During the last several decades, venous thromboembolism (VTE) has been identified as a preventable health condition. The gaps in clinical practice have led to an increased incidence of VTE. The lack of using existing evidence-based VTE prevention guidelines in practice has limited the implementation of VTE risk assessment stratifications and affected the appropriateness and timeliness of addressing pharmacologic and mechanical prophylaxis. The purpose of the scholarly project was to educate practitioners on existing VTE prevention practice guidelines. The practice-focused question explored whether an educational learning activity on evidence-based VTE prevention guidelines improved the awareness, knowledge, and compliance with existing evidence-based VTE guidelines of practitioners that assess and treat patients at risk for VTE. The theoretical framework for the project was Lewin's change process theory. A total of 38 participants comprised registered nurses (82%), physicians (5%), nurse practitioners (2%), and nonclinical personnel (11%). A program evaluation was provided to determine the effectiveness of the project. The findings showed that practitioners participated in the learning activity to improve knowledge (48%), increase VTE awareness (43%), and would change the management and treatment of patients at risk for VTE (39%). Hospitalized patients at risk for VTE can benefit from the results of this project through a change in clinical practice that might decrease the incidence of VTE and potentially bring about social change by reducing the number of preventable deaths.

Class of 2012 Abstract / Specific Aims: The purpose of this study was to evaluate the effectiveness of various post-operative prophylaxis methods in lung transplant patients by comparing the incidence of venous thromboembolism (VTE) before and after the implementation of a standardized hospital order set at the University of Arizona Medical Center (UAMC) in April 2007. Methods: Paper and electronic medical charts were retrospectively reviewed if patients had a lung transplant date between October 31, 2003 – October 31, 2010. A computerized database was used to collect demographic data, length of stay (LOS), comorbid conditions, prophylaxis type (including dose/frequency), and date/type of thromboembolic events in the post-operative period prior to discharge and up to 1-year post- discharge. Main Results: Ninety-two patient charts were included in the study with 35 charts in the pre-order set (“Before”) group and 57 charts in the post- order set (“After”) group. All baseline characteristics were similar between groups except age (mean age difference 8.1 yrs, p=0.003), use of mycophenolate (Before n=24, After n=54; p=0.002), and use of medications that increase risk of VTE (Before n=6, After n=2; p=0.05). The April 2007 protocol significantly increased the number of patients receiving any method of prophylaxis (p<0.0001). However, receiving prophlyaxis did not significantly reduce event rates or readmissions due to VTE. Conclusions: Although implementation of the April 2007 protocol did not significantly reduce VTE event rates and readmissions, VTE prophylaxis should continue to remain a priority. Adherence to the implemented protocol may reduce the number of patients left without effective methods of prophylaxis.

Venous thromboembolism (VTE) which includes pulmonary embolism (PE), or deep venous thrombosis (DVT) poses an important disease burden, however, much remains unknown about the risk factors that cause it. In recent years, more attention has focused on medications that play a role in the development of drug-induced venous thrombosis. The three studies in this dissertation explore the risk of VTE in relation to the use of specific pharmacologic agents; glucocorticoids, 5ARIs and statins in three distinct patient populations with; asthma, benign prostatic hyperplasia (BPH) and hypercholesterolemia, using different approaches to address the inevitable confounding present in etiologic pharmacoepidemiologic research. Using a nested case-control design for the first two studies and cohort design for the last, we assessed the risk of VTE in relation to timing of drug exposure, duration of use, number, and dose of prescriptions. The base populations comprised subjects who received at least one prescription for any of the pharmacologic agents of interest (during 1995–2015 for study 1 and 2 and 1995–2018 for study 3) in the UK-based Clinical Practice Research Datalink. We used descriptive analyses as well as conditional logistic regression and Poisson regression models to evaluate the relationship between these drugs and the risk of VTE. Study 1 examined the relationship between glucocorticoid use and venous thromboembolism among asthma patients age 20–59. We found that current and systemic glucocorticoid use was associated with an increased risk of VTE, with a dose-response relationship. Study 2 explored the relationship between VTE and 5ARI use compared to alpha blocker use among patients, age 40–79, with BPH. We observed that cumulatively high doses of 5ARI+/-AB increases the risk of incident VTE. In study 3, we examined the relationship between VTE and statin use compared to fibrate use among 40–79-year-old patients with hypercholesterolemia. We observed that statin use decreases the risk of incident VTE. These three studies in a large population-based database of high quality, efficiently evaluate the safety/unintended benefit of glucocorticoids, 5ARIS and statins, with the hope to guide the development of guidelines for their use in prolonged care of asthma, BPH and hypercholesterolemia, respectively. / 2023-08-25T00:00:00Z

