Original Article
Dehydration as a Possible Cause of Monthly Variation in the Incidence of Venous Thromboembolism
Clinical and Applied Thrombosis/Hemostasis 2016, Vol. 22(6) 569-574 ª The Author(s) 2016 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1076029616649435 cat.sagepub.com
Saad Elias, MD1, Ron Hoffman, MD1,2, Gleb Saharov, MS1, Benjamin Brenner, MD1,2, and Yona Nadir, MD, PhD1,2
Abstract Background: Monthly or seasonal changes in the incidence of venous thromboembolism (VTE) were previously reported; however, the mechanism of such variability is not completely understood. Methods: In the present retrospective single-center analysis, consecutive patients with proximal deep vein thrombosis and/or pulmonary embolism (PE) diagnosed between January 2009 and December 2013 were evaluated. Results: The study population included 1496 patients, 48% men, mean age 63 + 18 years. Most (82%) cases with VTE were provoked and 39% of patients had active cancer. Four months of peak incidence (3, 7, 10 and 11) were compared with 4 months of the lowest incidence (4, 5, 6, and 12), showing a significant difference in VTE numbers (597 vs 405 cases/year, P ¼ 0.001). In all subgroup analyses, including gender, provoked or unprovoked event and presence or absence of cancer, significant differences between the months of peak and lowest incidence remained. Blood urea nitrogen (BUN)–creatinine ratio was significantly higher in all cases in the peak incidence group compared to the lowest incidence group (24 + 1.5 vs 21 + 1.6, P ¼ 0.03). In patients with unprovoked VTE (n ¼ 269), levels of BUN and hematocrit were significantly increased in the peak incidence group compared to lowest incidence group (19.5 + 0.8 mg/dL vs 16 + 1.1 mg/dL, P ¼ 0.03; 39.2 + 0.3% vs 37.4 + 0.5%, P ¼ 0.01, respectively). Conclusions: The current study demonstrates that occurrence of VTE exhibits monthly variation also existing in patients with provoked events and even in those with cancer. Dehydration is suggested as a potential explanation to the month-related variation in incidence of VTE. Keywords DVT, PE, VTE, dehydration, month, season
Introduction
Methods Incidence of several major adverse cardiovascular events has Study Group been shown to exhibit a seasonal variation. These differences have been reported in acute myocardial infarction,1,2 sudden cardiac death,3 ischemic and hemorrhagic stroke,4,5 and aortic dissection.6,7 The issue of seasonal changes in the incidence of venous thromboembolism (VTE) was also been investigated, but the results appeared to be conflicting. Some studies showed an increased frequency of VTE in winter,8-13 others demonstrated a peak incidence of VTE in autumn,14,15 and some found no seasonal variation in this parameter.16,17 A meta-analysis including 17 studies revealed a significantly increased incidence of VTE in winter, peaking in January.18 Most of the studies were performed in Europe, a region characterized by a relatively cold climate compared to Israel located in the Middle East. The aim of the present study was to evaluate the presence of monthly variation in VTE occurrence in the Israeli population and to investigate affecting variables.
This retrospective single-center study was performed in a tertiary medical center providing services to the population of Northern Israel. The study was approved by the institutional review board (IRB) of the Rambam Health Care Campus (Haifa, Israel). Consecutive patients diagnosed with proximal deep vein thrombosis (DVT) and/or pulmonary embolism (PE) between January 2009 and December 2013 were evaluated. Inclusion criteria were age older than 18 years and 1
Department of Hematology, Thrombosis and Hemostasis Unit, Rambam Health Care Campus, Haifa, Israel 2 The Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel Corresponding Author: Yona Nadir, Department of Hematology, Thrombosis and Hemostasis Unit, Rambam Health Care Campus, Haifa, Israel. Email:
[email protected]
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Table 1. Characteristics of the Study Group.
1496 1116 (75%) 380 (25%) 149 (10%) 713 (48%) 63 + 18 1227 (82%) 269 (18%) 580 (39%)
Abbreviations: DVT, deep vein thrombosis; PE, pulmonary embolism; SD, standard deviation.
symptomatic proximal DVT and/or PE confirmed by radiology tests. The diagnosis of VTE was established using ultrasound Doppler imaging. The diagnosis of PE was confirmed by computerized tomography (CT) angiography or perfusion lung scan. In most cases of DVT, PE screening was performed only in cases of clinical suspicion.
Statistical Analysis Data were evaluated using SPSS software for Windows version 13.0 (SPSS Inc, Chicago, Illinois). Statistics was calculated by t test for independent variables. Values were reported as mean + standard error of the mean. Significance level was set at P < 0.05.
