Methionine-Loading and Random Homocysteine Tests Have No Added Value in Risk Assessment for Venous and Arterial Thrombosis.

Abstract Hyperhomocysteinemia is a risk factor for venous and arterial thrombosis. Different diagnostic strategies are used to identify subjects at risk of thrombosis, related to hyperhomocysteinemia. Measurements of fasting and methionine-loading levels are usually recommended. Alternatively, random homocysteine measurements may simplify the procedure. Random levels < 10 and > 20 μmol/l are considered to indicate normohomocysteinemia and hyperhomocysteinemia, respectively, while consecutive fasting and methionine-loading tests are required at levels 10–20 μmol/l. We performed a study to assess the most suitable strategy in a large cohort of families with hereditary (index) deficiencies of protein S, protein C or antithrombin. Random, fasting and methionine-loading homocysteine samples were measured in 713 relatives. According to predefined cut-off levels hyperhomocysteinemic and normohomocysteinemic relatives were identified and their absolute risks of thrombosis were compared. Relatives with random homocysteine levels > 20 μmol/l were not at risk of venous or arterial thrombosis compared to relatives with levels < 10 μmol/l (relative risks 0.9 [95% CI, 0.4–2.3] and 1.7 [0.5–5.7], respectively). Fasting hyperhomocysteinemia (homocysteine levels > 18.5 μmol/l) was associated with an increased risk of venous and arterial thrombosis (relative risks 2.6 [1.3–4.8] and 3.7 [1.5–8.4)], respectively) (Table). Relatives with normal fasting homocysteine levels, but methionine-loading hyperhomocysteinemia (homocysteine levels > 58.8 μmol/l) were not at risk; relative risk 0.8 (0.2–1.9) for venous thrombosis and 1.1 (0.2–3.9) for arterial thrombosis. Exclusion of relatives with an index deficiency did not alter the risk estimates, while annual incidences of normohomocysteinemic relatives decreased to 0.19% per year (0.12–0.29), which is comparable with the annual incidence in the normal population. As only fasting homocysteine identified subjects at risk of thrombosis, random homocysteine and methionine-loading tests can be omitted in clinical practice. Venous Thrombosis Observation Relatives Incidence/year (%) Relative Risk years with event (95% CI) (95% CI) * Methionine-loading performed in relatives with no fasting hyperhomocysteinemia Fasting Homocysteine No hyperhomocysteinemia 10408 55 0.53 (0.40–0.69) Reference Hyperhomocysteinemia 804 11 1.37 (0.68–2.45) 2.6(1.3–4.8) Methionine-loading test* No hyperhomocysteinemia 9341 50 0.54 (0.40–0.71) Reference Hyperhomocysteinemia 986 4 0.41 (0.11–1.04) 0.8(0.2–1.9) Arterial Thrombosis Fasting Homocysteine No hyperhomocysteinemia 11096 21 0.19 (0.12–0.29) Reference Hyperhomocysteinemia 1004 7 0.70 (0.28–1.44) 3.7(1.5–8.4) Methionine-loading test* No hyperhomocysteinemia10008 10008 19 0.19 (0.11–0.30) Reference Hyperhomocysteinemia 1000 2 0.20 (0.02–0.72) 1.1(0.2–3.9)

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No added value of the methionine loading test in assessment for venous thrombosis and cardiovascular disease risk

Thrombosis and Haemostasis ◽

10.1160/th05-07-0498 ◽

2006 ◽

Vol 95 (02) ◽

pp. 380-385 ◽

Cited By ~ 3

Author(s):

Miranda Keijzer ◽

Petra Verhoef ◽

George Borm ◽

Henk Blom ◽

Martin den Heijer

Keyword(s):

