Interactions Between Malignancy and Coagulation

Purushotham, Anand David (1992) Interactions Between Malignancy and Coagulation. MD thesis, University of Glasgow.

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There is evidence from clinical and experimental studies of a two-way relationship between cancer and the haemostatic system. Human cancer is associated with activation of haemostatic mechanisms, whilst animal studies of coumarin effects on metastasis suggest that coagulation may be implicated in the metastatic process. Warfarin inhibits, whilst the warfarin-dependent coagulation factor complex II, IX, X enhances, pulmonary tumour seeding in an animal model of metastasising mammary carcinoma. The purpose of this study was to investigate the mechanisms responsible for this effect of tumour enhancement by the coagulation factor complex II (prothrombin), IX, X. Initially, preliminary experiments were performed to validate the experimental tumour model used by previous workers. In particular, the effect of the factor complex II, IX, X on tumour cell aggregability and the influence of the timing and dose of administration of the factor complex on pulmonary metastasis were studied. The results of these experiments validated the results obtained by previous workers. In order to exclude the possibility that this effect of tumour enhancement by the factor complex is secondary to it's xenogeneic properties, a comparison was made between the prometastatic effects of human and rat coagulation factor complexes. The results of this experiment showed that both rat and human factor complexes enhanced pulmonary tumour seeding to an equal degree. In order to assess changes at the level of the pulmonary microcirculation on administration of tumour cells and the factor complex II, IX, X, a further study was performed to look at the passage of radiolabelled tumour cells through the pulmonary microcirculation. This study demonstrated a 20% increase in the number of tumour cells trapped in the lungs within the first hour of tumour cell and factor complex administration, when compared with the group that received tumour cells alone. These results suggest that an intravascular event may be responsible for the enhancement of metastasis previously demonstrated. Further animal studies demonstrated that individual purified components of the factor complex II, IX, X, and various combinations thereof, enhanced pulmonary tumour seeding to a similar degree. This suggests that they may do so via a common pathway (factor II), involving activation of the coagulation system. Evidence for activation of coagulation was demonstrated by estimating plasma fibrinopeptide A, a highly sensitive indicator of activation of the coagulation system. Based on these results, we hypothesised that factors II, IX, X, enhanced metastasis by encouraging tumour cell entrapment within a fibrin clot, in the pulmonary microcirculation. In a further experiment we demonstrated that fibrinolysis, using a "clot-lysis" dose of intravenous Streptokinase, reversed this effect of tumour enhancement. Furthermore, intravenous Streptokinase inhibited pulmonary tumour seeding even in the absence of exogenous factor complex II, IX, X. This inhibitory effect of Streptokinase on tumour seeding may have clinical implications with regard to the prescription of antimetastatic therapy in cancer patients.

Item Type: Thesis (MD)
Qualification Level: Doctoral
Additional Information: Adviser: P McCulloch
Keywords: Medicine
Date of Award: 1992
Depositing User: Enlighten Team
Unique ID: glathesis:1992-75192
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 19 Nov 2019 21:49
Last Modified: 19 Nov 2019 21:49

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