{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThrombomodulin (TM), the protein product of the THBD gene, is an integral membrane glycoprotein primarily expressed by vascular endothelial cells that orchestrates vascular homeostasis. By binding to thrombin, TM shifts thrombin’s substrate specificity so that protein C and thrombin‐activatable fibrinolysis inhibitor are activated, a process that underlies its potent anticoagulant, anti‑inflammatory, and cytoprotective functions. In addition, distinct domains of TM—notably its N‑terminal lectin region—mediate interactions with damage‐associated molecules and facilitate cell–cell adhesion, thereby contributing not only to hemostatic balance but also to the regulation of immune and inflammatory responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nTM expression and functionality are tightly controlled by an array of regulatory mechanisms. Its transcription is upregulated by agents such as statins through a KLF2‑dependent mechanism and exhibits circadian oscillation mediated by the CLOCK/BMAL2 complex. In contrast, proinflammatory cytokines, oxidized phospholipids, and specific RNA‑binding proteins (for example, HuR under septic conditions) can suppress TM expression via NF‑κB signaling and competition for transcriptional coactivators. In parallel, genetic mutations and polymorphisms in THBD have been linked to clinical syndromes including atypical hemolytic‑uremic syndrome, myocardial infarction, varicose veins, and late fetal loss. Epigenetic controls—for instance, retinoic acid–induced recruitment of SETD1A and activation of KLF4—further fine‑tune TM levels, underscoring its critical role as a determinant of endothelial function and as a potential predictor of outcomes in thrombotic and inflammatory disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its central role in coagulation regulation, TM is pivotal in several pathological and reparative contexts. In diabetic nephropathy, cerebral malaria, and settings of endothelial injury (such as following stent implantation or during acute lung injury), the TM–thrombin–protein C axis provides cytoprotection by reducing apoptosis and limiting aberrant fibrin deposition. Its extracellular lectin domain also contributes to cell–cell adhesion and suppression of tumor growth, while the soluble form of TM can bind and neutralize proinflammatory mediators like HMGB1, thereby mitigating pain and inflammatory signaling. Conversely, altered processing or mutation of THBD may provoke bleeding disorders or exacerbate inflammatory responses in chronic vascular diseases. Collectively, these observations highlight TM’s dual role in both safeguarding vascular integrity and modulating inflammation in diverse clinical scenarios."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "31"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Marlies Van de Wouwer, Désiré Collen, Edward M Conway "}, {"type": "b", "children": [{"type": "t", "text": "Thrombomodulin-protein C-EPCR system: integrated to regulate coagulation and inflammation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arterioscler Thromb Vasc Biol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/01.ATV.0000134298.25489.92"}], "href": "https://doi.org/10.1161/01.ATV.0000134298.25489.92"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15178554"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15178554"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "John Morser "}, {"type": "b", "children": [{"type": "t", "text": "Thrombomodulin links coagulation to inflammation and immunity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Curr Drug Targets (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2174/138945012799424606"}], "href": "https://doi.org/10.2174/138945012799424606"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22206250"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22206250"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Edward M Conway "}, {"type": "b", "children": [{"type": "t", "text": "Thrombomodulin and its role in inflammation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Semin Immunopathol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00281-011-0282-8"}], "href": "https://doi.org/10.1007/s00281-011-0282-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21805323"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21805323"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Sucharita Sen-Banerjee, Samy Mir, Zhiyong Lin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Kruppel-like factor 2 as a novel mediator of statin effects in endothelial cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circulation (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCULATIONAHA.104.525774"}], "href": "https://doi.org/10.1161/CIRCULATIONAHA.104.525774"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16043642"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16043642"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Norihiko Takeda, Koji Maemura, Shuichi Horie, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thrombomodulin is a clock-controlled gene in vascular endothelial cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M705692200"}], "href": "https://doi.org/10.1074/jbc.M705692200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17848551"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17848551"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Richard H Sohn, Clayton B Deming, David C Johns, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of endothelial thrombomodulin expression by inflammatory cytokines is mediated by activation of nuclear factor-kappa B."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2004-03-0928"}], "href": "https://doi.org/10.1182/blood-2004-03-0928"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15677570"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15677570"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "K K Wu, N Aleksic, C Ahn, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thrombomodulin Ala455Val polymorphism and risk of coronary heart disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circulation (2001)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/01.cir.103.10.1386"}], "href": "https://doi.org/10.1161/01.cir.103.10.1386"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11245641"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11245641"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Tara K Maga, Carla J Nishimura, Amy E Weaver, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mutat (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/humu.21256"}], "href": "https://doi.org/10.1002/humu.21256"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20513133"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20513133"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "F Franchi, E Biguzzi, I Cetin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in the thrombomodulin and endothelial protein C receptor genes in women with late fetal loss."