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  1. Article: All tangled up: interactions of the fibrinolytic and innate immune systems.

    Whyte, Claire S

    Frontiers in medicine

    2023  Volume 10, Page(s) 1212201

    Abstract: The hemostatic and innate immune system are intertwined processes. Inflammation within the vasculature promotes thrombus development, whilst fibrin forms part of the innate immune response to trap invading pathogens. The awareness of these interlinked ... ...

    Abstract The hemostatic and innate immune system are intertwined processes. Inflammation within the vasculature promotes thrombus development, whilst fibrin forms part of the innate immune response to trap invading pathogens. The awareness of these interlinked process has resulted in the coining of the terms "thromboinflammation" and "immunothrombosis." Once a thrombus is formed it is up to the fibrinolytic system to resolve these clots and remove them from the vasculature. Immune cells contain an arsenal of fibrinolytic regulators and plasmin, the central fibrinolytic enzyme. The fibrinolytic proteins in turn have diverse roles in immunoregulation. Here, the intricate relationship between the fibrinolytic and innate immune system will be discussed.
    Language English
    Publishing date 2023-06-02
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2775999-4
    ISSN 2296-858X
    ISSN 2296-858X
    DOI 10.3389/fmed.2023.1212201
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: All tangled up

    Claire S. Whyte

    Frontiers in Medicine, Vol

    interactions of the fibrinolytic and innate immune systems

    2023  Volume 10

    Abstract: The hemostatic and innate immune system are intertwined processes. Inflammation within the vasculature promotes thrombus development, whilst fibrin forms part of the innate immune response to trap invading pathogens. The awareness of these interlinked ... ...

    Abstract The hemostatic and innate immune system are intertwined processes. Inflammation within the vasculature promotes thrombus development, whilst fibrin forms part of the innate immune response to trap invading pathogens. The awareness of these interlinked process has resulted in the coining of the terms “thromboinflammation” and “immunothrombosis.” Once a thrombus is formed it is up to the fibrinolytic system to resolve these clots and remove them from the vasculature. Immune cells contain an arsenal of fibrinolytic regulators and plasmin, the central fibrinolytic enzyme. The fibrinolytic proteins in turn have diverse roles in immunoregulation. Here, the intricate relationship between the fibrinolytic and innate immune system will be discussed.
    Keywords fibrinolysis ; innate immune ; infection ; plasminogen ; thrombosis ; Medicine (General) ; R5-920
    Language English
    Publishing date 2023-06-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article: Editorial: Women in thrombosis.

    Whyte, Claire S / Panova-Noeva, Marina

    Frontiers in cardiovascular medicine

    2023  Volume 10, Page(s) 1159938

    Language English
    Publishing date 2023-02-21
    Publishing country Switzerland
    Document type Editorial
    ZDB-ID 2781496-8
    ISSN 2297-055X
    ISSN 2297-055X
    DOI 10.3389/fcvm.2023.1159938
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Location, location, location: Fibrin, cells, and fibrinolytic factors in thrombi.

    Narwal, Anuj / Whyte, Claire S / Mutch, Nicola J

    Frontiers in cardiovascular medicine

    2023  Volume 9, Page(s) 1070502

    Abstract: Thrombi are heterogenous in nature with composition and structure being dictated by the site of formation, initiating stimuli, shear stress, and cellular influences. Arterial thrombi are historically associated with high platelet content and more tightly ...

    Abstract Thrombi are heterogenous in nature with composition and structure being dictated by the site of formation, initiating stimuli, shear stress, and cellular influences. Arterial thrombi are historically associated with high platelet content and more tightly packed fibrin, reflecting the shear stress in these vessels. In contrast, venous thrombi are generally erythrocyte and fibrin-rich with reduced platelet contribution. However, these conventional views on the composition of thrombi in divergent vascular beds have shifted in recent years, largely due to recent advances in thromboectomy and high-resolution imaging. Interestingly, the distribution of fibrinolytic proteins within thrombi is directly influenced by the cellular composition and vascular bed. This in turn influences the susceptibility of thrombi to proteolytic degradation. Our current knowledge of thrombus composition and its impact on resistance to thrombolytic therapy and success of thrombectomy is advancing, but nonetheless in its infancy. We require a deeper understanding of thrombus architecture and the downstream influence on fibrinolytic susceptibility. Ultimately, this will aid in a stratified and targeted approach to tailored antithrombotic strategies in patients with various thromboembolic diseases.
    Language English
    Publishing date 2023-01-18
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2781496-8
    ISSN 2297-055X
    ISSN 2297-055X
    DOI 10.3389/fcvm.2022.1070502
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: "Super" SERPINs-A stabilizing force against fibrinolysis in thromboinflammatory conditions.

