VENOSTASIS, SUBCLINICAL VASCULITIS AND VON WILLEBRAND FACTOR ANTIGEN

Von Willebrand factor antigen (VW FAg) has been used as a markerfor vasculitis and raised levels have been shown to correlatewith active disease. The use of VW FAg levels in the diagnosisof vasculitic disorders has been proposed. However, certaincases of vasculitis have normal VW FAg levels and are difficultto diagnose; this is of importance because of the high mortalityassociated with these disorders. It has been suggested thatvenostatic stress can be used as a provocative test for stimulatingVW FAg release, thereby improving the speed and sensitivityof diagnosis. We tested this hypothesis in a mixed group of35 patients with vasculitis, systemic lupus erythematosus andrheumatoid arthritis and 16 controls. At baseline, althoughthe levels were not outside the laboratory range, the diseasegroups had raised VW FAg compared with the simultaneously testedcontrols. Venostatic stress increased VW FAg activity in alldisease groups, control levels also increased and differencesbetween controls and disease groups diminished in significance.Therefore venostatic stress with VW FAg measurement does notproduce a more sensitive test for vasculitis. Venostasis shouldbe avoided when measuring VW FAg levels. KEY WORDS: Von Willebrand factor antigen, Vasculitis, Endothelial stress Current address: Department of Surgery, University Hospitalof South Manchester, Nell Lane, Didsbury, Manchester M20 8LR.     

Circulating endothelial cell/leucocyte adhesion molecules in ischaemic heart disease

Increased levels of the endothelial markers soluble E-selectin ( P  = 0.011), soluble thrombomodulin ( P  = 0.0001) and von Willebrand factor (VWF, P  < 0.0001) were found in 116 patients with ischaemic heart disease compared to an equal number of age- and sex-matched asymptomatic controls. In a multivariate analysis of the markers versus the major risk factors for atherosclerosis, VWF correlated with total cholesterol ( P  = 0.002) and E-selectin with sex (lower in women, P  = 0.004) and triglycerides ( P  = 0.007). The data point to profound differences in the release mechanisms of these three endothelial cell products and suggests that further studies into the roles of these molecules in coronary artery disease are warranted.     

The relationship of circulating endothelial cells to plasma indices of endothelial damage/dysfunction and apoptosis in acute coronary syndromes: implications for prognosis

Summary. Background: While coronary artery disease has been linked to both endothelial damage and cellular apoptosis, their inter‐relationships and impact on cardiovascular (CV) outcomes has been barely explored. Aims: First, we investigated the inter‐relationships between circulating endothelial cells (CECs, and index of endothelial damage) and circulating plasma markers of endothelial damage/dysfunction [von Willebrand factor (VWF), soluble E selectin (sEsel)] and apoptosis [soluble Fas (sFas), Fas ligand (sFasL) and their ratio, sFas/sFasL] in patients presenting with acute coronary syndrome (ACS). Second, we assessed their prognostic values for major adverse CV events (MACE) in ACS. Methods: We studied 211 patients with ACS, who were compared with 60 healthy controls (HC) and 45 ‘disease controls’ (patients with stable coronary artery disease, CAD). Simultaneous blood samples for CECs (immunobead method), VWF, sESel, sFas and sFasL (ELISA) were taken within 24 h of presentation of ACS and at 48 h post admission. Results: CEC, sEsel and VWF levels were significantly higher among the ACS groups compared with the CAD and HC (P < 0.05) groups. sFas was higher (P = 0.016) and sFasL lower (P = 0.021) in ACS compared with controls (HC and CAD). There was a significant increase in sFas/sFasL ratio with increasing disease severity (P = 0.0004). There were significant correlations between CECs and both VWF and sEsel (both P < 0.01) but no correlations between CECs and either sFas or sFas ligand. On univariate survival analysis, CECs were associated with an increased risk of both MACE [hazard ratio (HR) 2.4 (95% CI 1.2–4.1); P = 0.009] and cardiovascular death [HR 2.95 (95% CI 1.01–8.81); P = 0.047]. On multivariate Cox regression analysis, only VWF (and not CECs) remained as an independent predictor of MACE [HR 1.02 (95% CI 1.005–1.040); P = 0.009]. Conclusion: CECs were associated with abnormal plasma indices of endothelial damage/dysfunction and not apoptosis, despite abnormalities of all these markers being associated with ACS. VWF remained as an independent predictor of MACE, on multivariate analysis.     