Chemotherapy-associated thrombosis is a common complication in cancer patients. Cancer patients have a 5- to 7-fold increased risk for a thrombotic event compared to healthy individuals. While the overall risk for a thrombotic event in lung cancer patients is approximately 1.4%, the rates of thrombosis vary depending on the stage of the disease and the chemotherapeutic agents used. Activation of coagulation after initiation of chemotherapy has been reported in clinical studies. However, the mechanisms by which lung cancer chemotherapy agents modulate coagulation in lung cancer patients are not completely understood. The focus of this thesis is to investigate the mechanisms by which chemotherapy agents cisplatin, carboplatin, gemcitabine, and paclitaxel (in platinum-based combinations) induce procoagulant effects utilizing in vitro and in vivo approaches. First, we investigated the mechanisms by which lung cancer chemotherapy modulates cell-surface tissue factor (TF) activity on endothelial cells (HUVEC), monocytes, and non-small cell lung carcinoma (NSCLC) A549 cells. We observed that treatment of all three cell lines with platinum-based lung cancer chemotherapy increased cell surface TF activity. We found that the increased TF activity on chemotherapy-treated monocytes was due to increased phosphatidylserine (PS) exposure, whereas the increased TF activity on HUVEC and A549 cells was due to protein disulfide isomerase (PDI)-mediated decryption of TF. These studies demonstrate that lung cancer chemotherapy agents can exert procoagulant effects by increasing PS exposure and by inducing TF decryption on healthy and tumour cells. Next, we determined the effects of lung cancer chemotherapy on the generation of microparticles (MP) and the impact of MPs on thrombin generation. Our in vitro and in vivo studies demonstrate that lung cancer chemotherapy agents increase the generation of TF- and PS-positive MPs from tumour cells and that the MPs contribute to thrombin generation in a FVII-dependent manner. We also investigated the role of cell-free DNA (CFDNA) in mediating procoagulant effects induced by lung cancer chemotherapy agents. We found that lung cancer chemotherapy agents induce CFDNA release from healthy host neutrophils and that this leads to additional generation of thrombin by the intrinsic pathway of coagulation. Lastly, CFDNA levels have been shown to increase in cancer models through formation of neutrophil extracellular traps (NETs). Formation of NETs by NETosis, a process by which neutrophils release extracellular web-like structures composed of DNA, histones, and granular proteins, is dependent on histone citrullination by protein arginine deaminase-4 (PAD-4). In addition, PAD4 inhibition prevents NET formation. Therefore, we wanted to demonstrate that the neutrophil-derived CFDNA release induced by lung cancer chemotherapy is PAD4-dependent. Chemotherapy treatment of PAD4 knockout mice failed to increase CFDNA levels. Furthermore, chemotherapy-treatment did not increase thrombin generation in PAD4 knockout mice. This suggests that chemotherapy-induced CFDNA release occurs through NETosis. In conclusion, lung cancer chemotherapy leads to increased thrombin generation which occurs through increased TF decryption, MP generation, and CFDNA release. Therefore, lung cancer chemotherapy results in simultaneous activation of the extrinsic and intrinsic pathways of coagulation. These studies provide novel insight into the mechanisms of lung cancer chemotherapy-associated thrombosis. / Thesis / Doctor of Philosophy (PhD)

Introduction: Thromboprophylaxis recommendations for hospitalized cancer are based on trials done for the general medically patients, as there are no randomized clinical trials(RCTs) looking at thromboprophylaxis in medically ill patients with cancer. Methods: To determine if thromboprophylaxis is safe and effective to prevent VTE these patients, a Systematic Review(SR) was done. A survey was performed to assess: clinical equipoise, trial design and minimally clinically important difference(MCID) for a potential trial. Lastly, a pilot study for an RCT was designed. Results: The pooled RR of VTE was 0.91 (95%CI:0.21 to 4.0;I2:68%) among hospitalized cancer patients receiving thromboprophylaxis compared to placebo. 63.9% believe there is clinical equipoise and 58.3% would consider participating in a RCT comparing different agents/dosing. The MCID for absolute reduction in symptomatic VTE between two arms was 2% and for “acceptable” increase in major bleeding events was 1%. Conclusion: The risk-benefit ratio of current doses of thromboprophylaxis administered to hospitalized cancer patients is unclear and additional RCTs are necessary.

