Physiology of the Blood

1. PHYO6200 Physiology of the Blood HAO Quan(??) Department of Physiology, LKS Faculty of Medicine Contact: qhao@hku.hk; tel: 2819-9194 Office: L4-48, Laboratory Building References: Medical Physiology, by R. Rhodes (Wolters Kluwer) Human Physiology, by Vander, Sherman & Luciano

2. PHYO6200 Composition and functions of Blood Four major roles: Transport of substances Defense against disease Arrest of bleeding Maintenance of a stable environment

3. PHYO6200 Transport Blood is the primary means of long-distance transport in the body: Oxygen, carbon-dioxide, and other gases Antibodies, acids and bases, ions, vitamins, nutrients, lipids, and water Heat

4. PHYO6200 Immunity Blood leukocytes, together with plasma proteins, detect and eliminate (in most cases) microorganisms.

5. PHYO6200 Hemostasis Hemostatic mechanisms can stop bleeding. The failure to control profuse bleeding after injury can quickly lead to exsanguination and death.

6. PHYO6200 Homeostasis The blood system helps maintain a steady state that provides an optimal internal environment for cell function: pH ion concentrations osmolality temperature nutrient supply vascular integrity

7. PHYO6200 The elements of blood An adult has ~ 5 L of whole blood 55% liquid portion (plasma); 45% cellular portion

8. PHYO6200 In Plasma Water (93%) Proteins (albumins, globulins and fibrinogen) Carbohydrates Ions (Na+,Cl-,HCO3-,K+,Ca+,HPO4-,Mg2+,…) Vitamins Lipids (fats)

9. PHYO6200 Cellular portion of blood Erythrocytes (red blood cells) Leukocytes (white blood cells) Thrombocytes (platelets)

10. PHYO6200 Blood cell formation Sites of haemopoiesis Fetus: 0-2 months – yolk sac 2-7 months – liver, spleen 5-9 months – bone marrow Infants: bone marrow of all bones Adults: bone marrow of ribs, skull, ……

11. PHYO6200 Erythrocytes (Red blood cells)

12. PHYO6200 Red cell formation (erythropoiesis) The hormone erythropoietin regulates erythropoiesis. About 90% of erythropoietin is produced by the kidney and 10% by the liver. Red cell precursors are stimulated by erythropoietin to proliferate, differentiate and produce hemoglobin.

13. PHYO6200 Hemoglobin The main function of the red blood cell (carrying O2 ) is performed by protein hemoglobin.

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15. PHYO6200 Normal breakdown of red blood cell Red cell destruction occurs after a mean lifespan of 120 days when the cells are removed by the macrophages of the reticuloendothelial system (RES). Iron is transported by protein transferrin from macrophages to bone marrows and stored as ferritin. Globin chains are broken down to amino acids which are re-utilized.

16. The delivery of iron (III) by human serum transferrin (hTF). PHYO6200

17. PHYO6200 Crystal structure of a human ferritinwww.pdb.org

18. PHYO6200 Blood groups and blood transfusion Blood transfusion involves the infusion from the donor to the recipient. Potentially fatal reactions (agglutination, capillary blockage, kidney failure) may occur if the donor red cell antigens and the recipient’s plasma antibodies are incompatible.

19. PHYO6200 Red cell antigens Individuals who lack a particular blood antigen may produce antibodies reacting with that antigen. The ABO and Rh are major blood group systems.

