DOI: 10.1084/jem.190.1.91. Targeted Inhibition of Intrinsic Coagulation Limits Cerebral Injury in Stroke without Increasing Intracerebral Hemorrhage

Targeted Inhibition of Intrinsic Coagulation Limits Cerebral Injury in Stroke without Increasing Intracerebral Hemorrhage

10.1084/jem.190.1.91

Crossref journal-article

Rockefeller University Press

The Journal of Experimental Medicine (291)

Abstract

Agents that restore vascular patency in stroke also increase the risk of intracerebral hemorrhage (ICH). As Factor IXa is a key intermediary in the intrinsic pathway of coagulation, targeted inhibition of Factor IXa–dependent coagulation might inhibit microvascular thrombosis in stroke without impairing extrinsic hemostatic mechanisms that limit ICH. A competitive inhibitor of native Factor IXa for assembly into the intrinsic Factor X activation complex, Factor IXai, was prepared by covalent modification of the Factor IXa active site. In a modified cephalin clotting time assay, in vivo administration of Factor IXai caused a dose-dependent increase in time to clot formation (3.6-fold increase at the 300 μg/kg dose compared with vehicle-treated control animals, P &lt; 0.05). Mice given Factor IXai and subjected to middle cerebral artery occlusion and reperfusion demonstrated reduced microvascular fibrin accumulation by immunoblotting and immunostaining, reduced 111In-labeled platelet deposition (42% decrease, P &lt; 0.05), increased cerebral perfusion (2.6-fold increase in ipsilateral blood flow by laser doppler, P &lt; 0.05), and smaller cerebral infarcts than vehicle-treated controls (70% reduction, P &lt; 0.05) based on triphenyl tetrazolium chloride staining of serial cerebral sections. At therapeutically effective doses, Factor IXai was not associated with increased ICH, as opposed to tissue plasminogen activator (tPA) or heparin, both of which significantly increased ICH. Factor IXai was cerebroprotective even when given after the onset of stroke, indicating that microvascular thrombosis continues to evolve (and may be inhibited) even after primary occlusion of a major cerebrovascular tributary.

Bibliography

Choudhri, T. F., Hoh, B. L., Prestigiacomo, C. J., Huang, J., Kim, L. J., Schmidt, A. M., Kisiel, W., Connolly, E. S., & Pinsky, D. J. (1999). Targeted Inhibition of Intrinsic Coagulation Limits Cerebral Injury in Stroke without Increasing Intracerebral Hemorrhage. The Journal of Experimental Medicine, 190(1), 91â100.

Authors 9

Tanvir F. Choudhri (first)
Brian L. Hoh (additional)
Charles J. Prestigiacomo (additional)
Judy Huang (additional)
Louis J. Kim (additional)
Ann Marie Schmidt (additional)
Walter Kisiel (additional)
E. Sander Connolly (additional)
David J. Pinsky (additional)

