Blood and Body Fluid

January 30, 2018 | Author: Anonymous | Category: Science, Health Science, Immunology
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Chapter 3 Blood Physiology • Blood composition and properties • Blood cells – – – –

Hematopoiesis RBC: function, anemia. WBC Platelet: function, coagulation and fibrinolysis.

• Blood grouping and transfusion

Introduction • Blood volume: 7~8% (70-80ml/kg B.W) – Plasma (60%) and cells (40%).

• Types of blood cells: – RBC (Erythrocytes), WBC (Leukocytes) and Platelets (Thrombocytes)

• Main function: – Maintain homeostasis • Buffering pH • Humoral regulation • Body temperature regulation

– Transportation: • Gases, nutrients, hormones, and so on.

– Host defense: • Immune reaction, coagulation.

Section 1 Components and Characteristic Water: 93-95% Plasma: 50-60%

Whole blood

Solutes: 5-7% Proteins: Nutrients Products Electrolytes: Others: urea, gases. WBC, Platelet: 1% RBC: 40-50% (male) 37-48% (female)

Blood Components • Water: – 93~95% (plasma); 65~68% (RBC); 81~86% (whole blood). – Solvent, humoral balance, osmotic pressure.

• Electrolytes: – Na+, K+, Mg2+, Cl-, HCO3-, etc. Cell shape, pH.

• Proteins: – Albumin: 40-48g/L. Colloidal osmotic pressure; carrier; buffer pH. – Globulin: 15-30g/L. Immune reaction: antibody; carrier. – Fibrinogen: 2-4g/L. Blood coagulation.

– Hemoglobin (Hb): • 120-160g/L (male), 110-150g/L (female) • Function: carry gases.

• Others: – carbohydrates, lipids, amino acid, pigments, hormones, gas (O2, CO2), and others like urea, uric acid.

Physical and chemical properties • Blood pH: – Normal interval: 7.35~7.45. • Regulated by lung and kidney.

• Viscosity: – Friction of molecules and cells in blood. – Relative viscosity: • Whole blood: 4~5 times to water (RBC). • Plasma: 1.6~2.4 times to water (Proteins). • Anemia or body fluid loss.

• Osmotic pressure – Definition: • An ability of a liquid to attract and retain water. It drives osmosis. 300mmol/L

– Composition and roles: • Crystal osmotic pressure: 298.7 mmol/L. – Maintain shape and size of cells. • Colloid osmotic pressure: 1.3 mmol/L. – Retain blood volume – Decide distribution of water between blood and interstitial fluid.

Section 2 Blood Cells

• Red blood cell • White blood cell • Platelet

Hemopoiesis • The process of blood generation. Cell Lineage


Daily Production Rate


120 days

2.5  109/L


7 hours

0.85  109/L


10 days

2. 5  109/L

• Ontogeny of Hematopoiesis – Prenatal stages: • First month: yolk sac. • Third month: liver • Fourth month: bone marrow

– Postnatal stages: • Bone marrow of almost any bone, predominatantly by flat bones and long bones.



Hemopoitic activity (%)

Yolk Sac

Bone morrow


Lymph nodes












Prenatal age (months) Proportion of Red Morrow (%)



100 Vertebrate


Sternum Femur







Postnatal age (years)





– Stage 1, hemopoietic stem cells: pluripotent uncommitted stem cells. – Stage 2, committed progenitor cell: unipotent committed stem cells. Includes: • • • •

Erythrocytic progenitor cell Megakaryocytic progenitor cell Granulocytic progenitor cell Lymphocytic progenitor cell

– Stage 3, precursors (cell): immature cells, differentiate functional cells. Including: • Ery. progenitor erythrocytes. • Mega. progenitor  platelets. • Gran. progenitor  granulocytes and monocytes. • Lym. progenitor  T and B lymphocytes.

• Hematopoietic growth factor and related molecules – Necessary for proliferation and differentation of hematopoietic cells in the marrow. – Colony-stimulating factors (CSF): see a table in next slide. – Cytokines: • IL-1, stem cell factor (SCF), etc. – Extracellular matrix proteins: • Sulfated glycosamimoglycans and heparin sulfate, may concentrate hematopoitic growth factors in local micro environment; • Fibronectin and hemonectin, mediate adhension of cells, and may serve a growth promoting function.

