The plasma kallikrein–kinin system and risk of cardiovascular disease in men

Abstract

Summary. Background: The plasma kallikrein-kinin system (PKKS) has been implicated in cardiovascular disease, but activation of the PKKS has not been directly probed in individuals at risk of coronary heart disease (CHD) or stroke. Objective: To determine the involvement of the PKKS, including factor XI, in cardiovascular disease occurring in a nested case-control study from the Second Northwick Park Heart Study (NPHS-II). Methods and results: After a median follow-up of 10.7 years, 287 cases of CHD and stroke had been recorded and 542 age-matched controls were selected. When FXIIa-C1 esterase inhibitor (C1-inhibitor) concentrations were divided into tertiles (lowest tertile as reference), the odds ratios (ORs) at 95% CIs for CHD were 0.52 (0.34-0.80) in the middle tertile and 0.73 (0.49-1.09) in the highest tertile (P = 0.01 for the overall difference; P = 0.01 for CHD and stroke combined). For kallikrein-C1-inhibitor complexes, the ORs for stroke were 0.29 (0.12-0.72) and 0.67 (0.30-1.52) in the middle and high tertiles, respectively (P = 0.02). FXIIa-C1-inhibitor and kallikrein-C1-inhibitor complexes were negatively related to smoking and fibrinogen (P < 0.005). FXIa-inhibitor complexes correlated strongly with FXIIa-inhibitor complexes. Conclusions: Lower levels of inhibitory complexes of the PKKS enzymes and particularly of FXIIa contribute to the risk of CHD and stroke in middle-aged men. This observation supports the involvement of the PKKS in atherothrombosis.

Epidemiologic and clinical data linking factors XI and XII to thrombosis

“…30 In the NPHS-II study, plasma levels of factor XIa complexes (fXIa-C1-INH and fXIa-AT-INH) were not associated with a greater risk of coronary heart disease in middle-aged male participants. 24 In agreement with this conclusion, the RATIO study demonstrated that elevated levels of fXIa complexes, 25 fXI:c, 31 and fXI:Ag 34 were not associated with a greater risk of MI in young women. In contrast to these studies, cross-sectional studies in patients at presention with acute coronary syndrome have demonstrated elevated levels of fXIa activity, 35 as well as fXIa-C1-INH and fXIa-AT-INH complexes.…”

“…24 In contrast, in the Risk of Arterial Thrombosis In relation to Oral contraceptives (RATIO) study, which also measured fXIIa-C1-INH levels, elevated (Ͼ90 th percentile) levels of the complex were associated with an increased risk of stroke, with an OR of 2.1 and a 95% CI of 1.3-3.5. Oral contraceptives increased the risk further.…”

“…29 However, the opposite effect was seen in the same study when fXIIa-C1-INH levels were measured. 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.…”

“…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.…”

Prekallikrein Deficiency in a Dog

“…But, on the other hand, thrombus formation [7] or severe bleeding tendency [4] has been reported in some cases. When a dog has a prolonged aPTT with no clinical symptoms, elucidating the deficient factor is necessary to discriminate between contact factor deficiencies showing no clinical symptoms and hemophilia A or B.…”