CoChat
Sign Up
Cited by 330Ferroptosis and cancer prognosisNeurological Disorders and TreatmentsNeurological diseases and metabolism

Thrombin induces ACSL4-dependent ferroptosis during cerebral ischemia/reperfusion

Open access
Tuo, Qing-zhang, Liu, Yu, Xiang, Zheng, Yan, Hong-Fa, Zou, Ting, Shu, Yang, Ding, Xu-long, Zou, Jin-jun +16 more·2022·Signal Transduction and Targeted Therapy
DOI 10.1038/s41392-022-00917-zPMC PMC8866433
Open this paper in CoChat — free accountOpen PDF

Abstract

Ischemic stroke represents a significant danger to human beings, especially the elderly. Interventions are only available to remove the clot, and the mechanism of neuronal death during ischemic stroke is still in debate. Ferroptosis is increasingly appreciated as a mechanism of cell death after ischemia in various organs. Here we report that the serine protease, thrombin, instigates ferroptotic signaling by promoting arachidonic acid mobilization and subsequent esterification by the ferroptotic gene, acyl-CoA synthetase long-chain family member 4 (ACSL4). An unbiased multi-omics approach identified thrombin and ACSL4 genes/proteins, and their pro-ferroptotic phosphatidylethanolamine lipid products, as prominently altered upon the middle cerebral artery occlusion in rodents. Genetically or pharmacologically inhibiting multiple points in this pathway attenuated outcomes of models of ischemia in vitro and in vivo. Therefore, the thrombin-ACSL4 axis may be a key therapeutic target to ameliorate ferroptotic neuronal injury during ischemic stroke.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41392-022-00917-z

Cites

5 of 5 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Each type of PLA2 has substrate-specific activity, and depending on the substrate, PLA2 can either promote or block ferroptosis.

    “Each type of PLA2 has a substrate-specific activity, and depending on the substrate, PLA2 can either promote or block ferroptosis (28–31).”

    From Secreted Apoe rewires melanoma cell state vulnerability to ferroptosis (2024) · cites this paper as [31]

  • In neuronal cells, thrombin-mediated increases in cPLA2α activity sensitized these cells to ferroptosis in an ASCL4-dependent manner.

    “Consistent with our results, a recent study showed that in neuronal cells, thrombin mediated increases in cPLA2α activity sensitized these cells to ferroptosis in an ASCL4-dependent manner (31).”

    From Secreted Apoe rewires melanoma cell state vulnerability to ferroptosis (2024) · cites this paper as [31]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 96

