Blood Handout PDF

# Composition of the blood ## Blood: Extracellular Fluid (ECF) - 5.6L (8% of weight) ## Composition of the blood - Plasma (55%) - 3.5L (5% of weight) - Clear Yellow fluid - Clots on standing; remaining fluid is serum ### Composition of Plasma  1. Water (90%) 2. Organic substances (9.1...

# Composition of the blood ## Blood: Extracellular Fluid (ECF) - 5.6L (8% of weight) ## Composition of the blood - Plasma (55%) - 3.5L (5% of weight) - Clear Yellow fluid - Clots on standing; remaining fluid is serum ### Composition of Plasma  1. Water (90%) 2. Organic substances (9.1%): protein, lipid, glucose, waste 3. Inorganic (0.9%): Na+, Cl-, HCO3-, phosphate, sulphate 4. Blood gases: O2, CO2, N2 - Cells (45%) 1. Red blood corpuscles 2. WBCs (leucocytes) 3. Platelets (thrombocytes) ## Plasma proteins (7.2-7.4 g/dl) - **Types:** - **Albumin** - (3.5-5 gm/dl) - Highest concentration - Lowest molecular weight - **Globulin** α, β, γ - (2.5) - **Fibrinogen** - (0.4) - **Prothrombin** - (0.01) - **Sites of Formation:** 1. Albumin, fibrinogen, prothrombin: **in liver** 2. Globulins: - 50% **in liver** (α, β) - 50% **in plasma cells** of Reticuloendothelial system (γ) - **Albumin/Globulin Ratio (A/G)** = 1.2-1.6. Decreased in: - Liver diseases (cirrhosis, hepatitis) - Kidney diseases (nephrosis) - Infection (↑y-globulins) - ↑loss of albumin in urine - **Synthesis of albumin** - ## Functions of Plasma Proteins 1. **Osmotic Function:** - Total osmotic pressure of plasma = 5000 mmHg - **Due to:** - **Colloidal (oncotic) pressure (65%)** - Plasma proteins (albumin) - 25 mmHg (Weak) - **Crystalloid osmotic pressure** - Crystalloids (Na+, Cl-, HCO3-) - Remaining (powerful) - **Power:** important osmotic effect - **Importance:** Cannot diffuse through capillary - **Cause:** Main re-absorptive (draw) force - Regulate fluid exchange and blood volume 2. **Capillary function:** Partially block capillary pores → ↓ permeability 3. **Transport:** By albumin & globulin (a & β), prevent loss of substances in urine. 4. **Defensive:** By γ-globulins (immunoglobulin) (antibodies) 5. **Blood clotting:** By prothrombin & fibrinogen 6. **Source of tissue protein:** Protein stores for tissue (Dynamic structures in continuous turnover) 7. **Viscosity:** due to fibrinogen (large size & elongated shape) - Blood is 3-5 times as viscous as water/ plasma is 1.5 times as viscous. - ↓prevent rapid flow of blood from arteries to veins - *Viscosity* prevents rapid flow of blood. - Responsible for resistance → maintains arterial blood pressure 8. **Buffer:** - 15% of buffering power of blood. - Maintain pH 7.4 in spite of addition of acids or alkalis. - **N.B.** RBCs is responsible for major part of blood viscosity ## Erythrocytes (RBCs) - **Shape:** biconcave discs - **Size:** 90µm² - **Count:** - **Sex:** - **Adult male:** 5.4 million/mm³ - **Female:** 4.8 million/mm³ - **Age:** - ↑in new born infants - ↑athletes & at high altitudes - ↓in old age - **Structure:** - No nuclei “corpuscles” - No mitochondria (Energy from anaerobic glycolysis) - Contain Hb, K - Carbonic anhydrase (C.A.) enzyme for CO2 transport - **Biconcave & plastic** → advantages: - ↑surface area - ↑flexibility → squeezed in capillaries without rupture - Minimal tension on membrane when volume is finite in venous blood due to CO2 transport ## Hemoglobin - red oxygen-carrying pigment of RBC’s - **Hemoglobin % (content):** Hemoglobin in grams / 100 ml blood - **Adult male:** 15-16 g/dl - **Female:** 13-14 