Body height, mobility, and risk of first and recurrent venous thrombosis

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1 Journal of Thrombosis and Haemostasis, 13: DOI: /jth ORIGINAL ARTICLE Body height, mobility, and risk of first and recurrent venous thrombosis L. E. FLINTERMAN,* A. VAN HYLCKAMA VLIEG,* F. R. ROSENDAAL* and S. C. CANNEGIETER* *Department of Clinical Epidemiology, Leiden University Medical Center; and Department of Thrombosis and Haemostasis, Leiden University Medical Center, Leiden, the Netherlands To cite this article: Flinterman LE, van Hylckama Vlieg A, Rosendaal FR, Cannegieter SC. Body height, mobility, and risk of first and recurrent venous thrombosis. J Thromb Haemost 2015; 13: Summary. Background: Tall people have an increased risk of a first venous thrombosis. Sedentary lifestyle has been shown to act synergistically with body height, especially during long-haul flights. Objective: To estimate the relation between height and risk of a first and recurrent venous thrombosis and a possible additional association with a mobile or an immobile lifestyle. Methods: Patients with a first venous thrombosis and control subjects were included between 1999 and 2004 (MEGA case control study). Patients were followed for recurrence for an average time of 5.1 years (MEGA follow-up study). Odds ratios and hazard ratios (HRs) per increase of 5 cm were calculated compared with a height of cm, separately and in combination with (im)mobility. Results: In 4464 patients who reported their height, we found an increasing risk of a first and recurrent event with height. For men, a 2.9-fold (95% confidence interval [CI] ) increased risk for first venous thrombosis was found for those between 195 and 200 cm and a 3.8-fold (95% CI ) higher risk for those > 200 cm compared with the reference category. For recurrence risk, the HRs were 1.7 (95% CI ) and 3.7 (95% CI ), respectively. For women, a 1.5-fold (95% CI ) and 3-fold (95% CI ) increased risk was found for those > 185 cm for first and recurrent venous thrombosis, respectively. For the tallest men and women, a slight additionally increased risk was observed for sedentary lifestyle. Conclusions: Tall men and women have an increased risk of first and recurrent venous thrombosis, possibly higher in combination with a sedentary lifestyle. Correspondence: Suzanne C. Cannegieter, Clinical Epidemiology C7-P, P.O. Box 9600, 2300 RC Leiden, the Netherlands. Tel.: ; fax: s.c.cannegieter@lumc.nl Received 3 June 2014 Manuscript handled by: I. Pabinger Final decision: I. Pabinger, 31 December 2014 Keywords: body height; life style; recurrence; risk; venous thrombosis. Introduction Tall people have an increased risk of a first venous thrombosis [1 6]. Body height affects venous pressure dynamics [7,8], so taller people may have more stasis in the legs, which could explain the increased risk. Because men are taller than women in general, most previous studies were restricted to men or only found an increased risk for men [2,4]. Prolonged seated immobility such as during work or long-haul flights has been found to be a risk factor for a first venous thrombosis [9 11] Prolonged seating induces compression of the popliteal vein and reduces blood flow from the lower leg. This association will most likely be stronger in tall people who may be seated in a more cramped position, leading to more compression of their popliteal vein than in people of average height. The combination of prolonged seating and being particularly tall was indeed found to increase the risk of thrombosis substantially during long-haul flights [10,11]. The same was found for short people, where we hypothesized that their feet may not reach the floor in standard seats [10,11]. It is not well known to what extent prolonged immobility during daily life affects the risk of venous thrombosis in tall or short people. The risk of a recurrent venous thrombotic event is generally high but is low in those with transient risk factors. Because height is a non-modifiable risk factor, it could well be that height also affects the risk of a recurrent event, particularly in combination with prolonged seating. Men have a higher risk of both first and recurrent venous thrombosis than do women, and we hypothesized that this could be explained by their generally greater height [12 14]. The aim of this study was to investigate the risk of a first and a recurrent venous thrombosis in relation to height in men and women separately, as well as the

