Stanley H. Silverman

Vascular endothelial growth factor and tissue factor in patients with established peripheral artery disease: a link between angiogenesis and thrombogenesis?

Increasing evidence points towards a prothrombotic state in atherosclerosis and its manifestations, such as peripheral artery disease (PAD), which is associated with thrombosis-related complications, such as acute limb ischaemia, graft thrombosis and stroke. We hypothesized that the increased risk of thrombogenesis in PAD may be related to abnormal angiogenesis and, thus, an increased risk of future vascular disease. To test this hypothesis, we measured plasma levels of tissue factor (TF) and related levels to indices of angiogenesis, that is vascular endothelial growth factor (VEGF) and its soluble receptor sFlt-1. We studied 234 patients (145 males; mean age 68.6+/-10 years) with proven PAD (ankle brachial pressure index <0.8) and compared them with 50 healthy controls. Levels of VEGF ( P =0.001) and TF ( P =0.043) were increased in patients compared with controls. There were significant correlations between VEGF and TF levels in both patients (Spearman r =0.351, P <0.001) and healthy controls (Spearman r =0.335, P =0.017). Amongst PAD patients, levels of VEGF were related to gender, with women having higher levels than men. There was no difference in the levels of sFlt-1 between the patients and controls, or between the subgroups of patients. There were however significant correlations between the levels of sFlt-1 and TF (Spearman r =0.268, P <0.001) and between sFlt-1 and VEGF (Spearman r =0.499, P <0.001). In conclusion, patients suffering from proven PAD have higher plasma levels of TF and VEGF compared with controls, with a significant correlation between the two. This suggests a link between the hypercoagulable state in PAD and the process of angiogenesis.

Peripheral arterial disease and Virchow’s triad

Peripheral arterial disease (PAD) is an important global healthcare problem associated with considerable morbidity and mortality. This disease is an important manifestation of atherosclerosis and the pathophysiological processes involved in its development, progression and complications are atherothrombosis and thromboembolism. Over 150 years ago, Virchow described a triad of abnormalities (abnormal blood flow, abnormal vessel wall and abnormal blood constituents) associated with thrombus formation (thrombogenesis). An improvement in biochemical techniques has allowed quantification of various components of Virchows triad, and as a consequence, there has been increasing interest in the measurement of such biomarkers in understanding the development and progression of PAD, as well as its symptomatic complications. This review discusses quantifiable components of Virchows triad that have been associated with PAD and their clinical utility as risk factors for PAD.

Evaluation of carotid plaque neovascularization using contrast ultrasound.

Contrast-enhanced ultrasound (CEUS) is increasingly used to improve visualization of carotid arteries. However, its reproducibility and utility for clinical research are not well established. The aim of the present study was to assess reproducibility of detection of carotid artery wall neovascularization using CEUS. Complete sequenced CEUS images from 10 individuals were analyzed for the presence of carotid arterial wall neovascularization. The images were acquired using Philips CompactXtreme CX50 ultrasound unit with an L12-3 probe and Bracco SonoVue contrast agent. The carotid wall neovascularization was graded by 2 independent observers with inter-/intraobserver agreement (κ) calculated. Interobserver κ values for intraplaque neovascularization (mean [95% confidence interval]) were 0.67 (0.40-0.94) for the left side. Interobserver κ values for intraplaque neovascularization were 0.65 (0.38-0.92). No study-related complications were observed. The CEUS method although semiquantitative shows moderate-to-strong intra- and interagreement for the results and can be used for clinical research purpose.

