Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.541840
Title: Disease pathogenesis, treatment effectiveness, and co-morbid burden among adult patients with primary immune thrombocytopenia (ITP)
Author: Sarpatwari, Ameet Vilas
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2010
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Abstract:
Background: Primary immune thrombocytopenia (ITP) is an autoimmune disease involving autoantibody-mediated platelet destruction, suboptimal platelet production, and T-cell-mediated platelet lysis. These processes cause a decreased peripheral blood platelet count (< 150 x 109/L), resulting in an increased susceptibility to bleeding events. While thecourse of primary ITP is often acute (< 6 months) among children, it is generally chronic in adults. Despite a marked increase in epidemiological research over the past decade, unresolved questions remain with regard to disease pathogenesis, treatment effectiveness, and co-morbid burden among adults with primary ITP. Objectives: 1. To launch a registry for adults with primary ITP in the United Kingdom (UK); 2. To evaluate associations of candidate single nucleotide polymorphisms (SNPs) with primary ITP; 3. To assess the effectiveness of 111In-labelled platelet studies in predicting outcomes from splenectomy; 4. To document health-related lifestyle concerns among patients; 5. To gauge the effectiveness of Helicobacter pylori (H. pylori) eradication in elevating platelet counts; 6. To characterise associations of primary ITP with both arterial and venous thromboembolic events (TEs). Data sources: 1. The UK Adult ITP Registry (17 centres, 327 patients); 2. The UK Adult ITP Registry-affiliated, 111In-Labelled Platelet Study Database (117 centres, 256 patients); 3. The Wellcome Trust Case-Control Consortium (WTCCC) 1958 British Birth Cohort (3,000 individuals); 4. The General Practice Research Database (GPRD) (500+ centres, 4 million+ patients); 5. The UK ITP Support Association Health-Related Lifestyle Survey (790 patients); 6. Systematic reviews of published epidemiological studies. Methods and Results: SNP Study: Caucasian patients from the UK Adult ITP Registry were gender-matched (1:3) with healthy controls from the WTCCC 1958 British Birth Cohort. Six functional candidate SNPs in cytokine or cytokine receptor genes were measured in cases and retrieved for controls from the European Genome-phenome Archive. Associations were evaluated using logistic regression models. A statistically significant per allele odds ratio (OR) of 1.34 (95% confidence interval [CI], 1.03-1.75) was observed for TNFA -308 g>a, implicating increased disease susceptibility among carriers of the rare allele. 111In Study: The effectiveness of autologous 111In-labelled platelet sequestration studies in predicting short (1-3 months), medium (6-12 months), and long-term (last follow-up) complete response (CR; count < 100 x 109/L) to splenectomy in patients with primary ITP was evaluated using multivariable logistic regression models. Significant adjusted (gender, age at splenectomy, and mean platelet lifespan) ORs were uncovered for short (7.47 [95% CI, 1.89-29.43]), medium (4.85 [95%CI, 1.04-22.54]) and long-term (5.39 [95% CI, 1.34-21.65]) CR in patients with purely or predominantly splenic versus mixed or hepatic splenic platelet sequestration, highlighting the utility of platelet sequestration studies as an adjunct predictive tool prior to splenectomy. H. pylori Eradication Study: A systematic literature review was conducted of studies evaluating the effects of H. pylori eradication on platelet count in patients with primary ITP. Twenty-five studies were identified, encompassing 696 evaluable patients. The weighted mean complete response (count > 100 x 109/L) and overall response (platelet count > 30 x 109/L) were 42.7% (95% CI, 31.8%-53.9%) and 50.3% (95% CI, 41.6%-59.0%), respectively. Observed responses were higher in countries with a higher prevalence of H. pylori infection and in patients with milder thrombocytopenia. These findings support the benefits of H. pylori detection and eradication in patients with primary ITP. Health-Related Lifestyle Study: A 43-question, closed-field questionnaire was used to identify health-related lifestyle concerns among patient members of the UK Adult ITP Support Association. Completed surveys were returned by 790 (44.7%) members, with nearly one-third of adults reporting having an elective surgery delayed due to a low platelet count and experiencing difficulty in obtaining travel insurance. Notably, 12.5% of all patients reported 'always' or 'often' missing work or school due to fatigue. These results highlight several promising avenues for future health-related quality of life (HRQoL) research. Thromboembolic Event Studies: Using the GPRD, 1,070 adults with primary ITP were matched (1:4) with 4,280 ITP-free controls by age, gender, practice, and observation time. Comparative risks of TEs were assessed using Cox proportional hazards models. Over a median time of 47.6 months (range: 3.0-192.5 months), adjusted hazard ratios of 1.58 (95% CI, 1.01-2.48) and 1.37 (95% CI, 0.94-2.00) were found for venous and arterial TEs, respectively. A similar investigation was conducted comparing age and sex-stratified incidence rates of TEs among patients in the UK Adult ITP Registry with population-based estimates for the general adult population, yielding significant standardised rate ratios of 2.43 (95% CI, 1.01-5.83) and 2.45 (95% CI,1.48-4.06) for venous and arterial TEs, respectively. These results collectively highlight an increased risk of venous and arterial TEs in adults with primary ITP. Conclusions: Primary ITP is a pro-inflammatory (i.e., TH-1-mediated), pro-thrombotic disease in adults. Available evidence supports testing for and eradication of H. pylori infection in patients with primary ITP and the utility of autologous 111Inlabelled platelet sequestration studies in identifying patients likely to respond to splenectomy. The development of a prospective, international registry will help assemble the sample sizes needed for promising further research, namely genome-wide disease association studies and investigations into the effects of the eradication of strain-specific H. pylori infection on platelet count, the precise relative risk of non-response to splenectomy in patients with mixed or hepatic platelet sequestration, and the associations of TEs with primary ITP in antiphospholipid antibody-negative.
Supervisor: Sanderson, Simon Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.541840  DOI: Not available
Keywords: Primary ITP ; Epidemiology ; Registry ; Autoimmune
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