Endothelial Function in Patients With Von Willebrand Disease.

In patients with von Willebrand disease (vWD) the interest in age-related comorbidities has grown, because the life expectancy of these patients has increased. The research question of this study was whether patients with vWD show a different endothelial function compared to the general population. A total of 37 patients with type 1 (n = 23), type 2 (n = 10) and type 3 (n = 4) vWD, 14 controls and 38 patients with coronary artery disease (CAD) were included in this study. Five markers of endothelial dysfunction (MOED) were determined. Moreover, the endothelial function was examined using the Itamar Endo-PAT. The reactive hyperemia index (RHI) was calculated from the results. The markers soluble intercellular adhesion molecule-1 (p = 0.171), P-Selectin (p = 0.512), interleukin-6 (p = 0.734) and monocyte chemoattractant protein-1 (p = 0.761) showed higher levels in patients with vWD, but were not significantly different compared to the control group. RHI was impaired in CAD-patients (1.855), whereas vWD patients had mean results of 1.870 and controls 2.112 (p = 0.367). In this study, the endothelial function measurements of patients with von Willebrand disease were not significantly different compared to healthy controls.

Whole blood ristocetin-induced platelet impedance aggregometry does not reflect clinical severity in patients with type 1 von Willebrand disease.

BACKGROUND: The haemorrhagic phenotype in patients with von Willebrand disease (VWD) is heterogeneous, and assays of von Willebrand factor ristocetin cofactor activity (VWF:RCo) do not always reflect clinical severity, especially in those individuals classed as type 1 VWD. Recent studies have shown that whole blood ristocetin-induced platelet agglutination (WB-RIPA) using an easy-to-use analyzer, Multiplate® platelet impedance technique, could be informative as a diagnostic test in VWD, although inconsistencies were evident in patients with the type 1 disorder, possibly associated with clinical symptoms. AIM: To investigate the relationship between WB-RIPA, bleeding scores (BS) and VWF-related measurements in type 1 VWD. METHODS: WB-RIPA assay using the Multiplate® was performed using whole blood from 55 patients with type 1 VWD. BS was determined using a standardized questionnaire. RESULTS: WB-RIPA values were significantly lower in type 1 VWD than in healthy controls (P < 0.0001). Weak correlations were apparent between WB-RIPA and VWF:RCo or VWF antigen (VWF:Ag; r = 0.22 or 0.28, respectively). There were significant differences in VWF:RCo (P = 0.036) and VWF:Ag (P = 0.0013) between patients with BS ≥4 (defined as abnormal bleeding tendency) and BS <4 (defined as no abnormal bleeding tendency), respectively. However, no significant difference was observed in WB-RIPA between the BS ≥4 group and BS <4 group. Overall, VWD patients with a WB-RIPA level >70 U did not seem to have an abnormal bleeding tendency, but low levels of WB-RIPA did not correlate with BS. CONCLUSION: WB-RIPA did not reflect clinical severity in type 1 VWD patients.

The Association of Aging With Von Willebrand Factor Levels and Bleeding Risk in Type 1 Von Willebrand Disease.

Little is known about aging in von Willebrand disease (VWD). It is uncertain whether VWD patients experience an age-related increase in von Willebrand factor (VWF) levels, and if so, it is unknown whether normalization of VWF levels with aging ameliorates bleeding risk. We aimed to determine the association of age with VWF levels and bleeding risk in patients with type 1 VWD. This is a retrospective chart review of patients with type 1 VWD presenting to the Hemophilia Clinic of Western Pennsylvania for regularly scheduled clinic visits. Data collected included VWF antigen level and condensed molecular and clinical markers for the diagnosis and management of Type 1 (MCMDM-1) VWD bleeding assessment tool (BAT) bleeding score based on bleeding symptoms during the previous 3 years. Thirty-nine patients participated in the study, and 32 were female. The average age of participants was 41.8 ± 18.0 years. The mean VWF antigen level was 0.83 ± 0.37 IU/mL, and the mean bleeding score was 2.51 ± 2.90. The bleeding score was inversely associated with age, ß = -0.080 (SE = 0.023), P < .01. There was a nonsignificant association between VWF antigen levels and age. To our knowledge, this is the first report showing an association between aging and decreased bleeding symptoms in patients with type 1 VWD. Determining whether or not bleeding risk is reduced in older patients with type 1 VWD is essential for optimal clinical management. Moreover, VWF concentrate is costly, and unwarranted use represents a significant waste of health-care dollars. These findings warrant further investigation.

Evaluation of a microfluidic flow assay to screen for von Willebrand disease and low von Willebrand factor levels.

