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National trends in venous thromboembolism-related mortality among pancreatic cancer patients in the United States, 1999–2020

Thrombosis Journal volume 23, Article number: 73 (2025) Cite this article

Abstract

Background

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Pancreatic ductal adenocarcinoma (PDAC) carries a high risk of venous thromboembolism (VTE), which significantly contributes to mortality. However, national trends in VTE-related deaths among this population remain poorly defined.

Methods

We conducted a cross-sectional analysis of U.S. mortality data from 1999 to 2020 using the CDC WONDER platform. Deaths were included if VTE was the underlying cause and pancreatic cancer a contributing cause. Age-adjusted mortality rates (AAMRs) were calculated, and Joinpoint regression was used to assess temporal trends, with subgroup analyses by sex, race/ethnicity, age, region, urbanization level, and place of death.

Results

A total of 20,373 VTE-related deaths occurred in pancreatic cancer patients. The overall AAMR was 0.36 per 100,000 population. A significant increase in mortality was observed, particularly from 2016 to 2020 (APC: 8.71%; p = 0.0039). Males had a higher AAMR than females (0.46 vs. 0.35). Black individuals experienced the highest mortality rate (0.62), followed by White (0.40) and Hispanic (0.36) populations. The burden increased sharply with age, peaking in the 75–84 age group (1.67). Geographic variation was notable, with the Midwest and West showing the highest AAMRs. Urban–rural differences were minimal, though trends rose in both settings. One-third (31.4%) of deaths occurred at home, highlighting potential gaps in outpatient management and end-of-life care.

Conclusion

VTE-related mortality in pancreatic cancer is rising, with disproportionate effects on older adults, males, and Black individuals. These findings highlight the need for tailored prevention strategies, equitable care access, and better integration of palliative services.

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid tumors, with a five-year survival rate of less than 10%, despite recent advancements in early detection and treatment [1]. Among its many complications, venous thromboembolism (VTE) stands out as a major contributor to morbidity and mortality. VTE, which includes deep vein thrombosis and pulmonary embolism, affects up to 41% of patients with pancreatic cancer during the course of their disease, making it one of the most thrombogenic malignancies [2].

The mechanisms underlying this elevated risk are multifactorial. PDAC tumor cells express high levels of tissue factor (TF), which activates the coagulation cascade and promotes thrombosis [3]. In addition, pancreatic tumors release procoagulant microparticles and promote the formation of neutrophil extracellular traps (NETs), further enhancing clot formation [4]. These biological processes reflect the tumor’s systemic inflammatory profile and may also contribute to its aggressive behavior.

Clinically, the presence of VTE in pancreatic cancer patients is associated with significantly worse outcomes. VTE is an independent predictor of early mortality and can complicate both curative and palliative treatment pathways [5]. In some cases, VTE may precede the diagnosis of pancreatic cancer, acting as a warning sign of underlying malignancy [6]. Despite this, the use of thromboprophylaxis remains inconsistent in real-world settings, often due to concerns about bleeding risk and limited consensus on which patients benefit most [7, 8].

Understanding national trends in VTE-related mortality among pancreatic cancer patients is essential for improving clinical care, guiding prophylaxis strategies, and identifying high-risk subgroups. This study aims to describe the burden and temporal patterns of VTE-related mortality in pancreatic cancer patients in the United States over a 22-year period, using population-based data.

Methods

Study design

We conducted a cross-sectional analysis of U.S. mortality data using the Centers for Disease Control and Prevention (CDC) Wide-ranging Online Data for Epidemiologic Research (WONDER) platform [9]. This publicly accessible source provides de-identified, population-based death certificate data for all U.S. residents. Our study covered the years 1999 through 2020 and focused on adults aged 25 years and older.

Deaths were selected using the International Classification of Diseases, 10th Revision (ICD-10) [10]. Venous thromboembolism (VTE) was defined using codes I26 (pulmonary embolism), I80 (phlebitis and thrombophlebitis), and I82 (other venous embolism and thrombosis). Pancreatic cancer was defined using code C25. We included only records in which a VTE code appeared as the underlying cause of death, and pancreatic cancer was listed as a contributing cause (Supplementary Table S1).

This study relied exclusively on publicly available, de-identified data and was therefore exempt from Institutional Review Board oversight. We followed the STROBE guidelines for reporting observational studies (Supplementary Table S2) [11].

Data extraction

Data were extracted for the total adult population and stratified by sex, race/ethnicity, ten-year age groups (25–34 through ≥ 85), U.S. Census region (Northeast, Midwest, South, West), urbanization level (metropolitan vs. non-metropolitan), state of residence, and place of death.

Race and ethnicity were recorded based on information typically provided by next of kin and reported by funeral directors. Urbanization level followed the 2013 National Center for Health Statistics (NCHS) Urban–Rural Classification Scheme [12]. Counties with ≥ 50,000 population were classified as metropolitan; all others were non-metropolitan.

Consistent with CDC WONDER guidance, we excluded annual data cells with fewer than 10 deaths to prevent unstable estimates. In some subgroups—particularly younger age groups and smaller racial/ethnic populations—this suppression limited longitudinal trend analyses.