Class of 2012 Abstract / Specific Aims: The purpose of this study was to evaluate the effectiveness of various post-operative prophylaxis methods in lung transplant patients by comparing the incidence of venous thromboembolism (VTE) before and after the implementation of a standardized hospital order set at the University of Arizona Medical Center (UAMC) in April 2007. Methods: Paper and electronic medical charts were retrospectively reviewed if patients had a lung transplant date between October 31, 2003 – October 31, 2010. A computerized database was used to collect demographic data, length of stay (LOS), comorbid conditions, prophylaxis type (including dose/frequency), and date/type of thromboembolic events in the post-operative period prior to discharge and up to 1-year post-discharge. Main Results: Ninety-two patient charts were included in the study with 35 charts in the pre-order set (“Before”) group and 57 charts in the post-order set (“After”) group. All baseline characteristics were similar between groups except age (mean age difference 8.1 yrs, p=0.003), use of mycophenolate (Before n=24, After n=54; p=0.002), and use of medications that increase risk of VTE (Before n=6, After n=2; p=0.05). The April 2007 protocol significantly increased the number of patients receiving any method of prophylaxis (p<0.0001). However, receiving prophlyaxis did not significantly reduce event rates or readmissions due to VTE. Conclusions: Although implementation of the April 2007 protocol did not significantly reduce VTE event rates and readmissions, VTE prophylaxis should continue to remain a priority. Adherence to the implemented protocol may reduce the number of patients left without effective methods of prophylaxis.

Objective Formulation of a clinical practice guideline (CPG) for the use of thromboprophylaxis (TP) in pediatric patients with a central venous catheter (CVC). Participants The development team consisted of five experts and a doctoral candidate acting as the primary author. Evidence The guideline was developed utilizing the Appraisal of Guidelines for Research and Evaluation (AGREE) II framework. A systematic review of the evidence was performed and evidence was graded using the American Academy of Pediatrics (2004) evidence classifications for CPG recommendations. An appraisal team evaluated the guideline quality utilizing the AGREE Plus platform rating the guideline as “highest quality.” Consensus Employing a modified Delphi methodology, members of the development team reviewed available evidence and voted on proposed Key Action Statements (KAS). Consensus is defined as 80% rating the KAS “usually appropriate.” Conclusion Five KAS are included in the final CPG. Each KAS indicates level of evidence, benefit-harm relationship, and level of recommendation. KAS 1. Providers of hospitalized children (0-18 years of age) may assess for VTE risk factors using the Skrocki VTE risk stratification tool if the patient has a CVC. (Evidence Quality:C, Rec. Strength: Option). KAS 2. Providers of hospitalized children should initiate targeted pharmacologic thromboprophylaxis (tpTP) at the time of CVC insertion or hospital admission (if CVC present on admission). (Evidence Quality: B, Rec. Strength: Strong Recommendation) KAS 3. Providers of hospitalized children with a CVC should implement mechanical thromboprophylaxis (mTP) if the child is immobile (Braden Q score <2) or moderate/ high risk for VTE using the Skrocki VTE risk stratification tool and have no contraindications to mTP. (Evidence Quality: B, Rec. Strength: Recommendation). KAS 4. Providers of hospitalized children with a CVC may prescribe systemic pharmacologic thromboprophylaxis (spTP) if the patient is found to be at high risk for VTE using Skrocki VTE risk stratification tool and the patient has no contraindications to spTP. (Evidence Quality: C, Rec. Strength: Option). KAS 5. Providers of hospitalized children should avoid femoral CVCs, multilumen CVCs and/or percutaneous insertion technique if their benefit does not clearly outweigh their risks. (Evidence Quality: B, Rec. Strength: Recommendation).