Cardiovascular Disease ◽

At Risk ◽

Venous Thrombosis ◽

Disease Risk ◽

Cardiovascular Disease Risk ◽

Added Value ◽

Loading Test ◽

Recurrent Venous Thrombosis ◽

Risk For Thrombosis ◽

Methionine Loading Test

SummaryHomocysteine isa risk factor for cardiovascular disease and venous thrombosis. Clinical guidelines differ in their recommendation whether or not to measure homocysteine after methionine loading. In this study, we investigated the added value of the methionine loading test next to fasting homocysteine levels for identifying subjects at risk for venous thrombosis or cardiovascular disease, using Receiver Operating Characteristic (ROC) curves.The analysis was performed in 185 patients with recurrent venous thrombosis, 130 patients with cardiovascular disease and 601 controls.The discriminatory power of the fasting homocysteine measurement alone for identifying subjects at risk of venous thrombosis expressed as the area under the ROC curve (AUC) was 0.61 (95%CI 0.56-0.66). Using both a fasting homocysteine measurement and a methionine loading test together yielded a similar AUC of 0.65 (95%CI 0.60-0.69), indicating no added value of methionine loading next to fasting homocysteine measurement in identifying subjects at risk for thrombosis. Similar results where found for cardiovascular disease, with anAUC of 0.62 (95%CI 0.57-0.67) for the fasting homocysteine measurement alone and an AUC of 0.62 (95%CI 0.57-0.67) for the combination of both the fasting and the postload homocysteine measurement. The methionine loading test has no added value next to measuring fasting homocysteine levels for identifying subjects at risk for venous thrombosis or cardiovascular disease and for that reason should not be used in clinical practice.

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The risk of venous and arterial thrombosis in hyperhomocysteinaemia is low and mainly depends on concomitant thrombophilic defects

Thrombosis and Haemostasis ◽

10.1160/th07-02-0138 ◽

2007 ◽

Vol 98 (08) ◽

pp. 457-463 ◽

Cited By ~ 23

Author(s):

Michiel Coppens ◽

Marlène van de Poel ◽

Saskia Middeldorp ◽

Karly Hamulyák ◽

Ivan Bank ◽

...

Keyword(s):

Risk Factors ◽

Relative Risk ◽

Venous Thrombosis ◽

Arterial Thrombosis ◽

Absolute Risk ◽

Adjusted Relative Risk ◽

Relative Risks ◽

Main Determinants ◽

Mild Hyperhomocysteinaemia ◽

Atherosclerotic Risk Factors

SummaryAs homocysteine-lowering treatment has not reduced the risk of recurrent thrombosis in recent clinical trials, we hypothesized that mild hyperhomocysteinaemia is an epiphenomenon or associated with a low absolute risk of thrombosis. In this retrospective study, we enrolled 478 evaluable first-degree relatives of consecutive patients with venous thrombosis or premature atherosclerosis, and hyperhomocysteinemia. Absolute risks of thrombosis and effects of concomitant thrombophilic defects were compared. Relative risks were adjusted for clustering in families, age, sex, and atherosclerotic risk factors, where appropriate. Annual incidence of venous thrombosis was 0.16% (95% confidence interval [CI], 0.08–0.30) in hyperhomocysteinemic relatives versus 0.11% (CI, 0.05–0.20) in normohomocysteinemic relatives; adjusted relative risk 1.6 (CI, 0.6–4.5). Annual incidences of arterial thrombosis were 0.34% (CI, 0.21–0.52) and 0.24% (CI, 0.15–0.37) in hyperhomocysteinemic and normohomocysteinemic relatives, respectively; adjusted relative risk 1.5 (CI, 0.6–3.5). Concomitance of multiple thrombophilic risk factors increased the risk of venous thrombosis in hyperhomocysteinemic relatives 20 fold, but a comparable effect was demonstrated in normohomocysteinemic relatives. We conclude that hyperhomocysteinaemia is associated with a low absolute risk of venous and arterial thrombosis. Concomitant thrombophilic defects are probably main determinants on the risk of venous thrombosis, rather than hyperhomocysteinaemia itself.

