Hematopoietic System Lecture Notes PDF

HEMATOPOIETIC SYSTEM Copyright Pass NPLEX 2018 1  HEMATOPOEITIC SYSTEM ▪ Description of Blood Cells ▪ Blood Cell Degradation ▪ Embryology/Anatomy/Physiology/Biochemistry Included Together ▪ Pathology...

HEMATOPOIETIC SYSTEM Copyright Pass NPLEX 2018 1  HEMATOPOEITIC SYSTEM ▪ Description of Blood Cells ▪ Blood Cell Degradation ▪ Embryology/Anatomy/Physiology/Biochemistry Included Together ▪ Pathology SAMPLE CASE 1 3-year-old male presents with epistaxis, pain, and vomiting. Physical examination reveals generalized lymphadenopathy. Lab test results confirm a diagnosis of acute lymphoblastic leukemia. 1. Acute lymphoblastic leukemia is characterized by _______________. A. Bence-Jones proteins in the urine B. Decreased numbers of all types of blood cells C. Tumor masses in multiple contiguous lymph nodes D. The presence of Reed-Sternberg cells in the bone marrow Copyright Pass NPLEX 2018 2  ▪ Answer: B - Decreased numbers of all types of blood cells ▪ Bence Jones proteins are found in multiple myeloma. ▪ Reed-Sternberg cells are seen in Hodgkin’s lymphoma SAMPLE CASE #2 57-year-old male presents with bone pain and lethargy. Imaging reveals the presence of punched-out, lytic lesions. He is diagnosed with multiple myeloma. 1. Which of the following is indicative of this condition? 1. Bence Jones proteins 2. Reed-Sternberg cells 3. Agammaglobulinemia 4. Hairy B cells Copyright Pass NPLEX 2018 3  ▪ Answer: A - Bence Jones proteins ▪ Light chain of antibodies that are found in the urine due to the excessive proliferation and deposition within the glomeruli of the kidneys. ▪ Reed-Sternberg cells are seen in Hodgkin’s lymphoma ▪ Hairy B cells are malignant B cells seen in leukemia. ▪ Agammaglobulinemia is characterized by the absence or very low levels of gamma globulin. BACKGROUND ▪ Blood is a specialized connective tissue ▪ Composed of extracellular matrix (plasma) and suspended RBCs, WBCs, and platelets. ▪ Blood is formed in bone marrow, liver, spleen, and lymphoid tissue in utero ▪ Exclusively formed in the bone marrow after birth ▪ Long bone in children and pelvis, cranium, vertebrae, and sacrum in adults Copyright Pass NPLEX 2018 4  CELL TYPES ▪ Erythrocytes ▪ Leukocytes ▪ Granulocytes ▪ Agranulocytes ▪ Platelets Image: Wikimedia Commons – Author: A. Rad Copyright Pass NPLEX 2018 5  Image: Wikimedia Commons – Author: Mikael Häggström and A. Rad ERYTHROCYTES ▪ Biconcave-shaped allows for a larger size relative to volume to optimize gas exchange ▪ RBC precursor cells are located in bone marrow ▪ Contain hemogloblin which is covalently bound to heme ▪ Average life span is 120 days Copyright Pass NPLEX 2018 6  LEUKOCYTES ▪ Smaller than RBCs ▪ Migrate through the endothelial cells of the blood vessels (diapedesis) ▪ Round-shaped within the bloodstream and pleomorphic within the connective tissue ▪ Include granulocytes and agranulocytes GRANULOCYTES Neutrophils ▪ Acute inflammation, phagocytic Eosinophils ▪ Immediate hypersensitivity/allergic and anti-parasitic responses Basophils ▪ Granules contain histamine Mast cells ▪ Allergy and anaphylaxis Copyright Pass NPLEX 2018 7  AGRANULOCYTES Lymphocytes T cells ▪ Helper T cells (CD4+) ▪ Suppressor T cells ▪ Killer T cells (CD8+) B cells ▪ Secrete immunoglobulins Natural Killer (NK) cells ▪ Specialized T helper cell-independent lymphocyte Monocytes ▪ Differentiate into macrophages in the tissue ▪ Phagocytic and antigen-presenting PLATELETS ▪ Non-nucleated cell fragments that arise from megakaryocytes within the bone marrow. ▪ Life span is less than 14 days Copyright Pass NPLEX 2018 8  HEMATOPOIESIS & HEMOSTASIS ▪ Hemoglobin ▪ Heme synthesis ▪ Hemostasis