Heme/Onc/ID Basic Medical Science I PDF

Heme/Onc/ID Basic Medical Science I Cathleen J. Ciesielski, Ph.D.  Objectives BMS 0.1 The student will identify anatomic features and correlate them with their spatial relationship to one another using appropriate terminology plus diagram the a...

Heme/Onc/ID Basic Medical Science I Cathleen J. Ciesielski, Ph.D.  Objectives BMS 0.1 The student will identify anatomic features and correlate them with their spatial relationship to one another using appropriate terminology plus diagram the anatomic position and the anatomical planes for: sagittal (median), coronal (frontal) and transverse (horizontal). BMS 0.4 The student will identify the following basic structures and characterize the relationship of the body systems to one another: integumentary system, fascia & potential spaces, mucous and serous membranes, skeletal system (cartilage, bones, joints), muscular system (muscle tissue), cardiovascular system (heart, blood & vessels), lymphoid system & nervous system. BMS 1.1 The student will identify the basic structures, functions and characterize their relationship to one another for the bone marrow derivatives of the skeletal system (erythrocytes, leukocytes & thrombocytes). BMS 1.2 The student will describe the cell nomenclature resulting in production of erythrocytes. BMS 1.3 The student will characterize hematopoiesis (erythrocytes, leukocytes & thrombocytes) in terms of histologic environment, role of regulatory cytokines, nutritional requirements, stem cell differentiation/proliferation, and maturation sequence of morphologic changes. BMS 1.4 The student will state the usual lifespan of erythrocytes and describe the process of cell removal, hemoglobin production and break-down, and bilirubin metabolism. BMS 1.5 The student will define mean corpuscular volume (MCV) and differentiate microcytosis, normocytosis, and macrocytosis.  Objectives BMS 1.11 The student will describe the molecular basis for activation, progression and control, and the observed physiologic effects associated with each of the following hemostasis processes: vascular constriction, platelet adhesion & aggression, coagulation (intrinsic & extrinsic pathways), fibrinolysis, von Willebrand factor. BMS 1.12 The student will define the role of vitamin K and calcium in coagulation.  Circulation System http://upload.wikimedia.org/wikipedia/commons/8/87/The_Principle_Organs_and_Vascular_and_Urino-Genital_Systems_of_a_Woman.jpg Consists of: Cardiovascular system Heart Blood vessels Lymphatic system BMS 0.4  Cardiovascular/Circulatory Vessels Moore BMS 0.4  Cardiovascular/Circulatory Vessels BMS 0.4 Moore  Cardiovascular/Circulatory Vessels Moore BMS 0.4  Circulation System: Blood vessels Arteries: blood travels away from the heart Veins: blood travels towards the heart BMS 0.4 Moore 1.15  Blood Vessels 1. Tunica intima (interna) is a layer of simple squamous epithelium (endothelium) 2. Tunica media is primarily smooth muscle 3. Tunica adventitia (externa) is the outer connective tissue layer anchoring the vessel into place Moore 1.15 BMS 0.4 Circulation System: Blood Vessels BMS 0.4  Circulation System: Venous Return & Backflow BMS 0.4 Moore 1.17  Systemic vs Pulmonary Circulation Legend : Schematic diagrams of the relation of the main branches of pulmonary arteries (A) and pulmonary veins (B) to the bronchial tree. The arteries follow the airways. Two mainstems of pulmonary vein penetrate independently into the lung on each side. LA, left atrium; RV, right ventricle. BMS 0.4  Systemic vs Pulmonary Circulation RV to pulmonary trunk to R/L pulmonary arteries to lungs to R/L pulmonary veins