Abstract 3318

Background:

Acquired von Willebrand syndrome (AVWS) due to loss of high molecular weight multimers (HMWM), is a frequent cause of bleeding in aortic stenosis (AS), and is reversed by valve replacement. The goal of this study was to explore predictors of AVWS in patients with AS.

Methods:

A total of 91 patients (59 men, median age 79 years) with AS (n=64) or heart valve replacement (n=27) were included. We recorded peripheral blood count, vital signs, mean gradient (MG), peak velocity (peak vel), aortic valve time velocity integral (AV-TVI), aortic valve area (AVA) and valve area index (AVAi), time velocity integral ratio (TVI ratio), VWF antigen (VWF:Ag), VWF activity by latex immunoturbidity assay (VWF:Lx), VWF multimer analysis, closure times of platelet function analyzer ADP and epinephrine cartridges (PFA-CADP and –CEPI). HMWM losses were graded as normal, mild or severe when compared to HMWM analyses of pooled plasma samples from normal donors. Potential predictors of HMWM loss were explored using logistic regression analysis.

Results:

Of the 91 patients, 42 (46%) had loss of HMWM (23 mild and 19 severe). In single variable logistic regression analysis, AVWS was associated with a low AVA (<1.0 cm2; OR=5.08, P<0.001), and low AVAi (<0.60 cm2/m2; OR=5.54, P<0.001), low TVI ratio (<0.25; OR=10.80, P<0.001), prolonged PFA-CADP (≥121 sec; OR=6.76, P<0.001), and low VWF:Lx/Ag (≤0.8; OR=8.06, P=0.008). Moderate peak vel (3–4 m/sec) and high peak vel (>4 m/sec) were associated with loss of HMWM (OR[vs. <3 m/sec]=5.80 and 37.70 respectively, P<0.001) as were moderate MG (25–40 mmHg) and high MG (>40 mmHg), (OR [vs. <25mmHg]=4.50 and 32.50 respectively, P<0.001). In exploratory multivariable analysis, mean gradient remained one of the strongest predictor of loss of HMWM. The estimated sensitivity of MG (≥25mmHg) in diagnosing AVWS was 83% (35/42, 95% CI: 69%-93%) and estimated specificity was 71% (35/49, 95% CI: 57%-83%). Considering the very strong correlation with mean gradient, we also considered the diagnostic utility of peak vel. Peak vel≥ 3 m/sec had a sensitivity of 89% (38/42, 95% CI: 77%-97%) and a specificity of 59% (29/49, 95% CI: 44%-73%) in detecting loss of HMWM.

Conclusion:

Our data suggest that mean gradient (>25 mmHg) and peak vel (≥ 3 m/sec), both derived from the Doppler aortic valve velocity envelope, are accurate predictors for AS-AVWS, and should be incorporated into algorithmic approaches to laboratory screening for AVWS.

Table:

Predictors of AS-AVWS (N=91)