Introduction: Thromboprophylaxis recommendations for hospitalized cancer are based on trials done for the general medically patients, as there are no randomized clinical trials(RCTs) looking at thromboprophylaxis in medically ill patients with cancer. Methods: To determine if thromboprophylaxis is safe and effective to prevent VTE these patients, a Systematic Review(SR) was done. A survey was performed to assess: clinical equipoise, trial design and minimally clinically important difference(MCID) for a potential trial. Lastly, a pilot study for an RCT was designed. Results: The pooled RR of VTE was 0.91 (95%CI:0.21 to 4.0;I2:68%) among hospitalized cancer patients receiving thromboprophylaxis compared to placebo. 63.9% believe there is clinical equipoise and 58.3% would consider participating in a RCT comparing different agents/dosing. The MCID for absolute reduction in symptomatic VTE between two arms was 2% and for “acceptable” increase in major bleeding events was 1%. Conclusion: The risk-benefit ratio of current doses of thromboprophylaxis administered to hospitalized cancer patients is unclear and additional RCTs are necessary.

Venous thromboembolism (VTE) is a common cardiovascular disease that frequently recurs and is associated with significant numbers of death annually. The influence of the hereditary risk factors is not yet firmly established but twin and family studies suggest that heritability is about 50%. Several genetic risk factors have been identified by genomeHwide association studies (GWAS) but they do not explain all of the missing heritability of VTE. NextHgeneration sequencing (NGS) has revolutionized the genetic analysis of disease and has been used to discover the genes underlying unsolved Mendelian disorders. It has also been used to identify rare alleles which may help explain the missing heritability for complex diseases. The study population of this study consisted of 32 randomly chosen VTE patients from the MATSHstudy (Malmö Thrombophilia Study). The seventeen genes that in earlier studies have been shown to be associated with VTE were examined and the identified VTEHrelated mutations were compared to the general population. The results showed that Ion TorrentHsequencing effectively provided good coverage and read depth in all of the sequenced genes. Optimization of the primer panels resulted in higher and more balanced coverage and the quality of the results in this study was on an overall high level. A total of 215 variants were detected – 62 in exons, 8 in splice and 145 in introns. One Mendelian mutation was detected in PROC and rare variants were found in F2 and FGG. The most common risk factor (F5 Leiden) was highly enriched with 25% in this study compared to 3% in a background population. / Venös tromboembolism (VTE) är en vanlig, ofta återkommande, kardiovaskulär sjukdom som associeras med åtskilliga dödsfall årligen. De ärftliga riskfaktorernas påverkan är inte fullständigt kartlagda ännu men tvillingH och familjestudier antyder att ärftligheten kan vara runt 50%. Ett flertal genetiska riskfaktorer har identifierats genom genome$wide association studies (GWAS) men de förklarar inte hela den saknade ärftlighetskomponenten för VTE. NästaHgenerationsHsekvensering (NGS) har revolutionerat den genetiska sjukdomsanalysen och har använts för att upptäcka de gener som ligger bakom tidigare olösta Mendelska sjukdomstillstånd. Man har även använt NGS för att identifiera rara alleler som kan hjälpa till att förklara de saknade ärftlighetskomponenterna för nedärvning av komplexa sjukdomar. Studiepopulationen I den här undersökningen utgjordes av 32 slumpmässigt utvalda VTEHpatienter från Malmö Thrombophilia Study (MATS). De sjutton gener som I tidigare studier har visat sig vara associerade med VTE undersöktes och de identifierade VTEHrelaterade mutationerna jämfördes med en normalpopulation. Resultaten visade att Ion TorrentHsekvensering ger bra täckningsgrad och läsdjup i alla de sekvenserade generna. Optimering av primerHpanelerna resulterade i en mer balanserad täckningsgrad och resultatkvaliteten i den här studien var på en generellt hög nivå. Totalt 215 varianter detekterades – 62 i exon, 8 i splice och 145 i introner. En Mendelsk mutation detekterades I PROC och rara varianter hittades i F2 och FGG. Den starkaste och vanligaste riskfaktorn (F5 Leiden) var högt anrikad i den här studien med 25% jämfört med 3% i en bakgrundspopulation.

