M.Tech. (Homoeopathy) / The purpose of this study was to determine the effect of the Homoeopathic remedy Arnica montana 12 CH on blood coagulation. For years Arnica montana has been used to treat injuries where there is bleeding and bruising. The arrest of bleeding is accomplished by a number of mechanisms,one of which is blood coagulation. The study was conducted using 21 volunteers with each person acting as his or her own control Two blood samples were collected from each patient over a three day period. After preparing fresh whole blood samples and platelet-poor plasma, full blood count and coagulation assays were run using the Cell-Dyn 1700 system and the Automated Coagulation Laboratory analyser respectively. The average from the two days were calculated and statistically analysed using the Two way ANDVA method of analysis. Results showed that the differences between the experimental group and the control group were too small to be statistically significant. This showed that Arnica montana 12 CH had no significant effect on blood coagulation. It is interesting to note that the alcohol group had almost the same results as the experimental group.

M.Tech.

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Zinc (Zn2+) is an abundant metal ion that circulates in the body. Within hemostasis, Zn2+ participates in platelet aggregation, coagulation, and fibrinolysis. At the site of injury, Zn2+ released from activated platelets accelerates coagulation and attenuates fibrinolysis. How Zn2+ regulates these processes on a molecular level has not been extensively examined. We hypothesized that Zn2+ released from platelets binds serine proteases involved in coagulation or fibrinolysis and modulates their proteolytic activity, thus controlling the rate of clot formation and lysis. We show that Zn2+ concentrations released from activated platelets are sufficient to modulate clot formation and fibrinolysis. We show in vitro that Zn2+ binds to fibrinogen with high affinity, accelerates fibrin monomer polymerization, and modifies clot structure. Zn2+ promotes clot stability by increasing fiber diameter, reducing fibrin fiber elasticity, and increases clot porosity. Although it might be predicted that these modifications would enhance clot degradation by enabling greater distribution of lytic enzymes through the more porous fibrin network, we showed the opposite. Thus, we demonstrated that Zn2+ binds to plasminogen activators and plasmin with high affinity and down-regulates their protease activity, which delays lysis. This adds to previous studies that showed that both coagulation and fibrinolysis are regulated by Zn2+ ions. These data support the functional role of Zn2+ in hemostasis. / Thesis / Doctor of Philosophy (PhD)

Two groups of New Zealand white rabbits were injected with homogenates from Tumorous-head (Tuh) and Wild-type (WT) Drosophila melanogaster. A third group was used as a saline injected control. Blood collected in both acute and chronic studies was subjected to various hematological and post mortem studies. The Tuh injected group showed a five-fold increase in thrombocytes (blood platelets) over the controls and four-fold increase over the wild-type group. Reduced clotting times were noted from acute to chronic studies in both tumorous and wild-type studies; however, the magnitude of change between the two groups was insignificant. Investigations involving electrophoretic banding patterns, differential blood cell counts, and comparative hematocrits, provided less significant results. The author concludes that the reduced clotting times reported in tumorous-head injected rabbits represent a decrease in bleeding time. This was caused by the more effective plugging of the damaged vessel by the increased number of platelets.

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Patients with valvular pathology who require heart valve replacement surgery are faced with the option between a bioprosthetic heart valve (BHV) or a mechanical heart valve (MHV). BHVs have a limited lifespan and are prone to structural degeneration. In contrast, MHVs are free from structural deterioration, but necessitate lifelong anticoagulation due to a more robust activation of coagulation. This is usually achieved in the outpatient setting with the use of vitamin K antagonists (VKAs), such as warfarin. Due to the cumbersomeness of managing warfarin with regular monitoring and its numerous food- and drug-drug interactions, other oral anticoagulants were sought. Within the last decade, the advent of the direct oral anticoagulants (DOACs) has largely supplanted warfarin and other VKAs for numerous indications, including stroke prevention in atrial fibrillation and prevention and treatment of venous thromboembolism. When evaluated in a clinical trial in patients with MHVs however, use of the thrombin-directed DOAC, dabigatran, led to an increase in both bleeding and clotting; prompting a halt to the study and a black box warning against the use of dabigatran and other DOACs in patients with MHVs. The cause of this failure at the time was not understood and prompted the investigations detailed in this thesis. The work described within this thesis sought primarily to understand why dabigatran failed to adequately provide thrombo-protection for patients with MHVs. Firstly, the mechanism of thrombin generation on MHVs was identified as being initiated and propagated through the contact and intrinsic pathways, respectively. Within this same work, a mechanism for the failure of dabigatran and the efficacy of warfarin was presented. It was shown that dabigatran concentrations of greater than 250ng/mL were required to suppress thrombin generation, whereas the same effect could be achieved with warfarin at an INR of 1.5 or greater. Secondly, the effect of the other DOACs, rivaroxaban and apixaban, on MHV-induced thrombin generation was assessed, and we showed that individually, these two DOACs were unable to suppress thrombin generation within clinically-relevant dosing regimens. We also evaluated a combination of dabigatran and rivaroxaban to determine whether the combination would be superior to either agent alone at suppressing MHV-induced thrombin generation. Lastly, the capacity of two assays – the ecarin chromogenic assay and the dilute thrombin time – to detect both on treatment and low levels of dabigatran is presented as a tool for clinicians to determine whether patients taking dabigatran can safely undergo procedures or whether they necessitate rapid reversal in emergent situations. / Thesis / Doctor of Philosophy (PhD)

Patients with prostate cancer (PC) are at high risk of developing migratory thrombosis compared to healthy individuals. This is due to the haemostatic abnormality as a result of the presence of cancer, and is referred to as Trousseau’s syndrome. Trousseau's syndrome leads to increased mortality among cancer patients, and is considered the second cause of death after cancer itself. We investigated the role of microvesicles (MVs), which are circular membrane compartments shed from cancer as well as from healthy cells, in the development of Trousseau’s syndrome. We compared the pro-coagulant activities between MVs derived from PC cell lines with different oncogenic and metastatic characteristics, using chromogenic assays to determine their thrombin generation. Microvesicles from the more aggressive DU145vIII and more metastatic PC3-MLN4 show increased thrombin generation compared to MVs derived from DU145 and PC3. We also compared thrombin generation in MVs extracted from plasma of PC patients of various cancer stages. MVs from PC patients with a metastasized tumour had increased thrombin generation compared to patients with localized tumours. Finally, we transfected the CHO cell line with the human protease-activated receptor 1 (hPAR1), the principal receptor of thrombin. PC MVs led to the activation of PAR1 in CHO (hPAR1), indicating thrombin generation. Our in vitro studies suggest a potential role of PC MVs in the migratory thrombosis observed in Trousseau’s syndrome, due to their independent ability to generate active thrombin. We also demonstrated that thrombin generation of PC-derived MVs correlated with the oncogenic and metastatic characteristics of prostate cancer. / Thesis / Master of Science (MSc)