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Title: The pathophysiology of paroxysmal nocturnal haemoglobinuria
Author: Kelly, Richard John
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2014
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Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, life-threatening condition caused by an expansion of a clone of haemopoietic stem cells (HSC) harboring a somatic mutation of the PIG-A gene. PNH blood cells are deficient in glycophosphatidylinositollinked (GPI) proteins rendering PNH erythrocytes susceptible to complement attack which leads to intravascular haemolysis and an increased tendency to develop thromboses. The survival of 79 consecutive patients treated with eculizumab was compared to both age and sex matched normal controls and to 30 similar patients managed in the era immediately prior to anti-complement therapy. The survival of those treated with eculizumab was no different that of the control group and was significantly better than the group with PNH that did not receive eculizumab (p=0.3). Transfusion requirements and documented thromboses were reduced with eculizumab. Sixty-six percent of transfusion dependent patients became transfusion independent and thrombotic events reduced from 5.6 to 0.8 events per 100 years. Eleven women were monitored through 15 pregnancies whilst on eculizumab. There was 1 first trimester miscarriage and 15 healthy babies born. There were no maternal deaths observed and no thrombotic events occurred in the pregnancy or the postpartum period. Eculizumab did not appear to cross the placenta or be expressed in breast milk. Thirty-five patients were evaluated for PIG-M mutations to see if this mutation was prevalent in PNH. No PIG-M promoter mutations were identified. Two genes were evaluated to see if secondary mutations affecting them could account for clonal expansion in PNH. Thirty-six patients underwent JAK2 V617F mutation analysis with 1 patient shown to have a JAK2 mutation. Forty-two patients were evaluated for increased HMGA2 levels by 2 different PCR methods. There was an overall reduction in HMGA2 expression in PNH patients as compared to normal controls. An in vitro model of the bone marrow in PNH was developed and 18 PNH bone marrow samples were evaluated using this model. Colony forming assays (CFA) showed an increase in colony formation when T-cells were removed from the PNH bone marrow samples. This improvement was reversed when the T-cells were added back to the experiments. This work supports an immune mechanism for the expansion of the PNH clone.
Supervisor: Doody, Gina ; Tooze, Reuben ; Hillmen, Peter Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available