Allogenic blood transfusions, although potentially life-saving, are associated with increased risk of infection, fluid overload, thrombosis, and death. Minimizing exposure to blood products is important for patients and the healthcare system. Antifibrinolytic lysine analogues are effective antihaemorrhagic agents used for the reduction of blood loss and subsequent need for transfusion. However, the pharmacologic mechanism of decreased clot breakdown would suggest the medications should increase the risk of venous thromboembolic adverse events. Trials of lysine analogue administration are often underpowered to detect the effect of these medications on thrombotic events. As lysine analogue use increases for blood loss reduction, there is an important need for research dedicated to the safety of lysine analogues, especially in patients who are at highest risk of venous thromboembolism. Through systematic review and meta-analyses, we investigated the use of lysine analogues in cancer patients, where VTE is particularly prevalent. We identified that only a small number of trials have been performed in cancer patients. Among available data, similar reduction of transfusion was observed in cancer patients treated with lysine analogues compared to non-cancer patients. However, we also found that existing data was grossly underpowered to determine the effect of lysine analogues on risk of VTE (Peto odds ratio (OR) 0.60; 95% CI 0.28-1.30). By administering lysine analogues topically, as opposed to intravenously, systemic absorption of the drug may be limited, and the occurrence of unwanted side-effects may be minimized. We also reviewed the published literature to determine if there was sufficient evidence to support topical application of tranexamic acid. Topically applied tranexamic acid effectively reduces both transfusion risk and blood loss and no increased risk of VTE events was observed (pooled OR=0.78, 95% CI 0.47 to 1.29). However, none of these studies included cancer patients and the vast majority of the trials were in orthopedic surgery. Lastly, we sought to determine the extent to which lysine analogues are currently used at a large tertiary care academic institution. In addition, we explored which factors influenced lysine analogue use, and areas of informational or study need. Surgeons reported low lysine analogue use, and the timing of administration varied considerably. Many surgeons (66%) believed a clinical trial was needed to demonstrate the efficacy of lysine analogues in their respective surgical field, and 59% felt a trial was needed to demonstrate that the medication was safe in their patient population. We confirmed that there are only a few studies evaluating the effect of lysine analogues in cancer patients and that many surgeons are concerned about the safety profile of these medications. Surgeons may feel more comfortable administering these agents topically as opposed to intravenously, and while this may be a safer option, there has been limited evaluation of this approach outside of orthopedic procedures.

Background: Arterial cannulation and intra-arterial (IA) fluid and blood resuscitation in the patients with severe shock is an easier approach compared with the intravenous (IV) access if concerns regarding the efficiency and safety of this approach are addressed. Objectives: We hypothesized that IA fluid resuscitation is more effective than IV resuscitation in restoring cardiac contractions (CC) of cardiac-arrested mice following severe hemorrhagic shock. Methods: Mice (N = 22) were anesthetized using ketamine/xylazine. Arterial and venous systems accessed through cannulation of the carotid artery and the Jugular vein, respectively. As much blood as possible was aspirated from the carotid artery access. Mice were observed until the complete cessation of chest wall motions. Following 30 seconds delay, IV (N = 5) and IA access (N = 6) were used for fluid resuscitation using Ringer Lactate (RL) in a similar volume to the aspirated blood. Mice were observed for restoration of chest wall motions. In phase-II of the study, after cessation of chest motions, mice (N = 11) underwent a thoracotomy and CCs were observed. In three mice, IV RL Infusion after cardiac arrest failed to restore CCs and was followed by IA RL infusion. In eight mice, following cardiac arrest intermittent IA RL infusion was performed. Results: While IV RL Infusion failed to restore chest motion in mice (N = 5), IA RL infusion restored chest motion in all mice examined (N = 6) (P = 0.0067). In three mice, IV RL infusion after cardiac arrest showed no effect on CC. After failure of venous infusion, IA RL infusion was performed which resulted in restoration of CC for 13.33 +/- 1.76 minutes. In eight mice, intermittent IA infusion of RL after cardiac arrest, sustained CC for 31.43 +/- 10.9 minutes (P = 0.017). Conclusions: IA fluid resuscitation is superior to IV resuscitation in hemorrhagic shock induced cardiac arrest.