Venous thromboembolism (VTE) is one of the most common cardiovascular diseases. KTH and its academic and industrial partners intend to develop a system to combat VTE by forcing movements of inactive muscles. An important part of this system is a unit that can sense muscular activity over time. Electromyography (EMG) is used to measure the activation potential of muscles. The goal of this thesis is to develop an EMG device that can measure bioelectric signals and convey this data to other devices. This thesis is mainly an exploration to identify the potential solution and more work is needed to develop the required system. The EMG device must be small, modular, battery powered and be able to communicate wirelessly with other devices. A functioning EMG system requires an appropriate amplification for the result to be legible and requires extensive filtering as well as detailed circuit board design to eliminate noise or interference that can affect the result.This project utilized a top down approach. An architecture of the EMG system was made and broken down into functional blocks. Each block was implemented separately and the whole solution was tested experimentally to ensure that all the specifications were fulfilled. To validate the EMG device, a series of reference images were used together with directly observing the correlation between muscle activation and its signal with an oscilloscope.The result was a fully functional EMG device that consisted of two PCB: a PCB with EMG circuitry (analog circuit) and a PCB with digital processing for communication (digital circuit). The EMG results were consistent between test subjects and could easily be correlated to muscle movement and force. The reference images indicated that it was functioning as intended. There was still 50 Hz common mode noise present in the EMG device which could have been due to its wide bandwidth and poor low frequency properties.The goals and requirements were fulfilled: a fully functional wireless, modular, small and battery driven EMG device was developed. The noise level of the EMG could have been lower and would need some further improvements. An integrated battery could be implemented to eliminate the need for users to provide a battery. An app could be developed in tandem with the EMG device, with friendly user interface, for healthcare personnel.The thesis workers strived to minimize the number of used components and power consumption. All components were RoHS certified and discarded components were collected for proper waste management. Energy consumption could have been further minimized in the digital PCB by implementing sleep mode and a watchdog timer. This thesis strived to implement as much of the 17 global sustainability goals set by the United Nations (UN). In conclusion, the main sustainability goal of this thesis was “3 – Good Health and well-being”. Other sustainability goals were “12 – Responsible consumption and production”, “13 – Climate action”, “15 – Life on land” were deemed to have been considered in this thesis. / Venös tromboemboli (VTE) är en av de vanligaste kardiovaskulära sjukdomarna. KTH och dess akademiska och industriella partner avser att utveckla ett system med uppdrag att bekämpa VTE genom att stimulera inaktiva muskler. Elektromyografi (EMG) används för att mäta musklernas aktiveringspotential. Syftet med denna avhandling är att utveckla en EMG-enhet som kan mäta bioelektriska signaler och överföra denna data till andra enheter. Ett fungerande EMG system kräver en lämplig förstärkning för att resultatet ska vara läsbart och kräver filtrering samt utförlig kretskortdesign för att eliminera brus/störningar som kan påverka resultatet negativt.Projektet använde en Top-Down strategi. En arkitektur av EMG-systemet genomfördes och sedan delades upp i funktionella block. Varje block implementerades separat och hela lösningen testades experimentellt för att säkerställa att alla specifikationer uppfylldes. För att validera EMG- enheten användes referensbilder tillsammans med att direkt observera sambandet mellan muskelaktivering och dess signal via ett oscilloskop.Resultatet var en helt funktionell EMG-enhet som bestod av två PCB: en PCB med EMG funktionalitet (analog krets) och en PCB med digital processering för kommunikation (digital krets). EMG mätningarna var konsistenta mellan testpersoner och kunde lätt korreleras med muskelrörelse och spänningskraft. Referensbilderna indikerade att den fungerade som avsedd. Det fanns fortfarande 50 Hz common mode brus i EMG-enheten, vilket kan ha orsakas av dess breda bandbredd och dåliga lågfrekvensegenskaper.Målen och kraven uppfylldes: en fullt funktionell trådlös, modulär, liten och batteridriven EMG- enhet. Brusnivån för EMG kunde ha varit lägre och skulle behöva ytterligare förbättringar. Ett integrerat batteri kunde implementeras för att eliminera användarnas behov av att tillhandahålla ett batteri. En applikation kunde ha utvecklats för EMG-enheten, med ett användarvänligt användargränssnitt, för vårdpersonal.Examensarbetarna strävade efter att minimera användning av komponenter och strömförbrukning under arbetsprocessen. Alla komponenter var RoHS-certifierade och kasserade komponenter insamlades för korrekt avfallshantering. Energiförbrukning kunde ha minimerats ytterligare i det digitala kretskortet genom att implementera sleep mode och en watchdog timer. I detta examensarbete var det önskvärt att implemnetera de 17 globala hållbarhetsmålen uppsatta av FN (Förenta Nationerna). Sammanfattningsvis uppfylldes huvudsakligen “3 – Good Health and well-being”. Hållbarhetsmålen ”12 - Ansvarig konsumtion och produktion”, ”13 – Klimatåtgärder”, ”15 - Liv på land” anses även att ha beaktas i denna avhandling.