Chronic Venous Insufficiency (CVI) is characterized by chronic venous hypertension from blood pooling in the lower limbs. The resulting symptoms include leg pain, varicose veins, fatigue, venous edema, skin pigmentation, inflammation, induration, and ulceration. Reflux from incompetent venous valves is a factor in up to 94% of individuals with CVI. Current treatments of CVI include compression stockings, drug therapy, vein disabling, venous stenting, and surgical correction with varying rates of success. However, a minimally invasive correction of deep venous reflux does not currently exist. A transcatheter prosthetic venous valve has the potential to be an effective, minimally invasive treatment for deep venous reflux which could treat up to 1.4 million individuals in the United States suffering from venous ulceration and make more than 1.7 billion dollars each year. Previously developed prosthetic venous valves have had problems with competency, patency, thrombogenicity, biocompatibility, and incorrect sizing. To meet the clinical need a prosthetic valve needs to be developed which succeeds where previous valves have failed. This thesis describes the design, analysis, pre-clinical testing, and evaluation of a novel prosthetic venous valve. Design specifications for an effective prosthetic venous valve were created. Verification tests were developed and performed which demonstrated that the valve met every design specification. Finite element and computational fluid dynamics simulations were performed to analyze the valve and calculated a maximum shear rate of 2300 s-1 in the valve during the high forward flow after a Valsalva maneuver. The valve is made of a biocompatible material that has low thrombogenicity, Poly(vinyl-alcohol) cryogel. On the average, the valve allows less than 0.5 mL/min of reflux at low and high retrograde pressures even after 500,000 cycles, indicating that it will reduce the reflux of individuals with venous reflux by more than 99.4%. The valve closes in less than 0.07 seconds and allows the distal pressure to rise to an average of 7% of the equilibrium pressure 30 seconds after a simulated ankle flexion. The valve increases the outflow resistance an average of 2.3 mmHg*min/L which is much less than obstruction levels,≥ 5 mmHg*min/L. The valve can fit in a 16 French catheter and is capable of percutaneous delivery. The base of the valve is 1.5 times the diameter of the vein in which it is to be implanted to help correct orientation upon deployment. Fluid behind the valve’s leaflets is ejected with a forward flow rate of 400 mL/min, suggesting that thrombus formation will not occur at this location. A stented valve remained patent in a porcine blood flow loop for 3 hours. The valve remains competent without buckling in a constricted vein at rest. The valve can expand to fit a vein with a maximum diameter 1.4 times the valve's initial diameter with low risk of tearing or leaflet prolapse. An IACUC protocol for a 12 week study to test the valve in sheep was prepared and approved. A study to evaluate the valve in humans is proposed with endpoints that can be tested for statistical significance and compared with other treatments for CVI. A set of valves which will correct reflux in the majority of common femoral, femoral, and popliteal deep veins is proposed and a sizing guide for surgeons is provided. The minimum distance between prosthetic valves placed in the same vein segment is 13 cm. A comparison of this valve with previously developed prosthetic venous valves and recommendations for work to be performed in the future are given. The valve proposed in this work is the only valve to meet all design specification for an effective prosthetic venous valve, and therefore shows great potential to be a minimally invasive treatment for deep venous reflux.

No description available.

No description available.

Class of 2009 Abstract / OBJECTIVES: To assess whether patients at University Medical Center (UMC) in Arizona who have indications for venous thromboembolism (VTE) prophylaxis receive treatment, determine whether appropriate pharmacologic VTE prophylaxis is implemented, and analyze the incidence of VTE associated with prescribed regimens. METHODS: Data were derived from a retrospective chart review on risk factors for VTE and prescription of pharmacological and non-pharmacological thromboprophylaxis. Two risk assessment models were used to evaluate adherence to treatment standards: the 2008 American College of Chest Physicians (ACCP) evidence-based consensus guidelines and the Caprini score. Clinical outcomes were evaluated with regard to proper thromboprophylaxis including assessment of appropriate time, type, intensity, and duration of treatment. RESULTS: A total of 366 patients met inclusion critera. Based on the Caprini score, 94% of patients were judged to be at risk for VTE. Of those at risk, 90% received thromboprophylaxis; however, only 35% of treated patients received proper thromboprophylaxis. Ten patients (2.7%) experienced a VTE during their hospital stay or within the following 6 months after discharge. There was not a significant difference in incidence of VTE with respect to treatment versus no treatment or proper versus improper prophylaxis (p=0.15 and 0.65, respectively); however, a favorable trend in incidence of VTE was observed for treated patients and patients treated with correct thromboprophylaxis based on risk assessment. CONCLUSIONS: Most patients at UMC who were indicated for VTE prophylaxis received treatment; however, the type, intensity, and duration of thromboprophylaxis were often inappropriate despite the existence of various guidelines.

