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1.
Haemophilia ; 21(5): e375-83, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26207643

ABSTRACT

INTRODUCTION: Von Willebrand disease (VWD) type 2N is characterized by a defective binding of factor VIII (FVIII) to von Willebrand factor (VWF) resulting in diminished plasma FVIII levels and a clinical phenotype mimicking mild haemophilia A. Several mutations in the FVIII binding site of VWF have been reported. AIM: This study aims to examine the effect of genotype on clinical phenotype in a cohort of VWD 2N patients. METHODS: Patients with at least one genetically confirmed 2N mutation were selected retrospectively from a cohort of patients with suspected VWD. Clinical and laboratory phenotypes including bleeding scores (BS) were obtained and analysed. RESULTS: Forty-two VWD 2N patients with a mean age of 44 years were included. Eleven patients were homozygous or compound heterozygous (genetically confirmed group) and 31 patients were heterozygously affected (carriers group). Statistically significant differences between genetically confirmed VWD 2N patients and carriers were found in FVIII activity, VWF antigen levels, VWF-FVIII binding capacity, FVIII/VWF antigen ratio (all P<0.001), VWF-ristocetin activity (p=0.001) and VWF collagen binding (P = 0.002). Median BS was 6 in genetically confirmed VWD 2N patients compared with 3 in carriers (P = 0.047). Haemarthrosis, muscle haematomas and postpartum haemorrhage were only reported in genetically confirmed 2N patients. CONCLUSION: Phenotypic analysis showed that all laboratory parameters are lower in genetically confirmed VWD 2N patients compared with heterozygous 2N carriers. The clinical phenotype in genetically confirmed VWD 2N patients is comparable to mild haemophilia A patients and more severe than heterozygous 2N carriers.


Subject(s)
Hemophilia A/pathology , von Willebrand Disease, Type 2/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Female , Hemorrhage/genetics , Heterozygote , Humans , Male , Middle Aged , Mutation/genetics , Phenotype
2.
Placenta ; 28(7): 709-13, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17137622

ABSTRACT

Although the aetiology of preeclampsia is unknown, there is substantial evidence that it finds its roots in abnormal placentation. Prerequisites for successful placentation include trophoblast invasion, degradation and remodelling of the uterine decidual extracellular matrix, and apoptosis without thrombosis. We tested this hypothesis by analysing the effect of functional polymorphisms in the genes coding for MMP9, MMP3 and annexin A5 on the risk of preeclampsia using a case-control design. In 163 women with preeclampsia and 163 controls we studied the association with polymorphisms in the MMP9 (-1562 C/T), MMP3 (-1612 5A/6A) and annexin A5 (-1 C/T) genes using logistic regression analysis. A lower prevalence of the rare T allele of the MMP9 (-1562 C/T) polymorphism in women with preeclampsia was found (odds ratio 0.48, 95% confidence interval 0.25-0.90). The distribution of the MMP3 (-1612 5A/6A) and annexin A5 (-1 C/T) gene polymorphisms were similar in cases and controls. Our results suggest that the MMP9-1562T allele is associated with a reduced risk of preeclampsia and therefore may protect against maladaptation of the spiral arteries and decreased decidual degradation. The elevated MMP9 concentrations reported to be associated with the -1562T allele might be essential for the development of an adequate maternal-fetal interface early in pregnancy by facilitating trophoblast apoptosis and degradation.


Subject(s)
Matrix Metalloproteinase 9/genetics , Pre-Eclampsia/genetics , Adult , Alleles , Annexin A5/genetics , Case-Control Studies , Female , Humans , Matrix Metalloproteinase 3/genetics , Polymorphism, Genetic , Pregnancy , Promoter Regions, Genetic/genetics
3.
Ann Rheum Dis ; 65(11): 1468-72, 2006 Nov.
Article in English | MEDLINE | ID: mdl-16449315

