von Willebrand factor and factor VIII as risk factors for arterial and venous thrombosis

2005 ◽  
Vol 42 (1) ◽  
pp. 49-55 ◽  
Author(s):  
Ida Martinelli
2008 ◽  
Vol 1 ◽  
pp. CCRep.S737
Author(s):  
Mari Terashima ◽  
Hiroshi Kataoka ◽  
Hirosei Horikawa ◽  
Hiroyuki Nakagawa ◽  
Toshiaki Taoka ◽  
...  

Background and purpose Previous studies have linked procoagulant factor VIII (F VIII) to an increased risk of venous thrombosis, whereas the relation between plasma von Willebrand factor (VWF) and venous thrombosis remains poorly understood. Elevated VWF levels are frequently found in patients with cerebral sinus and venous thrombosis (CSVT), always in association with high F VIII levels. We describe a patient with CSVT accompanied by elevated VWF levels without high F VIII levels. Case description A 23-year-old healthy man who had headache noticed difficulty in moving the right hand. On the following day, he lost consciousness and had partial seizures of the right hand. After regaining consciousness, weakness of the right extremities developed. The cranial angiogram confirmed occlusion of the superior sagittal sinus. The levels of VWF and F VIII were 238% and 101.9 IU/dl, respectively. We performed balloon percutaneous transluminal angioplasty and mechanical thrombectomy, leading to successful recanalization of the intracranial sinuses. VWF levels were decreased along with radiographic improvement, independently of F VIII. Conclusion VWF may contribute to CSVT and that inhibition of VWF activity potentially has a role in the future treatment of pathological conditions related to venous thrombosis.


Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1749-1749
Author(s):  
Anne Yael Nossent ◽  
Johanne H. Ellenbroek ◽  
Marijke Frolich ◽  
Frits R. Rosendaal ◽  
Rogier M. Bertina ◽  
...  

Abstract High levels of von Willebrand factor (VWF) and factor VIII (FVIII) are a risk factor for thrombosis. Determinants of high VWF and FVIII levels are poorly understood. Secretion of VWF from endothelial storage pools is regulated by vasopressin type-2 receptor (V2R). Previously, we have shown that a V2R variant, which has increased binding affinity for its ligand vasopressin (AVP), is associated with increased levels of VWF and FVIII1. Nephrogenic Diabetes Insipidus (NDI) is a disorder characterized by renal insensitivity to AVP, caused by mutations in the genes encoding V2R or the aquaporin 2 water channel (AQP2). AQP2 expression is enhanced by stimulation of V2R. Patients with NDI are unable to concentrate their pre-urine. We hypothesized that carriers of AQP2 mutations compensate excess fluid loss by up-regulating AVP release and V2R expression, resulting in increased VWF and FVIII secretion. To test this hypothesis, we set up the Factor Eight in Nephrogenic Diabetus Insipidus study (FENDI), which includes 13 NDI families: 14 NDI patients (12 V2R- and 2 AQP2-linked), 14 carriers (9 V2R- and 5 AQP2-linked) and 25 unaffected family members, as well as 48 unrelated healthy individuals. In addition, we looked at effects of common AQP2 gene variations in a case-control study on venous thrombosis, the Leiden Thrombophilia Study (LETS), which consists of 474 patients with a first deep vein thrombosis and 474 healthy controls, sex and age matched to the patients. In the FENDI, no differences were observed between NDI patients, carriers and unaffected individuals in markers for fluid homeostasis such as hematocrite, serum osmolality and blood pressure. AVP reached detectable levels in all carriers of AQP2 mutations, compared to 27% and 56% in unrelated and related unaffected individuals, respectively. AVP levels, were, when detectable, elevated in all patients and carriers. VWF propeptide, a measure of the VWF secretion rate, VWF antigen and FVIII activity were also highest in carriers of AQP2 mutations. In the LETS, we sequenced a 6.6 kb long genomic region around the AQP2 gene in 25 selected individuals. We identified 18 single nucleotide polymorphisms (SNPs), of which 16 were genotyped in the entire LETS. Although reliable haplotypes could not be formed, due to recombination, the SNPs were linked within 5 clusters. In three of these clusters, up to 2.5-fold increases in thrombosis risk were observed. In these same clusters we observed associations of the AQP2 SNPs with arterial blood pressure. However, none of the AQP2 SNPs were associated with VWF or FVIII levels in healthy controls of the LETS. In conclusion, increased AVP levels in carriers of NDI-causing AQP2 mutations appear associated with increased VWF secretion. Furthermore, in the LETS, common AQP2 gene variations are associated with the risk of venous thrombosis.


