Thomas W. Wakefield

Extracellular DNA traps promote thrombosis

Neutrophil extracellular traps (NETs) are part of the innate immune response to infections. NETs are a meshwork of DNA fibers comprising histones and antimicrobial proteins. Microbes are immobilized in NETs and encounter a locally high and lethal concentration of effector proteins. Recent studies show that NETs are formed inside the vasculature in infections and noninfectious diseases. Here we report that NETs provide a heretofore unrecognized scaffold and stimulus for thrombus formation. NETs perfused with blood caused platelet adhesion, activation, and aggregation. DNase or the anticoagulant heparin dismantled the NET scaffold and prevented thrombus formation. Stimulation of platelets with purified histones was sufficient for aggregation. NETs recruited red blood cells, promoted fibrin deposition, and induced a red thrombus, such as that found in veins. Markers of extracellular DNA traps were detected in a thrombus and plasma of baboons subjected to deep vein thrombosis, an example of inflammation-enhanced thrombosis. Our observations indicate that NETs are a previously unrecognized link between inflammation and thrombosis and may further explain the epidemiological association of infection with thrombosis.

The care of patients with varicose veins and associated chronic venous diseases: Clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum

The Society for Vascular Surgery (SVS) and the American Venous Forum (AVF) have developed clinical practice guidelines for the care of patients with varicose veins of the lower limbs and pelvis. The document also includes recommendations on the management of superficial and perforating vein incompetence in patients with associated, more advanced chronic venous diseases (CVDs), including edema, skin changes, or venous ulcers. Recommendations of the Venous Guideline Committee are based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system as strong (GRADE 1) if the benefits clearly outweigh the risks, burden, and costs. The suggestions are weak (GRADE 2) if the benefits are closely balanced with risks and burden. The level of available evidence to support the evaluation or treatment can be of high (A), medium (B), or low or very low (C) quality. The key recommendations of these guidelines are: We recommend that in patients with varicose veins or more severe CVD, a complete history and detailed physical examination are complemented by duplex ultrasound scanning of the deep and superficial veins (GRADE 1A). We recommend that the CEAP classification is used for patients with CVD (GRADE 1A) and that the revised Venous Clinical Severity Score is used to assess treatment outcome (GRADE 1B). We suggest compression therapy for patients with symptomatic varicose veins (GRADE 2C) but recommend against compression therapy as the primary treatment if the patient is a candidate for saphenous vein ablation (GRADE 1B). We recommend compression therapy as the primary treatment to aid healing of venous ulceration (GRADE 1B). To decrease the recurrence of venous ulcers, we recommend ablation of the incompetent superficial veins in addition to compression therapy (GRADE 1A). For treatment of the incompetent great saphenous vein (GSV), we recommend endovenous thermal ablation (radiofrequency or laser) rather than high ligation and inversion stripping of the saphenous vein to the level of the knee (GRADE 1B). We recommend phlebectomy or sclerotherapy to treat varicose tributaries (GRADE 1B) and suggest foam sclerotherapy as an option for the treatment of the incompetent saphenous vein (GRADE 2C). We recommend against selective treatment of perforating vein incompetence in patients with simple varicose veins (CEAP class C(2); GRADE 1B), but we suggest treatment of pathologic perforating veins (outward flow duration ≥500 ms, vein diameter ≥3.5 mm) located underneath healed or active ulcers (CEAP class C(5)-C(6); GRADE 2B). We suggest treatment of pelvic congestion syndrome and pelvic varices with coil embolization, plugs, or transcatheter sclerotherapy, used alone or together (GRADE 2B).

A validation study of a retrospective venous thromboembolism risk scoring method.