Statistical analysis

Annual death counts and population estimates were extracted from CDC WONDER. Age-adjusted mortality rates (AAMRs) were calculated using the direct method and standardized to the 2000 U.S. standard population. AAMRs were expressed per 100,000 population, with 95% confidence intervals (CIs) calculated using Poisson distribution assumptions.

Temporal trends were assessed using Joinpoint regression, applying log-linear models to estimate Annual Percent Change (APC) for each identified segment and Average Annual Percent Change (AAPC) across the full study period. The Joinpoint Regression Program (version 5.0.2) from the National Cancer Institute was used to perform the analysis [13]. The model began with a single linear segment and added joinpoints where statistically supported using the Monte Carlo permutation test [14].

The number and location of joinpoints were selected empirically based on best model fit. A p-value < 0.05 was considered statistically significant. Subgroup-specific models were fit separately for sex, race/ethnicity, age group, geographic region, urbanization level, and state of residence. For each segment, APCs and corresponding 95% CIs were reported.

Tests of parallelism were used to assess whether trends differed significantly across subgroups. All supplementary analyses and visualizations were conducted in Python (v3.11) using the statsmodels, scipy, and matplotlib libraries [15].

Results

Overall trends

From 1999 to 2020, there were 20,373 deaths in the United States linked to venous thromboembolism (VTE) in patients with pancreatic cancer. The overall age-adjusted mortality rate (AAMR) during this period was 0.36 per 100,000 population (95% CI: 0.34 to 0.38) (Table 1).

Table 1 Demographic characteristics of decedents with venous thromboembolism as the underlying cause of death and pancreatic cancer as a contributing cause, United States, 1999–2020
Full size table

Joinpoint regression showed three time periods with different trends. Between 1999 and 2005, the mortality rate increased slightly but not significantly (APC: 2.06%, 95% CI: –7.16 to 12.20; p = 0.6034). From 2005 to 2016, the increase continued slowly and was close to significance (APC: 1.36%, 95% CI: –0.27 to 3.02; p = 0.0923). A sharp and significant rise was seen from 2016 to 2020 (APC: 8.71%, 95% CI: 5.21 to 12.34; p = 0.0039). Overall, the average annual percent change (AAPC) was 2.72% (95% CI: 2.25 to 3.20; p < 0.0001), showing a steady increase in VTE-related mortality among pancreatic cancer patients over time (Table 2; Fig. 1).

Table 2 Annual percentage changes (APCs) and average annual percentage changes (AAPCs) in venous thromboembolism–related mortality among adults with pancreatic cancer, United States, 1999–2020
Full size table
Fig. 1
figure 1

. Trends in Venous Thromboembolism–Related Mortality with Pancreatic Cancer stratified by sex and overall, United States, 1999–2020

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Trends by gender

From 1999 to 2020, men with pancreatic cancer had higher VTE-related death rates than women. The age-adjusted mortality rate (AAMR) was 0.46 per 100,000 for men (95% CI: 0.42 to 0.50) and 0.35 for women (95% CI: 0.32 to 0.38) (Table 1).

In women, the death rate rose from 1999 to 2012 (APC: 3.10%; p = 0.0178), dropped between 2012 and 2014 (APC: –10.56%; p = 0.0354), then increased again from 2014 to 2020 (APC: 8.02%; p = 0.0255). Overall, the average annual increase (AAPC) was 2.72% (p < 0.001). In men, the rate increased slightly from 1999 to 2010 (APC: 1.93%; p = 0.2579), stayed mostly the same from 2010 to 2015, and then rose sharply from 2015 to 2020 (APC: 7.84%; p = 0.0047). The overall AAPC was 2.71% (p < 0.001), which was similar to that of women (Table 2; Fig. 1).

Trends by race/ethnicity

There were clear differences in VTE-related death rates among racial and ethnic groups. The highest age-adjusted mortality rate (AAMR) was in Black or African American individuals at 0.62 per 100,000 (95% CI: 0.59 to 0.64). This was followed by White (0.40), Hispanic (0.36), American Indian or Alaska Native (0.21), and Asian or Pacific Islander individuals (0.18) (Table 1).

For Black individuals, the rate increased from 1999 to 2012, dropped between 2012 and 2015 (APC: –9.32%; p = 0.0464), and rose again after 2015. Overall, the average annual increase (AAPC) was 2.20% (p < 0.0001). White individuals had a steady increase throughout the period, with the biggest rise after 2016 (APC: 8.69%; p = 0.0154). The overall AAPC was 2.72% (p < 0.0001). Among Hispanic individuals, there was no clear pattern year by year, but overall there was a significant rise in deaths (AAPC: 2.99%; p < 0.0001). Due to small numbers, trends couldn’t be calculated for American Indian or Alaska Native individuals. For Asian or Pacific Islanders, the trend was flat, with no significant change (AAPC: 0.81%; p = 0.7430) (Table 2; Fig. 2).

Fig. 2
figure 2

Trends in Venous Thromboembolism–Related Mortality with Pancreatic Cancer stratified by race/ethnicity, United States, 1999–2020

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Trends by urbanization status

VTE-related death rates among pancreatic cancer patients were similar in metro and non-metro areas. The age-adjusted mortality rate (AAMR) was 0.41 per 100,000 in metro areas (95% CI: 0.37 to 0.44) and 0.40 in non-metro areas (95% CI: 0.36 to 0.43) (Table 1).

