Abstract

The role of the intrinsic coagulation system on the risk of myocardial infarction is unclear. In the Study of Myocardial Infarctions Leiden (SMILE) that included 560 men younger than age 70 with a first myocardial infarction and 646 control subjects, we investigated the risk of myocardial infarction for levels of factor XI (factor XIc) and factor XII (factor XIIc). Furthermore, the risks for factor VIII activity (factor VIIIc) and factor IX activity (factor IXc) were assessed. Factor XIc was 113.0% in patients compared with 109.8% in control subjects (difference, 3.2%; 95% CI, 1.1%-5.4%). The risk of myocardial infarction adjusted for age for men in the highest quintile compared with those in the lowest quintile was 1.8-fold increased (ORadj, 1.8; 95% CI, 1.2-2.7). In contrast, factor XIIc among patients with myocardial infarction was lower than in control subjects, respectively, 93.0% and 98.6% (difference, 5.6%; 95% CI, 3.3%-7.9%). The odds ratio of myocardial infarction for men in the highest quintile versus those in the lowest quintile was 0.4 (ORadj, 0.4; 95% CI, 0.2-0.5). The highest risk was found among men with both high factor XIc and low factor XIIc (analyses in tertiles: ORadj, 6.4; 95% CI, 2.2-18.0). Factor VIIIc increased the risk of myocardial infarction although not dose dependently. Factor IXc increased the risk; odds ratio of myocardial infarction for men in the highest quintile versus those in the lowest quintile was 3.2 (ORadj, 3.2; 95% CI, 2.0-5.1). Thus, factors XIc and XIIc have opposite and synergistic effects on the risk of myocardial infarction in men; factor VIIIc and factor IXc increase the risk.

Introduction

Myocardial infarction occurs when a thrombus evolves on a ruptured atherosclerotic plaque followed by vessel occlusion.1  This exposes tissue factor to blood which triggers the extrinsic system of thrombin generation by the formation of tissue factor (TF)–factor VIIa complex and induces platelet adhesion, activation, and aggregation. The TF-factor VIIa complex activates factor X and factor IX, leading to the generation of thrombin and formation of fibrin.2  Once thrombin is formed, further thrombin is generated by activation of factor V, factor VIII, and factor XI.3  Thrombin generation also leads to activation of thrombin activatable fibrinolysis inhibitor (TAFI) resulting in down-regulation of fibrinolysis.4,5  Inhibition of factor XI in an experimental thrombosis model in rabbits leads to enhanced thrombolysis, thereby showing an antifibrinolytic effect of factor XIa.6  Factor XI inhibition in baboons does not prevent thrombus initiation, but it does seem to reduce thrombus growth rate, overall thrombus mass, and thrombo-occlusion, thereby leading to more favorable outcomes.7  Additionally, factor XI-deficient mice were protective from an induced arterial occlusion, suggesting that therapeutic inhibition of factor XI may be a reasonable strategy for treating or preventing thrombus formation.8  Thus, factor XI acts as a procoagulant and an antifibrinolytic factor, and dysregulation may increase the risk of thrombosis. However, factor XI deficiency does not confer protection against myocardial infarction.9  Elevated levels may even increase the risk,10  similarly to the increased risk of venous thrombosis.11 

Factor XI is part of the intrinsic coagulation system and can be activated by factor XII (Hageman factor) independently from thrombin.12  The traditional view is that low levels of factor XII increase the risk of venous thrombosis. Indeed, in one study factor XII levels were lower in patients who had a venous thrombosis compared with healthy blood donors,13  although in a large casecontrol study we found no relation between factor XII levels and venous thrombosis.14  Several case reports pointed out the occurrence of myocardial infarction in persons with factor XII deficiency.15,16  However, the few studies investigating the risk of myocardial infarction in persons with decreased levels gave conflicting results.10,17  Although coagulation factors such as fibrinogen and factor VII have been investigated intensively, the role of the intrinsic system in the development of thrombosis, including myocardial infarction, remains unclear.

In the Study of Myocardial Infarctions Leiden (SMILE) we investigated factor XI and factor XII coagulant activity in 560 men with a nonfatal myocardial infarction and 646 control subjects from the Netherlands and calculated risks of myocardial infarction with increasing quintiles of activity. Additionally, the roles of factor VIII and factor IX have been investigated as well. We extensively assessed the relationship of factor XI and factor XII with other markers of risk and adjusted the risk of myocardial infarction for cardiovascular risk factors that were found to be associated with these factors.

Materials and methods

Details of the Study of Myocardial Infarctions Leiden (SMILE) have been described elsewhere.18  Briefly, patients were men younger than age 70 with a first myocardial infarction that occurred between January 1990 and January 1996. The control group also consisted of men without a history of myocardial infarction and was frequency matched on age to the patients. Both patients and control subjects were born in the Netherlands. They completed a questionnaire and an interview took place prior to blood draw (see next paragraph). Questions referred to (former) smoking habits and alcohol use, diabetes, and current use of medications. In addition, for patients, diabetes and medication use prior to myocardial infarction was retrieved from discharge letters. A person was classified as having hypertension or hypercholesterolemia if he was taking prescription drugs for these conditions. Blood pressure was measured after a rest of at least 10 minutes with the person sitting in an upright position. The quetelet index was derived by dividing weight (in kilograms) by squared height (in meters), and obesity was defined as an index of 30 kg/m2 or above. All participants gave informed consent, and the study protocol was approved by the Institutional Review Board of the Leiden University Medical Center.

Fasting blood samples were drawn from the antecubital vein in Sarstedt Monovette tubes (Sarstedt, Nümbrecht, Germany) and obtained between July 1994 and February 1997. Blood in the first tube was allowed to clot, and the serum was used for measuring total cholesterol, high-density lipoprotein (HDL)–cholesterol, and triglyceride levels. Total cholesterol and triglyceride concentrations were measured using enzymatic assays adapted to a Hitachi 747 (Boehringer Mannheim, Mannheim, Germany), and HDL-cholesterol concentration was measured on a Hitachi 911 (Boehringer Mannheim). Blood taken in 0.109 mol/L trisodium citrate was centrifuged for 10 minutes at 3000g at room temperature. The citrated plasma was divided into aliquots in multiple tubes and immediately stored at –80°C. Factor XI activity (XIc), factor XII activity (XIIc), and factor IX activity (IXc) were measured in one-stage coagulation assays on a Behring Coagulation System (Dade Behring, Marburg, Germany) with protocols and reagents from the manufacturer. The factor XI and XII coagulant assays were standardized using commercial plasma (Standard Human Plasma from Dade Behring). The assigned values of the manufacturer were used, because at the time of analysis an international standard for either factor was not available. The factor IX coagulant assay was standardized with pooled plasma from more than 150 healthy hospital workers that was calibrated with 2 international standards (NIBSC 99/826 and NIBSC 01/618). Intra-assay variations for the coagulation assays were 6%, 6%, and 5% for factor XIc, XIIc, and IXc, respectively. In 6 patients and 6 control subjects factor IXc was not measured. For the analyses on factor IX levels, persons using oral anticoagulation medication were excluded (134 patients). Factor VIII (VIIIc) was measured in 2 dilutions by a one-stage clotting assay with factor VIII-deficient plasma and automated activated partial thromboplastin time (Organon Teknika, Boxtel, The Netherlands) on a STA (Diagnostic Stago; Boehringer Mannheim). Levels are expressed as IU/dL. Pooled normal plasma, calibrated against the WHO standard factor VIIIc (91/666) was used as a reference. In one control subject factor VIIIc was not measured. The median time between myocardial infarction and blood collection was 2.6 years, with a minimum of 6 months. To evaluate whether coagulation factors decreased after myocardial infarction in our study, we stratified the elapsed time since myocardial infarction into 1-year categories. Elapsed time since myocardial infarction did not relate to any coagulation factor (data not shown).