    Humphreys, Steven J / Whyte, Claire S / Mutch, Nicola J

    Frontiers in cardiovascular medicine

    2023  Volume 10, Page(s) 1146833

    Abstract: The superfamily of serine protease inhibitors (SERPINs) are a class of inhibitors that utilise a dynamic conformational change to trap and inhibit their target enzymes. Their powerful nature lends itself well to regulation of complex physiological ... ...

    Abstract The superfamily of serine protease inhibitors (SERPINs) are a class of inhibitors that utilise a dynamic conformational change to trap and inhibit their target enzymes. Their powerful nature lends itself well to regulation of complex physiological enzymatic cascades, such as the haemostatic, inflammatory and complement pathways. The SERPINs α2-antiplasmin, plasminogen-activator inhibitor-1, plasminogen-activator inhibitor-2, protease nexin-1, and C1-inhibitor play crucial inhibitory roles in regulation of the fibrinolytic system and inflammation. Elevated levels of these SERPINs are associated with increased risk of thrombotic complications, obesity, type 2 diabetes, and hypertension. Conversely, deficiencies of these SERPINs have been linked to hyperfibrinolysis with bleeding and angioedema. In recent years SERPINs have been implicated in the modulation of the immune response and various thromboinflammatory conditions, such as sepsis and COVID-19. Here, we highlight the current understanding of the physiological role of SERPINs in haemostasis and inflammatory disease progression, with emphasis on the fibrinolytic pathway, and how this becomes dysregulated during disease. Finally, we consider the role of these SERPINs as potential biomarkers of disease progression and therapeutic targets for thromboinflammatory diseases.
    Language English
    Publishing date 2023-04-19
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2781496-8
    ISSN 2297-055X
    ISSN 2297-055X
    DOI 10.3389/fcvm.2023.1146833
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: uPA-mediated plasminogen activation is enhanced by polyphosphate.

    Whyte, Claire S / Mutch, Nicola J

    Haematologica

    2021  Volume 106, Issue 2, Page(s) 522–531

    Abstract: ... containing clots (0.74 ± 0.06 vs. 1.17 ± 0.14 pM/s in P < 0.05). Analysis of tPA-mediated fibrinolysis ... 08 pM/s; P < 0.001) and accelerated fibrinolysis (t1/2 64.5 ± 1.7 min vs. 108.2 ± 3.8 min; P < 0.001 ...

