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Patients with a history of deep vein thrombosis and pulmonary embolism are at risk for a recurrent event. This is particularly true of patients with idiopathic events or events related to low risk triggers. In these patients extending anticoagulation beyond 3 to 6months may be warranted. Using clinical risk, biomarker analysis and risk stratification protocols we can make the best recommendations to patients with respect to the risks and benefits of ongoing therapy. Trials demonstrating benefit from low-dose aspirin for secondary prophylaxis may provide an option for patients in whom ongoing anticoagulation is deemed unsafe. In addition, recent introduction of the direct oral anticoagulants have expanded options for secondary prophylaxis for preventing venous thromboembolism recurrence.

Background In every field of medicine, comprehensive education should be delivered at the graduate level. Currently, no single specialty routinely provides a standardized comprehensive curriculum in venous and lymphatic disease. Method The American Board of Venous & Lymphatic Medicine formed a task force, made up of experts from the specialties of dermatology, family practice, interventional radiology, interventional cardiology, phlebology, vascular medicine, and vascular surgery, to develop a consensus document describing the program requirements for fellowship medical education in venous and lymphatic medicine. Result The Program Requirements for Fellowship Education in Venous and Lymphatic Medicine identify the knowledge and skills that physicians must master through the course of fellowship training in venous and lymphatic medicine. They also specify the requirements for venous and lymphatic training programs. The document is based on the Core Content for Training in Venous and Lymphatic Medicine and follows the ACGME format that all subspecialties in the United States use to specify the requirements for training program accreditation. The American Board of Venous & Lymphatic Medicine Board of Directors approved this document in May 2016. Conclusion The pathway to a vein practice is diverse, and there is no standardized format available for physician education and training. The Program Requirements for Fellowship Education in Venous and Lymphatic Medicine establishes educational standards for teaching programs in venous and lymphatic medicine and will facilitate graduation of physicians who have had comprehensive training in the field.

Objectives Venous leg ulcers (VLU) are the most severe clinical sequelae of venous reflux and post thrombotic syndrome. There is a consensus that ablation of refluxing vein segments and treatment of significant venous obstruction can heal VLUs. However, there is wide disparity in the use and choice of adjunctive therapies for VLUs. The purpose of this study was to assess these practice patterns among members of the American Venous Forum. Methods The AVF Research Committee conducted an online survey of its own members, which consisted of 16 questions designed to determine the specialty of physicians, location of treatment, treatment practices and reimbursement for treatment of VLUs Results The survey was distributed to 667 practitioners and a response rate of 18.6% was achieved. A majority of respondents (49.5%) were vascular specialists and the remaining were podiatrists, dermatologists, primary care doctors and others. It was found that 85.5% were from within the USA, while physicians from 14 other countries also responded. Most of the physicians (45%) provided adjunctive therapy at a private office setting and 58% treated less than 5 VLU patients per week. All respondents used some form of compression therapy as the primary mode of treatment for VLU. Multilayer compression therapy was the most common form of adjunctive therapy used (58.8%) and over 90% of physicians started additional modalities (biologics, negative pressure, hyperbaric oxygen and others) when VLUs failed compression therapy, with a majority (65%) waiting less than three months to start them. Medicare was the most common source of reimbursement (52.4%). Conclusions Physicians from multiple specialties treat VLU. While most physicians use compression therapy, there is wide variation in the selection and point of initiation for additional therapies once compression fails. There is a need for high-quality data to help establish guidelines for adjunctive treatment of VLUs and to disseminate them to physicians across multiple specialties to ensure standardized high-quality treatment of patients with VLUs.

Cardiac rehabilitation (CR) has proven morbidity and mortality benefits in cardiovascular disease, which directly correlates with exercise performance achieved. Many patients in CR exercise at sub-optimal levels, without obvious limitations. Occult lower-extremity peripheral artery disease (PAD) may be a determinant of diminished exercise capacity and reduced benefit obtained from traditional CR. In this prospective study of 150 consecutive patients enrolled in Phase II CR, we describe the prevalence of PAD, the utility of externally validated screening questionnaires, and the observed impact on CR outcomes. Abnormal ankle–brachial indices (ABI) (1.4) were observed in 19% of those studied. The Edinburgh Claudication Questionnaire was insensitive for detecting PAD by low ABI in this population, and the Walking Impairment Questionnaire and a modified Gardner protocol demonstrated a lack of typical symptoms with low levels of activity. Importantly, at completion of traditional CR, exercise improvement measured in metabolic equivalents (METs) was worse in those with a low ABI compared to those with a normal ABI (+1.39 vs +2.41 METs, p=0.002). In conclusion, PAD is common in patients in Phase II CR and often clinically occult. Screening based on standard questionnaires appears insensitive in this population, suggesting a need for a broad-based screening strategy with ABI measurements. In this study, undiagnosed PAD significantly attenuated improvements in exercise performance, which potentially has bearings on future clinical events.