In metro areas, the rate increased from 1999 to 2010 (APC: 2.87%), stayed mostly stable from 2010 to 2015, and then rose sharply from 2015 to 2020 (APC: 8.53%; p = 0.0035). The overall AAPC was 2.74% (p < 0.0001). In non-metro areas, the rate increased from 1999 to 2014, rose faster from 2014 to 2018, and then slightly declined from 2018 to 2020. None of these changes were statistically significant. Still, the overall AAPC was 2.88% (p < 0.0001), showing a steady upward trend (Table 2; Fig. 3).

Fig. 3
figure 3

Trends in Venous Thromboembolism–Related Mortality with Pancreatic Cancer stratified by urbanization level, United States, 1999–2020

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Trends by census region

VTE-related death rates among pancreatic cancer patients varied by region. The highest age-adjusted mortality rate (AAMR) was in the Midwest at 0.44 per 100,000 (95% CI: 0.41 to 0.48), followed by the West (0.43), Northeast (0.42), and South (0.37) (Table 1).

In the Northeast, the rate stayed about the same from 1999 to 2005, increased slightly through 2017, and then rose more sharply from 2017 to 2020. These changes were not statistically significant, but the overall AAPC was 1.87% (p < 0.0001). In the Midwest, there was a small jump from 1999 to 2001, followed by a slow increase until 2014, and a significant rise from 2014 to 2020 (APC: 6.57%; p = 0.0174). The overall AAPC was 2.48% (p < 0.0001). In the South, the rate went up from 1999 to 2010, dipped slightly from 2010 to 2015, and then increased again after 2015. The overall AAPC was 2.84% (p < 0.0001). In the West, the rate rose steadily from 1999 to 2016 and then increased more rapidly from 2016 to 2020. The overall AAPC was 3.36% (p < 0.0001), the highest among all regions (Table 2; Fig. 4).

Fig. 4
figure 4

Trends in Venous Thromboembolism–Related Mortality with Pancreatic Cancer stratified by U.S. Census region, 1999–2020

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Trends by state

There were clear differences in VTE-related death rates among U.S. states for patients with pancreatic cancer from 1999 to 2020.

The highest age-adjusted mortality rates (AAMRs) were observed in the District of Columbia (0.66 per 100,000; 95% CI: 0.50–0.86), Colorado (0.65; 95% CI: 0.59–0.71), and Connecticut (0.52; 95% CI: 0.46–0.58). California, while not having the highest AAMR (0.44; 95% CI: 0.42–0.46), accounted for the greatest proportion of total deaths (11.66%), reflecting its large population size. In contrast, lower AAMRs were reported in Alabama (0.30; 95% CI: 0.26–0.34) and Arkansas (0.32; 95% CI: 0.27–0.37). Overall, more populous and western states tended to have higher total death counts, though the adjusted rates varied only moderately (Fig. 5).

Fig. 5
figure 5

Geographic distribution of Venous Thromboembolism–Related Mortality with Pancreatic Cancer by state, United States, 1999–2020

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Trends by ten-year age group

VTE-related mortality among pancreatic cancer patients increased with age. The lowest age-adjusted mortality rate (AAMR) was observed in the 35–44 year group at 0.05 per 100,000 (95% CI: 0.03 to 0.06), while the highest was in the 75–84 year group at 1.67 (95% CI: 1.52 to 1.82). Individuals aged 85 years and older had an AAMR of 1.45 (95% CI: 1.32 to 1.58) (Table 1).

Most age groups showed rising mortality trends, especially after 2016. Among individuals aged 45–54, the mortality rate increased significantly between 2016 and 2020 (APC: 10.41%; p = 0.0116), with an overall average annual percent change (AAPC) of 2.26% (p < 0.0001). A similar pattern was seen in the 55–64 year group, where mortality steadily increased after 2016, resulting in an AAPC of 2.44% (p < 0.0001). For patients aged 65–74 years, the rate rose sharply from 2016 to 2020 (APC: 9.15%; p = 0.0081), with an overall AAPC of 2.45% (p < 0.0001). In the 75–84 year group, a similar sharp rise was observed in the final years (APC: 8.21%; p = 0.0033), and the AAPC was 1.91% (p < 0.0001). Among those aged 85 and older, there was a steady and significant increase between 2016 and 2020 (APC: 4.78%; p = 0.0127), with an AAPC of 1.21% (p < 0.0001) (Table 2; Fig. 6).

Fig. 6
figure 6

Crude Mortality Rates for Venous Thromboembolism–Related Deaths with Pancreatic Cancer stratified by ten-year age group and sex, United States, 1999–2020

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Place of death

Between 1999 and 2020, most VTE-related deaths among pancreatic cancer patients occurred in medical facilities while the patient was hospitalized. In total, 44.6% of these deaths took place in an inpatient setting. A significant proportion also occurred at home, accounting for 31.4% of all deaths (Table 1).

Other places of death were less common. Outpatient or emergency room settings accounted for 3.6% of deaths, while 0.3% were reported as dead on arrival. Only a very small number (0.06%) occurred in medical facilities where the status was unknown.

Discussion

In this nationwide study spanning 1999 to 2020, we identified a clear and sustained rise in venous thromboembolism (VTE)–related mortality among patients with pancreatic cancer in the United States. The overall age-adjusted mortality rate (AAMR) increased steadily throughout the study period, with a particularly sharp rise beginning in 2016. Joinpoint regression revealed three distinct phases, with the most recent segment demonstrating a statistically significant annual percent change (APC) of 8.71%, underscoring the growing burden of VTE in this high-risk population.