2001 ◽  
Vol 115 (1) ◽  
pp. 156-158 ◽  
Author(s):  
Pieter W. Kamphuisen ◽  
Jeroen C. J. Eikenboom ◽  
Frits R. Rosendaal ◽  
Ted Koster ◽  
Andrew D. Blann ◽  
...  

2014 ◽  
Vol 30 (8) ◽  
pp. 1057-1059 ◽  
Author(s):  
Nongnuch Sirachainan ◽  
Manasjitt Boonyatarp ◽  
Praguywan Kadegasem ◽  
Werasak Sasanakul ◽  
Anannit Visudtibhan ◽  
...  

1994 ◽  
Vol 647 (2) ◽  
pp. 265-272 ◽  
Author(s):  
Richard M. McCarron ◽  
David A. Doron ◽  
Anna-Leena Sire´n ◽  
Giora Feuerstein ◽  
Eliahu Heldman ◽  
...  

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 806-806
Author(s):  
Weihong Tang ◽  
Mary Cushman ◽  
Saonli Basu ◽  
David Green ◽  
Alexander P Reiner ◽  
...  

Abstract Abstract 806 Background Factor VIII and von Willebrand factor (vWF) are important components of the coagulation system that circulate together in plasma as a non-covalent complex. Increased circulating levels of FVIII activity (FVIII:C) and vWF antigen (vWF:Ag) in the top 25% of the population distribution are common risk factors for venous thromboembolism, the third leading vascular disease. FVIII and vWF are genetically controlled but their genetic determinants are not fully understood. Moreover, data from populations other than European Americans (EAs) are limited. We performed a genetic association study for plasma levels of FVIII:C and vWF:Ag using a gene-centric approach in the cohorts of NHLBI-funded Candidate gene Association Resource (CARe) consortium. Methods Nearly 50,000 single nucleotide polymorphisms (SNPs) located in about 2,100 candidate genes were genotyped in 18,556 EAs and 4,844 African Americans (AAs) from the Atherosclerosis Risk in Communities (ARIC), Coronary Artery Risk Development in Young Adults (CARDIA), Cardiovascular Health Study (CHS), Multi-Ethnic Study of Atherosclerosis (MESA), and Framingham Heart Study (FHS, EAs only). Measurements for FVIII:C and vWF:Ag were inverse normal transformed to normalize trait distribution, and adjusted for age, sex, study site and principal components to account for potential population stratification. Results across studies were combined within each ethnic group by meta-analysis. SNPs with minor allele frequency (MAF)-weighted sample size (MAFxN) < 10 were excluded from individual cohorts before the meta-analysis. The threshold for statistical significance was 2.0×10−6 after accounting for the number of independent tests. Results In EAs, four independent regions were identified with p<2.0×10−6, characterized by variants from KNG1 (best SNP rs698078, intronic, p= 4.26×10−7 for FVIII:C), ABO (rs529565, intronic, p<1.0×10−199 for both FVIII:C and vWF:Ag), vWF (rs1063856, missense, p=5.84 ×10−12 for FVIII:C and 1.06 ×10−19 for vWF:Ag), and F8/TMLHE (rs12557310, intronic, p=8.02 ×10−10 for FVIII:C). In AAs, three independent regions emerged, characterized by variants from ABO (rs8176693, intronic, p=2.51 ×10−114 for FVIII:C and 1.66 ×10−89 for vWF:Ag), MET1A (rs2236568, intronic, p=1.69 ×10−6 for FVIII:C), and vWF (rs2229446, missense, p=1.95 ×10−20 for FVIII:C and 1.13 ×10−16 for vWF:Ag). The regions marked by KNG1 and MAT1A have not been previously reported for association with FVIII:C. Notably, the variant rs2229446 in the vWF gene results in an arginine to glutamine substitution at position 2185, is associated with vW disease, and is only present in African, African American, and Asian samples of the HapMap population. Conclusions This large, gene-centric genetic association study for FVIII:C and vWF:Ag identified both new and known common loci. These findings expand our understanding of genetic determinants for the common risk factors for thrombosis in both EA and AA populations. Disclosures: No relevant conflicts of interest to declare.


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