La maladie thromboembolique veineuse (MTEV) résulte de l’interaction entre des facteurs environnementaux et génétiques. Cinq anomalies constitutionnelles constituent le bilan de thrombophilie (BT) : les déficits en AT, PC et PS, le facteur V Leiden et la mutation de la prothrombine. Seule la moitié des déficits « présumés » en PS trouvent une explication moléculaire. Dans le premier article, seuls les patients présentant une mutation délétère du gène de la PS (PROS1) étaient à risque de MTEV. Seuls des taux <30%, permettaient de dépister les mutations délétères. La mutation Heerlen située sur PROS1 est réputée neutre. Dans le second article, la mutation Heerlen était associée à un risque de MTEV de 6,57. De récentes études ont identifié une trentaine de polymorphismes associés à la MTEV. Cependant, leur impact dans les familles présentant un facteur biologique de risque est méconnu. De même, l’impact de facteurs environnementaux tels que l’obésité et le tabagisme est mal évalué dans ces familles. Dans le troisième article, la prise en compte de 5 facteurs de risque fréquents à effet faible (obésité, tabac, groupe sanguin et deux polymorphismes situés sur F11 et FGG) en complément du dépistage de l’anomalie familiale permettait de mieux caractériser le risque individuel. Nous avons testé la même stratégie dans une population spécifique de femmes sous contraceptifs oraux combinés (4ème article). Trois facteurs de risque fréquents (groupe sanguin, obésité et un polymorphisme de F11) étaient associés à un OR de 13 lorsqu’ils étaient combinés. Au total, la prise en compte de facteurs de risque fréquents à effet faible, permettait une meilleure évaluation du risque individuel. / Venous thromboembolism (VT) results from the interaction between environmental and genetic factors. Five inherited hemostatic defects are part of the thrombophilia screening (TS): AT, PC and PS deficiencies, factor V Leiden and prothrombin mutation. A molecular defect is identified in only half of assumed PS deficiencies. In the first article, only detrimental mutations (DM) located on PROS1 (PS gene) increased VT risk. Only free PS levels below 30% enabled the identification of DM. PS Heerlen mutation located within PROS1 has been considered neutral for a long time. In the second article, the association between PS Heerlen and VT has been tested in a sample of 4173 patients with VT history and 5970 healthy individuals. PS Heerlen was associated with a 6.57 increased risk of VT. Recent genome wide association studies identified nearly 30 polymorphisms associated with VT. However, the impact of such polymorphisms in families with known defects is uncertain. We therefore tested in a third article the association between 11 selected polymorphisms, obesity, smoking and VT in 651 families with known thrombophilia. Considering 5 common risk factors (obesity, smoking, ABO blood group, two polymorphisms located on FGG and F11) together with the TS resulted in a better assessment of VT risk in individuals from families with thrombophilia. We then applied the same strategy in a sample of women using combined oral contraceptives. Three common risk factors (non-O blood groups, obesity and a polymorphism located on F11), when combined, were associated with a 13 OR. In conclusion, considering common risk factors improved the individual assessment of VT risk.

Superficial venous thrombosis (SVT) is a common inflammatory and thrombotic pathology occurring within a superficial vein. SVT can result in distressing symptoms of redness and pain in the affected area and exposes patients to a risk of developing deep vein thrombosis (DVT) and pulmonary embolism (PE). Various therapeutic options are available to patients including anti-inflammatories, anti-coagulation and surgical procedures, however which of these therapies is the best first line treatment remains unknown. Several randomized controlled trials have been conducted addressing this question, yet methodological and design flaws have limited the translation of their results into a change of clinical practice. The following thesis consists of a multi-step process of reviewing the evidence to date followed by a process of engaging with clinician stakeholders with the goal of designing a randomized control trial that would provide a meaningful answer to patients and their clinicians. In the first step of this process, a systematic review of the literature was performed, including a meta-analysis to estimate pooled risk of developing symptomatic venous thromboembolic (VTE) complications in patients with isolated SVT following various treatments. These results were then presented to expert Canadian clinicians in a series of surveys using a Delphi process to determine the clinical trial design that would have the greatest impact on changing clinical practice. An additional survey of expert clinicians was conducted to determine current practice variation in the diagnosis, management, and follow up of patients with SVT, in order to design a clinical trial that best reflected current standard Canadian clinical practice. Our systematic review identified 15 articles and including 5775 patients. Quality and assessment of risk of bias was moderate for most included studies. The findings of our meta-analysis identified that Fondaparinux, at prophylactic dose, to had the lowest event rate of 2.0 events per 100 patient years of follow-up (95% CI 0.4 to 4.7, I2=33%) for the primary outcome of deep vein thrombosis (DVT) or pulmonary embolism (PE) during follow-up. Pooled event rates ranged from 8.6-16.6 events per 100 patient-years across other treatment categories, including placebo/observation only, with an event rate of 10.5 events per 100-patient years (95% CI 3.0 to 22.0). Heterogeneity was moderate to high for most pooled estimates, limiting the interpretation of these findings. Our survey of practice variation among expert Canadian clinicians revealed wide practice variation in in diagnosis and therapeutic management including sub-groups (e.g. cancer). There was agreement that clinical equipoise exists for the optimal treatment of SVT (77% of respondents), supporting the need for further research. Two rounds of surveys were performed using Delphi process methods, resulting in consensus for the design of a future randomized control trial (RCT). The agreed on design was for a randomized control trial comparing a direct oral anticoagulant (DOAC) such as Rivaroxaban, to Non-Steroidal Anti-Inflammatories (NSAIDs), using a non-inferiority RCT design with a non-inferiority margin of 3%. Future direction of this research will be to continue stakeholder engagement by engaging patients in the clinical trial design, followed by development of a pilot RCT protocol and application for peer-reviewed funding.

