Background

Albuminuria and estimated glomerular filtration rate (eGFR) are each associated with increased risk for cognitive impairment, but their joint association is unknown.

Study Design

Prospective cohort study.

Setting and Participants

A US national sample of 19,399 adults without cognitive impairment at baseline participating in the REGARDS )REasons for Geographic And Racial Disparities in Stroke) study.

Predictors

Albuminuria was assessed by the urine albumin-creatinine ratio (UACR) and GFR was estimated using the CKD-EPI (CKD Epidemiology Collaboration) equation.

Outcomes

Incident cognitive impairment was defined as a score of 4 or less on the Six-item Screener at the last follow-up visit.

Results

Over a mean follow-up of 3.8 ± 1.5 years, UACR 30 – 299 and ≥300 mg/g were independently associated with 31% and 57% higher risk for cognitive impairment, respectively, relative to individuals with UACR <10 mg/g. This finding was strongest among those with high eGFR and attenuated at lower levels (P=0.04 for trend). Relative an eGFR ≥60 ml/min/1.73m2, eGFR <60 ml/min/1.73m2 was not independently associated with cognitive impairment. However, after stratifying by UACR, eGFR <60 ml/min/1.73m2 was associated with 30% higher risk for cognitive impairment among participants with UACR <10 mg/g but not higher UACR levels (P=0.04 for trend).

Limitations

single measure of albuminuria and eGFR, screening test of cognition

Conclusions

When eGFR was preserved, albuminuria independently associated with incident cognitive impairment. When albuminuria was <10 mg/g, low eGFR independently associated with cognitive impairment. Albuminuria and low eGFR are complementary but not additive risk factors for incident cognitive impairment.

Inflammation biomarkers, including higher high-sensitivity C-reactive protein (hsCRP) levels, higher white blood cell (WBC) counts, and lower serum albumin levels, are associated with an increased risk of all-cause mortality. Many studies have examined these biomarkers individually, but less is known about their joint association with mortality. hsCRP, WBC count, and serum albumin were measured at baseline in the Reasons for Geographic and Racial Differences in Stroke Study cohort members, who were enrolled in 2003–2007. Over 4.5 years, there were 1,062 deaths in 17,845 participants. High-risk categories were defined as hsCRP or WBC levels above the 75th percentile (5.1 mg/L and 6.9 × 109 cells/L, respectively) and albumin levels below the 25th percentile (4.00 g/dL). The authors derived 4 groups that corresponded to 0 (n = 8,341), 1 (n = 6,277), 2 (n = 2,635), or 3 (n = 592) biomarkers in the high-risk category. After adjustment for age, sex, waist circumference, race, region, smoking, alcohol use, income, educational level, physical activity frequency, and medical history and compared with those with no biomarkers in the high-risk category, the hazard ratios for all-cause mortality for 1, 2, and 3 biomarkers in the high-risk category were 1.56 (95% confidence interval: 1.33, 1.82), 2.19 (95% confidence interval: 1.84, 2.62), and 2.96 (95% confidence interval: 2.30, 3.80), respectively (Ptrend < 0.0001). Adding the 3 inflammation biomarkers to a fully adjusted model improved risk discrimination by 23.7% (95% confidence interval: 9.3, 39.9). Measurement of more than 1 biomarker is more useful in risk prediction than single biomarkers.

Objectives

To estimate the likelihood of, and factors associated with, recovery from exhaustion in older adults

Design and Setting

Retrospective analysis of data from six annual examinations of a community-based cohort study

Participants

4584 men and women aged 69 years or older

Measurements

Exhaustion was considered present when a participant responded “a moderate amount” or “most of the time” to either of two questions: “How often have you had a hard time getting going?” and “How often does everything seem an effort?”

Results

Of the 964 participants who originally reported exhaustion, 634 (65.8%) were exhaustion-free at least once during follow up. When data from all time points were considered, 48% of exhaustion-reporters were exhaustion-free the following year. After adjustment for age, sex, race, education, and marital status, one-year recovery was less likely among individuals with worse self-rated health, ≥ six medications, obesity, depression, musculoskeletal pain, and history of stroke. In proportional hazards models, the following risk factors were associated with more persistent exhaustion over five years: poor self-rated health, ≥ six medications, obesity, and depression. Recovery was not less likely among participants with a history of cancer or heart disease.