2 Body height, mobility, and venous thrombosis 549 association of prolonged seated immobility in combination with body height. We studied this in a large unselected population of nearly 5000 patients with a first venous thrombosis, of whom nearly 700 developed a recurrence, and 5000 control subjects. Methods Study population The Multiple Environmental and Genetic Assessment (MEGA) study of risk factors for venous thrombosis is a large population-based case control study that included 4956 cases with a first venous thrombosis and 6297 control subjects between March 1999 and September Cases were included at six anticoagulation clinics, which monitor virtually all outpatient treatment with vitamin K antagonists; control subjects were either partners of the cases (n = 3297) or recruited through the use of random digit dialing (n = 3000) [15,16]. All participants of the MEGA study filled in an extensive questionnaire on risk factors for venous thrombosis. Questions were asked about the year previous to the thrombotic event. Body height was reported by 4464 (90%) cases and 5803 (92%) controls. The definition of immobility during the day was based on a combination of two questions: (i) How do you spend most of your day? (possible answers were standing, walking, sitting, or lying down) and (ii) How do you classify your daily activities regarding physical activity (an answer could be chosen from four categories ranging from light to heavy). The answers walking and standing and the two heavy categories of physical activity during the day were classified as mobile and all others as not mobile. If the two questions contradicted each other (23%), we used the answer to the question about daily physical activity as we considered this question more specific for prolonged seated immobility. If participants filled in just one of the two questions, only that question was taken into account. The question: How do you spend most of your day was filled in by 3117 (30%) participants, as this question was present in only part of the questionnaires. In total, 7414 (72%) participants filled in the question about their daily activity. When both questions were combined, information on physical activity was present for 8458 (82%) participants. Subsequently, a follow-up study was performed for the 4731 cases who participated in the MEGA case control study and agreed to participate in the follow-up study, with the aim to establish incidence rates of and risk factors for a recurrent event. Questionnaires about recurrent events were sent to all patients known to be alive. In addition, we checked the records of all patients at the anticoagulation clinics to find all possible recurrent events. Recurrences were confirmed with discharge letters using a decision rule, which was described previously (L.E. Flinterman, A. van Hylckama Vlieg, S. Le Cessie, S.C. Cannegieter, F.R. Rosendaal, unpublished data). A total of 673 patients developed a certain recurrence, while 219 subjects with uncertain recurrence were censored at time of possible recurrence. Body height as reported at time of first venous thrombosis and the association with prolonged immobility during daily life were studied as risk factors for recurrence. During follow-up, we had information on 4264 (90%) patients about their body height at baseline and on 3999 (85%) patients about physical activity at baseline. Statistical methods Height was divided in categories of 5 cm starting from 155 cm up to 200 cm. All participants shorter than 155 cm were grouped and formed the lowest height category. All subjects taller than 200 cm formed the highest height category. The category of cm contains the average body height of Dutch women during the study period. Because we wanted the same reference category for men and women, we chose this category as reference category as there were too few women in the category that contained the average body height for Dutch men ( cm) [17]. To determine the association between height and first venous thrombosis, odds ratios for the different height categories were calculated as estimates of the incidence rate ratio (relative risk). All odds ratios were adjusted for age to take the matching into account. Other factors were not taken into account as other risk factors for venous thrombosis do not influence a person s height and therefore cannot be confounders for the association. For determining the association between height and a recurrent event, incidence rates were calculated per height category (number of recurrences per height category per number of person-years per category). The HRs for recurrence per height category compared with those of average height ( cm) were calculated. The proportional hazard assumption was verified by evaluating the parallelism between the curves of the log-log survivor function. Overall risks of height for a first venous thrombosis in these data have been published earlier, so here we do not repeat the overall analysis but describe the results for first venous thrombosis for men and women separately [3]. For recurrent venous thrombosis, incidence rates and HRs were calculated overall and for men and women separately. We used 10-cm categories of height to study the combination of height and (im)mobility during daily life. For these analyses, we used a height of cm as reference category. These analyses were done for both first and recurrent venous thrombosis and for men and women separately. Lastly, to determine the effect of missing data on activity level, we performed a sensitivity analysis in which we first included all missing patients as active and next as inactive to see if the risk estimates would change.