References 35 Referenced 55

10.1056/NEJM199512143332401 / N. Engl. J. Med. / Tissue plasminogen activator for acute ischemic stroke by The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group (1995)
10.1001/jama.1995.03530130023023 / JAMA (J. Am. Med. Assoc.). / Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study by Hacke (1995)
10.1056/NEJM199512143332410 / N. Engl. J. Med. / Acute stroke—on the threshold of a therapy? by del Zoppo (1995)
10.1056/NEJM199607183350301 / N. Engl. J. Med. / Thrombolytic therapy with streptokinase in acute ischemic stroke by The Multicenter Acute Stroke Trial—Europe Study Group (1996)
10.1016/S0140-6736(97)03022-5 / Lancet. / Systematic review of evidence on thrombolytic therapy for acute ischaemic stroke by Wardlaw (1997)
10.1073/pnas.94.18.9779 / Proc. Natl. Acad. Sci. USA. / Neuronal death in the central nervous system demonstrates a non-fibrin substrate for plasmin by Tsirka (1997)
10.1523/JNEUROSCI.17-02-00543.1997 / J. Neurosci. / An extracellular proteolytic cascade promotes neuronal degeneration in the mouse hippocampus by Tsirka (1997)
10.1055/s-0038-1653411 / Thromb. Haemost. / Studies on the specific fibrinolytic effect of human extrinsic (tissue-type) plasminogen activator in human blood and in various animal species in vitro by Korninger (1981)
10.1038/384123b0 / Nature. / Neuronal cell death and tPA by Tsirka (1996)
10.1172/JCI116637 / J. Clin. Invest. / Extracellular proteolysis in the adult murine brain by Sappino (1993)
10.1038/377340a0 / Nature. / Excitotoxin-induced neuronal degeneration and seizure are mediated by tissue plasminogen activator by Tsirka (1995)
10.7326/0003-4819-105-6-825 / Ann. Intern. Med. / Intravenous heparin for the prevention of stroke progression in acute partial stable strokea randomized controlled trial by Duke (1996)
10.1161/01.STR.19.1.10 / Stroke. / Failure of heparin to prevent progression in progressing ischemic infarction by Haley (1988)
10.1161/01.STR.21.12.1657 / Stroke. / Natural history of progressive ischemic stroke in a population treated with heparin by Slivka (1990)
10.1001/archneur.1986.00520040066022 / Arch. Neurol. / Treatment of acute ischemic strokeopen trial with continuous intravenous heparinization by Ramirez-Lassepas (1986)
10.1111/j.1600-0404.1985.tb03229.x / Acta Neurol. Scand. / Anticoagulant-induced intracerebral bleeding in brain ischemiaevaluation in 200 patients with TIAs, emboli from the heart, and progressing stroke by Bogousslavsky (1985)
10.1161/01.STR.15.5.779 / Stroke. / Immediate anticoagulation of embolic strokebrain hemorrhage and management options by Cerebral Embolism Study Group (1984)
10.1172/JCI3338 / J. Clin. Invest. / Reduced microvascular thrombosis and improved outcome in acute murine stroke by inhibiting GP IIb/IIIa receptor–mediated platelet aggregation by Choudhri (1998)
10.1172/JCI118392 / J. Clin. Invest. / Cerebral protection in homozygous null ICAM-1 mice after middle cerebral artery occlusion. Role of neutrophil adhesion in the pathogenesis of stroke by Connolly (1996)
10.1161/01.RES.81.3.304 / Circ. Res. / Exacerbation of cerebral injury in mice which express the P-selectin geneidentification of P-selectin blockade as a new target for the treatment of stroke by Connolly (1997)
{'key': '2023072508440920800_R21', 'first-page': '523', 'article-title': 'Procedural and strain-related variables significantly affect outcome in a murine model of focal cerebral ischemia', 'volume': '38', 'author': 'Connolly', 'year': '1996', 'journal-title': 'Neurosurgery.'} / Neurosurgery. / Procedural and strain-related variables significantly affect outcome in a murine model of focal cerebral ischemia by Connolly (1996)
10.1161/01.RES.76.5.900 / Circ. Res. / Enhanced preservation of orthotopically transplanted rat lungs by nitroglycerin but not hydralazinerequirement for graft vascular homeostasis beyond harvest vasodilation by Naka (1995)
10.1161/01.STR.28.11.2296 / Stroke. / Use of a spectrophotometric hemoglobin assay to objectively quantify intracerebral hemorrhage in mice by Choudhri (1997)
10.1038/nm0298-228 / Nat. Med. / Tissue plasminogen activator (tPA) increases neuronal damage after focal cerebral ischemia in wild-type and tPA-deficient mice by Wang (1998)
10.1111/j.1600-0404.1992.tb05122.x / Acta Neurol. Scand. / The topography of microthrombi in ischemic brain infarct by Heye (1992)
{'key': '2023072508440920800_R26', 'first-page': '685', 'article-title': 'Factor IX of the blood coagulation systema review', 'volume': '62', 'author': 'Taran', 'year': '1997', 'journal-title': 'Biochemistry.'} / Biochemistry. / Factor IX of the blood coagulation systema review by Taran (1997)
10.1016/S0022-5223(98)00437-1 / J. Thorac. Cardiovasc. Surg. / Selective anticoagulation with active site-blocked Factor IXa suggests separate roles for intrinsic and extrinsic coagulation pathways in cardiopulmonary bypass by Spanier (1998)
10.1172/JCI115495 / J. Clin. Invest. / Active site-blocked Factor IXa prevents intravascular thrombus formation in the coronary vasculature without inhibiting extravascular coagulation in a canine thrombosis model by Benedict (1991)
10.1055/s-0038-1653839 / Thromb. Haemost. / Measurement of activated factor IX in factor IX concentratescorrelation with in vivo thrombogenicity by Gray (1995)
10.1172/JCI116863 / J. Clin. Invest. / Protease nexin-2/amyloid beta protein precursor. A tight-binding inhibitor of coagulation factor IXa by Schmaier (1993)
10.1038/291165a0 / Nature. / Relative proteolysis of the fibrinogen B beta chain by thrombin and plasmin as a determinant of thrombosis by Nossel (1981)
10.1055/s-0038-1642681 / Thromb. Haemost. / The molecular basis of platelet and endothelial cell interaction with neutrophils and monocytesrole of P-selectin and the P-selectin ligand, PSGL-1 by Furie (1995)
10.1038/359848a0 / Nature. / Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin by Palabrica (1992)
10.1016/0092-8674(89)90292-4 / Cell. / PADGEM proteina receptor that mediates the interaction of activated platelets with neutrophils and monocytes by Larsen (1989)
10.1172/JCI116709 / J. Clin. Invest. / Downregulation of human platelet reactivity by neutrophilsparticipation of lipoxygenase derivatives and adhesive proteins by Valles (1993)

