Inhibition of Arterial Thrombosis by a Soluble Tissue Factor Mutant and Active Site-blocked Factors IXa and Xa in the Guinea Pig
Summary The substrate recognition region of tissue factor contains two residues, Lys165 and Lys166, which are important for macromolecular substrate activation by the tissue factor:factor VIIa complex. Replacement of these two residues with alanine in a soluble version of human tissue factor resulte...
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| Veröffentlicht in: | Thrombosis and haemostasis 2001-03, Vol.85 (3), p.475-81 |
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| creator | Himber, Jacques Refino, Canio J. Burcklen, Louis Roux, Sébastien Kirchhofer, Daniel |
| description | Summary
The substrate recognition region of tissue factor contains two residues, Lys165 and Lys166, which are important for macromolecular substrate activation by the tissue factor:factor VIIa complex. Replacement of these two residues with alanine in a soluble version of human tissue factor resulted in a mutant, hTFAA, which can bind factor VIIa but forms an enzymatically inactive complex. We found that hTFAA inhibits the activity of guinea pig factor VIIa, allowing us to evaluate hTFAAs effects on thrombosis and hemostasis in a guinea pig model of recurrent arterial thrombosis. In addition to heparin, the effects of hTFAA were compared to active site inhibited factor IXa (F.IXai) and factor Xa (F.Xai). We found that hTFAA, F.IXai and F.Xai were potent antithrombotics and may possess a decreased risk of hemorrhage when compared to unfractionated heparin. When administered at a dose that inhibited thrombosis by about 90%, hTFAA neither affected cuticle bleeding nor the activated partial thromboplastin time, and had only a modest effect on the prothrombin time. At equi-efficacious doses, F.IXai, F.Xai and heparin prolonged bleeding times by 20% (p >0.5), 50% (p |
| doi_str_mv | 10.1055/s-0037-1615608 |
| format | Article |
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The substrate recognition region of tissue factor contains two residues, Lys165 and Lys166, which are important for macromolecular substrate activation by the tissue factor:factor VIIa complex. Replacement of these two residues with alanine in a soluble version of human tissue factor resulted in a mutant, hTFAA, which can bind factor VIIa but forms an enzymatically inactive complex. We found that hTFAA inhibits the activity of guinea pig factor VIIa, allowing us to evaluate hTFAAs effects on thrombosis and hemostasis in a guinea pig model of recurrent arterial thrombosis. In addition to heparin, the effects of hTFAA were compared to active site inhibited factor IXa (F.IXai) and factor Xa (F.Xai). We found that hTFAA, F.IXai and F.Xai were potent antithrombotics and may possess a decreased risk of hemorrhage when compared to unfractionated heparin. When administered at a dose that inhibited thrombosis by about 90%, hTFAA neither affected cuticle bleeding nor the activated partial thromboplastin time, and had only a modest effect on the prothrombin time. At equi-efficacious doses, F.IXai, F.Xai and heparin prolonged bleeding times by 20% (p >0.5), 50% (p <0.05) and 100% (p <0.01), respectively. In summary, our study demonstrates that, unlike heparin, specific inhibitors of factors VIIa, IXa and Xa can produce antithrombotic effects without or with only minimally disturbing normal hemostasis. The results further suggest that factor VIIa and factor IXa are especially promising targets for antithrombotic drug development.