Antonio Pagnan

A shorter von Willebrand factor survival in O blood group subjects explains how ABO determinants influence plasma von Willebrand factor

ABO blood groups greatly influence circulating von Willebrand factor (VWF) levels, and O group subjects have lower VWF values. In this study, we investigated whether ABO groups affect VWF survival by monitoring the post-DDAVP (1-desamino-8-d arginine vasopressin) time courses of VWF antigen (VWF:Ag), VWF collagen binding (VWF:CB), and factor VIII (FVIII) in 47 healthy subjects (28 O and 19 non-O blood groups). The elimination half-life (T1/2el) of VWF was found significantly shorter in O than in non-O subjects (10.0+/-0.8 hours vs 25.5+/-5.3 hours, respectively; P<.01), as was the T1/2el of VWF:CB (7.9+/-0.5 hours vs 20.9+/-4.5 hours; P<.01). A direct linear correlation was found between basal VWF:Ag and T1/2el, subjects with higher VWF levels having longer-surviving VWF. ABO blood groups appeared to strongly influence VWF clearance, but not its synthesis or release from endothelial cells. The VWF propeptide to VWF:Ag ratio, useful for predicting an increased VWF clearance, was found significantly higher in O than in non-O individuals (1.6+/-0.1 vs 1.2+/-0.5, P<.001), with values that correlated inversely with T1/2el (P<.001). Based on these findings, we conclude that the lower VWF values in O group individuals is attributable to a shorter VWF survival and circulating VWF values are strongly influenced by its half-life.

Venous thromboembolism and the risk of subsequent symptomatic atherosclerosis

Summary.  Background: Recently, we reported an association between asymptomatic carotid atherosclerosis and venous thromboembolism (VTE) of unknown origin. We hypothesized that patients with VTE of unknown origin would be at a higher risk of developing symptomatic atherosclerosis than patients with VTE induced by known risk factors. Methods: To examine this hypothesis, we studied 1919 consecutive patients followed prospectively after their first VTE episode. The primary outcome was non‐fatal and fatal symptomatic atherosclerotic disease in patients with VTE of unknown origin as compared to those with secondary VTE. An independent committee assessed all study outcomes, and adjusted hazard ratios (HR) were calculated using the Coxs proportional hazards model. Results: After a median follow‐up of 48 and 51 months, respectively, at least one symptomatic atherosclerotic complication was detected in 160 of the 1063 patients (15.1%) with VTE of unknown origin, and in 73 of the 856 (8.5%) with secondary VTE. After adjusting for age and other risk factors of atherosclerosis, the HR for symptomatic atherosclerotic complications in patients with VTE of unknown origin compared to those with secondary VTE was 1.6 (95% confidence intervals; CI: 1.2–2.0). When the analysis was restricted to patients without previous symptomatic atherosclerosis, the HR became 1.7 (95% CI: 1.1–2.4). Conclusions: Patients with VTE of unknown origin have a 60% higher risk of developing symptomatic atherosclerotic disease than do patients with secondary venous thrombosis.

Does Hemophilia Protect Against Atherosclerosis? A Case-Control Study

Whether carriers of hemophilia are protected against the development of atherosclerosis is controversial. In a case-control study, the presence of atherosclerosis was assessed and quantified with echo-color Doppler of all explorable arterial districts in 50 carriers of hemophilia and in 50 age-matched control individuals. All participants submitted to echo-color Doppler of carotid and femoral axis, of brachial arteries, and of the abdominal aorta. The presence and grade of atherosclerotic plaques were assessed, as well as the intima-media thickness (IMT). At least one atherosclerotic plaque was found in six cases (12.0%) versus 15 controls (30.0%); referring to the total number of plaques, 30% of them were evaluated in patients affected by decreased coagulation while 70% in subjects with normal levels of FVIII. In all the examined districts, the mean IMT was significantly lower in patients with hemophilia than in controls. Hemophilia protects against asymptomatic atherosclerosis.

Intimal medial thickening of common carotid artery as indicator of coronary artery disease

The authors investigated the relation between coronary atherosclerosis, angiographically detected, and intimal-medial (I-M) thickening of the common carotid artery (CCA), as measured by high-resolution B-mode ultrasound system. They studied 31 patients with coronary artery disease (CAD) and 23 healthy control subjects. I-M thickening of CCAs and atheromatous plaques at the carotid bifurcation were evaluated. A score system was defined (range 0-20) based on the absence or presence of atherosclerotic lesions at common and internal carotid arteries. A coronary angiography score was defined based on the presence of atherosclerotic lesions at nine coronary arterial segments (range 0-36) . The thickness of CCAs (M ±SD) in CAD patients was significantly higher (1.45 ±0.95 mm) than in controls (0.87 ±0.10 mm, P < 0.005), and an I-M thickening of 1.1 mm or more was specific and positively predictive of CAD. A significant positive correlation between coronary and carotid score was observed (P < 0.028, r=0.373). The study suggests that I-M thickening could be helpful for the identification of patients at risk for CAD.

