~85% of human plasma fibrinogen. Thrombinbinds to its substrate, fibrinogen, through an anion- Low-affinity thrombin binding activity reflects thrombin ex- binding sitecommonlyreferred to as ‘exosite 1’ (1,2). Howell osite1bindinginEdomain of fibrin, as recentlydetailedbyana- recognized nearly acenturyago that the fibrin clot itself exhibits lysesofthrombin-fibrin -
Tranexamic Acid in the Treatment of Residual Chronic Subdural Hematoma: a Single-Centre, Observer-Blinded, Randomized Controlled Trial (Trace)
TRANEXAMIC ACID IN THE TREATMENT OF RESIDUAL CHRONIC SUBDURAL HEMATOMA: A SINGLE-CENTRE, OBSERVER-BLINDED, RANDOMIZED CONTROLLED TRIAL (TRACE) by Adriana Micheline Workewych A thesis submitted in conformity with the requirements for the degree of Master of Science Institute of Medical Science University of Toronto © Copyright by Adriana Micheline Workewych 2018 TRANEXAMIC ACID IN THE TREATMENT OF RESIDUAL CHRONIC SUBDURAL HEMATOMA: A SINGLE-CENTRE, OBSERVER-BLINDED, RANDOMIZED CONTROLLED TRIAL (TRACE) Adriana Micheline Workewych Master of Science Institute of Medical Science University of Toronto 2018 ABSTRACT Chronic subdural hematoma (CSDH) is a frequent consequence of head trauma, particularly in older individuals. Given the aging of populations globally, its incidence is projected to increase substantially. Hyperfibrinolysis may be central to CSDH enlargement by causing excessive clot degradation and liquefaction, impeding resorption. The only current standard treatment for CSDH is surgery, however, up to 31% of residual hematomas enlarge, requiring reoperation. Tranexamic acid (TXA), an antifibrinolytic medication that prevents excessively rapid clot breakdown, may help prevent CSDH enlargement, potentially eliminating the need for repeat surgery. To evaluate the feasibility of conducting a trial investigating TXA efficacy in residual CSDH, we conducted an observer-blinded, pilot randomized controlled trial (RCT). We showed this trial was feasible and safe, reporting only minor to moderate AEs, and an attrition rate of 4%. The results from this study will inform the conduct of a double-blinded RCT investigating TXA efficacy in post-operative CSDH management. ii ACKNOWLEDGEMENTS First, I would like to thank my supervisor Dr. Michael Cusimano, my mentor for nearly six years. You have always given me more opportunity than I could have ever hoped for – I could not ask for a more dedicated teacher. -
The Plasmin–Antiplasmin System: Structural and Functional Aspects
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Bern Open Repository and Information System (BORIS) Cell. Mol. Life Sci. (2011) 68:785–801 DOI 10.1007/s00018-010-0566-5 Cellular and Molecular Life Sciences REVIEW The plasmin–antiplasmin system: structural and functional aspects Johann Schaller • Simon S. Gerber Received: 13 April 2010 / Revised: 3 September 2010 / Accepted: 12 October 2010 / Published online: 7 December 2010 Ó Springer Basel AG 2010 Abstract The plasmin–antiplasmin system plays a key Plasminogen activator inhibitors Á a2-Macroglobulin Á role in blood coagulation and fibrinolysis. Plasmin and Multidomain serine proteases a2-antiplasmin are primarily responsible for a controlled and regulated dissolution of the fibrin polymers into solu- Abbreviations ble fragments. However, besides plasmin(ogen) and A2PI a2-Antiplasmin, a2-Plasmin inhibitor a2-antiplasmin the system contains a series of specific CHO Carbohydrate activators and inhibitors. The main physiological activators EGF-like Epidermal growth factor-like of plasminogen are tissue-type plasminogen activator, FN1 Fibronectin type I which is mainly involved in the dissolution of the fibrin K Kringle polymers by plasmin, and urokinase-type plasminogen LBS Lysine binding site activator, which is primarily responsible for the generation LMW Low molecular weight of plasmin activity in the intercellular space. Both activa- a2M a2-Macroglobulin tors are multidomain serine proteases. Besides the main NTP N-terminal peptide of Pgn physiological inhibitor a2-antiplasmin, the plasmin–anti- PAI-1, -2 Plasminogen activator inhibitor 1, 2 plasmin system is also regulated by the general protease Pgn Plasminogen inhibitor a2-macroglobulin, a member of the protease Plm Plasmin inhibitor I39 family. -
Path Ggf 5 2020.Pdf
