Aspects of Complement Activation in Thrombocytopenic Disorders

Sammanfattning: The complement system is an essential effector of both innate and acquired immune responses. Due to its destructive potential, tight regulation is required. The contribution of complement has been associated with the pathogeneses in a wide range of diseases. In this thesis, aspects of complement activation were investigated in disorders characterized by thrombocytopenia.In papers I and II, clinical characteristics, complement analyses, and genetic screening for rare variants encoding complement proteins were retrospectively investigated in a cohort suspected to suffer from atypical hemolytic uremic syndrome. In paper I, a population (n = 134) was identified whose phenotypes indicated the possibility of a diagnosis of complement-mediated atypical hemolytic uremic syndrome. In conclusion, laboratory complement analyses and clinical data were consistent with a possible underdiagnosis at the time of discharge. In paper II, recruited patients (n = 20) were subjected to follow-up investigations. Clinical outcomes and the phenotypical relevance of identified genetic variants were assessed. A diagnostic scheme compliant with the American College of Medical Genetics and Genomics guidelines was presented. In addition to identifying several previously described genetic variants, a novel likely disease-contributing missense variant in the complement factor H gene (c.3450A>G, p.I1150M) was identified. In conclusion, the study illustrated the risk of misdiagnosis and the importance of a comprehensive assessment to reach a diagnosis.In paper III, complement and platelet activation biomarkers were prospectively investigated in thrombocytopenic patients (n = 43) receiving prophylactic platelet transfusions during inpatient care in the hematological department. Neither complement nor platelet activation was shown to correlate with the corrected count increment. In conclusion, complement and platelet activation were not demonstrated contributing to a poor post-transfusion platelet response.In summary, this thesis has contributed to the growing knowledge of diseases potentially affected by complement activation.