Venous thromboembolism (VTE) occurs when a blood clot breaks loose and travels freely in the blood. Deep vein thrombosis (DVT) is a blood clot in a deep vein, most often in the lower extremities, which may break off and travel to the lungs, causing a pulmonary embolism (PE). PEs can cause acute cardiopulmonary collapse and death [1], and, when not fatal, may be associated with chronic complications such as post-thrombotic syndrome and chronic thromboembolic pulmonary hypertension [2]. The social and economic costs associated with VTE are significant [3] and lead to decreased quality of life for patients and caretakers. Therefore, it is critical to identify factors contributing to increased VTE incidence to improve monitoring of those at risk and to enable proper and timely prevention and treatment.

Several VTE risk factors have been identified and include old age, inherited thrombophilia, surgery, and cancer and other comorbidities; additionally, VTE is more common in women than in men [4]. Because many of these factors are unchangeable and unavoidable, identifying and leveraging environmental factors contributing to VTE likely represents a better approach for VTE prediction and prevention. Seasonal variation is a proposed environmental factor associated with VTE incidence, with several studies reporting a seasonal or monthly variation in the incidence of VTE [5-16]. However, some studies failed to detect an association between season and VTE [17] or reported only a small association [18]. These results may be due to differences in the definition of seasonal or monthly variation across studies; however, differences in annual climate patterns and geography as well as ethnicity (and therefore, genetics) may play a role. For example, the genetic factors associated with VTE in Asian populations are fundamentally different from those in Western populations [19,20].

Whether seasonal variation affects VTE in Asian populations remains unclear. A previous retrospective study of 1,495 Korean VTE patients indeed reported an increased risk of VTE in winter [21]; however, the number of patients evaluated was relatively small, and over 90% of patients were inpatient cases diagnosed in tertiary teaching hospitals [21]. We therefore conducted a nationwide epidemiologic study to evaluate the extent of seasonal and monthly variation in VTE incidence among the Korean population from January 2009 to December 2013. We also evaluated the impact of age, sex, cancer, and thromboembolism type on seasonal and monthly VTE variation to fully elucidate the factors affecting VTE seasonal variation.

Here, using data available in a nationwide database, we demonstrate seasonal and monthly variation in VTE incidence in the Korean population. We assessed NHIS claims records for over 59,000 VTE patients, making this the largest study of its kind in an Asian population. Our results agree with several other studies [5,6,8,9,11,14] and a meta-analysis [16] in other populations also reporting an association between seasonal climate change and VTE incidence. We specifically observed highest incidence of VTE in the winter months, which may be due to a thrombophilia caused by increased fibrinogen and red blood cell aggregation in the cold environment [24]. Seasonal variation has also been pathophysiologically explained by the circannual rhythm (endogenously generated, year-long biological rhythms), which has been proposed in other systemic vascular disorders [25-28].

The only other study in another population that rivals the size of ours is a United States-based study comprised of 7,682,000 VTE patients diagnosed between 1979 and 1999 [17]. Unlike our study and many others, VTE incidence was not associated with season. These contrasting results were previously partly explained by the usage of different analysis methods across studies [29,30]. Additionally, the United States study is older than most; therefore, although the number of patients was large, they were diagnosed mostly in 1980s and 1990s, which likely does not reflect the current medical environment with improved early screening and diagnostic techniques for VTE. Our study, which is large-scale, better reflects the current medical landscape, and takes place in a geographical region with sharp seasonal climate differences therefore yields more reliable and realistic conclusions regarding seasonal variation of VTE incidence.

In our study, seasonal variation was stronger in patients with PE, with a particularly strong association between PE incidence and the winter season. This result aligns with other studies reporting seasonable variability for other potentially fatal vascular conditions, such as myocardial infarction [25,28], stroke [26], and aortic dissection [27], as well as with several reports in the 1990s describing a higher incidence of fatal PE in winter [5,7,8,13]. Several studies have also reported seasonal variation in the incidence of non-fatal PE [10,12]. Moreover, recently published studies showed that the seasonal variation of PE incidence was affected by age of patients [11,14], in line with our study, and suggest that for younger patients, other factors including inherited thrombophilia or diagnosis of cancer may have a stronger impact on the incidence of PE.

