Common carotid intima-media thickness and von Willebrand factor serum levels in rheumatoid arthritis female patients without cardiovascular risk factors

High atherosclerosis prevalence was found in rheumatoid arthritis (RA), and the von Willebrand factor (vWF) was shown to be a marker for endothelial damage. The aim of this study was to evaluate the association of intima-media thickness of the left common carotid artery with vWF serum levels in rheumatoid arthritis patients without cardiovascular risk factors. We included 55 RA female patients, each with at least 5 years of duration of the disease, and 20 healthy female subjects as members of the control group. The vWF, cholesterol, triglycerides, and the immune variables—rheumatoid factor and reactive C protein—were evaluated. The media thickness and intima-media thickness (IMT) in patients and in the control subjects were assessed by Doppler ultrasound of the left common carotid artery. Although the ages for RA patients and healthy female controls were not different, the IMT of the left common carotid artery (IMT CCA) in rheumatoid arthritis patients was increased in comparison with healthy control measurements, the mean being 0.67 mm (SD 0.18) vs 0.58 mm (SD 0.10) with a p value 0.01. The vWF serum levels showed differences in RA patients from those in control patients, 145.6 (SD 30.08) vs 121.8 (SD 37.17), respectively, with p=0.007. A correlation was also found between vWF with IMT CCA in the RA patients: r=0.390 and p<0.05. We concluded that the measurements of the left common carotid artery intima-media thickness together with the von Willebrand factor serum levels could give valuable information about the artery status and the atherosclerosis process in early stages in patients with rheumatoid arthritis without cardiovascular risk factors.     

Exercise induced release of von Willebrand factor: evidence for hypoxic reperfusion microvascular injury in rheumatoid arthritis.

Experimental evidence suggests that rheumatoid synovitis may be perpetuated by the generation of reactive oxygen species during hypoxic reperfusion injury. The latter occurs because increased intra-articular pressure during exercise exceeds synovial capillary perfusion pressure, impairing blood flow. The object of this study was to establish a marker for and the mechanism of synovial hypoxic reperfusion injury. Von Willebrand factor (vWF) is only released from endothelial cells and platelets and is an in vivo and in vitro marker of endothelial injury. In vivo exercise induced changes in plasma vWF were therefore investigated in patients with rheumatoid arthritis (RA) compared with controls and in vitro vWF release by human umbilical vein endothelial cells subjected to hypoxia reperfusion. Pre-exercise plasma vWF levels were 1001 and 817 IU/l, increasing after exercise to 1658 and 845 IU/l in patients with RA and controls respectively. Von Willebrand factor release from human umbilical vein endothelial cells followed a biphasic pattern, occurring during both hypoxia and reperfusion. Hypoxia reperfusion induced vWF release by human umbilical vein endothelial cells in vitro suggests that exercise induced vWF release in patients with RA is best explained by synovial hypoxic reperfusion injury. This study supports evidence that generation of reactive oxygen species plays a principal part in synovial hypoxic reperfusion injury and suggests vWF as a useful marker of this phenomenon.     

The von Willebrand factor A-1 domain binding aptamer BT200 elevates plasma levels of von Willebrand factor and factor VIII: a first-in-human trial

von Willebrand factor (VWF) and factor VIII (FVIII) circulate in a noncovalent complex in blood and promote primary hemostasis and clotting, respectively. A new VWF A1-domain binding aptamer, BT200, demonstrated good subcutaneous bioavailability and a long half-life in non-human primates. This first-in-human, randomized, placebo-controlled, double-blind trial tested the hypothesis that BT200 is well tolerated and has favorable pharmacokinetic and pharmacodynamic effects in 112 volunteers. Participants received one of the following: a single ascending dose of BT200 (0.18-48 mg) subcutaneously, an intravenous dose, BT200 with concomitant desmopressin or multiple doses. Pharmacokinetics were characterized, and the pharmacodynamic effects were measured by VWF levels, FVIII clotting activity, ristocetin-induced aggregation, platelet function under high shear rates, and thrombin generation. The mean half-lives ranged from 7-12 days and subcutaneous bioavailability increased dose-dependently exceeding 55% for doses of 6-48 mg. By blocking free A1 domains, BT200 dose-dependently decreased ristocetin-induced aggregation, and prolonged collagen-adenosine diphosphate and shear-induced platelet plug formation times. However, BT200 also increased VWF antigen and FVIII levels 4-fold (P<0.001), without increasing VWF propeptide levels, indicating decreased VWF/FVIII clearance. This, in turn, increased thrombin generation and accelerated clotting. Desmopressin-induced VWF/FVIII release had additive effects on a background of BT200. Tolerability and safety were generally good, but exaggerated pharmacology was seen at saturating doses. This trial identified a novel mechanism of action for BT200: BT200 dose-dependently increases VWF/FVIII by prolonging half-life at doses well below those which inhibit VWF-mediated platelet function. This novel property can be exploited therapeutically to enhance hemostasis in congenital bleeding disorders.     

