Figure - available from: Scientific Reports
This content is subject to copyright. Terms and conditions apply.
Colorized scanning electron micrograph of blood clot made by re-calcifying platelet-rich plasma. Platelets and microvesicles are colored blue and fibrin is tan. The micrograph illustrates the specific and intimate interactions between platelets and fibrin in blood clots and demonstrates that most fibrin fibers originate from platelet aggregates, where much of the thrombin is generated, while platelet-derived microvesicles decorate the fibrin fibers.

Colorized scanning electron micrograph of blood clot made by re-calcifying platelet-rich plasma. Platelets and microvesicles are colored blue and fibrin is tan. The micrograph illustrates the specific and intimate interactions between platelets and fibrin in blood clots and demonstrates that most fibrin fibers originate from platelet aggregates, where much of the thrombin is generated, while platelet-derived microvesicles decorate the fibrin fibers.

Source publication
Article
Full-text available
The formation of platelet thrombi is determined by the integrin αIIbβ3-mediated interactions of platelets with fibrinogen and fibrin. Blood clotting in vivo is catalyzed by thrombin, which simultaneously induces fibrinogen binding to αIIbβ3 and converts fibrinogen to fibrin. Thus, after a short time, thrombus formation is governed by αIIbβ3 binding...

Similar publications

Article
Full-text available
The Use of Glycoprotein IIb/IIIa Inhibitors in Patients with ST Elevation Myocardial Infarction Treated without Thrombectomy Device Mohammad El Garhy1,2*, Marc-Alexander Ohlow1, Alaa Abd El- Raheim2, Alaa Ibrahim2, Nieren Okasha3 and Bernward Lauer1 Abstract Aims: In this study we aim to evaluate the benefit of GPIs in patients with STEMI treated w...

Citations

... Platelets contain the β3 and β1 integrin subfamily including α2β1, α5β1, α6β1, αIIbβ3 and α v β3 ). Integrin αIIbβ 3 (glycoprotein IIb-IIIa) which is widely expressed in platelet and megakaryocyte plays a crucial role in the platelet thrombi formation (Höök et al. 2017). Considering the critical role of glycoprotein IIb-IIIa in the pathophysiology of unstable angina and non-ST-segment elevation myocardial infarction, pharmacologic blockade of glycoprotein IIb/IIIa integrin receptor has been considered as a promising therapeutic approach for alleviating the coronary thrombus (Cannon 2003). ...
Article
As a group of heterodimeric and transmembrane glycoproteins, integrin receptors are widely expressed in various cell types overall the body. During cardiovascular dysfunction, integrin receptors apply inhibitory effects on the antioxidative pathways, including nuclear factor erythroid 2–related factor 2 (Nrf2)-Kelch like eCH Associated Protein 1 (Keap1)/antioxidant response element (ARe) and interconnected mediators. As such, dysregulation in integrin signaling pathways influences several aspects of cardiovascular diseases (CvDs) such as heart failure, arrhythmia, angina, hypertension, hyperlipidemia, platelet aggregation and coagulation. So, modulation of integrin pathway could trigger the downstream antioxidant pathways toward cardioprotection. Regarding the involvement of multiple aforementioned mediators in the pathogenesis of CvDs, as well as the side effects of conventional drugs, seeking for novel alternative drugs is of great importance. Accordingly, the plant kingdom could pave the road in the treatment of CvDs. Of natural entities, polyphenols are multi-target and accessible phytochemicals with promising potency and low levels of toxicity. The present study aims at providing the cardioprotective roles of integrin receptors and downstream antioxidant pathways in heart failure, arrhythmia, angina, hypertension, hyperlipidemia, platelet aggregation and coagulation. The potential role of polyphenols has been also revealed in targeting the aforementioned dysregulated signaling mediators in those CvDs.