20. PHYO6200 ABO antigens wikipedia.org The H antigen is an essential precursor to the ABO blood group antigens. The H locus is located on chromosome 19. It contains 3 exons that span more than 5 kb of genomic DNA, and it encodes a fucosyltransferase that produces the H antigen on RBCs. The H antigen is a carbohydrate sequence with carbohydrates linked mainly to protein (with a minor fraction attached to ceramide moiety). It consists of a chain of ß-D-galactose, ß-D-N-acetylglucosamine, ß-D-galactose, and 2-linked, a-L-fucose, the chain being attached to the protein or ceramide. The ABO locus is located on chromosome 9. It contains 7 exons that span more than 18 kb of genomic DNA. Exon 7 is the largest and contains most of the coding sequence. The ABO locus has three main alleleic forms: A, B, and O. The A allele encodes a glycosyltransferase that bonds a-N-acetylgalactosamine to D-galactose end of H antigen, producing the A antigen. The B allele encodes a glycosyltransferase that joins a-D-galactose bonded to D-galactose end of H antigen, creating the B antigen. In case of O allele the exon 6 contains a deletion that results in a loss of enzymatic activity. The O allele differs slightly from the A allele by deletion of a single nucleotide - Guanine at position 261. The deletion causes a frameshift and results in translation of an almost entirely different protein that lacks enzymatic activity. This results in H antigen remaining unchanged in case of O groups.

21. PHYO6200 Diagram showing the carbohydrate chains which determine the ABO blood group, wikipedia.org

22. PHYO6200 ABO system

23. PHYO6200 Transfusion compatibility

24. PHYO6200 Rh blood group system This is the second most clinically important blood group system. IgG anti-RhD antibodies in RhD- individuals may develop after exposure to RhD+ red blood cells following blood transfusion or during pregnancy.

25. PHYO6200 Blood clot formation The normal hemostatic response to vascular damage involves platelets, endothelial cells and coagulation factors. Hemostasis (the physiological process to stop bleeding) is organized into four steps.

26. PHYO6200 Step 1 – constriction An immediate vasoconstriction of the vessel and reflex constriction of adjacent small arteries is responsible for an initial slowing of blood flow the area of injury.

27. PHYO6200 Step 2 – Primary platelet plug formation Platelets are irregularly shaped, disk-like fragments (1.5 – 3.0 µm) of their precursor cell, the megakaryocyte. Platelet adhesion is potentiated by von Willebrand factor (VWF). Ruptured cells at the site of tissue injury release adenosine diphosphate (ADP), which causes platelets to aggregate at the damaged site. The unstable primary plug produced by these platelets reactions in the first minute or so following injury is sufficient to provide temporary control of bleeding.

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29. PHYO6200 Step 3 – Stabilization of the platelet plug by fibrin Both the extrinsic and intrinsic pathways of coagulation are activated with the formation of activated factors. Activation of factors particularly by thrombin catalyzes the generation of fibrin. Fibrous strands of fibrin eventually form a stable blood clot.

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31. PHYO6200 Strands of fibrin (biomaterials)

32. PHYO6200 Step 4 – Clot retraction & fibrinolysis Clot retraction reduces the size of the injured area, making it easier for wound healing. Fibrinolysis is the dissolution of the fibrin clot, which is mainly a function of the protease, plasmin.

33. PHYO6200 White blood cells & Host defense This part will be covered in PHYO6100 (Cell Biology)

34. PHYO6200 BLOOD AND IMMUNE DISORDERS Anemia - defined as a hemoglobin concentration in the blood of less than 13.5 g/dL in adult males and less than 11.5 g/dL in adult females. Causes: Defective hemoglobin or red cell synthesis Excess loss or destruction of red cells

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36. PHYO6200 Hemoglobin The main function of the red blood cell (carrying O2 ) is performed by protein hemoglobin.

37. PHYO6200 Classification Anemia is classified by the size of red blood cells, mean corpuscular volume (MCV). If the cells are smaller than normal (< 80 fl), the anemia is said to be microcytic; if they are normal size (80-100 fl), normocytic; and if they are larger than normal (> 100 fl), the anemia is classified as macrocytic.

38. PHYO6200 Causes of microcytic anemia Iron deficiency anemia may arise from chronic blood loss or dietary deficiency. The pathogenesis of anemia of chronic disorders (chronic inflammation or malignancy) appears to be related to decreased release of iron from macrophages to plasma, reduced red cell lifespan and an inadequate erythropoietin response to anemia caused by the effects of cytokines on erythropoiesis. Thalassaemias are a heterogeneous group of genetic disorders which result from a reduced rate of synthesis of ? or ? globin chains. Whereas hemoglobin pattern may help to detect ?-thalassaemia trait, DNA tests need to be conducted for identification of ?-thalassaemia trait.