</description><identifier>ISSN: 0340-6245</identifier><identifier>EISSN: 2567-689X</identifier><identifier>DOI: 10.1055/s-0037-1615608</identifier><identifier>PMID: 11307818</identifier><identifier>CODEN: THHADQ</identifier><language>eng</language><publisher>Stuttgart: Schattauer Verlag für Medizin und Naturwissenschaften</publisher><subject><![CDATA[Amino Acid Substitution ; Animals ; Arterial Occlusive Diseases - drug therapy ; Arterial Occlusive Diseases - etiology ; Arterial Occlusive Diseases - prevention & control ; Biological and medical sciences ; Bleeding Time ; Blood and lymphatic vessels ; Cardiology. Vascular system ; Carotid Artery Thrombosis - drug therapy ; Carotid Artery Thrombosis - etiology ; Carotid Artery Thrombosis - prevention & control ; Catalytic Domain ; Disease Models, Animal ; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous ; Factor IXa - antagonists & inhibitors ; Factor IXa - pharmacology ; Factor VIIa - drug effects ; Factor VIIa - metabolism ; Factor Xa - pharmacology ; Factor Xa Inhibitors ; Fibrinolytic Agents - administration & dosage ; Fibrinolytic Agents - pharmacology ; Guinea Pigs ; Heparin - administration & dosage ; Heparin - pharmacology ; Humans ; Medical sciences ; Review Article ; Solubility ; Thromboplastin - administration & dosage ; Thromboplastin - genetics ; Thromboplastin - pharmacology ; Thrombosis - drug therapy ; Thrombosis - etiology ; Thrombosis - prevention & control]]></subject><ispartof>Thrombosis and haemostasis, 2001-03, Vol.85 (3), p.475-81</ispartof><rights>2001 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c613t-fcec2b97e6112c8ba8b3e48918dcb5bc9923dad5015f31a34ccbe6e1f7e8a6f43</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.thieme-connect.de/products/ejournals/pdf/10.1055/s-0037-1615608.pdf$$EPDF$$P50$$Gthieme$$H</linktopdf><linktohtml>$$Uhttps://www.thieme-connect.de/products/ejournals/html/10.1055/s-0037-1615608$$EHTML$$P50$$Gthieme$$H</linktohtml><link.rule.ids>314,776,780,3003,3004,27903,27904,54537,54538</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=925044$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11307818$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Himber, Jacques</creatorcontrib><creatorcontrib>Refino, Canio J.</creatorcontrib><creatorcontrib>Burcklen, Louis</creatorcontrib><creatorcontrib>Roux, Sébastien</creatorcontrib><creatorcontrib>Kirchhofer, Daniel</creatorcontrib><title>Inhibition of Arterial Thrombosis by a Soluble Tissue Factor Mutant and Active Site-blocked Factors IXa and Xa in the Guinea Pig</title><title>Thrombosis and haemostasis</title><addtitle>Thromb Haemost</addtitle><description>Summary
The substrate recognition region of tissue factor contains two residues, Lys165 and Lys166, which are important for macromolecular substrate activation by the tissue factor:factor VIIa complex. Replacement of these two residues with alanine in a soluble version of human tissue factor resulted in a mutant, hTFAA, which can bind factor VIIa but forms an enzymatically inactive complex. We found that hTFAA inhibits the activity of guinea pig factor VIIa, allowing us to evaluate hTFAAs effects on thrombosis and hemostasis in a guinea pig model of recurrent arterial thrombosis. In addition to heparin, the effects of hTFAA were compared to active site inhibited factor IXa (F.IXai) and factor Xa (F.Xai). We found that hTFAA, F.IXai and F.Xai were potent antithrombotics and may possess a decreased risk of hemorrhage when compared to unfractionated heparin. When administered at a dose that inhibited thrombosis by about 90%, hTFAA neither affected cuticle bleeding nor the activated partial thromboplastin time, and had only a modest effect on the prothrombin time. At equi-efficacious doses, F.IXai, F.Xai and heparin prolonged bleeding times by 20% (p >0.5), 50% (p <0.05) and 100% (p <0.01), respectively. In summary, our study demonstrates that, unlike heparin, specific inhibitors of factors VIIa, IXa and Xa can produce antithrombotic effects without or with only minimally disturbing normal hemostasis. The results further suggest that factor VIIa and factor IXa are especially promising targets for antithrombotic drug development.