3 550 L. E. Flinterman et al Results For the case control setup, a total of 4464 patients and 5803 controls reported their body height and therefore were included; 45.9% of patients and 46.2% of controls were men. Median age of the patients was 54.9 years (5th 95th percentile ) for men and 45.8 (5th 95th percentile ) for women. Median age of the control subjects was 48.4 (5th 95th percentile ) for men and 48.0 (5th 95th percentile ) for women. Among the 4365 patients who reported body height and participated in the follow-up study, 648 recurrent events were identified during follow-up. The mean duration of follow-up was 5 years. The overall recurrence rate among these patients was 28.5 (95% CI ) per 1000 person-years. First venous thrombosis For men, a steadily increasing risk of a first venous thrombosis with higher body height was found, with an up to 3.8-fold increased risk (95% CI ) for the tallest men (> 200 cm) compared with subjects with a height of cm (Table 1). This association was less strong for women, with a 1.5-fold higher risk (95% CI ) for the tallest women (> 185 cm) compared with the same reference group. For men, a higher risk was also found for the shortest participants (< 155 cm) compared with subjects with a height of cm, although numbers were small here (OR 3.7, CI ). Seated immobility was associated with an overall 1.2- fold (95% CI ) increase in risk of first venous thrombosis for men and a 1.4-fold (95% CI ) increase in risk for women. When seated immobility during daily life was analyzed jointly with body height, we found the highest risk in the tallest men (200 tallest) who were not mobile most of the day (OR 4.7, CI 95% ) compared with men with a height of cm who were mobile during the day. This joint association of height and immobility was present only in the tallest category (Table 2). For women in all categories of body height, a slightly higher risk of a first venous thrombosis was seen when Table 1 Body height as risk factor for a first venous thrombosis Men (N = 4729) Women (N = 5538) Height (cm) N Cases N Controls OR adj (95% CI)* Height (cm) N Cases N Controls OR adj (95% CI)* Smallest ( ) Smallest ( ) ( ) ( ) ( ) ( ) (ref) (ref) ( ) ( ) ( ) ( ) ( ) ( ) ( ) 185 tallest ( ) ( ) ( ) 201 Tallest ( ) OR, odds ratio; 95% CI, 95% confidence interval; OR adj, adjusted odds ratio. *Odds ratios were adjusted for age. Table 2 Body height and seated immobility in daily life in relation to risk of first venous thrombosis Men (N = 4558) Women (N = 4614) First venous thrombosis Body height (cm) Mobile Cases (N) Controls (N) OR adj * Cases (N) Controls (N) OR adj * Smallest 160 Yes ( ) ( ) Smallest 160 No ( ) ( ) Yes No ( ) ( ) Yes ( ) ( ) No ( ) ( ) Yes ( ) ( ) No ( ) ( ) Yes ( ) No ( ) 201 tallest Yes ( ) 201 tallest No ( ) OR adj, adjusted odds ratio. *Odds ratio adjusted for age. For women, this category is 180 tallest.

4 Body height, mobility, and venous thrombosis 551 these women were mainly seated during the day. The largest risk was found for women of cm who were not mobile (HR 3.1, CI 95% ) compared with mobile women of cm (Table 2). For recurrent venous thrombosis, we also observed a gradual increase in risk with body height (Table 3A), which attenuated somewhat after adjustment for age and sex. When we stratified on sex, we found an increase in risk for both tall men and tall women. Of 14 men who were taller than 200 cm, five developed a recurrent event, leading to an incidence rate of 111 per 1000 person-years (95% CI ) and an HR of 3.7 (95% CI ) compared with male subjects with a height of cm; for women of cm, we found an HR of 3.0 (95% CI ) compared with female subjects with a height of cm (Table 3B,C). In short women (< 155 cm), we found a 1.7-fold (95% CI ) Table 3 Body height as a risk factor for a recurrent venous thrombosis. A: Overall N = 4365 Height (cm) N Total N rec IR (95% CI) HR (95% CI) HR adj (95% CI)* Smallest ( ) 1.5 ( ) 1.6 ( ) ( ) 0.6 ( ) 0.6 ( ) ( ) 0.7 ( ) 0.8 ( ) ( ) 1 (ref) 1 (ref) ( ) 1.1 ( ) 0.9 ( ) ( ) 1.5 ( ) 1.1 ( ) ( ) 1.7 ( ) 1.2 ( ) ( ) 2.2 ( ) 1.5 ( ) ( ) 1.5 ( ) 1.0 ( ) ( ) 2.4 ( ) 1.6 ( ) ( ) 3.2 ( ) 3.6 ( ) B: Men N = 1949 Height (cm) N Total N rec IR (95% CI) HR (95% CI) HR adj (95% CI)* Smallest ( ) 1.2 ( ) 1.2 ( ) ( ) 1 (ref) 1 (ref) ( ) 1.0 ( ) 1.0 ( ) ( ) 1.1 ( ) 1.2 ( ) ( ) 1.2 ( ) 1.3 ( ) ( ) 1.4 ( ) 1.5 ( ) ( ) 1.0 ( ) 1.1 ( ) ( ) 1.5 ( ) 1.7 ( ) 201 tallest ( ) 3.2 ( ) 3.7 ( ) C: Women N = 2315 Height (cm) N Total N rec IR (95% CI) HR (95% CI) HR adj (95% CI)* Smallest ( ) 1.7 ( ) 1.7 ( ) ( ) 0.6 ( ) 0.6 ( ) ( ) 0.7 ( ) 0.7 ( ) ( ) 1 (ref) 1 (ref) ( ) 0.9 ( ) 0.9 ( ) ( ) 1.1 ( ) 1.2 ( ) ( ) 0.7 ( ) 0.7 ( ) 186 tallest ( ) 2.9 ( ) 3.0 ( ) rec, recurrences; IR, incidence rate; HR, hazard ratio; 95% CI, 95% confidence interval; HR adj, adjusted hazard ratio. *A: adjusted for age and sex, B and C: age. Per 1000 person-years.

