Bleeding Risk Profile in Patients With Symptomatic Peripheral Artery Disease.

PURPOSE: To assess the bleeding risk profile using the HAS-BLED score in patients with symptomatic peripheral artery disease (PAD). METHODS: A post hoc analysis was performed using data from a series of 115 consecutive patients (mean age 72.4±11.4 years; 68 men) with symptomatic PAD undergoing endovascular revascularization. The endpoint of the study was to assess bleeding risk using the 9-point HAS-BLED score, which was previously validated in cohorts of patients with and without atrial fibrillation. For the purpose of this study, the low (0-1), intermediate (2), and high-risk (≥3) scores were stratified as low/intermediate risk (HAS-BLED <3) vs high risk (HAS-BLED ≥3). RESULTS: The mean HAS-BLED score was 2.76±1.16; 64 (56%) patients had a HAS-BLED score ≥3.0. Patients with PAD Rutherford category 5/6 ischemia had an even higher mean HAS-BLED score (3.20±1.12). Logistic regression analysis revealed aortoiliac or femoropopliteal segment involvement, chronic kidney disease, as well as Rutherford category 5/6, to be independent risk factors associated with a HAS-BLED score ≥3. CONCLUSION: Patients with PAD, especially those presenting with Rutherford category 5/6 ischemic symptoms, have high HAS-BLED scores, suggesting increased risk for major bleeding. Prospective clinical validation of the HAS-BLED score in patients with PAD may help with the risk-benefit assessment when prescribing antithrombotic therapy.

Renal artery duplex ultrasound criteria for the detection of significant in-stent restenosis.

OBJECTIVES: To define velocity criteria by ultrasonography for the detection of hemodynamically significant (>60%) renal artery in-stent restenosis (ISR). BACKGROUND: The restenosis rate after renal artery stenting ranges between 10% and 20%. While duplex ultrasound criteria have been validated for native renal artery stenosis, there are no uniformly accepted validated criteria for stented renal arteries. METHODS: Vascular laboratory databases from two academic medical centers were retrospectively reviewed for patients who underwent renal artery stenting followed by duplex ultrasound evaluation and angiography (CT angiography or catheter angiography) as the gold standard. RESULTS: A cohort of 132 stented renal arteries that had angiographic comparisons was analyzed. Eighty-eight renal arteries demonstrated 0-59% stenosis while 44 renal arteries revealed 60-99% stenosis by angiography. Both the mean peak systolic velocity (PSV) and the renal artery-to-aortic ratio (RAR) were significantly higher in renal arteries with 60-99% restenosis compared with those with 0-59% restenosis (PSV: 382 cm/sec ± 128 vs. 129 cm/sec ± 62, P<0.001; RAR: 5.3 ± 2.4 vs. 2.1 ± 1.0, P <0.001). The optimal PSV and RAR cutoffs for detecting 60-99% ISR were calculated by receiver operator characteristics curve analysis. The velocity criteria that are associated with these results will be discussed. CONCLUSION: Duplex ultrasonography is an accurate technique to identify significant restenosis in stented renal arteries. The PSV and RAR cutoffs for detecting renal artery ISR are higher than those in native, unstented renal arteries. A normal duplex ultrasound after renal artery stenting virtually excludes significant restenosis.

Buerger disease (thromboangiitis obliterans).

Buerger disease is a nonatherosclerotic vasculitis that is triggered by substantial exposure to tobacco. This disease usually affects small- and medium-sized arteries in the upper and lower extremities. All clinicians who take care of patients with peripheral arterial disease should know the clinical features and diagnostic evaluation of Buerger disease. In this article, we review the clinical presentation and diagnostic criteria for Buerger disease. We describe the diagnostic work-up of patients suspected of having Buerger disease and discuss the typical findings on noninvasive arterial studies and angiography. Lastly, we review the management of these patients, including medical therapy, with an emphasis on smoking cessation, as well as the potential role of revascularization, both surgical and endovascular.

Noninvasive Testing in Peripheral Arterial Disease.

Most patients suspected of having peripheral arterial disease should undergo noninvasive vascular testing to confirm the diagnosis, and to determine the severity and extent of the disease. This article reviews practical aspects of commonly used noninvasive tests for lower extremity peripheral arterial disease, including the ankle-brachial index, segmental limb pressures, pulse volume recordings, duplex ultrasonography, computed tomography angiography, and magnetic resonance angiography.

Ineligibility for anticoagulation in patients with atrial fibrillation.

Although anticoagulation therapy markedly reduces the risk of stroke in patients with atrial fibrillation, up to 50% of these patients are deemed ineligible for anticoagulation. In this manuscript we provide a framework to assess the net clinical benefit of anticoagulation in patients with atrial fibrillation with an increased risk of bleeding. We also review recent data related to the novel oral anticoagulants targeting thrombin or factor Xa, and discuss how the introduction of these agents raises the distinction between eligibility for vitamin K antagonist therapy specifically, and eligibility for anticoagulation in general.

Effect of caffeine on platelet inhibition by clopidogrel in healthy subjects and patients with coronary artery disease.

