Red cell distribution width is associated with incident venous thromboembolism (VTE) and case-fatality after VTE in a
general population
Trygve S. Ellingsen1,2, Jostein Lappegård1,2, Tove Skjelbakken1,2,3, Sigrid K. Brækkan1,2,3 and John-Bjarne Hansen1,2,3
1K.G. Jebsen Thrombosis Research and Expertise Center, Department of Clinical Medicine, University of Tromsø, Norway
2Hematological Research Group, Department of Clinical Medicine, University of Tromsø, Norway
3Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway
Correspondence to: Trygve S. Ellingsen, Hematological research group (HERG), Department of Clinical Medicine, University of Tromsø, N-9037 Tromsø, Norway
e-mail: trygve.s.ellingsen@uit.no, telephone: +47 958 73 223
The authors report no potential conflicts of interest
Running title: RDW and risk of VTE and mortality after VTE
Keywords: Red cell distribution width, venous thromboembolism, recurrence, mortality
Word count abstract: 199
Word count text without references: 3526 Number of tables: 5
Number of figures: 3 Number of references: 39
Supplementary material: 1 table
Extra table
What is known on this topic What this paper adds - RDW is associated with cardiovascular
disease, cardiovascular mortality and all-cause mortality
- Confirms that RDW is a risk factor for incident VTE in the general population
- Recent studies have suggested that RDW is associated with incident VTE
- RDW is a predictor of all-cause mortality in VTE-patients
- RDW does not predict VTE recurrence
Abstract
Recent studies suggest an association between red cell distribution width (RDW) and incident venous thromboembolism (VTE). We aimed to investigate the impact of RDW on risk of incident and recurrent VTE, and case-fatality, in a general population.
RDW was measured in 26 223 participants enrolled in the Tromsø Study in 1994-95. Incident and recurrent VTE events and deaths during follow-up were registered until January 1, 2012.
Multivariate Cox proportional hazards regression models were used to calculate hazard ratios (HR) with 95% confidence intervals (CI).
There were 647 incident VTE events during a median of 16.8 years of follow-up. Individuals with RDW in the highest quartile (RDW≥13.3%) had 50% higher risk of an incident VTE than those in the lowest quartile (RDW<12.5%). The association was strongest for unprovoked deep vein thrombosis (HR highest versus lowest quartile of RDW: 1.9, 95% CI 1.2-3.2). VTE patients with baseline RDW≥13.3% had 30% higher risk of all-cause mortality after the initial VTE event than VTE patients with RDW<13.3%. There were no association between RDW and risk of recurrent VTE.
Our findings suggest that high RDW is a risk factor of incident VTE, and that RDW is a predictor of all-cause mortality in VTE patients.
Introduction
Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third most common life-threatening cardiovascular disease and a major cause of morbidity and mortality.1 The incidence increases markedly with age, from about 1 per 10 000 per year in young adults, to 1 per 100 per year in the elderly.2,3 VTE is a complex, multifactor disease with several acquired and inherited risk factors,4-6 but the cause is still unknown in 30-50% of the cases.7
Red cell distribution width (RDW), a measurement of the variation of circulating erythrocyte volume (the coefficient of variation of red blood cell volume), is expressed in percentage and normally reported as part of the routine blood cell count.8 RDW is traditionally used in the differential diagnosis of anemia. In addition to microcytic anemia, high RDW can be caused by conditions that modify the shape of the red blood cells due to premature release of immature cells into the bloodstream (severe blood loss), hemoglobinopathies (e.g. sickle cell anemia), hemolysis or hemolytic anemia.9 Several recent prospective studies and a meta-analysis have shown that a high RDW is associated with risk of cardiovascular disease and total mortality.10-15 Moreover, an association between high RDW and mortality has been reported in patients with coronary disease, cerebral infarction and acute PE.16-19
Recently, a large case-control study (the MEGA study) showed an association between
increasing RDW and risk of VTE.20 These findings were supported by a small case-control study reporting that increased RDW was associated with deep vein thrombosis.21 In both studies, blood samples were collected after the thrombotic event. It is therefore impossible to determine
whether high RDW is an actual risk factor or a consequence of VTE, as long as an acute VTE event is accompanied by a prolonged inflammatory response, and inflammatory processes are known to influence RDW.22,23 Data from the Malmö Diet and Cancer Study, a Swedish
population-based cohort study of middle-aged and elderly individuals, confirmed the association between RDW and future risk of VTE.24 Whether RDW is associated with recurrence or
mortality in VTE patients have not been investigated. Therefore, the purpose of the present study was to investigate the association between RDW and risk of incident and recurrent VTE in a large cohort recruited from a general population. Moreover, we investigated the association between RDW and case-fatality and all-cause mortality among VTE-patients.
