White Blood Cell Count Measured Prior to Cancer Development Is Associated with Future Risk of Venous Thromboembolism – The Tromsø Study

Abstract

BackgroundElevated white blood cell (WBC) count is associated with risk of venous thromboembolism (VTE) in cancer patients initiating chemotherapy. It is not known whether the risk of VTE by WBC count in cancer patients is causal or merely a consequence of the malignant disease. To address this question, we studied the association between WBC count, measured prior to cancer development, and risk of VTE in subjects who did and did not develop cancer during follow-up in a prospective population-based study.MethodsBaseline characteristics, including WBC and neutrophil counts, were measured in 24304 initially cancer-free subjects who participated in the Tromsø Study in 1994-1995. Incident cancer diagnosis and VTE events were registered up to September 1, 2007. In the cancer cohort, WBC and neutrophil counts were measured in average 7.1 years before cancer development. Cox-regression models were used to calculate hazard ratios (HRs) for VTE by WBC and neutrophil counts as categorized variables (<40th, 40-80th, and >80th percentile) with 95% confidence intervals (CIs).ResultsDuring follow-up, 1720 subjects developed cancer and there were 388 VTE events, of which 116 occurred in the cancer-group (6.9 per 1000 person-years) and 272 in the cancer-free group (1.1 per 1000 person-years). In those who developed cancer, WBC count above the 80th percentile (≥8.6x109 cells/L) was associated with a 2.4-fold higher risk (HR 2.36, 95% CI: 1.44-3.87) of VTE compared to WBC count below the 40th percentile (<6.4x109 cells/L). No association was found between WBC count and VTE in those who stayed cancer-free (HR 0.94, 95% CI 0.65-1.36). Similar findings were observed for neutrophils.CommentPre-cancer WBC count was associated with risk of VTE in cancer patients, but not in cancer-free subjects. Our findings suggest that leukocytes may play a causal role in cancer-related VTE rather than only reflecting the low-grade inflammation associated with cancer.

Catheter-Related Thrombosis in Patients with Lymphoma or Myeloma Undergoing Autologous Stem Cell Transplantation

“…Our data suggest that higher WBC peak at mobilization and stem cell engraftment could increase the risk for thrombosis, although we lacked statistical significance. The connection between leukocytosis, particularly neutrophilia, and thrombosis in cancer patients is under active investigation 19, 20 21, 22 For example Khorana risk score for VTE in cancer patients was developed to predict the risk for cancer patients depending of type of cancer. 23 Using the predictive model, diagnosis of Hodgkin’s lymphoma, elevated prechemotherapy platelet count, and leukocyte count above 11 × 10/L each independently increase VTE risk.…”

Venous thrombosis and cancer: from mouse models to clinical trials

“…Finally, a study by Blix et al . in Tromsø found that cancer patients with a high pre‐cancer leukocyte count (≥ 8.6 × 10 9 cells L −1 ) (20% of the patients) had a 2.4‐fold higher risk of VTE than those with a lower leukocyte count (< 6.4 × 10 9 cells L −1 ). Leukocytosis is also related to poor prognosis in cancer patients .…”

Venous thromboembolism risk prediction in ambulatory cancer patients: Clinical significance of neutrophil/lymphocyte ratio and platelet/lymphocyte ratio

“…Consistent with this hypothesis, an approximately twofold higher risk of VTE was demonstrated in patients with elevated NLR, which is in agreement with the experimental demonstration that neutropenia confers protection against DVT amplification in an in vivo model 17 and with the clinical observation that white blood cell and neutrophil counts measured prior to cancer development are associated with future VTE risk in a prospective populationbased study. 18 An appealing hypothesis recently drawn to explain the causal relationship between neutrophils and cancer-associated VTE was founded on the capability of cancer microenvironment to predispose neutrophils to release neutrophil extracellular traps (NETs). 19 NET formation, indeed, has been implicated in lung thrombosis in a breast carcinoma model 20 and in thrombus organization in human VTE.…”