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The Risk of Venous and Arterial Thrombosis in Hyperhomocysteinemic Subjects Is Caused by Elevated Factor VIII:C Levels.

Blood ◽

10.1182/blood.v108.11.273.273 ◽

2006 ◽

Vol 108 (11) ◽

pp. 273-273 ◽

Cited By ~ 1

Author(s):

Willem M. Lijfering ◽

Nic J.G.M. Veeger ◽

Jan-Leendert P. Brouwer ◽

Marlene H.W. van de Poel ◽

Jan van der Meer

Keyword(s):

Relative Risk ◽

Venous Thrombosis ◽

Arterial Thrombosis ◽

Vitamin B6 ◽

Absolute Risk ◽

Factor V Leiden ◽

Protein S ◽

Factor V ◽

Increased Risk ◽

Thrombophilia Screening

Abstract Hyperhomocysteinemia is demonstrated as a risk factor for venous and arterial thrombosis. Experimental evidence suggests that its thrombogenic propensity results from endothelial dysfunction and injury followed by platelet and fibrin formation. However, lowering homocysteine concentrations with vitamin B6, B12 or folic acid has not resulted in a reduced risk of recurrent venous and arterial thrombosis in large prospective clinical trials. This suggests that hyperhomocysteinemia is a surrogate for another thrombophilic related specimen. As high factor VIII:C levels are associated with an increased risk of both venous and arterial thrombosis, and with endothelial injury, we hypothesize that hyperhomocysteinemia and factor VIII:C levels are closely related to each other. Therefore, we performed a study to assess the absolute risk of thrombosis in hyperhomocysteinemia and the effects of elevated factor VIII:C levels on this risk in a large cohort of families with hereditary (index) deficiencies of protein S, protein C or antithrombin. Hyperhomocysteinemia was defined as a fasting plasma homocysteine level above 18.5 μmol/l and factor VIII:C levels were elevated when higher than 150%. A total of 405 relatives were included. Median factor VIII:C levels in hyperhomocysteinemic relatives (n=26, 6%) were 169%, compared to 136% in normohomocysteinemic relatives (P=0.004) (Figure) and were more often elevated (65 vs. 38%, P=0.006). Other thrombophilic defects, including the index deficiencies, factor V Leiden and the prothrombin mutation were equally divided. Hyperhomocysteinemia was associated with an increased risk of venous and arterial thrombosis (relative risk’s 2.6 [1.3–4.8] and 3.7 [1.5–8.4)], respectively). Relatives with elevated factor VIII:C levels were also at risk; relative risk 2.3 (1.4–4.0) for venous thrombosis and 2.3 (1.0–5.1) for arterial thrombosis. After excluding all relatives with elevated factor VIII:C levels, relative risk for venous thrombosis and hyperhomocysteinemia dropped to 1.3 (0.2–9.8) and nil relatives had arterial thrombosis. These results suggest that hyperhomocysteinemia indeed is an epiphenomenon for elevated factor VIII:C levels and therefore homocysteine measurements can be omitted in risk assessment for venous and arterial thrombosis when factor VIII:C measurements are incorporated in thrombophilia screening. Figure Figure

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Antiphospholipid antibodies and thrombosis: association with acquired activated protein C resistance in venous thrombosis and with hyperhomocysteinemia in arterial thrombosis

Thrombosis and Haemostasis ◽

10.1160/th04-03-0138 ◽

2004 ◽

Vol 92 (12) ◽

pp. 1312-1319 ◽

Cited By ~ 11

Author(s):

Jeannine Kassis ◽

Carolyn Neville ◽

Joyce Rauch ◽

Lambert Busque ◽

Erika Chang ◽

...

