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The aim of this PhD was to elucidate the factors that influence anticoagulation response to the oral anticoagulants, warfarin and non-vitamin K antagonist oral anticoagulants (NOACs). Identification of the factors which influence clinical response to these agents could lead to improvements in patient management and treatment safety. In a cross-sectional study, the mean TTR over a 12 months period was significantly higher in hospital monitored patients (78%) (P=0.001) compared to those monitored in general practice (71%) or at their homes (68%). Domiciliary monitored patients had the least TTR among the three groups although they had the highest numbers of dose changes and INR monitoring events. In a further longitudinal study of patients on warfarin for up to 14 years, the TTR according to age was significantly lower in home monitored patients, with this group having a higher probability of having poor anticoagulation control (TTR ≤65%). In an ex-vivo study, rivaroxaban in vitamin K deficient older subjects produced a greater prolongation of both PT and modified PT, and a greater suppression in the rate and amount of thrombin generation compared to vitamin K replete younger subjects. Therefore, poor vitamin K intake could play a role in the reported incidences of bleeding associated with NOACs We had previously demonstrated that daily vitamin K supplementation causes an increase in warfarin daily dose requirement which varies between different patients and is related to VKORC1 genotype. Based upon these observations we set out to test our hypothesis that patients on warfarin therapy with the VKORC1(-1639)GG polymorphism could have poorer anticoagulation control than those with GA or AA genotypes as a result of variable dietary intake of vitamin K. However, the study results failed to confirm this hypothesis. Patients on warfarin therapy scheduled for an invasive surgery have to stop taking the drug for a fixed number of days to avoid peri-operative bleeding. However, there is variance in the rate by which INR falls after stopping warfarin. I found that patients with CYP2C9 variant alleles (CYP2C9*2*2 or CYP2C9*2*3) were >8 times (95% CI = 2.25–33.25) more likely to have INR of ≥ 1.5 before the planned day of surgery than those with wild-type genotype. In a further study, patient age and CYP2C9 *2*2 & *2*3 ii genotype were found to significantly influence the time required to reach an INR of 1.5 following warfarin cessation. VKORC1 genotype had no effect on the rate of INR decline.

CFS is a chronic debilitating illness characterised by undue physical and mental fatigue and fatigueability, alterations of mood and recurrent low-grade fever, pharyngitis, lymphadenopathy, myalgia, arthralgia and sleep disturbance. Depression and cognitive dysfunction are the two other facets of CFS. Incidence in the UK is estimated to be around 1.3/1000 of the population. CFS causes considerable human suffering and poses a substantial economic burden on both patients and health providers. The illness is generally thought to be multiaetiologic in origin. An immunologic dysfunction associated with a persistent or reactivated viral infection is believed to be one principle aetiopathogenic mechanism. In a small, open-labelled, randomised study interferon-alpha was effective in improving the functional abilities in a subset of patients who were Coxsackie immunoglobulin M-positive (IgM). In this open- labelled, cross-over study we attempted to substantiate the latter finding and also investigate the functional, psychiatric and immunologic dysfunction in these patients and their relationship to improvement. 48 adult patients satisfying the Oxford criteria were enrolled of whom 25 received immediate treatment and 23 after a three months period of observation. As more specific ELISA tests for enterovirus IgM antibodies became available, all patients tested negative and the relationship of this antibody to outcome could not be retested. Using the Short Form-36 (SF-36) which measures eight aspects of patient's physical and emotional well-being and the general health questionnaire (GHQ) as a specific gauge of psychological health we substantiated the severe impact of the illness on all aspects of physical and psychological health in sufferers. Immunologically, there was evidence of both immunoactivation as suggested by the significantly increased relative expression of class II antigens in CD4 and CDS cells and reduced CD28 expression on CDS cells and of increased expression of the apoptosis repressor complex bcl-2 and bcl-2/bax in both CD4 and CDS cells. Additionally, lower (worse) SF-36 scores correlated with higher (worse) GHQ scores and class II antigen expression and lower CD28 display on CDS cells. Similarly, those with worse GHQ, mental and emotional health scores had lower phytohemagglutinin (PHA) proliferative responses. The former findings attest to a probable unifying mechanism causing both immune dysfunction and clinical morbidity while the latter findings have a bearing on a neuroimmune 'cross-talk'. None of the patients improved significantly during observation without treatment. At six months post-therapy, of 33 patients who completed a course of 3-6 million units of interferon alpha for 12 weeks, 14 rated themselves as improved. Of the latter, six rated themselves as much improved. On an 'intention to treat' basis, this represents 14 out of 48 recruited (29.2%). Improvement was gradual and stepwise, usually noticed by patients within three months of stopping interferon alpha. Improvement was associated with a similar trend in clinical, functional and psychological impairments. More importantly, improvers had lower CD28 and PHA proliferative responses at baseline, the increase of which with treatment mirrored the improvement in the SF-36 and GHQ. As the abnormalities in these two immune parameters might be related to a viral infection, improvement with treatment could be related to an interferon-antiviral effect.