HEMATOPOIETIC SYSTEM HEMATOPOEITIC SYSTEM 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 ▪ Description of Blood Cells acute lymphoblastic leukemia. ▪ Blood Cell Degradation 1. Acute lymphoblastic leukemia is characterized by _______________. ▪ Embryology/Anatomy/Physiology/Biochemistry A. Bence-Jones proteins in the urine Included Together B. Decreased numbers of all types of blood cells C. Tumor masses in multiple contiguous lymph nodes ▪ Pathology D. The presence of Reed-Sternberg cells in the bone marrow SAMPLE CASE #2 ▪ Answer: B - Decreased numbers of all types of blood cells 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. ▪ Bence Jones proteins are found in multiple myeloma. ▪ Reed-Sternberg cells are seen in Hodgkin’s lymphoma 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 1 BACKGROUND ▪ Answer: A - Bence Jones proteins ▪ Blood is a specialized connective tissue ▪ Light chain of antibodies that are found in the urine due to the excessive proliferation and ▪ Composed of extracellular matrix (plasma) and suspended RBCs, WBCs, and deposition within the glomeruli of the kidneys. platelets. ▪ Reed-Sternberg cells are seen in Hodgkin’s lymphoma ▪ Hairy B cells are malignant B cells seen in leukemia. ▪ Blood is formed in bone marrow, liver, spleen, and lymphoid tissue in utero ▪ Agammaglobulinemia is characterized by the absence or very low levels of gamma ▪ Exclusively formed in the bone marrow after birth globulin. ▪ Long bone in children and pelvis, cranium, vertebrae, and sacrum in adults CELL TYPES ▪ Erythrocytes ▪ Leukocytes ▪ Granulocytes ▪ Agranulocytes ▪ Platelets Image: Wikimedia Commons – Author: 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 Image: Wikimedia Commons – Author: Mikael Häggström and A. Rad Copyright Pass NPLEX 2018 2 LEUKOCYTES GRANULOCYTES ▪ Smaller than RBCs Neutrophils ▪ Acute inflammation, phagocytic ▪ Migrate through the endothelial cells of the blood vessels (diapedesis) ▪ Round-shaped within the bloodstream and pleomorphic within the connective tissue Eosinophils ▪ Immediate hypersensitivity/allergic and anti-parasitic responses ▪ Include granulocytes and agranulocytes Basophils ▪ Granules contain histamine Mast cells ▪ Allergy and anaphylaxis AGRANULOCYTES PLATELETS Lymphocytes ▪ Non-nucleated cell fragments that arise from megakaryocytes within the bone Tcells marrow. ▪ Helper T cells (CD4+) ▪ Suppressor T cells ▪ Life span is less than 14 days ▪ Killer T cells (CD8+) Bcells ▪ Secrete immunoglobulins Natural Killer (NK) cells ▪ Specialized T helper cell-independent lymphocyte Monocytes ▪ Differentiate into macrophages in the tissue ▪ Phagocytic and antigen-presenting HEMATOPOIESIS & HEMOGLOBIN HEMOSTASIS ▪ Oxygen-binding protein in red blood cells ▪ Hemoglobin ▪ One hemoglobin (Hb) molecule can carry up to 4 oxygen molecules each bound ▪ Heme synthesis to one of its four heme molecules. ▪ Hemostasis ▪ 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 3 OXYGEN HEME SYNTHESIS CARRYING 2,3-BPG 2,3-BPG ▪ Occurs primarily in the bone marrow and liver ▪ Right shift = O2 dissociates ▪ Key regulatory enzyme is delta-aminolevulinate synthase from hemoglobin easily ▪ Cofactor = vitamin B6 (pyridoxal phosphate) ▪ 2,3-bisphosphoglycerate (BPG) is a byproduct of glycolysis in ▪ Uroporphyrinogen III decarboxylase does not require a co-factor unlike most RBCs and stabilizes the tense other decarboxylase enzymes. form of hemoglobin (decreases ▪ Synthesis is inhibited by lead because ALA dehydratase contains zinc. its affinity for O2) ▪ Lead binds the sulfhydryl groups in ferrochelatase ▪ Binding of CO2 to hemoglobin ▪ Negative feedback control of ALA synthase by the final heme product and high causes it to release oxygen iron levels. (Bohr effect) Image: Wikimedia Commons – Author: Ratznium 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. Image: Wikimedia Commons – Author: Wmheric 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: Jng46 Image: Wikimedia Commons – Author: Johndheathcote Copyright Pass NPLEX 2018 4 ▪ 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. PATHOLOGY 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 DISEASES INVOLVING PATHOLOGY PRODUCTION OF BLOOD ▪ Diseases involving production of blood cells ▪CELLSAnemias ▪ Iron deficiency anemia ▪ Hemolytic anemias ▪ Macrocytic anemia ▪ Clotting abnormalities ▪ Aplastic anemia ▪ Blood & lymph neoplasms ▪ Polycythemia vera ▪ Lymph node diseases ▪ Secondary polycythemia ▪ Infectious diseases of the blood ANEMIAS IRON DEFICIENCY ANEMIA ▪ Any condition that causing the total number of RBCs, the amount of Hb, or the ▪ Due to chronic blood loss, increased need for blood and oxygen (pregnancy), volume of packed RBCs to decrease. deficiency intake or poor absorption. ▪ Caused hypoxia in tissues ▪ Microcytic, hypochromic anemia ▪ General symptoms include dyspnea on exertion, fatigue, dizziness, tinnitus, ▪ Fatigue, lethargy, pale mucous membranes, low Hb, low RBC, low hematocrit, headache small RBCs, low MCV, MCH and MCHC, low serum ferritin and iron. ▪ Long-term anemia can cause pallor, tachycardia, systolic ejection murmur, ▪ Long-term deficiency can result in chronic fatigue, low energy, and depression. orthostatic hypotension. ▪ Severe deficiency can result in gastritis, glossitis, Plummer-Vinson syndrome Copyright Pass NPLEX 2018 5 MACROCYTIC ANEMIA ▪ Vitamin B12 or folic acid deficiency or malabsorption which affects DNA synthesis. Pernicious anemia ▪ Folic acid deficiency can be caused by alcoholism, pregnancy, intestinal ▪ An autoimmune disease that reduces the absorption of food-bound B12 by destroying malabsorption, and folic acid antagonists intrinsic factor (IF) ▪ Megaloblastic anemia – enlarged abnormal prescursor cells in the bone marrow. ▪ Anti-parietal Ab and anti-intrinsic factor Ab ▪ Chief cells are damaged resulting in achlorhydria and lack of pepsinogen secretion ▪ 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, ▪ Autoimmune atrophic gastritis often results. increased serum/urine methylmalonic acid (B12 deficiency), high serum ▪ Complications include recurrent GI infection and the same issues as B12 deficiency homocysteine levels (folate deficiency), polysegmented neutrophils, pancytopenia ▪ Complications include dementia, depression, glossitis, stomatitis, paranoia, neuropathies, ataxia, hyperreflexia, death APLASTIC ANEMIA POLYCYTHEMIA VERA ▪ Severe anemia that results from a loss of the precursor cells of RBCs ▪ Myeloproliferative disorder that result in the neoplastic clonal proliferation of myeloid stem cells within the marrow. ▪ Results from toxic exposure (drugs, radiation, chemicals) or viral infection. ▪ Results in an increased number of circulating RBCs, increased hemoglobin, and a ▪ Bone marrow is hypocellular and all cell lines are decreased (peripheral moderate increase in circulating granulocytes and platelets. pancytopenia). ▪ Splenomegaly and decrease erythropoietin results. ▪ Weakness, fatigue, vertigo, irritability, tinnitus, facial flushing,extremity pain/erythema, blue/black spots on the skin can occur. SECONDARY POLYCYTHEMIA HEMOLYTIC ANEMIAS ▪ Secondary to another condition that causes an increased need for RBCs ▪ Sickle cell anemia ▪ High altitude exposure,