Objectives:Validate a retrospective venous thromboembolism (VTE) risk scoring method, which was developed at the University of Michigan Health System and based on the Caprini risk assessment model, and assess the confounding effects of VTE prophylaxis. Background:Assessing patients for risk of VTE is essential to initiating appropriate prophylaxis and reducing the mortality and morbidity associated with deep vein thrombosis and pulmonary embolism. Methods:VTE risk factors were identified for 8216 inpatients from the National Surgical Quality Improvement Program using the retrospective scoring method. Logistic regression was used to calculate odds ratios (OR) for VTE within 30 days after surgery for risk factors and risk level. A bivariate probit model estimated the effects of risk while controlling for adherence to prophylaxis guidelines. Results:Distribution of the study population by risk level was highest, 52.1%; high, 36.5%; moderate, 10.4%; and low, 0.9%. Incidence of VTE within 30 days was overall 1.4%; by risk level: highest, 1.94%; high, 0.97%; moderate, 0.70%; low, 0%. Controlling for length of hospitalization (>2 d) and fiscal year, pregnancy or postpartum (OR = 8.3; 1.0–68, P < 0.05), recent sepsis (4.0; 1.4–10.9, P < 0.01), malignancy (2.3; 1.5–3.3, P < 0.01), history of VTE (2.1; 1.1–4.1, P < 0.05), and central venous access (1.8; 1.1–3.0, P < 0.05) were significantly associated with VTE. Risk level was significantly associated with VTE (1.9; 1.3–2.6, P < 0.01). The bivariate probit demonstrated significant correlation between the probability of VTE and lack of adherence to prophylaxis guidelines (&rgr; = 0.299, P = 0.013). Conclusion:The retrospective risk scoring method is valid and supports use of individual patient assessment of risk for VTE within 30 days after surgery.

Renal Artery Aneurysms: A 35-year Clinical Experience With 252 Aneurysms in 168 Patients

ObjectiveTo define the relevance of treating renal artery aneurysms (RAAs) surgically. Summary Background DataMost prior definitions of the clinical, pathologic, and management features of RAAs have evolved from anecdotal reports. Controversy surrounding this clinical entity continues. MethodsA retrospective review was undertaken of 168 patients (107 women, 61 men) with 252 RAAs encountered over 35 years at the University of Michigan Hospital. Aneurysms were solitary in 115 patients and multiple in 53 patients. Bilateral RAAs occurred in 32 patients. Associated diseases included hypertension (73%), renal artery fibrodysplasia (34%), systemic atherosclerosis (25%), and extrarenal aneurysms (6.5%). Most RAAs were saccular (79%) and noncalcified (63%). The main renal artery bifurcation was the most common site of aneurysms (60%). RAAs were often asymptomatic (55%), with a diagnosis made most often during arteriographic study for suspected renovascular hypertension (42%). ResultsSurgery was performed in 121 patients (average RAA size 1.5 cm), including 14 patients undergoing unilateral repair with contralateral RAA observation. The remaining 47 patients (average RAA size 1.3 cm) were not treated surgically. Operations included aneurysmectomy and angioplastic renal artery closure or segmental renal artery reimplantation, aneurysmectomy and renal artery bypass, and planned nephrectomy for unreconstructable renal arteries or advanced parenchymal disease. Eight patients underwent unplanned nephrectomy, being considered a technical failure of surgical therapy. Dialysis-dependent renal failure occurred in one patient. There were no perioperative deaths. Late follow-up (average 91 months) was available in 145 patients (86%). All but two arterial reconstructions remained clinically patent. Secondary renal artery procedures included percutaneous angioplasty, branch embolization, graft thrombectomy, and repeat bypass for late aneurysmal change of a vein conduit. Among 40 patients with clearly documented preoperative and postoperative blood pressure measurements, 60% had a significant decline in blood pressure after surgery while taking fewer antihypertensive medications. Late RAA rupture did not occur in the nonoperative patients, but no lessening of this group’s hypertension was noted. ConclusionSurgical therapy of RAAs in properly selected patients provides excellent long-term clinical outcomes and is often associated with decreased blood pressure.

Mechanisms of Venous Thrombosis and Resolution

Venous thromboembolism is a significant health care problem in the US. In this review, the unique role of inflammation to the venous thrombotic process is emphasized as well as the potential role of abnormalities of fibrinolytic mechanisms to the thrombotic process. Inflammation influences not only thrombogenesis but also thrombus resolution and vein wall remodeling, and these interactions are also discussed. Knowledge of molecular and immunologic mechanisms for venous thrombosis and its resolution should allow for the future development of targeted therapies.

von Willebrand factor-mediated platelet adhesion is critical for deep vein thrombosis in mouse models.

