Alwan, Ferras; (2025) Prognostic Factors in Thrombotic Thrombocytopenic Purpura. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Thrombotic Thrombocytopenic Purpura (TTP) is a rare disorder in which ADAMTS13 deficiency, either congenital (cTTP) or acquired (immune-TTP), leads to circulating ultra-large VWF multimers and microthrombi formation with potentially catastrophic results. Alongside laboratory studies, the UK TTP Registry was used to assess the prognostic impact of several variables. 312 immune mediated-TTP episodes were evaluated to assess the impact of anti-ADAMTS13 antibody, ADAMTS13 antigen, troponin and neurological symptoms on prognosis. A raised troponin conferred a sixfold increase in mortality (12.1% vs 2.0%, p=0.04), whilst neurological symptoms increased the risk ninefold (20% vs 2.2%, p<0.0001). Both antibody and antigen levels affected outcomes with 27.3% mortality seen in those with antibody levels in the highest quartile and antigen levels in the lowest quartile. 73 cTTP patients had genetic analysis. Mutation location affected onset age with pre-spacer domain mutations more associated with earlier presentation (p=0.0011). Prophylactic ADAMTS13 replacement despite normal blood counts improved subacute symptoms such as headache, lethargy and abdominal pain and decreased stroke incidence. In separate research, a shear flow assay was developed to replicate ADAMTS13-VWF binding in cTTP. Analysis of 22 patients showed increase thrombus formation which improved with ADAMTS13 replacement and the addition of antiplatelet therapy to prophylactic regimens appeared to offer the most comprehensive reduction in microthrombi formation. For both cTTP and immune-TTP, neurological symptoms at presentation are an especially important factor with an impact on long term morbidity. MRI scanning of 131 patients after an acute event found those with neurological symptoms were significantly more likely to have an abnormal cerebral MRI compared to a headache only (80% vs. 18%, p<0·0001). An abnormal MRI was associated with lower verbal and performance IQ, suggestive of functional decline (verbal IQ 85 vs. 99, p=0·02, performance IQ 83 vs. 100, p=0·02).

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