BIOLOGY 2F03 Chapter Notes - Chapter 7-8: Bone Marrow Failure, Cd59, National Party Of Honduras
20 May 2018
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- PNH
1. Synthesis & importance of GPI
• GPI is a highly conserved protein bound to the outer half of the CSM
• Synthesis of GPI:
o PIG-A adds glucosamine to IP3 on the surface of the ER
o Flippase internalises the complex and mannose domains are added in the ER lumen
o Phospho-ethanolamine residues are also added in ER
• GP anchors a number of proteins, including CD59 and other complement regulators, enzymes,
adhesion molecules and co-receptors
o Proteins are usually attached to phosphor-ethanolamine residues
• CD59 usually competes with c9 for binding sites in the C5b-7 complex; hence it prevents MAC
assembly and thus complement-mediated lysis
2. Molecular basis of PNH
• SOMATIC MUTATION in PIG-A gene on X-chromosome
o Only one mutation is needed to cause disease; women can get it
o Mutations have been mapped to multiple points across the 6 exons of the PIG-A gene
• The mutation tends to occurs solely in HSCs
o = loss of GPI synthesis = loss of GPi anchored proteins from CSM of all HSc derivatives
o amplified effect of oe utatio
• 70% of mutations are inactivating which means there is complete GPI loss; worse phenotype
o 30% of mutations are missense = partial GPI loss; better phenotype
o You can have one type of mutation in one HSC; and another in another; giving two sub-
clones
• CD59, CD24 and FLAER (GPI binding protein) are useful diagnostic markers
• The idea is that there is a fluid dynamic between the proportion of normal/mutated HSCs; and that
when the balance is tipped too far; symptoms occur
3. Clinical features of PNH
• Intravascular haemolysis = anaemia + haemoglobinuria
o It can lead to acute renal failure
o Bone marrow failure, iron deficiency and folate deficiency can all further contribute to
anaemia
• IV haemolysis = free Hb in blood = effects of depleted NO
o Coaguloation related - Vasoconstiriction, thrombosis, platelet activation
o SMC related - oesophageal spasms, erectile dysfunction
• Venous (and arterial) thromboembolism
o Due to platelet activation from low CD59 levels, low uPAR, low NO and microparticle release
following lysis
o Not all patients are affected and it seems to be more common in the west than east
o Hence PNH is probably contributory but not sufficient to cause thrombosis
o Can cause budd chiari and stroke
o Diagnosi with MRA/ US+doppler
• Bone marrow failure and cytopenias (see below)
4. Treatment of PNH
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Document Summary
It can lead to acute renal failure: bone marrow failure, iron deficiency and folate deficiency can all further contribute to anaemia. Lowers transfusion dependence; 49% of patients did not require a single transfusion: reduces frequency of thromboembolic events; especially in patients where >50% of granulocytes carry the mutation. Improves quality of life & survival: other treatments needed include vaccination against meningococcus/pneumococcus/haemophilus due to increased risk of infection. It is generally reserved for young aptients with moderate/severe bone marrow failure as they are at an increased risk of developing mds/aml. 3. 24 - haemophagocytic lymphohistiocytosis (hlh: normal cytotoxic t cell response to viral infection. It starts with the following 2 interactions between ctl and apc: receptor - hla1-tcr, coreceptor - b7-cd28. Inability to lyse target cells: uncontrolled proliferation of t cells, nk cells and macrophages, cytokine storm; extensive production of cytokines eg tl1, il6, tnfa.