</description><subject>Amino Acid Substitution</subject><subject>Animals</subject><subject>Arterial Occlusive Diseases - drug therapy</subject><subject>Arterial Occlusive Diseases - etiology</subject><subject>Arterial Occlusive Diseases - prevention & control</subject><subject>Biological and medical sciences</subject><subject>Bleeding Time</subject><subject>Blood and lymphatic vessels</subject><subject>Cardiology. Vascular system</subject><subject>Carotid Artery Thrombosis - drug therapy</subject><subject>Carotid Artery Thrombosis - etiology</subject><subject>Carotid Artery Thrombosis - prevention & control</subject><subject>Catalytic Domain</subject><subject>Disease Models, Animal</subject><subject>Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous</subject><subject>Factor IXa - antagonists & inhibitors</subject><subject>Factor IXa - pharmacology</subject><subject>Factor VIIa - drug effects</subject><subject>Factor VIIa - metabolism</subject><subject>Factor Xa - pharmacology</subject><subject>Factor Xa Inhibitors</subject><subject>Fibrinolytic Agents - administration & dosage</subject><subject>Fibrinolytic Agents - pharmacology</subject><subject>Guinea Pigs</subject><subject>Heparin - administration & dosage</subject><subject>Heparin - pharmacology</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Review Article</subject><subject>Solubility</subject><subject>Thromboplastin - administration & dosage</subject><subject>Thromboplastin - genetics</subject><subject>Thromboplastin - pharmacology</subject><subject>Thrombosis - drug therapy</subject><subject>Thrombosis - etiology</subject><subject>Thrombosis - prevention & control</subject><issn>0340-6245</issn><issn>2567-689X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqtks-L1DAUx4so7rh69SgBwVvXpG3S9Dgs-2NgRWFH2Ft4SV9t1jYZk1TZm3_6dnbKCII3T4-QT77fx_ebLHvL6BmjnH-MOaVlnTPBuKDyWbYquKhzIZu759mKlhXNRVHxk-xVjPeUMlE1_GV2wlhJa8nkKvu9cb3VNlnviO_IOiQMFgay7YMftY82Ev1AgNz6YdIDkq2NcUJyCSb5QD5NCVwi4FqyNsn-RHJrE-Z68OY7tgsVyeYOnph5WEdSj-Rqsg6BfLHfXmcvOhgivlnmafb18mJ7fp3ffL7anK9vciNYmfLOoCl0U6NgrDBSg9QlVrJhsjWaa9M0RdlCyynjXcmgrIzRKJB1NUoQXVWeZh8Ourvgf0wYkxptNDgM4NBPUdU15U3D2QyeHUATfIwBO7ULdoTwoBhV-8xVVPvM1ZL5_ODdojzpEds_-BLyDLxfAIgGhi6AMzYeuabgtNovmB-o1FscUd37Kbg5kX_b2gMfTQ8pwYThKJmO7ak5d9UDjj4m2J-Ndwldmi-C6efG1FOhSgqpRnBTNMHukipqylTs_S_Vp3GYvcx_9Io7NPMf-9uvfAR6qeky</recordid><startdate>20010301</startdate><enddate>20010301</enddate><creator>Himber, Jacques</creator><creator>Refino, Canio J.</creator><creator>Burcklen, Louis</creator><creator>Roux, Sébastien</creator><creator>Kirchhofer, Daniel</creator><general>Schattauer Verlag für Medizin und Naturwissenschaften</general><general>Schattauer GmbH</general><general>Schattauer</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20010301</creationdate><title>Inhibition of Arterial Thrombosis by a Soluble Tissue Factor Mutant and Active Site-blocked Factors IXa and Xa in the Guinea Pig</title><author>Himber, Jacques ; Refino, Canio J. ; Burcklen, Louis ; Roux, Sébastien ; Kirchhofer, Daniel</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c613t-fcec2b97e6112c8ba8b3e48918dcb5bc9923dad5015f31a34ccbe6e1f7e8a6f43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Amino Acid Substitution</topic><topic>Animals</topic><topic>Arterial Occlusive Diseases - drug therapy</topic><topic>Arterial Occlusive Diseases - etiology</topic><topic>Arterial Occlusive Diseases - prevention & control</topic><topic>Biological and medical sciences</topic><topic>Bleeding Time</topic><topic>Blood and lymphatic vessels</topic><topic>Cardiology. Vascular system</topic><topic>Carotid Artery Thrombosis - drug therapy</topic><topic>Carotid Artery Thrombosis - etiology</topic><topic>Carotid Artery Thrombosis - prevention & control</topic><topic>Catalytic Domain</topic><topic>Disease Models, Animal</topic><topic>Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous</topic><topic>Factor IXa - antagonists & inhibitors</topic><topic>Factor IXa - pharmacology</topic><topic>Factor VIIa - drug effects</topic><topic>Factor VIIa - metabolism</topic><topic>Factor Xa - pharmacology</topic><topic>Factor Xa Inhibitors</topic><topic>Fibrinolytic Agents - administration & dosage</topic><topic>Fibrinolytic Agents - pharmacology</topic><topic>Guinea Pigs</topic><topic>Heparin - administration & dosage</topic><topic>Heparin - pharmacology</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Review Article</topic><topic>Solubility</topic><topic>Thromboplastin - administration & dosage</topic><topic>Thromboplastin - genetics</topic><topic>Thromboplastin - pharmacology</topic><topic>Thrombosis - drug therapy</topic><topic>Thrombosis - etiology</topic><topic>Thrombosis - prevention & control</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Himber, Jacques</creatorcontrib><creatorcontrib>Refino, Canio J.