... To demonstrate the feasibility of a targeting system based on PH for anti-tumor therapy, it is necessary to experimentally confirm the specific interaction of PH with target molecules and the consequent drug release. In this study, collagen and fibrin were selected as target molecules because the platelets have an inherent affinity for the molecules [40][41][42][43][44]. In tumor tissues, inflammation continuously takes place which often damages the blood vessel. ...
Article
Full-text available
The objective of this study is to construct a platelet-mediated delivery system for drug-incorporated nanospheres. Nanospheres of poly(lactic-co-glycolic acid) (PLGA-NS) with different sizes and surface properties were prepared by changing the preparation parameters, such as the type of polymer surfactant, the concentration of polymer surfactant and PLGA, and the stirring rate. When incubated with platelets, PLGA-NS prepared with poly(vinyl alcohol) suppressed the platelet activation. Scanning electron microscopic and flow cytometry examinations revealed that platelets associated with PLGA-NS (platelet hybrids, PH) had a similar appearance and biological properties to those of the original platelets. In addition, the PH with PLGA-NS specifically adhered onto the substrate pre-coated with fibrin to a significantly great extent compared with PLGA-NS alone. When applied in an in vitro model of tumor tissue which was composed of an upper chamber pre-coated with fibrin and a lower chamber culturing tumor cells, the PH with PLGA-NS incorporating an anti-tumor drug were delivered to the tumor cells through the specific adhesion onto the upper chamber and, consequently, drug release from the upper chamber took place, resulting in the growth suppression of tumor cells. It is concluded that the drug delivery system based on PH is promising for tumor treatment.
... The fibrin network also interacts with platelets via a surface integrin receptor αIIbβ3 [41], and this enhances platelet aggregation [41]. As thrombin induces the fibrinogen-platelet interaction it simultaneously converts fibrinogen to fibrin, therefore, with time, polymerised fibrin becomes the ligand for activated platelet surface receptor αIIbβ3 [41]. ...
... The fibrin network also interacts with platelets via a surface integrin receptor αIIbβ3 [41], and this enhances platelet aggregation [41]. As thrombin induces the fibrinogen-platelet interaction it simultaneously converts fibrinogen to fibrin, therefore, with time, polymerised fibrin becomes the ligand for activated platelet surface receptor αIIbβ3 [41]. ...
... The fibrin network also interacts with platelets via a surface integrin receptor αIIbβ3 [41], and this enhances platelet aggregation [41]. As thrombin induces the fibrinogen-platelet interaction it simultaneously converts fibrinogen to fibrin, therefore, with time, polymerised fibrin becomes the ligand for activated platelet surface receptor αIIbβ3 [41]. This results in a platelet-fibrin meshwork that enables clot contraction, which occurs through the action of myosin II and actin proteins in the platelets [42]. ...
Article
Full-text available
Fibrinogen is one of the key molecular players in haemostasis. Thrombin-mediated release of fibrinopeptides from fibrinogen converts this soluble protein into a network of fibrin fibres that form a building block for blood clots. Thrombin-activated factor XIII further crosslinks the fibrin fibres and incorporates antifibrinolytic proteins into the network, thus stabilising the clot. The conversion of fibrinogen to fibrin also exposes binding sites for fibrinolytic proteins to limit clot formation and avoid unwanted extension of the fibrin fibres. Altered clot structure and/or incorporation of antifibrinolytic proteins into fibrin networks disturbs the delicate equilibrium between clot formation and lysis, resulting in either unstable clots (predisposing to bleeding events) or persistent clots that are resistant to lysis (increasing risk of thrombosis). In this review, we discuss the factors responsible for alterations in fibrin(ogen) that can modulate clot stability, in turn predisposing to abnormal haemostasis. We also explore the mechanistic pathways that may allow the use of fibrinogen as a potential therapeutic target to treat vascular thrombosis or bleeding disorders. Better understanding of fibrinogen function will help to devise future effective and safe therapies to modulate thrombosis and bleeding risk, while maintaining the fine balance between clot formation and lysis.