Background - Current guidelines suggest that all cancer patients with venous thrombosis be treated with long-term low molecular weight heparin. Whether treatment strategies should vary according to clinical characteristics remains unknown. // Systematic review - A systematic review was performed to determine current understanding of the association between malignancy characteristics in patients with cancer-associated VTE and the risk of VTE recurrence. Four retrospective and 6 prospective studies were included. They suggest that lung cancer, metastases, and adenocarcinomas confer an increased the risk of recurrence and breast cancer a low risk. // Survey - I performed survey to evaluate thrombosis experts’ opinion about the low risk of VTE recurrence they would consider acceptable for patients with cancer- associated thrombosis 103 specialists participated. 80% of respondents agreed that a risk of recurrent VTE during anticoagulation below 7% is low enough. 92% agreed that a CPR that categorizes risk of recurrence is relevant. // Retrospective Study - I performed a single retrospective cohort study to assess the feasibility of derivation of a CPR that stratifies VTE recurrence risk in patients with cancer–associated thrombosis. The study included 543 patients. A multivariate analysis selected female, lung cancer and prior history of VTE as high risk predictors and breast cancer and stage I disease as low risk. // Conclusion - Patients with cancer-associated thrombosis do have varying risks of recurrent VTE depending on clinical characteristics.

Statement of the problem The primary objective of this thesis was to determine the best study design to evaluate the safety and effectiveness of an intermediate dose of low molecular weight heparin for secondary prevention of pregnancy associated VTE (PAVTE). An RCT was deemed unfeasible,so the use of a single arm study with prior evaluation of feasibility with a pilot study is proposed. // Methods - A systematic review was conducted to evaluate the efficacy of current strategies used for secondary prevention of PAVTE.A survey was used to elicit the non-inferiority margin. // Results - The pooled proportion of recurrent VTE in patients treated with full dose LMWH was 0.012(95% CI 0.006 to 0.02) and the rate of major bleeding was 0.025(95% CI=0.01 to 0.041). The non-inferiority margin was elicited at 2.5%. // Conclusions - Although a randomized controlled trial should be conducted whenever possible, in certain scenarios they are unfeasible. Therefore, an alternative study design should perhaps be used to evaluate the safety and efficacy of therapeutic strategies.

Introduction: Venous disease impairs the quality of life, necessitates time off work and causes venous ulcers. The focus of this thesis is to explore strategies to prevent chronic venous insufficiency (CVI) and venous ulceration. Aims 1. To identify a population at risk of developing venous ulcers 2. To study the pressure profile required by elastic stockings to halve transit venous time 3. To explore the role of compression following ankle fracture Methods: Data was collected from 231 patients with venous ulcers and age and sex matched 210 controls to identify risk factors for venous ulceration. Univariate and multivariate analysis of potential risk factors was undertaken to identify those that independently predict this risk. After identifying the population at risk, prophylactic strategies were developed. The effect of Engineered Compression Stockings (ECS) delivering 15mmHg, 25mmHg and 35mmHg pressure at the ankle on the calf venous transit time and volume was measured to determine the ideal pressure profile required to halve transit venous time, which should be appropriate for DVT prophylaxis. A dorsal foot vein was cannulated in 15 healthy volunteers with no venous disease. The transit time (secs) for ultrasound contrast from a foot vein to the popliteal vein was measured using duplex ultrasound. Calf volumes were recorded by water displacement. ECS delivering 25mmHg of pressure around the ankle were compared with no compression in a randomized controlled trial (RCT) in 90 patients within 72 hours of ankle fracture. Patients were randomised to either i) ECS and air-cast boot or ii) a liner and air-cast boot and were followed at 2, 4, 8, 12 weeks and 6 months. The primary outcome was functional recovery measured using the Olerud Molander Ankle Score (OMAS). Secondary outcomes were i) The American Orthopaedic Foot and Ankle Score (AOFAS), ii) SF12v2 Quality of Life score (QoL), iii) pain, and iv) frequency of DVT. Results The risk factors significantly associated with venous ulceration on multivariate analysis included a history of Deep Vein Thrombosis (DVT), phlebitis, hip replacement, poor mobility, weight/kg>100Kg, varicose veins (VV), family history of VV and weight (kg) between 75-100kg. A simple diagnostic scoring system was derived from this regression analysis with scores of . 3 predicting a 6.7% annual risk and of < 1 a 0.6% risk. Mean transit time without compression was 35, 32 and 33 secs while standing, sitting and lying. Transit time was consistently halved by ECS delivering 25mmHg to 14, 13 and 14 secs respectively (p<0.001). Mean leg volume whilst standing was reduced significantly from 3447ml with no ECS to 3259ml, 3161ml and 3067ml with ECS applying 15, 25 and 35mmHg respectively (p<0.001). ECS in ankle fracture patients reduced ankle swelling at all time points and significantly improved mean OMAS score at six months to 98 compared with 67 for the liner (p<0.001). AOFAS and SF12v2 scores were also significantly improved (p<0.001, p= 0.016). Of 86 patients with duplex imaging at four weeks, only five (12%) of the 43 ECS patients had a DVT compared with 10 (23%) of the 43 controls (p= 0.26). Conclusions: The risk score for venous ulcers will allow us to undertake RCTs on the prevention of leg ulceration. The pressure profile required to halve transit venous time is 25mmHg. The frequency of asymptomatic DVT following ankle fracture is sufficient to justify prophylaxis. Compression has a potential role in the management of ankle fractures by improving functional outcome and QoL. These studies facilitate research into the prevention of venous disease.