BACKGROUND: Diabetes mellitus continues to grow in global prevalence and to consume an increasing amount of health care resources. One of the key areas of morbidity associated with diabetes is the diabetic foot. To improve the care of patients with diabetic foot and to provide an evidence-based multidisciplinary management approach, the Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medicine developed this clinical practice guideline. METHODS: The committee made specific practice recommendations using the Grades of Recommendation Assessment, Development, and Evaluation system. This was based on five systematic reviews of the literature. Specific areas of focus included (1) prevention of diabetic foot ulceration, (2) off-loading, (3) diagnosis of osteomyelitis, (4) wound care, and (5) peripheral arterial disease. RESULTS: Although we identified only limited high-quality evidence for many of the critical questions, we used the best available evidence and considered the patients' values and preferences and the clinical context to develop these guidelines. We include preventive recommendations such as those for adequate glycemic control, periodic foot inspection, and patient and family education. We recommend using custom therapeutic footwear in high-risk diabetic patients, including those with significant neuropathy, foot deformities, or previous amputation. In patients with plantar diabetic foot ulcer (DFU), we recommend off-loading with a total contact cast or irremovable fixed ankle walking boot. In patients with a new DFU, we recommend probe to bone test and plain films to be followed by magnetic resonance imaging if a soft tissue abscess or osteomyelitis is suspected. We provide recommendations on comprehensive wound care and various débridement methods. For DFUs that fail to improve (>50% wound area reduction) after a minimum of 4 weeks of standard wound therapy, we recommend adjunctive wound therapy options. In patients with DFU who have peripheral arterial disease, we recommend revascularization by either surgical bypass or endovascular therapy. CONCLUSIONS: Whereas these guidelines have addressed five key areas in the care of DFUs, they do not cover all the aspects of this complex condition. Going forward as future evidence accumulates, we plan to update our recommendations accordingly.

There are many clinical and laboratory biomarkers that play a role in venous thromboembolism management. In clinical care, biomarkers may be used along with clinical risk scores to exclude venous thromboembolism. In addition, they can be used to determine venous thromboembolic risk, determine the risk of recurrent venous thromboembolism, as well as risk stratify patients for adverse clinical outcomes during therapy. Having a working knowledge of and the ability to use biomarkers is important in all aspects of venous thromboembolism management.

Noninvasive vascular laboratory determinations for peripheral arterial disease (PAD) often combine pulse volume recordings (PVRs), segmental pressure readings (SPs), and Doppler waveform traces (DWs) into a single diagnostic report. Our objective was to assess the corresponding diagnostic values for each test when subjected to interpretation by 4 vascular specialists.A total of 2226 non-invasive diagnostic reports were reviewed through our institutional database between January 2009 and December 2011. Data from noninvasive records with corresponding angiograms performed within 3 months led to a cohort of 76 patients (89 limbs) for analysis. Four vascular specialists, blinded to the angiographic results, stratified the noninvasive studies as representative of normal,50% "subcritical," or ≥50% "critical" stenosis at the upper thigh, lower thigh, popliteal, and calf segments using 4 randomized noninvasive modalities: (1) PVR alone; (2) SP alone; (3) SP+DW; and (4) SP+DW+PVR. The angiographic records were independently graded by another 3 evaluators and used as a standard to determine the noninvasive diagnostic values and interobserver agreements for each modality. Statistical tests used include the Fleiss-modified kappa analysis, Kruskal-Wallis analysis of variance with Dunn's multiple comparison test, the Kolmogorov-Smirnov test, and the unpaired t-test with Welch's correction.Interobserver variance for all modalities was high, except for SP. When surveying for any stenosis (50% and ≥50%), sensitivity (range 25-75%) was lower than specificity (range 50-84%) for all modalities. When surveying for critical stenosis only (≥50%), sensitivity (range 27-54%) was also lower than specificity (range 68-92%). Accuracy for detecting any stenosis with SP+DW was significantly higher than with PVR alone (66 ± 7% vs. 56 ± 12%, P = 0.017). There was a significant reduction in accuracy when including incompressible readings within the SP-only analysis compared with exclusion of incompressible vessels (P = 0.0006). However, the effect of vessel incompressibility on accuracy was removed with the addition of DW (P = 0.17) to the protocol.SP has the greatest interobserver agreement in evaluation of PAD and can be used preferentially for PAD stratification. Given the lower accuracy of PVR for detecting either subcritical or critical disease, PVR tests can be omitted from the noninvasive vascular examination without a significant reduction in overall diagnostic value and can be reserved for patients with incompressible vessels.