</creatorcontrib><creatorcontrib>Burcklen, Louis</creatorcontrib><creatorcontrib>Roux, Sébastien</creatorcontrib><creatorcontrib>Kirchhofer, Daniel</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Thrombosis and haemostasis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Himber, Jacques</au><au>Refino, Canio J.</au><au>Burcklen, Louis</au><au>Roux, Sébastien</au><au>Kirchhofer, Daniel</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of Arterial Thrombosis by a Soluble Tissue Factor Mutant and Active Site-blocked Factors IXa and Xa in the Guinea Pig</atitle><jtitle>Thrombosis and haemostasis</jtitle><addtitle>Thromb Haemost</addtitle><date>2001-03-01</date><risdate>2001</risdate><volume>85</volume><issue>3</issue><spage>475</spage><epage>81</epage><pages>475-81</pages><issn>0340-6245</issn><eissn>2567-689X</eissn><coden>THHADQ</coden><abstract>Summary
The substrate recognition region of tissue factor contains two residues, Lys165 and Lys166, which are important for macromolecular substrate activation by the tissue factor:factor VIIa complex. Replacement of these two residues with alanine in a soluble version of human tissue factor resulted in a mutant, hTFAA, which can bind factor VIIa but forms an enzymatically inactive complex. We found that hTFAA inhibits the activity of guinea pig factor VIIa, allowing us to evaluate hTFAAs effects on thrombosis and hemostasis in a guinea pig model of recurrent arterial thrombosis. In addition to heparin, the effects of hTFAA were compared to active site inhibited factor IXa (F.IXai) and factor Xa (F.Xai). We found that hTFAA, F.IXai and F.Xai were potent antithrombotics and may possess a decreased risk of hemorrhage when compared to unfractionated heparin. When administered at a dose that inhibited thrombosis by about 90%, hTFAA neither affected cuticle bleeding nor the activated partial thromboplastin time, and had only a modest effect on the prothrombin time. At equi-efficacious doses, F.IXai, F.Xai and heparin prolonged bleeding times by 20% (p >0.5), 50% (p <0.05) and 100% (p <0.01), respectively. In summary, our study demonstrates that, unlike heparin, specific inhibitors of factors VIIa, IXa and Xa can produce antithrombotic effects without or with only minimally disturbing normal hemostasis. The results further suggest that factor VIIa and factor IXa are especially promising targets for antithrombotic drug development.</abstract><cop>Stuttgart</cop><pub>Schattauer Verlag für Medizin und Naturwissenschaften</pub><pmid>11307818</pmid><doi>10.1055/s-0037-1615608</doi><tpages>-393</tpages></addata></record> |
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| ispartof | Thrombosis and haemostasis, 2001-03, Vol.85 (3), p.475-81 |
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| language | eng |
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| subjects | Amino Acid Substitution Animals Arterial Occlusive Diseases - drug therapy Arterial Occlusive Diseases - etiology Arterial Occlusive Diseases - prevention & control Biological and medical sciences Bleeding Time Blood and lymphatic vessels Cardiology. Vascular system Carotid Artery Thrombosis - drug therapy Carotid Artery Thrombosis - etiology Carotid Artery Thrombosis - prevention & control Catalytic Domain Disease Models, Animal Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous Factor IXa - antagonists & inhibitors Factor IXa - pharmacology Factor VIIa - drug effects Factor VIIa - metabolism Factor Xa - pharmacology Factor Xa Inhibitors Fibrinolytic Agents - administration & dosage Fibrinolytic Agents - pharmacology Guinea Pigs Heparin - administration & dosage Heparin - pharmacology Humans Medical sciences Review Article Solubility Thromboplastin - administration & dosage Thromboplastin - genetics Thromboplastin - pharmacology Thrombosis - drug therapy Thrombosis - etiology Thrombosis - prevention & control |
| title | Inhibition of Arterial Thrombosis by a Soluble Tissue Factor Mutant and Active Site-blocked Factors IXa and Xa in the Guinea Pig |
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