Antiphospholipid antibodies and the protein C pathway

• Main Author: Gardiner, Christopher
• Published: University College London (University of London) 2008
• Subjects: 618
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.498607

The antiphospholipid syndrome (APS) is characterised by the presence of antiphospholipid antibodies (aPA) associated with thrombosis (arterial and venous) and pregnancy morbidity. This thesis has aimed to investigate the frequency of protein C pathway defects in patients with aPA and to study clinical correlates examine the mechanisms of antiphospholipid interference in the protein C pathway and to assess activated protein C (APC) resistance in patients with aPA in terms of thrombin generation. Although have I have discovered a high degree of heterogeneity in the phenotype of patients with APS, I have demonstrated APC resistance and increased thrombin generation in the majority of patients with APS. While in some cases, APC resistance is clearly immunoglobulin mediated, it is a multifactorial phenomenon with many confounding variables. My data suggest that immunoglobulin dependent APC resistance may occur through P2 glycoprotein-I dependent and independent mechanisms. In a detailed study of women with a history of pregnancy morbidity, I have found evidence for an underlying prothrombotic condition, which is due in part to a deficiency of tissue factor pathway inhibitor. This is associated with resistance to APC and increased thrombin generation, both of which may be attenuated through the restoration of normal TFPI levels by low molecular weight heparin.