  1. [1]GBD 2016 Stroke Collaborators. Global, regional, and national burden of stroke, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 18, 439–458 (2019). PMC6494974 30871944
  2. [2]Hankey GJ Stroke Lancet 2017 389 641 654 27637676
  3. [3]Feigin VL Global, regional, and country-specific lifetime risks of stroke, 1990 and 2016 N. Engl. J. Med 2018 379 2429 2437 30575491 PMC6247346
  4. [4]Campbell BCV Ischaemic stroke Nat. Rev. Dis. Prim. 2019 5 70 31601801
  5. [5]Lipton P Ischemic cell death in brain neurons Physiol. Rev. 1999 79 1431 1568 10508238
  6. [6]GBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol. 20, 795–820 (2021). PMC8443449 34487721
  7. [7]Yepes M Roussel BD Ali C Vivien D Tissue-type plasminogen activator in the ischemic brain: more than a thrombolytic Trends Neurosci. 2009 32 48 55 18963068
  8. [9]Pu H Protease-independent action of tissue plasminogen activator in brain plasticity and neurological recovery after ischemic stroke Proc. Natl Acad. Sci. USA 2019 116 9115 9124 30996120 PMC6500126
  9. [10]Yeo LL Timing of recanalization after intravenous thrombolysis and functional outcomes after acute ischemic stroke JAMA Neurol. 2013 70 353 358 23599933
  10. [11]Tuo QZ Zhang ST Lei P Mechanisms of neuronal cell death in ischemic stroke and their therapeutic implications Med. Res. Rev. 2022 42 259 305 33957000
  11. [12]Daniele SG Brain vulnerability and viability after ischaemia Nat. Rev. Neurosci. 2021 22 553 572 34290397
  12. [14]Lei P Motor and cognitive deficits in aged tau knockout mice in two background strains Mol. Neurodegener. 2014 9 29 25124182 PMC4141346
  13. [15]Lei P Clioquinol rescues Parkinsonism and dementia phenotypes of the tau knockout mouse Neurobiol. Dis. 2015 81 168 175 25796563
  14. [16]Tuo QZ Tau-mediated iron export prevents ferroptotic damage after ischemic stroke Mol. Psychiatry 2017 22 1520 1530 28886009
  15. [17]Li, C. et al. Nuclear receptor coactivator 4-mediated ferritinophagy contributes to cerebral ischemia-induced ferroptosis in ischemic stroke. Pharmacol. Res. 174, 105933 (2021). 34634471
  16. [18]Alim I Selenium drives a transcriptional adaptive program to block ferroptosis and treat stroke Cell 2019 177 1262.e25 1279.e25 31056284
  17. [19]Tuo, Q. Z. et al. Characterization of selenium compounds for anti-ferroptotic activity in neuronal cells and after cerebral ischemia-reperfusion injury. Neurotherapeutics18, 2682–2691 (2021). PMC8804037 34498224
  18. [20]Yan HF Ferroptosis: mechanisms and links with diseases Signal Transduct. Target. Ther. 2021 6 49 33536413 PMC7858612
  19. [21]Stockwell BR Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease Cell 2017 171 273 285 28985560 PMC5685180
  20. [22]Dixon SJ Ferroptosis: an iron-dependent form of nonapoptotic cell death Cell 2012 149 1060 1072 22632970 PMC3367386
  21. [23]Zhou Y Metascape provides a biologist-oriented resource for the analysis of systems-level datasets Nat. Commun. 2019 10 1523 30944313 PMC6447622
  22. [24]Donovan FM Pike CJ Cotman CW Cunningham DD Thrombin induces apoptosis in cultured neurons and astrocytes via a pathway requiring tyrosine kinase and RhoA activities J. Neurosci. 1997 17 5316 5326 9204916 PMC6793831
  23. [25]Lebrero, P. et al. Cellular plasmalogen content does not influence arachidonic acid levels or distribution in macrophages: a role for cytosolic phospholipase A(2)γ in phospholipid remodeling. Cells8, 799 (2019). PMC6721556 31370188
  24. [26]Kramer RM Roberts EF Manetta JV Hyslop PA Jakubowski JA Thrombin-induced phosphorylation and activation of Ca(2+)-sensitive cytosolic phospholipase A2 in human platelets J. Biol. Chem. 1993 268 26796 26804 8253817
  25. [27]Kramer RM Differential activation of cytosolic phospholipase A2 (cPLA2) by thrombin and thrombin receptor agonist peptide in human platelets. Evidence for activation of cPLA2 independent of the mitogen-activated protein kinases ERK1/2 J. Biol. Chem. 1995 270 14816 14823 7782348