Antithrombotic therapy in peripheral vascular disease

Atherosclerotic peripheral vascular disease is symptomatic as intermittent claudication in 2-3% of men and 1-2 % of women aged over 60 years. However, the prevalence of asymptomatic peripheral vascular disease, generally shown by a reduced ankle to brachial systolic pressure index, is three to four times greater. Peripheral vascular disease is also a significant cause of hospital admission, and is an important predicator of cardiovascular mortality. Pain at rest and critical ischaemia are usually the result of progression of atherosclerotic disease, leading to multilevel arterial occlusion. Other causes of arterial insufficiency—including fibromuscular dysplasia, inflammatory conditions, and congenital malformations—are much rarer. ![][1] Ischaemic ulcer on foot Therapeutic objectives in peripheral vascular disease include relieving symptoms and preventing the disease, and any associated events, progressing. View this table: Antithrombotic therapy in peripheral vascular disease The symptoms of peripheral vascular disease are progressive. A claudicating patient encouraged to exercise tends to report a symptomatic improvement. This effect is generally not accepted to be an improvement in the diseased segment of blood vessel, but the formation of collateral vessels perfusing the ischaemic tissue. Vasodilating agents, such as naftidrofuryl, have little value in managing claudication and peripheral vascular disease as their effect is small and does not stop progression of the disease. Cilostazol has been shown to increase absolute walking distance in some patients by up to 47%. However, it has no clear antithrombotic effect and has not been shown to stop disease progression. Unfortunately, not all progression is amenable to improvement and, without the appropriate risk factor management, progression to rest pain and necrosis can be rapid. The role of aspirin as an antiplatelet agent has been shown to be beneficial beyond doubt. In peripheral vascular disease it reduces the frequency of thrombotic events in the peripheral arteries and reduces overall cardiovascular mortality in claudicating patients. The dose … [1]: /embed/graphic-1.gif

Indices of Thrombogenesis, Endothelial Damage and Platelet Function following Percutaneous Peripheral Artery Angiography and Angioplasty for Peripheral Vascular Disease

We hypothesised that there would be alterations in markers of endothelial damage/dysfunction, platelet activation and thrombogenesis in patients with peripheral vascular disease (PVD) as a result of undergoing diagnostic angiography and therapeutic angioplasty. To test this hypothesis, we measured sequential changes in von Willebrand factor (vWf, an index of endothelial damage/dysfunction), tissue factor (TF, an index of thrombogenesis) and soluble P-selectin (sP-sel, an index of platelet activation) in 52 consecutive patients (32 male; mean age 69 years, SD 10) who were undergoing elective angiography and angioplasty for PVD. Patients with PVD had significantly higher vWf and sP-sel levels compared to healthy controls (both p < 0.001), but median TF levels were not significantly different (p = 0.344). In the whole group, there was a significant reduction in sP-sel levels (p < 0.001, paired t test) post-angiography/angioplasty, but no significant change in vWf and TF levels. In patients undergoing angiography only, there was a significant drop in mean sP-sel (p < 0.001, paired t test) and vWf (p = 0.044) values after the procedure, whilst TF levels were not significantly changed (p = 0.370, Mann-Whitney U test). In patients undergoing angioplasty and stent, mean sP-sel levels fell immediately after the procedure (p = 0.001, paired t test), but there were no statistically significant changes in vWf and TF-levels. In conclusion, there appears to be a reduction in plasma sP-sel levels following angioplasty and stenting for PVD, suggesting alterations in platelet physiology, which may be accompanied by some alterations in the endothelium. The possibility that these changes may have pathophysiological implications for understanding platelet and endothelial reactions to angiography and associated interventions (that is, angioplasty and stent) needs to be explored.

Alterations of Thrombogenesis, Endothelial Damage and Oxidative Stress with Reperfusion during Femoral Artery Bypass Surgery for Peripheral Vascular Disease

Peripheral vascular disease (PVD) is a significant cause of cardiovascular morbidity. We hypothesised that there would be significant alterations of thrombogenesis, platelet activation and endothelial damage, which could be associated with abnormal oxidative stress during femoral artery bypass surgery for PVD, where the femoral artery is cross-clamped (causing acute ischaemia) and reperfused (following revascularisation). To test this hypothesis, we measured sequential changes in von Willebrand factor (vWF, and index of endothelial damage/dysfunction), tissue factor (TF, an index of thrombogenesis) and soluble P-selectin (sP-sel, an index of platelet activation) as well as lipid hydroperoxides (LPO, an index of oxidative stress) in 28 consecutive patients undergoing elective peripheral artery bypass surgery. Mean baseline vWF and sP-sel levels in PVD patients (before clamping) were significantly higher compared with age- and sex-matched controls (unpaired t test, both p < 0.05), but there were no significant differences in TF and LPO levels. There was a correlation between TF and vWF (Spearman’s, r = 0.374, p = 0.05), as well as between sP-sel and vWF at the start of surgery (r = 0.467, p = 0.012). The patients undergoing peripheral artery bypass surgery had a mean femoral artery clamp time of 28 min (standard deviation 14 min; range 11–65 min). There were no significant overall changes in sP-sel, vWF, TF and LPO with femoral artery cross-clamping and reperfusion (repeated measures ANOVA, p = NS). In conclusion, we found that during ischaemia-reperfusion during peripheral arterial bypass surgery, thrombogenesis (as measured by plasma TF) and oxidative damage (as measured by LPO) within the affected leg does not increase in the immediate perioperative period. Further studies are required to assess the mechanism(s) of ischaemia-reperfusion injury in PVD, and the contributory role(s) of the endothelium and platelets.