Conclusion

Exhaustion is common in old age but is quite dynamic, even among those with a history of cancer and congestive heart failure. Recovery is especially likely among seniors who have a positive perception of their overall health, take few medications, and are not obese or depressed. These findings support the notion that resiliency is associated with physical and psychological well-being.

Background.

There is growing interest in determining the degree of anemia, which is clinically significant. The goal of this study was to determine the association between hemoglobin concentration and cognitive impairment in a large sample of U.S. adults.

Methods.

We used cross-sectional data from 19,701 adults participating in the REasons for Geographic And Racial Differences in Stroke study. Cognitive impairment was defined as a score of 4 or less on the six-item screener. Hemoglobin was analyzed in 1 g/dL increments relative to the World Health Organization (WHO) threshold (<13 g/dL for men and <12 g/dL for women).

Results.

The mean hemoglobin concentration was 13.7 ± 1.5 g/dL. The prevalence of cognitive impairment increased from 4.3% among individuals with a hemoglobin >3 g/dL above the WHO threshold to 16.8% for those with a hemoglobin ≥2 g/dL below the WHO threshold. After adjustment for demographics, chronic health conditions, health status, and inflammation, the association between reduced hemoglobin and cognitive impairment was attenuated and no longer significant, including among those with hemoglobin ≥2 g/dL below the WHO threshold (odds ratio 1.39, 95% confidence interval = 0.94–2.04). A test for linear trend was of borderline significance (p value = .06). For 94% of the sample within 2 g/dL of the WHO threshold, there was no relationship between hemoglobin concentration and the odds of cognitive impairment. The associations did not differ by sex and race.

Conclusions.

Within a large sample of community-dwelling adults, there was no significant association between hemoglobin concentration and cognitive impairment after multivariable adjustment.

Background

Chronic kidney disease (CKD) and albuminuria are associated with increased risk of all-cause mortality.

Study Design

Prospective observational cohort study

Setting and Participants

17,393 participants (mean age, 64.3 ± 9.6 years) in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study.

Predictor

Estimated glomerular filtration rate (eGFR), urinary albumin-creatinine ratio (ACR).

Outcome

All-cause mortality (710 deaths); median duration of follow-up: 3.6 years.

Measurements and Analysis

Categories of eGFR (90– <120, 60–<90, 45–<60, 30–<45, and 15–<30 mL/min/1.73 m2) and urinary ACR (<10 mg/g or normal, 10–<30 mg/g or high normal, 30–300 mg/g or high, and >300 mg/g or very high). Cox’s proportional hazards models were adjusted for demographic factors, cardiovascular covariates, and hemoglobin.

Results

The background all-cause mortality rate for participants with normal ACR, eGFR of 90–<120 mL/min/1.73 m2 and no CHD was 4.3 deaths/1,000 person-years. Higher ACR was associated with an increased multivariable adjusted hazard ratio for all-cause mortality within each eGFR category. Reduced eGFR was associated with higher adjusted hazard ratio for all-cause mortality for participants with high normal (P value = 0.01) and high (P value <0.001) ACR values, but not for those with normal or very high ACR values.

Limitations

Only one laboratory assessment for serum creatinine and ACR was available

Conclusions

Increased albuminuria was an independent risk factor for all-cause mortality. Reduced eGFR was associated with increased mortality risk among those with high normal and high ACR. The mortality rate was low in the normal ACR group and increased in the very high ACR group but did not vary with eGFR in these groups.