Hemostasis Hemostasis and Thrombosis Normal hemostasis is a consequence of tightly regulated processes that maintain blood in a fluid state in normal vessels, yet also permit the rapid formation of a hemostatic clot at the site of a vascular injury. Thrombosis involves blood clot formation within intact vessels. Both hemostasis and thrombosis involve three components: the vascular wall, platelets and the coagulation cascade. Elements of the Hemostatic process • Endothelium • Anti-thrombosis • Pro-thrombosis • Platelets • Platelet-endothelial cell interaction • Coagulation cascade http://www.as.miami.edu/chemistry/2086/chapter_21/NEW-Chap21_class_part1_files/image002.jpg After initial injury there is a brief period of arteriolar vasoconstriction mediated by reflex neurogenic mechanisms and augmented by the local secretion of factors such as endothelin (a potent endothelium-derived vasoconstrictor) The effect is transient, however, and bleeding would resume if not for activation of the platelet and coagulation systems. Endothelial injury exposes highly thrombogenic subendothelial extracellular matrix (ECM), facilitating platelet adherence and activation. Activation of platelets results in a dramatic shape change (from small rounded discs to flat plates with markedly increased surface area), as well as the release of secretory granules. Within minutes the secreted products recruit additional platelets (aggregation) to form a hemostatic plug; this process is referred to as primary hemostasis. http://www.ouhsc.edu/platelets/Platelet%20Pic s/Platelets3.jpg http://medcell.med.yale.edu/histology/blood_bone_marr ow_lab/images/platelets_em.jpg Tissue factor is also exposed at the site of injury. Also known as factor III and thromboplastin, tissue factor is a membrane-bound procoagulant glycoprotein synthesized by endothelial cells. It acts in conjunction with factor VII (see below) as the major in vivo initiator of the coagulation cascade, eventually culminating in thrombin generation. -
RIASTAP®, Fibrinogen Concentrate (Human) Lyophilized Powder for Solution for Intravenous Injection
HIGHLIGHTS OF PRESCRIBING INFORMATION -------------------------------------CONTRAINDICATIONS ------------------------------------ These highlights do not include all the information needed to use RIASTAP • Known anaphylactic or severe systemic reactions to human plasma-derived products (4). safely and effectively. See full prescribing information for RIASTAP. ---------------------------------WARNINGS AND PRECAUTIONS---------------------------- RIASTAP®, Fibrinogen Concentrate (Human) • Monitor patients for early signs of anaphylaxis or hypersensitivity reactions and if necessary, discontinue administration and institute appropriate treatment (5.1). Lyophilized Powder for Solution for Intravenous Injection • Thrombotic events have been reported in patients receiving RIASTAP. Weigh the benefits of administration versus the risks of thrombosis (5.2). Initial U.S. Approval: 2009 • Because RIASTAP is made from human blood, it may carry a risk of transmitting ------------------------------------RECENT MAJOR CHANGES--------------------------------- infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent Indications and Usage (1) 06/2021 and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent (5.3). Dosage and Administration (2.2) 07/2020 -------------------------------------ADVERSE REACTIONS-------------------------------------- ----------------------------------INDICATIONS AND USAGE----------------------------------- • The most serious adverse reactions observed are thrombotic episodes (pulmonary RIASTAP, Fibrinogen -
Fibrin Induces Release of Von Willebrand Factor from Endothelial Cells
Fibrin induces release of von Willebrand factor from endothelial cells. J A Ribes, … , C W Francis, D D Wagner J Clin Invest. 1987;79(1):117-123. https://doi.org/10.1172/JCI112771. Research Article Addition of fibrinogen to human umbilical vein endothelial cells in culture resulted in release of von Willebrand factor (vWf) from Weibel-Palade bodies that was temporally related to formation of fibrin in the medium. Whereas no release occurred before gelation, the formation of fibrin was associated with disappearance of Weibel-Palade bodies and development of extracellular patches of immunofluorescence typical of vWf release. Release also occurred within 10 min of exposure to preformed fibrin but did not occur after exposure to washed red cells, clot liquor, or structurally different fibrin prepared with reptilase. Metabolically labeled vWf was immunopurified from the medium after release by fibrin and shown to consist of highly processed protein lacking pro-vWf subunits. The contribution of residual thrombin to release stimulated by fibrin was minimized by preparing fibrin clots with nonstimulatory concentrations of thrombin and by inhibiting residual thrombin with hirudin or heating. We conclude that fibrin formed at sites of vessel injury may function as a physiologic secretagogue for endothelial cells causing rapid release of stored vWf. Find the latest version: https://jci.me/112771/pdf Fibrin Induces Release of von Willebrand Factor from Endothelial Cells Julie A. Ribes, Charles W. Francis, and Denisa D. Wagner Hematology Unit, Department ofMedicine, University ofRochester School ofMedicine and Dentistry, Rochester, New York 14642 Abstract erogeneous and can be separated by sodium dodecyl sulfate (SDS) electrophoresis into a series of disulfide-bonded multimers Addition of fibrinogen to human umbilical vein endothelial cells with molecular masses from 500,000 to as high as 20,000,000 in culture resulted in release of von Willebrand factor (vWf) D (8). -