The increase in VTE-related mortality was not uniform across all demographic groups. Males exhibited consistently higher AAMRs than females, though both sexes experienced parallel upward trends. Older adults—particularly those aged 75 years and above—had the highest mortality rates, reflecting the accumulation of prothrombotic risk factors with age. We also observed striking racial and ethnic disparities, with Black individuals experiencing the highest mortality burden. Regional and state-level variation further highlighted geographic disparities, suggesting underlying differences in care access, healthcare infrastructure, and resource distribution. Notably, nearly one-third of VTE-related deaths occurred at home, raising important concerns about end-of-life care quality, outpatient VTE recognition, and the role of palliative services. These findings provide a comprehensive national overview of the evolving impact of VTE among pancreatic cancer patients. They underscore the urgency for improved risk stratification, equitable preventive strategies, and targeted interventions to curb this rising mortality trend.

The elevated risk of VTE in pancreatic cancer stems from a complex interplay between tumor biology and host responses. Pancreatic ductal adenocarcinoma (PDAC) is characterized by overexpression of tissue factor (TF) on tumor cells, which directly activates the coagulation cascade and drives thrombin generation [16]. Additionally, PDAC is associated with the release of procoagulant microparticles, systemic inflammation, and neutrophil extracellular trap (NET) formation—all contributing to a hypercoagulable state [17]. These prothrombotic mechanisms are not incidental but rather reflect the aggressive nature of PDAC and may facilitate tumor progression and metastasis via thrombin-mediated pathways [18].

Clinically, VTE is more than a complication; it often marks a turning point in the disease trajectory. Several studies have demonstrated that VTE is an independent predictor of poor survival in pancreatic cancer, associated with both early mortality and treatment interruptions [19]. The onset of VTE may restrict therapeutic options due to bleeding risk or necessitate hospitalization, further diminishing quality of life and survival outcomes. Moreover, VTE can serve as an early indicator of occult malignancy, with pancreatic cancer frequently identified in patients presenting with unprovoked thromboembolism [20].

Despite a well-established understanding of VTE pathophysiology and consequences, underdiagnosis and undertreatment persist in the pancreatic cancer population. While guidelines advocate thromboprophylaxis in high-risk patients, implementation remains inconsistent—often hindered by concerns over bleeding, particularly in those with advanced disease or poor performance status [21]. The increasing VTE-related mortality observed in our study may reflect missed opportunities for early identification, risk-based intervention, and consistent use of prophylactic anticoagulation.

Our findings also reveal substantial disparities in VTE-related mortality across demographic groups. Males consistently exhibited higher AAMRs than females, consistent with broader VTE epidemiology [22]. The underlying mechanisms of sex-based differences remain unclear but may involve hormonal influences, distinct cancer biology, comorbidities, and behavioral factors. Differential access to care, treatment uptake, and physician prescribing practices may further exacerbate these gaps. Age was a dominant factor in VTE-related mortality. Individuals aged 75 years and older exhibited the highest rates, with notable increases in recent years. Age-related hypercoagulability—driven by elevated prothrombotic factor levels, endothelial dysfunction, and decreased mobility—is further intensified in cancer patients by chemotherapy, central venous access devices, and tumor-induced inflammation [23]. Importantly, anticoagulation in older adults is often underutilized due to bleeding concerns, polypharmacy, and frailty, which may contribute to the elevated mortality rates in this group [24]. Racial disparities were particularly striking in our analysis. Black individuals experienced the highest VTE-related mortality rates among all racial and ethnic groups. Prior studies have consistently demonstrated elevated VTE risk and poorer outcomes in Black patients, even after controlling for comorbidities and socioeconomic status [25]. This multifactorial disparity likely reflects a combination of biological predisposition, reduced access to preventive care, diagnostic delays, and lower anticoagulation prescription rates [26]. Structural inequities—including disparities in insurance coverage and systemic healthcare biases—further compound these risks.

We also observed significant geographic variation in VTE-related mortality, with differences across U.S. Census regions and states. The Midwest and West exhibited higher AAMRs than the South, while populous states such as California contributed disproportionately to national VTE-related deaths. These patterns may be attributed to regional differences in healthcare infrastructure, access to specialized oncology and thrombosis care, and uptake of evidence-based thromboprophylaxis practices. Geographic disparities in cancer outcomes are well documented and often linked to differences in provider density, hospital quality, and adherence to clinical guidelines [27]. In the context of VTE, variability in imaging availability, anticoagulation management, and access to multidisciplinary care may contribute to unequal outcomes [28]. Furthermore, many non-metropolitan areas—highlighted in our analysis—may lack timely diagnostic and treatment resources, increasing the risk of missed or delayed VTE management [29]. Socioeconomic factors also play a key role in shaping regional disparities. States with higher proportions of underinsured residents or limited Medicaid expansion often face challenges in cancer care delivery and experience worse health outcomes [30]. Differences in health literacy, cultural attitudes toward medical care, and patient engagement with preventive strategies may also influence regional patterns of VTE diagnosis and treatment.