Deep vein thrombosis (DVT) and its complication, pulmonary embolism, are frequent causes of disability and mortality. Although blood flow disturbance is considered an important triggering factor, the mechanism of DVT initiation remains elusive. Here we show that 48-hour flow restriction in the inferior vena cava (IVC) results in the development of thrombi structurally similar to human deep vein thrombi. von Willebrand factor (VWF)-deficient mice were protected from thrombosis induced by complete (stasis) or partial (stenosis) flow restriction in the IVC. Mice with half normal VWF levels were also protected in the stenosis model. Besides promoting platelet adhesion, VWF carries Factor VIII. Repeated infusions of recombinant Factor VIII did not rescue thrombosis in VWF(-/-) mice, indicating that impaired coagulation was not the primary reason for the absence of DVT in VWF(-/-) mice. Infusion of GPG-290, a mutant glycoprotein Ibα-immunoglobulin chimera that specifically inhibits interaction of the VWF A1 domain with platelets, prevented thrombosis in wild-type mice. Intravital microscopy showed that platelet and leukocyte recruitment in the early stages of DVT was dramatically higher in wild-type than in VWF(-/-) IVC. Our results demonstrate a pathogenetic role for VWF-platelet interaction in flow disturbance-induced venous thrombosis.

P-selectin and leukocyte microparticles are associated with venous thrombogenesis.

OBJECTIVES P-selectin inhibition has been found to limit venous thrombosis. We hypothesize that elevated levels of P-selectin will amplify thrombosis, mediated by procoagulant microparticles (MPs). METHODS Male mice (Mus musculus, n659), 20 to 25 grams, underwent IVC ligation to induce thrombosis. Groups consisted of wild type (WT) C57BL/6 controls, mice with high circulating levels of soluble P-selectin (CT), P-selectin gene-interrupted knockout mice (PKO), and E- and P-selectin gene-interrupted mice (EPKO). Additional groups were used to evaluate the ability of a P-sel antagonist (rPSGL-Ig) and an antibody directed against PSGL-1 to downregulate the effects of P-sel in CT mice and WT mice administered soluble P-sel at time of thrombosis. Animals were sacrificed on days 2 and 6 after IVC ligation. Thrombus mass (TM), vein wall morphometrics, and serum leukocyte/platelet microparticles (MPs) were evaluated by means of double-stained fluorescence-activated cell scanning analysis, and soluble P- and E-sel protein determination by ELISA. RESULTS At days 2 and 6 in phase I of the experiment, significant differences (P <.01) in TM were noted between groups, with CT animals having the largest thrombi (50% and 57% increase in TM compared to WT at days 2 and 6) while EPKO mice had the smallest thrombi. Statistically, greater levels of neutrophils and total inflammatory cells were noted in the vein walls of CT animals at day 2 compared with WT and PKO animals. A significant difference was noted between CT and EPKO for neutrophils, monocytes, and total inflammatory cells, also at day 2. At day 6, the only statistically significant difference was found for monocytes, with a higher number in the CT animals than in WT animals. The evaluation of MPs revealed that the CT mice had a mixed leukocyte (MAC-1) and platelet (CD41) MP population that was also present in WT and PKO mice on day 2 and day 6. EPKO mice revealed a primarily platelet-derived MP population. Of interest, the CT mice with the highest TM showed a high amount of mean channel fluorescence for MAC-1 (phycoerythrin) antibody, indicative of leukocyte MPs. CT mice revealed statistically higher levels of soluble P-selectin at days 2 and 6. In phase 2, an antibody directed against PSGL-1 was more effective than rPSGL-Ig in decreasing TM and limiting leukocyte-derived MP fluorescence. CONCLUSIONS This study demonstrates that high circulating levels of P-selectin are associated with increased thrombosis, whereas a lack of P-selectin and E-selectin is associated with a lessening of thrombosis. Additionally, leukocyte MPs are associated with venous thrombus formation. These data suggest the importance of selectins to venous thrombogenesis and show that P-selectin and leukocyte-derived MPs should be good targets to limit venous thrombus formation.

