By specifically analysing for the various active principles of plasma, platelets, tissues and their fractions, much new information has been obtained concerning the role of lipoids and platelets in blood coagulation and in the hemostatic mechanisms in health and disease. Analysed components are studied in artificial clotting systems, especially a two-stage thrombin- forming system. Some 86 cases of bleeding disorders, 32 new born normal infants and their mothers, and many normal adult bloods have been analysed with respect to components of the clotting and hemostatic functions. The detailed considerations embodied in the thesis are encompassed under the following heads: 1) the importance of certain lipoids, especially cephalin 2) the normal need, in plasma clotting, for platelets, 3) the particular significance of a platelet component, which has many analogies to cephalin, in the thromboplastic system, 4) potentiation of the thromboplastic actions of cephalin, of platelets, and of tissue thromboplastin (to some extent) by a variety of experimental additives. Part of this may be explained as a 'thromboplastin generation' through co-participation of certain plasmatic components (antihemophilic globulin, PTC" etc. ) . Part, however, may be the result of certain proteolytic enzymes, particularly trypsin, 'disaggregating' lipoproteins and thus rendering their phospholipid (and sometimes calcium) available for participation in the clotting reactions, 5) possible Ca-containing and lipid-containing 'intermediates’ in the thrombin-forming reactions, 6) myelin figure formation as an explanation of ‘alterations' of platelets and certain other formed elements such as thrombocytes, megakaryocytes, and stromatolytic erythrocytes 7) the multiplicity of factors which platelets may contribute to the blood clotting and hemostatic mechanisms 8) the occurrence of many clinical disorders due to deficiency of platelet functions. Thrombocytopenias denote deficient numbers ('counts' and total bulk in body). Thrombocytopathies are deficiencies of specific platelet components, e . g. thromboplastic factor, accelerator, vasoconstrictor (5-hydroxy tryptamine), or retractor factor. Such deficiencies can be clinically significant even when the platelet count is normal. Bleeding in leukaemias, uremias, etc. may often be accounted for in these terms, 9) the nature and modes of action of heparin and other 'antithromboplastic’ inhibitors, and of some antiproteases, in relation to the mechanisms discussed 10) the ‘cephalin availability theory' of the author, as a useful working hypothesis to explain the importance of the natural thromboplastic phospholipid. Lipid release from platelet, tissue, or possibly plasma sources may very well be the long-obscure 'trigger mechanism' which initiates blood coagulation.

Stroke is a devastating, neurological dysfunction due to brain blood supply disturbance. It is responsible for increasingly high rate of mortality and disability worldwide. This thesis comprises two original studies involving 868 patients at risk of ischemic stroke and/or hemorrhagic stroke. The first study investigated aspirin’s effect among patients with intracranial hemorrhage. Unlike Caucasians which hemorrhagic strokes account for 10-15% of all strokes; in Chinese, intracranial hemorrhages strike up to 35%. After such, anti-platelet agent like aspirin is often avoided for fear of recurrent intracranial hemorrhages, despite compelling indications. However, clinical data is limited. In this single-centered observational study, we included 440 consecutive Chinese patients with a first spontaneous intracranial hemorrhage surviving the first month performed during 1996-2010. 56 patients (12.7%) of these 440 patients were prescribed aspirin after intracranial hemorrhage (312 patient-aspirin years). After a mean follow-up of 62.2 ± 1.8 months, 47 patients had recurrent intracranial hemorrhage(10.7%, 20.6 per 1,000 patient years). Patients prescribed aspirin did not have higher risk of recurrent intracranial hemorrhage compared with those without (22.7 per 1,000 patient-aspirin years vs. 22.4 per 1,000 patient years, p=0.70). Multivariate analysis identified age > 60 years and hypertension as independent predictors for recurrent intracranial hemorrhage. In a subgroup analysis: the incidence of combined vascular events including recurrent intracranial hemorrhage, ischemic stroke, and acute coronary syndrome was statistically lower in patients prescribed aspirin