to LA LV to aorta to systemic arteries to arterioles to capillaries to systemic venules to veins to either superior or inferior vena cava to RA Moore BMS 0.4  Blood Vessel Names Moore BMS 0.4 Blood Return from Body Towards Lungs L. Brachiocephalic v. R. Brachiocephalic v. R. Pulmonary a L. Pulmonary a. Pulmonary Trunk Superior Vena Cava Inferior Vena Cava Anterior BMS 0.4  L. Common L. Subclavian a. Carotid a. R. Brachiocephalic a. Aortic Ascending Aorta arch L. Pulmonary R. Pulmonary Veins Veins Descending Aorta Anterior Blood Return From Lungs to Body BMS 0.4 Lymphatic System 1. return of interstitial fluid to the circulation system (blood volume) 2. immune protection primary lymphatic organs secondary lymphatic structures 3. transport of dietary fats BMS 0.4 Junqueira  Blood Capillary systemic vessels Lymphatic System Return of overflow interstitial fluid to blood: ▪ Lymph is essentially plasma without the plasma proteins ▪ Interstitial fluid travels into open lymphatic capillaries (open Lymphatic circulation) Capillary now called lymph (green) lymph moves from lymphatic capillaries to lymphatic vessels ▪ Lymph fluid in lymphatic vessels Lymph Node passes lymph nodes for immune surveillance before traveling towards subclavian veins Moore 1.18 BMS 0.4 Lymphatic System Order of Lymph Fluid Flow: in general, lymph travels towards heart ▪ Interstitial fluid flows into lymphatic capillaries than lymphatic vessels ▪ From the lymphatic vessels lymph flows first into afferent vessel ▪ Lymph travels through lymph nodes & exits via efferent vessel ▪ Lymph than moves into lymphatic trunks and lastly into ▪ Lymphatic Ducts where lymph will be able to drain into subclavian veins 19 Moore 1.18 BMS 0.4  Lymphatic System Several Lymphatic Trunks ▪ Jugular trunks (paired) drains head & neck ▪ Subclavian trunks (paired) drains upper limb ▪ Bronchomediastinal trunks (paired) ▪ Lumbar trunks (paired) ▪ Intestinal trunk (unpaired) from intestinal trunk, lymph flows into the cisterna chyli (dilated sac @ L1-L2) (lymph from lumbar trunk also drains into cisterna chyli) Moore 1.18 BMS 20 0.4  Skeletal System: General Functions ▪ Protection: bone composed of collagen (for strength) and calcium-phosphate salts (resists bend) ▪ Support bone composed of collagen (for strength) and calcium-phosphate salts (resists bend) ▪ Lever for movement ▪ Storage of minerals ▪ Hematopoiesis BMS 0.4  Skeletal System ▪ Bone Marrow is stored inside of bone: Red Bone Marrow: responsible for the production of formed elements Yellow Bone Marrow: inactive red bone marrow; can be converted back to red bone marrow BMS 0.4  Skeletal System ▪ Bone Marrow located: medullary cavity of long bones spongy bone of epiphyseal ends of long bones spongy bone of flat bones BMS 0.4  Red Blood Cell Production ▪ Fetal growth Yolk sac Liver and spleen, lymph nodes Bone marrow ▪ All bones produce red blood cells until age 5 ▪ Long bones produce bone marrow until age 20 ▪ Adults: spongy bone found in: Vetebrae, sternum, ribs, and ilia (iliac bone) Junqueira BMS 1.1  Blood Is specialized fluid of connective tissue Contains cells suspended in a fluid matrix (extracellular matrix) BMS 1.1 Five Functions of Blood 1. Transport of dissolved substances ▪ nutrients, vitamins, minerals, oxygen & hormones towards interstitial fluid (toward cells) ▪ waste material, carbon dioxide & hormones from the interstitial fluid (from the cells) 2. Regulation of pH (acid/base) and ions 3. Restriction of fluid losses at injury sites 4. Defense against toxins and pathogens 5. Stabilization of body temperature (heat distribution) BMS 1.1 Three General Characteristics of Blood 38°C (100.4°F) is normal temperature Blood volume (liters) = 7% of body Weight (kilograms): adult male: 5 to 6 liters adult female: 4 to 5 liters High viscosity (~45% solids) Slightly alkaline pH (7.35–7.45) physiological pH of blood: 7.40 (weak base) BMS 1.1 Composition of Whole Blood ◼ Plasma: – water – plasma proteins – other solutes ◼ Formed elements: – red blood cells – white blood cells – platelets BMS 1.1  Centrifuged Blood Fractionation: ▪ process of separating whole blood for clinical analysis into plasma and formed elements BMS 1.1  Centrifuged Blood ▪ Plasma straw colored liquid at top of tube 55% of the sample (blood) ▪ Buffy coat middle slightly gray-white layer composed of leukocytes & platelets 1% of plasma proteins) and the complement system Junqueira Table BMS 1.1  Composition of Blood Plasma Other Solutes (~1% of Blood Plasma) Help establish and maintain membrane Electrolytes (eg, sodium, potassium, calcium, potentials, maintain pH balance, and regulate chloride, iron, bicarbonate, and hydrogen) osmosis (control of the percentages of water and salt in the blood) Nutrients (eg, amino acids, glucose, cholesterol, Energy source; precursor for synthesizing other vitamins, fatty acids) molecules Respiratory gases (eg, oxygen: >2% dissolved in plasma, 98% bound to hemoglobin within Oxygen is needed for aerobic cellular erythrocytes; and carbon dioxide: ~7% respiration; carbon dioxide is a waste product dissolved in plasma, ~27% bound to produced by cells during this process hemoglobin within erythrocytes, ~66% converted to HCO3) Waste products serve no function in the blood Wastes (breakdown products of metabolism) plasma; they are merely being transported to (eg, lactic acid, creatinine, urea, bilirubin, the liver and kidneys where they can be ammonia) removed from the blood BMS 1.1 Junqueira Table  Platelets (Thrombocytes) ▪ Cell fragments (non-nucleated) separated from the cytoplasmic extensions of megakaryocytes in the bone marrow ▪ Function in the blood clotting system release their granules upon contact with collagen (or other material outside of endothelium or contents of plasma) ▪ Circulation Circulates for about 10 days Primarily removed by spleen 2/3 are reserved for emergencies BMS 1.1  Platelets (Thrombocytes) Junqueira BMS 1.1  Role of Platelets ▪ Fibrin network: water-insoluble clot Covers platelet plug Traps blood cells Seals off area ▪ Clot Retraction ▪ Clot Removal BMS 1.1 Platelet Production ▪ Also called thrombocytopoiesis: Occurs in bone marrow Under hormonal control Thrombopoietin (TPO) Inteleukin-6 (IL-6) Multi-CSF ▪ Megakaryocytes (giant cells): Remain in the bone marrow Manufacture platelets from their cytoplasm Release platelets into the circulation BMS 1.10  Megakarocyte Junqueira BMS 1.1  Platelets: Medical Applications Nonsteroidal Anti-inflammatory Agents ▪ Inhibitory effect on platelet function blocks local prostaglandin synthesis, which is needed for platelet aggregation, contraction and exocytosis to sites of injury can result in abnormally slow blood clotting BMS 1.1  Bleeding Disorders ▪ Vessel defects Vitamin C deficiency (impaired collagen) Bacterial & viral infections ▪ Platelet disorders Thrombocytopenia Thrombocytopathy ▪ Genetic Factors BMS 1.14 Vessel Wall Abnormalities: Pathogenesis ▪ Blood vessel walls are lined with endothelial cells, which control vascular permeability, flow of molecules, local cellular interactions, angiogenesis and portions of the inflammatory response. ▪ Normal healthy endothelium is anti- thrombotic. ▪ If stimulated, endothelium becomes prothrombotic. This activates coagulation pathways, inhibits fibrinolysis, & activates