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.

To review the literature on treatment of venous thromboembolism (VTE) and prevention of cardioembolic stroke with direct-acting oral anticoagulants (DOACs) in low- and high-body-weight patients and to make recommendations regarding agent selection and dosing in these patient populations. Summary: The selection and optimal dosing of DOACs in low- and high-body-weight patients has not yet been fully elucidated by clinical trials; however, evidence suggests that issues of both safety and efficacy in patients at the extremes of body weight may warrant careful consideration when selecting a DOAC for such patients. This review provides a thorough discussion of the use of DOACs in the treatment of VTE and prevention of cardioembolic stroke in patients at the extremes of body weight and provides guidance regarding agent selection. Conclusion: While the published evidence on use of DOACs in patients at extremes of body weight is sparse, apixaban and rivaroxaban appear to have the most favorable safety and efficacy profiles. Edoxaban and dabigatran should be avoided.

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.

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.

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

Orientador: Izolete Aparecida Thomazini Santos / Coorientador: Celso Roberto Passeri / Banca: Meliza Goi Roscani / Banca: Cleuza Camilo Atique / Resumo: O tromboembolismo venoso (TEV) é uma patologia grave de alta incidência mundial, e, quando não diagnosticada precocemente e tratada adequadamente, pode evoluir causando sérias complicações como a trombose venosa profunda (TVP) e a embolia pulmonar (EP). Em pacientes oncológicos essas afecções são responsáveis por altas taxas de morbidade e mortalidade. Foi realizado um estudo observacional, descritivo e retrospectivo, para avaliar os prontuários de pacientes com suspeita de diagnóstico de trombose venosa profunda no Hospital Amaral Carvalho no ano de 2011. Nesse estudo, obtivemos 118 pacientes com suspeita de TVP, estes foram divididos em dois grupos, sendo G1 grupo de pacientes em tratamento clínico e G2, grupo de pacientes em tratamento cirúrgico, com idade variando de 04 a 91 anos. Destes, trinta e oito pacientes tiveram o diagnóstico de TVP confirmado por exame US-Doppler, considerado padrão ouro. A evolução da TVP se deu nos membros inferiores e superiores. As principais comorbidades apontadas foram hipertensão, diabetes e problemas cardiovasculares. Percebeu-se também recorrência e reinternações devido à evolução da TVP. Durante a realização do presente estudo, demonstrou-se principalmente que pacientes hospitalizados com câncer têm um alto risco para evolução ao tromboembolismo venoso e, muitas vezes, este risco pode ser diminuído com o uso de tromboprofilaxia farmacológica ou prevenção mecânica. Diante disso, o estudo contribui para proposta de protocolo na prevenção do tromboembolismo venoso profundo em pacientes oncológicos. Por intermédio desta proposta, o profissional da enfermagem se sentirá mais preparado para avaliar e prevenir a evolução da intercorrência durante o tratamento oncológico, assim como estará estruturado e apto a pontuar o grau de risco durante os encontros da Comissão de Tromboembolismo Venoso / Abstract: Venous thromboembolism (VTE) is a severe disease with high incidence worldwide, and, if it is not diagnosed early and properly treated, VTE can evolve and cause serious complications such as deep vein thrombosis (DVT) and pulmonary embolism (PE). In cancer patients these diseases are responsible for high morbidity and mortality rates. We conducted an observational, descriptive and retrospective study to evaluate the medical records of patients with suspected deep venous thrombosis at Amaral Carvalho Hospital in 2011. For this study, we obtained 118 patients with suspected DVT, which were divided into two groups; G1, group of patients in clinical treatment and G2 the group of patients in surgical treatment, aged 04 - 91 years. Among these, thirty-eight patients were diagnosed with DVT confirmed by using US-Doppler exam, considered as gold standard. The evolution of DVT occurred in lower and upper limbs. The major comorbidities identified were; hypertension, diabetes and cardiovascular problems. It was also perceived recurrence and readmission due to the evolution of DVT. During the present study, it was shown that especially patients hospitalized with cancer have a high risk for evolution to venous thromboembolism and, often, this risk can be decreased by the use of pharmacological thromboprophylaxis or mechanical prevention. Thus, the estudy contributes to the proposed protocol for the prevention of deep venous thromboembolism in cancer patients. Through this proposal, the nursing professional will feel better prepared to assess and prevent the development of complications during cancer treatment, as well as structured and will be able to score the degree of risk during the meetings of the Venous Thromboembolism Committee / Mestre