Effects of factor IX or factor XI deficiency on ferric chloride-induced carotid artery occlusion in mice.
Factor XI (FXI) and factor IX (FIX) are zymogens of plasma serine proteases required for normal hemostasis. The purpose of this work was to evaluate FXI and FIX as potential therapeutic targets by means of a refined ferric chloride (FeCl(3))-induced arterial injury model in factor-deficient mice. Various concentrations of FeCl(3) were used to establish the arterial thrombosis model in C57BL/6 mice. Carotid artery blood flow was completely blocked within 10 min in C57BL/6 mice by application of 3.5% FeCl(3). In contrast, FXI- and FIX-deficient mice were fully protected from occlusion induced by 5% FeCl(3), and were partially protected against the effect of 7.5% FeCl(3). The protective effect was comparable to very high doses of heparin (1000 units kg(-1)) and substantially more effective than aspirin. While FXI and FIX deficiencies were indistinguishable in the carotid artery injury model, there was a marked difference in a tail-bleeding-time assay. FXI-deficient and wild-type mice have similar bleeding times, while FIX deficiency was associated with severely prolonged bleeding times (>5.8-fold increase, P < 0.01). Given the relatively mild bleeding diathesis associated with FXI deficiency, therapeutic inhibition of FXI may be a reasonable strategy for treating or preventing thrombus formation.
Wang
X
X
Department of Thrombosis Research, Bristol-Myers Squibb Company, Pennington, NJ 08534, USA. xinkand.wang@bms.com
Cheng
Q
Q
Xu
L
L
Feuerstein
G Z
GZ
Hsu
M-Y
MY
Smith
P L
PL
Seiffert
D A
DA
Schumacher
W A
WA
Ogletree
M L
ML
Gailani
D
D
D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000293:injuries; D001241:Aspirin / Q000494:pharmacology; D001760:Bleeding Time; D001783:Blood Flow Velocity; D002339:Carotid Arteries / Q000187:drug effects*; D002340:Carotid Artery Diseases / Q000473:pathology; D002712:Chlorides; D004305:Dose-Response Relationship, Drug; D005164:Factor IX / Q000502:physiology*; D005172:Factor XI / Q000502:physiology*; D005173:Factor XI Deficiency / Q000473:pathology*; D005290:Ferric Compounds / Q000494:pharmacology*; D005838:Genotype; D002836:Hemophilia B / Q000473:pathology*; D006493:Heparin / Q000737:chemistry / Q000494:pharmacology; D006720:Homozygote; D051379:Mice; D008810:Mice, Inbred C57BL; D010974:Platelet Aggregation; D012039:Regional Blood Flow / Q000187:drug effects; D013927:Thrombosis / Q000473:pathology / Q000628:therapy; D013997:Time Factors
D002712:Chlorides; D005290:Ferric Compounds; D005164:Factor IX; D006493:Heparin; D005172:Factor XI; D001241:Aspirin; C024555:ferric chloride