Methods
Study population
Study participants were recruited from the fourth (1994-95) survey of the Tromsø Study. The entire population aged ≥25 years living in the municipality of Tromsø, Norway, were invited to participate. The population is predominately Caucasians of Norwegian origin, with no known sickle cell disease or thalassemia. A detailed description of the study design and population has been published elsewhere.25 A total of 27 158 subjects aged 25-97 years participated in the study (77% of the eligible population). The regional committee of medical and health research ethics approved the study, and all participants gave their written consent to participate. Persons who did not give their written consent to medical research (n=202), those not officially registered as inhabitants of the municipality of Tromsø at date of study enrolment (n=45), persons with known VTE before baseline (n=57) and those with missing RDW measurement (n=631) were excluded.
Accordingly, a total of 26 223 participants were included in the study. Incident and recurrent VTE events, and mortality among the VTE patients, were recorded from the date of enrolment through the end of follow-up, January 1, 2012.
Baseline measurements
Baseline information was collected by self-administered questionnaires, blood samples and a physical examination. Blood samples were collected from an antecubital vein and analyzed at the department of Clinical Chemistry, University Hospital of North Norway. The blood samples were taken at the date of inclusion (in 1994/ 1995). For measurement of blood cell count (including RDW), 5 ml of blood was drawn into a vacutainer tube containing EDTA as an anticoagulant and analyzed within 12 hours in an automa ted blood cell counter (Coulter
Counter®, Coulter Electronics, Luton, UK). RDW was calculated by dividing the standard deviation of the mean corpuscular volume (MCV) by MCV and multiplying by 100 to express the result as a percentage.9 Height and weight were measured wearing light clothes and no shoes.
Body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters (kg/m2). Information on smoking habits, family history of cardiovascular diseases, hormone therapy (women only) and concurrent diseases was obtained from standard, validated self-administered questionnaires.
Venous thromboembolism: identification and validation
All VTE events during follow-up were identified by searching the hospital discharge diagnosis registry, the autopsy registry and the radiology procedure registry at the University Hospital of North Norway as previously described.26 The hospital discharge diagnosis registry covers both hospitalizations and outpatient clinic visits. The University Hospital of North Norway is the only hospital in the region, and all diagnostic radiology and hospital care is provided exclusively by this hospital. The medical record for each potential case of VTE was reviewed by trained personnel, and a VTE event was considered verified and recorded when presence of clinical signs and symptoms of DVT or PE were combined with objective confirmation tests (by compression ultrasonography, venography, spiral computed tomography, perfusion-ventilation scan, pulmonary angiography, autopsy), and resulted in a VTE diagnosis that required treatment, as previously described in detail.26 VTE cases from the autopsy registry were recorded when the death certificate indicated VTE as cause of death or a significant condition associated with death.
The VTE events were classified as provoked and unprovoked depending on the presence of provoking factors at the time of diagnosis, as previously described.26 Provoking factors were
recent surgery or trauma (within the previous 8 weeks), acute medical conditions (acute myocardial infarction, ischemic stroke or major infectious disease), active cancer,
immobilization (bed rest >3 days, wheelchair use or long-distance travel) or any other specific factors described by a physician in the medical record (e.g. intravascular catheter).
Recurrent VTE was defined as symptomatic, objectively confirmed DVT or PE at (i) another location than the first VTE, or at (ii) the same location as the first VTE in cases where the recurrence occurred more than 7 days after the initial event and recanalization of the initial thrombus was documented.
Case-fatality
Information on case-fatality was obtained by linkage to the National Causes of Death registry kept by Statistics Norway.