g/dl. - **Newborn:** 19 g/dl due to relative intrauterine hypoxia ## Functions of RBCs - **A. Functions of Hb:** 1) **Gases Transport:** (O2 from lung to tissue; CO2 from tissue to lung) * **C.A** CO+H2O → H2CO3 → H+ + HCO3- - minimal change in PH 2) **Buffer H** inside RBCs (formed during CO2 transport) - 6 times buffering > plasma proteins - Deoxy-Hb (dissociate less, form weak acid) strong buffer > oxyhemoglobin - **B. Functions of Membrane:** 1) Biconcave & Plastic: 2) **Keeps Hb inside**. If Hb is free in plasma → renal failure. - Pass kidney → block renal tubule - ↑blood viscosity → ↑ blood pressure & cardiac work - ↑colloidal osmotic pressure → prevent filtration → ↑ blood volume & cardiac work - **Life span: 120 days.** - **Fate of RBCs:** Old RBCs (fragile), Rupture when pass via narrow vessel in spleen → release Hb → broken ## Erythropoiesis - Formation of new RBCs ## Sites: - **In fetus:** Liver & spleen - **After birth:** Red bone marrow of all bones - **By age:** Red marrow in long bones → inactive (replaced by fat) - Only flat membranous bones: skull, sternum, ribs, vertebrae, pelvis - **After 20 y:** ## Factors Affecting Erythropoiesis - **1. O2 supply - Role of Erythropoietin:** ↑RBCs production in hypoxia - **Hypoxia (O2) as in:** - **Hemorrhage** - **High altitude** - **Heart failure** - **Lung diseases** - **Athletes** - **loss of RBCs** - **↓O2 tension** - **↓blood flow** - **↓O2 diffusion** - **Relative O2 deficiency (↑requirements)** - **Hypoxia** → stimulate erythropoietin release from - kidneys: 85% / liver: 15% - **Anemia** develops in kidney diseases and nephrectomy - **Mechanism of action of erythropoietin:** accelerates steps of erythropoiesis (↓ maturation time) - **Stimulation of secretion of erythropoietin:** 1. Alkalosis (high altitude), androgens, adenosine 2. β agonists 3. Cobalt salts 4. Hypoxia (main stimulus) - **II. Hormones:** - Thyroxin (regulate metabolism) - Glucocorticoids - Androgens stimulate erythropoietin formation - **III. Healthy Bone Marrow:** bone marrow (site of erythropoiesis) - **Bone marrow destroyed by:** X-rays, radiation, antibiotic (chloramphenicol), sulpha drugs, malignant tumor - **Result:** all blood cells → aplastic anemia - **IV. Healthy Liver:** forms - Globin of hemoglobin - 15% of erythropoietin. - Stores vitamin B12 and iron (liver diseases associated with anemia) - **V. Diet:** + **A. Proteins:** High biological value (contain essential amino acids) of animal origin for formation of globin part of hemoglobin. + **B. Vitamins:** esp. vitamin C, B12 and folic acid. - **1. Vitamin B12 = Cyanocobalamine = Extrinsic Factor = Maturation Factor** - **Functions of vitamin B12:** essential for - DNA formation & nuclear maturation of RBCs (division of RBCs) - Formation of myelin sheath - **Absorption of vitamin B12:** - Parietal cells of fundus of stomach → intrinsic factor combine with vitamin B12 (extrinsic) - Protect vitamin B12 from digestion by GIT enzymes - Absorbed from terminal ileum to blood - **Causes of deficiency:** - Absence of intrinsic factor due to atrophy of gastric mucosa (autoimmune as Pernicious anemia) or gastrectomy. - Intake (rare) - Absorption: diseases of lower ileum. - store: Liver diseases - **Effect of deficiency:** - Macrocytic anemia: due to Failure of division of erythroblast in bone marrow → ↓ number, ↑size (fragile) → ↓ life span. - Neurological symptoms - **Treatment of deficiency:** Vitamin B12 injection. - **2. Folic Acid:** one of vitamin B