Means were calculated with standard deviations (SDs) and the appropriate 95% confidence intervals (CIs). Differences between mean values were tested by means of analysis of variance (ANOVA). Quintiles of coagulation factors were defined on the basis of the distribution among control subjects. The lowest quintile was used as a reference category for calculating odds ratios (ORs). Odds ratios were calculated as an approximation of relative risks. Unconditional logistic regression was used to adjust for age (ORadj) and other cardiovascular risk factors. The 95% confidence intervals (95% CIs) of odds ratios were calculated based on the standard errors from the logistic model. Quintiles of total cholesterol, HDL-cholesterol, and triglyceride levels were also defined on the basis of the distribution among control subjects. However, in the logistic regression model the 3 lipid levels were included as continuous variables. Triglyceride levels used in the model were 10log-transformed. SPSS for Windows version 12.0.1 (SPSS, Chicago, IL) was used for all statistical analyses.

Results

Detailed characteristics of patients and control subjects have been described before.18  The mean age of patients was 56.2 years (SD, 9.0 years) and of control subjects 57.3 years (SD, 10.8 years). Risk factors as smoking, obesity, diabetes, hypertension, and hypercholesterolemia were more often found in patients than in control subjects, with the most striking contrasts in younger persons (Table 1).

Table 1.

Characteristics of patients and control subjects



Overall

Younger than 50 y
Characteristic
Patients
Control subjects
Patients
Control subjects
N   560   646   154   160  
Mean age, y (SD)   56.2 (9.0)   57.3 (10.8)   44.4 (4.2)   42.5 (6.9)  
Smoking tobacco use, no. (%)     
    No   211 (37.7)   431 (67.7)   35 (22.7)   94 (58.8)  
    Yes   349 (62.3)   215 (33.3)*  119 (77.3)   66 (41.3)* 
Alcohol use, no. (%)     
    Never   86 (15.4)   64 (9.9)   13 (8.4)   15 (9.4)  
    Occasionally   24 (4.3)   21 (3.3)   4 (2.6)   5 (3.1)  
    Regularly   450 (80.4)   561 (86.6)*  137 (89.0)   140 (87.5)  
Quetelet index,no. (%)     
    Less than 20 kg/m2  5 (0.9)   10 (1.6)   3 (1.9)   4 (2.5)  
    Between 20 and 25 kg/m2  153 (27.4)   186 (28.8)   37 (24.0)   57 (35.6)  
    Between 25 and 30 kg/m2  305 (54.6)   343 (53.2)   80 (51.9)   78 (48.8)  
    At least 30 kg/m2  96 (17.2)   106 (16.4)   34 (22.1)   21 (13.1)* 
Diabetes, no. (%)     
    Absent   534 (95.4)   624 (96.6)   147 (95.5)   157 (98.1)  
    Present   26 (4.6)   22 (3.4)   7 (4.5)   3 (1.9)  
Hypertension, no. (%)     
    Absent   454 (81.1)   539 (83.4)   143 (92.9)   153 (95.6)  
    Present   106 (18.9)   107 (16.6)   11 (7.1)   7 (4.4)  
Hypercholesterolemia, no. (%)     
    Absent   548 (97.9)   635 (98.3)   151 (98.1)   159 (99.4)  
    Present
 
12 (2.1)
 
11 (1.7)
 
3 (1.9)
 
1 (0.6)
 


Overall

Younger than 50 y
Characteristic
Patients
Control subjects
Patients
Control subjects
N   560   646   154   160  
Mean age, y (SD)   56.2 (9.0)   57.3 (10.8)   44.4 (4.2)   42.5 (6.9)  
Smoking tobacco use, no. (%)     
    No   211 (37.7)   431 (67.7)   35 (22.7)   94 (58.8)  
    Yes   349 (62.3)   215 (33.3)*  119 (77.3)   66 (41.3)* 
Alcohol use, no. (%)     
    Never   86 (15.4)   64 (9.9)   13 (8.4)   15 (9.4)  
    Occasionally   24 (4.3)   21 (3.3)   4 (2.6)   5 (3.1)  
    Regularly   450 (80.4)   561 (86.6)*  137 (89.0)   140 (87.5)  
Quetelet index,no. (%)     
    Less than 20 kg/m2  5 (0.9)   10 (1.6)   3 (1.9)   4 (2.5)  
    Between 20 and 25 kg/m2  153 (27.4)   186 (28.8)   37 (24.0)   57 (35.6)  
    Between 25 and 30 kg/m2  305 (54.6)   343 (53.2)   80 (51.9)   78 (48.8)  
    At least 30 kg/m2  96 (17.2)   106 (16.4)   34 (22.1)   21 (13.1)* 
Diabetes, no. (%)     
    Absent   534 (95.4)   624 (96.6)   147 (95.5)   157 (98.1)  
    Present   26 (4.6)   22 (3.4)   7 (4.5)   3 (1.9)  
Hypertension, no. (%)     
    Absent   454 (81.1)   539 (83.4)   143 (92.9)   153 (95.6)  
    Present   106 (18.9)   107 (16.6)   11 (7.1)   7 (4.4)  
Hypercholesterolemia, no. (%)     
    Absent   548 (97.9)   635 (98.3)   151 (98.1)   159 (99.4)  
    Present
 
12 (2.1)
 
11 (1.7)
 
3 (1.9)
 
1 (0.6)
 

Data for patients refer to the period prior to myocardial infarction, apart from quetelet index.

*

Chi-square test; P < .05.

For 1 patient and 1 control subject, quetelet index was missing.

Mean factor XIc among patients with myocardial infarction was 113.0% (CI, 111.5%-114.4%) and varied between 55% and 160%. For control subjects mean factor XIc was 109.8% (CI, 108.2%-111.3%), with a corresponding range between 56% and 194%. Factor XIc in patients was 3.2% (CI, 1.1%-5.4%) higher compared with control subjects. A 10% increase in factor XIc was associated with a 1.09-fold increased in risk of myocardial infarction (ORadj, 1.09; 95% CI, 1.02-1.15). The distribution of patients and control subjects by quintiles of factor XIc is shown in Table 2. The risk of myocardial infarction was increased for each quintile of factor XI compared with the lowest quintile (levels equal or below 94%). In other words, the risk was decreased for men in the lowest quintile compared with those with higher levels. The risk of myocardial infarction adjusted for age for men in the highest quintile compared with those in the lowest quintile was 1.8-fold increased (ORadj, 1.8; 95% CI, 1.2-2.7). For men younger than age 50 even higher risks were found, 3- to 4-fold increased compared with the lowest quintile. Further adjustment for cardiovascular risk factors and factor XIIc increased the odds ratios. Excluding persons who were using aspirin at time of blood draw (128 patients and 36 control subjects) in our overall analyses did not materially change the results, the difference in factor XIc between patients and control subjects remained the same (3.2% [CI, 0.9%-5.5%]). Excluding 134 patients who were using anticoagulants at the time of blood draw increased the difference between patients and control subjects to 5.6% (CI, 3.2%-7.9%). Consequently, the relative risk of myocardial infarction became even more pronounced for each quintile increase of factor XI compared with the lowest quintile and showed a dose-response relationship.