Hematopoietic growth factors Growth Factors

Function: stimulate progenitor of the followings:

GM-CSF (granulocytemacrophage CSF)


G-CSF (granulocyte CSF)


M-CSF (macrophage CSF)


EPO (Erythropoietin)


IL-1,3,6 (Interleukin-3, 1, 6)

Myeloid lineage

TPO (Thrombopoietin)


Red blood cells (erythrocytes) • Circular, biconcave discs without nuclei. 7~8m, thickness 1~2.5 m.

• Cell count and volume: – Hematocrit: Percentage of blood volume occupied by packed cell volume.

– Volume: • 4.5~5.51012/L, average 5.01012/L (male). • 3.8~4.61012/L, average 4.21012/L (female).

• Physical properties – Permeability: – Deformation: – Fragility and hemolysis: • Isosmotic solution and lower osmotic solution – Suspension stability: • The erythrocytes are very stable in suspension. • Cause: repelling force of same charge and bigger surface area.

• Erythrocytes Sedimentation Rate (ESR): Sedimentated distance of RBC after one hour. – 0~15 mm/h (male), 0~20 mm/h (female). – Ratio of Surface area/Volume of RBC. – Albumin, globulin, fibrinogen, and cholesterol. – Rouleaux: RBC aggregate.

• Function of RBC: – The main constituent of RBC is hemoglobin. – To deliver O2 to tissues by hemoglobin.

Hemoglobin (HB) • HB is made up of two polypeptide  chains and  chains. • Each polypeptide has alpha helical segments folded and bent into a globular configuration, with a heme ring within a pocket where the iron molecule can interact with oxygen.

• Hb formation materials: – Protein: enough intake from food. – Iron: 3-4g/person. Mainly in Hb (70%). • Degrading Hb: 95%. • Absorbed from small intestine: 1mg/d, 5%. • Microcytic hypochromic anemia: Lack of iron.

• RBC Maturation factors: – Vitamin B12: • Cobalamine, 2~5g/d. • Produced by gut bacteria (esp. in ruminants). Good sources include meat, liver, fish, eggs and milk. • Absorbed in terminal ileum with intrinsic factor’ help. • Function: Improve utilization of FA.

– Folic acid: • • • •

FA is essential for the synthesis DNA. Synthesized by microorganisms and higher plants. Good sources are green leafy vegetables, yeast and organ meats. Absorbed in the proximal jejunum.

– Lack of folic acid and vitb12: give rise to immature cells due to DNA synthesis derangement. – Megaloblast anemia.

•Regulation of erythropoiesis: Hypoxia:  EPO RBC Hemopoitic stem cell (uncommitted progenitor)  Erythrocytic progenitor (committed progenitor)  EPO Pronormblast (precursor)  Normoblast, Reticulocyte  Mature RBC (without nucleus)

• Erythropoietin (EPO): – A glycoprotein, 34kd. Produced in interstitial cells in cortical kidney such as fibroblast, endothelial cells.

– Roles: • Erythrocytic progenitor proliferate and differentiate to precursor. • Accelerate precursor proliferation and differentiation. • Promote bone marrow release reticulocytes. • Renal type anemia: EPO production decrease

• Other hormones: – Androgen, thyroid hormone, parathyroid hormone,etc.

• RBC destruction: – Life span of RBC is about 120 days. Older cells

White blood cells (leucocyte) • WBC: – 4~10109/L, average is 7109/L. – Include: • neutrophil, eosinophil, basophil • monocyte, lymphocyte.

– Protection, execute specific and non-specific immune reaction.

• Physical and chemical properties – Chemotaxis: attracted by chemical substances released by bacteria and foreign substances. – Movement: Move to chemotaxic source – Phagocytosis: engulf and digest

Composition and functions • Neutrophil: – 10~12m, 2.0~7.0109/L, 60-70%. – Function: • Phagocytosis: older cells, becteria, dead tissues, and other foreign substances. • To execute non-specific immune activity in first front.