Aims: The Pulmonary Embolism in Syncope Italian Trial reported 17.3% prevalence of pulmonary embolism (PE) in patients admitted with syncope. We investigated the prevalence of venous thromboembolism [VTE, including PE and deep vein thrombosis (DVT)] in syncope vs. non-syncope admissions and readmissions, and if syncope is an independent predictor of VTE. Methods and results: We conducted an observational study of index admissions of the 2013-14 Nationwide Readmission Database. / National Institutes of Health / Revisión por pares

Background: A D-dimer threshold <500ug/L has high negative predictive value (NPV) for venous thromboembolism (VTE), but is non-specific. Two strategies increase the specificity and utility (defined as the proportion of patients with a negative test) of D-dimer testing: 1) using a higher D-dimer threshold with increasing age (IAIT Strategy); and 2) using a high threshold in low clinical pretest probability (CPTP) patients and the standard threshold in moderate CPTP patients (CPTP Strategy). It is unknown whether the gain in specificity of the IAIT Strategy is simply due to using a higher threshold in some patients and whether the CPTP Strategy has better diagnostic accuracy than the IAIT Strategy. Methods: In a retrospective analysis of 1649 outpatients with suspected VTE, I compared the diagnostic accuracy of the IAIT Strategy to 1) its opposite: using a higher D-dimer threshold with decreasing age (DAIT strategy); 2) using a higher D-dimer threshold in all patients (Median Age Strategy); and 3) the CPTP Strategy. Results: The NPV of both the IAIT and DAIT Strategies was 99.6% and the NPV of the Median Age Strategy was 99.7%. The utility was almost identical in the IAIT and DAIT Strategies (50.9% vs. 50.6%) and greater in the Median Age Strategy (53.9%, p<0.001). The NPV of the CPTP and IAIT Strategies were 99.6% and 99.7%, respectively. The utility was higher in the CPTP Strategy than the IAIT Strategy (56.1% vs. 50.9%, p<0.001). Conclusions: The NPV and utility of using a higher D-dimer threshold in older patients (IAIT Strategy) is the same as using a higher D-dimer threshold in younger patients. The CPTP Strategy had the greatest utility while maintaining a high NPV and therefore appeared to be the optimal strategy of D-dimer interpretation. / Thesis / Master of Health Sciences (MSc)

This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu).

Over seven million Americans suffer from Chronic Venous Insufficiency (CVI), a painful and debilitating disease that affects the superficial and deep veins of the legs. Problems associated with CVI include varicose veins, bleeding, ulcerations, severe swelling, deep vein thrombosis, and pulmonary embolism, which may lead to death. The presence of CVI results from damaged (incompetent) one-way vein valves in leg veins. These valves normally allow forward flow of blood to the heart, and prevent blood from pooling at the feet. However, incompetent valves allow reflux of blood, causing clinical problems. There are few effective clinical therapies for treating CVI. Vein valve transplantation is a surgical option for treatment. However, it is often difficult to find suitable donor valves. Very few prosthetic valves developed in the past have demonstrated sufficient clinical or mechanical functionality. Persistent problems include thrombus formation, leaking valves, and valves that do not open at physiologic pressure gradient. The primary objective of this research was to develop a clinically relevant functional prosthetic vein valve. The novel prosthetic valve is flexible, biocompatible, has low thrombogenecity, and is easy to manufacture. It was designed to address well-defined consumer needs and functional design requirements. The valve was required to 1) withstand 300 mmHg of backpressure with leakage less than 1.0 mL/min, 2) open with a pressure gradient less than 5 mmHg, and 3) meet criteria 1 and 2 after 500,000 cycles of operation. The valve met these design requirements in bench testing. The valve can open with a pressure gradient of 2.6 0.7 mmHg, and can withstand 300 mmHg with leakage less than 0.5 mL/min. The valve remained functional after opening and closing over 500,000 times. The valve presented in this research is operationally functional, and is a potential solution for treating venous incompetence in CVI patients.