Statistical analyses
Statistical analyses were performed with STATA version 12.0 (Stata corporation, College Station, TX, USA) and R (version 2.15.1 for Windows). RDW was categorized into quartiles based on the distribution of baseline RDW in the population (quartile 1: 10.7-12.4%, quartile 2:
12.5-12.7%, quartile 3: 12.8-13.2% and quartile 4: 13.3-30.5%). An extra cut-off point was established at the 95th percentile (RDW range 14.4-30.5%). Age-adjusted baseline characteristics according to quartiles of RDW were assessed by analyses of variance (ANOVA). For analyses on the association between RDW and incident VTE, person-time of follow-up was calculated from the date of enrolment (1994/95) to the date when a VTE event was first diagnosed, to the date when the participant died or moved from the municipality of Tromsø, or to the end of the
study period (January 1st, 2012). Crude incidence rates (IR) were calculated and expressed as number of events per 1000 person-years at risk. Cox proportional hazard regression models were used to obtain crude, age- and sex-adjusted and multivariable adjusted hazard ratios (HR) with 95% confidence intervals (CI) for VTE by increasing RDW. The proportional hazards
assumption was tested by Schoenfeld residuals. Interactions between RDW and age or sex were tested by including cross product terms in the Cox-regression models. We found no interactions and the proportional hazard assumption was not violated. The lowest RDW quartile was used as reference in the Cox models. The multivariate model included age, sex, BMI, smoking,
cardiovascular disease, mean platelet volume, white blood cell count, hemoglobin and mean corpuscular volume. The multivariate analyses were repeated after exclusion of participants with anemia (defined as hemoglobin levels <12.0 g/dL in females and <13.0 g/dL in men).
Additionally, subgroup analyses calculated HRs of provoked and unprovoked VTE, DVT and PE across quartiles of RDW. To further investigate the effect of age on the relationship between RDW and VTE we stratified into age groups (<50, 50-74 and ≥70 years) and compared the risk of VTE for subjects in quartile 4 versus quartiles 1-3 (reference group).
For analyses of the association between RDW and recurrence, person-time was calculated from the date of the first VTE event to the date of recurrent VTE, date of migration, date of death or end of the study period (January 1, 2012). For analyses of the association between RDW and death after VTE, person-time was calculated from the date of the first VTE event to the date of death, date of migration or end of the study period (January 1, 2012). Cox-regression analyses were used to calculate HRs of recurrent VTE or death, respectively, for those with RDW ≥13.3%
(upper population-based quartile level) compared with RDW <13.3%. The 10-year survival after the initial VTE event in those with RDW ≥13.3% and <13.3%, adjusted for age, sex, BMI,
smoking, cardiovascular disease, mean platelet volume, white blood cell count, hemoglobin and mean corpuscular volume (MCV), were presented in a survival plot. Finally, we used Cox- regression to calculate the 1-year risk of recurrence and mortality after the initial VTE event.
Results
There were 647 incident VTE events during a total of 365 850 person-years of follow-up (median 16.8 years). The overall crude incident rate of VTE was 1.8 (95% CI 1.6-1.9) per 1000 person-years. The mean RDW levels were similar (12.9%) in men and women. Age adjusted baseline characteristics across categories of RDW are shown in Table 1. The mean age increased markedly across increasing quartiles of RDW. Moreover, mean platelet count, white blood cell count, the proportion of smokers, anemic subjects and participants with cardiovascular disease increased with increasing RDW, whereas the mean corpuscular volume and hemoglobin concentration decreased.
Among the VTE patients, 59% had DVT and 41% had PE (Table 2). Moreover, 273 (42.2%) of the events were unprovoked. Cancer was the most common provoking factor, with 23.1% of the VTE-events being cancer-related.
There was an association between RDW and risk of VTE (Table 3). Crude incidence rates (IRs) of VTE increased from 1.1 per 1000 person-years (95% CI 0.9-1.3) for those with RDW-levels in the lowest quartile, to 2.9 per 1000 person-years (95% CI 2.5-3.3) for those with RDW-levels in the highest quartile. Likewise, the age- and sex-adjusted HRs for VTE increased with
increasing RDW. Study participants with RDW in quartile 4 (RDW 13.3 - 30.5%) had 50%
higher risk of VTE (HR 1.5, 95% CI 1.2-1.8) than those with RDW in quartile 1 (RDW ≤12.4%).
The association remained unchanged after further adjustment for BMI, smoking, cardiovascular disease, mean platelet volume, white blood cell count, hemoglobin and MCV, with a
multivariate-adjusted HR of 1.5 (95% CI 1.2-1.8) for upper versus lower quartile of RDW. The
risk of VTE increased further for those with RDW values above the 95th percentile (RDW 14.4 - 30.5%) as they had a 1.8-fold higher risk than participants in the lower quartile (HR 1.8, 95% CI 1.2-2.6). Multivariate cumulative hazard estimates for VTE by increasing quartiles of RDW are shown in Figure 1. The figure demonstrates an increase in risk of VTE for the participants with RDW values in the upper quartile, and that the risk persisted over time. When RDW was
modeled as a continuous variable, a linear dose-response relationship between RDW and risk of VTE was found (Figure 2), confirming the trend seen in Table 3. A 1-SD (0.935%) increase in RDW was associated with a 20% increased risk of venous thromboembolism (HR 1.2, 95% CI 1.1-1.3). Exclusion of subjects with anemia had no impact on the results (Supplementary table 1). The risk of VTE was higher in quartile 4 compared to quartiles 1-3 in all age strata (Table 4).