Dates

Type	When
Created	23 years ago (July 26, 2002, 12:48 p.m.)
Deposited	2 years ago (July 25, 2023, 5:55 a.m.)
Indexed	11 months, 2 weeks ago (Sept. 9, 2024, 2:38 a.m.)
Issued	26 years, 1 month ago (July 1, 1999)
Published	26 years, 1 month ago (July 1, 1999)
Published Online	26 years, 1 month ago (July 5, 1999)
Published Print	26 years, 1 month ago (July 1, 1999)

Funders 0

None

BibTeX

@article{Choudhri_1999, title={Targeted Inhibition of Intrinsic Coagulation Limits Cerebral Injury in Stroke without Increasing Intracerebral Hemorrhage}, volume={190}, ISSN={1540-9538}, url={http://dx.doi.org/10.1084/jem.190.1.91}, DOI={10.1084/jem.190.1.91}, number={1}, journal={The Journal of Experimental Medicine}, publisher={Rockefeller University Press}, author={Choudhri, Tanvir F. and Hoh, Brian L. and Prestigiacomo, Charles J. and Huang, Judy and Kim, Louis J. and Schmidt, Ann Marie and Kisiel, Walter and Connolly, E. Sander and Pinsky, David J.}, year={1999}, month=jul, pages={91–100} }

