{
    "abstract": "Neutrophils can release extracellular traps (NETs) in infectious, inflammatory and thrombotic diseases. NETs have been detected in deep vein thrombosis, atherothrombosis, stroke, disseminated intravascular coagulation and trauma. We have previously shown that haemodynamic forces trigger rapid NETosis within sterile occlusive thrombi in vitro. Here, we tested the effects of thrombin, fibrin and fibrinolysis on shear-induced NETosis by imaging NETs with Sytox Green during microfluidic perfusion of factor XIIa-inhibited or thrombin-inhibited human whole blood over fibrillar collagen (\u00b1tissue factor). For perfusions under venous pressure drops (19\u2009mm Hg/mm-clot), thrombin generation did not alter the near-zero level of NET generation. In contrast, production of thrombin/fibrin led to a twofold reduction in neutrophil accumulation and a sixfold reduction in NET generation after 30 minutes of arterial perfusion (163\u2009mm Hg/mm-clot). Exogenously added tissue type plasminogen activator (tPA) drove robust fibrinolysis; however, tPA did not trigger NETosis under venous flow. In contrast, tPA did enhance NET generation in clots subjected to arterial pressure drops. After 45 minutes of arterial perfusion, clots treated with 30\u2009nM tPA had a threefold increase in total NET production and a twofold increase in normalized NET generation (measured as deoxyribonucleic acid:neutrophil) compared with fibrin-rich clots. Blocking fibrin polymerization resulted in similar level of NET release seen in tPA-treated clots, whereas \u03b5-aminocaproic acid abolished the NET-enhancing effect of tPA. Therefore, fibrin suppresses NET generation and the absence of fibrin promotes NETs. We demonstrated that shear-induced NETosis was strongly inversely correlated with fibrin in sterile occlusive clots.",
    "authors": [
        {
            "affiliation": "Department of Chemical and Biomolecular Engineering, Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, Pennsylvania, United States.",
            "firstname": "Xinren",
            "initials": "X",
            "lastname": "Yu"
        },
        {
            "affiliation": "Department of Chemical and Biomolecular Engineering, Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, Pennsylvania, United States.",
            "firstname": "Scott L",
            "initials": "SL",
            "lastname": "Diamond"
        }
    ],
    "conclusions": null,
    "copyrights": "Georg Thieme Verlag KG Stuttgart \u00b7 New York.",
    "doi": "10.1055/s-0039-1678529",
    "journal": "Thrombosis and haemostasis",
    "keywords": [],
    "methods": null,
    "publication_date": "2019-02-06",
    "pubmed_id": "30722079\n15001782\n17384648\n16548892\n22980329\n26185250\n22684106\n25569217\n25163512\n28267716\n21098229\n26320263\n26673780\n25622091\n26712312\n28990587\n28073784\n22451716\n27574188\n24674135\n25547404\n27488091\n25774524\n20798043\n24366358\n27919911\n27919911\n23293023\n25789443\n21976662\n29438080\n29156107\n20473398\n22516070\n18390930\n19657316\n29191910\n23601328\n25527775",
    "results": null,
    "title": "Fibrin Modulates Shear-Induced NETosis in Sterile Occlusive Thrombi Formed under Haemodynamic Flow.",
    "xml": "<Element 'PubmedArticle' at 0x7885055a9e40>"
}