Dysregulated Coagulation in Haemodialysis - Vascular access and Cerebrovascular disease

Uraemia confers a prothrombotic tendency in tandem with a bleeding diathesis through platelet dysfunction that is most evident in patients with renal failure who are dependent on haemodialysis. This form of renal replacement therapy accentuates this clinical paradox by its procoagulant nature and the use of regular anticoagulation to prevent dialysis circuit and vascular access thrombotic dysfunction. This thesis evaluates such dysregulated coagulation in the extracorporeal circuit, the central venous catheter and dialyser, and in the twin substrates of cerebrovascular disease, thromboembolism and haemorrhage. Firstly the comparative effect of catheter site on thrombosis is evaluated by the jugular and translumbar routes before examining catheter type as a determinant in a randomised, controlled clinical trial. Subsequently novel use of catheter flow monitoring as a predictive tool for thrombotic dysfunction is presented and the efficacy of thrombolytic therapies assessed. Lastly a prospective pharmacokinetic evaluation of tinzaparin in dialysis circuit anticoagulation which revealed a novel influence of gender on anti-factor Xa activity. Stroke incidence and risk is examined in one of the largest studies to date before two specific risk factors for thromboembolic stroke are examined, intracranial arterial calcification and transient ischaemic attack. A potential association between intracranial arterial calcification and this stroke subtype is described for the first time in haemodialysis and results from the first prospective screening study for transient ischaemic attack in haemodialysis are presented. Finally renal dysfunction is shown to be a determinant of thrombolytic efficacy in acute ischaemic stroke. All these studies advance our understanding of thrombotic catheter dysfunction, its thrombolytic management and the behaviour of tinzaparin in haemodialysis. In addition they afford unique insights into cerebrovascular disease in haemodialysis that challenge traditional paradigms of a pathology with high incidence in these patients