Background Carotid intima media thickness (CIMT) progresses faster in HIV-infected adults on antiretroviral therapy (ART) than the general population. It is unclear if the rate of progression is similarly faster in ART-naive, HIV-infected adults. Methods This was a 48-week prospective cohort study to compare change in CIMT and inflammation markers in ART-naive, HIV-infected adults in no immediate need of ART (HIV-positive/ART-naive) and age/sex/body mass index (BMI)-matched controls (HIV-negative). Results A total of 85 HIV-positive/ART-naive and 45 HIV-negative participants were enrolled. In the HIV-positive/ ART-naive group, median baseline CD4+ T-cell count and HIV-1 RNA were 535 cells/mm3 and 6,916 copies/ml. Baseline common carotid artery (CCA) and bulb CIMTs were similar between groups. Changes in CIMT to 48 weeks at both sites were not different within- or between-groups (median [IQR] change in HIV-positive/ART-naive versus HIV-negative CCA CIMT -0.0071 mm [-0.0267–0.0233] versus 0.0113 mm [-0.0117–0.0306]; P=0.19 between-groups; and bulb CIMT 0.0017 mm [-0.0367–0.06167] versus 0.01 mm [-0.0383–0.0625]; P=0.54). After adjustment for cardiovascular disease (CVD) risk factors, change in CCA CIMT was greater in HIV-negative participants (-0.0046 versus 0.0177 mm for HIV-positive/ART-naive versus HIV-negative; P=0.01). In HIV-positive/ART-naive, interleukin (IL)-6, soluble tumour necrosis factor-α receptor (sTNFR)-II, vascular cell adhesion molecule-1 and intercellular adhesion molecule (ICAM)-1 were higher at both time points and D-dimer was higher at week 48 ( PConclusions In ART-naive HIV-infected adults at low risk of HIV disease progression and low cardiovascular risk, CIMT progression rate was similar to matched controls. In addition to traditional CVD risk factors, higher levels of sTNFR-I predicted greater bulb CIMT changes.

The noninvasive assessment of the critically ischemic limb has evolved from air plethysmography for pulse volume wave recordings and quantitative pressure evaluation to imaging of occlusive arterial lesions utilizing duplex color ultrasonography which produces highly reliable and reproducible data. This physiologic and anatomic data have practical implications for pre-interventional planning, operative guidance, and post-interventional surveillance in critical limb ischemia (CLI). Adjunctive diagnostic measures have become available with the advances in technology over the past decades to determine oxygen tension and microvascular pressures for poorly perfused distal extremities and feet which utilize transcutaneous oximetry, laser Doppler, and near-infrared spectroscopy. Fluorescence angiography is also now among the newest of the commercially available modalities that can be offered at the bedside for both qualitative and quantitative evaluation of skin perfusion in ischemic distal extremities.

Post-thrombotic syndrome frequently affects patients following deep vein thrombosis. The clinical signs and symptoms of post-thrombotic syndrome reflect the underlying pathophysiology of venous obstruction, venous reflux as well as acute and chronic inflammation. Patients with post-thrombotic syndrome are at risk for long-term consequences including decreased quality of life, lost work productivity, and increased health expenditures. Unfortunately, despite recognition of pathophysiology and the clinical, physical, and economic impact of PTS, there have been few advances in prevention. PTS continues to be a frustrating condition to both prevent and manage. Preventing post-thrombotic syndrome begins with preventing deep vein thrombosis. In the setting of acute deep vein thrombosis-using available medical therapies to prevent the development of post-thrombotic syndrome is imperative. Patients should be provided optimal medical therapy with anticoagulation, maintaining therapeutic anticoagulation as much of the time as possible. Use of compression stockings, while contentious, are a low risk intervention which may provide benefit and are unlikely to be associated with harm. In the appropriate patient, considering endovenous procedures to decrease the thrombus burden and provide optimal preservation of venous valve function may be warranted.

The generalized term 'peripheral vascular disease' (PVD) may be used to refer to vascular disorders in any non-coronary arterial bed. The more specific term 'peripheral arterial disease' (PAD) is used to refer to a more specific process, atherosclerotic disease of the lower extremities. PAD is common. Conservative estimates suggest more than 8 million Americans may be affected by PAD. Since atherosclerosis is a systemic process, PAD should be identified as a coronary heart disease risk equivalent. However, PAD remains an under-diagnosed and under-recognized risk for cardiovascular morbidity and mortality. PAD symptoms may range from non-specific ambulatory leg complaints, to typical symptoms of intermittent claudication to critical limb ischaemia with rest pain, gangrene or ulceration. These symptoms directly impact quality of life and may affect functional capacity. There are two therapeutic goals for patients with PAD: first, to reduce the risk of cardiovascular events and second, to manage the lower extremity symptoms. This manuscript reviews the medical management of patients with PAD, briefly discussing the goals of cardiovascular risk factor modification and then focusing on pharmacological management strategies for patients with intermittent claudication and critical limb ischaemia.

Background D-Dimer elevations have been associated with a striking increase in mortality in HIV-infected patients. However, D-Dimer has not been directly linked to endothelial dysfunction in HIV. Methods In this cross-sectional study, we used flow-mediated dilation (FMD) of the brachial artery to measure endothelial function and several biomarkers to measure systemic inflammation and coagulation activation in HIV-infected adults on stable antiretroviral therapy with HIV-1 RNA levels Results Analysis included 98 subjects (88% male, median age 47.5 years, CD4+ T-cells 578.5 cells/mm3); all on ART (52% on protease inhibitors). The only factors independently associated with FMD were D-Dimer and body mass index. Conclusions We show for the first time an independent association between D-Dimer and endothelial dysfunction in virologically suppressed, HIV-infected adults on stable antiretroviral therapy, potentially explaining the link between D-Dimer and mortality in HIV.

