Novel Biomarkers Associated with Deep Venous Thrombosis: A Comprehensive Review

Primary and recurrent venous thromboembolic disease (VTE, deep venous thrombosis and pulmonary embolism) remain a significant source of morbidity and mortality in the hospitalized patient. Non-specific subjective complaints and lack of specific objective findings related to acute deep venous thrombosis (DVT) and pulmonary embolism (PE) complicate the diagnosis. There remains no single serum marker available to exclusively confirm the diagnosis of VTE. While D-dimer is highly sensitive and useful for diagnostic exclusion, it lacks the specificity necessary for diagnostic confirmation resulting in the need for a variety of additional studies (i.e.: duplex ultrasound, venography, V/Q scanning, helical thoracic and pelvic CT scans and pulmoary angiography). There is evolving research supporting the utility of various plasma markers as novel “biomarkers” for VTE including selectins, microparticles, interleukin-10 and other cytokines. This review attempts to examine recent literature assessing the utility of P-selectin, microparticles, D-dimer, E-selectin, thrombin, interleukins and fibrin monomers in the diagnosis and guidance of therapy for VTE

Decreased venous thrombosis with an oral inhibitor of P selectin

BackgroundP-selectin inhibition with protein therapeutics such as antibodies or soluble ligands given intravenously can decrease thrombosis in a mouse ligation model of venous thrombosis. In this study, we hypothesized that oral inhibition of P selectin with a novel oral nonprotein inhibitor (PSI-697) would decrease thrombosis and circulating microparticle populations. This study evaluated the effects on thrombosis and circulating microparticle populations in this murine venous thrombosis model.MethodsMice underwent inferior vena cava ligation to induce thrombosis. Mice with high circulating level of P selectin, Delta Cytoplasmic Tail (^CT), mice gene-deleted for both E- and P-selectin knockout (EPKO), and wild-type C57BL/6 mice (WT) were studied without and with administration of PSI-697 in food (100 mg/kg daily) from 2 days before thrombosis until the end of the study. Animals were killed 2 and 6 days later. Evaluations included thrombus weight (TW), vein wall morphometrics, microparticle quantification by using fluorescence-activated cell sorter analysis, and vein wall enzyme-linked immunosorbent assays for interleukin (IL)-10, P selectin, and monocyte chemotactic protein 1.ResultsPSI-697 significantly decreased TW in WT and ^CT mice, with a treated vs nontreated TW of 132 ± 24 vs 228 ± 29 × 10−4 g (P = .014) and 166 ± 19 vs 281 ± 16 × 10−4 g (P = .001), respectively. At day 6, the effect was significant only in the ^CT group (P < .05). Drug therapy at day 2 significantly increased vein wall monocytes in WT mice and increased monocytes and total inflammatory cells in ^CT animals. A significant decrease in neutrophils and total inflammatory cells was seen in EPKO mice at day 2 with therapy. Therapy significantly increased platelet-derived microparticles and total microparticles in ^CT mice on day 2. Changes in treated WT and treated EPKO animals were not significant compared with respective vehicle treatments at day 2. On day 6, therapy significantly decreased total microparticles in EPKO animals. Vein wall expression of IL-10 increased in all groups with therapy at day 2 (n = 18) and was significantly increased in WT (2687.5 ± 903 pg/mL vs 636 ± 108 pg/mL total protein; P = .038) and ^CT (2078 ± 295 pg/mL vs 432 ± 62 pg/mL total protein; P = .001) mice. Therapy significantly decreased vein wall P selectin, monocyte chemotactic protein 1, and IL-10 levels at day 6.ConclusionsPSI-697 decreased thrombosis. P-selectin inhibition allowed vein wall inflammatory cell extravasation in this model of complete ligation. Circulating microparticles (platelet-derived microparticles and total microparticles) increased with P-selectin inhibition, possibly because of decreased consumption into the thrombus. In summary, the oral administration of an inhibitor to P selectin provides significant TW reduction.Clinical RelevanceDeep venous thrombosis is a significant national health problem in the general population. The average annual incidence of deep venous thrombosis is approximately 250,000 cases per year. The selectin family of adhesion molecules is thought to be largely responsible for the initial attachment and rolling of leukocytes on stimulated vascular endothelium. Recent studies have explored the possible therapeutic implications of P-selectin inhibition to modulate venous thrombosis. For example, prophylactic dosing of a recombinant P-selectin ligand decreases venous thrombosis in a dose-dependent fashion in both feline and nonhuman primate animal models. Additionally, treatment of 2-day iliac thrombi with a recombinant protein, P-selectin inhibitor, significantly improves vein reopening in nonhuman primates. It is interesting to note that P-selectin inhibition decreases thrombosis without adverse anticoagulation. On the basis of the results from these previous studies, the use of P-selectin antagonism is a logical therapeutic approach to treat venous thrombosis. All inhibitors developed to date are either proteins or small molecules with low oral bioavailability that require intravenous or subcutaneous injection. This study evaluates, for the first time, a novel orally bioavailable inhibitor of P-selectin (PSI-697)