Single variable analysisMultivariable analysis1
VariableOR (95% CI)p-valueOR (95% CI)p-value
Gender (male) 0.79 (0.33–1.87) 0.59 0.61 (0.20–1.82) 0.37 
Age (years) 1.20 (0.84–1.78) 0.34 0.96 (0.62–1.54) 0.86 
Patient type (AS vs. valve replacement) 12.48 (3.86–56.47) <0.001 3.03 (0.65–16.69) 0.17 
Aortic stenosis symptoms 1.58 (0.67–3.73) 0.30 0.27 (0.05–1.01) 0.076 
Current use of coumadin 0.14 (0.04–0.39) <0.001 0.23 (0.06–0.83) 0.031 
Current use of aspirin 1.35 (0.58–3.19) 0.49 1.29 (0.44–3.88) 0.64 
GFR (60 vs. <60) 1.96 (0.80–5.05) 0.15 2.25 (0.71–7.73) 0.18 
Atrial fibrillation 0.56 (0.22–1.36) 0.21 0.86 (0.27–2.73) 0.80 
Left ventricular hypertrophy 2.02 (0.80–5.21) 0.14 1.17 (0.34–3.89) 0.80 
Heart rate (10 bpm increase) 1.30 (0.92–1.90) 0.15 1.15 (0.75–1.77) 0.52 
Systolic blood pressure ≥(140 mmHg 2.41 (0.99–6.04) 0.052 3.41 (1.06–12.39) 0.047 
Platelet (100 unit increase) 2.12 (1.02–4.77) 0.053 3.83 (1.53–10.85) 0.006 
Hemoglobin (1 unit increase) 0.95 (0.72–1.24) 0.69 1.08 (0.76–1.55) 0.67 
Mean Gradient  <0.001  <0.001 
<25 mmHg 1.00 (reference)  1.00 (reference)  
25–40 mmHg 4.50 (1.36–15.77)  4.50 (1.36–15.77)  
>40 mmHg 32.50 (9.47–140.35)  32.50 (9.47–140.35)  
Peak velocity(m/sec)  <0.001 NA  
<3 m/sec 1.00 (reference)    
3–4 m/sec 5.80 (1.70–23.70)    
>4 m/sec 37.70 (10.15–179.37)    
Aortic valve area <1.0 cm 2 5.08 (2.09–13.06) <0.001 NA  
Aortic TVI (10 cm increase) 1.73 (1.41–2.21) <0.001 NA  
TVI Ratio<0.252 10.80 (4.08–31.91 <0.001 NA  
Aortic valve area index<0.60 cm2 5.54 (2.30–14.09) <0.001 NA  
vWF: Lx/Ag = 0.8) 2 8.06 (1.99–54.58) 0.009 NA  
PFA collagen ADP closure time ≥ 121 sec 6.76 (2.72–18.04) <0.001 NA  
Single variable analysisMultivariable analysis1
VariableOR (95% CI)p-valueOR (95% CI)p-value
Gender (male) 0.79 (0.33–1.87) 0.59 0.61 (0.20–1.82) 0.37 
Age (years) 1.20 (0.84–1.78) 0.34 0.96 (0.62–1.54) 0.86 
Patient type (AS vs. valve replacement) 12.48 (3.86–56.47) <0.001 3.03 (0.65–16.69) 0.17 
Aortic stenosis symptoms 1.58 (0.67–3.73) 0.30 0.27 (0.05–1.01) 0.076 
Current use of coumadin 0.14 (0.04–0.39) <0.001 0.23 (0.06–0.83) 0.031 
Current use of aspirin 1.35 (0.58–3.19) 0.49 1.29 (0.44–3.88) 0.64 
GFR (60 vs. <60) 1.96 (0.80–5.05) 0.15 2.25 (0.71–7.73) 0.18 
Atrial fibrillation 0.56 (0.22–1.36) 0.21 0.86 (0.27–2.73) 0.80 
Left ventricular hypertrophy 2.02 (0.80–5.21) 0.14 1.17 (0.34–3.89) 0.80 
Heart rate (10 bpm increase) 1.30 (0.92–1.90) 0.15 1.15 (0.75–1.77) 0.52 
Systolic blood pressure ≥(140 mmHg 2.41 (0.99–6.04) 0.052 3.41 (1.06–12.39) 0.047 
Platelet (100 unit increase) 2.12 (1.02–4.77) 0.053 3.83 (1.53–10.85) 0.006 
Hemoglobin (1 unit increase) 0.95 (0.72–1.24) 0.69 1.08 (0.76–1.55) 0.67 
Mean Gradient  <0.001  <0.001 
<25 mmHg 1.00 (reference)  1.00 (reference)  
25–40 mmHg 4.50 (1.36–15.77)  4.50 (1.36–15.77)  
>40 mmHg 32.50 (9.47–140.35)  32.50 (9.47–140.35)  
Peak velocity(m/sec)  <0.001 NA  
<3 m/sec 1.00 (reference)    
3–4 m/sec 5.80 (1.70–23.70)    
>4 m/sec 37.70 (10.15–179.37)    
Aortic valve area <1.0 cm 2 5.08 (2.09–13.06) <0.001 NA  
Aortic TVI (10 cm increase) 1.73 (1.41–2.21) <0.001 NA  
TVI Ratio<0.252 10.80 (4.08–31.91 <0.001 NA  
Aortic valve area index<0.60 cm2 5.54 (2.30–14.09) <0.001 NA  
vWF: Lx/Ag = 0.8) 2 8.06 (1.99–54.58) 0.009 NA  
PFA collagen ADP closure time ≥ 121 sec 6.76 (2.72–18.04) <0.001 NA  

- Odds ratios (ORs), 95% confidence intervals (CIs), and corresponding p-values result from logistic regression analysis.

1

Multivariable models are adjusted for mean gradient.

2

Variable was not included in multivariable analyses due to strong collinearity with mean gradient.

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Disclosures:

No relevant conflicts of interest to declare.

Topics:
aortic valve stenosis, von willebrand disease, acquired, antigens, aspirin, atrial fibrillation, epinephrine, hemoglobin, hemorrhage, left ventricular hypertrophy, screening

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Author notes

*

Asterisk with author names denotes non-ASH members.

© 2011 by The American Society of Hematology
2011
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