ALTERED LEVELS OF SOLUBLE ADHESION MOLECULES IN RHEUMATOID ARTHRITIS, VASCULITIS AND SYSTEMIC SCLEROSIS

We compared the levels of soluble adhesion molecules E-selectin(sE-selectin), intercellular adhesion molecule-1 (sICAM-1) andvascular cell adhesion molecule-1 (sVCAM-1) alongside von Willebrandfactor (vWf), CRP and rheumatoid factor in 40 patients withRA, 38 with systemic sclerosis (SSc), 35 with vasculitis andin 80 asymptomatic controls. Adhesion molecules were measuredin serum by ELISA, rheumatoid factor by sheep red blood cellagglutination and CRP by immunonephelometry. Compared to controls,increased sE-selectin was found in patients with RA (P = 0.0015),vasculitis (P = 0.0003) and SSc (P = 0.0126), whilst raisedsICAM-1 was found in RA (P < 0.0003), vasculitis (P <0.0003) and SSc (P < 0.0378). sVCAM was lower in RA thanin controls (P = 0.0102), but was unchanged in vasculitis orin SSc. vWf was raised in RA (P = 0.0102), vasculitis (P <0.0003) and SSc (P < 0.0003). In a Spearman's rank analysisof all the data, vWf correlated with sVCAM-1 and sICAM-1 (bothP < 0.001), sE-selectin with sICAM-1 (P < 0.001) and sVCAMwith sICAM-1 (P < 0.005). Levels of rheumatoid factor correlatedwith those of sE-selectin (P = 0.003) and sVCAM-1 (P < 0.012),but there were no correlations between any index and CRP. Thestrongest correlations within the RA group were between sICAMand sVCAM (P = 0.001), in vasculitis it was between sE-selectinand sICAM (P < 0.001), and in SSc it was between sE-selectinand sVCAM (P = 0.019). These data suggest that the differinglevels of vWf, sE-selectin and sICAM-1 in the inflammatory vasculitidesmay be useful in establishing a rolefor leucocyte/endothelialadhesion in these diseases. KEY WORDS: Vasculitis, Rheumatoid arthritis, Systemic sclerosis, von Willebrand factor, Soluble E-selectin, Soluble ICAM-1, Soluble VCAM-1     

Endothelium activation related increase of soluble intercellular adhesion molecule-1 in human schistosomiasis. Lack of correlation with serology

Soluble intercellular adhesion molecule-1 (sICAM-1) level was measured in sera from 41 patients with Schistosoma mansoni schistosomiasis and compared with the sICAM-1 level in 41 healthy subjects. A significant increase in serum sICAM-1 was observed in patients with schistosomiasis compared with control subjects. As they were inhabitants of the French Antilles, the patients were, however, not settled in a malaria endemic zone, allowing this cause of sICAM-1 enhancement to be eliminated. No correlation was found between the level of sICAM-1 and the schistosomiasis serological titre. Such results favour the hypothesis of an activation of vascular endothelial cells due to egg deposition.     

Hemostatic cardiovascular risk factors,common carotid–intima medial thickness and peripheral arterial disease in South Asians and African Caribbeans: a substudy to the Ethnic‐Echocardiographic Heart of England Screening (E‐ECHOES) Study

Summary. Objective: To determine whether ethnic differences exist in inflammatory (interleukin‐6 and C‐reactive protein) and hemostatic biomarkers (soluble P‐selectin [sP‐sel], von Willebrand factor [VWF], and fibrin D‐dimer) between South Asian (people originating from India, Pakistan, and Bangladesh) and African Caribbean (Black Caribbean and Black African) groups, the two largest minority ethnic groups in the UK; and to determine associations between these biomarkers and common carotid intima–media thickness and peripheral artery disease (PAD). Patients and methods: We recruited 572 subjects (356 South Asian and 216 Black) aged ≥ 45 years as a substudy to a community screening project, the Ethnic‐Echocardiographic Heart of England Screening (E‐ECHOES) study. All subjects completed an interviewer‐led questionnaire, anthropometric measurements were taken, and blood sampling was performed if consent was granted. Ankle brachial pressure index (ABPI) was calculated, and the common carotid intima–media thickness (CCIMT) was measured. PAD was defined as ABPI < 0.9. ELISA was used to quantify inflammatory and hemostatic biomarkers. Results: The incidence of hypertension (> 70%) and diabetes (> 27%) was high, but non‐significantly different between the two ethnic groups. South Asians had higher platelet count and sP‐sel levels than African Caribbeans (P < 0.0001 for both), despite there being no significant difference in antiplatelet medication. African Caribbeans had higher D‐dimer levels (P = 0.0052). Among South Asians, VWF correlated with ABPI (P = 0.047) and mean (P = 0.002) and maximum CCIMT (P = 0.011) on univariate analysis, and remained an independent predictor of mean and maximum CCIMT on multivariate analysis with traditional cardiovascular risk factors (P = 0.034 and P = 0.046, respectively). In African Caribbeans, D‐dimer levels were was higher in PAD than in normal ABPI participants (P = 0.04), and was associated with ABPI in both univariate analysis (P = 0.014) and multivariate analysis (P < 0.0001) with traditional cardiovascular risk factors. Conclusion: Ethnic differences are evident in inflammatory and hemostatic factors, as well as in their associations with CCIMT and PAD. These may reflect differences in cardiovascular risk factors or pathophysiologic processes that characterize each ethnic group.     

Circulating endothelial cell markers in peripheral vascular disease: relationship to the location and extent of atherosclerotic disease

We examined the relationship between specific endothelial cell markers soluble E-selectin, von Willebrand factor and soluble thrombomodulin and the location or extent of atherosclerosis by analysing plasma samples from 200 patients with symptomatic peripheral vascular disease and 213 age- and sex-matched asymptomatic control subjects. Using ELISA s, we found increased von Willebrand factor and thrombomodulin (both P  < 0.0001) in the patients relative to the control subjects, but no significant change in soluble E-selectin. Soluble thrombomodulin was increased in patients with disease at one locus (i.e. of the carotid or iliac/femoral arteries), with an additional significant increase in patients with disease at multiple loci (i.e. any combination of carotid, coronary or iliac/femoral artery disease). No marker differentiated carotid artery disease from iliac/femoral artery disease. We conclude that von Willebrand factor is a marker of generalized atherosclerosis, but that soluble thrombomodulin is related to the extent of disease. Further research into these endothelial cell products are warranted to explore their diagnostic and/or prognostic potential.