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 - 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.

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.

Venous thromboembolism (VTE) is a chronic illness that affects nearly 10 million people every year worldwide. Anticoagulant therapy with direct oral anticoagulants is the mainstay of treatment for patients with VTE, and should be continued for at least 3-6 months. Thereafter, a decision should be made to discontinue anticoagulation or continue it indefinitely. This decision is most challenging for patients with a first unprovoked VTE because of uncertainty in estimates for the long-term benefits (e.g., reduction in recurrent VTE) and harms (e.g., increase in major bleeding) of extended anticoagulation, and the trade-offs between them. The overarching aim of this doctoral thesis was to address these key evidence gaps that are pertinent to making decisions regarding the duration of anticoagulation for patients with a first unprovoked VTE. The first three studies of this thesis synthesized contemporary and reliable estimates for the long-term risks and consequences of recurrent VTE and major bleeding, with and without extended anticoagulation (parameters that can influence the clinical and cost-effectiveness of discontinuing versus continuing anticoagulation indefinitely). Broadly, these systematic reviews and meta-analyses found that: 1) the long-term risks and consequences of major bleeding during extended anticoagulation are considerable, particularly with vitamin K antagonists as well as in older patients, patients using antiplatelet therapy, and in patients with kidney disease, a history of bleeding, or anemia; and 2) the long-term risks of recurrent VTE during extended anticoagulation and major bleeding after discontinuing anticoagulation are reassuringly low but not negligible. The fourth study incorporated the synthesized evidence to compare the lifetime clinical benefits, harms, and costs of discontinuing versus continuing anticoagulation indefinitely. This decision analytic modelling study showed that indefinite anticoagulation is unlikely to either result in a net clinical benefit or be cost-effective in all (i.e., unselected) patients with a first unprovoked VTE. Findings from this thesis can serve to impact clinical practice and health policy by informing patient prognosis to guide shared decision-making regarding the duration of treatment for unprovoked VTE, and informing future research to ultimately identify which patients should receive anticoagulation indefinitely in order to maximize health benefits for the available healthcare resources.

1. Abstract 1.1. Background It is uncertain whether 1) patient’s characteristics (e.g., age, weight, height, and sex) influence anti-Xa heparin levels (hereafter referred to as "heparin levels"), or 2) if heparin levels influence recurrent venous thromboembolism (VTE) or bleeding events, in patients with acute VTE treated with weight-adjusted therapeutic-dose subcutaneous (SC) unfractionated heparin (UFH) or SC low-molecular weight heparin (LMWH). To determine if either association exist, we analyzed data from the Fixed-Dose Heparin (FIDO) study, in which patients were randomized to either SC UFH or SC LMWH, each given in fixed weight-adjusted doses and overlapped with 3 month of warfarin therapy for treatment of acute VTE. 1.2. Methods During the original study, 708 patients were asked to participate in a sub-study that would measure peak heparin levels while they were treated with heparin. 408 patients provided blood samples and met the eligibility criteria for the analyses in this thesis. Linear regression was used to examine the influence of patients’ baseline characteristics (e.g., age, weight, height, body mass index [BMI], sex) on heparin levels. The influence of other factors (e.g., type of heparin [UFH or LMWH]) on heparin levels was also assessed. Logistic regression was used to examine the association of heparin levels with the outcomes of 1) recurrent VTE during 3 months of follow up, and 2) bleeding events in the first 10 days of follow up. 1.3. Results: Mean heparin levels were 0.695 in patients treated with UFH, 0.698 in those treated with dalteparin and 1.034 in those treated with enoxaparin (p<0.001; R2=0.08 for variability accounted for by type of heparin). In a univariable analysis, heparin levels increase by 0.04 IU/ml (95% CI 0.02-0.07; p=0.001; R2=0.03) for every 10-kg increment in weight, by 0.02 IU/ml (95% CI 0.01-0.03; p<0.001; R2=0.04) for each unit of BMI, and by 0.03 IU/ml (95% CI 0.01-0.05; p=0.001; R2=0.03) for every 10 mol/l increment in creatinine. In a multivariable analysis, weight, BMI, and creatinine still influenced heparin levels, after adjusting for type of heparin and timing of blood sample withdrawal. Although heparin levels increased with weight, the magnitude was not large enough to suggest altering the current weight-based dosing method for LMWH. Other baseline factors such as age, height, type of VTE, creatinine clearance and hospitalization status did not influence heparin levels in patients treated with UFH or LMWH. In a univariable analysis, when heparin levels were treated as a continuous variable, higher heparin levels were associated with a lower risk of recurrent VTE at 90-days in patients treated with LMWH (OR 0.04, 95% CI 0.003-0.550, for each 1.0 IU/ml increase in heparin levels), but not in patients treated with UFH (OR 1.46, 95% CI 0.37-5.58, for each 1.0 IU/ml increase in heparin levels). In addition, higher heparin levels were associated with a higher risk of bleeding at 10-days in patients treated with UFH (OR 3.32, 95% CI 1.30-8.46 for each 1 IU/ml increase in heparin levels) but not in patients treated with LMWH (OR 3.77, 95% CI 0.42-33.92, for each 1.0 IU/ml increase in heparin levels). In a multivariable analysis, the association of heparin levels with VTE at 90-days in patients receiving LMWH (lower VTE events) and with bleeding events at 10-days in patients receiving UFH (higher bleeding events) persisted after adjusting for antiplatelet use at baseline and diagnosis of cancer at baseline. When heparin levels were treated as a dichotomous variable (subtherapeutic vs. non-subtherapeutic levels and supratherapeutic vs. non-supratherapeutic levels), the proportion of patient with recurrent VTE was significantly higher in patients with subtherapeutic levels compared with non-subtherapeutic levels in patients receiving LMWH (8.6% vs. 1.3%, p = 0.01). No significant difference was found in the proportion of patients with subtherapeutic levels and non-subtherapeutic levels in patients receiving UFH (0% vs. 3.4%, χ2=0.15, p= 0.70). The test of interaction supported the decision to analyze LMWH and UFH groups separately (p=0.02). Finally, the proportion of patient with bleeding was higher in patients with supratherapeutic compared with non-supratherapeutic heparin levels (6.5% vs. 1.5%, χ2=7.65, p=0.01). The test of interaction did not support the decision to analyze LMWH and UFH groups separately (p=0.13). 1.4. Conclusions Although it was possible to identify factors that were associated with heparin levels in patients who had been treated with weight-adjusted UFH or LMWH, none of these associations were strong enough to suggest that variables other than weight should influence SC heparin dosing. Subtherapeutic heparin levels were associated with a higher risk of recurrent VTE in patients treated with LWMH but not UFH, and supratherapeutic heparin levels were associated with a higher risk of bleeding in patients treated with UFH but not LMWH. Indirectly, these findings suggest that adjusting UFH or LMWH dose in response to heparin levels might improve clinical outcomes. / Thesis / Master of Science (MSc)