White blood cells (WBCs) mediate immune systems and consist of various subtypes with distinct roles. Elucidation of the mechanism that regulates the counts of the WBC subtypes would provide useful insights into both the etiology of the immune system and disease pathogenesis. In this study, we report results of genome-wide association studies (GWAS) and a replication study for the counts of the 5 main WBC subtypes (neutrophils, lymphocytes, monocytes, basophils, and eosinophils) using 14,792 Japanese subjects enrolled in the BioBank Japan Project. We identified 12 significantly associated loci that satisfied the genome-wide significance threshold of P<5.0×10−8, of which 9 loci were novel (the CDK6 locus for the neutrophil count; the ITGA4, MLZE, STXBP6 loci, and the MHC region for the monocyte count; the SLC45A3-NUCKS1, GATA2, NAALAD2, ERG loci for the basophil count). We further evaluated associations in the identified loci using 15,600 subjects from Caucasian populations. These WBC subtype-related loci demonstrated a variety of patterns of pleiotropic associations within the WBC subtypes, or with total WBC count, platelet count, or red blood cell-related traits (n = 30,454), which suggests unique and common functional roles of these loci in the processes of hematopoiesis. This study should contribute to the understanding of the genetic backgrounds of the WBC subtypes and hematological traits.

Author Summary

White blood cells (WBCs) are blood cells that mediate immune systems and defend the body against foreign microorganisms. It is well known that WBCs consist of various subtypes of cells with distinct roles, although the genetic background of each of the WBC subtypes has yet to be examined. In this study, we report genome-wide association studies (GWAS) for the 5 main WBC subtypes (neutrophils, lymphocytes, monocytes, basophils, and eosinophils) using 14,792 Japanese subjects. We identified 12 significantly associated genetic loci, and 9 of them were novel. Evaluation of the associations of these identified loci in cohorts of Caucasian populations demonstrated both ethnically common and divergent genetic backgrounds of the WBC subtypes. These loci also indicated a variety of patterns of pleiotropic associations within the hematological traits, including the other WBC subtypes, total WBC count, platelet count, or red blood cell-related traits, which suggests unique and common functional roles of these loci in the processes of hematopoiesis.

White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count—6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count—17q21; basophil count- 3p21 near RPN1 and C3orf27; lymphocyte count—6p21, 19p13 at EPS15L1; monocyte count—2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds.

Author Summary

WBC traits are highly variable, moderately heritable, and commonly assayed as part of clinical complete blood count (CBC) examinations. The counts of constituent cell subtypes comprising the WBC count measure are assayed as part of a standard clinical WBC differential test. In this study we employed meta-analytic techniques and identified ten associations with WBC measures at seven genomic loci in a large sample set of over 31,000 participants. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We confirm previous associations of WBC traits with three loci and identified seven novel loci. We also utilize a number of additional analytic methods to infer the functional relatedness of independently implicated loci across WBC phenotypes, as well as investigate direct functional consequences of these loci through analyses of genomic variation affecting the expression of proximal genes in samples of whole blood. In addition, subsequent collaborative efforts with studies of WBC traits in African-American and Japanese cohorts allowed for the investigation of the effects of these genomic variants across populations of diverse continental ancestries.

Background and Objective

Warfarin reduces stroke risk by about 60% in patients with atrial fibrillation (AF). Differences in awareness and treatment of AF may contribute to racial and geographic disparities in stroke mortality. The objective was to examine predictors of awareness of the diagnosis of AF and treatment with warfarin.

Methods

REasons for Geographic and Racial Differences in Stroke (REGARDS) is a national, population-based, longitudinal study of 30,239 blacks and whites ≥ 45 years old with oversampling from African Americans and the southeastern stroke belt states. Participants were enrolled Jan 2003–Oct 2007. Data were collected using telephone interview, in-home evaluation, and self-administered questionnaires. The main variable of awareness of AF was defined by a positive answer to “Has a doctor or other health professional ever told you that you had atrial fibrillation?” and whether there was evidence of treatment on the basis of an in-home medications inventory.

Results

From baseline ECG, 432 individuals (88 black and 344 white) had AF. Of these, 88% (360/409) had at least one additional CHADS2 stroke risk factor and 60% (258/432) were aware of their AF. The odds of blacks being aware of their AF were one-third that of whites (OR=0.32 {95% CI: 0.20-0.52}). Among those aware, the odds of blacks being treated with warfarin were only one-fourth as great as whites (OR=0.28 {0.13-0.60}).

Conclusion

Blacks were less likely than whites to be aware of having atrial fibrillation or to be treated with warfarin. Potential reasons for the racial disparity in warfarin treatment warrant further investigation.

Background

Thrombosis and inflammation are critical in stroke etiology, but associations of coagulation and inflammation gene variants with stroke, and particularly factor VII levels are inconclusive.