  26. [28]Börsch-Haubold AG Identification of the phosphorylation sites of cytosolic phospholipase A2 in agonist-stimulated human platelets and HeLa cells J. Biol. Chem. 1998 273 4449 4458 9468497
  27. [29]De Meyer SF Thromboinflammation in stroke brain damage Stroke 2016 47 1165 1172 26786115
  28. [30]Ye F Garton HJL Hua Y Keep RF Xi G The role of thrombin in brain injury after hemorrhagic and ischemic stroke Transl. Stroke Res. 2021 12 496 511 32989665 PMC8005504
  29. [31]Butcher KS Dabigatran treatment of acute noncardioembolic ischemic stroke Stroke 2020 51 1190 1198 32098609
  30. [32]Kan CF Singh AB Stafforini DM Azhar S Liu J Arachidonic acid downregulates acyl-CoA synthetase 4 expression by promoting its ubiquitination and proteasomal degradation J. Lipid Res. 2014 55 1657 1667 24879802 PMC4109760
  31. [33]Begley CG Ioannidis JP Reproducibility in science: improving the standard for basic and preclinical research Circ. Res. 2015 116 116 126 25552691
  32. [34]Tuo QZ Zou JJ Lei P Rodent models of vascular cognitive impairment J. Mol. Neurosci. 2021 71 1 12 33107013
  33. [35]Wright HJ CDCP1 drives triple-negative breast cancer metastasis through reduction of lipid-droplet abundance and stimulation of fatty acid oxidation Proc. Natl Acad. Sci. USA 2017 114 E6556 E6565 28739932 PMC5559020
  34. [36]Doll S ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition Nat. Chem. Biol. 2017 13 91 98 27842070 PMC5610546
  35. [37]Coughlin SR Thrombin signalling and protease-activated receptors Nature 2000 407 258 264 11001069
  36. [38]Mao Y Zhang M Tuma RF Kunapuli SP Deficiency of PAR4 attenuates cerebral ischemia/reperfusion injury in mice J. Cereb. Blood Flow Metab. 2010 30 1044 1052 20087365 PMC2949190
  37. [39]Lyden P Direct thrombin inhibitor argatroban reduces stroke damage in 2 different models Stroke 2014 45 896 899 24473182 PMC3995814
  38. [40]Sokolova E Reiser G Prothrombin/thrombin and the thrombin receptors PAR-1 and PAR-4 in the brain: localization, expression and participation in neurodegenerative diseases Thromb. Haemost. 2008 100 576 581 18841278
  39. [41]Riek-Burchardt M Striggow F Henrich-Noack P Reiser G Reymann KG Increase of prothrombin-mRNA after global cerebral ischemia in rats, with constant expression of protease nexin-1 and protease-activated receptors Neurosci. Lett. 2002 329 181 184 12165407
  40. [42]Xi G Reiser G Keep RF The role of thrombin and thrombin receptors in ischemic, hemorrhagic and traumatic brain injury: deleterious or protective? J. Neurochem. 2003 84 3 9 12485396
  41. [43]Chen B Thrombin activity associated with neuronal damage during acute focal ischemia J. Neurosci. 2012 32 7622 7631 22649241 PMC3383068
  42. [44]Gluck N Schwob O Krimsky M Yedgar S Activation of cytosolic phospholipase A2 and fatty acid transacylase is essential but not sufficient for thrombin-induced smooth muscle cell proliferation Am. J. Physiol. Cell Physiol. 2008 294 C1597 C1603 18385289
  43. [45]Kramer RM p38 mitogen-activated protein kinase phosphorylates cytosolic phospholipase A2 (cPLA2) in thrombin-stimulated platelets. Evidence that proline-directed phosphorylation is not required for mobilization of arachidonic acid by cPLA2 J. Biol. Chem. 1996 271 27723 27729 8910365
  44. [46]Sergeeva M Strokin M Wang H Ubl JJ Reiser G Arachidonic acid and docosahexaenoic acid suppress thrombin-evoked Ca2+ response in rat astrocytes by endogenous arachidonic acid liberation J. Neurochem. 2002 82 1252 1261 12358772
  45. [47]Ross S Thrombin causes pseudopod detachment via a pathway involving cytosolic phospholipase A2 and 12/15-lipoxygenase products Cell Growth Differ. 2000 11 19 30 10672900
  46. [48]Sato T The mechanism of thrombin-induced prostacyclin synthesis in human endothelial cells with reference to the gene transcription of prostacyclin-related enzymes and Ca2+ kinetics J. Pharm. Toxicol. Methods 1999 41 173 182 10691023
  47. [49]McNicol A Shibou TS Translocation and phosphorylation of cytosolic phospholipase A2 in activated platelets Thromb. Res. 1998 92 19 26 9783670