Table 2.

Risk of myocardial infarction with increasing quintile of factor XIc and factor XIIc overall and in men younger than age 50




Patients

Control subjects

OR (95% CI)*

OR (95% CI)

OR (95% CI)
Factor XIc      
    Overall, N   560   646     
        55%-94%   69   133   1§  1§  1§ 
        95%-103%   117   136   1.7 (1.1-2.4)   1.9 (1.3-2.7)   2.0 (1.0-3.8)  
        104%-112%   117   121   1.8 (1.2-2.7)   2.2 (1.5-3.4)   2.7 (1.4-5.3)  
        113%-126%   132   128   2.0 (1.3-2.9)   2.9 (1.9-4.4)   2.7 (1.4-5.3)  
        127%-194%   125   128   1.8 (1.2-2.7)   3.2 (2.1-4.9)   2.5 (1.2-5.1)  
    Younger than 50 y, no.   154   160     
        55%-94%   9   34   1§  1§  1§ 
        95%-103%   31   31   3.4 (1.4-8.4)   4.2 (1.7-10.7)   12.7 (1.4-113.6)  
        104%-112%   39   31   4.1 (1.7-9.9)   5.5 (2.1-14.0)   19.5 (2.1-178.0)  
        113%-126%   30   29   3.3 (1.3-8.3)   4.4 (1.7-11.5)   14.8 (1.6-136.1)  
        127%-194%   45   35   4.4 (1.9-10.5)   6.6 (2.5-17.3)   19.0 (2.0-182.0)  
Factor XIIc      
    Overall, N   560   646     
        23%-79%   144   132   1§  1§  1§ 
        80%-95%   133   132   0.9 (0.6-1.3)   0.8 (0.5-1.1)   1.0 (0.6-1.8)  
        96%-106%   132   122   1.0 (0.7-1.4)   0.8 (0.5-1.1)   1.0 (0.6-1.7)  
        107%-118%   95   131   0.6 (0.4-0.9)   0.5 (0.3-0.7)   0.7 (0.4-1.3)  
        119%-164%   56   129   0.4 (0.2-0.5)   0.2 (0.1-0.4)   0.3 (0.1-0.6)  
    Younger than 50 y, no.   154   160     
        23%-79%   29   32   1§  1§  1§ 
        80%-95%   38   33   1.2 (0.6-2.4)   1.1 (0.5-2.3)   0.7 (0.2-2.0)  
        96%-106%   33   28   1.3 (0.6-2.8)   1.1 (0.5-2.3)   0.9 (0.3-2.7)  
        107%-118%   30   31   1.1 (0.5-2.2)   0.8 (0.4-1.7)   1.0 (0.4-2.7)  
        119%-164%
 
24
 
36
 
0.7 (0.4-1.5)
 
0.4 (0.2-1.0)
 
0.3 (0.1-1.0)
 



Patients

Control subjects

OR (95% CI)*

OR (95% CI)

OR (95% CI)
Factor XIc      
    Overall, N   560   646     
        55%-94%   69   133   1§  1§  1§ 
        95%-103%   117   136   1.7 (1.1-2.4)   1.9 (1.3-2.7)   2.0 (1.0-3.8)  
        104%-112%   117   121   1.8 (1.2-2.7)   2.2 (1.5-3.4)   2.7 (1.4-5.3)  
        113%-126%   132   128   2.0 (1.3-2.9)   2.9 (1.9-4.4)   2.7 (1.4-5.3)  
        127%-194%   125   128   1.8 (1.2-2.7)   3.2 (2.1-4.9)   2.5 (1.2-5.1)  
    Younger than 50 y, no.   154   160     
        55%-94%   9   34   1§  1§  1§ 
        95%-103%   31   31   3.4 (1.4-8.4)   4.2 (1.7-10.7)   12.7 (1.4-113.6)  
        104%-112%   39   31   4.1 (1.7-9.9)   5.5 (2.1-14.0)   19.5 (2.1-178.0)  
        113%-126%   30   29   3.3 (1.3-8.3)   4.4 (1.7-11.5)   14.8 (1.6-136.1)  
        127%-194%   45   35   4.4 (1.9-10.5)   6.6 (2.5-17.3)   19.0 (2.0-182.0)  
Factor XIIc      
    Overall, N   560   646     
        23%-79%   144   132   1§  1§  1§ 
        80%-95%   133   132   0.9 (0.6-1.3)   0.8 (0.5-1.1)   1.0 (0.6-1.8)  
        96%-106%   132   122   1.0 (0.7-1.4)   0.8 (0.5-1.1)   1.0 (0.6-1.7)  
        107%-118%   95   131   0.6 (0.4-0.9)   0.5 (0.3-0.7)   0.7 (0.4-1.3)  
        119%-164%   56   129   0.4 (0.2-0.5)   0.2 (0.1-0.4)   0.3 (0.1-0.6)  
    Younger than 50 y, no.   154   160     
        23%-79%   29   32   1§  1§  1§ 
        80%-95%   38   33   1.2 (0.6-2.4)   1.1 (0.5-2.3)   0.7 (0.2-2.0)  
        96%-106%   33   28   1.3 (0.6-2.8)   1.1 (0.5-2.3)   0.9 (0.3-2.7)  
        107%-118%   30   31   1.1 (0.5-2.2)   0.8 (0.4-1.7)   1.0 (0.4-2.7)  
        119%-164%
 
24
 
36
 
0.7 (0.4-1.5)
 
0.4 (0.2-1.0)
 
0.3 (0.1-1.0)
 
*

Adjusted for age.

Adjusted for age and either factor XIIc or factor XIc, each as continuous factor.

Adjusted for age, either factor XIIc or factor XIc each as a continuous factor; total cholesterol, HDL-cholesterol, and triglyceride levels; quetelet index; smoking; alcohol use; and diabetes, excluding persons having hypertension.

§

Reference group.