HEMOGLOBIN ▪ Oxygen-binding protein in red blood cells ▪ One hemoglobin (Hb) molecule can carry up to 4 oxygen molecules each bound to one of its four heme molecules. ▪ Oxygen binding causes hemoglobin to transform from a tense configuration into its relaxed form to facilitate oxygen binding. ▪ Hemoglobin is one of the major buffers of pH in the blood. Copyright Pass NPLEX 2018 9  OXYGEN CARRYING 2,3-BPG 2,3-BPG ▪ Right shift = O2 dissociates from hemoglobin easily ▪ 2,3-bisphosphoglycerate (BPG) is a byproduct of glycolysis in RBCs and stabilizes the tense form of hemoglobin (decreases its affinity for O2) ▪ Binding of CO2 to hemoglobin causes it to release oxygen (Bohr effect) Image: Wikimedia Commons – Author: Ratznium HEME SYNTHESIS ▪ Occurs primarily in the bone marrow and liver ▪ Key regulatory enzyme is delta-aminolevulinate synthase ▪ Cofactor = vitamin B6 (pyridoxal phosphate) ▪ Uroporphyrinogen III decarboxylase does not require a co-factor unlike most other decarboxylase enzymes. ▪ Synthesis is inhibited by lead because ALA dehydratase contains zinc. ▪ Lead binds the sulfhydryl groups in ferrochelatase ▪ Negative feedback control of ALA synthase by the final heme product and high iron levels. Copyright Pass NPLEX 2018 10  Image: Wikimedia Commons – Author: Wmheric HEMOSTASIS ▪ Vascular spasm restricts blood loss to allow the platelet plug to form. ▪ Platelets adhere to collagen via von Willebrand factor (vWF) which is secreted by endothelial cells and platelets. ▪ Coagulation ▪ Extrinsic or intrinsic pathway ▪ Heparin ▪ Stored in mast cells and basophils and released at sites of injury ▪ Prevents new clots from forming by binding to antithrombin thus activating it and inhibiting thrombin and clotting factor Xa. Copyright Pass NPLEX 2018 11  Image: Wikimedia Commons – Author: Jng46 BLOOD CELL DEGRADATION ▪ The spleen and other reticuloendothelial organs split hemoglobin into heme and globin. ▪ The heme ring is opened up by heme oxygenase into biliverdin and CO. ▪ Albumin carries bilirubin to the liver because it isn’t water soluble. ▪ Bilirubin is conjugated to two glucuronides by two isoforms of UDP-glucuronosyl transferase. ▪ Bilirubin diglucuronide is actively transported into the bile for excretion. ▪ Within the intestine gut flora can deconjugate the bilirubin and convert it to urobilinogen. ▪ Urobilinogens can be reabsorbed and oxidized back to bilirubin by hepatocytes. Image: Wikimedia Commons – Author: Johndheathcote Copyright Pass NPLEX 2018 12  ▪ Iron from hemoglobin is stored bound to hepatic protein ferritin. ▪ If ferritin is saturated, iron is deposited within the cell hemosiderin. ▪ Hepcidin is the key regulator of iron absorption. ▪ Ferroportin is a transport protein for iron on erythrocytes. ▪ Hepcidin synthesis decreases when Fe levels are low by binding to ferroportin. ▪ Transferrin is a protein that transports iron in the blood. Vitamin C increases iron absorption within the intestines. Heme iron-containing molecules: ▪ Hemoglobin, myoglobin, cytochrome P450 enzymes, peroxidases, catalase Non-heme iron-containing molecules: ▪ Xanthine oxidase, ribonucleotide reductase, 5’-deiodinase PATHOLOGY Copyright Pass NPLEX 2018 13  PATHOLOGY ▪ Diseases involving production of blood cells ▪ Hemolytic anemias ▪ Clotting abnormalities ▪ Blood & lymph neoplasms ▪ Lymph node diseases ▪ Infectious diseases of the blood DISEASES INVOLVING PRODUCTION OF BLOOD CELLS ▪ Anemias ▪ Iron deficiency anemia ▪ Macrocytic anemia ▪ Aplastic anemia ▪ Polycythemia vera ▪ Secondary polycythemia Copyright Pass NPLEX 2018 14  ANEMIAS ▪ Any condition that causing the total number of RBCs, the amount of Hb, or the volume of packed