Haptoglobin phenotype 2-2 as a potentially new risk factor for spontaneous venous thromboembolism

Abstract

BACKGROUND AND OBJECTIVES: Haptoglobin (Hp) is a plasma protein that binds free hemoglobin and thus prevents catalysis of reactive oxygen species by the Fenton reaction. A genetic polymorphism has been described that leads to the generation of two distinct alleles, Hp1 and Hp2, which define three major haptoglobin phenotypes, denoted Hp1-1, Hp2-1 and Hp2-2. Hp2-2 has been reported to be associated with the risk of atherosclerosis and coronary heart disease. In our study we investigated the association of haptoglobin genotype and phenotype with the risk of spontaneous venous thromboembolism (VTE). DESIGN AND METHODS: One hundred and twenty-eight patients with a history of spontaneous deep vein thrombosis (70 women, 58 men), 105 with spontaneous symptomatic pulmonary embolism (58 women, 47 men) and 122 healthy controls (60 women, 62 men) were enrolled. Haptoglobin levels were measured immunonephelometrically and phenotypes were detected by polyacrylamide gel electrophoresis and subsequent immunoblotting. RESULTS: The Hp2-2 phenotype was significantly more prevalent in patients (42%) than in controls (30%) and significantly increased the risk for VTE in univariable (odds ratio=1.6, 95% confidence interval [1.0-2.6], p=0.04) and multivariable analyses (odds ratio=1.9 [1.0-3.4], p=0.04). Hp2-2 (n=134) was associated with significantly lower haptoglobin levels (median=89.7 mg/dL) than Hp2-1 (n=170, median = 123.5 mg/dL, p<0.001) or Hp1-1 (n=51, median=142.8 mg/dL, p<0.001). INTERPRETATION AND CONCLUSIONS: Our study gives the first evidence that Hp2-2 represents a risk factor for spontaneous VTE, presumably through a pathophysiological mechanism similar to that in arterial disease.