Mean factor XIIc among patients with myocardial infarction was lower than in control subjects, respectively, 93.0% (CI, 91.3%-94.6%) and 98.6% (CI, 97.0%-100.2%), with a difference of 5.6% (CI, 3.3%-7.9%). The range among patients varied from 23% to 139%, whereas the range among control subjects varied from 37% to 164%. A 10% increase in factor XIIc was associated with a 0.87-fold decreased risk of myocardial infarction (ORadj, 0.87; 95% CI, 0.82-0.92). The risk of myocardial infarction was decreased for men with factor XIIc levels in the upper 2 quintiles each with levels above 107% (Table 2). The odds ratio of myocardial infarction for men in the highest quintile versus those in the lowest quintile was 0.4 (ORadj, 0.4; 95% CI, 0.2-0.5). Among men younger than age 50 the risk seemed to be decreased only in those with factor XIIc of 119% or more (ORadj, 0.7; 95% CI, 0.4-1.5). Further adjustment for cardiovascular risk factors and factor XIc slightly changed the odds ratios. Excluding persons who were using aspirin at the time of blood draw in our overall analyses did not materially change the results, the difference in factor XIc between patients and control subjects remained the same (5.5 [CI, 3.0-8.1]). However, excluding anticoagulant users in our overall analyses decreased the difference in factor XIIc between patients and control subjects to 3.5% (CI 0.9%-6.0%). Persons with factor XIIc in the highest quintile remained at a decreased risk of myocardial infarction (ORadj, 0.5; 95% CI, 0.4-0.8).

Mean factor VIIIc among patients with myocardial infarction was 126.3 IU/dL (CI, 123.6-129.1 IU/dL) and varied between 51 and 277 IU/dL. For control subjects mean factor VIIIc was 123.4 IU/dL (CI, 120.8-126.0 IU/dL), with a corresponding range between 53 and 273 IU/dL. Factor VIIIc in patients was 2.9 IU/dL (CI, –0.9 to 6.7 IU/dL) higher compared with control subjects. The distribution of patients and control subjects by quintiles of factor VIIIc is shown in Table 3. The risk of myocardial infarction appeared to be increased for most quintiles compared with the lowest quintile, and overall increased slightly after adjustment for cardiovascular risk factors and factor IXc. Mean factor IXc among patients with myocardial infarction was higher than in control subjects, respectively, 96.6% (CI, 95.5%-97.7%) and 93.2% (CI, 92.2%-94.2%), with a difference of 3.4% (CI, 1.9%-4.9%). The range among patients varied from 35% to 135%, whereas the range among control subjects varied from 32% to 134%. The risk of myocardial infarction was increased for men in each quintile compared with the lowest quintile, and even more increased for men younger than age 50 (Table 3). Overall, adjustment for cardiovascular risk factors and factor VIIIc slightly changed the odds ratios.

Table 3.

Risk of myocardial infarction with increasing quintile of factor VIIIc overall and factor IXc




Patients

Control subjects

OR (95% CI)*

OR (95% CI)

OR (95% CI)
Factor VIIIc      
    Overall, N   560   645     
        50-93 IU/dL   86   137   1  1  1 
        94-110 IU/dL   102   122   1.4 (0.9-2.0)   1.4 (0.9-2.1)   2.1 (1.1-3.9)  
        111-130 IU/dL   137   134   1.7 (1.2-2.4)   1.9 (1.3-2.9)   1.8 (1.0-3.5)  
        131-152 IU/dL   134   125   1.8 (1.3-2.7)   2.4 (1.6-3.6)   2.6 (1.3-5.0)  
        153-277 IU/dL   101   127   1.4 (0.9-2.0)   1.5 (1.0-2.4)   1.6 (0.8-3.4)  
    Younger than 50 y, no.   154   160     
        50-93 IU/dL   39   50   1  1  1 
        94-110 IU/dL   37   29   1.7 (0.9-3.3)   1.6 (0.8-3.3)   1.7 (0.6-4.5)  
        111-130 IU/dL   33   42   1.1 (0.6-2.0)   1.1 (0.5-2.0)   0.8 (0.3-2.2)  
        131-152 IU/dL   26   19   1.8 (0.9-3.8)   1.9 (0.9-4.1)   2.1 (0.7-6.4)  
        153-277 IU/dL   19   20   1.2 (0.6-2.6)   1.0 (0.4-2.2)   0.8 (0.2-3.0)  
Factor IXc§      
    Overall, N   420   640     
        12%-82%   40   130   1  1  1 
        83%-91%   91   143   2.5 (1.6-3.9)   2.5 (1.6-3.9)   2.7 (1.4-5.3)  
        92%-97%   93   122   3.0 (1.9-4.8)   3.0 (1.9-4.9)   3.0 (1.5-6.2)  
        98%-104%   105   134   3.1 (2.0-4.9)   3.2 (2.0-5.1)   3.7 (1.8-7.8)  
        105%-135%   91   111   3.2 (2.0-5.1)   3.3 (2.0-5.4)   2.9 (1.3-6.8)  
    Younger than 50 y, no.   119   158     
        12%-82%   17   69   1  1  1 
        83%-91%   22   32   2.6 (1.2-5.6)   2.6 (1.2-5.6)   2.0 (0.6-6.1)  
        92%-97%   26   23   4.1 (1.9-9.0)   4.8 (2.1-10.9)   5.5 (1.7-17.5)  
        98%-104%   32   17   7.0 (3.2-15.6)   9.2 (3.9-21.8)   9.5 (2.7-33.2)  
        105%-135%
 
22
 
17
 
5.0 (2.2-11.4)
 
6.2 (2.6-14.9)
 
3.1 (0.7-13.5)
 



Patients

Control subjects

OR (95% CI)*

OR (95% CI)

OR (95% CI)
Factor VIIIc      
    Overall, N   560   645     
        50-93 IU/dL   86   137   1  1  1 
        94-110 IU/dL   102   122   1.4 (0.9-2.0)   1.4 (0.9-2.1)   2.1 (1.1-3.9)  
        111-130 IU/dL   137   134   1.7 (1.2-2.4)   1.9 (1.3-2.9)   1.8 (1.0-3.5)  
        131-152 IU/dL   134   125   1.8 (1.3-2.7)   2.4 (1.6-3.6)   2.6 (1.3-5.0)  
        153-277 IU/dL   101   127   1.4 (0.9-2.0)   1.5 (1.0-2.4)   1.6 (0.8-3.4)  
    Younger than 50 y, no.   154   160     
        50-93 IU/dL   39   50   1  1  1 
        94-110 IU/dL   37   29   1.7 (0.9-3.3)   1.6 (0.8-3.3)   1.7 (0.6-4.5)  
        111-130 IU/dL   33   42   1.1 (0.6-2.0)   1.1 (0.5-2.0)   0.8 (0.3-2.2)  
        131-152 IU/dL   26   19   1.8 (0.9-3.8)   1.9 (0.9-4.1)   2.1 (0.7-6.4)  
        153-277 IU/dL   19   20   1.2 (0.6-2.6)   1.0 (0.4-2.2)   0.8 (0.2-3.0)  
Factor IXc§      
    Overall, N   420   640     
        12%-82%   40   130   1  1  1 
        83%-91%   91   143   2.5 (1.6-3.9)   2.5 (1.6-3.9)   2.7 (1.4-5.3)  
        92%-97%   93   122   3.0 (1.9-4.8)   3.0 (1.9-4.9)   3.0 (1.5-6.2)  
        98%-104%   105   134   3.1 (2.0-4.9)   3.2 (2.0-5.1)   3.7 (1.8-7.8)  
        105%-135%   91   111   3.2 (2.0-5.1)   3.3 (2.0-5.4)   2.9 (1.3-6.8)  
    Younger than 50 y, no.   119   158     
        12%-82%   17   69   1  1  1 
        83%-91%   22   32   2.6 (1.2-5.6)   2.6 (1.2-5.6)   2.0 (0.6-6.1)  
        92%-97%   26   23   4.1 (1.9-9.0)   4.8 (2.1-10.9)   5.5 (1.7-17.5)  
        98%-104%   32   17   7.0 (3.2-15.6)   9.2 (3.9-21.8)   9.5 (2.7-33.2)  
        105%-135%
 
22
 
17
 
5.0 (2.2-11.4)
 
6.2 (2.6-14.9)
 
3.1 (0.7-13.5)
 
*

Adjusted for age.