Keyword(s):

Venous Thrombosis ◽

Antiphospholipid Antibodies ◽

Arterial Thrombosis ◽

Protein C ◽

Complete Blood Count ◽

Tertiary Care ◽

Activated Protein C ◽

Factor V Leiden ◽

Activated Protein C Resistance ◽

Increased Risk

SummaryAlthough antiphospholipid antibodies (aPL) are associated with thrombosis, it is not known who with aPL is at higher risk for thrombosis. It was the aim of this cross-sectional study to investigate how thrombophilic factors contribute to venous or arterial thrombosis in aPL-positive individuals. In outpatient test centres at two tertiary care hospitals, two hundred and eight (208) persons requiring aPL testing were matched by age, gender and centre to 208 persons requiring a complete blood count. Persons were classified as aPL-positive (having anticardiolipin, lupus anticoagulant and/or anti-β2-glycoprotein I antibodies) or aPL-negative. Several thrombophilic factors were studied using logistic regression modelling. Results showed that the aPL-positive group had three-fold more events (37%) than the aPL-negative group (12%). In unadjusted analyses, clinically important associations were observed between factor V Leiden and venous thrombosis, hyperhomocysteinemia and arterial thrombosis, and activated protein C resistance (APCR) and venous thrombosis (OR, 95% CI = 4.00, 1.35-11.91; 4.79, 2.03-11.33; and 2.03, 1.03-3.97, respectively). After adjusting for recruitment group, persons with both APCR and aPL had a three-fold greater risk (OR, 95% CI = 3.31, 1.30-8.41) for venous thrombosis than those with neither APCR nor aPL. Similarly, after adjusting for hypertension, family history of cardiovascular disease, gender and recruitment group, persons with both hyperhomocysteinemia and aPL had a five-fold increased risk (OR, 95% CI = 4.90, 1.37-17.37) for arterial thrombosis compared to those with neither risk factor. In conclusion, APCR phenotype and hyperhomocysteinemia are associated with a higher risk of venous and arterial thrombosis, respectively, in the presence of aPL.

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Abstract 15714: Prediction of Sudden Cardiac Death With Automated High-Throughput Analysis of T-Wave Heterogeneity in Standard 12-Lead Electrocardiogram

Circulation ◽

10.1161/circ.130.suppl_2.15714 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Tuomas Kenttä ◽

Bruce D Nearing ◽

Kimmo Porthan ◽

Jani T Tikkanen ◽

Matti Viitasalo ◽

...

Keyword(s):

At Risk ◽

Relative Risk ◽

Sudden Cardiac Death ◽

General Population ◽

Cardiac Death ◽

Left Ventricular ◽

Adjusted Relative Risk ◽

T Wave ◽

Increased Risk ◽

Patients At Risk

Introduction: Noninvasive identification of patients at risk for sudden cardiac death (SCD) remains a major clinical challenge. Abnormal ventricular repolarization is associated with increased risk of lethal ventricular arrhythmias and SCD. Hypothesis: We investigated the hypothesis that spatial repolarization heterogeneity can identify patients at risk for SCD in general population. Methods: Spatial R-, J- and T-wave heterogeneities (RWH, JWH and TWH, respectively) were automatically analyzed with second central moment technique from standard digital 12-lead ECGs in 5618 adults (46% men; age 50.9±12.5 yrs.) who took part in Health 2000 Study, an epidemiological survey representative of the entire Finnish adult population. During average follow-up of 7.7±1.4 years, a total of 72 SCDs occurred. Thresholds of RWH, JWH and TWH were based on optimal cutoff points from ROC curves. Results: Increased RWH, JWH and TWH (Fig.1) in left precordial leads (V4-V6) were univariately associated with SCD (P<0.001, each). When adjusted with clinical risk markers (age, gender, BMI, systolic blood pressure, cholesterol, heart rate, left ventricular hypertrophy, QRS duration, arterial hypertension, diabetes, coronary heart disease and previous myocardial infarction) JWH and TWH remained as independent predictors of SCD. Increased TWH (≥102μV) was associated with a 1.9-fold adjusted relative risk (95% confidence interval [CI]: 1.2 - 3.1; P=0.011) and increased JWH (≥123μV) with a 2.0-fold adjusted relative risk for SCD (95% CI: 1.2 - 3.3; P=0.004). When both TWH and JWH were above threshold, the adjusted relative risk for SCD was 3.2-fold (95% CI: 1.7 - 6.2; P<0.001). When all heterogeneity measures (RWH, JWH and TWH) were above threshold, the risk for SCD was 3.7-fold (95% CI: 1.6 - 8.6; P=0.003). Conclusions: Automated measurement of spatial J- and T-wave heterogeneity enables analysis of high patient volumes and is able to stratify SCD risk in general population.