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40. PHYO6200 Causes of Normocytic Anemia Hemodilution after acute blood loss Anemia of chronic disorders ? some cases of chronic inflammation and malignancy Renal diseases (inadequate secretion of erythropoietin) Many hemolytic anemias (excessive destruction of erythrocytes) Bone marrow failure e.g. post-chemotherapy (toxic drugs) and infiltration by carcinoma Mixed B12/ folate and iron deficiency

41. PHYO6200 Causes of Macrocytic Anemia Hemolysis or hemorrhage (associated with increased reticulocyte count) Megaloblastic or non-megaloblastic anemias (associated with normal or low reticulocyte count) - Megaloblastic: vitamin B12 or folate deficiency - Non-megaloblastic: Liver diseases, alcohol, some cases of other diseases

42. PHYO6200 BLEEDING DISORDERS Abnormal bleeding may result from Thrombocytopenia (low platelet count) Platelet function defects Defective coagulation Vascular disorders

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46. PHYO6200 Causes of Thrombocytopenia Failure of Platelet Production This may be due to selective megakaryocyte depression (induced by drugs, chemicals or viral infections) or as part of general bone marrow failure. Increased Destruction of Platelets Immune (idiopathic, drug-induced, infections and other causes) Disseminated intravascular coagulation (DIC) Abnormal Distribution of Platelets Dilutional Loss Massive transfusion of stored blood to bleeding patients

47. PHYO6200 Platelet Function Defects Hereditary Disorders Several rare inherited disorders may produce abnormal platelet functions leading to defective formation of the platelet plug, e.g. in Glanzmann’s disease, primary platelet aggregation fails to occur because of deficiency of membrane glycoproteins IIb and IIIa. Acquired Disorders Antiplatelet Drugs - Aspirin causes impairment of platelet function by inhibition of cyclooxygenase with impaired thromboxane A2 synthesis. It is used for the prevention of thromboembolic events in patients with symptomatic atherosclerotic disease. - Clopidogrel causes impairment of platelet aggregation by inhibiting the binding of ADP to its platelet receptor. Like aspirin, it is used for the prevention of thromboembolic events in patients with symptomatic atherosclerotic disease. Uraemia (a kidney failure) Hyperglobulinaemia (a liver disease) Myeloproliferative and Myelodysplastic Disorders

48. PHYO6200 Disorders of Coagulation Hereditary Deficiencies of Blood Coagulation Factors Hemophilia A ? Factor VIII deficiency Hemophilia B [Christmas disease] ? Factor IX deficiency Acquired Disorders of Coagulation Deficiency of vitamin K-dependent coagulation factors Liver disease Disseminated intravascular coagulation Coagulation deficiency caused by inhibitors Overdosage with anticoagulants Massive transfusion syndrome

49. PHYO6200 Vascular Bleeding Disorders The vascular disorders are a heterogeneous group of conditions characterized by easy bruising and spontaneous bleeding from the small vessels. The underlying abnormality rests in the vessels themselves or the connective tissues around the vessels. Hereditary hemorrhagic telangiectasia Dilated microvascular swellings develop in the skin, mucous membranes and internal organs. Acquired vascular defects Such as simple easy bruising, purpura associated with infection and many other causes.

50. PHYO6200 Review Describe the major functions of blood in regards to transport, protection, and homeostasis Identify the major components in blood Explain the functions of red blood cells and their formation, destruction and recycling Explain why the donor and recipient blood need to be compatible Discuss the phases of blood clotting from immediate actions to wound healing Calculate the volume of a red blood cell (assuming disk-shape, 7.0µm diameter, 2.5µm thick); Define the 3 types of anemias based on MCV Outline the likely causes of coagulation disorders