JSON

{
  "indexed": {
    "date-parts": [
      [
        2024,
        9,
        9
      ]
    ],
    "date-time": "2024-09-09T06:38:20Z",
    "timestamp": 1725863900173
  },
  "reference-count": 35,
  "publisher": "Rockefeller University Press",
  "issue": "1",
  "content-domain": {
    "domain": [
      "rupress.org"
    ],
    "crossmark-restriction": true
  },
  "published-print": {
    "date-parts": [
      [
        1999,
        7,
        1
      ]
    ]
  },
  "abstract": "<jats:p>Agents that restore vascular patency in stroke also increase the risk of intracerebral hemorrhage (ICH). As Factor IXa is a key intermediary in the intrinsic pathway of coagulation, targeted inhibition of Factor IXa\u2013dependent coagulation might inhibit microvascular thrombosis in stroke without impairing extrinsic hemostatic mechanisms that limit ICH. A competitive inhibitor of native Factor IXa for assembly into the intrinsic Factor X activation complex, Factor IXai, was prepared by covalent modification of the Factor IXa active site. In a modified cephalin clotting time assay, in vivo administration of Factor IXai caused a dose-dependent increase in time to clot formation (3.6-fold increase at the 300 \u03bcg/kg dose compared with vehicle-treated control animals, P &amp;lt; 0.05). Mice given Factor IXai and subjected to middle cerebral artery occlusion and reperfusion demonstrated reduced microvascular fibrin accumulation by immunoblotting and immunostaining, reduced 111In-labeled platelet deposition (42% decrease, P &amp;lt; 0.05), increased cerebral perfusion (2.6-fold increase in ipsilateral blood flow by laser doppler, P &amp;lt; 0.05), and smaller cerebral infarcts than vehicle-treated controls (70% reduction, P &amp;lt; 0.05) based on triphenyl tetrazolium chloride staining of serial cerebral sections. At therapeutically effective doses, Factor IXai was not associated with increased ICH, as opposed to tissue plasminogen activator (tPA) or heparin, both of which significantly increased ICH. Factor IXai was cerebroprotective even when given after the onset of stroke, indicating that microvascular thrombosis continues to evolve (and may be inhibited) even after primary occlusion of a major cerebrovascular tributary.</jats:p>",
  "DOI": "10.1084/jem.190.1.91",
  "type": "journal-article",
  "created": {
    "date-parts": [
      [
        2002,
        7,
        26
      ]
    ],
    "date-time": "2002-07-26T16:48:33Z",
    "timestamp": 1027702113000
  },
  "page": "91-100",
  "update-policy": "http://dx.doi.org/10.1084/jem.crossmarkpolicy",
  "source": "Crossref",
  "is-referenced-by-count": 55,
  "title": "Targeted Inhibition of Intrinsic Coagulation Limits Cerebral Injury in Stroke without Increasing Intracerebral Hemorrhage",
  "prefix": "10.1084",
  "volume": "190",
  "author": [
    {
      "given": "Tanvir F.",
      "family": "Choudhri",
      "sequence": "first",
      "affiliation": [
        {
          "name": "aFrom the Department of Neurological Surgery, Columbia University College of Physicians and Surgeons, New York 10032"
        }
      ]
    },
    {
      "given": "Brian L.",
      "family": "Hoh",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "aFrom the Department of Neurological Surgery, Columbia University College of Physicians and Surgeons, New York 10032"
        }
      ]
    },
    {
      "given": "Charles J.",
      "family": "Prestigiacomo",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "aFrom the Department of Neurological Surgery, Columbia University College of Physicians and Surgeons, New York 10032"
        }
      ]
    },
    {
      "given": "Judy",
      "family": "Huang",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "aFrom the Department of Neurological Surgery, Columbia University College of Physicians and Surgeons, New York 10032"
        }
      ]
    },
    {
      "given": "Louis J.",
      "family": "Kim",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "aFrom the Department of Neurological Surgery, Columbia University College of Physicians and Surgeons, New York 10032"
