Haplotypes encoding the factor VIII 1241Glu variation, factor VIII levels and the risk of venous thrombosis \ud \ud

Levels of factorVIII (FVIII) are associated with the risk of venous thrombosis.The FVIII variation D1241E has been reported to be associated with decreased levels of FVIII. Our objective was to study whether D1241E is associated with levels of FVIII and the risk of venous thrombosis and whether this association is caused by D1241E or another linked variation.We analyzed the association of three FVIII gene haplotypes encoding 1241E (further denoted as HT1, HT3, and HT5) with FVIII levels and thrombosis risk. This analysis was performed in the Leiden Thrombophilia Study (LETS). The control populations of two case-controls studies on arterial thrombosis in men and women, respectively, were used to confirm the effects observed on FVIII:C in the LETS.In men,HT1 was associated with a 6% re- duction in FVIII:C and with a reduced risk of venous thrombosis [odds ratio 0.4 (CI95 0.2–0.8)]. Logistic regression showed that the risk reduction was only partially dependent of the reduction in FVIII levels. HT1 showed no effects in women on either FVIII:C or risk of thrombosis.The number of carriers of HT3 and HT5 was too low to make an accurate estimate of the risk of venous thrombosis. Neither HT3 nor HT5 showed effects on levels of FVIII:C.When we consider that all three haplotypes encoding 1241E show different effects on FVIII:C and thrombosis risk, it is possible that D1241E is not the functional variation. However, FVIII gene variations do contribute to both levels of FVIII and the risk of thrombosi

Maternal TLR4 and NOD2 Gene Variants, Pro-Inflammatory Phenotype and Susceptibility to Early-Onset Preeclampsia and HELLP Syndrome

Background: Altered maternal inflammatory responses play a role in the development of preeclampsia and the hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. We examined whether allelic variants of the innate immune receptors toli-like receptor 4 (TLR4) and nucleotide-binding oligomerization domain (NOD2), that impair the inflammatory response to endotexin are related to preeclampsia and HELLP syndrome. Methods and Finding: We determined five common mutations in TLR4 (D299G and T399I and NOD2 (R70W, G908R and L1007fs) in 340 primiparous women with a histo

Negatively charged phospholipids stimulate factor XI activation by thrombin

Introduction: Coagulation factor XI (FXI) is the zymogen of the serine-protease FXIa, which contributes to thrombin formation by activating factor IX. FXI can be activated by factor XIIa or thrombin, but thrombin-catalysed FXI activation is highly inefficient, unless stimulated by polyanions such as dextran sulphate (DXS) or polyphosphate (PolyP). Aim: To investigate whether negatively charged phospholipids can also enhance thrombin-catalysed FXI activation and to determine the dependence of this reaction on phospholipid concentration and composition, thrombin exosites and ionic strength. Methods: FXI was incubated with thrombin in the absence and presence of DXS, PolyP or phospholipid vesicles, and FXIa generation was followed using a chromogenic substrate. The role of thrombin exosites was probed using specific aptamers. The ionic strength was varied using either sodium chloride (NaCl) or tetrapropylammonium chloride. Results: Similar to DXS and PolyP, phospholipid vesicles with a high percentage of phosphatidic acid or phosphatidylserine enhanced thrombin-catalysed FXI activation by 1–2 orders of magnitude. Moreover, thrombin and FXI bound to negatively charged phospholipids in direct binding assays. Both thrombin exosites contributed to the ability of thrombin to bind to phospholipids and activate FXI, with a predominance of exosite II. Decreasing the ionic strength greatly stimulated FXI activation by thrombin, both in the absence and presence of phospholipids. However, at equal ionic strength, the reaction was more efficient with NaCl than with tetrapropylammonium chloride, suggesting a specific stimulatory effect of Na+. Conclusions: Negatively charged phospholipids, just as DXS and PolyP, stimulate FXI activation by thrombin via a ‘template mechanism’