Intravascular ultrasound imaging as a novel tool for the diagnosis of endofibrosis

Given the rise of high-intensity sport athletes and the paucity of literature on endofibrosis, we describe a novel adjunctive imaging technique to aid in diagnosis. A 41-year-old female triathlete presented with exercise-limiting claudication. Results of lower extremity magnetic resonance angiography, provocative Doppler, angiogram, and digital subtraction angiography with papaverine were nondiagnostic. Intravascular ultrasound imaging was able to delineate an abnormal segment of the proximal external iliac artery with intimal hypertrophy. We report intravascular ultrasound imaging as a superior imaging modality to definitively diagnose endofibrosis and assist proper planning and operative treatment of patients with endofibrosis

A Comparison of Training Experience, Training Satisfaction, and Job Search Experiences between Integrated Vascular Surgery Residency and Traditional Vascular Surgery Fellowship Graduates

BACKGROUND: The first 2 integrated vascular residents in the United States graduated in 2012, and in 2013, 11 more entered the job market. The purpose of this study was to compare the job search experiences of the first cohort of integrated 0 + 5 graduates to their counterparts completing traditional 5 + 2 fellowship programs. METHODS: An anonymous, Web-based, 15-question survey was sent to all 11 graduating integrated residents in 2013 and to the 25 corresponding 5 + 2 graduating fellows within the same institution. Questions focused on the following domains: training experience, job search timelines and outcomes, and overall satisfaction with each training paradigm. RESULTS: Survey response was nearly 81% for the 0 + 5 graduates and 64% for the 5 + 2 graduates. Overall, there was no significant difference between residents and fellows in the operative experience obtained as measured by the number of open and endovascular cases logged. Dedicated research time during the entire training period was similar between residents and fellows. Nearly all graduates were extremely satisfied with their training and had positive experiences during their job searches with respect to starting salaries, numbers of offers, and desired practice type. More 0 + 5 residents chose academic and mixed practices over private practices compared with 5 + 2 fellowship graduates. CONCLUSIONS: Although longer term data are needed to understand the impact of the addition of 0 + 5 graduating residents to the vascular surgery work force, preliminary survey results suggest that both training paradigms (0 + 5 and 5 + 2) provide positive training experiences that result in excellent job search experiences. Based on the current and future need for vascular surgeons in the work force, the continued growth and expansion of integrated 0 + 5 vascular surgery residency positions as an alternative to traditional fellowship training is thus far justified

Graft infection after endovascular abdominal aortic aneurysm repair

IntroductionAlthough the natural history and management of infected open abdominal aortic aneurysm (AAA) repair is well described, only sporadic case reports have described the fate of patients with infected endografts placed in the abdominal aorta. The present study describes a tertiary referral center's experience with infected endovascular aneurysm repairs (EVARs).MethodsThe medical records of 1302 open and endovascular aortic procedures were queried from January 2000 to January 2010. The cases were reviewed for prior aortic procedures, prosthetic implants, and etiology of current open procedure. Demographics, operative details, and perioperative courses were documented.ResultsNine patients (1 woman) with a mean age of 71 years had an EVAR that later required an open procedure for explantation and surgical revision for suspected infection. All grafts were explanted through a midline transperitoneal approach, with a mean time to explant of 33 months. The explanted endografts included 4 Zenith (Cook, Bloomington, Ind), 2 Ancure (Endovascular Technologies, Menlo Park, Calif), 2 Excluders (Gore, Flagstaff, Ariz), and 1 AneuRx (Medtronic, Minneapolis, Minn). Eight of the nine original EVARs were performed at other hospitals; 1 patient had EVAR and open explant at the University of Michigan. All patients had preoperative computed tomography scans, except one who was transferred in extremis with a gastrointestinal hemorrhage. Three patients also had a tagged leukocyte scan, and two had magnetic resonance imaging to further reinforce the suspicion of infection before explantation and bypass planning. Rifampin-soaked Hemashield (Boston Scientific) in situ grafts were used in four patients, with extra-anatomic (axillary-bifemoral) bypass used in the other five. The in situ group had no positive preoperative or postoperative cultures, with the exception of the unstable patient who died the day of surgery. For the other five patients, positive tissue cultures were found for Bacteroides, Escherichia coli, coagulase-negative Staphylococcus, Streptococcus, and Candida. Three patients were found to have aortic-enteric fistula, two of whom died before discharge from the hospital. The remaining seven survived to discharge. Average length of stay was 22 days, with a median follow-up of 11 months.ConclusionThis series of infected EVARs is the largest group of infected AAA endografts reported to date. Because EVAR of AAAs is presently the most common method of repair, development of endograft infection, while rare, can be managed with acceptable mortality rates. Patients presenting with aortic-enteric fistula after EVAR appear to have a more virulent course