McGill University PHGY209 Blood Lectures 3-5 PDF

BLOOD Lecture 3 Melissa A. Vollrath McIntyre Rm. 1234 514.398.2410 [email protected] Kalenga Lubembele [email protected] Jasmine Chen [email protected] Victoria Lu vic...

BLOOD Lecture 3 Melissa A. Vollrath McIntyre Rm. 1234 514.398.2410 [email protected] Kalenga Lubembele [email protected] Jasmine Chen [email protected] Victoria Lu [email protected]  Summary of Blood Lecture 2 Diffusion is responsible for the exchange of nutrients, gases, and wastes across the capillary wall The STARLING FORCES determine the distribution of fluid ECF volume between the Plasma and the ISF Filtration (bulk flow) – due to hydrostatic pressure tends to “push out” the fluid inside the capillaries Osmotic Flow – C.O.P. due to plasma proteins tends to “pull in” or retain fluid inside the capillaries  Summary of Blood Lecture 2 Plasma Protein Functions Conditions leading to Edema accumulation of excess fluid in the interstitial spaces Decreased Plasma Protein (reduced C.O.P.) Increased Hydrostatic Pressure Increased Capillary Permeability Obstruction of Lymphatic Drainage Whole Centrifuged Blood Blood Plasma Buffy Layer (WBCs, Platelets) Blood Cells different types & functions RBCs  Blood Cells ZEISS Microscopy, "Human blood with red blood cells, T cells (orange) and platelets (green)  Blood Cell Progenitors Red Blood Cells Platelets White Blood Cells Erythrocytes Thrombocytes Leukocytes Number: 5 x 106/µL 250,000-400,000/µL 8,000-10,000/µL Diameter: 7.2 µm 2-3 µm 10-18 µm Lifespan: 120 days 7-8 days hours-years  Hematopoiesis All blood cells are derived from a common, multipotential (pluripotential) hematopoietic stem cell Erythopoiesis: production of Red Blood Cells Erythrocytes Thrombopoiesis: production of Platelets Thrombocytes Leukopoiesis: production of White Blood Cells Leukocytes  Hematopoiesis general pattern three types of committed stem cells self-replication Leukopoiesis Leukocytes Pluripotential Multipotential Stem Cell Thrombopoiesis Platelets Erythropoiesis Erythrocytes 1. Division INDUCER STIMULANT 2. Differentiation Cytokines – substances (proteins or peptides) which are released by one cell and affect the growth, development, and activity of another cell Cytokines that influence the proliferation and differentiation of blood cell precursors are known as Hematopoietic Growth Factors (HGFs)  Sites of Hematopoiesis Bone Marrow Prenatal POSTNATAL  Sites of Hematopoiesis Axial Skeleton Flat bones of skull Shoulder blades Sternum Vertebrae Ribs Pelvis Proximal epiphyses of long bones Long Bones Prenatal Postnatal Femur Epiphysis Diaphysis Epiphysis  RBCs FUNCTION: facilitate transport of respiratory gases  RBC Shape and Dimensions “biconcave” disk 0.8 µm 2.6 µm Shape due to presence of “spectrin” a fibrous protein, forming a flexible network linked to cell membrane Advantages of Shape Maximal surface area and minimal diffusion distance Increases the efficiency of O2 and CO2 diffusion Advantages of Shape Maximal surface area and minimal diffusion distance Increases the efficiency of O2 and CO2 diffusion High degree of flexibility Allows RBCs to squeeze through narrow capillaries  Numerical and Morphological Values for RBCs CBC = complete blood count RBC, WBC, platelet count, Hematocrit, Hb concentration Cell Size – Normocytic – Microcytic – Macrocytic Cell Shape – Sickle cell – Spherocyte  RBC Numbers Males: 5.1 – 5.5 x 106/µL Females: 4.5 - 4.8 x 106/µL ~25 x 1012 in 5L of blood Rate of production = Rate of destruction ~2 x 106/second  RBC Components RBC Composition NOTE: RBCs contain no subcellular organelles No Nucleus, No Mitochondria RBCs have important Enzyme Systems RBC Composition Glycolytic Enzymes Generate Energy Generate energy anaerobically Carbonic Anhydrase CO2 Transport Converts CO2 to bicarbonate which is easier to transport  *Each molecule of Hb can bind a maximum of 4 O2 molecules When combined with O2 = HbO2 = oxyhemoglobin When oxygen is released from Hb = deoxyhemoglobin Hemoglobin Structure 200-300 x 106 Hb molecules/RBC MW = 64 KDa  O2 O2 Fe++ Fe++ In lungs, Hb becomes HEME β α HEME saturated with O2 appears bright red GLOBIN In tissues, O2 HEME HEME dissociates from Hb α β appears dark red Fe++ Fe++ O2 O2 *Each molecule of Hb can bind a maximum of 4 O2 molecules  Hemoglobin Functions Transport of O 2 Hb + O2 HbO2  Hemoglobin Functions O2 Solubility in plasma is very low: 0.3 ml O2/100 ml plasma Due to Hb, O2 Solubility in blood is high: 20 ml O2/100 ml blood  Hemoglobin Functions Transport of O2 Hb + O2 HbO2 Transport of CO2 Acts as a buffer Why have Hb inside the red blood cell? rather than dissolved in plasma  Hemoglobin Functions Transport of O2 Hb + O2 HbO2 Transport of CO2 Acts as a buffer Why have Hb inside the red blood cell? (rather than dissolved in plasma) ▪ Plasma Viscosity ▪ Plasma C.O.P. ▪ loss via the kidney  Hemoglobin Values Males: 16 g/100 ml blood Females: 14 g/100 ml blood When Hb is fully saturated with O 2, each gram of Hb holds 1.34 ml O2 Therefore, the O2 carrying capacity of blood is: 20 ml O2/100 ml blood (15 grams x 1.34 ml = 20) Factors affecting ability of Hb to bind and release O2 1. Temperature 2. Ionic Composition 3. pH 4. pCO2 5. Intracellular enzyme concentration  Erythropoiesis 2 - 3 x 106 RBCs produced per second Where are RBCs made? How are they produced? How is production regulated? Sites of Hematopoiesis Axial Skeleton Flat bones of skull Shoulder blades Sternum Vertebrae Ribs Pelvis Proximal epiphyses of long bones Long Bones PRENATAL POSTNATAL Hematopoiesis Injection of Bone Marrow Stem Cells can reconstitute ALL Hematopoietic Cell Types *Under the influence of Hematopoietic Growth Factors (cytokines) RBC Precursor Proliferation myeloid Divison and Differentiation 3 – 5 days 24 hours Erythropoietin Reticulocyte RBC  Red Cell Precursor Proliferation 3 – 5 days 1. Decrease in size 2. Loss of nucleus and organelles 18 µm 3. Accumulation of Hb 7 µm  Reticulocytes Normal Reticulocyte Count < 1 % of RBCS Reticulocyte Index: reflects the amount of effective erythropoiesis in the bone marrow Factors determining # of RBCs O2 requirements O2 availability  Variation in RBC count at different altitudes Altitude pO2 RBC 1000’s feet mmHg x 106/µL 0.7 150 4.5 4.4 120 5.2 12.0 100 6.8 15.6 90 7.8 18.2 85 8.3 *Don’t need to know these values, but understand the trend: RBC # increases with decreased O2  Erythropoietin - EPO A glycoprotein hormone/cytokine produced mainly by the kidney Stimulus for release is Hypoxia which may result from decreased RBC count, decreased availability of O2 in blood, or increased tissue demand for O2 EPO… has been purified, sequenced, the gene has been cloned, and artificial EPO has been produced by recombinant DNA technology Regulation of Erythropoiesis Senses Hypoxia Kidney Increases Release of Erythropoietin  Increased Oxygen in Plasma Increased RBC production Kidney senses hypoxia Increased Stimulation Erythropoietin of Bone Marrow in Plasma  Increased Oxygen in Plasma Increased RBC production Senses Increased O2 Kidney Increased Stimulation Erythropoietin of Bone Marrow in Plasma  Increased Oxygen in Plasma X Increased RBC production Kidney Senses Increased O2 Decreases Release of Erythropoietin X X Increased Stimulation Erythropoietin of Bone Marrow in Plasma  Regulation of Erythropoiesis Erythropoietin, released from the kidney due to hypoxia, stimulates the bone marrow to produce more RBCs, thereby maintaining O2 HOMEOSTASIS This is an example of negative feedback BLOOD Lecture 4 Melissa A. Vollrath McIntyre Rm. 1234 514.398.2410 [email protected] Kalenga Lubembele [email protected] Jasmine Chen [email protected] Victoria Lu [email protected]  Summary of Blood Lecture #3 General pattern of Hematopoiesis Characteristics of Red Blood Cells – functions – numbers, size & shape – contents Hemoglobin – structure, function