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A lower risk of recurrent venous thrombosis in women compared with men is explained by sex-specific risk factors at time of first venous thrombosis in thrombophilic families

Blood ◽

10.1182/blood-2009-04-215418 ◽

2009 ◽

Vol 114 (10) ◽

pp. 2031-2036 ◽

Cited By ~ 42

Author(s):

Willem M. Lijfering ◽

Nic J. G. M. Veeger ◽

Saskia Middeldorp ◽

Karly Hamulyák ◽

Martin H. Prins ◽

...

Keyword(s):

Risk Factors ◽

Relative Risk ◽

Venous Thrombosis ◽

Lifetime Risk ◽

First Episode ◽

Adjusted Relative Risk ◽

Men And Women ◽

Increased Risk ◽

The Difference ◽

Recurrent Venous Thrombosis

Abstract Why men appear to have an increased risk of recurrent venous thrombosis compared with women is unknown. In a cohort study of families with thrombophilia, lifetime risk of recurrent venous thrombosis was assessed in men and women (n = 816). Adjusted relative risk of recurrence was 1.6 (95% CI, 1.3-2.0) in men compared with women. Women were younger at time of their first event (mean, 34 years vs 44 years; P < .001) and at time of recurrence (40 years vs 48 years, P < .001). After excluding provoked first and recurrent venous thrombosis, adjusted relative risk was 1.2 (95% CI, 0.8-1.7), although mean age at recurrence was comparable in men and women (50 years vs 49 years, P = .595). In women with a hormonal first event, median interval between first event and recurrence was 10.4 years versus 2.7 years in men (P < .001). This difference was not observed when only unprovoked events were considered (P = .938). The difference in lifetime risk of recurrent venous thrombosis between men and women in thrombophilic families can be explained by a younger age of women at time of first venous thrombosis due to hormonal risk factors, and a longer interval between a provoked first episode of venous thrombosis and recurrence in women.

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Need for Increased Promotion of Physical Activity Among Adults at Risk for Alzheimer’s Disease: A Brief Report

Journal of Physical Activity and Health ◽

10.1123/jpah.2014-0554 ◽

2015 ◽

Vol 12 (12) ◽

pp. 1601-1604 ◽

Cited By ~ 5

Author(s):

Paul D. Loprinzi

Keyword(s):

Physical Activity ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

At Risk ◽

Family History ◽

Sedentary Behavior ◽

Beneficial Effects ◽

Increased Risk ◽

History Of ◽

Not At Risk

Background:We have a limited understanding of the physical activity (PA) and sedentary levels among individuals at risk and not at risk for developing Alzheimer’s disease (AD), which was the purpose of this study.Methods:Data from the 2003–2004 NHANES were used, from which 3015 participants were evaluated with 416 indicating a family history of AD. Physical activity and sedentary behavior were assessed via accelerometry with individuals at risk for AD self-reporting a family history of AD.Results:For the entire sample, those at risk for AD engaged in more sedentary behavior than those not at risk (494.9 vs. 477.9 min/day, P = .03, respectively). Similarly, those at risk for AD engaged in less total MVPA than those not at risk (22.4 vs. 24.3 min/day, P = .05, respectively). Results were also significant for various subgroups at risk for AD.Conclusion:Despite the beneficial effects of PA in preventing AD and prolonging the survival of AD, adults at risk for AD tend to engage in more sedentary behavior and less PA than those not at risk for AD. This finding even persisted among minorities (Hispanics and non-Hispanic blacks) who are already at an increased risk of developing AD.