    Abstract Tissue plasminogen activator (tPA) and urokinase (uPA) differ in their modes of action. Efficient tPA-mediated plasminogen activation requires binding to fibrin. In contrast, uPA is fibrin independent and activates plasminogen in solution or when associated with its cellular receptor uPAR. We have previously shown that polyphosphate (polyP), alters fibrin structure and attenuates tPA and plasminogen binding to fibrin, thereby down-regulating fibrinolysis. Here we investigate the impact of polyP on uPA-mediated fibrinolysis. As previously reported polyP of an average chain length of 65 (polyP65) delays tPA-mediated fibrinolysis. The rate of plasmin generation was also delayed and reduced 1.6-fold in polyP65-containing clots (0.74 ± 0.06 vs. 1.17 ± 0.14 pM/s in P < 0.05). Analysis of tPA-mediated fibrinolysis in real-time by confocal microscopy was significantly slower in polyP65-containing clots. In marked contrast, polyP65 augmented the rate of uPA-mediated plasmin generation 4.7-fold (3.96 ± 0.34 vs. 0.84 ± 0.08 pM/s; P < 0.001) and accelerated fibrinolysis (t1/2 64.5 ± 1.7 min vs. 108.2 ± 3.8 min; P < 0.001). Analysis of lysis in real-time confirmed that polyP65 enhanced uPA-mediated fibrinolysis. Varying the plasminogen concentration (0.125 to 1 μM) in clots dose-dependently enhanced uPA-mediated fibrinolysis, while negligible changes were observed on tPA-mediated fibrinolysis. The accelerating effect of polyP65 on uPA-mediated fibrinolysis was overcome by additional plasminogen, while the down-regulation of tPA-mediated lysis and plasmin generation was largely unaffected. PolyP65 exerts opposing effects on tPA- and uPA-mediated fibrinolysis, attenuating the fibrin cofactor function in tPA-mediated plasminogen activation. In contrast, polyP may facilitate the interaction between fibrin-independent uPA and plasminogen thereby accelerating plasmin generation and downstream fibrinolysis.
    MeSH term(s) Fibrinolysin ; Fibrinolysis ; Humans ; Plasminogen ; Polyphosphates ; Tissue Plasminogen Activator ; Urokinase-Type Plasminogen Activator
    Chemical Substances Polyphosphates ; Plasminogen (9001-91-6) ; Tissue Plasminogen Activator (EC 3.4.21.68) ; Fibrinolysin (EC 3.4.21.7) ; Urokinase-Type Plasminogen Activator (EC 3.4.21.73)
    Language English
    Publishing date 2021-02-01
    Publishing country Italy
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2333-4
    ISSN 1592-8721 ; 0017-6567 ; 0390-6078
    ISSN (online) 1592-8721
    ISSN 0017-6567 ; 0390-6078
    DOI 10.3324/haematol.2019.237966
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Atorvastatin-mediated inhibition of prenylation of Rab27b and Rap1a in platelets attenuates their prothrombotic capacity and modulates clot structure.

    Jalal, Mohammed M / Whyte, Claire S / Coxon, Fraser P / Mutch, Nicola J

    Platelets

    2023  Volume 34, Issue 1, Page(s) 2206921

    Abstract: Statins inhibit the mevalonate pathway by impairing protein prenylation via depletion of lipid geranylgeranyl diphosphate (GGPP). Rab27b and Rap1a are small GTPase proteins involved in dense granule secretion, platelet activation, and regulation. We ... ...

    Abstract Statins inhibit the mevalonate pathway by impairing protein prenylation via depletion of lipid geranylgeranyl diphosphate (GGPP). Rab27b and Rap1a are small GTPase proteins involved in dense granule secretion, platelet activation, and regulation. We analyzed the impact of statins on prenylation of Rab27b and Rap1a in platelets and the downstream effects on fibrin clot properties. Whole blood thromboelastography revealed that atorvastatin (ATV) delayed clot formation time (
    MeSH term(s) Humans ; Adenosine Diphosphate/metabolism ; Atorvastatin/pharmacology ; Blood Platelets/metabolism ; Fibrinogen/metabolism ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology ; Prenylation ; rab GTP-Binding Proteins/metabolism ; rap1 GTP-Binding Proteins/metabolism ; Thrombosis/drug therapy ; Thrombosis/metabolism
    Chemical Substances Adenosine Diphosphate (61D2G4IYVH) ; Atorvastatin (A0JWA85V8F) ; Fibrinogen (9001-32-5) ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; rab GTP-Binding Proteins (EC 3.6.5.2) ; Rab27B protein, human (EC 3.6.1.-.) ; rap1 GTP-Binding Proteins (EC 3.6.5.2) ; RAP1A protein, human
    Language English
    Publishing date 2023-02-21
    Publishing country England
    Document type Journal Article
    ZDB-ID 1034283-7
    ISSN 1369-1635 ; 0953-7104
    ISSN (online) 1369-1635
    ISSN 0953-7104
    DOI 10.1080/09537104.2023.2206921
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: Novel therapeutics and emerging technology in haemostasis and thrombosis: highlights from the British society for haemostasis and thrombosis annual meeting.