Erythropoiesis – where, how, regulation Reticulocytes – significance Erythropoietin – synthesized in renal cortex – stimulated by hypoxia – acts on committed RBC precursors – negative feedback regulation Regulation of Erythropoiesis Senses Hypoxia Kidney Increases Release of Erythropoietin  Increased Oxygen in Plasma Increased RBC production Kidney senses hypoxia Increased Stimulation Erythropoietin of Bone Marrow in Plasma  Increased Oxygen in Plasma Increased RBC production Senses Increased O2 Kidney Increased Stimulation Erythropoietin of Bone Marrow in Plasma  Increased Oxygen in Plasma X Increased RBC production Kidney Senses Increased O2 Decreases Release of Erythropoietin X X Increased Stimulation Erythropoietin of Bone Marrow in Plasma  Severe accidental hemorrhage Less Hb available for O2 transport Reduced supply of O2 to kidneys X Increased production & release of erythropoietin Negative Increased production of erythrocyte precursors in bone marrow feedback loop Increased discharge of young erythrocytes in blood More RBCs and more Hb for O2 transport Erythropoietin Action EPO Accelerates Maturation Pluripotent Committed Reticulocytes Stem Cell Stem Cell EPO Stimulates Mature Proliferation RBC  Hormonal Effects on Erythropoietin Testosterone increases release of Erythropoietin increases sensitivity of RBC precursors to Erythropoietin Estrogen has opposite effects Destruction of RBCs Life Span of RBCs 120 days during that time, each RBC travels the equivalent of 300 miles Nothing prolongs RBC lifespan Old RBCs are recognized and are removed from the circulation by highly phagocytic cells known as Macrophages (in the liver and spleen) Phagocytosis of old RBCs Macrophage old RBC Phagocytosis of old RBCs Macrophage “engulfs” RBC Phagocytosis of old RBCs RBC “digested” contents released  Phagocytosis of old RBCs Macrophage destruction of RBCs RBCs and recycling of 120 days components in circulation Globin RBC “digested” Hb contents released Fe Heme Amino acid pool Bilirubin 1mg/dL Transferrin Fe Fe Liver Ferritin Bone Marrow STORAGE Site of RBC in Liver production Spleen and Intestinal Gut Tract  Phagocytosis of old RBCs Macrophage destruction of RBCs RBCs and recycling of 120 days components in circulation Globin RBC “digested” Hb contents released Fe Heme Amino acid pool Bilirubin >1mg/dL Transferrin Fe Fe Liver Ferritin Bone Marrow STORAGE Site of RBC in Liver production Spleen and Intestinal Gut Tract Jaundice Jaundiced Adult Healthy Adult https://teachmesurgery.com/hpb/presentations/jaundice/ https://dhawy.com/digestive-health-conditions/jaundice/ Neonatal Jaundice Phototherapy  Phagocytosis of old RBCs Causes of Jaundice RBCs Excessive Hemolysis 120 days in circulation RBC “digested” Hb contents released Heme Bilirubin > 1mg/dL Liver Damage Liver Bile Duct Bone Marrow Site of RBC Obstruction production Intestinal Tract Normal Dynamics for RBCs Production = Destruction Abnormal Dynamics Production > Destruction Polycythemia Production < Destruction Anemia How do we evaluate? Clinical Indices ⎼ Number of RBCs ⎼ Amount of Hb ⎼ Hematocrit  Hematocrit The percentage of Blood Volume occupied by Red Blood Cells  70% 70% 45% Normal Polycythemia Dehydration ?  45% 30% 30% Fluid Normal Anemia Retention Hemoglobin Values Normal Polycythemia 16 g% Hb > 18 g% Hb 5 - 5.5 x 106 RBCs/µL > 6 x 106 RBCs/µL Relative Polycythemia due to decreased plasma volume Absolute Polycythemia may be Physiological or Pathological Physiological Polycythemia Is a secondary effect that occurs due to… higher O2 needs or lower O2 availability - at high altitude - increased physical activity - chronic lung disease - heavy smoking 70% Pathological Polycythemia Is a primary effect that can occur due to… - Tumors of cells producing EPO - Unregulated RBC production by bone marrow Example: Polycythemia vera - 7 - 8 x 106 RBCs/µL - Ht ~70% due to stem cell dysfunction 70% Why is Polycythemia a