Topic 2 hemoglobin structure types RBC destrcution and Bilirubim metabolism.pptx

Hematology lecture notes

1. Haemoglobin: structure, function and types RBC: destruction and Bilirubin metabolism

2. Haemoglobin It comprises approximately 95% of the cytoplasmic content of RBCs RBC plasma membrane efficiently protect Hb from denaturation in the plasma and loss through the kidneys. Free Hb (may be from RBC destruction) has a short life span Function: Transport O 2 to Tissues and CO 2 from Tissues Participate in main acid-based balance (by binding and releasing hydrogen ions and transports nitric oxide (NO))

3. Haemoglobin structure It comprises: two different pairs of polypeptide chains Four heme groups , (each heme group imbedded in each of the four polypeptide chains)

4. Synthesized in the mitochondria and cytoplasm of RBC precursors ( pro erythrob last → reticulocyte ) Heme group positioned near the surface (in pockets) of each of globin proteins Ferrous bind O 2 reversibly; Fe 2+ bind O 2 whereas oxidized ferric ion (Fe 2+ ) does not bind O 2 Oxidized hemoglobin is also called methaemoglobin Structure of the heme group

5. H H Heme Biosynthesis Major site : Bone marrow & Liver cellular compartment involved: Mitochondria cytosol Defect in any of the enzyme(s) cause a disease called Porphyrias

6. Haemoglobin Each globin protein loop forming a cleft loop for heme group.

7. Globin polypeptide structure Haemoglobin consist of two identical pairs of unlike polypeptide . Variation in amino acid sequence give raise to different Hb protein

8. Globin polypeptide structure The different globin polypeptide encoded by two gene cluster: chromosome 11 ( β -like cluster) and chromosome 16 ( α -like cluster)

9. Different members of β –like and α -like gene clusters are produced during development. Complete Hb composition ( β –like and α -like) at during development. Haemoglobin (Hb) expression NB : A Hb molecule comprise two pairs of unidentical polypeptides (each pair consist of one member of β –like and α -like gene cluster)

10. Haemoglobin (Hb) Function Oxygen transport Hb reversibly bind O 2 -molecule In the lungs, high Hb require high affinity to take up O2 In the tissues, Hb require low affinity to unload O2 Each of the four iron atom in Hb can bind to one molecule of O2 Affinity to bind relate to partial pressure (define as the amount of oxygen required to saturate 50% of Hb.) At Low O 2 - tension (low O 2 levels), Hb has low O 2 - affinity (tissues) At high O 2 tension (high O 2 levels), Hb has high O 2 - affinity (lungs)

11. Haemoglobin (Hb) Function Oxygen transport When a molecule of O 2 bind to heme groups, the tetramer conformation changes and affinity of O 2 of the remaining heme groups increases. Meaning that Hb becomes readily oxygenated thereafter. Therefore, Hb is easily saturated in the lungs ( ↑ O 2 ) In tissues, Hb easily release O 2 ( ↓ O 2 ) Hb affinity for ( ↑ O 2 ) drop when Decreasing in pH (tissues) Increased 2,3-bisphosphoglycerate (stabilise deoxygenated Hb). It is released as Hb oxygenation continuous

12. Haemoglobin (Hb) Function Carbon dioxide transport Second vital function of Hb In tissues CO 2 diffuse into Venous blood & react with H 2 O, forming bicarbonic acid (H 2 CO 3 ) Next, (H 2 CO 3 ) dissociated to H + and bicarbonate (HCO 3 - ) H + bind oxygenated Hb and promote O 2 release for take-up by tissues. Simultaneously HCO 3 - accumulate and diffuse across RBC membrane into plasma while chloride diffuse into RBCs (CO 2 is transported by venous to lungs as HCO 3 )

13. Haemoglobin (Hb) Function Carbon dioxide transport In lungs the process is reverse H + released from deoxygenated Hb ( HHb )and promote O 2 uptake. H + released combine with HCO 3 - accumulate form CO 2 and H 2 O CO 2 diffuse out RBCs and is exhaled. The ability of Hb to bind to H + confers a buffering effect of Hb.

14. Haemoglobin (Hb) Function Carbon dioxide transport Plasma RBC RBC

15. Haemoglobin (Hb) Function Nitric oxide (NO) transport Hb involved in binding, inactivating and transport of NO No is secreted by vascular endothelial cells It causes relaxation of the vascular wall smooth muscle and vasodilation. Free NO has a short have life. Some diffuse in RBC and bind Hb to form S- nitrohemoglobin . There Hb have been proposed to preserve and transport NO to hypoxic ( ↓ O 2 ) microvascular areas to increase vasodilation and blood flow and delivery of O 2 NO is released from Hb where the low O 2 tension to promote vasodilation

16. Red blood cell destruction

17. Red blood cell have life span of 120 days i.e from reticulocytes released into circulation to sequestration of the senescent RBC in the reticuloendothelial cells of the liver and spleen. Like most cells, RBCs experience enzyme distortion during normal cell catabolism However, RBC lack of a nucleus makes it impossible to replenish new enzymes As a result, RBC under functional decline. They have enzyme sufficient for 120 days Lack of mitochondria make RBC reliant of glycolysis for energy generation. A decline of glycolytic enzyme in central to the process of ageing called senescence followed by destruction Red blood cell destruction

18. This is achieved via two major mechanisms: Macrophage-Mediated Hemolysis (Extravascular Hemolysis ) Mechanical Hemolysis (Fragmentation or Intravascular Hemolysis ) Mechanism of Red blood cell destruction

19. The spleen: Has a substantial volume of blood at any given time. It’s also a stressful environment for cells & RBC movement in the red pulp is sluggish As cell flow stagnate, glycolysis slows down due to rapid glucose depletion in plasma. Low pH ensues which oxidise iron. Since maintenance of reduced iron is energy dependent, Iron oxidation causes RBC to Use more energy (glycolysis) Accelerate catabolism of enzymes. RBC ageing ensue Macrophage-Mediated Hemolysis (Extravascular Hemolysis )

20. Effect of glucose depletion and deterioration of glycolysis: ATP ↓ ATP-dependent membrane systems begin to fail i.e enzymes maintaining location and reduction of membrane phospholipids. membrane lipids and proteins are oxidized ATP-dependent maintenance of intracellular Na + /K + balance fail: Na + / increase while K + decreases Consequently, water enter into RBC and, RBC is deformed (biconcave → spherical shape) RBC become rigid and cannot squeeze(splenic sieve)through the narrow spaces of the spleen. RBC become trapped and are ingested by macrophages. Macrophage-Mediated Hemolysis (Extravascular Hemolysis )

21. A small proportion of RBC die in the lumen blood vessels i.e intravascularly) Haemolysis of RBC in the blood vessels is via Traumatic stress: Caused by turbulence in the heart chambers. Mechanical stress These process lead to fragmentation and release of cell contents in surrounding plasma Thus this process is called fragmentation or intravascular hemolysis .. haptoglobin and hemopexin (backup protection system) salvage hemoglobin to prevent iron loss via urine. Mechanical Hemolysis (Fragmentation or Intravascular Hemolysis )

22. Bilirubin metabolism

23. By-products of RBC destruction Bilirubin is excreted

24. Protoporphyrin catabolism Protoporphyrin

25. Protoporphyrin Catabolism Increased bilirubin cause yellowing of; Skin ( Jaundice ) Plasma & tissue ( icterus ) Infections such as hepatitis can cause jaundice