The strong association between season and PE incidence may have several explanatory mechanisms. First, inhalation of cold air produces a considerable increase in blood viscosity [31], increasing the risk for thrombophilia during the cold winter season [32]. Second, pulmonary infections and aggravation of pulmonary diseases such as chronic pulmonary obstructive disease are more common in winter [33]. Inflammation of pulmonary blood vessels caused by these conditions may provoke de novo PE or complicate recovery from DVT-caused pulmonary vascular clots. Third, sepsis also occurs more frequently in winter [34], and considering that the surface area of the pulmonary vasculature is larger than that of the lower extremities, pulmonary inflammation may be more likely to facilitate PE. Finally, during winter season air pollutants are elevated [35], particularly in big cities, and this may be responsible for the seasonal variation of PE, as in other cardiovascular diseases [36]. Future studies considering these factors will be critical to fully characterize the relationship between season and PE incidence and inform clinicians regarding best practices for early PE detection at different times of year.

Unlike PE, reports of seasonal variation in DVT incidence are conflicting. Some early studies reported no seasonal or monthly variation in patients with DVT, but they also did not indicate whether DVT patients had concomitant PE or not, which may skew results [6,37]. An Italian study of 1,164 consecutive cases of DVT reported at a single institution from 1998 to 2002 revealed a peak in DVT incidence in winter, with a lower incidence in summer [9]; however, 793 patients (68.1%) had concomitant PE a variable which was not controlled for. The Italian multicenter MASTER study (January 2002 to November 2004 [32]) did evaluate DVT and PE seasonal variability separately in 2,119 VTE patients (72.7% of patients had DVT alone) reporting seasonal variation in the incidence of both VTE and PE, with peak incidence in winter and lowest incidence in summer [38]. Similar observations were reported using data from the Swedish Hospital Discharge Register from 1987 to 2010, but a family history of VTE was a confounding factor when considering seasonal variation in DVT incidence [14]. In our study, we consider DVT and PE separately, and observed a weak, insignificant association between season and DVT incidence. The association was even weaker in younger patients and in those with cancer, suggesting that seasonal variation is a relatively weak contributor to VTE occurrence compared to inherited thrombophilia or combined malignancy. This observation supports a nationwide Swedish family study in Sweden [14]; however, doctors and patients should not assume that these results indicate that young patients or patients with cancer should dismiss the risk of VTE in winter.

Detection of low-burden, isolated DVT has improved drastically, which may explain the less prominent seasonal variation in patients with DVT alone, and we propose that it can be assumed that earlier stage, minimally or asymptomatic DVT can occur without the influence of seasonal change. For those with earlier staged DVT, which often presents as DVT alone, factors other than seasonal variation seem to be more influential on DVT incidence. Further studies are needed to evaluate these potential explanations for the lack of seasonal variation in DVT incidence.

Our study has several limitations. First, the information in the HIRA database was insufficient to discern between provoked and unprovoked VTE or to sub-divide patients into of VTE into inpatient or outpatient. Because we collected VTE patients with cancer according to having diagnostic code for cancer at the time of diagnosis, we could not clearly discern actual status of cancer for each patient. We could not evaluate provoking conditions such as surgery, bone fracture, or pregnancy. However, such provoking factors themselves are not likely to occur in particular seasons. If DVT is diagnosed first in practice then co-existing PE was confirmed later, physician may not have registered additional diagnostic code for PE. For this reason, there is a risk of overestimation of the incidence of isolated DVT. Despite some of these limitations, our study clearly demonstrated seasonal variation in overall VTE incidence in the Korean population and identified sub-groups for which this association is strongest. This study would be a springboard to further studies designed to inform improved VTE detection, prevention, and patient education in Korea and Asian population.