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Br J Haematol (2001)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1046/j.1365-2141.2001.02964.x"}], "href": "https://doi.org/10.1046/j.1365-2141.2001.02964.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11552992"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11552992"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Yesim Dargaud, Jean Yves Scoazec, Simone J H Wielders, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Characterization of an autosomal dominant bleeding disorder caused by a thrombomodulin mutation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2014-10-604553"}], "href": "https://doi.org/10.1182/blood-2014-10-604553"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25564403"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25564403"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Hidemi Ishii, Tsuyoshi Tezuka, Hiroyuki Ishikawa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Oxidized phospholipids in oxidized low-density lipoprotein down-regulate thrombomodulin transcription in vascular endothelial cells through a decrease in the binding of RARbeta-RXRalpha heterodimers and Sp1 and Sp3 to their binding sequences in the TM promoter."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2002-08-2428"}], "href": "https://doi.org/10.1182/blood-2002-08-2428"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12576329"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12576329"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Zilong Li, Baoyu Chen, Xinyu Weng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The histone methyltransferase SETD1A regulates thrombomodulin transcription in vascular endothelial cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta Gene Regul Mech (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbagrm.2018.06.004"}], "href": "https://doi.org/10.1016/j.bbagrm.2018.06.004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29940355"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29940355"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Yuan-Chung Kao, Li-Wha Wu, Chung-Sheng Shi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Downregulation of thrombomodulin, a novel target of Snail, induces tumorigenesis through epithelial-mesenchymal transition."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.01021-09"}], "href": "https://doi.org/10.1128/MCB.01021-09"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20713448"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20713448"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "John A Heit, Tanya M Petterson, Whyte G Owen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thrombomodulin gene polymorphisms or haplotypes as potential risk factors for venous thromboembolism: a population-based case-control study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Thromb Haemost (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1538-7836.2005.01187.x"}], "href": "https://doi.org/10.1111/j.1538-7836.2005.01187.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15842356"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15842356"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Yi-Heng Li, Jyh-Hong Chen, Wei-Chuan Tsai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Synergistic effect of thrombomodulin promoter -33G/A polymorphism and smoking on the onset of acute myocardial infarction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Thromb Haemost (2002)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11848462"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11848462"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Chiu-Hung Yeh, Liang-Yi Hung, Chin Hsu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RNA-binding protein HuR interacts with thrombomodulin 5'untranslated region and represses internal ribosome entry site-mediated translation under IL-1 beta treatment."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Cell (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1091/mbc.e07-09-0962"}], "href": "https://doi.org/10.1091/mbc.e07-09-0962"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18579691"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18579691"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Sivaramakrishna P Rachakonda, Olaf Penack, Sascha Dietrich, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Single-Nucleotide Polymorphisms Within the Thrombomodulin Gene (THBD) Predict Mortality in Patients With Graft-Versus-Host Disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Oncol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1200/JCO.2013.54.4056"}], "href": "https://doi.org/10.1200/JCO.2013.54.4056"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25225421"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25225421"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Piergiorgio Stortoni, Monia Cecati, Stefano R Giannubilo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Placental thrombomodulin expression in recurrent miscarriage."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Reprod Biol Endocrinol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1477-7827-8-1"}], "href": "https://doi.org/10.1186/1477-7827-8-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20051099"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20051099"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Berend Isermann, Ilya A Vinnikov, Thati Madhusudhan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Med (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nm1667"}], "href": "https://doi.org/10.1038/nm1667"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17982464"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17982464"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Christopher A Moxon, Samuel C Wassmer, Danny A Milner, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss of endothelial protein C receptors links coagulation and inflammation to parasite sequestration in cerebral malaria in African children."