In subgroup analyses, participants in the highest RDW quartile had a 1.4-fold (95% CI 1.0-1.9) higher risk of provoked VTE compared with the lowest quartile of RDW, while the risk of unprovoked VTE was 1.6 times (95% CI 1.1-2.2) higher for those in quartile 4 than those in quartile 1 (Supplementary table 2). Further analyses of pulmonary embolism (PE) and deep vein thrombosis (DVT) showed a consistent association between RDW and risk of DVT. Compared with the reference group, participants with RDW values in quartile 4 had a 1.4-fold (95% CI 1.0- 2.1) higher risk of provoked DVT and a 1.9-fold (95% CI 1.2-3.2) higher risk of unprovoked DVT. There was a trend for higher risk of PE by increasing RDW, though the risk estimates were not statistically significant. In the multivariate model, study participants with RDW levels in the upper quartile had a hazard ratio of 1.3 (95%, CI 0.8-2.2) for provoked PE and 1.2 (95%
CI 0.7-2.1) for unprovoked PE compared to the lowest quartile (Supplementary table 2).
VTE patients were followed on average 4.4 years after the initial event (range: 1 day to 17.1 years). During this period 299 (46%) VTE patients died and 100 (15%) experienced a recurrent VTE. Subjects in the highest RDW quartile had a 30% higher risk of death during follow-up (HR 1.3 95% CI 1.0-1.7), whereas there were no differences in risk of recurrence according to RDW levels (HR 1.1, 95% CI 0.7-1.6) (Table 5). Within one year after the incident VTE event, 42 patients (6%) experienced a recurrent VTE and 157 died (24%). RDW was not associated with risk of VTE recurrence or mortality during the first year after the initial VTE event (Table 5).
Discussion
Previous case-control studies20,21 and a cohort study24 suggest that RDW is associated with incident VTE. In our large population-based cohort study, we confirmed a dose-dependent risk of incident VTE by RDW, and in subgroup analyses we disclosed that the risk estimate was particularly high for unprovoked DVT. Furthermore, incident VTE patients with high RDW were at increased risk of mortality, while RDW levels were not associated with risk of recurrence after the initial VTE event.
To the best of our knowledge, the present study is the first study to show that high RDW is associated with higher risk of mortality in incident VTE patients. RDW has recently attracted attention due to its ability to predict cardiovascular event rate,15,16,22 cardiovascular mortality10,17 and all-cause mortality.11-13 RDW was found to predict long-term mortality independent of hemoglobin levels in patients undergoing percutaneous coronary intervention,17 and to be
associated with mortality regardless of anemia in patients with acute myocardial infarction.27 The all-cause mortality risk was reported to increase by 22% for every 1% increase in RDW.11
Furthermore, a meta-analysis of 7 community-based studies showed a graded increased risk of death associated with higher RDW in older adults with and without age-associated disease.12 In addition to arterial cardiovascular mortality, our findings suggest that RDW, measured several years before the initial VTE event, also predict mortality in VTE patients.
Previous observational studies have suggested an association between RDW and incident venous thrombosis. In a large population-based case-control study of 2473 VTE patients and 2935 controls, Rezende et al found a strong and consistent association between RDW and risk of
VTE.20 Individuals with RDW above the 95th percentile (RDW>14.1%) had a 3-fold higher risk of VTE compared to those with RDW values between the 5th and 95th percentiles (RDW range 11.7-14.1%). Moreover, patients with DVT (n=216) had higher RDW than controls (n=215) referred to duplex ultrasonography with suspicion of DVT.21 A recent population-based cohort study by Zöller et al found that individuals with RDW in the upper quartile had a 1.7-fold higher risk of VTE than those in the lower quartile.24 Similarly, we found that individuals with RDW in the upper quartile had a 1.5-fold higher risk of incident VTE compared with those in the lowest quartile of RDW. Subgroup analyses in our study revealed that the association between RDW and VTE was mostly driven by an association between RDW and unprovoked DVT.
