Intrinsic Coagulation Activation and the Risk of Arterial Thrombosis in Young Women

Abstract

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. Methods and 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 (nϭ205) and ischemic stroke (nϭ175) 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. (Circulation.

Epidemiologic and clinical data linking factors XI and XII to thrombosis

“…In these younger women, levels of fXIa-C1-INH and fXIa-AT-INH complexes above the 90 th percentile were associated with an elevated risk of stroke (OR ϭ 2.8; 95% CI, 1.6-4.7 and OR ϭ 2.3, 95% CI, 1.4-4.0, respectively). 25 Unlike the case with fXII, the use of an antigen assay to measure plasma fXI levels (fXI:Ag) was in agreement with the conclusion using enzymeinhibitor complexes. 34 Therefore, the available data overall seem to support a link between high fXI levels and IS risk.…”

“…24 In the RATIO study, neither higher nor lower levels of fXIIa-C1-INH levels were associated with MI in younger women. 25 The same conclusion was reached when fXII:Ag levels were measured in these patients. 34 In the Study of Myocardial Infarctions Leiden (SMILE) study, levels of fXII:c were evaluated as a risk factor for MI in 560 men and 646 controls younger than 70 with a first MI.…”

“…John Hageman's death from pulmonary embolism occurred 12 days after he sustained pelvic fractures, during which time he was largely 20 Age Ͼ45 y (462) Low fXII (fXII:Ag) VTE No VTE also not associated with high fXII NPHS-II 24 Males age 50-63 y at intake (2997) Low fXII (fXIIa-C1-INH) IS Yes RATIO 25 Females age 18-50 y with IS (175) High fXII (fXIIa-C1-INH) IS Yes Risk further increased by OCPs RATIO 34 Females age 18-50 y with IS (175) High fXII (fXII:Ag) IS No fXII:Ag not correlated with fXIIa-C1-INH ARIC 26 Age 45-54 y at intake (15 792) High fXII (fXII:c) IS No Case-control within ARIC cohort NPHS-II 29 Males age 50-63 y at intake (2997) High fXII (fXIIa:Ag) CHD Yes NPHS-II 24 Males age 50-63 y at intake (2997) High fXII (fXIIa-C1-INH) CHD No RATIO 25 Females immobile. 10 Although fXII deficiency per se was considered to be a risk factor for VTE, 11 in retrospect, this conclusion was likely explained by reporting bias.…”

“…Oral contraceptives increased the risk further. 25 It is unclear whether this discrepancy was explained by sex or age differences or some other factor. However, when fXII:Ag levels were assayed in the same patients and controls, no association with stroke risk was apparent, suggesting that the analyte being measured likely accounted for the divergent conclusions.…”

Demographic and Geographic Vascular Risk Factor Differences in European Young Adults With Ischemic Stroke

“…20 Our study was unable to depict the prevalence of such risk factors, however, and despite recent advances 21 investigating risk factors predisposing to premature stroke, particularly in women, should be among the main targets of epidemiological and genetic stroke investigation. In contrast to female preponderance at younger ages, males increasingly predominated in all age groups after age of 34 years in all the regions.…”