Acute thrombotic and thromboembolic occlusion of atherosclerotic vessels are events that precipitate most heart attacks and strokes. In arterial stenotic flow, thrombus formation is shear dependent and may or may not lead to complete occlusion of the vessel. Platelets in whole blood adhere to collagen-coated surfaces and as they accumulate the resistance of the stenosis increases because of the decreasing passageway of the occluded stenosis. As a model of blood clotting in stenoses, porcine blood is heparinized and perfused over tubular glass test sections that are coated with collagen type I. Each test section has a preexisting stenosis and its severity varies so that higher percent stenoses produce higher shear rates on the blood. The hypothesis of this thesis is that high shear rates due to stenosis in arteries are a necessary feature for occlusive thrombosis.

Thrombin activatable fibrinolysis inhibitor (TAFI) is a human plasma-derived zymogen that is activated through proteolytic cleavage by thrombin, thrombin in complex with thrombomodulin, or plasmin. Active TAFI attenuates fibrinolysis by removing carboxyl-terminal lysine residues from partially degraded fibrin, thereby inhibiting a potent positive feedback loop in the fibrinolytic cascade. In addition to the plasma pool of TAFI arising from expression in the liver, a distinct pool of TAFI has been reported to be present in platelets. While the antifibrinolytic effect of plasma-derived TAFI has been well-documented by in vitro and in vivo clot lysis assays, characterization of the platelet-derived form has been limited. Here, we not only confirm the presence of TAFI in the medium of washed, thrombin-stimulated platelets, but also that platelet-derived TAFI is capable of attenuating platelet-rich thrombus lysis in vitro independently of plasma TAFI using a novel thrombus lysis assay. Fluorescent thrombi were generated by suspending washed human platelets in plasma immunodepleted of TAFI containing fluorescently-labeled human fibrinogen such that the only TAFI present in the system was of platelet origin. Following platelet activation and clot retraction induced by thrombin, t-PA-dependent platelet-rich thrombus lysis was observed by removal of timed aliquots from the medium of retracted thrombi followed by measurement of fluorescence. When supplementary thrombomodulin was added to the thrombus medium, a 2.3-fold reduction in lysis rate was observed, indicating platelet-derived TAFI could attenuate the fibrinolytic cascade in vitro. Furthermore, when supplementary recombinant TAFI (rTAFI) was included in the medium, platelet-derived TAFI and rTAFI were observed to combine for greater inhibition of fibrinolysis. Taken together, these observations indicate that the secretion of platelet-derived TAFI can augment concentrations of TAFI already present in plasma to enhance attenuation of the fibrinolytic cascade. This could be significant at sites of vascular damage or regions of pathological thrombosis, where activated platelets are known to accumulate and secrete the contents of their granules. Finally, we have purified platelet-derived TAFI from platelet releasates for future characterization studies and mass spectrometry. / Thesis (Master, Biochemistry) -- Queen's University, 2009-09-24 14:22:42.5

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Thesis (Ph. D.)--Case Western Reserve University, 2008. / [School of Medicine] Department of Cell Biology. Includes bibliographical references.

Statement of the problem: The type and duration of pharmacological thromboprophylaxis post major abdominal surgery remains controversial. Methods of investigation: A systematic review and pooled analysis of literature was performed to assess the risk benefit ratio of the different pharmacological thromboprophylaxis agents compared to placebo or no thromboprophylaxis post major abdominal surgery. A survey of the clinical practice among both general surgeons and thrombosis expert was conducted. Results: The systematic review demonstrated that all five pharmacological thromboprophylaxis regimens were associated with similar rates of overall VTE. The 95% CI of the different estimates overlapped indicating no statistically significant difference between any of the pharmacological interventions and placebo. While all the surgeons and thrombosis experts recommended thromboprophylaxis post major abdominal surgery, over 70% of them recommended it during hospitalization only. Conclusion: Pharmacological thromboprophylaxis was not associated with a significant benefit in reducing the rate of overall VTE events post major abdominal surgery. There is an agreement between general surgeons and thrombosis experts in using LMWH for thromboprophylaxis post major abdominal surgery. However, there is still equipoise around the use of pharmacological thromboprophylaxis post discharge.

