Intrinsic pathway of coagulation and arterial thrombosis.
Formation of a fibrin clot is mediated by a group of tightly regulated plasma proteases and cofactors. While this system is essential for minimizing blood loss from an injured blood vessel (hemostasis), it also contributes to pathologic fibrin formation and platelet activation that may occlude vessels (thrombosis). Many antithrombotic drugs target key elements of the plasma coagulation mechanism such as thrombin and factor Xa, based on the premise that plasma elements contributing to thrombosis are primarily those involved in hemostasis. Recent studies with genetically altered mice raise questions about this paradigm. Deficiencies of the intrinsic pathway proteases factor XII and factor XI are not associated with abnormal hemostasis in mice, but impair formation of occlusive thrombi in arterial injury models, indicating that pathways not essential for hemostasis participate in arterial thrombosis. If factor XII or factor XI make similar contributions to thrombosis in humans, these proteases could be ideal targets for drugs to treat or prevent thromboembolic disease with minimal risk of therapy-associated bleeding.
Gailani
David
D
Hematology/Oncology Division, Vanderbilt University, 777 Preston Research Building, 2220 Pierce Ave, Nashville, TN 37232-6307, USA. dave.gailani@vanderbilt.edu
Renné
Thomas
T
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology / Q000627:therapeutic use; D001777:Blood Coagulation / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D005172:Factor XI / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005173:Factor XI Deficiency / Q000097:blood* / Q000235:genetics; D005174:Factor XII / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005175:Factor XII Deficiency / Q000097:blood* / Q000235:genetics; D005337:Fibrin / Q000378:metabolism; D006487:Hemostasis / Q000187:drug effects / Q000235:genetics; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000097:blood / Q000150:complications; D051379:Mice; D018345:Mice, Knockout; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000097:blood / Q000209:etiology; D013923:Thromboembolism / Q000097:blood* / Q000235:genetics / Q000517:prevention & control; D013927:Thrombosis / Q000097:blood* / Q000235:genetics / Q000517:prevention & control
D000925:Anticoagulants; D011480:Protease Inhibitors; D005174:Factor XII; D005337:Fibrin; D005172:Factor XI