RDW values below 16.5% are currently considered normal in our hospital laboratory. In the present population-based study, 99.6% of the study population had RDW equal to or lower than 16.5%. Thus, our findings raise the question whether it is time to reconsider the current
laboratory cut-off values. The risk of VTE, however, increased significantly already from the 75th percentile (RDW≥13.3%), and those with RDW values above the 95th percentile (RDW≥14.4%) had 80% higher risk of VTE.. Future studies should investigate the clinical usefulness of RDW values above 13.3% for prediction of arterial and venous thromboembolic diseases.
The present study is the first to explore the impact of RDW on the risk of recurrent VTE in a general population. We found that RDW was not associated with risk of recurrence. The
phenomenon that a risk factor is associated with a first but not a second VTE event holds true for many exposures (e.g. age, factor V Leiden),29 and can be explained by the thrombosis potential model.5 Every individual with a first venous thrombosis has proven to be able to reach the
thrombosis threshold. Thus, when risk of recurrence in patients with a first venous thrombosis is assessed, subjects with high RDW are compared with subjects with low RDW who for some other reason (e.g. genetic variants, cancer etc.) developed their first venous thrombotic event and therefore are at equally high risk of recurrent VTE.
The prothrombotic mechanisms underlying the observed association between RDW and incident venous thrombosis and mortality remain unsettled. Since RDW is a statistical concept, it is likely to assume that RDW is a marker of other underlying biological mechanism(s) or conditions. It has been reported that increased cardiovascular mortality by RDW is confined to those with anemia.20 To explore the impact of anemia on the relation between RDW and VTE risk, we adjusted for hemoglobin level in our multivariable model, and additionally performed analyses in which anemic participants were excluded. The risk estimates for incident VTE by RDW in our study were not affected by adjustment for hemoglobin, or by excluding subjects with anemia.
This demonstrates that anemia does not explain the strong association between RDW and venous thrombosis. Iron deficiency without anemia has previously shown to affect health issues,29–31 and may here specifically attenuate iron-dependent scavenger functions of oxidative stress that may promote inflammation.32 Lack of consistent associations between inflammation markers and VTE risk in previous observational studies28,29, and no impact on the risk estimates by adjustment for white blood cell count in our study, suggest that inflammation is not an important confounder for the relation between RDW and VTE risk.
Several lines of evidence support the notion that increased variability in red blood cell size may promote stasis and hypercoagulability, i.e. two important components of Virchow’s triad
involved in the pathogenesis of venous thrombosis. Increased RDW has been associated with decreased red blood cell deformability,30 and red cell deformability has been related to
erythrocyte aggregation and altered blood viscosity.31 Hematocrit, one of the major determinants of blood viscosity, has been shown to predict future risk of venous thrombosis,32 and increased erythrocyte aggregation was reported to promote thrombosis in a rabbit model.33 Similar to RDW, inherited hypercoagulability caused by FV-Leiden favor development of DVT rather than
PE.34,35 Taken together, this supports the concept that hypercoagulability or erythrocyte
aggregation may play an important role in promoting thrombosis formation in individuals with high RDW. However, there are no studies on the direct effect of RDW on blood viscosity.
Studies on coal-water-slurries, latex dispersions and silica-based suspensions found that increasing the particle size distribution width decreased the viscosity via improved packing ability.36-38 Hence, it may be suggested that an increase in RDW enhances the packing ability of red blood cells, resulting in complex 3D clumps which in turn increase the local blood viscosity and thereby facilitates thrombus formation.31
Major strengths of our study is the clear temporal sequence between exposure and outcomes, the large number of participants recruited from a general population, the long-term follow-up and the well assessed information on RDW level and potential confounders. The high attendance rate reduces the risk of selection bias and makes the study population representative for the general population. Since there is only one hospital providing radiological imaging and hospital care (both in and out-patients) in the region, the chance of missed outcome events in our study is low.
Some limitations of the study need to be addressed. The RDW was only measured at baseline, and could possibly have changed during the relatively long follow-up. However, this type of
non-differential misclassification generally leads to underestimation of true associations.
Underlying medical conditions such as malignancy, lung, heart, kidney and inflammatory diseases may potentially influence the RDW. Unfortunately, we did not have information on all these conditions at baseline.
In conclusion, we found a dose-dependent relation between RDW and future risk of incident VTE, and a higher risk of mortality among VTE patients with high RDW. Further studies are warranted to confirm our original findings and to explore the underlying mechanism(s).
Author contributions
TSE analyzed the data and drafted the manuscript. JL and TS interpreted the results and revised the manuscript. SKB and JBH designed the study, contributed with data collection, and revised the manuscript. All authors read and approved the final version of the manuscript.
