Chronic Neutrophilia: A Risk Factor for VTE?.

Leukocytosis has been linked to the pathogenesis of thrombosis and, in prior studies, has been associated with increased risk of thrombotic events in patients with cancer and essential thrombocythemia. While risk factors for venous thromboembolism (VTE) have been extensively studied, to our knowledge, no attempts have been made to explore the association of neutrophilia with VTE in the general population. Our objective was to determine whether chronic neutrophilia is independently associated with an increased risk of VTE.

Data were obtained from the hospital electronic medical record system. All patients (age ≥ 21) who were seen at the Montefiore Medical Center primary care clinics (Bronx, NY) and had at least 3 complete blood cell (CBC) counts performed, 2–24 months apart, between January 1, 2006 and January 1, 2012, were included. Patients with diagnosed disorders that might elevate white blood cell (WBC) count such as the leukemias, polycythemia vera, essential thrombocythemia, and sickle cell disease, were excluded from the study. Patients on medications known to cause leukocytosis such as steroids and lithium were also removed from our cohort. ICD-9 diagnoses, CBC counts, demographics, smoking status, body mass index (BMI) and hemoglobin A1C values were recorded. Patients were also stratified according to WHO-defined BMI criteria into six groups: Underweight (BMI <18.5), Normal (BMI 18.5–24.9), Overweight (BMI 25–29.9), Obese Class I (BMI 30–34.9), Obese Class II (BMI 35–39.9), and Obese Class III (BMI ≥ 40). Neutrophilia was defined as an absolute neutrophil count (ANC) of ≥7.8 x10⁹/L, representing two standard deviations above the mean. Chronic neutrophilia was defined as having had three elevated ANC results 2–24 months apart. Patients were designated as diabetic if they had: a) diabetes mellitus entered as ICD-9 diagnosis at any point within 6 years before or after the initial CBC, or b) had a hemoglobin A1C ≥ 6.5% during this time. For certain analyses, cohorts were stratified by diabetes and smoking status. VTE rates between groups were compared by chi-square analysis of proportions. Two tailed t-tests and chi-square analysis were used to assess the effect of chronic neutrophilia as appropriate. Odds ratios (OR) were estimated with logistic regression models. A two-tailed alpha of 0.05 was used to denote significance.

Data on 34,508 Bronx primary care clinics patients were collected; 12,993 (37.7%) were diabetic and 6,698 (19.4%) were smokers. In this cohort, 1,619 (4.7%) patients were diagnosed with VTE. There was a significantly higher rate of VTE in patients with chronic neutrophilia in our overall population (7.1% vs. 4.7%, p=0.006). Excluding diabetics and smokers did not decrease the relative risk (6.9% vs. 3.3%, p=0.01). We found that the risk of VTE increased with rising degree of obesity (Class I: OR 1.22, 95%CI: 1.04, 1.43 p=0.016; Class II: OR 1.55, 95%CI: 1.29, 1.86 p<0.001; Class III: OR 2.19 95%CI: 1.80, 2.65 p<0.001). Patients in the Overweight category were not at higher risk. There was an association of VTE with diabetes (OR 1.41, 95%CI: 1.27, 1.57 p<0.001) and, to a lesser degree, smoking (OR 1.16, 95%CI: 1.02, 1.31 p=0.024). Multiple regression analysis demonstrated that chronic neutrophilia was independently associated with VTE (OR 1.42, 95%CI: 1.02, 1.98 p=0.04). When stratified by age, we found the relationship between VTE and neutrophilia to be most significant in patients between 40 and 70 years old (OR 1.75, 95%CI: 1.15, 2.64 p=0.008). In this group, the association of VTE with neutrophilia was more pronounced than that with diabetes, smoking, and Obesity Class II.

The risk of VTE increases with diabetes, smoking and obesity. Chronic neutrophilia is also independently associated with VTE, supporting a role for leukocytes in venous thrombosis.

No relevant conflicts of interest to declare.