Results The study group included 1496 patients diagnosed with proximal DVT and/or PE: 1160 (75%) cases of proximal DVT, 380 (25%) cases of PE, and 149 (10%) cases of combined presentation (Table 1). One thousand two hundred twenty four (82%) cases were provoked and 269 (18%) were unprovoked. Patients with active cancer comprised 580 (39%) cases (Table 1). Seven hundred thirteen (48%) patients were males. The mean age was 63 + 18 years. Males were younger than females (59 + 17 vs 65 + 18, P ¼ 0.0001). The age difference remained throughout all the months of the year (Figure 1).
Monthly Distribution of DVT and/or PE Cases were most frequent in November and least frequent in May (163 vs 83, P ¼ 0.001, Figure 2A). Average monthly temperature and humidity in Haifa are presented in Figure 2B and Figure 2C. November is in the autumn and May is in the spring (Figure. 2B). Humidity is relatively constant throughout the year (Figure 2C). The 4 months of the peak disease incidence (March, July, October, and November, n ¼ 597) were compared to the 4 months of the lowest incidence (April, May, June, and December, n ¼ 405), showing a statistically significant difference (P ¼ 0.001, Figure 3). The difference between the peak and the lowest incidence months was observed in both genders, although it was more prominent in men than in women (P ¼ 0.001, P ¼ 0.02,
70 65 Age (years)
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60 55 50 45 40
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Figure 1. Effect of gender on deep vein thrombosis (DVT) and/or pulmonary embolism (PE) incidence throughout all the months of the year. Seven hundred thirteen (48%) patients were men (light gray line) and 783 (52%) patients were women (dark gray line). The mean age of men and women were 59 +17 years and 65 + 17 years, respectively, P ¼ 0.0001. The difference was observed throughout all the months of the year.
Figure 3). This difference also remained when cases were divided into provoked (P ¼ 0.002, Figure 3) and unprovoked (P ¼ 0.005, Figure 3). Even in patients with cancer, presenting a specific type of the provoked cases, the difference persisted (P ¼ 0.02, Figure 3).
Blood Urea Nitrogen and Hematocrit in DVT and/or PE Cases Blood urea nitrogen (BUN) –creatinine ratio was significantly higher in all cases in the 4 peak compared to the 4 lowest incidence months (P ¼ 0.03). The difference between the groups remained significant in both provoked and unprovoked cases (P ¼ 0.03, P ¼ 0.05, respectively). Although the difference between the peak and lowest incidence months in terms of BUN or hematocrit (HCT) was not observed in the provoked cases, in cases with cancer, or in relation to gender, a significant difference was found in the unprovoked cases (19.5 + 0.8 mg/dL vs 16.3 + 1.1 mg/dL, P ¼ 0.03 and 39.2 + 0.3% vs 37.8 + 0.5%, P ¼ 0.01, respectively, Figure 4). Levels of creatinine, hemoglobin, white blood cells, platelets, mean corpuscular volume, and albumin did not demonstrate significant intermonth difference either within the group as a whole or between the subgroups.
Discussion The present study revealed monthly variations in the incidence of VTE in the study population. In Israel, April, May, and June are the spring months and October and November are the autumn months. Hence according to the results of the current study, the occurrence of VTE is lowest in spring and highest in
Elias et al
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Figure 2. Monthly distribution of deep vein thrombosis (DVT) and/or pulmonary embolism (PE). A, Cases were most frequent in November and least frequent in May (163 vs 83, P ¼0.001). Four months of the peak occurrence (March, July, October and November, n ¼ 597) were compared to 4 months of the lowest occurrence (April, May, June, and December, n ¼ 405). Average monthly temperature and humidity in Haifa are presented (B and C). April, May, and June are the spring months and October and November are the autumn months (B). Humidity is relatively constant throughout the year (C).
autumn (Figure 2). Consistent with these findings, Manfredini et al, in a large multicenter Italian study of 2119 cases, found that VTE was most frequent in autumn and less frequent in spring.15 Interestingly, in our study, this difference persisted in the provoked cases. Even in patients with such a major risk factor as active cancer, monthly variation in the VTE occurrence still remained (Figure 3), implying a significant impact of the season on this parameter. The gender difference in the incidence of VTE above the age of 50 years, found in the present study (Figure 1), had been previously demonstrated.19 It may be attributed to the end of female reproductive age. This difference, according to our results, remained throughout the year. At our hospital, patients with proximal DVT or PE are hospitalized. Patients who are released from the emergency department with recommendations for home therapy are very rare, and patients who are not referred to the emergency department are even rarer, although it is possible that this small group of patients has not been included in the study database. As patients with all types of thrombosis are referred to our hospital as well as to local hospitals, no recruitment bias in some VTE subtypes was expected.