        }
      ]
    },
    {
      "given": "Ann Marie",
      "family": "Schmidt",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "bFrom the Department of Medicine, Columbia University College of Physicians and Surgeons, New York 10032"
        }
      ]
    },
    {
      "given": "Walter",
      "family": "Kisiel",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "cDepartment of Pathology, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131"
        }
      ]
    },
    {
      "suffix": "Jr.",
      "given": "E. Sander",
      "family": "Connolly",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "aFrom the Department of Neurological Surgery, Columbia University College of Physicians and Surgeons, New York 10032"
        }
      ]
    },
    {
      "given": "David J.",
      "family": "Pinsky",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "bFrom the Department of Medicine, Columbia University College of Physicians and Surgeons, New York 10032"
        }
      ]
    }
  ],
  "member": "291",
  "published-online": {
    "date-parts": [
      [
        1999,
        7,
        5
      ]
    ]
  },
  "reference": [
    {
      "key": "2023072508440920800_R1",
      "doi-asserted-by": "crossref",
      "first-page": "1581",
      "DOI": "10.1056/NEJM199512143332401",
      "article-title": "Tissue plasminogen activator for acute ischemic stroke",
      "volume": "333",
      "author": "The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group",
      "year": "1995",
      "journal-title": "N. Engl. J. Med."
    },
    {
      "key": "2023072508440920800_R2",
      "doi-asserted-by": "crossref",
      "first-page": "1017",
      "DOI": "10.1001/jama.1995.03530130023023",
      "article-title": "Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study",
      "volume": "274",
      "author": "Hacke",
      "year": "1995",
      "journal-title": "JAMA (J. Am. Med. Assoc.)."
    },
    {
      "key": "2023072508440920800_R3",
      "doi-asserted-by": "crossref",
      "first-page": "1632",
      "DOI": "10.1056/NEJM199512143332410",
      "article-title": "Acute stroke\u2014on the threshold of a therapy?",
      "volume": "333",
      "author": "del Zoppo",
      "year": "1995",
      "journal-title": "N. Engl. J. Med."
    },
    {
      "key": "2023072508440920800_R4",
      "doi-asserted-by": "crossref",
      "first-page": "145",
      "DOI": "10.1056/NEJM199607183350301",
      "article-title": "Thrombolytic therapy with streptokinase in acute ischemic stroke",
      "volume": "335",
      "author": "The Multicenter Acute Stroke Trial\u2014Europe Study Group",
      "year": "1996",
      "journal-title": "N. Engl. J. Med."
    },
    {
      "key": "2023072508440920800_R5",
      "doi-asserted-by": "crossref",
      "first-page": "607",
      "DOI": "10.1016/S0140-6736(97)03022-5",
      "article-title": "Systematic review of evidence on thrombolytic therapy for acute ischaemic stroke",
      "volume": "350",
      "author": "Wardlaw",
      "year": "1997",
      "journal-title": "Lancet."
    },
    {
      "key": "2023072508440920800_R6",
      "doi-asserted-by": "crossref",
      "first-page": "9779",
      "DOI": "10.1073/pnas.94.18.9779",
      "article-title": "Neuronal death in the central nervous system demonstrates a non-fibrin substrate for plasmin",
      "volume": "94",
      "author": "Tsirka",
      "year": "1997",
      "journal-title": "Proc. Natl. Acad. Sci. USA."
    },
    {
      "key": "2023072508440920800_R7",
      "doi-asserted-by": "crossref",
      "first-page": "543",
      "DOI": "10.1523/JNEUROSCI.17-02-00543.1997",
      "article-title": "An extracellular proteolytic cascade promotes neuronal degeneration in the mouse hippocampus",
      "volume": "17",
      "author": "Tsirka",
      "year": "1997",
      "journal-title": "J. Neurosci."
    },
    {
      "key": "2023072508440920800_R8",
      "doi-asserted-by": "crossref",
      "first-page": "561",
      "DOI": "10.1055/s-0038-1653411",