Acknowledgement
The authors thank participants of The Tromsø Study for their important contributions.
K.G. Jebsen TREC is supported by an independent grant from the K.G. Jebsen Foundation.
Conflict of Interest Statements
The authors report no potential conflicts of interest.
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Table legends
Table 1. Age-adjusted baseline characteristics of the study population (n=26 223) by quartiles of red cell distribution width (RDW). Values are given as percentages with absolute numbers in brackets or as means ± one standard deviation
Table 2. Characteristics of venous thromboembolic (VTE) patients (n=647) at the time of the VTE diagnosis
Table 3. Incidence rates (IRs) and hazard ratios (HRs) with 95 % confidence intervals (CIs) for venous thromboembolism (VTE) by quartiles and above the 95th percentile of red cell distribution with (RDW).
Table 4. Incidence rates (IR) and hazard ratios (HRs) with 95% confidence intervals for venous thromboembolism (VTE) in different age strata.
Table 5. Incidence rates (IRs) and hazard ratios (HRs) with 95 % confidence intervals for death and recurrence after a venous thromboembolic (VTE) diagnosis (n=631) by red cell distribution width (RDW)
Supplementary table 2. Incidence rates (IR) and hazard ratios (HRs) with 95%
confidence intervals for provoked and unprovoked venous thromboembolism (VTE), pulmonary embolism (PE) and deep vein thrombosis (DVT) by quartiles of red cell distribution width (RDW).
Figure Legends
Figure 1: Cumulative hazard estimates for VTE by quartiles of RDW. The Tromsø Study 1994-2011. The model is adjusted for age, sex, body mass index, smoking, self- reported cardiovascular disease, hemoglobin, mean corpuscular volume, mean platelet volume, white blood cell count and platelet count.
Figure 2: Dose-response relationship between RDW and risk of VTE obtained by generalized linear regression. The regression model is adjusted for age, sex, body mass index, smoking, self-reported cardiovascular disease, hemoglobin, mean corpuscular volume, mean platelet volume, white blood cell count and platelet count. The solid line shows hazard ratios (HRs) and the shaded area shows 95% confidence intervals (CI). The density plot shows the distribution of RDW and the white vertical lines indicate 2.5th, 25th, 50th, 75th and 97.5th percentiles.
Figure 3: Survival after a venous thromboembolic event according to levels of RDW.
The survival model is adjusted for age, sex, body mass index, smoking, cardiovascular disease, mean platelet volume, white blood cell count, hemoglobin and mean corpuscular volume.
Tables Table 1
RDW quartile 1 quartile 2 quartile 3 quartile 4
N 8164 5078 6649 6332
RDW range (%) 10.7-12.4 12.5 - 12.7 12.8 - 13.2 13.3 - 30.5
Age (years) 41 ± 13 45 ± 14 49 ± 15 54 ± 16
Sex (male, %) 46.2 (3788) 49.2 (2509) 49.5 (3303) 45.1 (2819) BMI (kg/m2) 25.0 ± 3.5 25.2 ± 3.7 25.2 ± 3.9 25.2 ± 4.2 Smoking (%) 28.3 (2522) 34.1 (1782) 40.1 (2619) 46.9 (2738) Self-reported CVD* (%) 5.8 (237) 6.1 (246) 6.7 (491) 8.1 (764) Hemoglobin (g/dL) 14.2 ± 1.1 14.2 ± 1.1 14.1 ± 1.1 13.7 ± 1.4 Mean platelet volume (fl) 8.7 ± 0.9 8.7 ± 0.9 8.7 ± 0.9 8.7 ± 0.9 Mean corpuscular volume (fl) 89 ± 3.4 89 ± 3.5 89 ± 3.8 88 ± 5.8 Platelets (109/L) 248 ± 51.5 249 ± 52.4 252 ± 54.6 262 ± 65.8
WBC (109/L) 6.9 ± 1.8 7.1 ± 2.1 7.2 ± 2.0 7.4 ± 2.2
Anemia (%)** 2.0 (187) 2.5 (125) 3.5 (222) 12.6 (787)
*CVD: Cardiovascular disease
** Anemia defined as hemoglobin levels <12.0 g/dL in females and <13.0 g/dL in men
Table 2
% (n)
Deep vein thrombosis 59.2 (383)
Pulmonary embolism 40.8 (264)
Unprovoked 42.2 (273)
Clinical risk factors
Estrogens (female only) 10.7 (37)
Heredity* 2.3 (15)
Pregnancy/puerperium (women only) 0.6 (2)
Other medical conditions+ 22 (143)
Surgery 14.7 (95)
Trauma 7.6 (49)
Acute medical conditions§ 15.0 (97)
Cancer¤ 23.3 (151)
Immobilization£ 21.3 (138)
Other** 4.8 (31)
*VTE in first degree relative before aged 60 years
+ Includes other diseases within the previous year (myocardial infarction, ischemic stroke, heart failure, inflammatory bowel disease, chronic infections, chronic obstructive
pulmonary disease or myeloproliferative disorders)
¤ cancer is defined as active malignancy at the time of the event
§ Includes myocardial infarction, ischemic stroke or major infectious disease
£ Immobilization includes bed rest > 3 days, travel with car, boat, train or by air > 4 hour within last 14 days, or other type of immobilization
** Other provoking factor described by a physician in the medical record (intravascular catheter etc)
Table 3.