• Monocytes: – 15~30m, 0.12 ~ 0.8109/L, 3 ~ 8%. – Monocytes-macrophages system: • Monocytes (in blood) wander into tissues and become macrophages (50 ~ 80 m). Stronger phagocytosis. • Contain many kinds of cytokines such as CSF, ILs, TNF, INF-a,b.

– Roles: • Engulf and clear: bacteria, vermins, older, necrotic tissues, dead neutrophils, dead cells and fragments. • Activate lymphocytes to execute specific immune response. • Recognize and kill cancer cells. • Produce CSF, Ils, TNF, INF-, , regulate growth of granulocytes.

• Lymphocytes: – 0.8~4.0109/L, 20 ~ 40%. – Development of lymphocyte: • T lymphocyte: – lymphocytic stem cells  T lymphocytes (thymus gland).

• B lymphocyte: – lymphocytic stem cells  B lymphocytes (lymphoid tissue).

– Functions: • T lymphocytes: cellular type of immunity • B lymphocytes: humoral immunity

• Eosinophils – 0.02~0.5 109/L, 0.5~5%. – Functions: • Inhibit allergic reaction induced by basophils: – Produce PGE to inhibit secretion of basophils; – Engulf substances secreted by basophils; – Secrete matters to hydrolyze histamine and 5-HT. • Phagocytic action to some worms.

• Basophils – 0.0~1.0  109/L, 0~1%. – Large cytoplastmic granules contain heparin, 5hydroxytryptamine and histamine. – Function: • Secrete heparin blood to prevent coagulation. • Wander into tissue and become mast cell. • Induce allergy.

Platelet • Hemostasis: – The process of blood clotting and then the subsequent dissolution of the clot. Platelet  activation  adhension  aggregation  clot  thrombus  FDP



ADP and TXA2




Blood Coagulation


• Anatomic physiology of platelet: – 2~4 m, thickness 1m.

Fibrinogen GP IIb/III a Phospholipid


Ca2+ Receptor




– Membrane: • Receptor: For adhension, aggregation and coagulation. • Phospholipid: provides the lipid cofactors needed for coagulation reactions.

– Granules in platelet: • -granules: coagulation factors, growth factors (e.g. PDGF). • -granules (dense bodies): Ca2+, ADP and serotonin. – Volume: 100~300 109/L in adult. • Thrombocytopenia: 1000109/L,  Thrombosis

• Physical properties – Adhesion: • Mediated by von Willebrand factor (vWF). • vWF is producted and stored in a-granules of platelets. Also synthesized by megakaryocytes. • Function of vWF: – To act as a bridge between glycoprotein on the surface of platelets (GPIb/IX) and collagen fibrils. – Serves as a carrier protein for factor VIII.

• von Willebrand Disease (vWD): deficiency in vWF a patient with long bleeding time, a low level of factor vWF/VIII complex. • Bernard-Soulier Syndrome:deficiency of glycoprotein Ib/IX.

– Aggregation: • Activated platelets aggregate together. • Activation of platelets: induced by thrombin. – – – –

Thrombin + receptor  initiate signal cascade. G-protein, and phospholipase C(PLC-g). PLC-g  IP3 and DAG formation. IP3  Ca2+ , and DAG  PKC.

• Mechanisms: – Ca2+  phospholipase A2 (PLA2) arachidonic acid  thromboxane A2 (TXA2) – PKC ADP  fibrinogen to adhere to two platelet surface glycoproteins (GPIIb and GPIIIa)  fibrinogen-induced platelet aggregation. – Glanzmann-Thrombasthenia, deficiency of glycoprotein IIb/IIIa.

• Contractile function: – PLC-g  Ca2+  myosin light chain kinase (MLCK) – MLCK  phosphorylation of light chain of myosin – Myosin interacts with actin – Platelet morphology, motility, and clot retraction.

• Roles of platelet: – Platelet clot formation at the site of vessel injury (primary hemostasis); – Enhance activation of coagulation factors to solidify platelet clot by interlacing with fibrin (secondary hemostasis).