Ethnic variation in von Willebrand factor levels can influence the diagnosis of von Willebrand disease

The amount and function of von Willebrand factor (VWF), measured against a panel of laboratory tests, is the normal basis for the diagnosis of von Willebrand's disease (VWD). The normal range for each test is usually obtained by assaying samples from a cross section of the local population or from a manufacturer's kit insert. While collecting normal controls for another study, population from Durban in South Africa, with its distinct ethnic mix of Africans, Indians and Caucasians were also studied. Previously, Indians from their subcontinent have not been looked at separately and compared with Africans and Caucasians. It is confirmed in a previous study (Miller, Dilley, Richardson, Craig, Evatt. (2001) American Journal of Hematology 67, 125) that African Americans had significantly higher VWF:Ag and FVIII levels when compared with Caucasians. In addition, it was found that there was a significant difference in VWF:Ag levels between Indians and Africans, and between Caucasians and Africans, whereas no significant difference between Indians and Caucasians. Africans, Indians and Caucasians with blood group O showed significantly lower VWF:Ag and FVIII than the other ABO blood groups. Normal ranges of VWF for different blood groups are well established and this information should be utilized while considering a diagnosis of VWD. It is proposed here that the influence of racial origin should also be considered in the clinical and laboratory evaluation of VWD.     

Treatment of von Willebrand disease with a high-purity factor VIII/von Willebrand factor concentrate: a prospective, multicenter study.

Among patients with von Willebrand disease (VWD) who are unresponsive to desmopressin therapy, replacement with plasma-derived concentrates is the treatment of choice. Because prospective studies are lacking, such treatment has been largely empirical. A multicenter, prospective study has been conducted in 81 patients with VWD (15 patients with type 1, 34 with type 2, and 32 with type 3 disease) to investigate the efficacy of a high-purity factor VIII/von Willebrand factor (FVIII/VWF) concentrate for treatment of bleeding and surgical prophylaxis. Two preparations of the concentrate-one virally inactivated with solvent detergent, the other with an additional heat-treatment step--were evaluated. Pharmacokinetic parameters were similar for both preparations. Using pre-established dosages based on the results of pharmacokinetic studies, 53 patients were administered either preparation for the treatment of 87 bleeding episodes, and 39 patients were treated prophylactically for 71 surgical or invasive procedures. Sixty-five (74.7%) and 10 (11.5%) of the bleeding episodes were controlled with 1 or 2 infusions, respectively. Patients with severe type 3 VWD typically required more infusions and higher doses, at shorter time intervals, than did patients with generally milder types 1 and 2. Among patients undergoing surgical procedures, blood loss was lower than that predicted prospectively, and losses exceeding the predicted value did not correlate with the postinfusion skin bleeding time. In conclusion, the concentrate effectively stopped active bleeding and provided adequate hemostasis for surgical or invasive procedures, even in the absence of bleeding time correction.     

Quantitative measurement of carotid atherosclerosis in relation to levels of von Willebrand factor and fibrinolytic variables in plasma--a 2-year follow-up study