RDW
(range, %) Person-years Events Crude
IR* (95% CI)
Unadjusted HR (95% CI)
Age and sex-adjusted HR (95% CI)
Multiadjusted**
HR (95% CI) Quartile 1
(10.7-12.4) 117 186 126 1.1 (0.9-1.3) Ref Ref Ref
Quartile 2
(12.5 - 12.7) 75 502 110 1.5 (1.3-1.8) 1.4 (1.1-1.8) 1.1 (0.9-1.4) 1.1 (0.8-1.4) Quartile 3
(12.8 - 13.2) 93 593 173 1.8 (1.6-2.1) 1.7 (1.4-2-2) 1.1 (0.9-1.4) 1.1 (0.9-1.4) Quartile 4
(13.3 - 30.5) 82 569 238 2.9 (2.5-3.3) 2.7 (2.2-3.4) 1.5 (1.2-1.8) 1.5 (1.2-1.8)
>95th percentile
(14.4 - 30.5) 14 821 42 2.8 (2.1-3.8) 2.7 (1.9-3.9) 1.6 (1.1-2.2) 1.8 (1.2-2.6)
* Incidence rates are per 1000 person-years
**Adjusted for age, sex, body mass index, smoking, cardiovascular disease, mean platelet volume, white blood cell count, hemoglobin and mean corpuscular volume at baseline.
Table 4.
RDW (range, %)
Person-
years Events Crude
IR* (95% CI)
Crude
HR (95% CI)
Multiadjusted*
* HR (95% CI) Age 25-49
Quartile 1-3 194 959 122 0.6 (0.5-0.7) ref Ref
Quartile 4 41 513 43 1.0 (0.8-1.4) 1.7 (1.2-2.3) 1.7 (1.2-2.5) Age 50-74
Quartile 1-3 81 977 251 3.0 (2.7-3.5) ref Ref
Quartile 4 35 588 147 4.1 (3.5-4.9) 1.4 (1.1-1.7) 1.8 (1.4-2.3) Age 74-97
Quartile 1-3 6 345 36 5.7 (4.1-7.9) Ref ref
Quartile 4 5 469 48 8.8 (6.6-11.6) 1.6 (1.0-2.5) 1.5 (0.9-2-5)
Table 5.
RDW Person-
years Events Crude IR* (95% CI)
Age and sex- adjusted HR (95% CI)
Multiadjusted
** HR (95%
CI) Death after VTE (all deaths)
Quartile 1-3 1827 149 8 (7-10) ref ref
Quartile 4 1000 134 13 (11-16) 1.3 (1.0-1.7) 1.3 (1.0-1.7)
Death within one year after VTE
Quartile 1-3 322 85 26 (21-33) ref ref
Quartile 4 187 56 30 (23-39) 1.0 (0.7-1.4) 0.9 (0.6-1.3)
VTE Recurrence (all)
Quartile 1-3 1639 61 4 (3-5) ref ref
Quartile 4 855 39 5 (3-6) 1.1 (0.7-1.6) 1.1 (0.7-1.6)
VTE Recurrence within one year
Quartile 1-3 314 25 8 (5-12) ref ref
Quartile 4 180 17 9 (6-15) 1.1 (0.6-2.1) 1.1 (0.6-2.1)
* Incidence rates are per 1000 person-years
**Adjusted for age, sex, body mass index, smoking, cardiovascular disease, mean platelet volume, white blood cell count, hemoglobin and mean corpuscular volume
Figures Figure 1
Figure 2
Figure 3
Supplementary table 2.