  48. [50]Dennis EA Diversity of group types, regulation, and function of phospholipase A2 J. Biol. Chem. 1994 269 13057 13060 8175726
  49. [51]Dennis EA Cao J Hsu YH Magrioti V Kokotos G Phospholipase A2 enzymes: physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention Chem. Rev. 2011 111 6130 6185 21910409 PMC3196595
  50. [52]Tang D Chen X Kang R Kroemer G Ferroptosis: molecular mechanisms and health implications Cell Res. 2021 31 107 125 33268902 PMC8026611
  51. [53]Li D Li Y The interaction between ferroptosis and lipid metabolism in cancer Signal Transduct. Target. Ther. 2020 5 108 32606298 PMC7327075
  52. [54]Peng Z Chang Y Fan J Ji W Su C Phospholipase A2 superfamily in cancer Cancer Lett. 2021 497 165 177 33080311
  53. [56]Sun WY Phospholipase iPLA(2)β averts ferroptosis by eliminating a redox lipid death signal Nat. Chem. Biol. 2021 17 465 476 33542532 PMC8152680
  54. [57]Lin J Association of Lp-PLA2-A and early recurrence of vascular events after TIA and minor stroke Neurology 2015 85 1585 1591 26311748 PMC4642142
  55. [58]Tian Y The associations of stroke, transient ischemic attack, and/or stroke-related recurrent vascular events with Lipoprotein-associated phospholipase A2: a systematic review and meta-analysis Medicine 2017 96 e9413 e9413 29390564 PMC5758266
  56. [59]Delgado P Lipoprotein-associated phospholipase A(2) activity is associated with large-artery atherosclerotic etiology and recurrent stroke in TIA patients Cerebrovasc. Dis. 2012 33 150 158 22178747
  57. [60]Zhou F Liu Y Shi H Huang Q Zhou J Relation between lipoprotein-associated phospholipase A(2) mass and incident ischemic stroke severity Neurol. Sci. 2018 39 1591 1596 29938341
  58. [61]Han L Prognostic value of lipoprotein-associated phospholipase A(2) mass for all-cause mortality and vascular events within one year after acute ischemic stroke Atherosclerosis 2017 266 1 7 28934604
  59. [62]Alvarez-Pérez FJ Verde I Lipoprotein-associated phospholipase A(2) and stroke Rev. Neurol. 2009 49 88 94 19598138
  60. [63]Ugidos IF Neuroprotective effect of 2-hydroxy arachidonic acid in a rat model of transient middle cerebral artery occlusion Biochim. Biophys. Acta Biomembr. 2017 1859 1648 1656 28315303
  61. [64]Phillis JW O’Regan MH The role of phospholipases, cyclooxygenases, and lipoxygenases in cerebral ischemic/traumatic injuries Crit. Rev. Neurobiol. 2003 15 61 90 14513863
  62. [65]Adibhatla RM Hatcher JF Citicoline decreases phospholipase A2 stimulation and hydroxyl radical generation in transient cerebral ischemia J. Neurosci. Res. 2003 73 308 315 12868064
  63. [66]Cui L Neuroprotection of early and short-time applying atorvastatin in the acute phase of cerebral ischemia: down-regulated 12/15-LOX, p38MAPK and cPLA2 expression, ameliorated BBB permeability Brain Res. 2010 1325 164 173 20167207
  64. [67]Zhang J Barasch N Li RC Sapirstein A Inhibition of cytosolic phospholipase A(2) alpha protects against focal ischemic brain damage in mice Brain Res. 2012 1471 129 137 22819928
  65. [68]Kagan VE Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis Nat. Chem. Biol. 2017 13 81 90 27842066 PMC5506843
  66. [69]Shlobin, N. A., Har-Even, M., Itsekson-Hayosh, Z., Harnof, S. & Pick, C. G. Role of thrombin in central nervous system injury and disease. Biomolecules11, 562 (2021). PMC8070021 33921354
  67. [70]Akiyama H Ikeda K Kondo H McGeer PL Thrombin accumulation in brains of patients with Alzheimer’s disease Neurosci. Lett. 1992 146 152 154 1491781
  68. [71]Kandil EA Sayed RH Ahmed LA Abd El Fattah MA El-Sayeh BM Modulatory role of Nurr1 activation and thrombin inhibition in the neuroprotective effects of dabigatran etexilate in rotenone-induced Parkinson’s disease in rats Mol. Neurobiol. 2018 55 4078 4089 28585189
  69. [72]Han MH Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets Nature 2008 451 1076 1081 18278032
  70. [73]Davalos D Early detection of thrombin activity in neuroinflammatory disease Ann. Neurol. 2014 75 303 308 24740641 PMC4049631
  71. [74]Itsekson-Hayosh Z Minimal traumatic brain injury in mice: protease-activated receptor 1 and thrombin-related changes J. Neurotrauma 2016 33 1848 1854 26537880
