title: A comparison of the effects of factor XII deficiency and prekallikrein deficiency on thrombus formation.
abstract: Studies with animal models implicate the plasma proteases factor XIIa (FXIIa) and α-kallikrein in arterial and venous thrombosis. As congenital deficiencies of factor XII (FXII) or prekallikrein (PK), the zymogens of FXIIa and α-kallikrein respectively, do not cause bleeding disorders, inhibition of these enzymes may have therapeutic benefit without compromising hemostasis. The relative contributions of FXIIa and α-kallikrein to thrombosis in animal models are not clear. We compared mice lacking FXII or PK to wild type mice in established models of arterial thrombosis. Wild type mice developed carotid artery occlusion when the vessel was exposed to a 3.5% solution of ferric chloride (FeCl3). FXII-deficient mice were resistant to occlusion at 5% FeCl3 and partially resistant at 10% FeCl3. PK-deficient mice were resistant at 3.5% FeCl3 and partially resistant at 5% FeCl3. Mice lacking high molecular weight kininogen, a cofactor for PK activation and activity, were also partially resistant to thrombosis at 5% FeCl3. Induction of carotid artery thrombosis with Rose Bengal was delayed in FXII-deficient mice compared to wild type or PK-deficient animals. In human plasma supplemented with silica, DNA or collagen to induce contact activation, an antibody to the FXIIa active site was more effective at preventing thrombin generation than an antibody to the α-kallikrein active site. Similarly, the FXIIa antibody was more effective at reducing fibrin formation in human blood flowing through collagen coated-tubes. The findings suggest that inhibitors of FXIIa will have more potent anti-thrombotic effects than inhibitors of α-kallikrein.
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Yasin
authors.initials: Y
authors.lastname: Kokoye
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Ivanov
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Qiufang
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN, USA; Department of Bioengineering and Organic Chemistry, Tomsk Polytechnic University, Tomsk, Russia.
authors.forename: Anton
authors.initials: A
authors.lastname: Matafonov
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN, USA.
authors.forename: S Kent
authors.initials: SK
authors.lastname: Dickeson
authors.affiliation: Dyax Corp., Burlington, MA, USA.
authors.forename: Shauna
authors.initials: S
authors.lastname: Mason
authors.affiliation: Dyax Corp., Burlington, MA, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sexton
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden; Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Renné
authors.affiliation: Department of Hematology and Oncology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: McCrae
authors.affiliation: Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Edward P
authors.initials: EP
authors.lastname: Feener
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN, USA. Electronic address: dave.gailani@vanderbilt.edu.
authors.forename: David
authors.initials: D
authors.lastname: Gailani
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D001778:Blood Coagulation Disorders / Q000150:complications* / Q000235:genetics; D005174:Factor XII / Q000037:antagonists & inhibitors / Q000235:genetics*; D005175:Factor XII Deficiency / Q000150:complications* / Q000235:genetics; D017353:Gene Deletion; D006801:Humans; D007610:Kallikreins / Q000037:antagonists & inhibitors / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D011288:Prekallikrein / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics*; D065840:Protective Factors; D013927:Thrombosis / Q000209:etiology* / Q000235:genetics* / Q000517:prevention & control
chemical_list: D005174:Factor XII; D011288:Prekallikrein; D007610:Kallikreins
keywords: Factor XII; Factor XIIa; Prekallikrein; Thrombosis; α-Kallikrein