Adjusted for age and either factor IX (excluding anticoagulant users) or factor VIIIc, each as a continuous factor.

Adjusted for age, either factor IX (excluding anticoagulant users) or factor VIIIc each as a continuous factor; total cholesterol, HDL-cholesterol, and triglyceride levels; quetelet index; smoking; alcohol use; and diabetes, excluding individuals having hypertension.

§

Excludes anticoagulant users.

Reference group.

In control subjects no associations were found between factor XIc and smoking, alcohol use, or diabetes (Table 4). Obese persons with a quetelet index of 30 kg/m2 or above had higher levels of factor XIc compared with lean persons with a quetelet index below 20 kg/m2. No associations were found between factor XIIc and any of these cardiovascular risk factors. Systolic and diastolic blood pressures were not associated with factor XIc or factor XIIc. Hypertension as determined by medication use was not associated with clotting factor levels; the difference in factor XIc between 107 men with hypertension versus 539 without hypertension was –2.2% (CI, –6.4% to 1.9%) and in factor XIIc –1.9% (CI, –6.4% to 2.5%). Factor XIc was associated with total cholesterol levels and with triglyceride levels in control subjects (Table 5). Factor XIc increased with every increase in quintile of total cholesterol and triglyceride level. No associations were found with HDL-cholesterol levels. Similar results were found for factor XIIc. Hypercholesterolemia as determined by medication use was not associated with levels; the difference in factor XIc between 11 men with hypercholesterolemia versus 635 men without hypercholesterolemia was 0.2% (CI, –11.7% to 12.2%) and in factor XIIc 8.2% (CI, –4.6% to 20.9%).

Table 4.

Cardiovascular risk factors among control subjects and the association with factor XIc and factor XIIc


Risk factor

No. of subjects

Mean factor XIc, % (CI)

P*

Mean factor XIIc, % (CI)

P*
Smoking tobacco use      
    Never   117   107.0 (103.7-110.3)    98.4 (94.5-102.3)   
    Former   314   110.2 (107.9-112.5)    99.6 (97.2-101.9)   
    Current   215   110.6 (107.9-113.3)   .25   97.3 (94.4-100.3)   .5  
Alcohol use      
    Never   64   106.1 (100.6-111.4)    98.3 (93.1-103.4)   
    Occasionally   21   109.0 (103.1-114.9)    96.2 (86.9-105.5)   
    Regularly   561   110.0 (108.3-111.6)   .65   98.7 (96.9-100.5)   .9  
Quetelet index      
    Less than 20 kg/m2  10   106.7 (92.0-121.4)    97.8 (86.0-109.6)   
    Between 20 and 25 kg/m2  186   104.0 (101.5-106.5)    96.3 (93.1-99.4)   
    Between 25 and 30 kg/m2  343   111.4 (109.3-113.6)    99.0 (96.7-101.3)   
    At least 30 kg/m2  106   114.3 (110.2-118.4)   <.001   101.2 (97.4-105.0)   .3  
Diabetes      
    Absent   624   109.7 (108.1-111.3)    98.7 (97.0-100.3)   
    Present
 
22
 
111.0 (101.1-120.8)
 
.78
 
96.6 (86.9-106.2)
 
.6
 

Risk factor

No. of subjects

Mean factor XIc, % (CI)

P*

Mean factor XIIc, % (CI)

P*
Smoking tobacco use      
    Never   117   107.0 (103.7-110.3)    98.4 (94.5-102.3)   
    Former   314   110.2 (107.9-112.5)    99.6 (97.2-101.9)   
    Current   215   110.6 (107.9-113.3)   .25   97.3 (94.4-100.3)   .5  
Alcohol use      
    Never   64   106.1 (100.6-111.4)    98.3 (93.1-103.4)   
    Occasionally   21   109.0 (103.1-114.9)    96.2 (86.9-105.5)   
    Regularly   561   110.0 (108.3-111.6)   .65   98.7 (96.9-100.5)   .9  
Quetelet index      
    Less than 20 kg/m2  10   106.7 (92.0-121.4)    97.8 (86.0-109.6)   
    Between 20 and 25 kg/m2  186   104.0 (101.5-106.5)    96.3 (93.1-99.4)   
    Between 25 and 30 kg/m2  343   111.4 (109.3-113.6)    99.0 (96.7-101.3)   
    At least 30 kg/m2  106   114.3 (110.2-118.4)   <.001   101.2 (97.4-105.0)   .3  
Diabetes      
    Absent   624   109.7 (108.1-111.3)    98.7 (97.0-100.3)   
    Present
 
22
 
111.0 (101.1-120.8)
 
.78
 
96.6 (86.9-106.2)
 
.6
 
*

P value of ANOVA.

For 1 control subject quetelet index was missing.

Table 5.

Factor XIc and factor XIIc by quintile of total cholesterol, HDL cholesterol, and triglyceride levels among control subjects




No. of subjects

Mean factor XIc, % (CI)

Mean Factor XIIc, % (CI)
Total cholesterol level,*mM    
    Less than 5.02   128   102.1 (99.0-105.1)   91.6 (88.2-95.0)  
    5.02-5.57   129   107.3 (104.1-110.5)   98.5 (95.1-102.0)  
    5.58-6.08   129   108.3 (104.9-111.6)   96.4 (92.6-100.2)  
    6.09-6.79   128   112.1 (108.6-115.8)   101.1 (97.3-104.9)  
    At least 6.80   131   118.6 (115.0-122.2)   105.0 (101.3-108.8)  
    P   <.001   <.001  
HDL cholesterol level,mM    
    Less than 1.06   128   106.8 (103.3-110.3)   94.7 (91.0-98.4)  
    1.06-1.22   128   111.9 (108.0-115.7)   97.8 (94.3-101.4)  
    1.23-1.38   130   109.6 (106.2-113.0)   99.1 (95.5-102.7)  
    1.39-1.61   129   111.8 (108.7-115.0)   102.3 (98.5-106.2)  
    At least 1.62   128   108.6 (105.0-112.2)   98.9 (95.0-102.7)  
    P   .20   .08  
Triglyceride level,§mM    
    Less than 0.83   125   105.9 (102.6-109.3)   96.1 (92.5-99.6)  
    0.83-1.09   131   106.4 (102.9-109.9)   95.3 (91.5-99.1)  
    1.10-1.41   131   109.4 (106.1-112.8)   98.0 (94.2-101.7)  
    1.42-2.03   128   111.3 (107.9-114.7)   101.3 (97.7-105.0)  
    At least 2.04   130   115.5 (111.8-119.1)   102.2 (98.3-105.8)  
    P
 