Objectives

To test the associations between 736 single nucleotide polymorphisms (SNP) between tagging haplotype patterns of 130 coagulation and inflammation genes, and stroke events in the 5,888 participants ≥ 65 of the observational Cardiovascular Health Study cohort.

Patients

/Methods: With 16 years of follow-up, age and sex-adjusted Cox models were used to estimate associations of SNPs and factor VIIc levels with future stroke.

Results

815 strokes occurred in 5,255 genotyped participants without baseline stroke (748 ischemic strokes, 586 among whites). Among whites, 6 SNPs were associated with stroke with a nominal p <0.01: rs6046 and rs3093261 (F7 gene); rs4918851 and rs3781387 (HABP2 gene); rs3138055 (NFKB1A) and rs4648004 (NFKB1). Two of these SNPs were associated with factor VIIc levels (units = percent activity): rs6046 (β = −18.5, p = 2.38 × 10−83) and rs3093261 (β = 2.99, p = 3.93 × 10−6). Adjusting for age, sex, race, and cardiovascular risk factors, the association of factor VIIc quintiles (Q) with stroke were (HR: 95% CI): Q1 (reference); Q2 (1.4; 1.1, 1.9); Q3 (1.1; 0.8, 1.5); Q4 (1.5; 1.1, 2.0); Q5 (1.6; 1.2, 2.2). Associations between SNPs and stroke were independent of factor VIIc levels.

Conclusions

Variation in factor VII-related genes and factor VIIc levels were associated with risk of incident ischemic stroke in this elderly cohort, suggesting a potential causal role for factor VII in stroke etiology.

To examine the associations of three understudied hemostatic factors – D-dimer, factor VIIIc, and antiplasmin (PAP) complex -- with incident CVD and all cause mortality in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. Hemostatic factors were measured at baseline in 45–84 year olds (n =6,391) who were free of clinically recognized CVD. Over 4.6 years of follow-up, we identified 307 CVD events, 207 hard coronary heart disease (CHD) events, and 210 deaths. D-dimer, factor VIIIc, and PAP were not associated with CVD incidence after adjustment for other risk factors. In contrast, each factor was associated positively with total mortality, and D-dimer and factor VIIIc were associated positively with cancer mortality. When modeled as ordinal variables and adjusted for risk factors, total mortality was greater by 33% (95% CI = 15–54%) for each quartile increment of D-dimer, 26% (11–44%) for factor VIIIc, and 20% (4–38%) for PAP. This prospective cohort study did not find D-dimer, factor VIIIc, or PAP to be risk factors for CVD. Instead, elevated levels of these three hemostatic factors were associated independently with increased risk of death. Elevated D-dimer and factor VIIIc were associated with increased cancer death.

Tissue factor pathway inhibitor (TFPI) inhibits tissue factor, a potent coagulation initiator. Limited evidence suggests that low TFPI levels are associated with increased risk of venous thrombosis (VTE). We measured total TFPI in a nested case-control study in the Longitudinal Investigation of Thromboembolism Etiology. Control subjects were frequency matched 2:1 to cases on age, sex, race, and cohort. Odds ratio for VTE by TFPI levels were computed using logistic regression models adjusting for age, race, sex, coagulation factors (factors VII, VIII, IX, XI, D-dimer), and body mass index. To evaluate for greater than additive interactions, we calculated the percent relative excess risk due to interaction between TFPI and other VTE risk factors. 534 cases of VTE occurred and matched to 1091 controls. Mean baseline TFPI in ng/mL (standard deviation) in those who developed VTE and controls was 36.4 (12.8) and 35.0 (11.1), respectively. Higher TFPI was associated with male sex, age, body mass index, factors VII, VIII, IX, XI, and D-dimer. TFPI level did not differ by ethnicity, factor V Leiden, or prothrombin G20210A. Compared with those in the upper 95%, the bottom 5% of TFPI had an age-, sex-, race-, and study-adjusted odds ratio (95% CI) of 1.35 (0.86, 2.12) for VTE. Adjusting for factors VII, VIII, IX, and XI the odds ratio was 1.93 (1.05, 3.53). Further addition of D-dimer and BMI to this model the odds ratio was 1.70 (0.98, 2.93). Low TFPI did not demonstrate greater than additive interaction with other VTE risk factors.