... Cells of the blood clot interact with fibrin through a cell surface integrin-driven mechanism mediated by Arg-Gly-Asp (RGD) adhesive sequences (Mosesson, 2005). Fibrin binds to integrin α IIb β 3 (present on platelets) (Höök et al., 2017), integrin α M β 2 /Mac-1 (neutrophils, monocytes, macrophages and mast cells) (Gailit et al., 1997) and integrin α V β 3 (fibroblasts, endothelial cells) (Flick et al., 2004;Gawaz et al., 1997) , (Fig. 3). Cell binding leads to the activation of specific intracellular signalling pathways, which drive blood-clot formation and ECM remodelling, suggesting that cell adhesion to the fibrin matrix is a key step in the triggering of tissue regeneration. ...
Article
Full-text available
Tissue engineering-based endodontic therapies, designed to regenerate the dental pulp (DP) in the devitalised endodontic space, have been proposed to improve tooth longevity compared to conventional root-filling therapies. Their aim is to restore tooth vitality and major DP functions necessary to maintain tooth health such as immunosurveillance, sensitivity and healing/repair/regenerative capacities. Several formulations based on the use of fibrin, the main component of the blood clot matrix, recently gave valuable results in the regeneration of the human DP. This review describes recent fibrin-based scaffolds designed for that purpose. After having presented the various strategies for DP regeneration, the main fibrin-based scaffolds reported so far for clinical use in endodontics were reviewed. Particular emphasis was given to hydrogel devices that may be improved by incorporation of bioactive molecules that stimulate vascularisation and tissue neoformation or provide antibacterial properties. Data indicate that fibrin-based scaffolds constitute a highly favourable environment for mesenchymal stem cells, which is maintained upon functionalisation. Additional knowledge is needed to understand how fibrin and functionalising agents affect adhesion, survival, proliferation, migration and differentiation of cells incorporated in the scaffold or which will colonise it from neighbouring host tissues. This knowledge is needed to adapt the hydrogel formulation for various clinical conditions.
... Fibrinogen adsorption was further suggested to facilitate electron transfer from fibrinogen to graphene to germanium. Electron loss from fibrinogen has been shown to unfold and lead to formation of the fibrinopeptide and fibrin monomer, competent for polymerization 70,71 , and fibrin is known to have a strong interaction with platelets through the α III β II b integrin 72 . Thus, graphene acting as an electron acceptor and transporter, resulting in electron extraction from fibrinogen, could lead to enhanced platelet activation as illustrated in Fig. 6b. ...
Article
Full-text available
Graphene, an allotrope of carbon, consists of a single layer of carbon atoms with uniquely tuneable properties. As such, graphene-based materials (GBMs) have gained interest for tissue engineering applications. GBMs are often discussed in the context of how different physicochemical properties affect cell physiology, without explicitly considering the impact of adsorbed proteins. Establishing a relationship between graphene properties, adsorbed proteins, and cell response is necessary as these proteins provide the surface upon which cells attach and grow. This review highlights the molecular adsorption of proteins on different GBMs, protein structural changes, and the connection to cellular function. Graphene-based materials are widely studied in biomedical applications, but a full picture of their interactions with proteins and cells remains elusive. Here the molecular basis for the effect of graphene-based materials on cell fate and in tissue engineering is reviewed.
... Platelet activation and subsequent platelet-tumor cell aggregates have been shown to enhance metastatic dissemination [17]. This process is facilitated by fibrin, which can interact with tumor cells and platelets through integrins, leading to the formation of thick fibrin coats on the CTC-platelet aggregates [100]. Such aggregates help the tumor cells survive the fluid shear stress in circulation and physically shield the tumor epitopes from immune surveillance, primarily by the natural killer (NK) cells. ...
