Red Blood Cell Disorders Flashcards
Features of red cell membrane
-No nucleus
-No mitochondria
-Lack the HLA antigen - human leucocyte antgen
-highly flexible - can deform in shape to increase length by 250%
Func + structure of RBCs
-O2 transport - reactive oxygen species (ROS)
-CO2 transport - formation of HCO3
-H+ transport maintaining pH
large surface for diffusion of gases
cytoskeletal proteins for elasticity
membrane as an osmometer (Na/K ATPase)
How does Sickle Cell Haemoglobin HbS occur
-When glutamic acid is replaced by valine at position 6 along the ß chain
-Results in insolubility and crystallisation of the deoxygenated hb molecules (deoxy hb)
-The cell then takes up the sickle or tactoid shape
-Re-oxygenation results in rapid reversal but this can only be maintained for a short time
What does sickle cell anaemia occur from?
Homozygosity for the Bs gene
What is sickle cell trait?
Heterozygous for the Bs gene
What does sickling depend on?
-Deoxygenating - problems arise in situations of O2 deprivation e.g under anaesthesia or high altitude
-Dehydration and fever can increase the sickling process and the conc of HbS within the cell
When are patients that are heterozygous sickle cell trait affected by the sickle cells?
-Under normal circumstances - no in-vivo sickling
-Problems occur in situations of O2 deprivation e.g under anaesthesia or high altitude
-Pregnant women can be more likely to lose their baby
What can the heterozygous (HbSS) Sickle cell help prevent
Death by malaria
red cell membrane components?
-Double layer of protein (50%), phospholipids (20%), cholesterols (20%), carbohydrates (10%)
-Carbs only occur on external surface - proteins are either peripheral or integral penetrating the lipid bilayer
What proteins are involved in maintaining the bi concave shape of red cells?
Spectrin (alpha and beta), ankyrin, protein 4.1 and actin
-Look at diagram of rbc membrane
What are the principle transmembrane glycoproteins and what do they do?
-Band 3, glycoprotein A (GPA) and Rh associated glycoprotein (RhAG)
-Func in providing recognition, transport and anchorage sites
What happens when static shear stress is applied to the RBC membrane?
-Lipids and proteins diffuse within the lipid bilayer
What are protein components of the red cell membrane with transport functions and what do they transport?
-Band 3: major anion transporter and central to gas exchange by exchanging the bicarbonate ion and chloride
-Aquaporin: transporter of H20, O2 and CO2
-Glut-1: involved in glucose and L-dehydroascorbic acid transport
-Kidd (blood group) antigen: urea transport
-RhD protein antigen: associated w ammonia and CO2 transport
What are the enzymes present in the RBC membrane
Na/K/Ca ATPase, carbonic anhydrase, alkaline phosphatase, lactate dehydrogenase
What genes are mutated in Hereditary Spherocytosis?
Genes producing Spectrin and Ankyrin - affcets the protein interactions between the skeleton membrane and lipid bilayer of the red cell membrane
What are the 2 deficiency options in spherocytosis?
A) Spectrin /Ankyrin deficiency - reduced density of membrane skeleton destabilises overlying lipid bilayer
B) Band 3/ protein 4.2 deficiency - loss of band 3 lipid-stabilising effect
-release of microvesicles
What happens in hereditary elliptocytosis?
-The cytoskeleton is disrupted at the alpha - beta spectrin linkages or at the spectrin-actin-4.1 R junctional complexes
Biochemical pathways involved in red cell metabolism?
-The anaerobic glycolytic (Embeden-Meyerhof) pathway - plays a major role in supplying energy in the form of ATP to cell
-The Rapaport-Leubering Shunt - is a side shute of the above pathway, produces 2-3 DPG - major role in relation to oxygen affinity between Hb and tissues
-The Pentose Phosphate Pathway/ Hexose Monophosphate shunt - 10% of glycolysis occurs by this oxidative pathway which provides reducing power to the red cell in form of Glutathione and NADPH
What are the 2 ways glucose is metabolised in the RBCs?
a) Glycolytic or energy producing pathway provides ATP
b) Hexose monophosphate Shunt or protective pathway - provides NADPH
What do RBCs use ATP for?
-Phosphorylation of sugars and proteins
-ATPase driven ion pumps
-Maintenance of membrane asymmetry
-Maintenance of red cell shape and deformability using ATP dependent cytoskeleton
Look at Pentose phosphate pathway
Examples of common RBC enzymopathy disorders
- Pyruvate kinase deficiency
- Glucose-6-phosphate dehydrogenasew deficiency
- Pyrimidine 5’ nucleotidase deficiency
- Cytochrom b5 reductase deficiency
- Familial 2,3-bisphosphoglycerate deficiency
What happens in Pyruvate Kinase Deficiency?
-Key enzyme of glycolysis- sole source of energy for the red blood cell
-Catalyses the irreversible phosphoryl group transfer from phosphoenolpyruvate to ADP, yielding pyruvate + ATP -
-No ATP for Na K pumps to maintain cell shape
What happens in Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency?
-Most common metabolic disorder of RBCs
-X-chromosome linked hereditary transmission -women(heterozygous or homozygous) - men (hemizygous)
-The HMP shunt pathway metabolises 5-10% of glucose used by the RBC and this is critical for protecting red cells against oxidant injury
-Commonly characterised by acute hemolytic episodes in the setting of oxidative triggers like fava beans, infections and certain medications