  72. [75]Xi G Role of blood clot formation on early edema development after experimental intracerebral hemorrhage Stroke 1998 29 2580 2586 9836771
  73. [76]Jakaria, M., Belaidi, A. A., Bush, A. I. & Ayton, S. Ferroptosis as a mechanism of neurodegeneration in Alzheimer’s disease. J. Neurochem.159, 804–825 (2021). 34553778
  74. [77]Chen K Ferroptosis, a potential therapeutic target in Alzheimer’s disease Front. Cell Dev. Biol. 2021 9 704298 34422824 PMC8374166
  75. [78]Wu JR Tuo QZ Lei P Ferroptosis, a recent defined form of critical cell death in neurological disorders J. Mol. Neurosci. 2018 66 197 206 30145632
  76. [79]Xiong H Tuo QZ Guo YJ Lei P Diagnostics and treatments of iron-related CNS diseases Adv. Exp. Med. Biol. 2019 1173 179 194 31456211
  77. [80]Bao Z Prokineticin-2 prevents neuronal cell deaths in a model of traumatic brain injury Nat. Commun. 2021 12 4220 34244497 PMC8270965
  78. [81]Bao WD Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer’s disease Cell Death Differ. 2021 28 1548 1562 33398092 PMC8166828
  79. [82]Bao WD Targeting miR-124/Ferroportin signaling ameliorated neuronal cell death through inhibiting apoptosis and ferroptosis in aged intracerebral hemorrhage murine model Aging Cell 2020 19 e13235 33068460 PMC7681046
  80. [83]Rui T Deletion of ferritin H in neurons counteracts the protective effect of melatonin against traumatic brain injury-induced ferroptosis J. Pineal Res. 2021 70 e12704 33206394
  81. [84]Hoy, A. J., Nagarajan, S. R. & Butler, L. M. Tumour fatty acid metabolism in the context of therapy resistance and obesity. Nat. Rev. Cancer21, 753–766 (2021). 34417571
  82. [85]Chen X Kang R Kroemer G Tang D Broadening horizons: the role of ferroptosis in cancer Nat. Rev. Clin. Oncol. 2021 18 280 296 33514910
  83. [86]Del Re,DP Amgalan D Linkermann A Liu Q Kitsis RN Fundamental mechanisms of regulated cell death and implications for heart disease Physiol. Rev. 2019 99 1765 1817 31364924 PMC6890986
  84. [87]Fang X Ferroptosis as a target for protection against cardiomyopathy Proc. Natl Acad. Sci. USA 2019 116 2672 2680 30692261 PMC6377499
  85. [88]Fang X Loss of cardiac ferritin H facilitates cardiomyopathy via Slc7a11-mediated ferroptosis Circ. Res. 2020 127 486 501 32349646
  86. [89]Yan HF Tuo QZ Yin QZ Lei P The pathological role of ferroptosis in ischemia/reperfusion-related injury Zool. Res. 2020 41 220 230 32314558 PMC7231469
  87. [90]Yu Y Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis Blood 2020 136 726 739 32374849 PMC7414596
  88. [91]Wang H Characterization of ferroptosis in murine models of hemochromatosis Hepatology 2017 66 449 465 28195347 PMC5573904
  89. [92]Xu Y Li X Cheng Y Yang M Wang R Inhibition of ACSL4 attenuates ferroptotic damage after pulmonary ischemia-reperfusion FASEB J. 2020 34 16262 16275 33070393
  90. [94]Pefanis A Ierino FL Murphy JM Cowan PJ Regulated necrosis in kidney ischemia-reperfusion injury Kidney Int. 2019 96 291 301 31005270
  91. [95]Deng F Sharma I Dai Y Yang M Kanwar YS Myo-inositol oxygenase expression profile modulates pathogenic ferroptosis in the renal proximal tubule J. Clin. Investig. 2019 129 5033 5049 31437128 PMC6819105
  92. [96]Li Y Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion Cell Death Differ. 2019 26 2284 2299 30737476 PMC6889315
  93. [97]Xu S The emerging role of ferroptosis in intestinal disease Cell Death Dis. 2021 12 289 33731703 PMC7969743
  94. [98]Aho K Cerebrovascular disease in the community: results of a WHO collaborative study Bull. World Health Organ. 1980 58 113 130 6966542 PMC2395897
  95. [99]Huuskonen MT The copper bis(thiosemicarbazone) complex Cu(II)(atsm) is protective against cerebral ischemia through modulation of the inflammatory milieu Neurotherapeutics 2017 14 519 532 28050710 PMC5398983
  96. [100]Wang Q Efficient production of dual recombinant adeno-associated viral vectors for factor VIII delivery Hum. Gene Ther. Methods 2014 25 261 268 25093498 PMC4142791