OBJECTIVES

To investigate whether anemia predicts worsening white matter hyperintensities (WMH) in older community-dwellers.

DESIGN

Prospective cohort study.

SETTING

Older community-dwellers.

PARTICIPANTS

One thousand eight hundred forty-six Cardiovascular Health Study (CHS) participants (mean age 73.7±4.4 years, 41% men, 15.6% African-Americans).

MEASUREMENTS

Participants had hemoglobin measured and a brain MRI in 1992–93, and a second brain MRI in 1997–98. Anemia was defined according to WHO criteria (hemoglobin <12 g/dl in women and <13 g/dl in men). Worsening WMH was determined by standardized side-by-side readings.

RESULTS

After 5 years, WMH worsened in 517 participants (28%). Progression was not associated with anemia in the whole sample, in gender- or race-strata or in other pre-specified subgroups (participants with renal dysfunction or diabetes), except in participants with high blood pressure (≥140/90 mmHg). Among the 678 participants with high blood pressure, those with anemia (10.5%) had a 1.79-fold increased risk of WMH worsening (95%CI 1.06–2.98; p for interaction between anemia and high blood pressure = 0.013), independent of demographics, baseline WMH, cardiovascular risk factors and comorbidities, medications, renal function, inflammation and incident stroke (logistic regression models). There was no increased risk in anemic participants with normal blood pressure.

CONCLUSION

Anemia may contribute to WMH worsening in older adults with high blood pressure.

Erythrocyte measures are heritable and have important health implications, yet their genetic determinants are largely unknown. We performed genome-wide association analyses in 24,167 European-ancestry individuals for six erythrocyte traits and identified associations at 23 loci (P values 5×10-8 to 1×10-57). Replication testing in an independent set of 9,456 European-ancestry individuals showed strong evidence of association in all 23 loci in meta-analysis of the discovery and replication cohorts. Our findings include previously identified loci (HBS1L/MYB, HFE, TMPRSS6, TFR2, SPTA1) and novel associations (EPO, TFRC, SH2B3, and 15 other loci). This study has identified novel determinants of erythrocyte traits, offering insight into common variants underlying variation in erythrocyte measures.

Background

TIMI Risk Index (TRI) is a simple bedside score that predicts 30-day mortality in ST-elevation myocardial infarction (MI) patients. We sought to evaluate whether TRI was predictive of long-term mortality and clinical events.

Methods

In the TIMI II trial, 3153 patients (mean age 57 ±10 years, 82% men) were randomized to invasive (n=1583) versus conservative (n=1570) strategy post-fibrinolysis with median follow-up of 3 years. TRI was divided into the 5 previously-specified groups. Primary endpoint was all-cause mortality. Secondary analyses included recurrent MI, congestive heart failure (CHF), and combined endpoints.

Results

When compared to Group 1, mortality in Group 5 was more than 5-fold higher (HR 5.83, p<0.0001), and was also increased in Group 4 (HR 2.80, p<0.0001) and Group 3 (HR 1.96, p=0.002) (c statistic 0.69). No difference was seen between Groups 1 and 2 (p=0.74). A similar increasing gradient effect was seen across TRI strata with Group 5 having the highest risk for CHF (HR 4.13, p<0.0001), and composite death/CHF (HR 4.35, p<0.0001) over Group 1. There was no difference in recurrent MI between the groups (p=0.22). After controlling for other risk indicators, the relationship between TRI and mortality remained significant: Group 5 (HR 4.11, p<0.0001), Group 4 (HR 2.14, p=0.0009), Group 3 (HR 1.69, p=0.02). When stratified by TRI groups, no differences in mortality or composite death/MI were found between treatment strategies.

Conclusion

The simple TRI can predict increased long-term mortality, CHF, and composite death/CHF.