RBCs to decrease. ▪ Caused hypoxia in tissues ▪ General symptoms include dyspnea on exertion, fatigue, dizziness, tinnitus, headache ▪ Long-term anemia can cause pallor, tachycardia, systolic ejection murmur, orthostatic hypotension. IRON DEFICIENCY ANEMIA ▪ Due to chronic blood loss, increased need for blood and oxygen (pregnancy), deficiency intake or poor absorption. ▪ Microcytic, hypochromic anemia ▪ Fatigue, lethargy, pale mucous membranes, low Hb, low RBC, low hematocrit, small RBCs, low MCV, MCH and MCHC, low serum ferritin and iron. ▪ Long-term deficiency can result in chronic fatigue, low energy, and depression. ▪ Severe deficiency can result in gastritis, glossitis, Plummer-Vinson syndrome Copyright Pass NPLEX 2018 15  MACROCYTIC ANEMIA ▪ Vitamin B12 or folic acid deficiency or malabsorption which affects DNA synthesis. ▪ Folic acid deficiency can be caused by alcoholism, pregnancy, intestinal malabsorption, and folic acid antagonists ▪ Megaloblastic anemia – enlarged abnormal prescursor cells in the bone marrow. ▪ Fatigue, lethargy, low RBC, low Hb, low hematocrit, large cells (increased MCV, MCH, and normal MCHC), ferritin and iron levels normal, low serum B12, low serum folate, increased serum/urine methylmalonic acid (B12 deficiency), high serum homocysteine levels (folate deficiency), polysegmented neutrophils, pancytopenia ▪ Complications include dementia, depression, glossitis, stomatitis, paranoia, neuropathies, ataxia, hyperreflexia, death Pernicious anemia ▪ An autoimmune disease that reduces the absorption of food-bound B12 by destroying intrinsic factor (IF) ▪ Anti-parietal Ab and anti-intrinsic factor Ab ▪ Chief cells are damaged resulting in achlorhydria and lack of pepsinogen secretion ▪ Autoimmune atrophic gastritis often results. ▪ Complications include recurrent GI infection and the same issues as B12 deficiency Copyright Pass NPLEX 2018 16  APLASTIC ANEMIA ▪ Severe anemia that results from a loss of the precursor cells of RBCs ▪ Results from toxic exposure (drugs, radiation, chemicals) or viral infection. ▪ Bone marrow is hypocellular and all cell lines are decreased (peripheral pancytopenia). POLYCYTHEMIA VERA ▪ Myeloproliferative disorder that result in the neoplastic clonal proliferation of myeloid stem cells within the marrow. ▪ Results in an increased number of circulating RBCs, increased hemoglobin, and a moderate increase in circulating granulocytes and platelets. ▪ Splenomegaly and decrease erythropoietin results. ▪ Weakness, fatigue, vertigo, irritability, tinnitus, facial flushing,extremity pain/erythema, blue/black spots on the skin can occur. Copyright Pass NPLEX 2018 17  SECONDARY POLYCYTHEMIA ▪ Secondary to another condition that causes an increased need for RBCs ▪ High altitude exposure, right-to-left shunts, shock, abnormal Hb ▪ Can also be caused by inappropriate production of erythropoietin by tumors (renal cell carcinoma and hepatocellular carcinoma) ▪ Pheochromocytoma and Cushing’s syndrome can also cause this condition. ▪ High erythropoietin (EPO) results HEMOLYTIC ANEMIAS ▪ Sickle cell anemia ▪ Thalassemias ▪ Hereditary spherocytosis ▪ Glucose-6-phosphate dehydrogenase deficiency Copyright Pass NPLEX 2018 18  HEMOLYSIS ▪ Destruction of RBCs ▪ Can cause anemia ▪ Jaundice, hemosiderosis, and usual anemia symptoms ▪ Causes include: ▪ Mechanical trauma to cells ▪ Heart valves, clots ▪ Complement-induced damage ▪ Extravascular hemolysis (within the spleen) SICKLE CELL ANEMIA ▪ Abnormal hemoglobin (HbS) is produced due to a genetic disease. ▪ People who are heterozygous for the gene are generally asymptomatic. ▪ Those who are homozygous for the defective gene results in deformed