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2013-03-490219"}], "href": "https://doi.org/10.1182/blood-2013-03-490219"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23741007"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23741007"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Huey-Chun Huang, Guey-Yueh Shi, Shinn-Jong Jiang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thrombomodulin-mediated cell adhesion: involvement of its lectin-like domain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M305216200"}], "href": "https://doi.org/10.1074/jbc.M305216200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12951323"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12951323"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Ling Wang, Julie A Bastarache, Nancy Wickersham, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Novel role of the human alveolar epithelium in regulating intra-alveolar coagulation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Respir Cell Mol Biol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1165/rcmb.2005-0425OC"}], "href": "https://doi.org/10.1165/rcmb.2005-0425OC"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17099142"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17099142"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Takayuki Ikezoe, Jing Yang, Chie Nishioka, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thrombomodulin protects endothelial cells from a calcineurin inhibitor-induced cytotoxicity by upregulation of extracellular signal-regulated kinase/myeloid leukemia cell-1 signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arterioscler Thromb Vasc Biol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/ATVBAHA.112.251157"}], "href": "https://doi.org/10.1161/ATVBAHA.112.251157"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22796578"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22796578"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Juan M Jiménez, Varesh Prasad, Michael D Yu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Macro- and microscale variables regulate stent haemodynamics, fibrin deposition and thrombomodulin expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J R Soc Interface (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1098/rsif.2013.1079"}], "href": "https://doi.org/10.1098/rsif.2013.1079"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24554575"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24554575"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Agustin O Pineda, Angelene M Cantwell, Leslie A Bush, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The thrombin epitope recognizing thrombomodulin is a highly cooperative hot spot in exosite I."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M205009200"}], "href": "https://doi.org/10.1074/jbc.M205009200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12068020"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12068020"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Yun-Yan Hsu, Guey-Yueh Shi, Cheng-Hsiang Kuo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thrombomodulin is an ezrin-interacting protein that controls epithelial morphology and promotes collective cell migration."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FASEB J (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1096/fj.12-204917"}], "href": "https://doi.org/10.1096/fj.12-204917"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22593542"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22593542"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "Junichi Tanaka, Yukari Seki, Hiroyasu Ishikura, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Recombinant human soluble thrombomodulin prevents peripheral HMGB1-dependent hyperalgesia in rats."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Br J Pharmacol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/bph.12396"}], "href": "https://doi.org/10.1111/bph.12396"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24004409"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24004409"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Kuan-Chieh Wang, Yi-Heng Li, Guey-Yueh Shi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Membrane-Bound Thrombomodulin Regulates Macrophage Inflammation in Abdominal Aortic Aneurysm."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arterioscler Thromb Vasc Biol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/ATVBAHA.115.305529"}], "href": "https://doi.org/10.1161/ATVBAHA.115.305529"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26338301"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26338301"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Robert L Lobato, William D White, Joseph P Mathew, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thrombomodulin gene variants are associated with increased mortality after coronary artery bypass surgery in replicated analyses."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circulation (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCULATIONAHA.110.008334"}], "href": "https://doi.org/10.1161/CIRCULATIONAHA.110.008334"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21911804"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21911804"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "N Aleksic, A R Folsom, M Cushman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Prospective study of the A455V polymorphism in the thrombomodulin gene, plasma thrombomodulin, and incidence of venous thromboembolism: the LITE Study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Thromb Haemost (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1046/j.1538-7836.2003.00029.x"}], "href": "https://doi.org/10.1046/j.1538-7836.2003.00029.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12871544"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12871544"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "Kuan-Liang Liu, Kuang-Tso Lee, Chih-Hsiang Chang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Elevated plasma thrombomodulin and angiopoietin-2 predict the development of acute kidney injury in patients with acute myocardial infarction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Crit Care (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/cc13876"}], "href": "https://doi.org/10.1186/cc13876"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24886544"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24886544"}]}]}]}