problem? – increases blood viscosity – slow blood flow can lead to blood clots Anemia A decrease in the oxygen-carrying capacity of blood Measurements defining Anemia: – Decreased RBC count Males: < 4 x 106/µL Females: < 3.2 x 106/µL – Decreased Hb content Males: < 11 g% Females: < 9 g% Classification of Anemias Morphologic Size: Microcytic Normocytic Macrocytic < 80 µm3 80-94 µm3 > 94 µm3 Color: Normochromic Hypochromic ~33% Hb < 33% Hb Classification of Anemias Size: Normocytic Macrocytic Microcytic Color: Normochromic Hyperchromic Hypochromic  Red Cell Precursor Proliferation 3 – 5 days 1. Decrease in size 2. Loss of nucleus and organelles 18 µm 3. Accumulation of Hb 7 µm Classification of Anemias Etiologic Diminished Production Ineffective Maturation Increased RBC Destruction/ Reduced RBC Survival Diminished Production – Abnormality at site of production (bone marrow) – Inadequate stimulus – Inadequate raw materials Diminished Production – Abnormality at site of production (bone marrow) – Inadequate stimulus – Inadequate raw materials Aplastic (Hypoplastic) Anemia Etiology: unknown exposure to radiation chemicals or drugs Classification: Normocytic, Normochromic Diminished Production – Abnormality at site of production (bone marrow) – Inadequate stimulus – Inadequate raw materials Stimulation Failure Anemia Etiology: renal disease (less EPO production) Classification: Normocytic, Normochromic Diminished Production – Abnormality at site of production (bone marrow) – Inadequate stimulus – Inadequate raw materials Iron Deficiency Anemia (most common type) Etiology: increased requirement for Fe (infancy, adolescence, pregnancy) inadequate supply of Fe (dietary deficiency, failure to absorb, loss of Fe in hemorrhage) Classification: Microcytic, Hypochromic Iron (Fe) Total Amount in Body 4g 65% Hb 30% stored 5% myoglobin 1% enzymes Daily Intake in Diet : ~15 - 20 mg Daily absorption from gut: depends on needs of the body Males: ~1 mg Fe/day Females: ~2 mg Fe/day who menstruate Normal erythropoiesis requires 25 mg Fe/day Normal RBC destruction releases 25 mg Fe/day of this 25 mg Fe… 1 mg Fe/day is lost 24 mg Fe/day is recycled Males: require 1 mg dietary Fe/day Females: require 2 mg dietary Fe/day who menstruate Menstrual loss: ~50 ml blood/month 1g Hb contains 3.5 mg Fe, 15g Hb/100 ml of blood is ~50 mg Fe Therefore, menstruating females lose ~25 mg Fe/month and thus require ~50 mg Fe/month or ~2 mg Fe/day Classification of Anemias Etiologic Diminished Production Ineffective Maturation Increased RBC Destruction/ Reduced RBC Survival  Ineffective Maturation Maturation Failure Anemia Etiology: Deficiencies of Vitamin B12 and Folic Acid (both are required for DNA synthesis) Inadequate supply of Fe (dietary deficiency, failure to absorb, loss of Fe in hemorrhage) Classification: Macrocytic, Normochromic Vitamin B12 Folic Acid Found only in Found in leafy greens animal products Usually, dietary absence, Usually, failure overcooking vegetables to absorb some forms of intestinal disease - e.g., sprue – may interfere with the absorption of Folic Acid and Vit. B12 Vitamin B12 Absorption Intrinsic Factor Deficiency Pernicious Anemia ileum Classification of Anemias Etiologic Diminished Production Ineffective Maturation Increased RBC Destruction/ Reduced RBC Survival RBC Survival Disorders Hemolytic Anemias – may be accompanied by jaundice Etiology: Congenital Acquired (toxins, drugs, antibodies) Abnormal RBC Membrane Structure Example: hereditary spherocytosis: less flexible, more fragile Abnormal Enzyme Systems abnormal metabolism Abnormal Hb structure Examples: Sickle Cell Disease Thalassemia – deficient synthesis of globin amino acid chains BLOOD Lecture 5 Melissa A. Vollrath McIntyre Rm. 1234 514.398.2410 [email protected] Kalenga Lubembele [email protected] Jasmine Chen [email protected] Victoria Lu [email protected]  Summary of Lecture 4 Characteristics of Red Blood cells – functions, numbers