Essentials von Willebrand factor (VWF) function is shear stress dependent. Platelet accumulation in a microfluidic assay correlates with VWF levels. The microfluidic assay discriminates type 1 von Willebrand disease from healthy controls. The microfluidic flow assay detects responses to therapeutic intervention (DDAVP). SUMMARY: Background von Willebrand disease (VWD) is a mucocutaneous bleeding disorder with a reported prevalence of 1 in 10 000. von Willebrand factor (VWF) function and platelet adhesion are regulated by hemodynamic forces that are not integrated into most current clinical assays. Objective We evaluated whether a custom microfluidic flow assay (MFA) can screen for deficiencies in VWF in patients presenting with mucocutaneous bleeding. Methods Whole blood from individuals with mucocutaneous bleeding was assayed in a custom MFA. Results Thirty-two patients with type 1 VWD (10/32) or reported mucocutaneous bleeding were enrolled. The platelet adhesion velocity (r = 0.5978 for 750 s-1 and 0.6895 for 1500 s-1 ) and the maximum platelet surface area coverage (r = 0.5719 for 750 s-1 and 0.6633 for 1500 s-1 ) in the MFA correlated with VWF levels. Furthermore, the platelet adhesion velocity at 750 s-1 (type 1 VWD, mean 0.0009761, 95% confidence interval [CI] 0.0003404-0.001612; control, mean 0.003587, 95% CI 0.002455-0.004719) and at 1500 s-1 (type 1 VWD, mean 0.0003585, 95% CI 0.00003914-0.0006778; control, mean 0.003132, 95% CI 0.001565-0.004699) differentiated type 1 VWD from controls. Maximum platelet surface area coverage at 750 s-1 (type 1 VWD, mean 0.1831, 95% CI 0.03816-0.3281; control, mean 0.6755, 95% CI 0.471-0.88) and at 1500 s-1 (type 1 VWD, mean 0.07873, 95% CI 0.01689-0.1406; control, mean 0.6432, 95% CI 0.3607-0.9257) also differentiated type 1 VWD from controls. We also observed an improvement in platelet accumulation after 1-desamino-8-d-arginine vasopressin (DDAVP) treatment at 1500 s-1 (pre-DDAVP, mean 0.4784, 95% CI 0.1777-0.7791; post-DDAVP, mean 0.8444, 95% CI 0.7162-0.9726). Conclusions These data suggest that this approach can be used as a screening tool for VWD.

Spontaneous recurrent hematuria and hematospermia: Unique manifestations of von Willebrand disease type I. Case report.

In this report we describe the case of a patient with unrecognized von Willebrand disease (vWD), in whom the only presenting symptoms were spontaneous and recurrent hematuria with bladder tamponade, associated with recurrent hematospermia. The diagnosis was made only after several admissions to the hospital. We suggest to include coagulopathies such as vWD as part of the evaluation in patients with unexplained genito-urinary bleeding.

Assessment of a cohort of primarily pediatric patients with a presumptive diagnosis of type 1 von Willebrand disease with a novel high shear rate, non-citrated blood flow device.

BACKGROUND: A precise approach to the diagnosis of von Willebrand disease (vWD) remains elusive. One important reason is that vWD is a blood flow-related disorder: a vW Factor-platelet GPIb binding defect exists in this condition under the high shear-rate (> 1000 sec-1 in whole blood; > 3000 sec-1 in PRP) conditions of physiologic blood flow which exist in the arterioles of mucous membranes, from which most bleeding in vWD occurs. METHODS: We therefore studied 28 patients (mean 18.9 yrs) with vWD, diagnosed according to the 2007 NHLBI clinical guidelines, and 26 healthy controls (mean 17.5 yrs). Blood was collected into a plastic tube containing 4 U/ml FC dalteparin, 1.75 µg/ml of the Tab (anti-CD41) monoclonal antibody directed against platelet GPIIb, and 1.0 µg/ml of an ALEXA 555-conjugated rabbit anti-mouse second antibody. Within 30-90 min, the blood was then withdrawn at 667 and 1330 sec(-1) through a special flow chamber allowing for real-time epifluorescence digital videomicroscopy of platelets interacting with a microfibrillar collagen substrate. With MetaMorph software (Universal Imaging) we quantified the percent area (PA) covered by and total volume (TV) of adherent platelet aggregates within a 435 µm × 580 µm field of view. RESULTS: At 667 sec(-1) after 1 min PA and TV were similar for patients and controls, but at 1330 sec(-1) PA was 9.32 ± 4.21 (mean ± SD) for patients, a value lower (p < 0.001) than the 12.8 ± 3.39 for controls. TV was (1.43 ± 0.91) x 10(4) for patients, a value also lower (p < 0.001) than the (2.22 ± 0.77) x 10(4) for controls. PA or TV was below the 2.5th percentile for controls in 10 patients (36%) and both PA and TV were below the 2.5th percentile in eight. CONCLUSIONS: The novel flow device found that PA and TV were significantly reduced under high shear stress in vWD patients compared to normal controls. However, there was some overlap between the vWD and the control group, suggesting that some vWD patients had normal platelet adhesion/aggregation under the conditions studied. Further study with a higher shear rate appears indicated.