• Platelet function disorders: – Disorders of platelet adhesion: • Bernard-Soulier Syndrome: deficiency of glycoprotein Ib/IX.

– Disorders of platelet aggregation: • Glanzmann-Thrombasthenia, deficiency of glycoprotein IIb/IIIa.

– Disorders of platelet secretion: • Alpha or Dense Granules Deficiency.

– Disorders of platelet procoagulant activity: • Platelets fail to promote activation of the blood clotting proteins.

– Acquired platelet function disorders: • Drugs like aspirin, non-steroidal anti-inflammatory drugs like indomethacin, ibuprofen.

Blood coagulation • A process of blood from liquid to colloid. A serious of enzymes reactions.

• Coagulation factors: – Factors involved in the blood coagulation – Attentions: • FIII come from tissue, others from plasma. • FIV is Ca2+, and others are proteins. • FII, VII, IX, XII exist as proenzymes.


Trivial Name(s)

Pathwa y


Fletcher factor

Intrinsi c

High molecular weight kininogen (HMWK)

contact activation cofactor; Fitzgerald, Flaujeac Williams factor

Intrinsi c









Tissue Factor

Extrins ic

Contains N-term. gla segment -





Proaccelerin, labile factor, accelerator (Ac-) globulin


VI (Va)



Proconvertin, serum prothrombin conversion accelerator (SPCA), cothromboplastin

Extrins ic

Endopeptidase with gla residues


Antihemophiliac factor A, antihemophilic globulin (AHG)

Intrinsi c

Protein cofactor


Christmas Factor, antihemophilic factor B,plasma thromboplastin component (PTC)

Intrinsi c

Endopeptidase with gla residues


Stuart-Prower Factor


Endopeptidase with gla residues


Plasma thromboplastin antecedent (PTA)

Intrinsi c



Hageman Factor

Intrinsi c



Protransglutaminase, fibrin stabilizing factor (FSF), fibrinoligase



Protein cofactor This is Va, redundant to Factor V

clotting cascade

Stage 1: Formation of prothrombin activator. Stage 2: Conversion of prothrombin to thrombin.

Stage 3: conversion of fibrinogen to fibrin

• Difference of stage 1: – Prothrombin-converting enzyme: Xa, Ca2+, V, PL. – Difference of factor Xa: • Intrinsic stage: – Start from XII. The intrinsic pathway requires factors VIII, IX, X, XI, and XII. Also required are the proteins prekallikrein and high-molecular-weight kininogen, as well as Ca2+ and phospholipids secreted from platelets.

• Extrinsic stage: – Start from FIII (TF), is initiated at the site of injury in response to the release of TF. – TF is a cofactor in the factor VIIa – Factor VIIa, cleaves factor X to factor Xa

Prevention of coagulation • Plasma inhibitors • Fibrinolysis • Role of the endothelial cells

Plasma inhibitors Inhibitor

Mol. Weight (kD)


Plasma Conc. (mg/ml)

Antithrombin III


Antiserine protease










Protein c


Anti-factor V and Viii


• Antithrombin III: – Nonspecific protease inhibitors – Produced in liver and endothelial cells – Inhibit active sites of FIXa,FXa,FXIa,FXIIa, thrombin.

• Protein C: – Vitamin K-dependent protein – Is activated to activited protein C (aPC) by thrombin in presence of endothelial cell-derived cofactor thrombomodulin. – aPC inactivates FV and FVIII in presence of another vitamin K-dependent cofactor: protein S. – See next slide.

Anticoagulation pathway VIII







+ Va




Thrombin FI


• Heparin: – – – – –

A polysaccharide produced in basophilic mast cells Distributed in the pericapillary tissue. Abundant in lung, heart, liver, muscle tissues. Inhibit thrombin conversion. Promote antithrombin III activity.

• Calcium ions precipitants: – Sodium citrate

Fibrinolysis • Fibrinolysis: – Process of liquefaction of fibrin



plasmin Inhibitor


fibrin degradation products

Activator: Tissue plasminogen activator (tPA), urokinase. Plasmin, a serine protease, is inhibited by 2-antiplasma.

• tPA: – Released from vascular endothelial cells following injury; – Binds to fibrin and is consequently activated.