BACKGROUND: It has been proposed that the mechanism of action of the new risk factors for myocardial infarction and stroke, von Willebrand factor (vWF), tissue plasminogen activator (tPA) and tissue plasminogen activator inhibitor-1 (PAI-1) could possibly be mediated via a primary effect on atherogenesis but there is little data to substantiate this. DESIGN: A prospective single-centre cohort study of progression of atherosclerosis. METHODS: Carotid plaque area was quantitated by two-dimensional (2D) ultrasound in 258 subjects at entry and after 1 and 2 years. Plasma and serum samples were drawn at baseline and serum lipids and plasma levels of haemostatic factors were measured. RESULTS: The traditional risk factors, smoking, total cholesterol, hypertension and male gender explained 51% of the variance in plaque area at baseline and 48% at 1-year follow-up. There were small positive associations of plaque area with vWF, tPA and tPA/PAI-1 complex and a tendency to negative associations with PAI-1 levels, independent from the traditional risk factors. The additional explanatory power of the haemostatic factors did not exceed 3%. CONCLUSION: The data accord with a marginal role in atherogenesis of vWF and tPA, and underline the major impact of smoking, hypertension and cholesterol on carotid plaque area progression.     

Relationship of serum IgG rheumatoid factor to IgM rheumatoid factor and disease activity in rheumatoid arthritis

Rheumatoid factors (RF) constitute the major autoantibodies in rheumatoid arthritis (RA). RF are directed against IgG Fc, are polyclonal, and are predominantly of the IgG and IgM classes. RF may participate in both synovial and extraarticular inflammation in RA, although the precise roles of serum IgG and IgM RF are unclear. The purpose of our study was to correlate serum IgG RF with serum IgM RF levels measured by radioimmunoassay and with clinical disease activity in 42 prospectively evaluated seropositive RA patients. IgM RF correlated with IgG RF levels and articular disease activity. IgG RF correlated with IgM RF but not with articular disease activity when adjusted for IgM RF.     

Postpartum von Willebrand factor levels in women with and without von Willebrand disease and implications for prophylaxis

The aim of this study was to elucidate the fall in von Willebrand factor (VWF) and factor VIII activity (FVIII) after childbirth in women with and without von Willebrand disease (VWD). VWF:RCo, VWF:Ag, and FVIII were obtained in the third trimester of pregnancy, on admission for childbirth, and 10 times postpartum. Specimens were processed within 4 h and analysed centrally. Means were calculated at each time point. Forty women (40 pregnancies) without VWD and 32 women (35 pregnancies) with VWD were enrolled. 15/32 with VWD were treated (30% of those with type 1 and all of those with type 2) in 17 pregnancies. Treatments prior to delivery consisted of desmopressin (2/17), VWF concentrate (15/17) and after delivery VWF concentrate (16/17). Duration of treatment was 0–21 days (median 6). VWF levels peaked at 250% of baseline – 4 h postpartum in women with VWD and 12 h postpartum in women without VWD. Thereafter, VWF levels fell rapidly, approached baseline at 1 week and reached baseline at 3 weeks. Except immediately postpartum, when the levels among treated cases were higher, levels among women with VWD appeared to parallel, but were lower than those among women without VWD. Levels were lowest among those who received treatment. VWF levels fall rapidly after childbirth. Except immediately postpartum, current treatment strategies do not raise VWF levels to the levels of women without VWD or even to the levels of women with milder, untreated VWD. Consequently, women with VWD may be at risk of postpartum haemorrhage despite treatment.     

Effects of antirheumatic therapy on serum lipid levels in patients with rheumatoid arthritis: a prospective study

BACKGROUND: Patients with newly diagnosed rheumatoid arthritis have adverse serum lipid profiles. We sought to determine the effects of treating rheumatoid arthritis with antirheumatic drugs on these abnormal lipid levels. SUBJECTS AND METHODS: We studied 42 patients with newly diagnosed rheumatoid arthritis who had not been treated with corticosteroids or disease-modifying antirheumatic drugs. We measured serum lipid profiles at baseline and 1 year later, and determined whether there were differences in the changes in lipid levels between patients who met the American College of Rheumatology criteria for a 20% improvement in rheumatoid arthritis and those who did not. RESULTS: Of the 42 patients, 27 (64%) met the criteria for a 20% improvement in rheumatoid arthritis during the 12-month study. In these patients, mean high-density lipoprotein (HDL) cholesterol levels increased by 21% (P <0.001), apolipoprotein A-I levels increased by 23% (P <0.001), and the ratio of low-density lipoprotein (LDL) cholesterol to HDL cholesterol level decreased by 13% (P = 0.10). There were significant between-group differences (responders-nonresponders) in the mean 12-month changes in HDL cholesterol levels (8.0 mg/dL; 95% confidence interval [CI]: 3 to 13 mg/dL; P = 0.002), apolipoprotein A-I levels (21 mg/dL; 95% CI: 8 to 33 mg/dL; P = 0.003), and the LDL cholesterol to HDL cholesterol ratio (-0.6; 95% CI: -0.1 to -1.0; P = 0.03), but not in LDL cholesterol, apolipoprotein B-100, or lipoprotein(a) levels. CONCLUSION: Active rheumatoid arthritis is associated with an adverse lipid profile that improves substantially following effective treatment of rheumatoid arthritis. This improvement may reduce the risk of cardiovascular disease.     