RBCs. ▪ Can obstruct capillaries and are removed and destroyed by the spleen ▪ Severe hemolytic anemia, chronic leg ulcers, infarcts of the lungs and spleen, vaso-occlusive painful crisis (limbs, back, chest, abdomen), and aplastic crises Copyright Pass NPLEX 2018 19  THALASSEMIAS ▪ Genetic disorders characterized by deficient production of either of the two globin chains of hemoglobin. ▪ Hypochromic, microcytic anemia ▪ Beta-thalassemias is the most common form in the Mediterranean and US ▪ Major and minor forms ▪ Defects in the beta chain of hemoglobin ▪ Major: anemia, splenomegaly, distortion of the facial and long bones, hemosiderosis ▪ Minor: generally asymptomatic ▪ Alpha-thalassemias is most common in Southeast Asia ▪ Results from a defect of one or more of 4 alpha hemoglobin genes ▪ The higher the number of deletion the more clinical abnormalities GLUCOSE-6 PHOSPHATE DEHYDROGENAGE DEFICIENCY ▪ X-linked disorder which causes hemolytic anemia during oxidative stress and is caused by a number of drugs ▪ G6PD is the rate-limiting enzyme for the HMP shunt ▪ It maintains NADPH levels and reduced glutathione Copyright Pass NPLEX 2018 20  HEREDITARY SPHEROCYTOSIS ▪ Genetic defect that causes spherical red blood cells that get stuck in the spleen and destroyed ▪ Autosomal dominant ERYTHROBLASTOSIS FETALIS ▪ Occurs when the mother and fetus have different blood types ▪ Mother is Rh- but baby is Rh+ where the mother generates antibody against the Rh antigens ▪ ABO incompatibility ▪ Hemolysis results in elevated bilirubin levels and jaundice. ▪ Risk of kernicterus, hepatosplenomegaly ▪ No complications occur in the initial pregnancy. ▪ In subsequent pregnancies, maternal antibodies cross the placenta and lyse fetal RBCs which causes anemia, hypoalbuminemia, and possibly high-output heart failure, or fetal death. ▪ Maternal sensitization and antibody production due to Rh incompatibility can be prevented by giving the woman Rh immune globulin. Copyright Pass NPLEX 2018 21  CLOTTING ABNORMALITIES ▪ Disseminated intravascular coagulation (DIC) ▪ Hemophilia ▪ Thrombocytopenia ▪ Von Willebrand’s disease ▪ Vitamin K deficiency DISSEMINATED INTRAVASCULAR COAGULATION ▪ Common hemorrhagic syndrome that occurs after uncontrolled activation of clotting factors and fibrinolytic enzymes throughout small blood vessels. ▪ Triggered by massive tissue damage, sepsis, pregnancy, cancer ▪ Caused by the release of tissue thromboplastin or activation of the intrinsic pathway of coagulation ▪ Results in prolonged PT, APTT, bleeding and thrombin time ▪ Acute DIC results in fibrin deposition everywhere and platelets and clotting factors are consumed ▪ Fibrin degradation products (D-dimers) inhibit fibrin polymerization and block platelet function. ▪ Outcome is lethal tissue necrosis and bleeding. ▪ Chronic DIC occurs primarily as a result of certain cancers, retained dead fetuses, hemangiomas, and aneurysms. Copyright Pass NPLEX 2018 22  HEMOPHILIA ▪ Blood coagulation disorders due to absence, deficiency, impaired activity of clotting factors which results in prolonged bleeding. ▪ X-linked recessive ▪ Hemophilia A - Factor VIII deficiency ▪ Normal bleeding time, platelet count, prothrombin time but prolonged activated partial thromboplastin time ▪ Bleeding occurs in the muscles, subcutaneous tissues, and joints. ▪ Hemophilia B - Factor IX deficiency ▪ Similar to Hemophilia A ▪ Hemophilia C (Autosomal Recessive) - Factor XI deficiency ▪ Mild (5-40% of factor levels) ▪ Asymptomatic or experience prolonged bleeding only after serious injury ▪ Moderate (1-5% normal factor levels) ▪ Prolonged bleeding after injuries and occasional spontaneous bleeding. ▪ Severe (