size, shape, life span, contents, destruction Hemoglobin – structure, function, breakdown and recycling - Jaundice Erythropoiesis – where, how, regulation Reticulocytes – significance Erythropoietin – stimulus, site of synthesis, site of action, feedback regulation Polycythemia – Physiological vs. Pathological Anemia – ”A decrease in the oxygen-carrying capacity of blood” Types of Anemia know Failure to produce RBCs the causes Failure of RBC maturation and Failure of RBC survival clinical signs Classification of Anemias Etiologic Diminished Production Ineffective Maturation Increased RBC Destruction/ Reduced RBC Survival  Ineffective Maturation Maturation Failure Anemia Etiology: Deficiencies of Vitamin B12 and Folic Acid (both are required for DNA synthesis) Inadequate supply of Fe (dietary deficiency, failure to absorb, loss of Fe in hemorrhage) Classification: Macrocytic, Normochromic Vitamin B12 Folic Acid Found only in Found in leafy greens animal products Usually, dietary absence, Usually, failure overcooking vegetables to absorb some forms of intestinal disease - e.g., sprue – may interfere with the absorption of Folic Acid and Vit. B12 Vitamin B12 Absorption Intrinsic Factor Deficiency Pernicious Anemia ileum Classification of Anemias Etiologic Diminished Production Ineffective Maturation Increased RBC Destruction/ Reduced RBC Survival RBC Survival Disorders Hemolytic Anemias – may be accompanied by jaundice Etiology: Congenital Acquired (toxins, drugs, antibodies) Abnormal RBC Membrane Structure Example: hereditary spherocytosis: less flexible, more fragile Abnormal Enzyme Systems abnormal metabolism Abnormal Hb structure Examples: Sickle Cell Disease Thalassemia – deficient synthesis of globin amino acid chains Blood Loss – Hemorrhage external internal bleeding into tissues Hematoma accumulation of blood in tissues Arrest of Bleeding – Hemostasis Do not confuse Hemostasis with Homeostasis Hemostasis The arrest of bleeding following vascular injury due to several interacting, overlapping mechanisms: Primary vascular Hemostasis response Begins within seconds of injury, lasts only minutes clot Secondary platelet formation Hemostasis response Hemostasis Vascular Injury Vasoconstriction Platelet Plug Formation Blood Clot Formation  Vascular Response (vasoconstriction) damaged blood Smooth muscle cells vessel in vessel wall respond to injury by contracting Opposed endothelial blood cells stick together flow Platelet Response – white thrombus damaged blood vessel Platelet Plug white thrombus blood flow Platelet Structure ~ 2-4 µm diameter NO nucleus Many granules – containing factors for vasoconstriction, platelet aggregation, clotting, growth, etc. many filaments, microtubules, mitochondria, sER ~ 250,000/µL Life Span: 7-10 days Sites of Hematopoiesis Long Bones Hematopoeisis Injection of Bone Marrow Stem cells can reconstitute ALL hematopoietic Cell Types Platelet Production Thrombopoietin mostly from liver  Platelet Plug Formation Prostacyclin, NO von Willebrand collagen (Vasodilators) Factor Endothelial Cells Thromboxane A2 ADP Blood Vessel Platelets PF3 Serotonin 1. Adhesion 2. Activation and release of cytokines 3. Aggregation 4. Consolidation Platelet Plug Formation Platelets Damaged Vascular Collagen Endothelial Injury Exposure Cells Platelet Activation Adhesion Release of Von ADP Willebrand TXA2 Factor Serotonin PF3 Aggregation Platelet Plug WhiteThrombus Blood Clot Formation Platelets Damaged Vascular Collagen Endothelial Injury Exposure Cells Platelet Activation Adhesion Release of Von ADP Willebrand TXA2 Factor Serotonin PF3 Aggregation Coagulation Pathway Thrombin Platelet Plug WhiteThrombus Blood Clot Red Thrombus Exposed collagen binds & activates platelets Platelet factors are released & attract more platelets Platelet factors also promote coagulation Platelet Functions - Release vasoconstricting agents / cytokines - Form Platelet Plug (White