platelets. -Endothelium-derived vasoconstrictors such as endothelia cells secreting endothelin, are platelet activators & promotes thrombosis BMS 1.14 Three Types of Formed Elements 1. Red blood cells (RBCs) or erythrocytes: ▪ transport oxygen 2. White blood cells (WBCs) or leukocytes: ▪ part of the immune system 3. Platelets or thrombocytes: ▪ cell fragments involved in clotting BMS 1.1  Hemostasis The cessation of bleeding: vascular phase ▪ A cut triggers vascular spasm (local myogenic spasm) ▪ Short-term platelet phase coagulation phase BMS 1.11 Upon chemical of Physical Damage of Endothelial Cells: Activates Thrombocytes 1. Endothelial cells contract: expose basal lamina to bloodstream 2. Endothelial cells release: chemical factors ADP, tissue factor, and prostacyclin local hormones endothelins function: stimulate smooth muscle contraction and cell division 3. Endothelial cell membranes become “sticky”: seal off blood flow BMS 1.11 Two Steps of the Platelet Phase (Activated Thrombocytes (begins 15 seconds after injury) Platelet adhesion (attachment): to sticky endothelial surfaces to basal laminae to exposed collagen fibers Platelet aggregation (stick together): forms platelet plug closes small breaks BMS 1.11 Activated Platelets (Aggregation): Cell-to-Cell Adhesion & Release Clotting Compounds Adenosine diphosphate (ADP) Thromboxane A 2 and serotonin Clotting factors Platelet-derived growth factor (PDGF) Calcium ions von Willebrand’s factor: bridge from vessel wall to platelet Platelet receptor Glycoprotein (GP)IIb/GPIIIa: allows fibrinogen to bridge aggregating platelets BMS 1.11 Platelet Plug: Size Restriction Prostacyclin: released by endothelial cells inhibits platelet aggregation Inhibitory compounds: released by other white blood cells BMS 1.11 Coagulation Phase Fibrin network (from a positive feedback mechanism ▪ Covers platelet plug ▪ Traps blood cells ▪ Seals off area ▪ Clotting Factors (pro-coagulants): Twelve factors proteins or ions in plasma required for normal clotting most of the protein factors are produced by the liver except factor III, IV & VIII platelets produce fibrinogen, fibronectin, factor V & factor VIII BMS 1.11 Pro vs Anti-Blood Clot BMS 1.11 Plasma Clotting Factors Ia: Fibrin IIa: Thrombin (or thromboplastin) (ionized calcium) (or labile factor) -------------(activated V) (or prothrombinogen) -(anti-hemolytic factor ) (or PTC) (or fibrin-stabilizing factor) PTC = Plasma Thromboplastin Component PTA = Plasma Thromboplastin antecedent BMS 1.11 Coagulation Phase ▪ Blood clotting (coagulation): Involves a series of steps converts circulating fibrinogen into water-insoluble fibrin Why does fibrin need to be water-insoluble? ▪ Bleeding time Normally, a small puncture wound stops bleeding in 1–4 minutes BMS 1.11 The Coagulation Phase or Common Pathway: forms water-insoluble fibrin ▪ Begins 30 seconds or more after the injury BMS 1.11 Cascade Reactions ▪ Chain reactions of enzymes and proenzymes ▪ Form THREE pathways Extrinsic Intrinsic Common ▪ Calcium ions (Ca2+) and Vitamin K are both essential to the clotting process BMS 1.11/1.12 Three Coagulation Pathways A. Extrinsic pathway: Tissue Factor Pathway Begins in the vessel wall (outside blood stream) Damaged cells release tissue factor (TF) TF + other compounds = enzyme complex Activates Factor X of the Common Pathway BMS 1.11  Coagulation Pathway (tissue factor) BMS 1.11  Extrinsic Pathway 1. Tissue trauma → release of tissue factor or tissue thromboplastin (TTP) or tissue factor (III) from traumatized tissue; tissue factor is a proteolytic enzyme 2. Tissue factor activates Factor VII to Factor VIIa 3. Tissue factor + Ca+2 + VIIa activates Factor X (now the common pathway is activated) 4. Tissue factor + Ca+2 (factor IV) + Xa + Va = prothrombin activator 5. Prothrombin activator splits prothrombin into thrombin rapid and explosive in nature (15 seconds) self accelerating: thrombin activates Factor V which increases the reactivity of prothrombin activator BMS 1.11 Three Coagulation Pathways B. Intrinsic pathway: Contact Activation Pathway Begins with circulating proenzymes (within bloodstream) Activation of enzymes by collagen Activated by platelets release factors (e.g., PF–3) Series of reactions that activate Factor X & the Common Pathway BMS 1.11  Coagulation Pathway (tissue factor) BMS 1.11 Intrinsic Pathway 1. Trauma or exposure to collagen - activates Factor XII (Hageman factor) & platelets to release of platelet factor 3 2. XIIa + enzymes activates Factor XI (PTA) 3. Ca+2+ XIa activates Factor IX (PTC or Christmas factor) 4. Ca+2 + IXa + VIIIa activates Factor X (now the common pathway is activated) 5. Ca+2 (factor IV) + Xa + Va = prothrombin activator 6. Prothrombin activator splits prothrombin into thrombin BMS 1.11  Coagulation Pathway ▪ Common pathway: Where intrinsic and extrinsic pathways converge (tissue factor) BMS 1.11 Three Coagulation Pathways C. Common Pathway ▪ Enzymes activate Factor X ▪ Forms enzyme prothrombinase ▪ Converts prothrombin to thrombin ▪ Thrombin (IIa) converts fibrinogen (I) to fibrin (Ia) BMS 1.11  Coagulation Pathway INSIDE OUTSIDE BMS 1.11 PT vs PTT ▪ Prothrombin time (PT) & partial thromboplastin time (PTT) are laboratory measurements used to examine how long clotting takes PT assesses the extrinsic pathway (VII) & common pathway PTT assesses the intrinsic pathway (XII, XI, IX, VIII) & common pathway BMS 1.11 Functions of Thrombin (IIa) ▪ Beside helping to convert fibrinogen to fibrin & cross-link fibrin (XIIIa) ▪ More Procoagulant roles forms positive feedback loop by trigging generation of factors V, VIII & XI = accelerates clotting ▪ Anti-coagulant role binds thrombomodulin (TM) on endothelial cells & a natural anticoagulant TM helps to activate Protein C & Protein C will inhibit Factor V (which is need for the Common Pathway) BMS 1.11 Thrombi & Emboli ▪ An abnormal clot is a thrombus ▪ When it floats it’s an embolus ▪ Thromboembolic conditions caused by… Endothelial roughening Atherosclerosis Infection Trauma Heart valves By-pass surgery Slow flow prolonged air travel long-term bed immobilization BMS 1.16  Bleeding Disorders ▪ Vessel defects Vitamin C deficiency (impaired collagen) Bacterial & viral infections ▪ Platelet disorders Thrombocytopenia: abnormally low platelet count Thrombocytosis: abnormally high platelet count Thrombocytopathy ▪ Genetic Factors BMS 1.14 Thrombocytopenia Inadequate number of platelets Possible causes: ▪ Autoimmune diseases, such as lupus & rheumatoid arthritis immune system mistakenly attacks & destroys platelets ▪ Drug induced: alcohol, thiazide, diuretics ▪ Bone marrow failure: viral infection, leukemia, nutritional deficiencies, chemo/radiation therapy ▪ Hyper-splenism: increase in size leads to destruction of platelets BMS 1.14 Thrombocythemia (Thrombocytosis): ▪ Platelets are acute phase reactants: numbers increase in response to stimuli ▪ Likely due to overproduction of pro-inflammatory cytokines ▪ Pathophysiology Clonal disorder of multipotent hematopoietic progenitor cell JAK2 mutation in 50% cases large platelets BMS 1.14 Reactive Thrombocytosis: ▪ Definition: Elevated platelet count in response to a trigger. ▪ Not due to bone marrow over-production or clonal expansion of progenitor cells ▪ (Causes include): Iron deficiency