Anti-platelet therapy: is it all over in peripheral artery disease?

Peripheral artery disease (PAD) is probably much more common and important than we perceive, ranging in prevalence from 6% among patients over the age of 55 years to 18% based of Caucasian European populations (1). The prevalence of PAD rises with age, to 20% in those over 70 and even up to 60% in those over 85 years old (2). Patients with PAD have a three-fold risk of myocardial infarction, stroke, or death from cardiovascular causes (3). PAD is also well associated with a high amputation risk and poor quality of life, especially affecting those with diabetes, therefore creating a substantial economic burden (4). The most recognised clinical manifestation of PAD is intermittent claudication of the lower limbs. This “pain” however intermittent is caused by ischaemia secondary to atherosclerotic arterial narrowing and is clearly a manifestation of systemic atherosclerosis (3). Indeed, a low ankle brachial pressure index (ABI) has been shown to be predictive of coronary heart disease and all-cause mortality (4) (relative risk 1.60;95% confidence interval [CI] 1.32–195) (5). Over a five-year period, those with an ABI ≤0.9 have a two-fold risk of a cardiovascular event compared to those with an ABI >0.9 (6). The Framingham Offspring Study in 1999 reported a PAD prevalence of 90% in those who undergoing coronary angiography (7). Yet, PAD remains the most undermanaged, underdiagnosed, and understudied of all manifestations of atherosclerotic disease. Known risk factors of other atherosclerotic disease are similar for PAD, and include age, smoking, high blood pressure and hyperlipidaemia. Disease risk factor modification studies have suggested that risk factor control itself is inadequate, and other therapeutic requirements are necessary in PAD. Other pathophysiological processes, such as low-grade inflammation may be involved, as the latter is independent risk factor for PAD (8, 9). Most recently, homocysteine, C-reactive protein, fibrinogen, lipoprotein, hypercoaguability and increased platelet activity have all been implicated as risk factors for atherosclerosis (10, 11). In PAD, the main pathological process of obstruction of the arteries is caused by atherothrombosis, embolism, arteritis, and aneurysms (12). Platelets play an important role in the process of thrombosis at the site of plaque formation (13). Platelet activation markers, such as soluble CD40 ligand and P-selectin (14) levels, have been increased in studies of patients with PAD (15, 16). Urinary 11-dehydrothromboxane B2 has also been found to be increased in PAD, implicating a further platelet component (13). The modern management of PAD is largely directed to symptom control but emphasis is directed mainly to prevention of systemic complications with ‘best medical therapy’, with percutaneous or surgical revascularisation being considered where optimised medical therapy fails. Indeed, the similarities between atherosclerotic risk factors and the role of platelets in both cardiovascular and cerebrovascular diseases have led to extensive extrapolation of evidence derived from coronary artery disease to PAD, for example, with regard to the use of anti-platelet agents (17, 18). In this issue of Thrombosis and Haemostasis, Basili et al. (19) report results of a meta-analysis of 29 clinical randomised trials on anti-platelet therapy in PAD, assessing their prevention of cardiovascular Correspondence to: Mr. A. S. Jaipersad University of Birmingham Centre for Cardiovascular Sciences City Hospital, Birmingham B18 7QH, UK E-mail: tonyjaipersad@btinternet.com