Clinical characteristics and surgical management of vascular complications in patients undergoing cardiac catheterization: Interventional versus diagnostic procedures☆

The purpose of this report is to define the clinical characteristics and outcome of surgical management of vascular complications after interventional cardiac catheterization and to contrast them to those after diagnostic cardiac catheterization. From October 1985 to December 1989, 101 patients were treated for 106 vascular complications after 1866 interventional and 5046 diagnostic cardiac catheterizations at the University of Michigan Medical Center. Interventional catheterizations resulted in 69 vascular complications in 64 patients (frequency 3.4%). The most common interventions included coronary angioplasty (34), of which 10 required percutaneous partial cardiopulmonary bypass, intraaortic balloon pump placement (14), and aortic valvuloplasty (11). Interventional catheter-related complications included hemorrhage (33), arterial thrombosis (18), pseudoaneurysm formation (12), catheter embolization (2), thromboembolism (2), as well as arteriovenous fistula, pseudoaneurysm, and arterial dissection (1 each). Fifteen of these 69 patients (24%) had suffered acute myocardial infarction just before their catheterization. Surgical repair was performed under local anesthesia in 70% of patients. Major vascular reconstructions were required in 9% of patients. Three percent of the involved lower extremities had to be amputated because of complications occurring after arterial puncture. Eight percent of the patients incurring vascular complications after interventional procedures died after operation. Diagnostic catheterizations resulted in 37 vascular complications in 37 patients (frequency 0.7%). In contrast to diagnostic cardiac catheterization, vascular complications after interventional cardiac catheterization occurred more frequently, were most often due to hemorrhage at the vascular access site, and occurred in high-risk, critically ill patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Management of venous leg ulcers: clinical practice guidelines of the Society for Vascular Surgery ® and the American Venous Forum.

Thomas F. O’Donnell Jr, MD, Marc A. Passman, MD, William A. Marston, MD, William J. Ennis, DO, Michael Dalsing, MD, Robert L. Kistner, MD, Fedor Lurie, MD, PhD, Peter K. Henke, MD, Monika L. Gloviczki, MD, PhD, Bo G. Eklof, MD, PhD, Julianne Stoughton, MD, Sesadri Raju, MD, Cynthia K. Shortell, MD, Joseph D. Raffetto, MD, Hugo Partsch, MD, Lori C. Pounds, MD, Mary E. Cummings, MD, David L. Gillespie, MD, Robert B. McLafferty, MD, Mohammad Hassan Murad, MD, Thomas W. Wakefield, MD, and Peter Gloviczki, MD

Variation in Death Rate After Abdominal Aortic Aneurysmectomy in the United States: Impact of Hospital Volume, Gender, and Age

ObjectiveTo determine whether high-volume hospitals (HVHs) have lower in-hospital death rates after abdominal aortic aneurysm (AAA) repair compared with low-volume hospitals (LVHs). Summary Background DataSelect statewide studies have shown that HVHs have superior outcomes compared with LVHs for AAA repair, but they may not be representative of the true volume–outcome relationship for the entire United States. MethodsPatients undergoing repair of intact or ruptured AAAs in the Nationwide Inpatient Sample (NIS) for 1996 and 1997 were included (n = 13,887) for study. The NIS represents a 20% stratified random sample representative of all U.S. hospitals. Unadjusted and case mix-adjusted analyses were performed. ResultsThe overall death rate was 3.8% for intact AAA repair and 47% for ruptured AAA repair. For repair of intact AAAs, HVHs had a lower death rate than LVHs. The death rate after repair of ruptured AAA was also slightly lower at HVHs. In a multivariate analysis adjusting for case mix, having surgery at an LVH was associated with a 56% increased risk of in-hospital death. Other independent risk factors for in-hospital death included female gender, age older than 65 years, aneurysm rupture, urgent or emergent admission, and comorbid disease. ConclusionsThis study from a representative national database documents that HVHs have a significantly lower death rate than LVHs for repair of both intact and ruptured AAA. These data support the regionalization of patients to HVHs for AAA repair.