Article
Full-text available
A dynamic mucosal layer shields the epithelial cells lining the body cavities and is made up of high molecular weight, heavily glycosylated, multidomain proteins called mucins. Mucins, broadly grouped into transmembrane and secreted mucins, are the first responders to any mechanical or chemical insult to the epithelia and help maintain tissue homeostasis. However, their intrinsic properties to protect and repair the epithelia are exploited during oncogenic processes, where mucins are metamorphosed to aid the tumor cells in their malignant journey. Diverse domains, like the variable number tandem repeats (VNTR), sea urchin sperm protein enterokinase and agrin (SEA), adhesion-associated domain (AMOP), nidogen-like domain (NIDO), epidermal growth factor-like domain (EGF), and von Willebrand factor type D domain (vWD) on mucins, including MUC1, MUC4, MUC5AC, MUC5B, and MUC16, have been shown to facilitate cell-to-cell and cell-to-matrix interactions, and cell-autonomous signaling to promote tumorigenesis and distant dissemination of tumor cells. Several obstacles have limited the study of mucins, including technical difficulties in working with these huge glycoproteins, the dearth of scientific tools, and lack of animal models; thus, the tissue-dependent and domain-specific roles of mucins during mucosal protection, chronic inflammation, tumorigenesis, and hematological dissemination of malignant cells are still unclear. Future studies should try to integrate information on the rheological, molecular, and biological characteristics of mucins to comprehensively delineate their pathophysiological role and evaluate their suitability as targets in future diagnostic and therapeutic strategies.
... Blood Reviews xxx (xxxx) xxxx fibrinogen) [124]. Furthermore, platelet adhesion and spreading on FXIIIa occur through fibrinogen independent binding of αIIbβ3 and αVβ3 [125]. ...
Article
Full-text available
Haemostasis stops bleeding at the site of vascular injury and maintains the integrity of blood vessels through clot formation. This regulated physiological process consists of complex interactions between endothelial cells, platelets, von Willebrand factor and coagulation factors. Haemostasis is initiated by a damaged vessel wall, followed with a rapid adhesion, activation and aggregation of platelets to the exposed subendothelial extracellular matrix. At the same time, coagulation factors aggregate on the procoagulant surface of activated platelets to consolidate the platelet plug by forming a mesh of cross-linked fibrin. Platelets and coagulation mutually influence each other and there are strong indications that, thanks to the interplay between platelets and coagulation, haemostasis is far more effective than the two processes separately. Clinically this is relevant because impaired interaction between platelets and coagulation may result in bleeding complications, while excessive platelet-coagulation interaction induces a high thrombotic risk. In this review, platelets, coagulation factors and the complex interaction between them will be discussed in detail.
... That could explain an increase in platelet adhesion on all three adhesive protein-coated substrates when the upstream wall shear rate was raised to 11,560 s −1 (Figs. 2 and 3). Shear activation of GPIIb/IIIa increases platelet affinity for binding to fibrinogen and vWf leading to the irreversible adhesion and future thrombus growth [32,33]. Shear-induced activation of GPIa/IIa increases platelet affinity for binding to collagen [32]. ...
Article
Transient exposure to elevated shear forces is known to prime platelets for enhanced downstream adhesion, but how far downstream these priming effects persist is not known. In the present study, the platelet capture regions, prepared by immobilizing fibrinogen, collagen, or von Willebrand factor, were placed at three different distances from the upstream stenotic region to vary the elapsed time of circulating platelets downstream. Platelet adhesion increased with the increase of upstream wall shear rates from 1620 s⁻¹ to 11560 s⁻¹ for all three downstream proteins, but only the adhesion to fibrinogen increased significantly with the distance between the upstream stenotic region and the downstream capture region. In contrast, platelet adhesion to downstream collagen remained essentially independent on the distance and the adhesion to von Willebrand factor marginally increased with the distance after transient platelet exposure to upstream wall shear rates of 2145 s⁻¹ and 11560 s⁻¹. The results implied that the activation of fibrinogen receptor GPIIb/IIIa by transient exposure to high upstream wall shear rates progresses in a time-dependent manner during the downstream flow of platelets. The highly elevated upstream wall shear rate of 11560 s⁻¹ altered the morphology of many platelets adhered to downstream fibrinogen from their native ellipsoidal to spread circular form. The platelet shape analysis showed that longer periods of post-stenotic flow increased the surface coverage fraction of ellipsoidal platelet population and decreased the surface coverage fraction of fully spread platelets on fibrinogen for both transiently elevated upstream wall shear rates.