Isolated distal deep vein thrombosis (IDDVT) is a condition recently suggested to be a different entity to that of proximal disease. There is currently little evidence defining the clinical importance of detection and treatment. International guidelines vary regarding management advice.An observational cohort study, prospective service evaluation and pilot randomised controlled trial were performed within a United Kingdom ambulatory thrombosis service. This project aimed to describe the burden of disease and explore three poorly researched aspects of IDDVT assessment and management: whole-leg compression ultrasound (CUS) performed by non-physicians within an ambulatory framework as a principal diagnostic modality; clinical presentation data and risk profile in comparison to that of proximal disease; the feasibility of further interventional randomised research and the risk/benefit profile of therapeutic anticoagulation.Within this ambulatory cohort, IDDVT accounted for 49.7% of acute thrombosis and differed significantly to proximal disease regarding provocation and symptomatology at clinical presentation. A negative whole-leg CUS excluded deep vein thrombosis with an adverse event rate (diagnosis of symptomatic venous thromboembolism during the 3 month follow up period) of 0.47% (95% CI 0.08 to 2.62). Future interventional research was proved feasible within an ambulatory setting.The randomised controlled trial conducted within this project is the largest to date comparing therapeutic anticoagulation against conservative strategy for the management of acute IDDVT. Patients allocated to therapeutic anticoagulation had significantly less overall propagation of thrombus (Absolute risk reduction [ARR] 25.7%, 95% Confidence interval 5.9 to 44.3 p<0.01), less short-term symptomatic progression (ARR 16.7%, 95% CI 2.6 to 32.1 p=0.05) and a result trending towards significance for reduction in serious thromboembolic complications (ARR 11.4%, 95% CI -1.5 to 26.7 p=0.11).IDDVT is a condition of equal prevalence to proximal venous thrombosis, which varies significantly regarding risk profile and clinical presentation. Using a single whole leg CUS reported by a non-physician within an emergency department pathway is associated with a low adverse event rate. This contemporary data also suggests that therapeutic anticoagulation is beneficial for reduction of short-term complications in IDDVT. The risk of false positive diagnosis and excess anticoagulation remains.This data can inform and direct future design of adequately powered randomised studies, in order to attempt external validation of these findings.

Venous thromboembolism (VTE) is a common disorder which causes significant morbidity and mortality. Upper extremity deep vein thrombosis(UEDVT) is a relatively understudied subtype of VTE which is commonly associated with central venous catheters, cancer, and thrombophilia. The goal of this project was to better characterize the risk of UEDVT and to design and execute a pilot study that will demonstrate the efficacy of a strategy preventing the occurrence of VTE in a high-risk population for UEDVT. This M.Sc project, was conducted in three parts. Chapter 1 of the thesis outlines a systematic review of the literature which assessed the risk of VTE in UEDVT patients by search for and including data from studies with patients with prospectively enrolled symptomatic UEDVT. Chapter 2 describes the development and final protocol of the TRIM-Line pilot study, a randomized open-label study comparing 90 days of rivaroxaban 10mg po daily against the current standard of care (observation) in patients with active cancer and central venous catheters, two known risk factors for VTE. Finally in Chapter 3 the TRIM-Line study was executed as a pilot trial involving The Ottawa Hospital and the Juravinski Cancer Centre located in Hamilton. The study was conducted from March 2019 until February 2020. 105 patients underwent randomization at the two Canadian centres. The study met its prespecified feasibility endpoint average enrolment rate of 7.5 per month (95% CI:4.56, 10.44) at the coordinating Ottawa Hospital site and 2.0 per month (95% CI:0.87, 3.13) for the Juravinski Cancer Centre site. The randomized controlled trial met its enrollment targets and demonstrated that a full scale randomized controlled trial on the topic of prevention of cancer associated venous thromboembolism is feasible.

Symptomatic occlusion of the hepatic veins is a rare condition caused by tumour or thrombus arising either locally or by extension from the inferior vena cava. It is usually called the Budd-Chiari syndrome. The etiology remains unknown in over two-thirds of the patients. Its rarity and interest has led to a large number of individual case reports. 322 instances of symptomatic hepatic vein occlusion have been reported, of which 184 are single case publications. There are only six series of more than five cases (Nishikawa, 1910; Corinini and Oberson. 1937; Palnar, 1954; Parker, 1959; Gibson, 1960; Safouh and Shehata, 1965) and these have been largely drawn from autopsy records, although Palmer (1954) described seven patients seen during life. The clinical and pathological features of hepatic vein occlusion have been described in a number of papers (Hess, 1905; Thompson and Turnbull, 1912; Armstrong and Carnes, 1944; Kelsey and Comfort, 1945; Thompson, 1947; Parker, 1959; Gibson, 1960) during the one hundred and twenty years since the publication of Budd's treatise. However, accurate diagnosis has generally relied on autopsy, and detailed investigations have seldom been performed. Consequently, little is known of the roentgenographic and haemodynamic features. The diagnosis of liver disease has been revolutionized by such special techniques as percutaneous liver biopsy, portal pressure measurements, isotope scanning and selective arteriography and venography. This study describes six patients with the Budd-Chiari syndrome in whom these methods have been applied to establish the diagnosis, to ascertain the underlying cause and to assess the possibility of surgical intervention. Special attention has been given to hepatic venography and hepatography. The vascular pattern in the Budd-Chiari syndrome has been compared with that in normals and in patients with other diseases of the liver. Diagnostic features have been determined and an attempt made to evaluate compensatory changes in the lymphatic drainage and venous blood supply following hepatic vein obstruction. Alterations in portal dynamics have also been recorded. The clinical course has been followed and the effect of treatment assessed in each patient. Finally, the literature has been reviewed with particular reference to the diagnosis and treatment of hepatic vein thrombosis. The studies reported in this thesis were carried out during the tenure of a Research Fellowship in the Royal Free Hospital School of Medicine, and they were supported by a grant from the William Shepherd Bequest to the Royal Free Hospital. The special radiological procedures, haemodynamic studies, isotope investigations and laboratory work were personally performed with the exception of the scintillation scans, coeliac axis arteriograms and the other individual tests acknowledged overleaf.

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