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Relation between the Incidence of Invasive Cervical Cancer and the Screening Interval: Is a Five Year Interval Too Long?

Journal of Medical Screening ◽

10.1177/096914139600300307 ◽

1996 ◽

Vol 3 (3) ◽

pp. 140-145 ◽

Cited By ~ 17

Author(s):

Amanda Herbert ◽

K Stein ◽

T N Bryant ◽

Catherine Breen ◽

P Old

Keyword(s):

Cervical Cancer ◽

At Risk ◽

Relative Risk ◽

Short Interval ◽

Invasive Cervical Cancer ◽

Interval Cancers ◽

Pronounced Difference ◽

Screening Interval ◽

Relative Risks ◽

Screening Coverage

Objective –To examine the incidence of invasive cervical cancer per 100 000 women years at risk and relative risk according to screening history among eligible women aged 25–69 in Southampton and South West Hampshire during the three years after completion of the first round of comprehensive screening. Results –There was a significantly higher incidence of invasive cervical cancer in women who had not been screened during the preceding 0.5–5.5 years than in those who had been screened (relative risk (RR) 2.6; 95% confidence interval (CI) 1.6 to 4.3). Among the latter group of women (with interval cancers) there was a significantly higher incidence in those with a long interval of 3.5–5.5 years since their most recent smear than in those with a short interval of 0.5–3.5 years (RR 2.2; 95% CI 1.3 to 3.8). Among women with non-interval cancers, there was a significantly higher incidence among those who had no cytology record than among those who had been screened but were overdue for a smear (RR 3.0; 95% CI 1.2 to 7.3). When screen detected cancers were excluded from the figures the relative risks for all the comparative groups described above were greater, though the 95% confidence limits were wider because the numbers were smaller. The most pronounced difference in incidence was between symptomatic cancers in women with a short screening interval (5.8 per 100 000 women years at risk) and in women with no cytology record (71.3 per 100 000 years at risk). Most cancers were interval cancers (76%) because of the high screening coverage: 89.2% of eligible women aged 25–69 had been screened during the preceding 0.5–5.5 years. The overall incidence per 100 000 women years at risk approached that of interval cancers, and was nearer to that observed in the short than the long interval because 74.7% of women had been screened within 3.5 years. Conclusion –The results confirm the effectiveness of screening but suggest that a five year screening interval may be too long, at least during the early rounds of screening.

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Observation versus antiplatelet therapy as primary prophylaxis for thrombosis in low-risk essential thrombocythemia

Blood ◽

10.1182/blood-2010-01-263319 ◽

2010 ◽

Vol 116 (8) ◽

pp. 1205-1210 ◽

Cited By ~ 137

Author(s):

Alberto Alvarez-Larrán ◽

Francisco Cervantes ◽

Arturo Pereira ◽

Eduardo Arellano-Rodrigo ◽

Virginia Pérez-Andreu ◽

...

Keyword(s):