      "article-title": "Studies on the specific fibrinolytic effect of human extrinsic (tissue-type) plasminogen activator in human blood and in various animal species in vitro",
      "volume": "46",
      "author": "Korninger",
      "year": "1981",
      "journal-title": "Thromb. Haemost."
    },
    {
      "key": "2023072508440920800_R9",
      "doi-asserted-by": "crossref",
      "first-page": "123",
      "DOI": "10.1038/384123b0",
      "article-title": "Neuronal cell death and tPA",
      "volume": "384",
      "author": "Tsirka",
      "year": "1996",
      "journal-title": "Nature."
    },
    {
      "key": "2023072508440920800_R10",
      "doi-asserted-by": "crossref",
      "first-page": "679",
      "DOI": "10.1172/JCI116637",
      "article-title": "Extracellular proteolysis in the adult murine brain",
      "volume": "92",
      "author": "Sappino",
      "year": "1993",
      "journal-title": "J. Clin. Invest."
    },
    {
      "key": "2023072508440920800_R11",
      "doi-asserted-by": "crossref",
      "first-page": "340",
      "DOI": "10.1038/377340a0",
      "article-title": "Excitotoxin-induced neuronal degeneration and seizure are mediated by tissue plasminogen activator",
      "volume": "377",
      "author": "Tsirka",
      "year": "1995",
      "journal-title": "Nature."
    },
    {
      "key": "2023072508440920800_R12",
      "doi-asserted-by": "crossref",
      "first-page": "825",
      "DOI": "10.7326/0003-4819-105-6-825",
      "article-title": "Intravenous heparin for the prevention of stroke progression in acute partial stable strokea randomized controlled trial",
      "volume": "105",
      "author": "Duke",
      "year": "1996",
      "journal-title": "Ann. Intern. Med."
    },
    {
      "key": "2023072508440920800_R13",
      "doi-asserted-by": "crossref",
      "first-page": "10",
      "DOI": "10.1161/01.STR.19.1.10",
      "article-title": "Failure of heparin to prevent progression in progressing ischemic infarction",
      "volume": "19",
      "author": "Haley",
      "year": "1988",
      "journal-title": "Stroke."
    },
    {
      "key": "2023072508440920800_R14",
      "doi-asserted-by": "crossref",
      "first-page": "1657",
      "DOI": "10.1161/01.STR.21.12.1657",
      "article-title": "Natural history of progressive ischemic stroke in a population treated with heparin",
      "volume": "21",
      "author": "Slivka",
      "year": "1990",
      "journal-title": "Stroke."
    },
    {
      "key": "2023072508440920800_R15",
      "doi-asserted-by": "crossref",
      "first-page": "386",
      "DOI": "10.1001/archneur.1986.00520040066022",
      "article-title": "Treatment of acute ischemic strokeopen trial with continuous intravenous heparinization",
      "volume": "43",
      "author": "Ramirez-Lassepas",
      "year": "1986",
      "journal-title": "Arch. Neurol."
    },
    {
      "key": "2023072508440920800_R16",
      "doi-asserted-by": "crossref",
      "first-page": "464",
      "DOI": "10.1111/j.1600-0404.1985.tb03229.x",
      "article-title": "Anticoagulant-induced intracerebral bleeding in brain ischemiaevaluation in 200 patients with TIAs, emboli from the heart, and progressing stroke",
      "volume": "71",
      "author": "Bogousslavsky",
      "year": "1985",
      "journal-title": "Acta Neurol. Scand."
    },
    {
      "key": "2023072508440920800_R17",
      "doi-asserted-by": "crossref",
      "first-page": "779",
      "DOI": "10.1161/01.STR.15.5.779",
      "article-title": "Immediate anticoagulation of embolic strokebrain hemorrhage and management options",
      "volume": "15",
      "author": "Cerebral Embolism Study Group",
      "year": "1984",
      "journal-title": "Stroke."
    },
    {
      "key": "2023072508440920800_R18",
      "doi-asserted-by": "crossref",
      "first-page": "1301",
      "DOI": "10.1172/JCI3338",
      "article-title": "Reduced microvascular thrombosis and improved outcome in acute murine stroke by inhibiting GP IIb/IIIa receptor\u2013mediated platelet aggregation",
      "volume": "102",
      "author": "Choudhri",
      "year": "1998",
      "journal-title": "J. Clin. Invest."
    },