anemia Acute blood loss Allergic reactions Post splenectomy Cancer Hemolytic anemia Chronic kidney disease Inflammatory disorders (RA, Exercise CTD, celiac, etc.) AMI Major surgery Infections Pancreatitis Trauma Medications BMS 1.14 Thrombocytopathy Adequate number of platelets but abnormal function (dysfunctional thrombocytes = prolonged bleeding time, defective clot formation and/or tendency to hemorrhage) ▪ May be congenital or acquired Possible causes: ▪ Drug induced: aspirin (irreversibly binds to platelets) NSAIDS (reversibly binds to platelets) ▪ Bone marrow failure: viral ▪ Hypersplenism BMS 1.14 Hypocoagulable States ▪ Excess bleeding (hypocoagulable state) can result from: deficiencies in platelet number o thrombocytopenia deficiencies in platelet function o von Willebrand’s disease deficiencies of pro-coagulation proteins o many synthesized in the liver (i.e. liver failure) over-production of anti-coagulation proteins o overactive thrombomodulin, protein S, protein C and/or anti-thrombin III vitamin K deficiency: needed for II, VII, IX, X o the anti-coagulant Coumadin interferes with Vitamin K- dependent factors II, VII, IX and/or X BMS 1.11 Genetic Hypocoagulopathies Genetic (Hereditary) Disorders Three leading factor disorders ▪ #1 defect is von Willebrand disease (mutated vWF) autosomal dominant disorder bridge from vessel wall to platelet ▪ #2 defect is hemophilia A (mutated factor VIII) X-linked recessive disorder MC of hemophilia’s ▪ #3 defect is hemophilia B (mutated factor IX) X-linked recessive disorder ▪ Defect in hemophilia C (mutated factor XI) : rare autosomal recessive disorder BMS 1.14  Autosomal Dominant (AD) Disorders: Autosomal dominant inheritance affected person (only need one copy of gene to have the trait/disorder) has 50% chance of passing on the gene ▪ von Willebrand disease ▪ Huntington disease ▪ Factor V Leiden ▪ Neurofibromatosis ▪ Protein S Deficiency ▪ Myotonic dystrophy ▪ Protein C Deficiency ▪ Osteogenesis imperfecta ▪ Anti-thrombin II Deficiency ▪ Tuberous sclerosis ▪ Marfan Syndrome ▪ Polycystic kidney disease ▪ Ehlers Danlos syndrome ▪ Familial polyposis coli ▪ Achondroplasia ▪ Familial hypercholesterolemia ▪ Acute intermittent porphyria Khan Academy: Introduction to heredity BMS 1.6  X linked Recessive (XR) Disorders: X-linked inheritance affected male (only one X chromosome thus has trait/disorder) vs affected female (one X chromosome = carrier, both X chromosomes = have trait/disorder) ▪ Duchenne muscular dystrophy ▪ Hemophilias A (Factor VIII) can also be by spontaneous mutation ▪ Hemophilias B ( Factor IX) can also be by spontaneous mutation ▪ Chronic granulomatous disease ▪ Glucose-6-phosphate dehydrogenase deficiency ▪ Agammaglobulinemia ▪ Diabetes insipidus ▪ Lesch-Nyhan syndrome ▪ Fragile X syndrome – more common BMS 1.6  Autosomal Recessive (AR) Disorders: Autosomal recessive inheritance affected person (must have two copies of the (recessive )gene to have the trait/disorder) has 50% chance of passing on the gene Having one copy of the recessive gene = carrier ▪ Cystic fibrosis ▪ Sickle cell anemia ▪ Phenylketonuria ▪ Alpha Thalassemias ▪ Galactosemia ▪ Hemophilia C (Factor XI) ▪ Homocystinuria ▪ Congenital adrenal ▪ Lipid storage diseases hyperplasia ▪ α1 Antitrypsin deficiency ▪ Alkaptonuria ▪ Wilson disease ▪ Neurogenic muscular atrophies ▪ Hemochromatosis ▪ Friedreich ataxia ▪ Glycogen storage diseases ▪ Spinal muscular atrophy BMS 1.6 Control of Clotting Clot Retraction/Lysis ▪ Clot retracts after clot has formed: Platelets contract and pull torn area together Takes 30–60 minutes ▪ Fibrinolysis: Slow process of dissolving clot: thrombin