complex - **Functions:** DNA formation & nuclear maturation of RBCs (division of RBCs) - **Effect of deficiency:** Macrocytic anemia. - **Causes of deficiency:** - Intake (dietary deficiency) → pregnancy {requirements ↑} - Absorption → Diseases of small intestine - **Treatment of cancers** with antifolate cytotoxic drugs - **C. Iron:** functions: - **70%:** For formation of → hemoglobin. - **3%:** For formation of myoglobin. - **1%:** Co-factor by some oxidative enzymes, e.g., catalase, peroxidase & cytochrome. - **26%:** stored in liver and spleen (ferritin) - **Mechanism of Iron absorption, transport and storage:** - Dietary iron (ferric (Fe³⁺) non absorbable - Vitamin C (ascorbic acid) →Fe²⁺ (ferrous) - Gastric HCl dissolve, reduction. - **Phytic** acid (in cereals), oxalate & phosphates form insoluble iron salts→ prevent absorption - **Absorption:** in upper small intestine (duodenum) by active process. - **Carried:** by Transferrin in blood to - **Bone marrow** - Hemoglobin - **Muscle** - Myoglobin - **Excess stored in liver & spleen** - **Ferritin** - **Effect of deficiency:** Microcytic hypochromic anemia - **Causes of deficiency:** - **1- intake:** In infants fed milk (milk poor in iron), in females (pregnancy & lactation). - **2-absorption:** - Partial gastrectomy →↓ HCl (achlorhydria) - Vitamin C deficiency - Phytic acid, oxalates and phosphates in diet - Diseases of duodenum - **3- Chronic blood loss:** e.g. Excessive bleeding during menstruation, bleeding peptic ulcer, piles - Iron stores: insufficient - Dietary iron can't compensate for iron lost - **D. Trace Elements:** - Copper: co-factor for HB synthesis, not enter into its formation. - Cobalt: stimulates erythropoietin secretion & enters in vitamin B12 formation. - **ANEMIA:** Oxygen carrying of the blood due to ↓ number of RBCs or ↓ Hb content - **Classification & Causes of Anemia:** - **Normocytic Normochromic Anemia:** - ↓Number - Normal MCV - Normal MCH - **Causes:** - **1- Hemolytic Anemia (↑breakdown):** - Infection: streptococci, malaria - Incompatible blood transfusion - Snake venom, chemicals (benzene) - **2- Hemorrhagic Anemia** - **Blood Loss:** - Acute (sudden, rapid) - Body replaces plasma 1-3 days (diluted blood) - RBCs: 3-4 weeks - **3- Aplastic Anemia (Bone Marrow Depression)** - →↓all blood cells, causes.... - **Microcytic Hypochromic (Iron Deficiency Anemia)** - ↓Number - ↓MCV - ↓MCH - **Causes:** ............................................. - **Macrocytic Anemia (Megaloblastic Anemia)** - ↓ number - ↑MCV - ↑MCH - **Causes:**................................................ - **HEMOSTASIS:** Stoppage of bleeding from injured vessel. Consists of: - **A.** VC of injured vessel - **B.** Formation of Temporary platelet plug (platelet reactions) - **C.** Formation of clot → stabilize temporary plug - **I. Local Vasoconstriction:** ↓blood flow & allows platelets to adhere at site of injury. VC due to: - **1. Nervous reflexes:** initiated by pain sensation from traumatized vessel. - **2. Local myogenic contraction:** - Degree of contraction a amount of damage. - Transverse cut → spasm > longitudinal cut. - **3. Chemical substances:** serotonin, thromboxane A₂ released from platelets. - **II. Formation of Temporary Hemostatic Plug:** (platelet reactions): can stop blood loss completely in small injury. - **1. Platelet adhesion:** via receptors to exposed subendothelial collagen & von Willebrand factor. - **2. Platelet activation:** adhesion activates platelets → swell, change shape, pseudopodia release. - **3. Platelet Release:** of granules - **Dense granules:** non-protein e.g. ADP, serotonin, calcium. - **Alpha granules:** (proteins) e.g. Some clotting factors (factor 13), PDGF. - Platelet-derived growth factor (PDGF) → stimulate growth of endothelium, smooth muscles. - Platelet activating factor (PAF): derived from plt membrane. * Membrane phospholipids * PAF * Arachidonic acid * Cyclooxygenase * Prostaglandin * Thromboxane synthase (Of platelets) * Thromboxane Az * Prostacyclin synthase (Of healthy endothelium) * prostacyclin - **1.** VC - **2.** Platelet release - **3.** ↑Platelet aggregation - **1.** VD - **2.** Platelet release - **3.** Platelet aggregation - **Prostacyclin opposite to thromboxane A₂** → keeps platelet plug localized to site of injury & Prevent clot spread to healthy area - Aspirin inhibits COX → ↓ thromboxane A₂ & prostacyclin. - Endothelial cells can produce new COX within hours, Platelets cannot. - Daily intake of aspirin → ↓ clot formation & prevents myocardial infarctions. - **4. Platelet aggregation:** by ADP, thromboxane A₂, PAF → aggregation → more activation → more release → self-propagating process → end in platelet plug formation. - **5. Platelet pro-coagulant activity:** platelet factor 3 (PF3) exposed on platelet membrane → provide ideal surface for concentration & activation of clotting factors. - **6. Platelet irreversible fusion:** by ADP, platelet enzymes. - **III. Blood Coagulation (Blood Clotting)** - By clotting factors "plasma proteins" (β-globulins) - Proteolytic inactive enzymes; when activated activate other → clot formation. - **According to source of lipoprotein involved in clotting mechanism** - **A- Intrinsic Pathway:** Phospholipid from platelet (PF3) i.e. in plasma. - **1. XII** - Contact with subendothelial collagen (in vivo) - Contact with -ve charged wet surfaces e.g. glass (in vitro) - **2. Xlla** - Accelerated by (HMW) kininogens & kallikrein in plasma - **3. Xlla activate Xla** → activate IXa. - **4. IXa form complex with Villa (activated by thrombin)** PL + Ca²⁺ → activate Xa - **5. Prothrombin** PL, Ca²⁺, factor V Thrombin - **6. Soluble Fibrinogen** thrombin insoluble fibrin monomer + 2 polypeptide chains Polymerize XIII + Ca²⁺ loose mesh of fibrin - **7. Tight fibrin clot** - **8. Net:** formation of clot (Platelets, blood cells and plasma entangled in the clot). - **9. Contraction** of actin, myosin of platelets → clot retraction → squeezes serum - **10. Serum** devoid of prothrombin, fibrinogen, factors V, VIII, XIII (consumed in clotting) - **11. XIII** = Fibrin stabilizing factor activated by thrombin in presence of Ca²⁺. - **B- Extrinsic Pathway:** (phospholipids from outside) - **1. Damaged tissues** (in vivo) → release thromboplastin (TPL, factor III) → activate VII a (Vascular, connective tissue) - **2. Activate VII a** Ca²⁺ (TPL) PL → Activate IX a & X a - **Interaction between two systems:** - **1.** In the body, following injury, Clotting initiated by both systems simultaneously. - **2. Extrinsic system rapid** (15 sec); Intrinsic system slow (1-6 min). - **3. Extrinsic system → thrombin formation rapidly help activation of intrinsic system.