For unclear reasons, anemia is more common in American blacks than whites. The authors evaluated anemia prevalence (using World Health Organization criteria) among 19,836 blacks and whites recruited in 2003–2007 for the REasons for Geographic And Racial Differences in Stroke Renal Ancillary study and characterized anemia by 3 anemia-associated conditions (chronic kidney disease, inflammation, and microcytosis). They used multivariable models to assess potential causes of race differences in anemia. Anemia was 3.3-fold more common in blacks than whites, with little attenuation after adjusting for demographic variables, socioeconomic factors, and comorbid conditions. Increasing age, residence in the US southeast, lower income, vascular disease, diabetes, hypertension, and never smoking were associated with anemia. Age, diabetes, and vascular disease were stronger correlates of anemia among whites than blacks (P < 0.05). Among those with anemia, chronic kidney disease was less common among blacks than whites (22% vs. 34%), whereas inflammation (18% vs. 14%) and microcytosis (22% vs. 11%) were more common. In this large, geographically diverse cohort, anemia was 3-fold more common in blacks than whites with different characteristics and correlates. Race differences in anemia prevalence were not explained by the factors studied. Future research into the causes and consequences of anemia in different racial groups is needed.

Background

Inflammation markers and MetS are associated with risk of CHF. We evaluated whether combining inflammation markers and metabolic syndrome (MetS) provided additive information for incident congestive heart failure (CHF), and if incorporating inflammation markers to the MetS definition added prognostic information.

Methods and Results

We studied 4017 men and women ≥ 65 years old, without baseline CHF or diabetes, participating in the Cardiovascular Health Study, an observational study with 12.2 years follow-up and 966 cases of incident CHF. Baseline “C-reactive protein (CRP)-MetS” or “interleukin-6 (IL-6)-MetS” were defined as presence of 3 out of 6 components, with elevated CRP (≥3 mg/L) or IL-6 (≥2.21 pg/mL) as a 6th component added to ATPIII criteria. Cox models adjusted for CHF risk factors and incident coronary disease, were used to calculate HRs for CHF. MetS and elevated inflammation markers were independently associated with CHF risk (HRs, 95 % CI: 1.32, 1.16–1.51 for MetS; 1.53, 1.34–1.75 for CRP; 1.37, 1.19–1.55 for IL-6). There was a 20% relative excess risk attributed to the combination of MetS and CRP (95% CI −44% to 88%). CRP-MetS and IL-6-MetS definitions reclassified 18% and 13%, respectively of participants as MetS. Both CRP-MetS and IL-6-MetS increased risk of CHF by 60% compared to those without MetS.

Conclusion

MetS and inflammation markers provided additive information on CHF risk in this elderly cohort. Inflammation-incorporated MetS definitions identified more participants with the same risk level as ATPIII MetS. Considering inflammation markers and MetS together may be useful in clinical and research settings.

Background

Lower activated partial thromboplastin times are associated with higher levels of some coagulation factors and may represent a procoagulant tendency.

Methods

In the Atherosclerosis Risk in Communities Study, we studied the 13-year risk of venous thromboembolism in relation to baseline activated partial thromboplastin time in 13,880 individuals. We also studied 258 venous thromboembolism cases and 589 matched controls with measurements of additional coagulation factors.

Results

Adjusting for demographics and procoagulant factors reflected in the activated partial thromboplastin time (fibrinogen, factors VIII, IX, XI, and von Willebrand factor), participants in the lowest two quartiles of activated partial thromboplastin time compared with the fourth quartile had 2.4-fold (95% CI 1.4, 4.2) and 1.9-fold (95% CI 1.1, 3.2) higher risks of venous thromboembolism. The risk associated with activated partial thromboplastin times below the median was higher for idiopathic (OR 5.5; 95% CI 2.0, 15.5) than secondary venous thromboembolism (OR 1.74; 95% CI 0.88, 3.43). Subjects with both activated partial thromboplastin times below the median and factor V Leiden were 12.6-fold (95% CI 5.7, 28.0) more likely to develop venous thromboembolism compared to those with neither risk factor (p-interaction <0.01). A lower activated partial thromboplastin time also added to the thrombosis risk associated with obesity and elevated D-dimer.

Conclusions

A single determination of the activated partial thromboplastin time below the median increased the risk of future venous thromboembolism. Findings were independent of coagulation factor levels, and a low activated partial thromboplastin time added to the risk associated with other risk factors.