Biomechanical Thrombosis: the Dark Side of Force and Dawn of Mechano- Medicine
Open access Review Stroke Vasc Neurol: first published as 10.1136/svn-2019-000302 on 15 December 2019. Downloaded from Biomechanical thrombosis: the dark side of force and dawn of mechano- medicine Yunfeng Chen ,1 Lining Arnold Ju 2 To cite: Chen Y, Ju LA. ABSTRACT P2Y12 receptor antagonists (clopidogrel, pras- Biomechanical thrombosis: the Arterial thrombosis is in part contributed by excessive ugrel, ticagrelor), inhibitors of thromboxane dark side of force and dawn platelet aggregation, which can lead to blood clotting and A2 (TxA2) generation (aspirin, triflusal) or of mechano- medicine. Stroke subsequent heart attack and stroke. Platelets are sensitive & Vascular Neurology 2019;0. protease- activated receptor 1 (PAR1) antag- to the haemodynamic environment. Rapid haemodynamcis 1 doi:10.1136/svn-2019-000302 onists (vorapaxar). Increasing the dose of and disturbed blood flow, which occur in vessels with these agents, especially aspirin and clopi- growing thrombi and atherosclerotic plaques or is caused YC and LAJ contributed equally. dogrel, has been employed to dampen the by medical device implantation and intervention, promotes Received 12 November 2019 platelet thrombotic functions. However, this platelet aggregation and thrombus formation. In such 4 Accepted 14 November 2019 situations, conventional antiplatelet drugs often have also increases the risk of excessive bleeding. suboptimal efficacy and a serious side effect of excessive It has long been recognized that arterial bleeding. Investigating the mechanisms of platelet thrombosis -
BLOOD COAGULATION TESTS 17 Lea E
HEMATOLOGY: BLOOD COAGULATION TESTS 17 Lea E. Dela Peña Normal hemostasis involves a complex interaction among the vascular subendothe- OBJECTIVES lium, platelets, coagulation factors, and proteins that promote clot formation, clot degradation and inhibitors of these substances. Disruption in normal hemostasis can After completing this chapter, the result in bleeding or excessive clotting. Bleeding can be caused by trauma or damage reader should be able to to vessels, acquired or inherited deficiencies of coagulation factors, or physiological • Describe the role of platelets, disorders of platelets, whereas excessive clotting can result from abnormalities of the the coagulation cascade, and vascular endothelium, alterations in blood flow, or deficiencies in clotting inhibitors. fibrinolytic system in normal Clinicians must monitor the hemostasis process in individual patients to ensure hemostasis their safety from an imbalance in this complex system. For example, practitioners routinely order platelet tests in patients on certain antineoplastic medications to • List the laboratory tests used assess for thrombocytopenia. Likewise, clinicians closely monitor coagulation tests to assess platelets and discuss for patients receiving anticoagulants to prevent thromboembolic or hemorrhagic factors that may influence their complications. Overall, the hemostatic process is intricate and requires a clinician results knowledgeable in its dynamics for quality assessment. • List the laboratory tests used This chapter reviews normal coagulation physiology, -
Protein C Product Monograph 1995 COAMATIC® Protein C Protein C