Mechanisms involved in monthly or seasonal variation in VTE remain controversial. Nimako et al from the United Kingdom studied retrospectively 640 episodes of unprovoked PE in a single center. Lowest prevalence was in spring and was related to climate effects of decreased atmospheric pressure and increased temperature.20 Other studies indicating a correlation between prevalence of VTE and atmospheric pressure were published.21,22 To date, no study has evaluated simple parameters of dehydration such as BUN and HCT in correlation with monthly variation in VTE occurrence. Dehydration as a significant risk factor for the development of VTE was mainly studied in relation to air flights, bariatric surgeries, and ischemic strokes. 23-25 Additionally, in pediatric cerebral thrombosis, dehydration was found to be a major contributing factor.26 The effect of dehydration on the coagulation system was evaluated in a mouse model, showing a significant increase in the tendency to form clots in the dehydration state, which was alleviated by the addition of acetyl salicylic acid.27 In the present study, a significant monthly variation in the BUN– creatinine ratio was observed in all patients, whereas the difference in BUN and HCT was found only in patients with
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Peak 4 months Lowest 4 months 700
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600 P=0.002 Number of cases
500 400 P=0.001
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200 P=0.005 100 0
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Figure 3. Incidence of deep vein thrombosis and/or pulmonary embolism (PE) events in peak versus lowest incidence months. Four months of the peak incidence were compared to 4 months of the lowest incidence showing a statistically significant difference (P ¼ 0.001). This difference was observed in both genders although it was more prominent in men than in women (P ¼ 0.001, P ¼ 0.02, respectively). The difference also remained when the cases were divided into provoked (P ¼ 0.002), unprovoked (P ¼ 0.005), and with active cancer (P ¼ 0.02).
P=0.03
unprovoked VTE. Hence, the BUN–creatinine ratio may be considered a more sensitive marker of dehydration. The fact that the monthly variation was observed in patients with provoked VTE and in patients with cancer, with no significant difference in either BUN or HCT levels, does not exclude the involvement of dehydration. In the present study, patients in the provoked group had higher levels of BUN and lower levels of HCT compared to the unprovoked group (Figure 4). Patients with cancer are known to have increased prevalence of renal failure and anemia that may affect the evaluated parameters. In addition, we have no data on the patients’ meat diet composition or occult bleeding in the gastrointestinal tract that could increase the BUN. Possibly, measuring blood and/or urine osmolality would have strengthened the role of dehydration as a monthly risk factor in the provoked cases. Dehydration was suggested as a possible explanation to the finding, although no correlation with the temperature was revealed. We may only speculate that in hot weather people are accustomed to drinking more fluid, thus avoiding dehydration, whereas in winter, spring, and autumn, such awareness is less prominent. We did not find data in the literature regarding possible natural variation in BUN and hematocrit (HCT) in the Israeli population, thus this issue remains a limitation of our work. Interestingly, the seasonal pattern of depressive mood disturbances that are usually observed in the autumn and winter with remission in the spring or summer is well established. In a
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Figure 4. Blood urea nitrogen (BUN) and hematocrit (HCT) in deep vein thrombosis (DVT) and/or pulmonary embolism (PE) cases. The BUN– creatinine ratio was significantly higher in all the cases in the 4 peak compared to the 4 lowest incidence months (P ¼ 0.03). The difference between the groups remained significant in both provoked and unprovoked cases (P ¼ 0.03, P ¼ 0.05, respectively). Blood urea nitrogen and HCT in the unprovoked cases were significantly increased in the 4 peak compared to the 4 lowest incidence months (P ¼ 0.03, P ¼ 0.01, respectively). No significant difference in BUN and/or HCT was observed in the provoked cases.
Elias et al given year, about 5% of the US population experiences seasonal affective disorder, with symptoms present for about 40% of the year.28 Depressive mood may affect physical activity, and not only food intake but also drinking resulting in relative dehydration, hence contributing to an increased thrombosis risk. In addition, depression is characterized by high plasminogen-activating inhibitor 1 (PAI-1) levels augmenting the predisposition to thrombosis.29 Therefore, it is possible that increased incidence of depressive mood disturbances in the autumn contribute to the occurrence of VTE via dehydration, decreased physical activity, and elevated PAI-1. In conclusion, the present study emphasizes the need for regional assessment of monthly or seasonal variation in the occurrence of VTE in relation to the different climates. Interestingly, monthly variation was demonstrated not only in unprovoked cases but also in provoked cases and even in patients with cancer. Dehydration was suggested to be a possible contributing risk factor to these variations, although other mechanisms should be further investigated. Authors’ Note Saad Elias and Ron Hoffman contributed equally to this work.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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