Objectives Enhanced inflammation is evident in HIV infection, even with virological suppression. Outside HIV infection, studies show an independent association between higher total bilirubin and better endothelial function as well as a lower prevalence of coronary heart disease, possibly as a consequence of the anti-inflammatory and antioxidant effect of bilirubin. The aim of this study was to determine whether such an association exists in HIV-infected individuals. Methods A cross-sectional study was performed in HIV-1-infected adults on stable antiretroviral therapy (ART) to determine if a relationship exists between total bilirubin and endothelial function [flow-mediated dilation (FMD) of the brachial artery], inflammation [interleukin-6 (IL-6), soluble tumour necrosis factor receptors, C-reactive protein, and adhesion molecules], coagulation markers (fibrinogen and D-dimer) and oxidative stress (F 2-isoprostanes). Endpoints were compared based on total bilirubin levels and atazanavir status using distributionally appropriate, two-sample tests. Correlation coefficients were determined between total bilirubin and endpoints. Linear regression was used to model the relationship between total bilirubin (and atazanavir status) and FMD. Results A total of 98 adults were included in the study. Total bilirubin was higher in the atazanavir group when compared to the non-atazanavir group [median (interquartile range) 1.8 (1.1–2.6) vs. 0.6 (0.4–1.4) mg/dL; P

The peripheral arterial system includes all noncardiac arteries: the thoracic and abdominal aortas and their branches extending to visceral organs and both upper and lower extremities as well as the extracranial vessels. Although the awareness of peripheral arterial disease (PAD) has increased in the past decade, PAD remains underdiagnosed and undertreated. The development of PAD guidelines has helped increase awareness and define diagnostics and treatment strategies in PAD. 1,2 Atherosclerotic disease is the most common cause of PAD, but nonatherosclerotic vascular disease may cause similar symptoms and must be considered in patients presenting with vascular insufficiency. The differential diagnosis of patients presenting should therefore include entrapment syndromes at the thoracic outlet or popliteal fossa, cystic adventitial disease, fibromuscular dysplasia, endofibrosis of the iliac artery, embolism, thromboangiitis obliterans (Buerger disease), and vasculitis, such as Takayasu arteritis or giant cell arteritis. 3 Musculoskeletal syndromes associated with arthritis, compartment syndrome, myositis, orpseudoclaudicationmayalsopresentinasimilar fashion. From epidemiologic studies, approximately 12% of the adult population has PAD. At younger ages, PAD is more prevalent in men than in women; however, with advancing age, gender distribution is equal. 4 Disease prevalence increases with advancing age and cardiovascular risk factors. In one study, lower extremity PAD was identified in 29% of patients older than 70 years or patients older than 50 years with a history of smoking or diabetes. 5 Patients older than 70 years in the National Health and Nutrition Examination Survey and patients older than 65 years in the Framingham Heart Study had an increased risk of developing PAD, with a prevalence of 4.3% in patients older than 40 years compared with 14.5% in patients older than 70 years. 6 African Americans and Hispanics have an increased risk of PAD compared with Caucasians. Most patients with lower extremity PAD are asymptomatic, whereas others may experience nondescript leg symptoms. Typical symptoms associated with PAD include claudication, ischemic rest pain, ischemic ulcerations, and gangrene. Compared with age-matched controls, patients with asymptomatic PAD have poorer functional performance and quality of life as well as smaller calf muscle area and greater calf muscle fat. 7 In general, patients perform poorly on health-related quality-of-life questionnaires and have an increased rate of depression. These patients are at risk for recurrent hospitalizations, revascularizations, as well as limb loss. 2,8,9 More importantly, patients with PAD have a higher rate

In this 13-week, open-label, randomized study of the anti-inflammatory salsalate versus usual care, there were no significant improvements in flow-mediated dilation of the brachial artery, endothelial activation, inflammation or coagulation markers, homeostasis model assessment of insulin resistance or lipoproteins with salsalate or between groups in virologically suppressed, HIV-infected adults on antiretrovirals. Tinnitus and transaminitis occurred frequently in the salsalate group. Dose reduction due to toxicities encountered and low level of inflammation may explain these results.

Inferior vena cava (IVC) filter placement has increased dramatically over the past two decades. Filters are indicated to prevent pulmonary embolism in patients with venous thromboembolism (VTE) and a contraindication to anticoagulation or a complication of anticoagulation. Some of this increased use is the result of expanding relative indications for filter placement, including placement for primary prophylaxis. The US Food and Drug Administration has approved 11 filters for permanent deployment, two of which--the Günther-Tulip (Cook Medical, Bloomington, IN) and the OptEase (Cordis Endovascular, Miami Lakes, FL)--are optionally retrievable. Once anticoagulation is deemed safe, all patients should be fully anticoagulated to prevent propagation and recurrent thromboembolism. Complications related to IVC filters include procedure-related issues, device complications, and secondary VTE. Therefore, the decision regarding filter placement and/or retrieval must be individualized.