An often-overlooked dimension of VTE-related mortality in pancreatic cancer is the setting in which death occurs. In our study, nearly one-third of VTE-related deaths took place at home, while the remainder occurred primarily in hospital settings. This distribution raises important considerations about end-of-life care, recognition of thrombotic symptoms outside of clinical environments, and access to timely intervention. The high proportion of home deaths likely reflects a combination of factors. Some patients may have elected home-based palliative care, aligning with care goals that prioritize comfort over aggressive interventions [31]. Others may have succumbed to undiagnosed or untreated VTE events, especially if symptoms such as dyspnea or limb swelling were attributed to advanced cancer and not further investigated. In outpatient and hospice settings, the ability to diagnose and manage acute VTE is often limited due to a lack of imaging capabilities and laboratory support.

Existing literature highlights inconsistencies in the management of VTE during end-of-life care. Treatment decisions are often shaped by provider attitudes, uncertainty about prognosis, and fears of bleeding complications [32]. Although hospice and palliative care teams increasingly recognize the symptomatic burden of VTE—manifesting as painful swelling or respiratory distress—routine anticoagulation remains controversial [33]. A symptom-guided approach, rather than rigid adherence to standard protocols, has been proposed for managing thrombotic complications in this population [34].

The rising trend in VTE-related mortality among pancreatic cancer patients in our study aligns with, yet also expands upon, previous findings from clinical cohorts and population-based registries. Prior studies have primarily focused on VTE incidence rather than VTE-attributable mortality, making this study a unique contribution. For example, a large prospective registry by Frere et al. found that VTE developed in up to 41% of patients with pancreatic cancer during the course of treatment and was independently associated with worse overall survival [2]. However, national-level mortality data reflecting this impact over time have been lacking.

Our finding of a sharp increase in VTE-related deaths after 2016 is consistent with recent reports suggesting that cancer survival improvements may be unintentionally contributing to greater exposure time for thrombotic complications [35]. Longer survival with pancreatic cancer, aided by newer chemotherapy regimens such as FOLFIRINOX and nab-paclitaxel plus gemcitabine, may leave patients vulnerable to cumulative VTE risk. However, these regimens are also associated with high rates of treatment-related complications, including thrombosis [36]. Other studies, such as the Cancer-VTE Registry from Japan, have reported elevated VTE risk in PDAC, but with lower overall incidence compared to Western populations [8]. This may reflect differences in ethnicity, anticoagulation practices, or diagnostic surveillance. Our study, which shows both rising mortality and clear disparities across age, sex, and race, supports the need for contextualized, population-specific strategies in VTE prevention and management.

Furthermore, while many randomized trials have evaluated anticoagulation for VTE prevention in cancer patients—such as the CASSINI and AVERT trials [37, 38]—they have not focused exclusively on pancreatic cancer, nor have they evaluated long-term mortality trends. This reinforces the value of our analysis, which captures real-world outcomes in a particularly high-risk population.

Strengths and limitations

This study offers several key strengths that enhance its validity and relevance. First, it is the largest and most comprehensive analysis to date of venous thromboembolism (VTE)–related mortality among pancreatic cancer patients in the United States, using over two decades of population-based data. The use of nationally representative mortality data from the CDC WONDER platform ensures broad generalizability and minimizes selection bias. Additionally, the application of Joinpoint regression allowed for precise characterization of temporal trends, identifying critical inflection points—particularly the acceleration in VTE-related deaths after 2016. The inclusion of subgroup analyses by sex, race, age, geography, and place of death provides a multidimensional understanding of disparities and evolving risk patterns.

However, the study also has important limitations. Most notably, it relies on death certificate data, which are subject to underreporting and misclassification. VTE is often underdiagnosed in terminal cancer patients, especially outside hospital settings, which may lead to an underestimation of true mortality burden. Second, the database lacks clinical granularity—such as cancer stage, treatment modality, anticoagulant use, performance status, or the presence of other comorbidities—which limits our ability to adjust for confounding or explore causal mechanisms.

Furthermore, we cannot distinguish between incident and recurrent VTE events, nor assess whether VTE contributed directly or indirectly to death. The classification is based solely on coding, without clinical adjudication. Finally, while this study reveals disparities, it does not capture structural or behavioral factors (e.g., insurance status, access to palliative care, physician decision-making) that may explain observed differences in mortality outcomes. Despite these limitations, our findings provide valuable epidemiologic insight into the rising burden of thrombotic complications in pancreatic cancer and offer a strong foundation for future prospective and interventional studies.

Conclusion

This national analysis reveals a significant and sustained rise in VTE-related mortality among pancreatic cancer patients in the United States from 1999 to 2020, with particularly sharp increases observed in recent years. The burden of mortality was not evenly distributed—older adults, males, Black individuals, and residents of certain geographic regions experienced disproportionately higher death rates. These findings reflect not only the biological aggressiveness of pancreatic cancer and its thrombotic potential but also the limitations of current prevention strategies, disparities in care delivery, and gaps in end-of-life management.

Given the consistently high risk of thrombosis in this population, these results support the development of pancreatic cancer–specific VTE risk models, better integration of real-world data into prophylaxis guidelines, and targeted efforts to reduce disparities in diagnosis and care. Improving risk identification, standardizing thromboprophylaxis, and expanding access to palliative and supportive services could help reverse the upward trend in VTE-related deaths.

