AI Article Synopsis
Article Abstract
The minor gammaA/gamma' fibrinogen isoform contains a high affinity binding site for thrombin exosite II that is lacking in the major gammaA/gammaA fibrinogen isoform. We therefore investigated the biological consequences of the gamma' chain binding to thrombin. Thrombin-induced platelet aggregation was inhibited by gammaA/gamma' fibrinogen. Carboxyl terminal peptide fragment gamma'410-427 from the gamma' chain was also inhibitory, with an IC(50) of approximately 200 microM in whole plasma. Deletion of the peptide from either the amino or carboxyl end significantly decreased inhibition. In contrast to thrombin-induced platelet aggregation, aggregation induced by epinephrine, ADP, arachidonic acid, or SFLLRN peptide showed little inhibition by the gamma' peptide. The inhibition of thrombin-induced platelet aggregation was not due to direct inhibition of the thrombin active site, since cleavage of a small peptidyl substrate was 91% of normal even in the presence of 1 mM gamma'410-427. The gamma'410-427 peptide blocked platelet adhesion to immobilized thrombin under both static and flow conditions, blocked soluble thrombin binding to platelet GPIbalpha, and inhibited PAR1 cleavage by thrombin. These results suggest that the gamma' chain of fibrinogen inhibits thrombin-induced platelet aggregation by binding to thrombin exosite II. Thrombin that is bound to the gamma' chain is thereby prevented from activating platelets, while retaining its amidolytic activity.
Download full-text PDF |
Source |
|---|
Publication Analysis
Top Keywords
Similar Publications
Deficiency of neutrophil gelatinase-associated lipocalin elicits Hemophilia-like bleeding and clotting disorder.
Blood
December 2024
School of Basic Medicine, Qingdao University, Qingdao, China.
Coagulation is related to inflammation, but the key pathway, especially innate immune system and coagulation regulation, is not well understood and need to be further explored. Here, we demonstrated that neutrophil gelatinase-associated lipocalin (NGAL), an innate immune inflammatory mediator, is upregulated in thrombosis patients. Furthermore, it contributes to the initiation and amplification of coagulation, hemostasis, and thrombosis.
View Article and Find Full Text PDFAntithrombotic but not anticoagulant activity of the thrombin-binding RNA aptamer Apta-1.
Br J Pharmacol
December 2024
Cardiovascular Research Centre, School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
Background And Purpose: Pharmacological intervention of thrombosis is challenging, requiring a fined tune balance between beneficial antithrombotic effect versus risk of major bleeding complications. In this investigation, we elucidated the antithrombotic capacity of the novel 90-mer RNA aptamer Apta-1 and its underlying mechanism of action.
Experimental Approach: We utilized three independent in vivo animal models to establish antithrombotic activity and bleeding risk of Apta-1.
Design and Synthesis of Butylphthalide-Hydroxycinnamic Acid Hybrid Derivatives as Potential Antiplatelet Agents.
Chem Biodivers
November 2024
College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, 550004, People's Republic of China.
Thirty-eight novel butylphthalide-hydroxycinnamic acid hybrid derivatives were designed and synthesized to discover effective antiplatelet agglutination drugs. Among these compounds, 3 o gave the optimal inhibitory activity against AA-induced platelet aggregation in vitro and also exhibited better inhibition than the precursor 3-n-butylphthalide (NBP) against thrombin-induced platelet contraction, carrageenan-induced tail thrombosis, and FeCl-induced common carotid artery thrombosis. Further investigations on the anti-ischemic stroke activity revealed that compound 3 o exhibited a remarkable protective effect against ischemic/reperfusion brain injury.
View Article and Find Full Text PDF[Regulation of Reactive Oxygen Species on Platelet Activation and Apoptosis].
Zhongguo Shi Yan Xue Ye Xue Za Zhi
October 2024
Suzhou Medical College of Soochow University, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, State Key Laboratory of Radiation Medicine and Protection, Collaborative Innovation Center of Hematology, Suzhou 215006, Jiangsu Province, China.E-mail:
Objective: To investigate how reactive oxygen species (ROS) regulates the signal transduction of platelet activation and apoptosis, and to explore the relationship between platelet activation and apoptosis.
Methods: Platelets were directly stimulated with thrombin or pretreated with ROS inhibitor N-acetylcysteine (NAC) before being stimulated with thrombin, and then flow cytometry was used to detect the effects of thrombin and NAC on P-selectin expression, αⅡbβ3 activation, mitochondrial membrane potential depolarization, phosphatidylserine (PS) externalization, ROS expression and platelet aggregation.
Results: Thrombin could induce the production of ROS in platelets in a concentration- and time-dependent manner.
Phosphatidylserine-blocking nanoparticles inhibit thrombosis without increased bleeding in mice.
J Thromb Haemost
October 2024
Cardeza Foundation for Hematologic Research, Department of Medicine, Division of Hematology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. Electronic address:
Background: Phosphatidylserine (PS) is a procoagulant phospholipid enriched on surfaces of activated vascular cells including platelets, endothelium, monocytes, and microvesicles. As a molecular driver of thrombosis accessible to drug blockade, PS is an attractive pharmacologic target for modulating thrombogenesis, with potentially reduced bleeding risk compared to anticoagulant and antiplatelet therapies.
Objectives: Test antithrombotic capabilities of a liposomal formulation, Zn-dipicolylamine cyanine-3[22,22]/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (molar ratio, 3:97), designated as DPAL, which we previously described binds selectively to PS-enriched cell surfaces, compared with effects on bleeding, in mouse models.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!