Pulmonary embolism (PE) is a major health problem and a cause of worldwide morbidity and mortality. The current standard therapy for acute PE encourages admitting patients to the hospital for administration of parenteral anticoagulation therapy as a bridge to oral vitamin K antagonists. Prognostic models that identify patients with stable (nonmassive) acute PE (SPE) who are at low risk for adverse outcome have recently been reported. Based on these risk stratification models, hospital-based therapy is warranted for patients with PE who meet the criteria associated with a high risk for adverse outcome. However, a growing body of evidence suggests the feasibility of partial outpatient management and accelerated hospital discharge (AHD) in a subset of patients with SPE. Prospective validation of these risk stratification models for predicting patient suitability for AHD is needed.

A high school senior with a baseball scholarship presents with the acute onset of swelling in his nondominant arm. What is the most likely diagnosis and the most appropriate initial diagnostic test?

Superior vena cava (SVC) syndrome is associated with advanced malignancy of the chest. Extensive experience is published in the literature regarding the use of endovascular intervention for symptomatic relief in these individuals with limited survival. Symptomatic SVC obstruction may occur from benign conditions that may not alter life expectancy. There are few data regarding endovascular therapy in this setting. We retrospectively analyzed our experience using endovascular intervention for benign SVC obstruction in 19 patients. In our series, the mean age was 46.4 years; 58% were female and 14/19 cases were due to an intravascular device. All patients experienced symptomatic relief. Median follow-up was 28.8 months. Three patients required secondary procedures to maintain patency. Four patients had procedural complications, which did not affect the outcomes. One patient died from complications of anticoagulation at 24 months. Endovascular procedures aimed at relieving SVC stenosis seem to be effective in patients with benign disease.

Acquired hemophilia A is a life-threatening immune-mediated hemorrhagic disorder that is most often found in individuals older than 50 who present with an unexplained activated partial thromboplastin time (aPTT) prolongation and clinically significant bleeding. The prolonged aPTT associated with acquired hemophilia A reflects factor VIII activity deficiency due to neutralizing or clearing autoantibodies. Deep venous thrombosis, in contrast, is a veno-occlusive disorder associated with several distinct hypercoagulable states that can result in significant morbidity and mortality due to pulmonary embolism, thrombus extension, and the post-thrombotic syndrome. A prolonged a PYI in the setting of thrombosis may reflect the presence of a lupus anticoagulant. In the absence of accurate diagnosis and the immediate institution of specific therapy, both disorders can be fatal. Three cases of acquired factor VIII inhibitors that included a prolonged aPTT, bleeding, and duplex ultrasound evidence of deep venous thrombosis are presented. The diagnostic and therapeutic challenges posed by these cases as well as a proposed mechanism by which pathologic thrombosis can develop in a patient with a life-threatening bleeding disorder are discussed.

No single imaging study or blood test is 100% sensitive and specific for pulmonary embolism. A combination of pretest clinical probability assessment, noninvasive pulmonary imaging (V/Q scanning or spiral CT), and D-dimer testing seems prudent before pursuing pulmonary angiography.

The major venous societies in the United States share a common mission to improve the standards of medical practitioners, the educational goals for teaching and training programs in venous disease, and the quality of patient care related to the treatment of venous disorders. With these important goals in mind, a task force made up of experts from the specialties of dermatology, interventional radiology, phlebology, vascular medicine, and vascular surgery was formed to develop a consensus document describing the Core Content for venous and lymphatic medicine and to develop a core educational content outline for training. This outline describes the areas of knowledge considered essential for practice in the field, which encompasses the study, diagnosis, and treatment of patients with acute and chronic venous and lymphatic disorders. The American Venous Forum and the American College of Phlebology have endorsed the Core Content.

Angiography is the gold standard for imaging of the renal arteries; however, accurate imaging is possible using several noninvasive methods including duplex ultrasonography, spiral CT angiography, and MR angiography. Noninvasive imaging is used most frequently is diagnosing renal artery disease and during the preoperative planning for renal transplant donors and renal cancer surgery. In addition, noninvasive imaging is ideal for surveillance of restenosis following endovascular therapy (percutaneous transluminal angioplasty or stenting) or surgical revascularization. While intravenous digital subtraction angiography is not used often because of poor image quality, it is worth briefly discussing for historical purposes. Factors such as body habitus, renal function, and as institutional experience, expertise, and cost will influence the imaging modality recommended for any given patient.

Heparin-induced thrombocytopenia (HIT) is an under-recognized, limb- and life-threatening complication of pharmacologic heparin administration. Antibody formation against heparin complexed to platelet factor 4 (PF4) is central to the pathogenesis of HIT. Heparin: PF4 antibodies promote platelet activation and aggregation as well as excess thrombin generation which may lead to clinical thrombosis. HIT should be suspected in patients who develop thrombocytopenia with or without associated arterial or venous thrombosis while on heparin. HIT is a clinical diagnosis. Specialized HIT assays should be interpreted with care. The cornerstone of HIT management is the discontinuation of all forms of heparin exposure and the institution of anticoagulation with an alternative agent. The direct thrombin inhibitors lepirudin and argatroban are currently available and approved for use in patients with HIT.