• Urokinase: – Produced as the precursor, prourokinase by epithelial cells lining excretory ducts. – Role: to activate the dissolution of fibrin clots.

• plasminogen activator-inhibitors: – PAI-1 and PAI-2

Endothelial cells • Endothelium produces several inhibitors of hemostasis: – Prostaglandin I2: • secreted by endothelial cells and is a potent inhibitor of platelet aggregation.

– Thrombomodulin: • Enhances the activiation of protein C by thrombin and results in the inactivation of factor V and VIII.

– Heparans: • a heparin-like molecule, produced by endothelial cells. Increase the anticoagulant effect of antithrombin III.

– Plasminogen activator: • necessary for dissolution of fibrin clots, such as tPA.

Coagulation disorders • Hemophilia A: – Deficiency of FVIII. The disease severity usually parallels the factor VIII levels. – Serve (< 1% VIII): with spontaneous bleeding; – Moderate (1-5% VIII): with occasional bleeding, usually with trauma; – Mild (6-30% VIII): with bleeding only after surgery or trauma. – Therapy: administration of FVIII.

• Hemophilia B (Christmas Disease): – FIX deficiency. – Treatment requires IX-rich material: fresh frozen plasma (FFP) or lyophilized concentrates proagulatant proteins.

• Decreased production of coagulation factors: – E.g. Liver disease, vitamin K malabsorption, dietary deficiency of vitamin K.

• Inactivation of coagulation factors: – e.g. specific inhibitors, excessive activation of coagulation (DIC) and/or enzymatic destruction of coagulation factors.

Blood grouping and transfusion • The discovery of blood groups: – 1901, Austrian Karl Landsteiner discovered human blood groups. – Blood agglutination was an immunological reaction. – Awarded the Nobel Prize in Physiology or Medicine in 1930.

• Agglutination: – Agglutinogen: antigen on membrane of RBC. – Agglutinin: antibody in the plasma.

• RBC grouping: – ABO, Rh, MnSs, lewis – The differences in human blood are due to the presence or absence of certain protein molecules called antigens and antibodies.

ABO grouping Blood group A:A antigens on the surface of RBC, B antibodies in blood plasma. Blood group B:B antigens on the surface of RBC, A antibodies in blood plasma. Blood group AB:both A and B antigens on the surface of RBC, no A or B antibodies at all in blood plasma. Blood group O:neither A or B antigens on the surface of RBC, but you have both A and B antibodies in blood plasma

• Antigens and antibodies: – Antigens: • A, B. • Carbohydrate

– Antibodies: Antibody A and B. • Ig M: congenital, • Bigger Mr.

Rh grouping • Original discovery: – Rhesus monkey: Red cells  injected into rabbits  got serum  injected back to Rhesus monkey, or human  agglutination happens.

• Rh antigen and antibody – Antigen: D, E, C, c, e. • 99% Chinese people are Rh+ • Minority in China 2-5% is Rh• 15% western people are Rh– Antibody: IgG

Which blood group do you belong to?

A Rh+

B Rh+

AB Rh+

O Rh+

A Rh-

B Rh-

AB Rh-

O Rh-

Blood Transfusion • Clinical significance: – ABO and Rh blood groups must be compatible between the donor blood and the patient blood. – Agglutinated RBC clog blood vessels or crack to becomes toxic when HB outside the cell.

• Cross-match test: – Main lateral: donor’s RBC and recipient’s serum. – Co-lateral: donor’s serum and recipient’s RBC.

• Principle of blood transfusion: – Agglutination of main lateral: absolutely no. – Both of main and co-lateral do not agglutinate: – Co-lateral agglutinates but Main lateral: • slow and less amount of blood transfusion could be recommended.

People with blood group O are called “universal donors”.

People with blood group AB are called “universal receivers”.

• Clinical importance for Rh group: – Blood transfusion between Rh+ and Rh- persons. – A mother who is Rh- woman give birth a baby who is Rh+. – Preventive measure: given an injection of anti-Rh antibodies.

Donor RBC


Recipient RBC (co-lateral)

Serum (main lateral)

Cross match test

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