... Several important binding events are associated with precisely this spot due to the affinity to integrin receptors exposed on the cellular membrane (74)(75)(76). In the case of platelet binding, this RGD motif competes with the γ-chain, and the interaction between fibrin and integrin αIIbβ3 was previously proposed as a therapeutic target to destabilize thrombi (77,78). We envision that XL-MS can be used to study the interactions made by both platelets as well as endothelial cells to provide a molecular picture for these interactions. ...
Article
Full-text available
Upon activation, fibrinogen forms large fibrin biopolymers that coalesce into clots which assist in wound healing. Limited insights into their molecular architecture, due to the sheer size and the insoluble character of fibrin clots, have restricted our ability to develop novel treatments for clotting diseases. The, so far resolved, disparate structural details have provided insights into linear elongation; however, molecular details like the C-terminal domain of the α-chain, the heparin-binding domain on the β-chain, and other functional domains remain elusive. To illuminate these dark areas, we applied cross-linking mass spectrometry (XL-MS) to obtain biochemical evidence in the form of over 300 distance constraints and combined this with structural modeling. These restraints additionally define the interaction network of the clots and provide molecular details for the interaction with human serum albumin (HSA). We were able to construct the structural models of the fibrinogen α-chain (excluding two highly flexible regions) and the N termini of the β-chain, confirm these models with known structural arrangements, and map how the structure laterally aggregates to form intricate lattices together with the γ-chain. We validate the final model by mapping mutations leading to impaired clot formation. From a list of 22 mutations, we uncovered structural features for all, including a crucial role for βArg’169 (UniProt: 196) in lateral aggregation. The resulting model can potentially serve for research on dysfibrinogenemia and amyloidosis as it provides insights into the molecular mechanisms of thrombosis and bleeding disorders related to fibrinogen variants. The structure is provided in the PDB-DEV repository (PDBDEV_00000030).
... Integrin αIIbβ3 plays an important role in platelet aggregation in response to physiological agonists, and hence mediates thrombus formation [26,27]. We next investigated whether the impaired aggregation response would be associated with a commensurate inhibition of integrin αIIbβ3 activation. ...
Article
Full-text available
While changes in intracellular calcium levels is a central step in platelet activation and thrombus formation, the contribution and mechanism of receptor-operated calcium entry (ROCE) via transient receptor potential channels (TRPCs) in platelets remains poorly defined. In previous studies, we have shown that TRPC6 regulates hemostasis and thrombosis, in mice. In the present studies, we employed a knockout mouse model system to characterize the role of TRPC6 in ROCE and platelet activation. It was observed that the TRPC6 deletion (Trpc6 -/- ) platelets displayed impaired elevation of intracellular calcium, i.e., defective ROCE. Moreover, these platelets also exhibited defects in a host of functional responses, namely aggregation, granule secretion, and integrin αIIbβ3. Interestingly, the aforementioned defects were specific to the thromboxane receptor (TPR), as no impaired responses were observed in response to ADP or the thrombin receptor-activating peptide 4 (TRAP4). The defect in ROCE in the Trpc6 -/- was also observed with 1-oleoyl-2-acetyl-sn-glycerol (OAG). Finally, our studies also revealed that TRPC6 regulates clot retraction. Taken together, our findings demonstrate that TRPC6 directly regulates TPR-dependent ROCE and platelet function. Thus, TRPC6 may serve as a novel target for the therapeutic management of thrombotic diseases.