Cardigan, Rebecca Anne; (1998) An investigation into coagulation activation during extracorporeal circulation. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The objective of this thesis was to investigate coagulation activation during extracorporeal circulation. Two groups were selected for study: patients undergoing elective cardiac surgery requiring cardiopulmonary bypass (CPB) and critically ill patients in acute renal failure requiring continuous venovenous haemofiltration (CVVH). It was suspected that contact activation by the CVVH circuitry might cause the observed generation of thrombin during haemofiltration. However, there was no evidence of contact activation during CVVH. I therefore investigated activation of the tissue factor pathway. Initially during CVVH FVIIa generation was suppressed due to the release of TFPI by heparin. However, the TFPI response to heparin is tachyphylactic, as TFPI levels fell FVIIa generation occurred, coincidental to thrombin generation. This prompted the investigation of the tissue factor pathway during CPB where mechanisms of thrombin generation are not understood. During CPB, although there was an initial increase in FVIIa, the heparin released TFPI, which in contrast to CVVH was maintained throughout the procedure, suppressed FVIIa generation. Like CVVH, there was no evidence for contact activation. This suggested that thrombin generation during CPB did occur, but was not related to activation of either the contact system or tissue factor pathway. I therefore examined other potential mechanisms of thrombin generation at surfaces not detectable using conventional assays. The activation of FXII on the surface of lipoproteins and blood cells was investigated in vitro as a possible mechanism for coagulation activation which might lead to thrombin generation during CPB. FXIIa generation was demonstrated on triglyceride- rich lipoprotein particles and leucocyte surfaces, where it may be protected from inhibition by serpines. Enhanced activation and reduced inhibition of the tissue factor pathway was also demonstrated in blood from the pericardial cavity during CPB. Reinfusion of this blood to the patient was deemed likely to contribute to systemic coagulation activation during CPB.

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