Thrombus) - Release Clotting Factors - Participate in Clot Retraction - Promote Maintenance of Endothelial Integrity Petechia small red/purple spots caused by bleeding into the skin Abnormal Primary Hemostatic Response Leads to prolonged bleeding - Failure of Blood Vessel to constrict - Platelet deficiencies Numerical < 75,000/µL thrombocytopenia Functional congenital acquired Drugs, Toxins, Antibodies Aspirin (in small doses) inhibits synthesis and release of TXA2 Blood Clot – Red Thrombus Clot formation is a function of Plasma RBCs are not necessary for the process Clotting: initiated by injury to blood vessel wall results in sequential activation and interaction of a group of plasma proteins/clotting factors some clotting factors act as enzymes or co-factors in the presence of Ca++ and some phospholipid agents 3 stages: 1 Injury to vessel wall 2 --- 3 Clot formation (only visible stage) Protein factors named with Roman Numerals I-XIII in the order they were discovered  3 – 6 mins 15 – 20 secs INTRINSIC PATHWAY EXTRINSIC PATHWAY Exposed Collagen Tissue Factors (protein & XII XIIa phospholipid) released from damaged cells XI XIa VIIa VII Ca++ IX IXa IX Ca++ VIII VIIIa PF 1 X Xa X Ca++ ‘PROTHROMBINASE’ V Va PF XIII Ca++ Cross- links 2 Prothrombin Thrombin Fibrin XIIIa 3 Fibrinogen Fibrin  3 – 6 mins 15 – 20 secs INTRINSIC PATHWAY EXTRINSIC PATHWAY Exposed Collagen Tissue Factors (protein & XII XIIa phospholipid) released from damaged cells XI XIa VIIa VII Ca++ IX IXa IX Ca++ VIII VIIIa PF 1 X Xa X Ca++ ‘PROTHROMBINASE’ V Va PF XIII Ca++ Cross- links 2 Prothrombin Thrombin Fibrin XIIIa 3 Fibrinogen Fibrin INTRINSIC PATHWAY EXTRINSIC PATHWAY Damage to Damage to tissue blood vessel outside vessel PRO Interacting PRO Interacting PRO plasma factors THROM THROM plasma factors THROM BINASE + Ca++ + + Ca++ + PF3 BINASE BINASE Phospholipid Ca++  3 - 6 minutes 15 - 20 seconds INTRINSIC PATHWAY EXTRINSIC PATHWAY Damage to Damage to tissue blood vessel outside vessel PRO Interacting Interacting THROM plasma factors plasma factors BINASE plus Ca++ and plus Ca++ and PF3 Tissue Phospholipids Factor XIII Cross-linking Intrinsic Pathway Extrinsic Pathway 3-6 minutes 15-20 seconds The small amounts of THROMBIN generated rapidly by the Extrinsic Scheme, are sufficient to trigger its strongly positive feedback effects on the Intrinsic Scheme to generate larger quantities of THROMBIN Factors in Coagulation Ca++ Phospholipid Protein Plasma Factors* Clotting Factor Deficiencies Congenital Acquired Single-factor Multi-factor Hereditary deficiencies deficiencies factor VIII liver disease Hemophilia Vitamin K deficiency Vitamin K is cofactor in synthesis of Prothrombin, VII, IX, X Clot Retraction requires a contractile protein, thrombosthenin, released by platelets Clot Clotting is kept in check by… Inhibitors of platelet adhesion and Anticoagulants naturally-occurring chemicals that block one or more of the reactions of the coagulation scheme Clot Lysis (Fibrinolysis = Thrombolysis) Fibrin Plasminogen Plasmin Fibrin fragments Clot Lysis (Fibrinolysis = Thrombolysis) Plasminogen Activator Fibrin Plasminogen Plasmin Fibrin fragments Clot Lysis (Fibrinolysis = Thrombolysis) Intrinsic Extrinsic Proactivators Proactivators Factor XIIa Tissue Factors Endothelial Cell Factors Plasminogen Activator Fibrin Plasminogen Plasmin Fibrin fragments  Inhibitors of Platelet Adhesion (e.g., aspirin) Anticoagulant Drugs (interfere with clot formation) Coumarin – blocks synthesis of functional Prothrombin, VII, IX, X Heparin – promotes inhibition of THROMBIN activation and action Thrombolytic Drugs (promote clot lysis) Tissue Plasminogen Activator – t-PA Streptokinase  Summary of Lecture 5 Platelets – production – function Hemostasis – Primary – Secondary Platelet Plug formation – white thrombus Blood Clot – red thrombus Thrombin – Intrinsic vs. Extrinsic Clot retraction Clot Lysis Clotting Inhibitors and Deficiencies