We present what we believe is the first case in the literature of carcinoma of the lung presenting de novo as an intracardiac mass with bilateral, simultaneous popliteal artery embolization. Arterial thromboembolism of cardiac origin and in situ thrombosis of a preexisting atherosclerotic lesion or aneurysm account for the majority of cases of acute lower extremity ischemia. Less common causes include trauma, aortic dissection, venous ischemia, and foreign body or tissue embolization. Although the history, physical exam ination, and electrocardiographic findings may provide a likely explanation in many cases, noninvasive studies such as echocardiography may help further elucidate the embolic source.

This is a 96-week prospective cohort study of antiretroviral therapy (ART)-naive HIV-infected adults and matched healthy controls to assess progression of carotid intima media thickness (CIMT) and its relationship to inflammation. Median common carotid artery (CCA) CIMT increased significantly but similarly in both groups [CCA: 0.02 (interquartile range: 0-0.05); P < 0.01 within HIV-infected adults vs. 0.01 (0-0.05) mm; P < 0.01 within controls; and P = 0.83 between groups]. Change in bulb CIMT yielded similar results. Independent predictors of CCA CIMT progression in HIV-infected adults were higher systolic blood pressure, total cholesterol, and high sensitivity C-reactive protein. Independent predictors of bulb CIMT progression were higher non-high-density lipoprotein cholesterol and high sensitivity C-reactive protein. Other inflammation markers were not associated with CIMT progression.

Omega-3 fatty acids decrease cardiovascular disease (CVD) mortality possibly due to antiinflammatory effect. Inflammation and endothelial dysfunction likely play a role in the heightened CVD risk in HIV. Our goal was to evaluate the effect of omega-3 fatty acids primarily on endothelial function and inflammation in HIV-infected adults with moderate CVD risk on stable antiretroviral therapy. We conducted a 24-week, randomized, double-blind, placebo-controlled study to evaluate the effect of omega-3-acid ethyl esters 1 g twice a day. Flow-mediated dilation (FMD) of the brachial artery, lipoproteins and markers of inflammation, endothelial activation, coagulation, and insulin resistance were measured at entry and week 24. There were no within- or between-group differences in change in FMD over 24 weeks (mean change in FMD -0.13% vs. 1.5% for treatment vs. placebo; p=0.21). There were no between-group differences in changes in lipoprotein levels or biomarkers tested, except soluble tumor necrosis factor receptor-I, which favored omega-3-acid ethyl esters. Omega-3 fatty acids did not improve endothelial function or activation, coagulation, or insulin resistance in virologically suppressed, HIV-infected men with moderate CVD risk; however, inflammation tended to improve. This suggests that omega-3 fatty acids may not be potent enough to counteract the enhanced inflammation and endothelial dysfunction due to HIV and antiretrovirals.

Background— Critical limb ischemia portends a risk of major amputation of 25% to 35% within 1 year of diagnosis. Preclinical studies provide evidence that intramuscular injection of autologous CD34+ cells improves limb perfusion and reduces amputation risk. In this randomized, double-blind, placebo-controlled pilot study, we evaluated the safety and efficacy of intramuscular injections of autologous CD34+ cells in subjects with moderate or high-risk critical limb ischemia, who were poor or noncandidates for surgical or percutaneous revascularization (ACT34-CLI). Methods and Results— Twenty-eight critical limb ischemia subjects were randomized and treated: 7 to 1×10 5 (low-dose) and 9 to 1×10 6 (high-dose) autologous CD34+ cells/kg; and 12 to placebo (control). Intramuscular injections were distributed into 8 sites within the ischemic lower extremity. At 6 months postinjection, 67% of control subjects experienced a major or minor amputation versus 43% of low-dose and 22% of high-dose cell-treated subjects ( P =0.137). This trend continued at 12 months, with 75% of control subjects experiencing any amputation versus 43% of low-dose and 22% of high-dose cell-treated subjects ( P =0.058). Amputation incidence was lower in the combined cell-treated groups compared with control group (6 months: P =0.125; 12 months: P =0.054), with the low-dose and high-dose groups individually showing trends toward improved amputation-free survival at 6 months and 12 months. No adverse safety signal was associated with cell administration. Conclusions— This study provides evidence that intramuscular administration of autologous CD34+ cells was safe in this patient population. Favorable trends toward reduced amputation rates in cell-treated versus control subjects were observed. These findings warrant further exploration in later-phase clinical trials. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00616980