** - Also VIIa activates IX (intrinsic factor), X (common). - **4. In intravenous thrombosis**, clotting by intrinsic system, via exposure of subendothelial collagen. - **5. In test tube**, clotting by intrinsic system only (glass or addition of collagen). - **6. Action of Thrombin:** - Activates fibrinogen → fibrin - Activate fibrinogen group (5,8,13) - Accelerates actions of factors (9,10,11) - Accelerates formation of more thrombin from prothrombin - Accelerates platelet aggregation - Clot continues to grow until stopped by limiting reactions - **Anticlotting Mechanisms = Limiting Reactions:** - **Aim:** prevent blood clotting in healthy blood vessels & break down any already formed clots. - **A. General limiting reactions:** - Smooth vascular endothelium prevents activation of platelets & factor XII. - Rapid blood flow & removal of activated clotting factors & their inactivation in liver. - Heparin (natural anticoagulant). - **B. Specific limiting reactions:** - **1. Thromboxane A₂ & prostacyclin:** (the figure above) - **2. Antithrombin III:** bind & block activity of IX, X, XI and XII, (binding facilitated by heparin) -** 3. Fibrinolytic System:** - **Endothelial cell:** Except those in cerebral microcirculation - **Express Thrombomodulin** - **Thrombin** - **Protein C** → Activated protein C (APC) + Protein S - **Villa** → inactive Villa → Va → inactive Va - **Inactivates inhibitor of tissue plasminogen activator (t-PA)** - **Plasminogen** → Plasmin → Lyses fibrin - **Plasmin (fibrinolysin):** lyses fibrin & fibrinogen → fibrinogen degradation products (FDP) → inhibit thrombin. - **Anticoagulants:** - **Definition:** substances prevent blood clotting. - **A. In vitro anticoagulants:** prevent clotting outside body, e.g. in a test tube: - **1. Removal of Ca²⁺ ions:** Oxalates precipitate Ca²⁺ as salt - Citrates (used in blood transfusions) deionizing Ca²⁺ ions (bind them) - **2. Silicon coated tubes** prevent activation of factor XII & platelets. - **3. Heparin** - **B. In vivo anticoagulants:** prevent clotting in body. - **Heparin:** - Origin: Mast cells and basophils. - Mode of Action: Facilitates action of Antithrombin III. - Site of Action: In vivo and in vitro - Onset: Rapid - Duration: Short - Administration: I.V. and I.M. - Antidote: Protamine sulphate 1% - **Dicumarol:** - Plant - Competitive inhibition of vitamin K: - Inhibits formation of II, VII, IX, X - Only in vivo - Slow - long - Orally - Vitamin K - **Abnormalities of Hemostasis** - **1) Thrombocytopenic purpura:** - Platelet deficiency < 50,000/mm³ - Prolongation of bleeding time → subcutaneous hemorrhages (petechial) - **2) Vitamin K deficiency:** - Vitamin K: fat-soluble vitamin formed by intestinal bacterial flora. - Vitamin K → formation of factors II. VII, IX and X by liver. - **Causes of Deficiency:** - Absence of intestinal bacterial flora in newborn infants & adult with prolonged antibiotic - Obstruction of bile duct (as bile needed for absorption) - Prolongation of clotting time. - **3) Hemophilia:** - Congenital sex-linked disease (on X chromosome) - Recessive, carried by female to their males sons - 3 types: - Hemophilia A: absence of factor VIII (85%) - Hemophilia B: IX (10%) - Hemophilia C: XI (5%) - Characterized by severe bleeding even after mild trauma - Prolongation of clotting time. - **INTRINSIC SYSTEM** - XII → XIIa → HMW kininogen → Kallikrein - XI → Xla → HMW kininogen - IX → IXa → VIIIa → PL, Ca²⁺, Villa → TPL, Ca²⁺, PL, TPL - VIII → VIIIa → Ca²⁺, PL, Villa → Xa → PL, Ca²⁺, Va - X → Xa → Ca²⁺, PL, Va → Prothrombin → Thrombin → Fibrinogen → Fibrin → XII → XIIa → Stabilization - **EXTRINSIC SYSTEM** - TPL → TFI → VIIA → VII - **Ca²⁺ is required for all the reactions of blood clotting except the first 2 steps in intrinsic system.**