Study finds significant association between low bilirubin levels and venous thromboembolism

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Hakan Duman

A recent paper published by Hakan Duman (Recep Tayyip Erdoğan University, Rize, Turkey) and colleagues in the Journal of Vascular Surgery: Venous and Lymphatic Disorders has concluded that lower levels of bilirubin were significantly associated with venous thromboembolism (VTE), in a study of 103 VTE patients and a control group of 50.

The endogenous anti-inflammatory marker bilirubin is associated with atherothrombosis, as a possible antithrombotic agent that inhibits platelet activation and potentially organ infarction, the authors note. However, no studies known to Duman et al had previously investigated the role of bilirubin in VTE. This single-centre, case-control cross-sectional study found that bilirubin concentration “is independently associated with the presence of VTE”.

“Human life is in a state of equilibrium”, Duman tells Venous News. “The pathological process in the metabolism begins because of the negative side of this balance. Serum bilirubin levels, as an antioxidant, are also part of this balance. In our study, we showed that it may be associated with venous thrombosis. I think future studies will also reveal the unknown benefits.”

The study’s VTE arm included 34 patients with distal deep vein thrombosis (DVT), 30 patients with proximal DVT, and 39 patients with pulmonary embolism. In addition lower bilirubin levels in the VTE arm (0±2.6mmol/L vs. 7.3±3mmol/L; p=0.001), VTE patients also had higher levels of high-sensitivity C-reactive protein (hs-CRP) concentration (0.8 [0.3–2] mg/L vs. 1.1 [0.2–3] mg/L; p=0.008) and a higher white blood cell count (7.4±1.5 ×109/L vs. 8.2±2.7 ×109/L; p=0.02). Patients in the VTE subgroup of pulmonary embolism were found to have the lowest bilirubin and highest hs-CRP values, with significantly higher levels of bilirubin in the control arm as compared to the pulmonary embolism patients. Meanwhile, hs-CRP value showed a significant difference between all subgroups versus the control arm, and although white blood cell count was higher in the VTE arm, this difference was not significant.

The authors summarise previous literature, stating:

  • Atherothrombosis is considered a chronic inflammatory disease
  • VTE may cause inflammatory marker levels to rise
  • Because endothelial injury is a common mechanism in both arterial and venous thrombosis, inflammation may be a common risk factor
  • Previous reports suggested that antioxidant capacity increases in mild unconjugated hyperbilirubinemic individuals, and slightly elevated bilirubin may have a protective role in cardiovascular disease.
  • Bilirubin is a possible antithrombotic agent that inhibits platelet activation and, potentially, organ infarction, which could contribute to the reduced mortality rate in mildly hyperbilirubinemic individuals

Duman et al suggest in discussion of their findings, “Inflammation may be part of the event at various stages of haemostasis through the activation of coagulation or by the inhibition of the fibrinolysis and anticoagulant pathways. C-reactive protein levels are independently associated with cardiovascular disease and may play a role in the identification and stratification of individuals at risk of cardiovascular diseases.”

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