Background Studies suggest that vitamin D deficiency is a risk factor for cardiovascular disease and diabetes. Vitamin D deficiency is prevalent in HIV patients but the effect of vitamin D supplementation on cardiovascular risk in this population is unknown. Methods We conducted a randomized, double-blind, placebo-controlled trial among 45 HIV-infected adults in Cleveland (OH, USA) on stable antiretroviral therapy with durable virological suppression and a baseline serum 25-hydroxyvitamin D level of ≤20 ng/ml. Participants were randomized 2:1 to vitamin D3 4,000 IU daily or placebo for 12 weeks. The primary outcome was a change in flow-mediated brachial artery dilation (FMD). Results Baseline demographics were similar except for age (vitamin D versus placebo, mean ±sd 47 ±8 versus 40 ±10 years; P=0.009). Both groups had reduced FMD at baseline (median values 2.9% [IQR 1.6–4.8] for vitamin D versus 2.5% [IQR 1.7–6.4] for placebo; P=0.819). Despite an increase in the concentration of serum 25-hydroxyvitamin D from baseline to 12 weeks (5.0 ng/ ml [IQR -0.9–7.4] versus -1.9 ng/ml [IQR -4.0–0.1] for vitamin D versus placebo, respectively; P=0.003), there was no difference in FMD change (0.55% [IQR -1.05– 2.13] versus 0.29% [IQR -1.61–1.77]; P=0.748). Vitamin D supplementation was associated with a decrease in total and non-high-density lipoprotein cholesterol, and an increase in indices of insulin resistance. Conclusions Among HIV-infected individuals with vitamin D deficiency, supplementation with 4,000 IU vitamin D3 daily for 12 weeks modestly improved vitamin D status and cholesterol but worsened insulin resistance without change in endothelial function. The mechanisms of resistance to standard doses of vitamin D and the complex role of vitamin D in glucose metabolism in this population require further investigation.

The morbidity and mortality of venous thromboembolism remain underrecognized and underappreciated. Suspected pulmonary embolism should be risk stratified using a validated clinical risk prediction tool; intermediate to high clinical suspicion requires objective diagnostic testing to confirm or refute the diagnosis. Therapy with unfractionated heparin, low molecular weight heparin, or fondaparinux should be initiated while diagnostic testing is pursued. Conversion to vitamin K antagonists requires a minimum of 5 days’ overlap between the parenteral agent and the vitamin K antagonist. Anticoagulation should be continued for a minimum of 3 to 6 months. Longer or even indefinite therapy may be required with a persistent hypercoagulable state. In patients with cancer, low molecular weight heparin monotherapy for the initial 3 to 6 months is preferred. In stable patients with normal biomarkers and a normal echocardiogram, accelerated discharge and outpatient therapy may be considered. In patients with hemodynamic instability, systemic thrombolytic therapy, catheter-directed therapy, or surgical embolectomy may be considered. Cancer screening and/or thrombophilia testing should be pursued only if the findings will directly affect patient therapy or long-term care.

Idiopathic venous thromboembolism (VTE) can be the first sign of cancer, although how extensively one should search for cancer in a patient with idiopathic VTE is not clear. Treating VTE is more complex in cancer patients than in those without cancer. The authors discuss their approach to searching for undiagnosed cancer in patients with idiopathic VTE and to managing VTE in patients with cancer.

Abstract Current therapy for venous thromboembolism (VTE) includes the initiation of short acting parenteral agents, heparin, low-molecular-weight heparin, or fondaparinux, with subsequent conversion to oral warfarin therapy for the duration of anticoagulation. We present two patients who required long-term anticoagulation for VTE but because of gastrointestinal dysmotility issues were unable to use standard oral anticoagulation. Warfarin is water soluble and absorbed across the epithelium; therefore, we elected to administer warfarin sublingually in an effort to avoid the dysmotility issues while trying to achieve therapeutic anticoagulation. Using sublingual warfarin dosing we were able to achieve therapeutic anticoagulation without complications. Both patients required approximately 6 days to achieve a therapeutic International Normalized Ratio (INR). Neither patient reported adverse side effects related to the sublingual dosing. This unique form of warfarin delivery may be considered for patients with gastrointestinal dysmotility or other gastrointestinal issues which prevent oral use of medications.

Intermittent claudication (IC) is the classic complaint associated with peripheral arterial disease (PAD) and can significantly limit a patient’s lifestyle and workplace abilities. IC is defined as reproducible pain affecting the muscles of the lower extremities that begins and increases with activity and resolves with rest. The clinical goals of management include increasing walking distance and improving quality of life. A dedicated, supervised walking program is the foundation of IC management. In addition, two drugs have been approved by the US Food and Drug Administration for the treatment of IC: cilostazol and pentoxifylline. Other agents and treatment strategies have been investigated, and some show clinical promise.

Publisher Summary This chapter explores the thrombonic complications of vena cava filters. Venous thromboembolism (VTE) is optimally treated by anticoagulation. When anticoagulation must be withheld, inferior vena cava (IVC) interruption affords protection against major embolic events likely to be life threatening. IVC interruption has historically progressed from cava ligation to plication, caval clips, surgically inserted caval umbrellas and filters, and finally, to percutaneously inserted filters. Currently available devices include permanent filters that once deployed remain in place indefinitely, and optionally retrievable filters that may be left in place permanently or may be removed within a specified time frame (weeks to months depending on the device). Complications associated with the historic methods of caval interruption and devices have driven, and will continue to encourage, the modification and design of devices that have limited endothelial cell interactions, require smaller deployment tools, and use imaging friendly materials with reduced thrombogenicity. Current accepted indications for IVC filter use include contraindications to anticoagulation (active bleeding or recent hemorrhage), complications of anticoagulation, or thromboembolism (pulmonary embolism or recurrent/propagation of deep venous thrombosis) despite adequate anticoagulation.