Effects induced by olive oil-rich diet on erythrocytes membrane lipids and sodium-potassium transports in postmenopausal hypertensive women

Since we have observed that mo-nounsaturated fatty acids (MUFA) enriched diet modifies red cell membrane lipids and cation transport systems in normotensive subjects, we similarly evaluated a group of hypertensive patients undergoing an analogous dietary modification. In a group of 18 moderately hypertensive women, the diet was supplemented for two months with olive oil (about 45 g/day), which replaced an equal amount of seasoning fats. Before and after this period, red cell fatty acid composition was evaluated by gas-chromatography in order to verify diet compliance: a significant increase in oleic acid was observed, while the content of saturated and polyunsaturated fatty acids remained unchanged. After olive oil, maximal rates of Na-K pump (5580±329 vs 6995±390, plt;0.001) and Na-K cotransport ( Na-COT 544±52 vs 877±46, plt;0.001: K-COT 790±76 vs 1176±66, plt;0.001), cell Na content (9.58+0.4 vs 10.61 ±0.6, plt;0.03) and passive permeability for Na (936±74 vs 1836±102, plt;0.001 ) rose significantly. Although the reduction in maximal rate of the Li-Na CT after olive oil was not significant, it was the only cation transport parameter being correlated with the variations of membrane lipids, namely negatively with UFA (r=-0.528, plt;0.05) and positively with SFA (r=0.482, plt;0.005). The change in maximal rate of Li-Na CT was also correlated with the variation of systolic and diastolic BP (r=0.50, plt;0.03). No changes in membrane lipid composition and ion transport systems were observed in a group of 13 control patients kept on usual diet over the same period. Thus, olive oil supplementation affects the lipid composition of the cell membrane in hypertension. This change is in turn associated with a modification of membrane transport activity; in addition a significant reduction of blood pressure is obtained.

von Willebrand factor propeptide makes it easy to identify the shorter von Willebrand factor survival in patients with type 1 and type Vicenza von Willebrand disease.

Reduced von Willebrand factor (VWF) half‐life has been suggested as a new pathogenic mechanism in von Willebrand disease (VWD). The usefulness of VWF propeptide (VWFpp) in exploring VWF half‐life was assessed in 22 type 1 and 14 type Vicenza VWD patients, and in 30 normal subjects, by comparing the findings on post‐Desmopressin (DDAVP) VWF t1/2 elimination (t1/2el). The VWFpp/VWF antigen ratio (VWFpp ratio) was dramatically increased in type Vicenza VWD (13·02 ± 0·49) when compared to normal subjects (1·45 ± 0·06), whereas it appeared to be normal in all type 1 VWD patients (1·56 ± 0·7), except for the four carrying the C1130F mutation (4·69 ± 0·67). A very short VWF t1/2el was found in type Vicenza VWD (1·3 ± 0·2 h), while all type 1 VWD patients had a t1/2el similar to that of the controls (11·6 ± 1·4 and 15·4 ± 2·5 h respectively), except for the four patients carrying the C1130F mutation, who had a significantly shorter VWF survival (4·1 ± 0·2 h). A significant inverse correlation emerged between VWFpp ratio and VWF t1/2el in both VWD patients and normal subjects. The VWFpp ratio thus seemed very useful for distinguishing between type 1 VWD cases with a normal and a reduced VWF survival, as well as for identifying type Vicenza VWD.

Noninvasive study of arterial hypertension and carotid atherosclerosis.

We noninvasively evaluated the prevalence and severity of atherosclerotic lesions of the internal carotid artery in 146 nonobese, nondiabetic hypertensive patients who were free of cardiovascular symptoms. We found internal carotid artery disease in 63 patients (43%), 26 (18%) with unilateral disease and the other 37 (25%) with bilateral disease. Disease severity was correlated with age but not duration of hypertension, cholesterol level, or current smoking habit. We also followed disease progression and clinical outcome with respect to cardiovascular events for 3 years in a subgroup of 95 unselected patients. In 20 of the 93 survivors (21.5%) we noted progression of the atherosclerotic lesions that was predicted by neither risk factors nor initial status of the internal carotid artery. New neurologic symptoms developed in four survivors (4%) and symptoms of cardiac ischemia in six (6%). No survivor who developed new cerebrovascular symptoms showed progression of carotid disease. These data provide useful elements for a rational approach to prevention of the atherosclerotic complications of hypertension.