Risk Factors ◽

Cardiovascular Risk ◽

Venous Thrombosis ◽

Antiplatelet Therapy ◽

Essential Thrombocythemia ◽

Arterial Thrombosis ◽

Primary Prophylaxis ◽

Low Risk ◽

Increased Risk ◽

Risk Patients

Abstract The effectiveness of antiplatelet therapy as primary prophylaxis for thrombosis in low-risk essential thrombocythemia (ET) is not proven. In this study, the incidence rates of arterial and venous thrombosis were retrospectively analyzed in 300 low-risk patients with ET treated with antiplatelet drugs as monotherapy (n = 198) or followed with careful observation (n = 102). Follow-up was 802 and 848 person-years for antiplatelet therapy and observation, respectively. Rates of thrombotic events were 21.2 and 17.7 per 1000 person-years for antiplatelet therapy and observation, respectively (P = .6). JAK2 V617F–positive patients not receiving antiplatelet medication showed an increased risk of venous thrombosis (incidence rate ratio [IRR]: 4.0; 95% CI: 1.2-12.9; P = .02). Patients with cardiovascular risk factors had increased rates of arterial thrombosis while on observation (IRR: 2.5; 95% CI: 1.02-6.1; P = .047). An increased risk of major bleeding was observed in patients with platelet count greater than 1000 × 109/L under antiplatelet therapy (IRR: 5.4; 95% CI: 1.7-17.2; P = .004). In conclusion, antiplatelet therapy reduces the incidence of venous thrombosis in patients with JAK2-positive ET and the rate of arterial thrombosis in patients with associated cardiovascular risk factors. In the remaining low-risk patients, this therapy is not effective as primary prophylaxis of thrombosis, and observation may be an adequate option.

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Increased Risk of Cerebrovascular Events Is Associated with Elevated Factor XI Activity.

Blood ◽

10.1182/blood.v106.11.2626.2626 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2626-2626 ◽

Cited By ~ 1

Author(s):

David T. Yang ◽

Michele M. Flanders ◽

George M. Rodgers

Keyword(s):

Venous Thrombosis ◽

Functional Activity ◽

Arterial Thrombosis ◽

Population Characteristics ◽

Functional Assay ◽

Cerebrovascular Event ◽

Factor Xi ◽

Cerebrovascular Events ◽

Increased Risk ◽

Hs Crp

Abstract High levels of factor XI as measured by antigenic methods have been implicated as a risk factor for deep venous thrombosis, and there is limited evidence that increased factor XI activity as measured by a functional assay is associated with cardiovascular disease. In the current study, we evaluated factor XI antigen, factor XI functional activity and high-sensitivity C-reactive protein (hs-CRP) from 123 patients under the age of 55 with normal prothrombin and partial thromboplastin times undergoing evaluation for a hypercoagulable state. Of the 123 patients, 80 had a history suggestive of arterial thrombosis (65 with stroke symptoms, 13 with transient ischemic attack symptoms, and 2 with other arterial thrombi), 17 had a history of venous thrombosis, and 26 had indeterminate histories for arterial or venous thrombosis. 40 age- matched healthy subjects were used to determine the upper limit of normal for factor XI activity as defined by the 95th percentile value (141%). 17/80 (21%) of patients with arterial thrombosis and 3/17 (18%) of the patients with venous thrombosis had above normal factor XI activity levels. Based on this, those with elevated factor XI activity have a relative risk of 5.3 for a cerebrovascular event. Regression analysis demonstrates that factor XI activity appears to correlate with factor XI antigen level (slope=0.79 and R=0.67), but there is no correlation between factor XI activity or factor XI antigen levels and hs-CRP (R= −.003 and R=.096 respectively). Our findings suggest that elevated factor XI activity is associated with an increased risk for cerebrovascular events and confirms that elevated factor XI levels are also associated with increased risk for venous thrombosis. In addition, assessment of factor XI levels by two methods, both functional activity and antigenic level, appear to correlate with one another to a fair degree suggesting that increased activity is likely related to increased levels of the protein itself. Lastly, lack of correlation with hs-CRP suggests that factor XI is not an acute-phase reactant. Population Characteristics n Mean Age Median Age Range Male:Female Normals 40 39±9 41 23–55 15:25 Arterial Thrombosis 80 42±8 43 20–55 36:44 Venous Thrombosis 17 38±11 37 20–54 7:10 Factor XI ActivityLevels Normal Arterial Thrombosis Venous Thrombosis Factor XI Activity (%) Mean±SD 101±23 136±111 111±36 Median 100 117 113 Range 57–155 55–675 71–196 95th percentile 141 # Cases above 95th percentile 2/40 (5%) 17/80 (21.3%) 3/17 (17.6%)

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