All patients with neurologic diseases should receive perioperative VTE prophylaxis. The choice of mechanical, pharmacologic, or combined modalities of prophylaxis depends on both the underlying risk factors and surgical VTE risks. Prophylaxis and treatment options must be individualized to the patient. Prevention of VTE will help minimize the need for therapeutic treatment. Options for treatment include both inpatient and outpatient regimens using UFH or LMWH. In patients with an absolute or relative contraindication to anticoagulation, an IVC filter is an appropriate management strategy. Perioperative bridging therapy should be considered in patients with high or moderate risks for recurrent VTE.

Objective Deep venous thrombosis (DVT) is a major cause of morbidity and mortality after surgery for primary and metastatic brain tumors. Methods We conducted a confidential survey of American neurosurgeons interested in tumor surgery to assess DVT risk awareness and thromboprophylaxis patterns. Results Of the 172 respondents, 108 (63%) underestimated the DVT risk after brain tumor surgery. After operating on patients who had brain or spinal tumors, 81.4 and 78.5% of respondents, respectively, reported using DVT prophylaxis. After performing brain tumor surgery, 76.2% of respondents reported using solely mechanical methods of prophylaxis "always" or "most of the time." Conclusion American neurosurgeons tend to underestimate the risk of DVT associated with brain tumor surgery and to use mechanical thromboprophylaxis despite the availability of effective pharmacologic antithrombotics. A better appreciation of the risk of thrombosis, combined with clinical studies to address safety, may enhance the use of prophylaxis and the perceived safety of antithrombotics in this setting.

Venous thromboembolic disease, including deep venous thrombosis (DVT) and pulmonary embolism (PE), is an under-diagnosed and under-appreciated medical problem that results in significant patient morbidity and mortality. Inadequate venous thromboprophylaxis in surgical as well as medically ill patients results in DVT and PE that negatively impact patient outcomes and increase health-care costs. A high index of clinical suspicion combined with an evidence-based use of diagnostic tests helps identify patients with acute thrombosis. Failure to accurately and promptly diagnose and treat DVT and PE can result in excess morbidity and mortality due to postthrombotic syndrome, pulmonary hypertension, and recurrent thrombosis. Conversely, unnecessary anticoagulation provides risk in the absence of any tangible benefit. The immediate commencement of parenteral anticoagulant therapy with intravenous unfractionated heparin or a subcutaneous low molecular weight heparin (LMWH) upon presentation with DVT or PE (often even before objective diagnosis confirmation) is necessary to minimize propagation, embolization, and recurrence rates. We favor weight-based LMWH therapy in most of our patients with DVT because of the ability to treat exclusively or primarily in the outpatient setting. We still admit patients with PE for a minimum duration of 2 days for close observation. Subsequent conversion to oral anticoagulation with warfarin (target INR of 2.0 to 3.0 in most patients) should include an overlap with parenteral therapy of at least 4 to 5 days and until a stable target INR has been achieved. A minimum of 3 to 6 months of anticoagulation is recommended following a first episode of idiopathic DVT and any PE. A shorter course of therapy may be sufficient following a situational (eg, after surgery and postpartum) or calf DVT. Long-term, and at times lifelong, therapy should be considered in patients with thrombosis in the setting of a persistent acquired or inherited hypercoagulable state. Thrombolytic therapy probably should be reserved for young patients with iliofemoral DVT, any patient with a threatened limb due to impending venous limb gangrene, and those with PE who have objective evidence of cardiopulmonary compromise. Unfavorable risk-to-benefit and cost-to-benefit ratios make more extensive use of thrombolytics undesirable. The prevention of the postthrombotic syndrome with fitted, graduated compression garments and age- and gender-appropriate cancer screening are indicated in all patients with DVT in an attempt to minimize morbidity and mortality. Hypercoagulable state testing is indicated when the results of individual tests will significantly impact the choice of anticoagulant, intensity of therapy, therapeutic monitoring, family screening, family planning, prognosis determination, and most of all, duration of therapy.

Acute limb ischemia secondary to peripheral arterial thrombosis is a relatively uncommon but ominous form of vascular accident. Select inherited and acquired hypercoagulable states appear to contribute to an initial arterial thrombosis and, more importantly, recurrent thrombotic events. Mounting interest in hypercoagulability, the increased availability of hypercoagulable state "profiles," and enhanced ability to identify an abnormality in tested patients have promoted widespread testing. Unfortunately, widespread testing has had a limited beneficial impact on the management of acute limb ischemia. Ideally, costly and specialized testing should be limited to situations in which the results will have a tangible impact on patient care. Clear goals of testing should be determined before testing is performed. This article addresses a practical approach to hypercoagulable state testing in patients with acute limb ischemia with a focus on abnormalities that impact patient management.

We report a case of superior mesenteric vein thrombosis resulting from an inflamed duodenal diverticulum with associated inflammation of the uncinate process of the pancreas.