    {
      "key": "2023072508440920800_R19",
      "doi-asserted-by": "crossref",
      "first-page": "209",
      "DOI": "10.1172/JCI118392",
      "article-title": "Cerebral protection in homozygous null ICAM-1 mice after middle cerebral artery occlusion. Role of neutrophil adhesion in the pathogenesis of stroke",
      "volume": "97",
      "author": "Connolly",
      "year": "1996",
      "journal-title": "J. Clin. Invest."
    },
    {
      "key": "2023072508440920800_R20",
      "doi-asserted-by": "crossref",
      "first-page": "304",
      "DOI": "10.1161/01.RES.81.3.304",
      "article-title": "Exacerbation of cerebral injury in mice which express the P-selectin geneidentification of P-selectin blockade as a new target for the treatment of stroke",
      "volume": "81",
      "author": "Connolly",
      "year": "1997",
      "journal-title": "Circ. Res."
    },
    {
      "key": "2023072508440920800_R21",
      "first-page": "523",
      "article-title": "Procedural and strain-related variables significantly affect outcome in a murine model of focal cerebral ischemia",
      "volume": "38",
      "author": "Connolly",
      "year": "1996",
      "journal-title": "Neurosurgery."
    },
    {
      "key": "2023072508440920800_R22",
      "doi-asserted-by": "crossref",
      "first-page": "900",
      "DOI": "10.1161/01.RES.76.5.900",
      "article-title": "Enhanced preservation of orthotopically transplanted rat lungs by nitroglycerin but not hydralazinerequirement for graft vascular homeostasis beyond harvest vasodilation",
      "volume": "76",
      "author": "Naka",
      "year": "1995",
      "journal-title": "Circ. Res."
    },
    {
      "key": "2023072508440920800_R23",
      "doi-asserted-by": "crossref",
      "first-page": "2296",
      "DOI": "10.1161/01.STR.28.11.2296",
      "article-title": "Use of a spectrophotometric hemoglobin assay to objectively quantify intracerebral hemorrhage in mice",
      "volume": "28",
      "author": "Choudhri",
      "year": "1997",
      "journal-title": "Stroke."
    },
    {
      "key": "2023072508440920800_R24",
      "doi-asserted-by": "crossref",
      "first-page": "228",
      "DOI": "10.1038/nm0298-228",
      "article-title": "Tissue plasminogen activator (tPA) increases neuronal damage after focal cerebral ischemia in wild-type and tPA-deficient mice",
      "volume": "4",
      "author": "Wang",
      "year": "1998",
      "journal-title": "Nat. Med."
    },
    {
      "key": "2023072508440920800_R25",
      "doi-asserted-by": "crossref",
      "first-page": "450",
      "DOI": "10.1111/j.1600-0404.1992.tb05122.x",
      "article-title": "The topography of microthrombi in ischemic brain infarct",
      "volume": "86",
      "author": "Heye",
      "year": "1992",
      "journal-title": "Acta Neurol. Scand."
    },
    {
      "key": "2023072508440920800_R26",
      "first-page": "685",
      "article-title": "Factor IX of the blood coagulation systema review",
      "volume": "62",
      "author": "Taran",
      "year": "1997",
      "journal-title": "Biochemistry."
    },
    {
      "key": "2023072508440920800_R27",
      "doi-asserted-by": "crossref",
      "first-page": "860",
      "DOI": "10.1016/S0022-5223(98)00437-1",
      "article-title": "Selective anticoagulation with active site-blocked Factor IXa suggests separate roles for intrinsic and extrinsic coagulation pathways in cardiopulmonary bypass",
      "volume": "116",
      "author": "Spanier",
      "year": "1998",
      "journal-title": "J. Thorac. Cardiovasc. Surg."
    },
    {
      "key": "2023072508440920800_R28",
      "doi-asserted-by": "crossref",
      "first-page": "1760",
      "DOI": "10.1172/JCI115495",
      "article-title": "Active site-blocked Factor IXa prevents intravascular thrombus formation in the coronary vasculature without inhibiting extravascular coagulation in a canine thrombosis model",
      "volume": "88",
      "author": "Benedict",
      "year": "1991",
      "journal-title": "J. Clin. Invest."
    },
    {
      "key": "2023072508440920800_R29",