The serum levels of resistin in rheumatoid arthritis patients

OBJECTIVE: Adipocyte-derived resistin is a circulating protein implicated in insulin resistance, but the role of human resistin is uncertain because it is produced largely by macrophages. The aim of this study was to analyze serum resistin concentrations in rheumatoid arthritis (RA) patients to determine the role of resistin in human inflammatory diseases. MATERIALS AND METHODS: Resistin concentrations were assessed by ELISA in serum samples from 42 patients with RA. Serum samples from 38 healthy subjects acted as controls. We also evaluated the circulating levels of tumor necrosis factor- alpha (TNF-alpha) and disease activity markers in RA patients. RESULTS: In RA patients, serum resistin levels were significantly higher than those in healthy subjects. Serum resistin levels in RA patients were correlated with the RA disease activity markers, CRP and ESR. Furthermore, resistin levels in RA patients were significantly correlated with circulating levels of TNF-alpha. CONCLUSION: Serum resistin levels were significantly increased in RA patients and correlated with inflammatory markers and TNF-alpha, suggesting that resistin may play a role in the rheumatoid inflammatory process.     

Population differences in von Willebrand factor levels affect the diagnosis of von Willebrand disease in African-American women

Diagnosis of von Willebrand disease (vWD) is based on a panel of laboratory tests that measure the amount and function of von Willebrand factor (vWF). In population studies, vWF is higher in African Americans than Caucasians. Bleeding time, factor VIII activity (FVIII), vWF antigen (vWF:Ag), "vWF activity" ELISA (vWF:Act), ristocetin cofactor (vWF:RCof), and ristocetin-induced platelet aggregation (RIPA) were measured on 123 women with menorrhagia and 123 randomly selected control women; 70 cases and 76 controls were African American. Among controls, African Americans had significantly higher levels of vWF:Ag (mean 120 vs. 102 U/dl, P = 0.017). Among all subjects, African Americans had higher levels of vWF:Ag (mean 123 vs. 103, P = 0.001), vWF:Act (mean 101 vs. 89, P = 0.006), and FVIII (mean 118 vs. 104, P = 0.008). VWF:RCof did not differ between races (93 vs. 94 U/dl). RIPA was reduced in African Americans (P < 0.0001). In both races, women with type O blood differed significantly from those with other ABO types in vWF:Ag, vWF:Act, FVIII, and vWF:RCof. Based on criteria of two or more tests below race- and ABO-specific reference ranges, 6.5% of menorrhagia cases and 0.8% of controls were classified as having vWD, or its phenocopy. Among Caucasians, no controls and 7 cases (15.6%) were classified as affected, and in African Americans, 1 control (1.3%) and 1 case (1.4%) were so classified. Racial differences in vWF further complicate the issues surrounding diagnosis of vWD. The finding of increased vWF:Ag not accompanied by increased vWF:RCof has implications for understanding the structure-function relationships of vWF. Published 2001 Wiley-Liss, Inc.     

Protein C, protein S and von Willebrand factor levels correlate with bleeding symptoms: a population-based study