5 552 L. E. Flinterman et al increased risk with a height of cm as the reference. Overall, the same pattern in risk of recurrence related to body height was seen for men and women (Fig. 1). However, the recurrence rate for women was lower for almost each height. Seated immobility at time of first venous thrombosis was associated with an overall 1.1-fold (95% CI ) increased risk of recurrence in men and a 1.5-fold (95% CI ) increase in risk in women. When seated immobility was analyzed jointly with body height, we saw a possible higher risk for the combination only for the tallest category, which consisted solely of men (HR 8.7 [95% CI ] for immobile subjects > 200 cm vs. mobile subjects of height cm) (Table 4). In a sensitivity analysis to determine the effect of missing data on (im)mobility on the risk estimates, no substantial differences were observed when we performed a complete case analysis vs. including all missing patients as either active or inactive (data not shown). Discussion In this study, body height was positively associated with the risk of both first and recurrent venous thrombosis, particularly in the tallest men, in whom 3- to 4-fold increased risks were found for both types of events. Prolonged seated immobility appeared to further increase the risk of a first and a recurrent venous thrombosis mainly in the highest height categories. Previous studies have shown an increased risk of a first venous thrombosis with greater body height [1 6], but most used large categories of body height such as quartiles. The Dutch population is one of the tallest populations in the world and, together with our large study size, this allowed a finer categorization of height for men and women separately in our study. Our results on the combined association of height with immobility during daily life are in line with risks found before for tall and short people during long-haul flights [18]. To our knowledge, Incidence rate per 1000 person years Men Women Body height Fig. 1. Incidence rate of recurrent venous thrombosis per body height category for men and women separately. Bars indicate 95% confidence intervals. one previous study on the association of body height on recurrent venous thrombosis has been performed, in a large cohort of women > 65 years old [19]. In this study, height was split into three categories and a clear doseresponse relation was found, which was strongest for unprovoked first events with an HR of 2.20 (95% CI ) for heights > cm vs. those < cm. Our results are not directly comparable because our reference category was included in their highest height category. This study in a large group of patients shows that tall subjects are at increased risk of venous thrombosis and that body height is a risk factor for recurrent venous thrombosis. The explanation for an increased risk for tall men and women probably lies in their long legs, where stasis is more present due to a higher resting venous pressure [7]. Although generally a dose-response relation appears to be present with greater height and increasing risk, there may be a threshold (< 155 cm) below which the risk of (recurrent) venous thrombosis increases in short people, as has also been found in air travel studies [10,11]. An explanation may be that in some seats these individuals cannot plant their feet on the floor, which leads to compression of the popliteal vein and more stasis. Body height cannot fully explain the overall higher risk of recurrent venous thrombosis in men compared with women for two reasons. First, for men and women with the same body height, the incidence of recurrence was still 2-fold higher in men than in women (Fig. 1). Second, when we analyzed sex as a risk factor for recurrent venous thrombosis and adjusted the estimate for body height, the association of sex diminished only slightly, from 2.2 to 1.8. So even after adjustment for body height, an ~2-fold increase in risk for recurrence in men remains. Some limitations of this study need attention. First, both body height and mobility were self-reported. However, with respect to body