Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo

Brühl, Marie-Luise von; Stark, Konstantin; Steinhart, Alexander; Chandraratne, Sue; Konrad, Ildiko; Lorenz, Michael; Khandoga, Alexander G.; Tirniceriu, Anca; Coletti, Raffaele; Köllnberger, Maria; Byrne, Robert A.; Laitinen, Iina; Walch, Axel; Brill, Alexander; Pfeiler, Susanne; Manukyan, Davit; Braun, Siegmund; Lange, Philipp; Riegger, Julia; Ware, Jerry; Eckart, Annekathrin; Haidari, Selgai; Rudelius, Martina; Schulz, Christian; Echtler, Katrin; Brinkmann, Volker; Schwaiger, Markus; Preissner, Klaus T.; Wagner, Denisa D.; Mackman, Nigel; Engelmann, Bernd; Maßberg, Steffen

doi:10.1084/jem.20112322

Cited by 1,517 publications

(1,883 citation statements)

References 60 publications

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“…Thus, through distinct molecular interactions, thrombin both promotes and retards leukocyte trafficking, suggesting that targeting thrombin's specific molecular interactions, rather than global anticoagulant treatment, could modulate thromboinflammation with reduced impact on haemostasis. Dysregulated blood coagulation, platelet activation and endothelial dysfunction are common features of a broad range of thromboinflammatory disorders, including ischaemiareperfusion injury 39 , venous thromboembolism 40 , thrombotic microangiopathies 41 and transplant rejection 42,43 . The experimental needle injury method used in this study has enabled detailed insight into the mechanisms by which dysregulated thrombin generation on the surface of procoagulant endothelial cells may influence intravascular leukocyte trafficking in vivo.…”

Section: Discussionmentioning

confidence: 99%

Thrombin-dependent intravascular leukocyte trafficking regulated by fibrin and the platelet receptors GPIb and PAR4

et al. 2015

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Thrombin is a central regulator of leukocyte recruitment and inflammation at sites of vascular injury, a function thought to involve primarily endothelial PAR cleavage. Here we demonstrate the existence of a distinct leukocyte-trafficking mechanism regulated by components of the haemostatic system, including platelet PAR4, GPIba and fibrin. Utilizing a mouse endothelial injury model we show that thrombin cleavage of platelet PAR4 promotes leukocyte recruitment to sites of vascular injury. This process is negatively regulated by GPIba, as seen in mice with abrogated thrombin-platelet GPIba binding (hGPIba D277N ). In addition, we demonstrate that fibrin limits leukocyte trafficking by forming a physical barrier to intravascular leukocyte migration. These studies demonstrate a distinct 'checkpoint' mechanism of leukocyte trafficking involving balanced thrombin interactions with PAR4, GPIba and fibrin. Dysregulation of this checkpoint mechanism is likely to contribute to the development of thromboinflammatory disorders.

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Section: Discussionmentioning

confidence: 99%

Thrombin-dependent intravascular leukocyte trafficking regulated by fibrin and the platelet receptors GPIb and PAR4

et al. 2015

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“…1). Treatment of mice with DNase1 21,52 cleaved the NET scaffold and prevented thrombus formation underscoring the importance of NETs for DVT. 50 In vitro, NETs provide a tissue-type plasminogen activator (t-PA)-thrombolysis-resistant scaffold for blood clots.…”

Section: Microparticles (Mps) and Thrombosismentioning

confidence: 91%

“…71 Recently, mechanisms of DVT were analyzed with various models in sequence. 21 Intravital 2-photon and epifluorescence microscopic images have shown blood monocytes and neutrophils crawling along and adhering to the venous endothelium, thus initiating DVT. Myeloid cell-derived TF activates the extrinsic coagulation pathway, resulting in enormous intraluminal fibrin formation characteristic of DVT.…”

Section: Rate and Sequence Of Thrombus Organization In The Deep Veinsmentioning

confidence: 99%

Coagulation and the Vessel Wall in Pulmonary Embolism

Alias

Lang

2013

Pulm. circ.

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Venous thromboembolism comprises deep-vein thrombosis, thrombus in transit, acute pulmonary embolism, and chronic thromboembolic pulmonary hypertension (CTEPH). Pulmonary thromboemboli commonly resolve, with restoration of normal pulmonary hemodynamics. When they fail to resorb, permanent occlusion of the deep veins and/or CTEPH are the consequences. Apart from endogenous fibrinolysis, venous thrombi resolve by a process of mechanical fragmentation, through organization of the thromboembolus by invasion of endothelial cells, leukocytes, and fibroblasts leading to recanalization. Recent data utilizing various models have contributed to a better understanding of venous thrombosis and the resolution process that is directed at maintaining vascular patency. This review summarizes the plasmatic and cellular components of venous thrombus formation and resolution.

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“…The ability of NETs and histones to influence the coagulation cascade and actually initiate venous thrombosis8, 133, 134 is the most recent detail in the emerging field of NETosis research. Clinically, circulating nucleosomes are independent prognostic markers of disseminated intravascular coagulopathy (DIC)135 and some countries, notably Japan, are actively promoting the use of anticoagulants as histone detoxification agents in DIC 136.…”

Section: Molecular Basis Of Histone‐related Cellular and Tissue Injurymentioning

confidence: 99%

Biology, role and therapeutic potential of circulating histones in acute inflammatory disorders

Szatmary

Huang

Criddle

et al. 2018

J Cellular Molecular Medi

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Histones are positively charged nuclear proteins that facilitate packaging of DNA into nucleosomes common to all eukaryotic cells. Upon cell injury or cell signalling processes, histones are released passively through cell necrosis or actively from immune cells as part of extracellular traps. Extracellular histones function as microbicidal proteins and are pro‐thrombotic, limiting spread of infection or isolating areas of injury to allow for immune cell infiltration, clearance of infection and initiation of tissue regeneration and repair. Histone toxicity, however, is not specific to microbes and contributes to tissue and end‐organ injury, which in cases of systemic inflammation may lead to organ failure and death. This review details the processes of histones release in acute inflammation, the mechanisms of histone‐related tissue toxicity and current and future strategies for therapy targeting histones in acute inflammatory diseases.

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Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo

Abstract: Deep vein thrombosis initiation is mediated by cross talk between monocytes, neutrophils, and platelets.

Cited by 1,517 publications

References 60 publications

Thrombin-dependent intravascular leukocyte trafficking regulated by fibrin and the platelet receptors GPIb and PAR4

Thrombin-dependent intravascular leukocyte trafficking regulated by fibrin and the platelet receptors GPIb and PAR4

Coagulation and the Vessel Wall in Pulmonary Embolism

Biology, role and therapeutic potential of circulating histones in acute inflammatory disorders

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