von Willebrand factor abnormalities in aortic valve stenosis: Pathophysiology and impact on bleeding

Acquired von Willebrand syndrome (AVWS) may complicate severe aortic valve stenosis, due to a reduction in the haemostatically more efficient large von Willebrand factor (VWF) multimers. This study was designed to analyse the relevance of VWF abnormalities and haemorrhagic diathesis in severe aortic valve stenosis. Forty-one consecutive patients undergoing valve replacement were investigated: seven had minor bleeding symptoms in their recent history; 10 (24.3%) had a reduced VWF collagen binding (VWF:CB) to VWF antigen ratio, and 33 (80.5%) had a decrease in large VWF multimers. The shortage of large multimers was not associated with any accumulation of small VWF multimers (apparently ruling out any increased VWF proteolysis), nor was there any increase in VWF propeptide, which excludes a shorter VWF survival. The risk of developing VWF abnormalities was higher in patients with rheumatic valve disease than in degenerative cases (p=0.025) and in valves with <50% of residual endothelial cells (p=0.004). Bleeders differed from non-bleeders in that they had a higher mean transvalvular gradient and a more marked decrease in large VWF multimers. VWF abnormalities did not exacerbate peri-operative blood loss, however - a finding consistent with the full correction of these VWF abnormalities, seen already on the first postoperative day and persisting for up to six months after surgery. According to the data obtained in our cohort of patients VWF abnormalities are common in severe aortic stenosis, particularly in cases of rheumatic valve disease, but loss of the largest multimers does not seem to cause clinical bleeding in most patients.

Endothelial dysfunction in haemophilia patients

Summary.  Haemophilia patients may develop cardiovascular diseases, suggesting that their clotting defect does not protect them completely from atherosclerosis and its complications. We aimed to evaluate cardiovascular risk factors and, for the first time, the presence of endothelial dysfunction in middle‐aged haemophilia patients. We studied 40 patients with haemophilia A and B (24 with moderate–severe disease and 16 with mild disease), and 40 healthy controls. Flow‐mediated dilation (FMD), carotid ultrasound (US) intima media thickness (IMT), arterial blood pressure, body mass index (BMI), cholesterol, triglycerides, glucose, insulin, lipoprotein(a) and homocysteine levels were measured, and PAI‐1 and t‐PA levels before and after venous occlusion (VO), and antibodies to HIV, HBV and HCV were assayed. At least one cardiovascular risk factor was detected in 87.5% of patients, and 2 or more in 47.5% of cases. At US exam, none of the patients had significant carotid stenosis or significant differences in IMT compared to controls. In contrast, all the patients had a significant FMD impairment, associated with a reduced t‐PA release after VO in 70% of cases. PAI‐1 levels significantly correlated with BMI, triglycerides and insulin values. Fifteen haemophilia patients with chronic viral hepatitis and/or HIV infection showed a significantly lower FMD than patients without active infection. We found an endothelial dysfunction with impaired FMD and t‐PA release in our haemophilia patients, usually associated with cardiovascular risk factors. Other pathogenic mechanisms, such as chronic viral infections, are likely to be involved in this endothelial damage, however.

Polymorphisms in von Willebrand factor gene promoter influence the glucocorticoid-induced increase in von Willebrand factor: the lesson learned from Cushing syndrome

Cushing syndrome (CS) features high‐glucocorticoid secretion and an associated hypercoagulable state often involving an increase in von Willebrand factor (VWF). To identify any influence of VWF promoter on glucocorticoid haemostatic effects, four polymorphic positions (‐3267, ‐2708, ‐2659 and ‐2525) segregating as haplotypes 1 (GCAG) or 2 (CTGA) were analysed in 50 CS patients with high VWF (group I) and normal VWF (group II) levels, divided by ABO group. Genotype distribution differed significantly between the two groups: in group I, 25·8% had genotype 1/1, 22·6% had 2/2 and 38·7% had 1/2; in group II, 0% had genotype 1/1, 57·9% had 2/2 and 31·6% had 1/2 (P = 0·03). Patients’ genotypes also differed from those of controls (P = 0·003 for group I, P = 0·03 for group II). Haplotype 1 was prevalent in group I, haplotype 2 in group II (P = 0·002), both with frequencies differing from controls (P < 0·001 and P = 0·009). By odds ratio analysis, genotype 1/1 carried a 12 times greater risk of high‐VWF levels than genotype 2/2, and haplotype 1 carried a five times greater risk than haplotype 2. Our findings suggest that VWF promoter haplotypes influence the corticosteroid‐mediated increase in VWF.