height, misclassification would most likely be minor and random and equally present in cases and controls, which would at most have attenuated the results. Being mobile during the day has not been questioned in great detail in our questionnaires. The small additional increase in risk we observed for seated immobility may well be larger when mobility is assessed in more detail. Only 30% of the participants answered the question on how they spent most of the day. This did most likely not affect our results because we considered the question about physical activity, which was filled in by 72%, as the most accurate. Furthermore, a sensitivity analysis showed that missingness of this variable had no influence on the results. Another potential limitation is that we assessed body height while leg length may be more informative if we assume that the mechanism is through increased stasis in the legs [18]. Because greater body height already showed an increase in risk, an association with leg length is expected to be even stron-

6 Body height, mobility, and venous thrombosis 553 Table 4 Body height and mobility in daily life and risk of recurrent venous thrombosis for men and women combined (A) and separately (B) N = 3835 Body height (cm) Mobile N total N rec HR (95% CI) HRadj* (A) Smallest 160 Yes ( ) 0.6 ( ) Smallest 160 No ( ) 1.0 ( ) Yes (ref) 1 (ref) No ( ) 1.2 ( ) Yes ( ) 1.2 ( ) No ( ) 1.7 ( ) Yes ( ) 2.1 ( ) No ( ) 2.3 ( ) Yes ( ) 2.3 ( ) No ( ) 2.1 ( ) 201 tallest Yes ( ) 3.5 ( ) 201 tallest No ( ) 8.7 ( ) Men (N = 1869) Women (N = 1966) Body Height (cm) Mobile N total N Rec HR (95% CI) HRadj N total N Rec HR (95% CI) HRadj (B) Smallest 160 Yes ( ) 0.7 ( ) Smallest 160 No ( ) 1.2 ( ) Yes (ref) 1 (ref) (ref) 1 (ref) No ( ) 0.7 ( ) ( ) 1.3 ( ) Yes ( ) 0.7 ( ) ( ) 0.9 ( ) No ( ) 0.9 ( ) ( ) 1.6 ( ) Yes ( ) 0.9 ( ) ( ) 2.1 ( ) No ( ) 1.0 ( ) ( ) 1.1 ( ) Yes ( ) 0.9 ( ) No ( ) 0.9 ( ) 201 tallest Yes ( ) 1.5 ( ) 201 tallest No ( ) 3.3 ( ) cm, centimeters; N, number; HR, hazard ratio; 95% CI, 95% confidence interval; HR adj, adjusted hazard ratio. *Adjusted for age and sex. Adjusted for age. For women this category is 180 tallest. ger. Last, even though our study population consisted of almost 5000 cases with a first venous thrombosis, of whom 648 experienced a recurrent event, only a few patients were very tall or very short. Therefore, the statistical power in these subgroups was low and chance findings cannot be excluded. However, our results for first thrombosis are in line with earlier findings and the pattern for recurrence was the same as for first. As, in addition, these results are biologically plausible, we are confident that chance did not play a major role. In conclusion, in this population based study in 4464 patients with a first thrombosis of whom 631 had a recurrent event, we found an increased risk for both first and recurrent venous thrombosis with greater body height for both men and women. The association was more pronounced for tall subjects who are less mobile during the day. Addendum L. E. Flinterman analyzed and interpreted the data, wrote the manuscript, and approved the final version, A. van Hylckama Vlieg revised the manuscript and approved the final version, F. R. Rosendaal revised the manuscript and approved the final version, and S. C. Cannegieter contributed to the concept of the manuscript, interpreted the data, revised the manuscript, and approved the final version. Acknowledgements We thank the directors of the Anticoagulation Clinics of Amersfoort (M. H. H. Kramer, MD), Amsterdam (M. Remkes, MD), Leiden (F. J. M. van der Meer, MD), The Hague (E. van Meegen, MD; J. F. Geenhuizen, MD), Rotterdam (A. A. H. Kasbergen, MD; L. M. H. R akers, MD), and Utrecht (J. de Vries-Goldschmeding, MD; B. Frijling, MD) who made the recruitment of patients possible. The interviewers (J. C. M. van den Berg, B. Berbee, S. van der Leden, M. Roosen, and E. C. Willems of Brilman) performed the blood draws. I. de Jonge, MSc; R. Roelofsen, MSc; M. Streevelaar; L. M. J. Timmers, MSc; and J. J.

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