Data availability

The data that support the findings of this study are openly available in CDC WONDER at https://wonder.cdc.gov/, reference number N/A.

Abbreviations

AAPC:

Average Annual Percent Change

AAMR:

Age-Adjusted Mortality Rate

APC:

Annual Percent Change

CDC:

Centers for Disease Control and Prevention

CI:

Confidence Interval

ER:

Emergency Room

ICD-10:

International Classification of Diseases, 10th Revision

NETs:

Neutrophil Extracellular Traps

NCHS:

National Center for Health Statistics

PDAC:

Pancreatic Ductal Adenocarcinoma

STROBE:

Strengthening the Reporting of Observational Studies in Epidemiology

TF:

Tissue Factor

VTE:

Venous Thromboembolism

U.S.:

United States

References

  1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7–33. https://doi.org/10.3322/caac.21708.

    Article  PubMed  Google Scholar 

  2. Frere C, Bournet B, Gourgou S, Fraisse J, Canivet C, Connors JM, Buscail L, Farge D. BACAP consortium. incidence of venous thromboembolism in patients with newly diagnosed pancreatic cancer and factors associated with outcomes. Gastroenterology. 2020;Apr158(5):1346-1358.e4. https://doi.org/10.1053/j.gastro.2019.12.009. Epub 2019 Dec 14. PMID: 31843588.

    Article  Google Scholar 

  3. Hisada Y, Mackman N. Cancer-associated pathways and biomarkers of venous thrombosis. Blood. 2017;130(13):1499–506. https://doi.org/10.1182/blood-2017-03-743211.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Mauracher LM, Posch F, Martinod K, Grilz E, Däullary T, Hell L, Brostjan C, Zielinski C, Ay C, Wagner DD, Pabinger I, Thaler J. Citrullinated histone H3, a biomarker of neutrophil extracellular trap formation, predicts the risk of venous thromboembolism in cancer patients. J Thromb Haemost. 2018;16(3):508–18. https://doi.org/10.1111/jth.13951.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Kruger S, Haas M, Burkl C, Goehring P, Kleespies A, Roeder F, Gallmeier E, Ormanns S, Westphalen CB, Heinemann V, Rank A, Boeck S. Incidence, outcome and risk stratification tools for venous thromboembolism in advanced pancreatic cancer - a retrospective cohort study. Thromb Res. 2017;157:9–15. https://doi.org/10.1016/j.thromres.2017.06.021.

    Article  CAS  PubMed  Google Scholar 

  6. Sørensen HT, Mellemkjaer L, Olsen JH, Baron JA. Prognosis of cancers associated with venous thromboembolism. N Engl J Med. 2000;343(25):1846–50. https://doi.org/10.1056/NEJM200012213432504.

    Article  PubMed  Google Scholar 

  7. Dallos MC, Eisenberger AB, Bates SE. Prevention of venous thromboembolism in pancreatic cancer: breaking down a complex clinical dilemma. Oncologist. 2020;25(2):132–9. https://doi.org/10.1634/theoncologist.2019-0264.

    Article  PubMed  Google Scholar 

  8. Okusaka T, Saiura A, Shimada K, Ikeda M, Ioka T, Kimura T, Hosokawa J, Takita A, Oba MS. Incidence and risk factors for venous thromboembolism in the Cancer-VTE registry pancreatic cancer subcohort. J Gastroenterol. 2023;58(12):1261–71. https://doi.org/10.1007/s00535-023-02033-3.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Centers for Disease Control and Prevention, National Center for Health Statistics. Multiple cause of death 1999–2019 on CDC WONDER online Database, released in 2020. Data are from the Multiple Cause of Death Files, 1999–2019, as compiled from data provided by the 57 vital statistics jurisdictions through the Vital Statistics Cooperative Program. Available at: http://wonder.cdc.gov/mcd-icd10.html.

  10. Free 2019 ICD-10-CM Codes. Icd10data.com. Published 2019. Available at: https://www.icd10data.com/ICD10CM/Codes/Changes/New_Codes/1?year=2019.

  11. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP, STROBE Initiative. The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol. 2008;61(4):344–9. https://doi.org/10.1016/j.jclinepi.2007.11.008.

    Article  Google Scholar 

  12. Ingram DD, Franco SJ. NCHS Urban-Rural Classification Scheme for Counties. Vital Health Stat. 2013;2(2014):1–73.

    Google Scholar 

  13. Program Joinpoint Regression. Version 5.0.2 – Statistical methodology and applications branch. National Cancer Institute: Surveillance Research Program; May2023.

    Google Scholar 

  14. Kim HJ, Fay MP, Feuer EJ, Midthune DN. Permutation tests for joinpoint regression with applications to cancer rates. Stat Med. 2000F 15;19(3):335–51. https://doi.org/10.1002/(sici)1097-0258(20000215)19:3<335::aid-sim336>3.0.co;2-z.Erratum.In:StatMed2001Feb28;20(4):655. PMID: 10649300.

    Article  CAS  PubMed  Google Scholar 

  15. Seabold Skipper, Perktold Josef. Statsmodels: econometric and statistical modeling with python. 2010;92–96. https://doi.org/10.25080/Majora-92bf1922-011.