A blood transfusion may have important immunomodulatory effects and may carry certain risks which could be detrimental to the kidney transplant patient. The aim of this project is to examine the potential risks associated with post-transplant blood transfusions in kidney transplant recipients. We carried out a retrospective cohort study of all adult kidney transplant recipients at The Ottawa Hospital from 2002 to 2018 inclusive. We examined the risks for kidney transplant rejection, graft loss, death, infections and venous thromboembolic events (VTE) associated with the receipt of red blood cell transfusions (RBCTs) administered after kidney transplant. We calculated hazard ratios (HR) using Cox proportional hazards model with RBCT as a cumulative, time-varying exposure. Out of a total study population of 1,258 kidney transplants recipients, 37% received at least one RBCT. The receipt of a RBCT was not significantly associated with the risk for rejection, however it was associated with an increased risk for graft loss, death, infection and VTE. Important biases such as reverse causation and unmeasured confounding may account for some of these findings. That being said, our findings suggest clinicians should be judicious in their use of RBCT in kidney transplant patients.

COVID-19 is an infectious disease caused by the novel coronavirus. It presents as an acute respiratory illness, however, it also affects multiple other organ systems. One such unique manifestation is systemic coagulopathy involving arterial and venous systems. We present a 29-year-old woman with Hodgkin's lymphoma, who was diagnosed with COVID-19 infection prior to initiating chemotherapy. Two months after resolution of symptoms and testing negative for COVID-19, she presented with multiple acute thromboembolic complications of the infection, including bilateral jugular venous thrombosis, right atrial clot and arterial emboli in the brain resulting in cerebrovascular injury. These were thought to be delayed manifestations of the systemic coagulopathy secondary to infection. Also, some of these thromboembolic phenomena occurred while the patient was on anticoagulation, which emphasises the extensive hyperinflammatory state caused by the virus. This case highlights the importance of thromboprophylaxis especially in high-risk patients with this infection.