    Whyte, Claire S / Morrow, Gael B / Gauer, Julia S / Montague, Samantha J / Nicolson, Philip L R

    Frontiers in cardiovascular medicine

    2023  Volume 10, Page(s) 1225243

    Abstract: The 2023 annual meeting of the British Society for Haemostasis and Thrombosis (BSHT) was held in Birmingham, United Kingdom. The theme of this year's meeting was novel therapeutics and emerging technology. Here, the exciting research presented at the ... ...

    Abstract The 2023 annual meeting of the British Society for Haemostasis and Thrombosis (BSHT) was held in Birmingham, United Kingdom. The theme of this year's meeting was novel therapeutics and emerging technology. Here, the exciting research presented at the meeting is discussed.
    Language English
    Publishing date 2023-09-07
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2781496-8
    ISSN 2297-055X
    ISSN 2297-055X
    DOI 10.3389/fcvm.2023.1225243
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Factor XIII-A: An Indispensable "Factor" in Haemostasis and Wound Healing.

    Alshehri, Fahad S M / Whyte, Claire S / Mutch, Nicola J

    International journal of molecular sciences

    2021  Volume 22, Issue 6

    Abstract: Factor XIII (FXIII) is a transglutaminase enzyme that catalyses the formation of ε-(γ-glutamyl)lysyl isopeptide bonds into protein substrates. The plasma form, ... ...

    Abstract Factor XIII (FXIII) is a transglutaminase enzyme that catalyses the formation of ε-(γ-glutamyl)lysyl isopeptide bonds into protein substrates. The plasma form, FXIIIA
    MeSH term(s) Blood Vessels/metabolism ; Drug Delivery Systems ; Factor XIIIa/chemistry ; Factor XIIIa/metabolism ; Hemostasis ; Humans ; Models, Biological ; Wound Healing
    Chemical Substances Factor XIIIa (EC 2.3.2.13)
    Language English
    Publishing date 2021-03-17
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms22063055
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article: A Serpin With a Finger in Many PAIs: PAI-1's Central Function in Thromboinflammation and Cardiovascular Disease.

    Morrow, Gael B / Whyte, Claire S / Mutch, Nicola J

    Frontiers in cardiovascular medicine

    2021  Volume 8, Page(s) 653655

    Abstract: Plasminogen activator inhibitor 1 (PAI-1) is a member of the serine protease inhibitor (serpin) superfamily. PAI-1 is the principal inhibitor of the plasminogen activators, tissue plasminogen activator (tPA), and urokinase-type plasminogen activator (uPA) ...

    Abstract Plasminogen activator inhibitor 1 (PAI-1) is a member of the serine protease inhibitor (serpin) superfamily. PAI-1 is the principal inhibitor of the plasminogen activators, tissue plasminogen activator (tPA), and urokinase-type plasminogen activator (uPA). Turbulence in the levels of PAI-1 tilts the balance of the hemostatic system resulting in bleeding or thrombotic complications. Not surprisingly, there is strong evidence that documents the role of PAI-1 in cardiovascular disease. The more recent uncovering of the coalition between the hemostatic and inflammatory pathways has exposed a distinct role for PAI-1. The storm of proinflammatory cytokines liberated during inflammation, including IL-6 and TNF-α, directly influence PAI-1 synthesis and increase circulating levels of this serpin. Consequently, elevated levels of PAI-1 are commonplace during infection and are frequently associated with a hypofibrinolytic state and thrombotic complications. Elevated PAI-1 levels are also a feature of metabolic syndrome, which is defined by a cluster of abnormalities including obesity, type 2 diabetes, hypertension, and elevated triglyceride. Metabolic syndrome is in itself defined as a proinflammatory state associated with elevated levels of cytokines. In addition, insulin has a direct impact on PAI-1 synthesis bridging these pathways. This review describes the key physiological functions of PAI-1 and how these become perturbed during disease processes. We focus on the direct relationship between PAI-1 and inflammation and the repercussion in terms of an ensuing hypofibrinolytic state and thromboembolic complications. Collectively, these observations strengthen the utility of PAI-1 as a viable drug target for the treatment of various diseases.
    Language English
    Publishing date 2021-04-16
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2781496-8
    ISSN 2297-055X
    ISSN 2297-055X
    DOI 10.3389/fcvm.2021.653655
    Database MEDical Literature Analysis and Retrieval System OnLINE

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