Cited by

Sorted by citations

Authors
Tuo, Q.-Z., Liu, Y., Xiang, Z., Yan, H.-F., Zou, T., Shu, Y., Ding, X.-L., Zou, J.-J., Xu, S., Tang, F., Gong, Y.-Q., Li, X.-L., Guo, Y.-J., Zheng, Z.-Y., Deng, A.-P., Yang, Z.-Z., Li, W.-J., Zhang, S.-T., Ayton, S., Bush, A. I., Xu, H., Dai, L., Dong, B., & Lei, P.
Affiliations
  • Sichuan University (CN)
  • The University of Melbourne (AU)
Corresponding author
  • Dai, Lunzhi
  • Dong, Biao
  • Lei, Peng
ORCID
Venue
Signal Transduction and Targeted Therapy
Publisher
Springer Science and Business Media LLC
Published
2022-02-23
Volume
7
Issue
1
Pages
59-59
ISSN
2059-3635 (ISSN-L)
DOI
10.1038/s41392-022-00917-z
PMC
PMC8866433
OpenAlex
W4214725121
Cited by
330
References
5
Citations by year
2026: 63 · 2025: 96 · 2024: 94 · 2023: 56 · 2022: 20 · 2021: 1
FWCI
42.91
Type
journal article
Language
en
Open access
Licence
Locations
  • Signal Transduction and Targeted Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
Funders
National Natural Science Foundation of China (81722016, 82071191, 81801182)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
  • Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
  • Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
Keywords
thrombin, ferroptosis, ACSL4, cerebral ischemia-reperfusion injury, ischemic stroke, neuronal cell death, arachidonic acid mobilization, phosphatidylethanolamine, middle cerebral artery occlusion, lipid metabolism, therapeutic target
MeSH terms
Ferroptosis, Long-Chain-Fatty-Acid-CoA Ligase, Aged, Brain Ischemia, Coenzyme A Ligases, Humans, Thrombin, Reperfusion

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review