Protein C Product Monograph 1995 COAMATIC® Protein C Protein C Protein C, Product Monograph 1995 Frank Axelsson, Product Information Manager Copyright © 1995 Chromogenix AB. Version 1.1 Taljegårdsgatan 3, S-431 53 Mölndal, Sweden. Tel: +46 31 706 20 00, Fax: +46 31 86 46 26, E-mail: [email protected], Internet: www.chromogenix.se COAMATIC® Protein C Protein C Contents Page Preface 2 Introduction 4 Determination of protein C activity with 4 snake venom and S-2366 Biochemistry 6 Protein C biochemistry 6 Clinical Aspects 10 Protein C deficiency 10 Assay Methods 13 Protein C assays 13 Laboratory aspects 16 Products 17 Diagnostic kits from Chromogenix 17 General assay procedure 18 COAMATIC® Protein C 19 References 20 Glossary 23 3 Protein C, version 1.1 Preface The blood coagulation system is carefully controlled in vivo by several anticoagulant mechanisms, which ensure that clot propagation does not lead to occlusion of the vasculature. The protein C pathway is one of these anticoagulant systems. During the last few years it has been found that inherited defects of the protein C system are underlying risk factors in a majority of cases with familial thrombophilia. The factor V gene mutation recently identified in conjunction with APC resistance is such a defect which, in combination with protein C deficiency, increases the thrombosis risk considerably. The Chromogenix Monographs [Protein C and APC-resistance] give a didactic and illustrated picture of the protein C environment by presenting a general view of medical as well as technical matters. They serve as an excellent introduction and survey to everyone who wishes to learn quickly about this field of medicine. -
PROTEIN C DEFICIENCY 1215 Adulthood and a Large Number of Children and Adults with Protein C Mutations [6,13]
Haemophilia (2008), 14, 1214–1221 DOI: 10.1111/j.1365-2516.2008.01838.x ORIGINAL ARTICLE Protein C deficiency N. A. GOLDENBERG* and M. J. MANCO-JOHNSON* *Hemophilia & Thrombosis Center, Section of Hematology, Oncology, and Bone Marrow Transplantation, Department of Pediatrics, University of Colorado Denver and The ChildrenÕs Hospital, Aurora, CO; and Division of Hematology/ Oncology, Department of Medicine, University of Colorado Denver, Aurora, CO, USA Summary. Severe protein C deficiency (i.e. protein C ment of acute thrombotic events in severe protein C ) activity <1 IU dL 1) is a rare autosomal recessive deficiency typically requires replacement with pro- disorder that usually presents in the neonatal period tein C concentrate while maintaining therapeutic with purpura fulminans (PF) and severe disseminated anticoagulation; protein C replacement is also used intravascular coagulation (DIC), often with concom- for prevention of these complications around sur- itant venous thromboembolism (VTE). Recurrent gery. Long-term management in severe protein C thrombotic episodes (PF, DIC, or VTE) are common. deficiency involves anticoagulation with or without a Homozygotes and compound heterozygotes often protein C replacement regimen. Although many possess a similar phenotype of severe protein C patients with severe protein C deficiency are born deficiency. Mild (i.e. simple heterozygous) protein C with evidence of in utero thrombosis and experience deficiency, by contrast, is often asymptomatic but multiple further events, intensive treatment and may involve recurrent VTE episodes, most often monitoring can enable these individuals to thrive. triggered by clinical risk factors. The coagulopathy in Further research is needed to better delineate optimal protein C deficiency is caused by impaired inactiva- preventive and therapeutic strategies. -
Peptide-Mediated Inactivation of Recombinant and Platelet Plasminogen Activator Inhibitor-1 in Vitro
Peptide-mediated inactivation of recombinant and platelet plasminogen activator inhibitor-1 in vitro. D T Eitzman, … , S T Olson, D Ginsburg J Clin Invest. 1995;95(5):2416-2420. https://doi.org/10.1172/JCI117937. Research Article Plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of tissue-type plasminogen activator (t-PA) and urokinase plasminogen activator, is an important regulator of the blood fibrinolytic system. Elevated plasma levels of PAI-1 are associated with thrombosis, and high levels of PAI-1 within platelet-rich clots contribute to their resistance to lysis by t-PA. Consequently, strategies aimed at inhibition of PAI-1 may prove clinically useful. This study was designed to test the hypothesis that a 14-amino acid peptide, corresponding to the PAI-1 reactive center loop (residues 333-346), can rapidly inhibit PAI-1 function. PAI-1 (0.7 microM) was incubated with peptide (55 microM) at 37 degrees C. At timed intervals, residual PAI-1 activity was determined by addition of reaction mixture samples to t-PA and chromogenic substrate. The T1/2 of PAI-1 activity in the presence of peptide was 4 +/- 3 min compared to a control T1/2 of 98 +/- 18 min. The peptide also inhibited complex formation between PAI-1 and t-PA as demonstrated by SDS-PAGE analysis. However, the capacity of the peptide to inhibit PAI-1 bound to vitronectin, a plasma protein that stabilizes PAI-1 activity, was markedly attenuated. Finally, the peptide significantly enhanced in vitro lysis of platelet-rich clots and platelet-poor clots containing recombinant PAI-1.