Intrinsic coagulation activation and the risk of arterial thrombosis in young women: results from the Risk of Arterial Thrombosis in relation to Oral contraceptives (RATIO) case-control study.
BACKGROUND
Classically, intrinsic coagulation proteins are thought to have a minor role in hemostasis. Recently, these proteins, especially FXII, were implicated as possible key players in the pathogenesis of arterial thrombosis. This study aims to determine the risks of arterial thrombosis conferred by increased activation of intrinsic coagulation proteins in young women and the effect of oral contraceptive use on this association.


RESULTS
The Risk of Arterial Thrombosis In relation to Oral contraceptives (RATIO) study is a population-based case-control study including young women (age 18 to 50 years) with myocardial infarction (n=205) and ischemic stroke (n=175) and 638 healthy controls. Intrinsic coagulation protein activation was determined by measuring activated protein-inhibitor complexes. This complex is with C1 esterase inhibitor (FXIIa-C1-INH, FXIa-C1-INH, Kallikrein-C1-INH) or antitrypsin inhibitor (FXIa-AT-INH). Odds ratios (ORs) and corresponding confidence intervals (95% CIs) were calculated with logistic regression. High levels of protein activation (>90th percentile of controls) showed an increased risk of ischemic stroke: FXIIa-C1-INH (OR, 2.1; 95% CI, 1.3 to 3.5), FXIa-C1-INH (OR, 2.8; 95% CI, 1.6 to 4.7), FXIa-AT-INH (OR, 2.3; 95% CI, 1.4 to 4.0), and Kallikrein-C1 (OR, 4.3; 95% CI, 2.6 to 7.2). If anything, myocardial infarction risk was only increased by Kallikrein-C1-INH (OR, 1.5; 95% CI, 0.9 to 2.5). Oral contraceptive use further increased the risks.


CONCLUSIONS
High levels of activated proteins of the intrinsic coagulation system are associated with arterial thrombosis, whereas the strength of these associations differs for myocardial infarction and ischemic stroke. This contradicts similar analyses among men in the Northwick Park Heart Study. Together with the finding that oral contraceptive use further increases the risks, the question of whether the role of intrinsic coagulation proteins in the pathogenesis of arterial thrombosis is sex-specific is raised.
Siegerink
B
B
Department of Clinical Epidemiology, LUMC, Leiden, the Netherlands.
Govers-Riemslag
J W P
JW
Rosendaal
F R
FR
Ten Cate
H
H
Algra
A
A
D000293:Adolescent; D000328:Adult; D001777:Blood Coagulation / Q000502:physiology*; D001779:Blood Coagulation Factors / Q000502:physiology*; D001920:Bradykinin / Q000502:physiology; D016022:Case-Control Studies; D003276:Contraceptives, Oral / Q000009:adverse effects*; D005172:Factor XI / Q000502:physiology; D005174:Factor XII / Q000502:physiology; D005260:Female; D006801:Humans; D007610:Kallikreins / Q000502:physiology; D007704:Kininogens / Q000502:physiology; D008875:Middle Aged; D009203:Myocardial Infarction / Q000503:physiopathology; D011288:Prekallikrein / Q000502:physiology; D012307:Risk Factors; D020521:Stroke / Q000503:physiopathology; D013927:Thrombosis / Q000453:epidemiology* / Q000503:physiopathology*; D055815:Young Adult
D001779:Blood Coagulation Factors; D003276:Contraceptives, Oral; D007704:Kininogens; D005174:Factor XII; D005172:Factor XI; D011288:Prekallikrein; D007610:Kallikreins; D001920:Bradykinin