Yes / Health Services Research and Pharmacy Practice Conference Abstracts: Partnerships in Healthcare: Advancing Sustainable Medicines Optimisation 17–18 April 2023 University of Bradford.

Determining the prognosis or risk of an individual experiencing a specific health outcome within a certain time period is essential to improve health. An important aspect of prognostic research is the development of risk assessment models (RAMs). In support of the movement towards personalized medicine, health care professionals have employed RAMs to stratify an individual patient’s absolute risk of developing a health condition and select the optimal management strategy for that patient. The development of RAMs is generally conducted using data driven methods or through expert consensus. However, these methods present limitations. Accordingly, we recognized the need to select factors for RAM development or update that are evidence-based and clinically relevant using a structured and transparent approach. In this sandwich thesis, I highlight the methods used to select prognostic factors for VTE and bleeding RAMs for hospitalized medical patients. However, the same methods can be applied to any clinical outcome of interest. This work presents a conceptualized and tested novel mixed methods approach to select prognostic factors for VTE and bleeding in hospitalized medical patients that are evidence-based, clinically meaningful and relevant. Our findings may inform the development of new RAMs, the update of widely used RAMs, and external validation and prospective impact assessment studies. Also, these findings may assist decision makers in evaluating the risk of an individual having an outcome to optimize patient care. / Thesis / Doctor of Philosophy (PhD) / Measuring the probability of an individual experiencing a specific health outcome in a certain period of time based on that individual’s risk factors is important to improve health. Prediction tools are often used to calculate the probability of an outcome. Health care practitioners use prediction tools to assess an individual’s risk of a certain health outcome and in turn provide individualized management. Prediction tools include a number of agreed upon risk factors that should be assessed in order to best estimate the risk of an outcome. These risk factors are usually selected through exploring sets of data or by consulting a group of experts in the field. However, these methods have limitations. Therefore, we recognized that it is important, when developing prediction tools, to select risk factors that are evidence-based and clinically relevant by adopting a systematic, comprehensive, structured and transparent approach. These sets of risk factors can then aid health researchers when developing new prediction tools or updating existing ones and help clinicians predicting risk. In this thesis, I highlight the methods used to select factors for prediction tools that evaluate the risk of having a venous clot or a bleeding event in patients that are hospitalized for a medical condition. However, the same methods can be applied to any clinical condition and outcome of interest. This work presents a new approach that we conceptualized and tested to select risk factors for venous clots and bleeding events in hospitalized medical patients that are evidence-based, clinically meaningful and relevant. Our findings may inform the development of new prediction tools, the update of widely used tools, and the design of studies to validate these tools. Also, these findings may assist decision makers in evaluating the risk of an individual having an outcome to optimize patient care.

The aim of this thesis is to summarize the available data concerning the influence of trombophilic states on the process of pregnancy and to present the results obtained by investigating the prevalence of congenital trombophilia in infertile women and its influence on the success rate of assisted reproduction. It is aimed at those interested in the problematics - be it professionals, medical students or women planning pregnancy or cannot get pregnant. The theoretical part draws data from literature written by leading Czech experts in the field and from scientific journals, included are also foreign sources. The practical part was executed with the kind permission of the PRONATAL s.r.o. centre for assisted reproduction. Key words: venous thromboembolism, trombophilia, trombophylaxis, gravidity, mutation, screening