Although natural anticoagulant deficiencies are the established causes of thrombosis, their roles in bleeding are not fully studied. The objective is to correlate haemostatic factors with haemorrhagic symptoms quantified by a standardized questionnaire. Adult subjects were recruited from Bangkok and nearby provinces as part of routine health surveys/checkups. The validated MCMDM-1VWD form was used to assess their bleeding symptoms. At the same time, von Willebrand factor (VWF) activity, free protein S levels and protein C activity were measured. There were 5196 individuals. The mean age was 44.3 years (range 15-99) and 41% were male subjects. The mean bleeding score was -0.28 and 95% of subjects had scores between -2 and +2. The scores were lower in female subjects than in male subjects (-0.35 vs. -0.16, P < 0.001). Bleeding scores correlated negatively with age, VWF and protein C activities (Spearman's ρ-0.258, -0.091 and -0.098, respectively, all P < 0.001), but did not significantly correlate with protein S levels. Using multivariate analysis, female gender, VWF below 100 IU dL(-1), protein C below 100 IU dL(-1) and protein S over 150 IU dL(-1) significantly related to high (≥3) bleeding scores (adjusted odds ratio 1.95, 1.83, 1.56 and 2.84, P = 0.001, 0.001, 0.039 and 0.017, respectively). These findings may suggest interacting roles of VWF and natural anticoagulants in modifying bleeding symptoms.     

Changes in the levels of factor VIII and von Willebrand factor in the puerperium

To determine changes in Factor VIII (FVIII) and von Willebrand Factor (VWF) in the first 3 days of the puerperium. A prospective study assessing FVIII clotting activity, VWF activity and antigen levels in 95 women (with singleton uncomplicated pregnancies) during labour and on days 1, 2 and 3 of the puerperium. There were no significant differences in FVIII, VWF:Ag and VWF:CB on days 1 and 2 of the puerperium compared with levels during labour. There was a significant decrease in VWF:Ag (P = 0.009) and VWF:CB (P = 0.04) on day 3. Age, ethnicity, duration of labour and mode of delivery did not have any significant effect on the changes in FVIII and VWF levels. The pregnancy induced increase in FVIII and VWF is maintained in the first 48 h after delivery. VWF levels start to decline on day 3 postdelivery.     

Variation in the von Willebrand factor gene is associated with von Willebrand factor levels and with the risk for cardiovascular disease

High levels of von Willebrand factor (VWF) are associated with an increased risk for cardiovascular disease (CVD). Although VWF levels are strongly heritable and genetic susceptibility is an important risk factor for CVD, information on the contribution of common VWF gene variants to VWF levels and CVD risk is limited. In a case-control study of 421 young patients with a first event of acute coronary heart disease (CHD) or ischemic stroke (IS), and 409 healthy control participants (men aged ≤ 45 years, women aged ≤ 55 years), 27 haplotype-tagging single-nucleotide polymorphisms (ht-SNPs), covering the total common VWF gene variation, were selected and genotyped. The associations between these SNPs, VWF antigen (VWF:Ag) levels, VWF collagen-binding (VWF:CB) activity, and CVD risk was investigated. Two new associations were identified. For ht-SNP rs4764478 (intron 45), the increase in VWF:Ag levels and VWF:CB activity per minor allele was 0.082 (± 0.026) IU/mL (P = .001) and 0.096 (± 0.030) IU/mL (P = .002), respectively. ht-SNP rs216293 (intron 17) was associated with CVD risk (odds ratio, 1.44; 95% confidence interval [CI], 1.12-1.86 per minor allele). We confirmed the association between rs1063857 and CVD risk. Our data show that common variants in the VWF gene are associated with VWF levels and with the risk for CVD.     

Rheumatoid factor and serum IgG, IgM and IgA levels in rheumatoid arthritis with vasculitis.

The authors report a significant increase in the rheumatoid factor titre in rheumatoid arthritis patients with vasculitis. A significant rise in IgG and IgA levels was found in uncomplicated RA, when compared with a normal population. The IgM levels were not found to be elevated in this group of RA patients. In the RA patients with vasculitis, on the contrary, the three Ig classes are increased when compared with the normal population, and the IgM level is increased when compared with the uncomplicated RA group. Significant relation was found between log IgM and log R.F. titre in the RA group with vasculitis. It is shown that the mild reduction of serum (by dithiothreitol 0.004 M) causes a complete negativity of the R. F. in all cases. It is concluded that the haemagglutination and the latex precipitation in vitro are induced by IgM-R. F. and not by IgG and IgA-R. F. molecules. Only free sites of IgM-R.F. play a functional role in the determination of the R. F. -titre. The authors postulated that increase in IgM in RA patients with vasculitis is partially due to the presence of free IgM-R. F. molecules in serum. Finally it is concluded that hidden IgM-R. F. molecules in patients with lower R. F. titre are not quantified by immunodiffusion methods.