than without (52.4 per 1,000 patient-aspirin years, vs. 112.8 per 1,000 patient-years, p=0.04). Implications of the results: despite having a substantial risk for recurrent intracranial hemorrhage, post-intracranial hemorrhage ones are at risk for thrombotic vascular events and management goal should thus focus on ameliorating overall cardiovascular risk instead of preventing recurrent intracranial hemorrhage. Hence, thrombo-prophylaxis should still be considered. The second study investigated the relation between premature atrial complexes and new-onset atrial fibrillation together with other cardiovascular events. Premature atrial complexes though taken as benign phenomenon, are common in patients with underlying conditions such as coronary heart disease, chronic rheumatic heart disease. While prompt management of atrial fibrillation may prevent ischemic stroke, atrial fibrillation is often unfound until ischemic stroke occurs. In this study, 428 patients without atrial fibrillation but complained of palpitations, dizziness or syncope were recruited. 107 patients with >100 premature atrial complexes/day were defined to have frequent premature atrial complexes. After a mean follow-up of 6.1 ±1.3 years, 31 patients (29%) with frequent premature atrial complexes developed atrial fibrillation compared with 29 patients (9%) with premature atrial complexes?100/day (p<0.01). Cox regression analysis revealed: frequent premature atrial complexes, age>75 years and coronary artery disease were independent predictors. In secondary endpoint (ischemic stroke, congestive heart failure, and death), patients with frequent premature atrial complexes were more at risk than those without (34.5% vs. 19.3%) (Hazard ratio: 1.95, 95% confidence interval: 1.37-3.50, p=0.001). Cox regression analysis showed: age> 75 years, coronary artery disease and frequent premature atrial complexes were independent predictors. These permit early identification of high risks patients of new atrial fibrillation and other events, thus promoting appropriate preventive treatment. / published_or_final_version / Medicine / Master / Master of Philosophy

Understanding the differential bonding mechanics underlying bleeding disorders is of crucial importance to human health. In this research insight is provided into how four of these bleeding disorders (each with somewhat similar clinical characteristics), work at the molecular bond level. The bleeding diseases studied here can result from defects in the platelet glycoprotein (GP) Ibα the von Willebrand factor (vWF) molecule, or the ADAMTS-13 enzyme. Types 2B and 2M von Willebrand Disease (VWD) result in excess bleeding, yet type 2B has increased binding affinity between platelet GPIbα and vWF, while type 2M has decreased binding affinity between these two molecules. Platelet type VWD (pt-VWD) causes mutations in the GPIbα molecule and has similar characteristics to type 2B VWD. Further, in thrombotic thrombocytopenic purpura, bleeding results when there is a lack of active ADAMTS-13 enzyme. Each disease results in patient bleeding, but due to different mechanisms. This dissertation will explore the bonding mechanics between GPIbα and vWF and how they are altered in each disease state. To observe the GPIbα-vWF bonding mechanics, rolling velocities, transient tethering lifetimes, and tether frequency were determined using a parallel plate flow chamber. Data from these experiments suggest that wt-wt interactions are force dependent and have biphasic catch-slip bonding behavior. The data show that the shear stress at which the maximum mean stop time occurs differs between gain-of-function and loss-of-function mutations. Using similar methods, we study the changes resulting from pt-VWD mutations in GPIbα, and find that the catch bond seen for wt-wt interactions is lost for these mutations. Further, the data suggest that interactions with gain-of-function GPIbα mutations may be transport rather than force dependent. Finally, how the GPIbα-vWF tether bond changes for thrombotic thrombocytopenic purpura was also investigated to show that the bond lifetime in the absence of the enzyme is increased presenting a possible rationale for why bleeding occurs in this disease. Overall, the data show how the bonding mechanics of the GPIbα-vWF tether bond differ in four bleeding diseases. Further, these observations offer potential explanations for how these changes in the bonding mechanism may play a role in the observed patient bleeding.