RDW Person-
years
Events Crude
IR* (95% CI)
Unadjusted HR (95% CI)
Age and sex- adjusted HR (95% CI)
Multiadjusted HR** (95% CI) VTE
Provoked 365 850 374 1.0 (0.9-1.1)
Quartile 1 117 186 72 0.6 (0.5-0.8) Ref Ref Ref
Quartile 2 75 502 63 0.9 (0.7-1.1) 1.4 (1.0-2.0) 1.1 (0.8-1.6) 1.1 (0.8-1.5) Quartile 3 93 593 99 1.1 (0.9-1.3) 1.7 (1.3-2.4) 1.1 (0.8-1.5) 1.1 (0.8-1.4) Quartile 4 82 569 140 1.7 (1.4-2.0) 2.8 (2.1-3.8) 1.5 (1.1-2.0) 1.4 (1.0-1.9) Unprovoked 361 155 128 0.4 (0.3-0.4)
Quartile 1 117 186 54 0.5 (0.4-0.6) Ref Ref Ref
Quartile 2 75 502 47 0.6 (0.5-0.9) 1.4 (1.0-2.1) 1.1 (0.8-1.7) 1.1 (0.8-1.7) Quartile 3 93 593 74 0.8 (0.6-1.0) 1.7 (1.2-2.5) 1.1 (0.8-1.6) 1.2 (0.8-1.7) Quartile 4 82 569 98 1.2 (1.0-1.4) 2.7 (1.9-3.7) 1.4 (1.0-2.0) 1.6 (1.1-2.2) PE
Provoked 361 190 136 0.4 (0.3-0.4)
Quartile 1 116 156 24 0.2 (0.1-0.3) Ref Ref Ref
Quartile 2 71 644 25 0.3 (0.2-0.5) 1.7 (1.0-3.0) 1.3 (0.7-2.3) 1.3 (0.7-2.2) Quartile 3 92 308 39 0.4 (0.3-0.6) 2.1 (1.2-3.4) 1.3 (0.7-2.1) 1.2 (0.7-2.0) Quartile 4 81 082 48 0.6 (0.4-0.8) 3.0 (1.8-4.9) 1.5 (0.9-2.4) 1.3 (0.8-2.2) Unprovoked 361 155 128 0.4 (0.3-0.4)
Quartile 1 116 201 28 0.2 (0.2-0.3) Ref Ref Ref
Quartile 2 71 647 23 0.3 (0.2-0.5) 1.4 (0.8-2.3) 1.0 (0.6-1.8) 1.0 (0.6-1.8) Quartile 3 92 250 36 0.4 (0.3-0.5) 1.6 (1.0-2.7) 1.0 (0.6-1.7) 1.1 (0.6-1.7) Quartile 4 81 057 41 0.5 (0.4-0.7) 2.2 (1.4-3.5) 1.1 (0.7-1.9) 1.2 (0.7-2.1) DVT
Provoked 361 847 238 0.7 (0.6-0.7)
Quartile 1 116 353 48 0.4 (0.3-0.5) Ref Ref Ref
Quartile 2 71 718 38 0.5 (0.4-0.7) 1.3 (0.8-2.0) 1.0 (0.7-1.6) 1.0 (0.6-1.5) Quartile 3 92 459 60 0.6 (0.5-0.8) 1.6 (1.1-2.3) 1.0 (0.7-1.5) 1.0 (0.7-1.4) Quartile 4 81 317 92 1.1 (0.9-1.4) 2.8 (2.0-3.9) 1.5 (1.0-2.1) 1.4 (1.0- 2.1) Unprovoked 360 958 145 0.4 (0.3-0.5)
Quartile 1 116 081 26 0.2 (0.2-0.3) Ref Ref Ref
Quartile 2 71 594 24 0.3 (0.2-0.5) 1.5 (0.9-2.6) 1.2 (0.7-2.1) 1.2 (0.7-2.1) Quartile 3 92 185 38 0.4 (0.3-0.6) 1.8 (1.1-3.0) 1.2 (0.7-2.1) 1.3 (0.8-2.1) Quartile 4 81 098 57 0.7 (0.5-0.9) 3.1 (2.0-5.0) 1.8 (1.1-2.8) 1.9 (1.2-3.2)
* Incidence rates are pr. 1000 person-years
** Adjusted for age, sex, body mass index, smoking, cardiovascular disease, mean platelet volume, white blood cell count, hemoglobin and mean corpuscular volume at baseline.
