Abstract
Increased factor VIII (FVIII) levels are a prevalent and independent risk factor for venous thromboembolism (VTE). The low density lipoprotein receptor-related protein 1 (LRP1) has been associated with FVIII catabolism. After a median of 10 years of the first thrombotic episode, we evaluated FVIII activity levels in 75 patients with VTE and high FVIII levels and in 74 healthy controls. Subsequently, we evaluated the regions of F8 and LRP1 genes coding sites of affinity between these proteins, with the objective of determining genetic alterations associated with plasma FVIII levels. After a median time of 10 years after the VTE episode, FVIII levels were significantly higher in patients when compared to controls (158.6 IU/dL vs. 125.8 IU/dL; P ≤ 0.001]. Despite the fact that we found 14 genetic variations in F8 and LRP1 genes, no relationship was found between FVIII levels with these variations. We demonstrated a persistent increase of FVIII levels in patients with VTE, but in a much lower magnitude after 10 years when compared to 3-years after the episode. Moreover, we observed no relationship of genetic variations in the gene regions coding affinity sites between LRP1 and FVIII with FVIII levels.
Highlights
Genetic variations in sites of affinity between factor VIII (FVIII) and lipoprotein receptor-related protein 1 (LRP1) are not associated with high FVIII levels in venous thromboembolism
Despite the fact that we found 14 genetic variations in F8 and LRP1 genes, no relationship was found between FVIII levels with these variations
We identified 12 mutations/polymorphisms in the region of LRP1 gene, these were not associated with FVIII levels
Summary
Genetic variations in sites of affinity between FVIII and LRP1 are not associated with high FVIII levels in venous thromboembolism. We evaluated the regions of F8 and LRP1 genes coding sites of affinity between these proteins, with the objective of determining genetic alterations associated with plasma FVIII levels. We observed no relationship of genetic variations in the gene regions coding affinity sites between LRP1 and FVIII with FVIII levels. Venous thromboembolism (VTE) is a multifactorial disease, and increased levels of coagulation factor VIII (FVIII) have been established as a prevalent and independent risk factor for the first episode and recurrent VTE1–4. Several studies investigated the correlation between polymorphisms in LRP1 gene and plasma levels of FVIII and VTE14,23–26, only C663T polymorphism showed association with elevated FVIII levels and VTE risk[25]. Within the FVIII molecule, two high-affinity binding sites for LRP1 have been identified: the region 484–509 of the A2 domain and the region 1811–1818 of the A3 domain; and a low-affinity site in the region 2303–2333 of the C2 domain[30,31,32,33]
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