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.

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, in partial fulfilment of the requirements for the degree of Master of Medicine in the branch of Anaesthesiology Johannesburg, 2019 / Background Anaesthesia frequently involves administration of refrigerated intravenous drugs to patients. Often overlooked, maintenance of the cold chain forms a key component of pharmacovigilance for anaesthetists. However the South African national Department of Health guidelines on: “Cold Chain and Immunisation Operations Manual”, does not detail specific requirements for medically validated cold boxes. Consequently the risk of iatrogenic harm to patients from heat-sensitive pharmaceuticals in inappropriately temperature regulated cold boxes exists. Methods The research design was that of a descriptive, prospective and contextual study. Part I study population comprised the ambient air temperatures of the refrigerator and cold boxes used for storage of heat-sensitive pharmaceuticals in theatre at CHBAH taken at one minute intervals over eight hours. Part II study population was newly purchased cold boxes and cold packs for the purpose of assessing individual cold box thermal performance over eight hours. Results In Part I, only a single cold box (polystyrene box number 19) was able to maintain the recommended temperature range of 2 − 8°C for the eight hour period (4.35%). The refrigerator temperature time plot showed a significant deviation of temperature at approximately 30 minutes. In Part II, only fabric and polystyrene cold boxes with three cold packs in situ were able to maintain the recommended temperature of 2 − 8°C. Conclusion This study highlighted the failure of non-medically validated cold boxes to reliably maintain the temperature of heat-sensitive pharmaceuticals. / E.K. 2019

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by a low platelet count (less than 100 x 10^9 platelets/L) and an increased risk of bleeding. ITP is difficult to diagnose and manage due to the deficiencies in our understanding of the pathophysiological mechanisms leading to thrombocytopenia. Anti-platelet autoantibodies are believed to be the primary mechanism of thrombocytopenia in ITP. In this thesis, I demonstrate that autoantibodies can only be detected in half of all ITP patients; therefore, other mechanisms should be investigated. CD8+ T cells have been implicated as a mechanism of disease in ITP, but platelet-specific CD8+ T cells have yet to be identified. I have characterized CD8+ T cells in ITP patients and found that platelet-specific CD8+ T cells can be detected in ITP patients. These platelet-specific CD8+ T cells can also be detected in healthy individuals, so they are not specific to ITP. However, regulatory defects were observed in ITP patients and CD8+ T cell activity was elevated in ITP patients relative to healthy individuals and thrombocytopenic non-ITP patients. Investigating whether platelet-specific CD8+ T cells can actively participate in platelet destruction and underproduction will be an essential step towards better understanding the role of CD8+ T cells as a disease mechanism in ITP, which will lead to improvements in the management of ITP. / Thesis / Doctor of Philosophy (PhD) / Platelets are small blood cells that are involved in minimizing blood loss at the site of a wound by forming a plug. In a disease called immune thrombocytopenia (ITP), patients have a low platelet count, which can result in bleeding. The bleeding symptoms of ITP decrease the quality of life for ITP patients and can be life-threatening in rare cases. It is believed that ITP is caused by proteins produced by the immune system called antibodies. I found that the antibodies that cause ITP can only be detected in half of all ITP patients. Therefore, there are probably additional causes of ITP. It is suspected that CD8+ T cells might cause ITP in some patients. CD8+ T cells are part of the immune system and they typically destroy other cells that are cancerous or infected by viruses. CD8+ T cells might also destroy healthy cells, like platelets. My goal was to characterize CD8+ T cells in order to determine their role in ITP. I found that CD8+ T cells from ITP patients can target platelets, and that healthy people have these CD8+ T cells as well. In regard to CD8+ T cells that target platelets, the difference between ITP patients and healthy people appears to be related to immune system regulation and CD8+ T cell activity. In the future, we should focus on understanding how platelet-specific CD8+ T cells can cause a low platelet count in order to improve the clinical management of ITP.

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