and tissue plasminogen activator (t-PA): activate plasminogen Plasminogen produces plasmin: digests fibrin strands BMS 1.11 Autolysis of Clots (fibrinolytic system) ▪ Plasminogen forms plasmin when activated by tissue plasminogen activator (tPA) ▪ Injured tissues and vascular endothelium release tPA after tissue repair is complete and the blood clot is no longer needed to prevent bleeding ▪ Plasmin digests fibrin fibrinogen prothrombin (II) factors V, VIII, XII ▪ Plasminogen is trapped in the clot so that the clot can be dissolved slowly and not release ‘pieces’ into the circulation BMS 1.11 Clotting: Area Restriction (Checks & Balances to Prevent Venous Thrombosis or Hypercoagulable States) ▪ Anticoagulants (plasma proteins): anti-thrombin-III alpha-2-macroglobulin: can inhibit plasmin ▪ Heparin ▪ Thrombomodulin ▪ Protein C: stimulates plasmin formation plasmin: an enzyme that breaks down fibrin strands (Protein C is activated by thrombomodulin) ▪ Protein S: Vitamin K dependent anticoagulant that works with Protein C to stop factor V & VIII ▪ Prostacyclin also inhibits platelet aggregation BMS 1.11 BMS 1.11 Prevention of Blood Clotting 1. Endothelial Factors ▪ Endothelial cells smooth surface prevents activation ▪ Glycocalyx of endothelial cells repels platelets and clotting factors ▪ Thrombomodulin in endothelial tissue binds to thrombin (inactivated) ▪ Thrombomodulin-thrombin complex activates protein C ▪ Protein C inactivates Factors Va and VIIIa ▪ Trauma – loss of smoothness and glycocalyx, exposure of subendothelium collagen activates Factor XII and platelets BMS 1.11 Anti-Thrombin BMS 1.14 Prevention of Blood Clotting 2. Removal of Thrombin ▪ Fibrin fibers 85-90% of formed thrombin is trapped in the clot – prevents excessive spread of clotting ▪ Anti-thrombin III or anti-thrombin-heparin cofactor rapid removal of thrombin 3. Heparin combines with antithrombin III, increasing its effectiveness removal of Factors XIIa, XIa, IXa, Xa, & thrombin (IIa) released by mast cells released by basophils BMS 1.11 Inactivated by Heparin BMS 1.11 Hypercoagulability States: Prone to Clotting ▪ Conditions of Increased Platelet Function ▪ Conditions of Increased Clotting Activity ▪ Both predispose to thrombosis BMS 1.15 Hypercoagulability States: Increased Platelet Function ▪ Potential Problem: sticky platelets > platelet clots > blood flow disruption ▪ Causes: disturbed blood flow, endothelial damage, increased platelet activation ▪ Conditions include: Atherosclerosis Diabetes mellitus Smoking Elevated blood lipids Thrombosis Some malignancies, myeloproliferative disorders, and chronic inflammatory states, and post splenectomy BMS 1.15 Primary Thrombophilia: Prone to Clotting ▪ Factor V Leiden ▪ Protein Deficiencies ▪ Increased levels of Factors I, VIII, IX & X BMS 1.15 Factor V Leiden Genetic (Hereditary) Disorders ▪ Factor V Leiden Autosomal dominant inheritance gene mutation of Factor Va on chromosome 1 leads to mutation of factor V protein two changes in the coagulation cascade: o reduced anticoagulant function of Factor V o increased procoagulant role of Factor Va BMS 1.14  Factor V Leiden From: Medical and Surgical Complications Williams Obstetrics, 24e, 2013 Legend : Overview of the inherited thrombophilias and their effect(s) on the coagulation cascade. (Adapted from Seligsohn, 2001.) BMS 1.15 Inherited Thrombophilias: Protein S Deficiency ▪ Protein S (PS) – vitamin K dependent glycoprotein functions as cofactor for protein C made in liver, endothelial cells, & megakaryocytes levels increase with age. lower in females ▪ Inherited PS deficiency: autosomal dominant; homozygous dominant form (SS) mostly incompatible with life BMS 1.15  Protein S Deficiency From: Medical and Surgical Complications Williams Obstetrics, 24e, 2013 Legend : Overview of the inherited thrombophilias and their effect(s) on the coagulation cascade. (Adapted from Seligsohn, 2001.) BMS 1.15  Inherited Thrombophilias: Protein C Deficiency ▪ Autosomal dominant inheritance Rare to see homozygous form ▪ May be acquired as well (infection, septic shock) ▪ Protein C is a vitamin K-dependent protein, made in the liver ▪ Protein C is activated by thrombomodulin & Protein S ▪ Active protein C inactivates coagulation factors Va & VIIIa BMS 1.15 The Body’s Natural Anti- Coagulants: Protein C Protein S Antithrombin III BMS 1.15  Inherited thrombophilias: Antithrombin deficiency ▪ Anti-thrombin III (ATIII) is a potent inhibitor of the coagulation cascade. ▪ It is a non-vitamin K-dependent protease that inhibits coagulation by lysing thrombin and factor Xa. ▪ ATIII activity is markedly potentiated by heparin potentiation of anti-thrombin III activity is the principle mechanism by which both heparin and low molecular weight heparin result in anticoagulation BMS 1.15 *Antithrombin III: -lyses Thrombin and Xa -thus preventing thrombus formation BMS 1.15 Increased Clotting Activity: Pulmonary Embolism ▪ Pulmonary Embolism (PE) – part of the process called venous thromboembolic disease. Formation of extremity deep-vein thrombosis and embolic disease to the lungs ▪ Inheritable causes – Mutated natural anticoagulants- Mutated Antithrombin III will not inactivate thrombin Mutated Protein C/S will not inactivate factors V & VIII Mutated Factor V (Factor V Leiden) is not inactivated by protein C BMS 1.16 Acquired & Inherited Factors of DVT Formation DVTs vascular endothelium dysfunction/ injury activates coagulation cascade BMS 1.16 Primary Thrombophilia: Prone to Clotting ▪ Factor V Leiden ▪ Protein Deficiencies ▪ Increased levels of Factors I, VIII, IX & X uncommon causes of venous thrombosis not yet proven genetic, but suspected patients usually identified after a thrombotic event BMS 1.15 Secondary (Acquired) Thrombophilia: ▪ Heparin-induced thrombocytopenia (HIT) syndrome HIT results from antibody formation to platelet factor IV and heparin complex o Platelet aggregates are immunologically removed o Platelet aggregate antibodies bind to vessel walls, causing thrombosis (PE, stroke, MI) BMS 1.15 Disseminated Intravascular Coagulation (DIC): DIC can be translated as the spread of clots within the vessels ▪ Hypercoagulable state can lead to impaired blood flow ▪ DIC (or Consumptive Coagulopathy) can lead to both thrombosis and bleeding coagulation (extra clots which consume platelets) & fibrinolysis are abnormally active or break down of clots leading to high amounts of fibrin degradation products (FDP) ▪ Caused by many conditions: (typically caused by some underlying condition) severe sepsis (MC), trauma, OB complications, drugs, CA, liver disease, snake bites, leukemia/malignancy, shock, Rocky Mountain spotted fever Reminder of ‘normal’ clotting: Injury leads to platelet plug, leads to clotting (coagulation cascade), leads to termination of clotting, leads to removal of clot (fibrinolysis) BMS 1.14 Disseminated Intravascular Coagulation (DIC): Pathophysiology ▪ DIC initiated by massive/uncontrolled activation of coagulation Platelets, coagulation factors, and anticoagulants are consumed Severe hemorrhage, multiple organ failure, and micro-clots Uncontrolled production of fibrin due to exposure of blood to high levels of tissue factor, with suppression of anticoagulant mechanisms & abnormal fibrinolysis BMS 1.14 DIC Mechanism BMS 1.14