 
<.001
 
.03
 



No. of subjects

Mean factor XIc, % (CI)

Mean Factor XIIc, % (CI)
Total cholesterol level,*mM    
    Less than 5.02   128   102.1 (99.0-105.1)   91.6 (88.2-95.0)  
    5.02-5.57   129   107.3 (104.1-110.5)   98.5 (95.1-102.0)  
    5.58-6.08   129   108.3 (104.9-111.6)   96.4 (92.6-100.2)  
    6.09-6.79   128   112.1 (108.6-115.8)   101.1 (97.3-104.9)  
    At least 6.80   131   118.6 (115.0-122.2)   105.0 (101.3-108.8)  
    P   <.001   <.001  
HDL cholesterol level,mM    
    Less than 1.06   128   106.8 (103.3-110.3)   94.7 (91.0-98.4)  
    1.06-1.22   128   111.9 (108.0-115.7)   97.8 (94.3-101.4)  
    1.23-1.38   130   109.6 (106.2-113.0)   99.1 (95.5-102.7)  
    1.39-1.61   129   111.8 (108.7-115.0)   102.3 (98.5-106.2)  
    At least 1.62   128   108.6 (105.0-112.2)   98.9 (95.0-102.7)  
    P   .20   .08  
Triglyceride level,§mM    
    Less than 0.83   125   105.9 (102.6-109.3)   96.1 (92.5-99.6)  
    0.83-1.09   131   106.4 (102.9-109.9)   95.3 (91.5-99.1)  
    1.10-1.41   131   109.4 (106.1-112.8)   98.0 (94.2-101.7)  
    1.42-2.03   128   111.3 (107.9-114.7)   101.3 (97.7-105.0)  
    At least 2.04   130   115.5 (111.8-119.1)   102.2 (98.3-105.8)  
    P
 

 
<.001
 
.03
 
*

Cholesterol levels were missing for 1 control subject.

P value of ANOVA comparing factor XIc or factor XIIc by quintiles of each lipid.

HDL-cholesterol levels were missing for 3 control subjects.

§

Triglyceride levels were missing for 1 control subject.

Among control subjects factor XIc was associated with factor XIIc with every 1% increase in factor XIIc factor XIc increased with 0.4% (95% CI, 0.3%-0.5%). To disentangle the effect of factor XIIc from factor XIc, we looked at the effect of each factor adjusted for the other. Because univariate effects were opposite, and levels were associated in the same direction, adjustment led to higher risk estimates, that is, 3-fold increased risk (OR, 3.2; 95% CI, 2.1-4.9) for the highest quintile of factor XI, and 80% reduced risk (OR, 0.2; 95% CI, 0.1-0.4) for the highest quintile of factor XII (Table 2). Further adjustment for total cholesterol, HDL-cholesterol, and triglyceride levels and quetelet index did not much affect the odds ratios, neither did adjustment for factor IXc or factor VIIIc.

Tertiles were calculated based on the distribution among control subjects. Overall, men in the highest tertile of factor XIc had a 1.5-fold increased risk of myocardial infarction compared with men in the lowest tertile (ORadj, 1.5; 95% CI, 1.1-2.0). In contrast, men in the highest tertile of factor XIIc had a 60% decreased risk (ORadj, 0.4; 95% CI, 0.3-0.6) compared with those in the lowest tertile. The highest risk of myocardial infarction was found among men in the highest tertile of factor XIc and the lowest tertile of factor XIIc (ORadj, 6.4; 95% CI, 2.2-18.0) compared with men with the lowest factor XIc and highest factor XIIc tertiles (Table 6). Further adjustment for cardiovascular risk factors increased the odds ratios.

Table 6.

Combined risk of myocardial infarction by tertiles of factor XIc and factor XIIc


FXIc/FXIIc

Patients

Control subjects

OR (95% CI)*

OR (95% CI)
FXIc less than 100%     
    FXIIc more than 109%   5   26   1  1 
    FXIIc 91%-109%   44   72   3.3 (1.2-9.3)   4.5 (0.5-38.9)  
    FXIIc less than 91%   82   110   4.1 (1.5-11.1)   7.4 (0.9-61.4)  
FXIc 100%-116%     
    FXIIc more than 109%   28   76   1.9 (0.7-5.4)   2.5 (0.3-22.5)  
    FXIIc 91%-109%   84   85   5.3 (1.9-14.6)   15.0 (1.8-122.0)  
    FXIIc less than 91%   114   62   9.9 (3.6-27.2)   17.6 (2.1-145.0)  
FXIc more than 116%     
    FXIIc more than 109%   80   111   3.7 (1.4-10.1)   7.4 (0.9-60.5)  
    FXIIc 91%-109%   69   59   6.1 (2.2-17.0)   5.6 (0.6-47.9)  
    FXIIc less than 91%
 
54
 
45
 
6.4 (2.2-18.0)
 
11.6 (1.4-98.5)
 

FXIc/FXIIc

Patients

Control subjects

OR (95% CI)*

OR (95% CI)
FXIc less than 100%     
    FXIIc more than 109%   5   26   1  1 
    FXIIc 91%-109%   44   72   3.3 (1.2-9.3)   4.5 (0.5-38.9)  
    FXIIc less than 91%   82   110   4.1 (1.5-11.1)   7.4 (0.9-61.4)  
FXIc 100%-116%     
    FXIIc more than 109%   28   76   1.9 (0.7-5.4)   2.5 (0.3-22.5)  
    FXIIc 91%-109%   84   85   5.3 (1.9-14.6)   15.0 (1.8-122.0)  
    FXIIc less than 91%   114   62   9.9 (3.6-27.2)   17.6 (2.1-145.0)  
FXIc more than 116%     
    FXIIc more than 109%   80   111   3.7 (1.4-10.1)   7.4 (0.9-60.5)  
    FXIIc 91%-109%   69   59   6.1 (2.2-17.0)   5.6 (0.6-47.9)  
    FXIIc less than 91%
 
54
 
45
 
6.4 (2.2-18.0)
 
11.6 (1.4-98.5)
 

For patients, N = 560; for control subjects, N = 646.

*

Adjusted for age.

Adjusted for age, total cholesterol, HDL-cholesterol, and triglyceride levels; quetelet index; smoking; alcohol use; and diabetes, excluding persons having hypertension.

Reference group.

Discussion

Although positively associated, levels of factors XIc and XIIc had opposite and synergistic effects on the risk of myocardial infarction. Higher factor XIc increased the risk, whereas higher factor XIIc decreased the risk (ie, low factor XIIc increased the risk of myocardial infarction). Additionally, factor VIIIc and factor IXc increase the risk of myocardial infarction in men.

