Indexes of von Willebrand factor as biomarkers of aortic stenosis severity (from the Biomarkers of Aortic Stenosis Severity [BASS] study)

Abstract

We correlated von Willebrand factor (VWF) activity indexes and brain natriuretic peptide (BNP) with measures of aortic stenosis (AS) severity, bleeding, symptoms, and freedom from death or aortic valve replacement. Patients with AS (n = 66 [16 mild, 20 moderate, and 30 severe]) and aortic valve replacement (n = 21) were assessed with VWF antigen, VWF latex agglutination immunoturbidic activity, platelet function analyzer collagen plus adenosine diphosphate (PFA-CADP), VWF multimer ratio, and BNP level after echocardiography. In patients with AS, the mean gradient correlated with BNP (Spearman r = 0.29, p = 0.02), VWF latex agglutination immunoturbidic activity/VWF antigen ratio (r = -0.41, p <0.001), PFA-CADP (r = 0.49, p <0.001), and VWF multimer ratio (r = -0.76, p <0.001). The area under the curve for detection of severe AS was 0.62 (95% confidence interval [CI] 0.48 to 0.77) by elevated BNP, 0.81 (95% CI 0.69 to 0.92) by PFA-CADP closure time, 0.69 (95% CI 0.55 to 0.82) by VWF latex agglutination immunoturbidic activity/VWF antigen ratio, and 0.86 (95% CI 0.76 to 0.95) by VWF multimer ratio. For the VWF multimer ratio, a threshold of 0.15 yielded a sensitivity and specificity for severe AS of 77% and positive predictive value of 74%. Bleeding (in 14%) was associated with a prolonged PFA-CADP time and reduced VWF latex agglutination immunoturbidic activity/VWF antigen ratio. Symptoms were associated with elevated BNP and low Duke Activity Status Index score. In 66 patients with AS, freedom from death (n = 4) or aortic valve replacement (n = 22) was associated with PFA-CADP (p = 0.003), VWF high-molecular-weight multimers (p = 0.009), and VWF latex agglutination immunoturbidic activity/VWF antigen ratio (p <0.001) but not BNP (p = 0.32). In severe AS versus aortic valve replacement, the PFA-CADP and VWF multimer ratio differed (p <0.001), but BNP and the VWF latex agglutination immunoturbidic activity/VWF antigen ratio did not. In conclusion, the VWF activity indexes were associated with AS severity and bleeding and were predictive of cardiovascular outcomes.

Figure 1

Gel electrophoresis of von Willebrand factor in aortic stenosis patients with no, moderate, or severe loss of high-molecular-weight multimer. The quantitative ratio is the in-gel infrared intensity of bands higher than 15 to bands 2 through 15.

Figure 2

Aortic stenosis (AS) severity and biomarkers plotted in 66 AS patients (closed circles) and 21 aortic valve replacement patients (open circles). Cutoff gradient values are dashed lines for severe AS (>40 mm Hg) and moderate AS (25-40 mm Hg). Blue circles indicate patients with no loss of high-molecular-weight multimer (HMWM) and red circles indicate HMWM loss. A, von Willebrand factor multimer (VWF:mult) ratio. B, Platelet function analyzer collagen plus adenosine diphosphate (PFA-CADP) closure time. C, Ratio of von Willebrand factor latex agglutination immunoturbidic activity to von Willibrand factor antigen (VWF:Ltx/VWF:Ag). D, Brain nutriuretic peptide (BNP) level plotted on a base 2 log scale.

Figure 3

Receiver operating characteristic curves and areas under the curves for brain natriuretic peptide (BNP), the ratio of von Willebrand factor latex agglutination immunoturbidic activity to von Willibrand factor antigen (VWF:Ltx/VWF:Ag), platelet function analyzer collagen plus adenosine diphosphate (PFA-CADP) closure time, and von Willebrand factor multimer quantitative ratio (VWF:mult ratio).

Figure 4

Kaplan-Meier estimates of surgery-free survival. A, von Willebrand factor high-molecular-weight multimer (HMWM) loss vs normal. B, Platelet function analyzer collagen plus adenosine diphosphate (PFA-CADP) closure time >121 seconds vs ≤121 seconds. C, Ratio of von Willebrand factor latex agglutination immunoturbidic activity to von Willibrand factor antigen (VWF:Ltx/VWF:Ag) <0.8 vs ≥0.8. D, Brain natriuretic peptide (BNP) level, normal vs elevated. HR indicates hazard ratio.