Colon cancer is a significant risk factor for development of venous thromboembolism (VTE). We assessed trend and outcomes of VTE among hospitalized patients with colon cancer from a Nationwide Inpatient Sample. VTE is associated with higher inpatient mortality and disability but not with length of stay. Hospitalization related to VTE in colon cancer is increasing but mortality continues to decline. Introduction Venous thromboembolism (VTE) is a major cause of morbidity and mortality in hospitalized patients with colon cancer. We assessed nationwide population-based trends in rates of hospitalization and mortality from VTE among patients with colon cancer to determine its impact. Methods We queried the Nationwide Inpatient Sample (NIS) database entries from 2003 to 2011 to identify patients with colon cancer. Bivariate group comparisons between hospitalized patients with colon cancer with VTE to those without VTE were made. Multivariate logistic regression analysis was used to obtain adjusted odds ratios. The Cochrane-Armitage test for linear trend was used to assess occurrences of VTE and mortality rates among patients with colon cancer. Results The total number patients with colon cancer was 1,502,743, of which 41,394 (2.75%) had VTE. The median age of the study population was 69 years; 51.5% were women. After adjusting for potential confounders, compared with those without VTE, patients with colon cancer with VTE had significantly higher inpatient mortality (6.26% vs. 5.52%, OR 1.15, P < .001) and greater disability at discharge (OR 1.38, P < .001), but were not associated with longer length of stay (LOS) or cost of hospitalization. From 2003 to 2011, despite an increase in hospitalization rate with VTE in patients with colon cancer, their mortality steadily declined. Conclusion VTE in hospitalized patients with colon cancer is associated with a significantly higher inpatient mortality and greater disability, but not with longer LOS or cost of hospitalization. Furthermore, even though there has been a trend toward more frequent hospitalizations in this patient population, their mortality continues to decline.

Introduction: Haemodialysis arterio-venous fistula aneurysm (AAVF) prevalence varies between 7-43%. When they are symptomatic, they should be referred for treatment. It is unclear which is the optimal surgical treatment and if fistula flow reduction is beneficial for heart remodeling in patients with high-flow AAVF. Aims: (1) introduction of a new surgical technique - aneurysmorrhaphy using exoprothesis (AuE) and evaluation of its patency and complication rates. (2) analysis of flow reduction impact on heart remodeling in high-flow AAVF. (3) systematic review and meta- analysis of various surgical techniques to identify the best treatment option of haemodialysis arterio-venous fistula aneurysm. Methods: (1) retrospective analysis with prospectively collected surgical and postoperative data, patency evaluation using Kaplan - Meier curve, early and late complication rates analysis. (2) retrospective analysis prospectively collected echocardiographic parameters before and after surgery. (3) systematic review and meta- analysis following the PRISMA guidelines - registered in the international prospective register of prospective reviews PROSPERO (registration number: CRD42016029692). Results: (1) primary assisted patency rate at 12 months was 80 %, infection rate was 4.5 % and AAVF recurrence rate was 0...

Bakgrund I Sverige lever idag cirka 50 000 personer av venösa bensår och det är framför allt äldre personer som är drabbade. Patienter blir utsatta för fysiskt, psykiskt och socialt lidande, därtill upplevelse av vården samt ekonomiska konsekvenser. I vårdrelationen mellan patient och vårdgivare finns en viss risk att sjuksköterskor enbart fokuserar på såren och inte möter patientens unika behov. Denna studie fokuserar på de vardagliga upplevelserna av patienter med venösa bensår. Syfte Syftet med denna studie är att belysa patienters upplevelser av att leva med venösa bensår. Metod En litteraturöversikt används som metod i denna studie. Aktuell forskning i form av kvalitativa och kvantitativa vetenskapliga artiklar som bygger på empiriska studier söktes och granskades kritiskt, för att sedan sammanställas i en bedömninsgsmall. Vid sökning användes databaserna CINAHL och PubMed. Sökorden som användes i datainsamlingen var "venous ulcer", "experience", "quality of life" och "suffering". Totalt 16 artiklar inkluderades i resultatet. Resultat Resultatet sammanställdes i tre teman. Dessa teman var "Upplevelse av ångest och depression på grund av smärta och lukt från såret", "Smärta, lukt och läckage leder till social isolering och minskad funktionsförmåga" och "Beroende av sjukvård och närstående leder till förlorad självbestämmande". Slutsats Patienter med venösa bensår har en rad olika upplevelser som sammanhänger och påverkar varandra. Att sjuksköterskan lyssnar och visar empati för patientens egen upplevelse kan ge effektiv symptomlindring och kan vara avgörande för förbättring av livskvalitet för denna patientgrupp. Att ha ett holistiskt synsätt på patienten ökar sjuksköterskans möjlighet att utforma vården utifrån patientens upplevelser och därmed lindra lidande.