BACKGROUND: Clopidogrel inhibits the platelet P2Y12 receptor, leading to increased intracellular cyclic AMP (cAMP) levels. Caffeine also causes a rise in platelet cAMP. We aimed to test the effect of acute caffeine administration on platelet inhibition by clopidogrel, in healthy volunteers and patients with coronary artery disease. METHODS: Cohort 1: 12 healthy subjects were enrolled in a 2-week crossover study. Blood samples were drawn at baseline, 2, 4, and 24 hours after 300 mg clopidogrel intake. At the first week, 6 subjects received caffeine (300 mg pill, equivalent to a medium sized coffee drink) 30 minutes after clopidogrel. At week 2, the other 6 subjects received caffeine. One month later the effect of caffeine alone was tested. Platelet function was evaluated by aggregation in response to 5, 10, and 20 micromol/L adenosine diphosphate, 1 microg/mL collagen, and flow cytometric determination of P-selectin expression, PAC-1 binding, and vasodilator-stimulated phosphoprotein phosphorylation. Cohort 2: 40 patients with coronary artery disease receiving aspirin and clopidogrel (75 mg daily) for > or = 1 week were tested at baseline and 2.5 hours after caffeine (300 mg). RESULTS: In cohort 1 (crossover study), caffeine was associated with lower adenosine diphosphate-induced aggregation at 4 hours, lower activation markers at 2 hours, and lower vasodilator-stimulated phosphoprotein phosphorylation at 4 hours after clopidogrel. Caffeine alone had no effect on the assessed platelet surface biomarkers. In cohort 2, caffeine administration was associated with lower platelet activation markers (P-selectin, PAC-1 binding), without significant effect on aggregation. CONCLUSIONS: Acute caffeine administration after clopidogrel loading appears to be associated with enhanced platelet inhibition 2 to 4 hours after clopidogrel intake. The mechanism probably involves synergistic increase in cAMP levels.

Tissue-factor-bearing microvesicles arise from lipid rafts and fuse with activated platelets to initiate coagulation.

Tissue factor (TF) circulates in plasma, largely on monocyte/macrophage-derived microvesicles that can bind activated platelets through a mechanism involving P-selectin glycoprotein ligand-1 (PSGL-1) on the microvesicles and P-selectin on the platelets. We found these microvesicles to be selectively enriched in both TF and PSGL-1, and deficient in CD45, suggesting that they arise from distinct membrane microdomains. We investigated the possibility that microvesicles arise from cholesterol-rich lipid rafts and found that both TF and PSGL-1, but not CD45, localize to lipid rafts in blood monocytes and in the monocytic cell line THP-1. Consistent with a raft origin of TF-bearing microvesicles, their shedding was significantly reduced with depletion of membrane cholesterol. We also evaluated the interaction between TF-bearing microvesicles and platelets. Microvesicles bound only activated platelets, and required PSGL-1 to do so. The microvesicles not only bound the activated platelets, they fused with them, transferring both proteins and lipid to the platelet membrane. Fusion was blocked by either annexin V or an antibody to PSGL-1 and had an important functional consequence: increasing the proteolytic activity of the TF-VIIa complex. These findings suggest a mechanism by which all of the membrane-bound reactions of the coagulation system can be localized to the surface of activated platelets.

Platelet activation leads to activation and propagation of the complement system.

Inflammation and thrombosis are two responses that are linked through a number of mechanisms, one of them being the complement system. Various proteins of the complement system interact specifically with platelets, which, in turn, activates them and promotes thrombosis. In this paper, we show that the converse is also true: activated platelets can activate the complement system. As assessed by flow cytometry and immunoblotting, C3 deposition increased on the platelet surface upon cell activation with different agonists. Activation of the complement system proceeded to its final stages, which was marked by the increased generation of the anaphylotoxin C3a and the C5b-9 complex. We identified P-selectin as a C3b-binding protein, and confirmed by surface plasmon resonance binding that these two proteins interact specifically with a dissociation constant of 1 microM. Using heterologous cells expressing P-selectin, we found that P-selectin alone is sufficient to activate the complement system, marked by increases in C3b deposition, C3a generation, and C5b-9 formation. In summary, we have found that platelets are capable of activating the complement system, and have identified P-selectin as a receptor for C3b capable of initiating complement activation. These findings point out an additional mechanism by which inflammation may localize to sites of vascular injury and thrombosis.

Effect of P-selectin on phosphatidylserine exposure and surface-dependent thrombin generation on monocytes.

OBJECTIVE: Stimulation of monocytes with P-selectin induces the synthesis of an array of mediators of inflammation, as well as the expression of tissue factor (TF), the main initiator of coagulation. Because the membrane-bound reactions of coagulation are profoundly influenced by the presence of phosphatidylserine on the membranes of cells, factors that increase its expression may have an impact on coagulation. METHODS AND RESULTS: Using flow cytometry, we studied the effect of P-selectin on phosphatidylserine expression in blood monocytes and in the monocytic cells, THP-1. Soluble P-selectin at biologically relevant concentrations (0.31 to 2.5 microg/mL) induced a time-dependent increase in phosphatidylserine expression, an effect that could be inhibited with an anti-PSGL-1 blocking antibody, and by genistein, a tyrosine kinase inhibitor. Binding of activated platelets to THP-1 cells also resulted in a significant increase in phosphatidylserine expression that was dependent on PSGL-1. Consistent with the role of phosphatidylserine on surface-dependent reactions of coagulation, treatment of monocytic cells with soluble P-selectin led to increased thrombin generation. We excluded P-selectin induced apoptosis of monocyte as a mechanism for the increased phosphatidylserine exposure. CONCLUSIONS: In summary, we show that P-selectin, either soluble or in its membrane-bound form, induces phosphatidylserine exposure in monocytes through a mechanism dependent on PSGL-1.