ABSTRACT

BACKGROUND: Annexin A5 is thought to have a role in the pathophysiology of the antiphospholipid syndrome (APS)-a syndrome characterised by recurrent thrombosis and pregnancy morbidity. OBJECTIVE: To investigate whether anti-annexin A5 immunoglobulin (Ig)M or IgG antibodies, or the -1C-->T polymorphism of annexin A5, is a risk factor for thrombosis or miscarriage, and whether the -1C-->T polymorphism is correlated with APS. METHODS: A cohort study was carried out with a population of 198 patients with primary APS, systemic lupus erythematosus or lupus-like disease. For the detection of anti-annexin A5 antibodies and the measurement of annexin A5 plasma levels, ELISA-type methods were used. The annexin A5 -1C-->T mutation was detected by restriction fragment length polymorphism. RESULTS: 71 patients were positive for annexin A5 IgM or IgG antibodies, of whom 53 patients were positive for anti-annexin A5 IgG antibodies and 27 of 198 patients were positive for anti-annexin A5 IgM antibodies. The prevalence of IgM or IgG anti-annexin A5 antibodies was not significantly associated with thrombosis or miscarriage on multivariate analysis. The prevalence of the -1C-->T mutation in the annexin A5 gene (46/198 patients) was significantly associated with miscarriage (odds ratio 2.7, 95% confidence interval 1.1 to 6.7, independent risk factor). CONCLUSION: The detection of anti-annexin A5 antibodies does not seem relevant for estimating the risk for thrombosis or miscarriage in APS. The -1C-->T mutation was an independent risk factor for miscarriage, which is independent of APS.


Subject(s)
Annexin A5/genetics , Antiphospholipid Syndrome/genetics , Autoantibodies/blood , Polymorphism, Genetic , Abortion, Spontaneous/genetics , Abortion, Spontaneous/immunology , Adult , Annexin A5/blood , Annexin A5/immunology , Antiphospholipid Syndrome/blood , Antiphospholipid Syndrome/immunology , Enzyme-Linked Immunosorbent Assay/methods , Female , Genetic Predisposition to Disease , Humans , Immunoglobulin G/blood , Immunoglobulin M/blood , Lupus Erythematosus, Systemic/blood , Lupus Erythematosus, Systemic/genetics , Lupus Erythematosus, Systemic/immunology , Male , Pregnancy , Risk Factors , Thrombosis/genetics , Thrombosis/immunology
5.
Atherosclerosis ; 153(2): 363-71, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11164425

ABSTRACT

Fibrates are regarded as drugs of choice in hypertriglyceridemia (HTG). Downregulation of apolipoprotein (apo) C-III gene expression and upregulation of lipoprotein lipase (LPL) gene expression have been suggested to explain the hypolipidemic action of fibrates. This study was designed to study the effects of bezafibrate therapy on very low density lipoprotein (VLDL) susceptibility to lipolysis, VLDL binding to the low density lipoprotein (LDL) receptor and postheparin LPL activities in patients with HTG. VLDL lipolysis was studied with heparan sulfate proteoglycan-bound LPL. Binding affinity of VLDL to the LDL receptor was determined in J774 cells with 125I-labeled control LDL. Eighteen HTG patients were randomized to receive, in a double-blind placebo-controlled cross-over fashion, 400 mg bezafibrate once daily for 6 weeks. In response to bezafibrate therapy, plasma triglyceride and apoC-III levels decreased by 69 and 42%, respectively. HTG VLDL was lipolyzed less efficiently compared to control VLDL, and lipolysis did not improve by bezafibrate therapy. VLDL binding affinity to the LDL receptor was comparable between the control group and HTG group, and did not change upon bezafibrate therapy. However, the post-heparin LPL activity in the HTG patients increased from 153 to 192 U/l (P = 0.025). A strong inverse relation was observed between the change in LPL activities and the change in triglyceride levels (r = -0.62, P = 0.006). In conclusion, the hypolipidemic action of bezafibrate therapy in HTG may be attributed to increased LPL activity, whereas VLDL susceptibility to lipolysis and LDL receptor binding are not affected.


Subject(s)
Bezafibrate/administration & dosage , Hypertriglyceridemia/drug therapy , Hypolipidemic Agents/administration & dosage , Lipoprotein Lipase/metabolism , Adult , Double-Blind Method , Enzyme Activation , Female , Humans , Hypertriglyceridemia/metabolism , Lipolysis/drug effects , Lipoproteins, VLDL/metabolism , Male , Middle Aged , Receptors, LDL/metabolism , Substrate Specificity , Up-Regulation
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