In our Study of Myocardial Infarctions Leiden (SMILE) high factor XIc increased the risk of myocardial infarction, which is in accordance with a Swiss case-control study that included 200 patients with a history of myocardial infarction.10  Factor XIc has procoagulant and antifibrinolytic effects; thus, an increased risk of myocardial infarction in the presence of high factor XIc was to be expected and is in line with studies on venous thrombosis.11  However, the results of a recently published case-control study that included young women did not find a difference in level between 200 women with a first myocardial infarction and control subjects.19 

High factor XIIc decreased the risk of myocardial infarction in our study. In the second Northwick Park Heart Study among 1153 men aged 50 to 61 years in which only 104 coronary heart disease events occurred during the 7.8 years of follow-up, plasma factor XIIa was an independent risk factor. Men in the upper third had a higher risk compared with those in the middle tertile, but also those in the lower third seemed to have a higher risk.20  In a second analysis that included 1745 men high incidence rates were only found for those with high factor XIIa, with similar rates in the first and second third.21  In contrast, in the West of Scotland Coronary Prevention Study factor XIIa antigen did not predict the risk of a coronary event,22  neither did factor XIIc and antigen in other smaller studies.10,23  Our results could also be interpreted such that low factor XIIc increased the risk of myocardial infarction, which is in correspondence to the lower levels found in patients with venous thrombosis compared with healthy blood donors,13  although some studies had different results.14 

Factor VIIIc increased the risk of myocardial infarction about 1.4-fold or more, although not dose dependently. In the Risk of Arterial Thrombosis In relation with Oral Contraceptive use (RATIO) study, in which factor VIIIc was measured in the exact same way, the risk was more clearly increased among young women. In that particular study the risk decreased after adjustment for von Willebrand factor (VWF).19  Follow-up studies have also found associations between factor VIII and ischemic heart disease in men24-26  and a risk which reduced after adjustment for VWF.26  Factor IXc increased the risk of myocardial infarction, even more strongly among young men. This finding is in line with the results of the RATIO study among young women.19 

The risk of myocardial infarction was highest for men with both high factor XIc and low XIIc. This would suggest that the effect of factor XII on risk is not by activation of factor XI, but by an alternative mechanism. Previous studies have suggested that plasma levels of factor XIIa are related to plasma levels of cholesterol and triglyceride,23,27,28  but not HDL cholesterol.22  The present study corroborates these findings. However, we did not find any associations among factor XIIc and obesity, smoking, alcohol use, diabetes, or blood pressure, which is in contrast to a study among 2464 men aged 51 to 62 years in which positive associations were found between factor XIIa with body mass index, smoking, and blood pressure.27  Even though associations between factor XIIc and lipid levels clearly exist, the effect of factor XIIc on the risk of myocardial infarction remained present for men in the highest quintiles after adjusting for lipid levels and other cardiovascular risk factors, indicating that factor XIIc itself seems to have an effect on myocardial infarction.

Our results are in line with the current concept of coagulation and that in contrast to factor XI, factor XII is not involved in physiologic thrombin and fibrin formation. Patients deficient for factor XII do not bleed, and, although factor XII is essential for contact activation and the activated partial thromboplastin time, it has been assumed that factor XII does not contribute to clot formation. In contrast, factor XI is involved in normal thrombin and fibrin formation, and elevated levels of factor XI have previously been found to be associated with an increased risk of venous thrombosis.11  Also, factor XI-deficient mice were protected in models of arterial thrombosis.8 

However, a recent report showed that factor XII–deficient mice were protected in a model of lethal pulmonary embolism and had a defective arterial thrombosis formation, suggesting that factor XII also contributes to thrombin and fibrin formation.29  These results are in contradiction with our epidemiologic findings, in which we found an increased risk of myocardial infarction with low factor XIIc. One of the explanations might be that humans have evolved to a different mechanism of coagulation than mice. The presence of atherosclerosis plays an important role in the occurrence of myocardial infarction in humans, whereas vessels of the mice used in the models clearly differ in this aspect. An alternative explanation is that the potential functions of factor XII only become apparent at certain concentrations of factor XII. In our epidemiologic study, the concentration of factor XIIc in the subjects was not below 23%. In the mouse study, only homozygote-deficient mice were protected against arterial thrombosis. The heterozygote mice showed similar results compared with mice containing normal levels of factor XII, with nearly all vessels containing thrombi, a slightly lower time to occlusion and slightly more platelets per surface area.29  Because the used models were not designed or sensitive for enhanced thrombus formation, it can therefore not be excluded that heterozygote mice had enhanced thrombus formation. Taken together and on the basis of our findings, we can then speculate that lower levels of factor XII result in enhanced thrombus formation by decreased fibrinolysis or effects on inflammation and complement activation.30,31 

By necessity we studied patients who survived the myocardial infarction. It cannot be excluded that patients who died during the acute phase of the myocardial infarction had higher or lower coagulation levels. We think this is unlikely, however, because survival of a person after myocardial infarction is influenced by other factors, such as patient-induced delay and delay in providing effective assistance, which affect the timeframe from onset of symptoms to the start of interventions such as thrombolytic therapy.32  Several other factors influencing 30-day mortality are the level of systolic blood pressure, heart rate, Killip class, and localization of myocardial infarction.33  It does not seem likely that these 4 coagulation factors would play a role in this.

In conclusion, our results show that factors XIc and XIIc have an opposite and synergistic effect on the risk of myocardial infarction. If factor XIIc may be a new target for antithrombotic therapies as suggested before29  remains to be established. Both factor VIIIc and factor IXc increase the risk of myocardial infarction among men.

Authorship

Contribution: C.J.M.D. designed the overall study, performed the data collection and statistical analyses, and drafted the manuscript; J.C.M.M. designed the present study and was responsible for execution of the assays and participated in the writing of the manuscript; and F.R.R. designed the overall study and critically reviewed the analyses and the manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Prepublished online as Blood First Edition Paper, August 24, 2006; DOI 10.1182/blood-2005-12-023697.

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.

We thank Dr T. Renné, University of Würzburg, Germany, for sharing his data on the factor XII–deficient mice before publication. We thank the cardiologists of the departments of cardiology, Leiden University Medical Center; the general hospital Diaconessenhuis Leiden and F. J. M. van der Meer, head of the Leiden Anticoagulant Clinic, for their kind cooperation; and J. H. M. Souverijn for his assistance with the lipid measurements. We thank T. Visser for drawing blood samples and the personnel of the Department of Experimental Vascular Medicine of the Academic Medical Center for performing the laboratory measurements. We thank J. J. Schreijer and I. de Jonge for their secretarial and administrative support. We also express our gratitude to all individuals who participated in the Study of Myocardial Infarctions Leiden.

This work was supported by the Netherlands Heart Foundation (grant no. 92.345).

