Interactions between antiphospholipid antibodies, oral anticoagulants and haemostasis activation in thrombotic antiphospholipid syndrome

Antiphospholipid antibodies (aPL) are associated with an increased thromboembolic risk but the mechanism is unclear. Warfarin anticoagulation has traditionally been employed in thrombotic antiphospholipid syndrome (APS), but direct oral anticoagulants such as rivaroxaban have recently become available. The aims of this thesis were to: 1. Investigate the frequency, mechanism and clinical associations of activated protein C resistance (APCr) in thrombotic APS 2. Assess the effects of rivaroxaban on lupus anticoagulant tests 3. Investigate the efficacy of rivaroxaban in terms of thrombin generation (TG) and haemostasis activation markers in thrombotic patients with or without APS Thrombotic APS patients had greater APCr than disease controls. Nearly 50% of APS patients had anti-protein C (anti-PC) antibodies; those with high avidity antibodies had significantly greater APCr using either exogenous activated PC or activation of endogenous PC with Protac®. High avidity anti-PC antibodies were strongly associated with a severe thrombotic phenotype in APS. There was a wide variation in the sensitivity of thromboplastin reagents to rivaroxaban. Of the six commonly used thromboplastin reagents studied, Neoplastin®R was the most sensitive while Innovin® and Thromborel®S were the least sensitive. False positive dilute Russell’s viper venom time occurred in patients with therapeutic levels of rivaroxaban. Taipan /Ecarin venom clotting time ratio and Textarin time were not affected irrespective of the rivaroxaban level, enabling accurate detection of LA. In vitro studies showed that aPL did not influence the anticoagulant activity of rivaroxaban as measured by TG and anti-Xa assays. Both rivaroxaban and warfarin achieved effective anticoagulation, as assessed by inhibition of TG and in-vivo coagulation activation markers in patients with and without APS

Frequency of thrombocytopenia and heparin induced thrombocytopenia in patients receiving extracorporeal membrane oxygenation compared to cardiopulmonary bypass and the limited sensitivity of pre-test probability score

Objectives:To ascertain:i)the frequency of thrombocytopeniaand heparininducedthrombocytopenia (HIT), ii)positive predictive value (PPV) of the pre-test probability score (PTPS) in identifying HIT iii)clinical outcome of HITin adult patients receiving veno-venous (VV)-extracorporeal membraneoxygenation(ECMO)or veno-arterial (VA)-ECMO, comparedto cardiopulmonary bypass (CPB). Design: A single-centre, retrospective, observational cohort study from January 2016 to April 2018Setting: Tertiary referral centre for cardiac and respiratory failure Patients:Patients who received ECMOfor>48hrs or had CPB during specified period Interventions: None.Measurements and Main Results:Clinical and laboratory data were collected retrospectively. PTPS and HIT testing results were collected prospectively. Mean age (standard deviation) of the EMCO and CPB cohorts were 45.4 (±15.6) and 64.9 (±13), p< 0.00001.Median duration of CPB was 4.6 [2-16.5]hrs compared to 170.4[70-1008] hrson ECMO.Moderateand severethrombocytopenia were more common in ECMO compared to CPB throughout (p<0.0001).Thrombocytopenia increased in CPB patients on day2 but was 4normal in 83% compared to 42.3 % ofECMOpatients at day 10. Patients on ECMO also followed a similar pattern of platelet recoveryfollowing cessation of ECMO. The incidences of HIT in ECMO and CPB were 6.4% (19/298) and 0.6% (18/2998) respectivelyp<0.0001). There was no difference in prevalence of HIT in patients on VV-ECMO (9/156, 5.7%) vs VA-ECMO (11/142, 7.7%), p=0.81. The PPV of the PTPS in identifying HIT in patients post-CPB and on ECMO were 56.25% (18/32) and 25% (15/60) respectively. Mortalitywas not different with (6/19, 31.6%) or without (89/279, 32.2%) HIT in patients on ECMO,p=0.79. Conclusions Thrombocytopenia is already common at ECMO initiation. HIT is more frequent in both VV-and VA-ECMO compared to CPB. PPV of PTPSin identifying HIT was lower inECMO patients.HIT had no effect on mortality