      "doi-asserted-by": "crossref",
      "first-page": "675",
      "DOI": "10.1055/s-0038-1653839",
      "article-title": "Measurement of activated factor IX in factor IX concentratescorrelation with in vivo thrombogenicity",
      "volume": "73",
      "author": "Gray",
      "year": "1995",
      "journal-title": "Thromb. Haemost."
    },
    {
      "key": "2023072508440920800_R30",
      "doi-asserted-by": "crossref",
      "first-page": "2540",
      "DOI": "10.1172/JCI116863",
      "article-title": "Protease nexin-2/amyloid beta protein precursor. A tight-binding inhibitor of coagulation factor IXa",
      "volume": "92",
      "author": "Schmaier",
      "year": "1993",
      "journal-title": "J. Clin. Invest."
    },
    {
      "key": "2023072508440920800_R31",
      "doi-asserted-by": "crossref",
      "first-page": "165",
      "DOI": "10.1038/291165a0",
      "article-title": "Relative proteolysis of the fibrinogen B beta chain by thrombin and plasmin as a determinant of thrombosis",
      "volume": "291",
      "author": "Nossel",
      "year": "1981",
      "journal-title": "Nature."
    },
    {
      "key": "2023072508440920800_R32",
      "doi-asserted-by": "crossref",
      "first-page": "224",
      "DOI": "10.1055/s-0038-1642681",
      "article-title": "The molecular basis of platelet and endothelial cell interaction with neutrophils and monocytesrole of P-selectin and the P-selectin ligand, PSGL-1",
      "volume": "74",
      "author": "Furie",
      "year": "1995",
      "journal-title": "Thromb. Haemost."
    },
    {
      "key": "2023072508440920800_R33",
      "doi-asserted-by": "crossref",
      "first-page": "848",
      "DOI": "10.1038/359848a0",
      "article-title": "Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin",
      "volume": "359",
      "author": "Palabrica",
      "year": "1992",
      "journal-title": "Nature."
    },
    {
      "key": "2023072508440920800_R34",
      "doi-asserted-by": "crossref",
      "first-page": "305",
      "DOI": "10.1016/0092-8674(89)90292-4",
      "article-title": "PADGEM proteina receptor that mediates the interaction of activated platelets with neutrophils and monocytes",
      "volume": "59",
      "author": "Larsen",
      "year": "1989",
      "journal-title": "Cell."
    },
    {
      "key": "2023072508440920800_R35",
      "doi-asserted-by": "crossref",
      "first-page": "1357",
      "DOI": "10.1172/JCI116709",
      "article-title": "Downregulation of human platelet reactivity by neutrophilsparticipation of lipoxygenase derivatives and adhesive proteins",
      "volume": "92",
      "author": "Valles",
      "year": "1993",
      "journal-title": "J. Clin. Invest."
    }
  ],
  "container-title": "The Journal of Experimental Medicine",
  "original-title": [],
  "language": "en",
  "link": [
    {
      "URL": "https://rupress.org/jem/article-pdf/190/1/91/1694184/98-2162.pdf",
      "content-type": "application/pdf",
      "content-version": "vor",
      "intended-application": "syndication"
    },
    {
      "URL": "https://rupress.org/jem/article-pdf/190/1/91/1694184/98-2162.pdf",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "similarity-checking"
    }
  ],
  "deposited": {
    "date-parts": [
      [
        2023,
        7,
        25
      ]
    ],
    "date-time": "2023-07-25T09:55:27Z",
    "timestamp": 1690278927000
  },
  "score": 1,
  "resource": {
    "primary": {
      "URL": "https://rupress.org/jem/article/190/1/91/7941/Targeted-Inhibition-of-Intrinsic-Coagulation"
    }
  },
  "subtitle": [],
  "short-title": [],
  "issued": {
    "date-parts": [
      [
        1999,
        7,
        1
      ]
    ]
  },
  "references-count": 35,
  "journal-issue": {
    "issue": "1",
    "published-print": {
      "date-parts": [
        [
          1999,
          7,
          1
        ]
      ]
    }
  },
  "URL": "http://dx.doi.org/10.1084/jem.190.1.91",
  "relation": {},
  "ISSN": [
    "0022-1007",
    "1540-9538"
  ],
  "subject": [],
  "published": {
    "date-parts": [
      [
        1999,
        7,
        1
      ]
    ]
  }
}