1
DeWood MA, Spores J, Notske R, et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction.
N Engl J Med
.
1980
;
303
:
897
-902.
2
Davie EW, Fujikawa K, Kisiel W. The coagulation cascade: initiation, maintenance, and regulation.
Biochemistry
.
1991
;
30
:
10363
-10370.
3
von dem Borne PAK, Meijers JCM, Bouma BN. Feedback activation of factor XI by thrombin in plasma results in additional formation of thrombin that protects fibrin clots from fibrinolysis.
Blood
.
1995
;
86
:
3035
-3042.
4
von dem Borne PAK, Bajzar L, Meijers JCM, Nesheim ME, Bouma BN. Thrombin-mediated activation of factor XI results in a thrombin-activatable fibrinolysis inhibitor-dependent inhibition of fibrinolysis.
J Clin Invest
.
1997
;
99
:
2323
-2327.
5
Bouma BN, Meijers JCM. Fibrinolysis and the contact system: a role for factor XI in the down-regulation of fibrinolysis.
Thromb Haemost
.
1999
;
82
:
243
-250.
6
Minnema MC, Friederich PW, Levi M, et al. Enhancement of rabbit jugular vein thrombolysis by neutralization of factor XI. In vivo evidence for a role of factor XI as an anti-fibrinolytic factor.
J Clin Invest
.
1998
;
101
:
10
-14.
7
Gruber A, Hanson SR. Factor XI-dependence of surface- and tissue factor-initiated thrombus propagation in primates.
Blood
.
2003
;
102
:
953
-955.
8
Wang X, Cheng Q, Xu L, et al. Effects of factor IX or factor XI deficiency on ferric chloride-induced carotid artery occlusion in mice.
J Thromb Haemost
.
2005
;
3
:
695
-702.
9
Salomon O, Steinberg DM, Dardik R, et al. Inherited factor XI deficiency confers no protection against acute myocardial infarction.
J Thromb Haemost
.
2003
;
1
:
658
-661.
10
Merlo C, Wuillemin WA, Redondo M, et al. Elevated levels of plasma prekallikrein, high molecular weight kininogen and factor XI in coronary heart disease.
Atherosclerosis
.
2002
;
161
:
261
-267.
11
Meijers JCM, Tekelenburg WLH, Bouma BN, Bertina RM, Rosendaal FR. High levels of coagulation factor XI as a risk factor for venous thrombosis.
N Engl J Med
.
2000
;
342
:
696
-701.
12
Kurachi K, Fujikawa K, Davie EW. Mechanism of activation of bovine factor XI by factor XII and factor XIIa.
Biochemistry
.
1980
;
19
:
1330
-1338.
13
Gallimore MJ, Harris SL, Jones DW, Winter M. Plasma levels of factor XII, prekallikrein and high molecular weight kininogen in normal blood donors and patients having suffered venous thrombosis.
Thromb Res
.
2004
;
114
:
91
-96.
14
Koster T, Rosendaal FR, Briët E, Vandenbroucke JP. John Hageman's factor and deep-vein thrombosis: Leiden Thrombophilia Study.
Br J Haematol
.
1994
;
87
:
422
-424.
15
Lodi S, Isa L, Pollini E, Bravo AF, Scalvini A. Defective intrinsic fibrinolytic activity in a patient with severe factor XII-deficiency and myocardial infarction.
Scand J Haematol
.
1984
;
33
:
80
-82.
16
Penny WJ, Colvin BT, Brooks N. Myocardial infarction with normal coronary arteries and factor XII deficiency.
Br Heart J
.
1985
;
53
:
230
-234.
17
Halbmayer WM, Haushofer A, Radek J, et al. Prevalence of factor XII (Hageman factor) deficiency among 426 patients with coronary heart disease awaiting cardiac surgery.
Coron Artery Dis
.
1994
;
5
:
451
-454.
18
Doggen CJM, Manger Cats V, Bertina RM, Rosendaal FR. Interaction of coagulation defects and cardiovascular risk factors: increased risk of myocardial infarction associated with factor V Leiden or prothrombin 20210A.
Circulation
.
1998
;
97
:
1037
-1041.
19
Tanis BC, Algra A, van der Graaf Y, Helmerhorst FM, Rosendaal FR. Procoagulant factors and the risk of myocardial infarction in young women.
Eur J Haematol
.
2006
;
77
:
67
-73.
20
Cooper JA, Miller GJ, Bauer KA, et al. Comparison of novel hemostatic factors and conventional risk factors for prediction of coronary heart disease.
Circulation
.
2000
;
102
:
2816
-2822.
21
Zito F, Drummond F, Bujac SR, et al. Epidemiological and genetic associations of activated factor XII concentration with factor VII activity, fibrinopeptide A concentration, and risk of coronary heart disease in men.
Circulation
.
2000
;
102
:
2058
-2062.
22
Lowe GDO, Rumley A, McMahon AD, et al. Interleukin-6, fibrin D-dimer, and coagulation factors VII and XIIa in prediction of coronary heart disease.
Arterioscler Thromb Vasc Biol
.
2004
;
24
:
1529
-1534.
23
Kelleher CC, Mitropoulos KA, Imeson J, et al. Hageman factor and risk of myocardial infarction in middle-aged men.
Atherosclerosis
.
1992
;
97
:
67
-73.
24
Meade TW, Cooper JA, Stirling Y, et al. Factor VIII, ABO blood group and the incidence of ischaemic heart disease.
Br J Haematol
.
1994
;
88
:
601
-607.
25
Folsom AR, Wu KK, Rosamond WD, Sharrett AR, Chambless LE. Prospective study of hemostatic factors and incidence of coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study.
Circulation
.
1997
;
96
:
1102
-1108.
26
Rumley A, Lowe GDO, Sweetnam PM, Yarnell JWG, Ford RP. Factor VIII, von Willebrand factor and the risk of major ischaemic heart disease in the Caerphilly Heart Study.
Br J Haematol
.
1999
;
105
:
110
-116.
27
Miller GJ, Esnouf MP, Burgess AI, Cooper JA, Mitchell JP. Risk of coronary heart disease and activation of factor XII in middle-aged men.
Arterioscler Thromb Vasc Biol
.
1997
;
17
:
2103
-2106.
28
Altieri P, Devoto E, Spallarossa P, et al. Acute coronary syndromes do not promote prolonged in vivo FXII-dependent prothrombotic activity.
Thromb Res
.
2005
;
115
:
65
-72.
29
Renné T, Pozgajová M, Grüner S, et al. Defective thrombus formation in mice lacking coagulation factor XII.
J Exp Med
.
2005
;
202
:
271
-281.
30
Herwald H, Morgelin M, Olsen A, et al. Activation of the contact-phase system on bacterial surfaces: a clue to serious complications in infectious diseases.
Nat Med
.
1998
;
4
:
298
-302.
31
Ghebrehiwet B, Silverberg M, Kaplan AP. Activation of the classical pathway of complement by Hageman factor fragment.
J Exp Med
.
1981
;
153
:
665
-676.
32
Leitch JW, Birbara T, Freedman B, Wilcox I, Harris PJ. Factors influencing the time from onset of chest pain to arrival at hospital.
Med J Aust
.
1989
;
150
:
6
-10.
33
Lee KL, Woodlief LH, Topol EJ, et al. Predictors of 30-day mortality in the era of reperfusion for acute myocardial infarction. Results from an international trial of 41,021 patients. GUSTO-I Investigators.
Circulation
.
1995
;
91
:
1659
-1668.