  16. Ruf W, Yokota N, Schaffner F. Tissue factor in cancer progression and angiogenesis. Thromb Res. 2010;2(Apr;125 Suppl 2(0 2)):S36-8. https://doi.org/10.1016/S0049-3848(10)70010-4. PMID: 20434002; PMCID: PMC3827916.

    Article  Google Scholar 

  17. Hisada Y, Grover SP, Maqsood A, Houston R, Ay C, Noubouossie DF, Cooley BC, Wallén H, Key NS, Thålin C, Farkas ÁZ, Farkas VJ, Tenekedjiev K, Kolev K, Mackman N. Neutrophils and neutrophil extracellular traps enhance venous thrombosis in mice bearing human pancreatic tumors. Haematologica. 2020;105(1):218–25. https://doi.org/10.3324/haematol.2019.217083.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Palumbo JS, Talmage KE, Massari JV, La Jeunesse CM, Flick MJ, Kombrinck KW, Jirousková M, Degen JL. Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells. Blood. 2005;105(1):178–85. https://doi.org/10.1182/blood-2004-06-2272.

    Article  CAS  PubMed  Google Scholar 

  19. Cella CA, Di Minno G, Carlomagno C, Arcopinto M, Cerbone AM, Matano E, Tufano A, Lordick F, De Simone B, Muehlberg KS, Bruzzese D, Attademo L, Arturo C, Sodano M, Moretto R, La Fata E, De Placido S. Preventing venous thromboembolism in ambulatory cancer patients: the ONKOTEV study. Oncologist. 2017;22(5):601–8. https://doi.org/10.1634/theoncologist.2016-0246.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Liebman HA. Cancer prognosis in patients with venous thromboembolism (VTE) and patients with clinical and laboratory biomarkers predictive of VTE risk. Thromb Res. 2018;164(Suppl 1):S19–22. https://doi.org/10.1016/j.thromres.2018.01.040. PMID: 29703479.

    Article  CAS  PubMed  Google Scholar 

  21. Key NS, Khorana AA, Kuderer NM, Bohlke K, Lee AYY, Arcelus JI, Wong SL, Balaban EP, Flowers CR, Francis CW, Gates LE, Kakkar AK, Levine MN, Liebman HA, Tempero MA, Lyman GH, Falanga A. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update. J Clin Oncol. 2020;38(5):496–520. https://doi.org/10.1200/JCO.19.01461. Epub 2019 Aug 5 PMID: 31381464.

    Article  PubMed  Google Scholar 

  22. Cushman M. Epidemiology and risk factors for venous thrombosis. Semin Hematol. 2007;44(2):62–9. https://doi.org/10.1053/j.seminhematol.2007.02.004.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Heit JA. Epidemiology of venous thromboembolism. Nat Rev Cardiol. 2015;12(8):464–74. https://doi.org/10.1038/nrcardio.2015.83.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Tritschler T, Aujesky D. Venous thromboembolism in the elderly: a narrative review. Thromb Res. 2017;155:140–7. https://doi.org/10.1016/j.thromres.2017.05.015.

    Article  CAS  PubMed  Google Scholar 

  25. Zakai NA, McClure LA, Judd SE, Safford MM, Folsom AR, Lutsey PL, Cushman M. Racial and regional differences in venous thromboembolism in the United States in 3 cohorts. Circulation. 2014;129(14):1502–9. https://doi.org/10.1161/CIRCULATIONAHA.113.006472.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Beckman MG, Hooper WC, Critchley SE, Ortel TL. Venous thromboembolism: a public health concern. Am J Prev Med. 2010;38(4 Suppl):S495-501. https://doi.org/10.1016/j.amepre.2009.12.017. PMID: 20331949.

    Article  PubMed  Google Scholar 

  27. Onega T, Duell EJ, Shi X, Wang D, Demidenko E, Goodman D. Geographic access to cancer care in the U.S. Cancer. 2008;112(4):909–18. https://doi.org/10.1002/cncr.23229.

    Article  PubMed  Google Scholar 

  28. Essien UR, Holmes DN, Jackson LR 2nd, Fonarow GC, Mahaffey KW, Reiffel JA, Steinberg BA, Allen LA, Chan PS, Freeman JV, Blanco RG, Pieper KS, Piccini JP, Peterson ED, Singer DE. Association of race/ethnicity with oral anticoagulant use in patients with atrial fibrillation: findings from the outcomes registry for better informed treatment of atrial fibrillation II. JAMA Cardiol. 2018;3(12):1174–82. https://doi.org/10.1001/jamacardio.2018.3945.

    Article  PubMed  PubMed Central  Google Scholar 

  29. da Costa WL Jr, Guffey D, Oluyomi A, Bandyo R, Rosales O, Wallace CD, Granada C, Riaz N, Fitzgerald M, Garcia DA, Carrier M, Amos CI, Flowers CR, Li A. Patterns of venous thromboembolism risk, treatment, and outcomes among patients with cancer from uninsured and vulnerable populations. Am J Hematol. 2022;97(8):1044–54. https://doi.org/10.1002/ajh.26623.

  30. Jemal A, Lin CC, Davidoff AJ, Han X. Changes in insurance coverage and stage at diagnosis among nonelderly patients with cancer after the Affordable Care Act. J Clin Oncol. 2017D 10;35(35):3906–15. https://doi.org/10.1200/JCO.2017.73.7817. Epub 2017 Sep 8 PMID: 28885865.

    Article  PubMed  Google Scholar 

  31. Gomes B, Higginson IJ. Factors influencing death at home in terminally ill patients with cancer: systematic review. BMJ. 2006;332(7540):515–21. https://doi.org/10.1136/bmj.38740.614954.55.

    Article  PubMed  PubMed Central  Google Scholar 

  32. El-Jawahri A, Greer JA, Pirl WF, Park ER, Jackson VA, Back AL, Kamdar M, Jacobsen J, Chittenden EH, Rinaldi SP, Gallagher ER, Eusebio JR, Fishman S, VanDusen H, Li Z, Muzikansky A, Temel JS. Effects of early integrated palliative care on caregivers of patients with lung and gastrointestinal cancer: a randomized clinical trial. Oncologist. 2017;22(12):1528–34. https://doi.org/10.1634/theoncologist.2017-0227.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Noble SI, Finlay IG. Is long-term low-molecular-weight heparin acceptable to palliative care patients in the treatment of cancer related venous thromboembolism? A qualitative study. Palliat Med. 2005;19(3):197–201. https://doi.org/10.1191/0269216305pm1008oa.

    Article  PubMed  Google Scholar 

  34. Noble S. Venous thromboembolism in palliative care patients: what do we know? Thromb Res. 2020J;191(Suppl 1):S128–32. https://doi.org/10.1016/S0049-3848(20)30410-2. PMID: 32736771.

    Article  CAS  PubMed  Google Scholar 

  35. Mahajan A, Brunson A, Adesina O, Keegan THM, Wun T. The incidence of cancer-associated thrombosis is increasing over time. Blood Adv. 2022;6(1):307–20. https://doi.org/10.1182/bloodadvances.2021005590.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M, Groupe Tumeurs Digestives of Unicancer, PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–25. https://doi.org/10.1056/NEJMoa1011923.

    Article  CAS  PubMed  Google Scholar 

  37. Khorana AA, Soff GA, Kakkar AK, Vadhan-Raj S, Riess H, Wun T, Streiff MB, Garcia DA, Liebman HA, Belani CP, O’Reilly EM, Patel JN, Yimer HA, Wildgoose P, Burton P, Vijapurkar U, Kaul S, Eikelboom J, McBane R, Bauer KA, Kuderer NM, Lyman GH. CASSINI Investigators. Rivaroxaban for Thromboprophylaxis in High-Risk Ambulatory Patients with Cancer. N Engl J Med. 2019Feb 21;Feb 21;380(8):720–8. https://doi.org/10.1056/NEJMoa1814630. PMID: 30786186.

    Article  CAS  PubMed  Google Scholar 

  38. Carrier M, Abou-Nassar K, Mallick R, Tagalakis V, Shivakumar S, Schattner A, Kuruvilla P, Hill D, Spadafora S, Marquis K, Trinkaus M, Tomiak A, Lee AYY, Gross PL, Lazo-Langner A, El-Maraghi R, Goss G, Le Gal G, Stewart D, Ramsay T, Rodger M, Witham D, Wells PS. AVERT Investigators. Apixaban to Prevent Venous Thromboembolism in Patients with Cancer. N Engl J Med. 2019;Feb 21; 380(8):711–9. https://doi.org/10.1056/NEJMoa1814468. Epub 2018 Dec 4. PMID: 30511879.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, University of Khartoum, Faculty of Medicine, ElQasr Avenue, Khartoum, Sudan

    Ibrahim Nagmeldin Hassan & Nagmeldin Abuassa

  2. Al-Neelain University, Faculty of Medicine, Khartoum, Sudan

    Mohamed Ibrahim

  3. Karary University, Faculty of Medicine, Khartoum, Sudan

    Siddig Yaqub

  4. Sudan University of Science and Technology, Faculty of Medicine, Khartoum, Sudan

    Muhsin Ibrahim

  5. University of Bahri, Faculty of Medicine, Khartoum, Sudan

    Haythem Abdalla & Wafa Osman

  6. Omdurman Islamic University, Faculty of Medicine, Khartoum, Sudan

    Ghada Aljaili

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  1. Ibrahim Nagmeldin Hassan
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  4. Muhsin Ibrahim
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Contributions

Ibrahim Nagmeldin Hassan: conceptualization, methodology, project administration, visualization, writing – original draft, writing – review and editing. Mohamed Ibrahim: conceptualization, formal analysis, visualization, writing – original draft, writing – review and editing. Siddig Yaqub: project administration, validation, writing – original draft, writing – review and editing. Muhsin Ibrahim: writing – original draft, writing – review and editing. Haythem Abdalla: Project administration, Investigation, Data curation. Ghada Aljaili: Writing – review & editing, Project administration. Wafa Osman: Writing – review & editing, Project administration, Methodology. Nagmeldin Abuassa: writing – original draft, writing – review and editing. All authors read and approved the final manuscript.

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Correspondence to Ibrahim Nagmeldin Hassan.

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Hassan, I.N., Ibrahim, M., Yaqub, S. et al. National trends in venous thromboembolism-related mortality among pancreatic cancer patients in the United States, 1999–2020. Thrombosis J 23, 73 (2025). https://doi.org/10.1186/s12959-025-00764-2

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Thrombosis Journal

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