Tuesday, November 14 (ellen)

Lymphoid and Hematopoetic System Pathology – November 14, 2003 Disorders of hematopoietic and lymphoid systems ~ affects RBC, WBC, hemostasis ~ anemia – usually RBC disorder ~ WBC disorder usually malignant overgrowth ~ hemorrhagic diatheses = bleeding disorders (hemostatic problems) ~ see splenomegaly (hematopoietic diseases) and tumours of they thymus ~ lymphohematopoietic system not in a single anatomic site RBC Disorders ~ either anemia or erythrocytosis (increase RBC) ~ anemia – reduce O2 carrying capacity of blood ~ usually b/c loss of total circulating RBC ~ can see in subnormal hematocrit (HCT) and hemoglobin (Hb) concentrations ~ HCT – packed cell volume – how many % of blood is cellular Anemias ~ 1) hemorrhage: blood loss ~ 2) increased rate of RBC destruction (hemolytic anemia) ~ 3) anemia of diminished erythropoieses ~ 4) polycythemia Hemorrhage: Blood loss anemia ~ acute blood loss: threat of hypovolemic shock ~ normocytic normochronic (normal size, normal colour) ~ need increase EPO (made in LV, works on KI) which stimulates RBC production in several days ~ see reticulocytosis (represents marrow response) ~ chronic blood loss: Fe stores gradually deplete ~ don’t bring Fe into body properly Hemolytic Anemias – Increase rate of RBC Destruction ~ shortened survival d/t: ~ 1) inherent (maybe genetic) aka intracorpuscular RBC defects or ~ 2) external (extracorpuscular) factors (usually acquired) ~ general features: ~ 1) increase rate of RBC destruction ~ 2) reticulocytes – b/c compensatory increase in erythropoiesis ~ 3) iron – body retains everything that is a breakdown product ~ 4) erythroid hyperplasia in marrow and increase reticulocyte in peripheral blood ~ increase # of cells generating reticulocyte (immature cells)  pumped up production to make up for loss ~ occurs within: ~ 1) vascular compartment (intravascular hemolysis) ~ 2) mononuclear phagocyte

~ 3) reticuloendothelial system (extravascular hemolysis) ~ intravascular hemolysis – mechanical or chemical trauma ~ results in hemoglobinemea, hemoglobinuria, hemosiderinuria ~ can lead to acute tubular necrosis ~ extravascular hemolysis – occurs w/in phagocytes (of SP and LV) ~ remove RBC’s from circulation whenever RBCs are injured or altered ~ normally  RBC squeeze through SP sinusoids (b/w endothelium) ~ as RBC age  can’t squeeze through and get stuck and is therefore removed from SP from macrophage ~ liberate RBC and reuse heme and Fe ~ NOT associated with hemoglobinema and hemoglobinuria ~ may result in jaundice and bilirubin-rich gallstones ~ can accumulate Fe  secondary hemochromatosis Hereditary Spherocytosis ~ spectrin protein problem ~ inherited (intrinsic) defect in RBC membrane that makes the RBC sphere in shape and therefore less able to deform (to squeeze through SP sinusoids) ~ makes it more vulnerable to SP sequestration and destruction by macrophage ~ primary abnormality is in proteins that form the skeleton of the RBC ~ spectrin linked to ankyrin and glycophorin (help stabilize the shape) ~ less membrane stability  lose membrane fragments even though same volume  keep surface area to volume ratio decrease and get sphere shape ~ Tx: splenectomy, spectrin and RBC defect still there, but anemia is corrected Hemoglobinopathies ~ abnormal Hb structure ~ hereditary disorders characterized by presence of a structurally abnormal Hb ~ m/c mutation in gene encoding β-globin chain causing formation of sickle Hb (HbS)  sickle cell anemia Sickle Cell Anemia ~ should be glutamic acid but instead get valine amino acid on the 6th postion on βglobin chain ~ normal  mainly tetramers HbA (α2β2) ~ homozygotes, all HbA replaced by HbS, if heterozygotes, half HbA replaced by HbS ~ heterozygotes protected against Plasmodium falciparum (malaria) ~ gelation or crystallization – when going through deoxygenation, HbS molecules undergo polymerization ~ initially sickling can be treated with oxygenation ~ more episodes of sickling leads to accumulate Ca, lose K, and water  irreversible ~ 3 most factors influencing sickling: ~ 1) how many other abnormal Hb in cell ~ 2) concentration of HbS ~ 3) length of hypoxia exposure ~ 2 major consequences from RBC sickling

~ 1) decrease life span of RBC  pump up marrow and reticulocyte ~ 2) improper shape and size  occlude microvasculature Thalassemia ~ decrease either α or β chain, leading to anemia ~ autosomal codominant, heterozygous form (thalassemia minor) mildly symptomatic ~ homozygous form (thalassemia major) – severe hemolytic anemia ~ α chain: two genes on chromosome 11 ~ β chain: one gene on chromosome 16 Β Thalassemia ~ 2 types ~ 2 factors contribute to anemia: ~ 1) decrease Hb (decrease β globin)  decrease oxygen carrying ability and decrease colour (hypochromic) ~ 2) decrease β chain = relative increase α globin  these form insoluble aggregates in RBC = damage ~ see poikilocytosis (variation in cell shapes) and increase reticulocyte count Thalassemia major ~ abnormal form of Hb, stay with HbF (fetal form) which get continuously destroyed in body ~ decrease HbF and HbA ~ in children  organ failure, shorten life span, increase Fe from broken down RBC ~ systemic Fe overload leads to secondary hemochromatosis Thalassemia minor – mild Alpha Thalassemia ~ 4 possible degrees ~ usually see hemolytic anemia and ineffective erythropoiesis but less severe ~ still ineffective in delivering oxygen to tissues Glucose-6-Phosphate Dehydrogenase Deficiency ~ cell membrane is still deformable to get through SP sinusoids ~ although normal enzyme amount in RBC, they are decayed more rapidly ~ therefore, old RBCs, more enzyme deficient than normal, and they are more likely to be subject to oxidant stress ~ usually symptom free unless triggered by oxidant injury (ex: drugs, toxins, infections) ~ M/C – infections that trigger hemolysis d/t free radical release from phagocytic cells ~ hydrogen peroxide will accumulate and denature globin chains ~ pathopneumonic = Heinz bodies (denatured Hb in RBC that precipitate as inclusions) Immunohemolytic Anemias Warm antibody immunohemolytic anemias ~ IgG opsonizes RBC and causes phagocytosis by splenic macrophages Cold antibody immunohemolytic anemias

~ low affinity IgM Ab and they bind to RBC in distal body parts (below 30ºC) Hemolytic Anemias Resulting From Mechanical Trauma to Red Cells ~ cardiac valve prostheses or by narrowing and partial vasculature obstruction ~ 1) prosthetic valves – RBC damage by stress from pressure and turbulent flow ~ 2) microangiopathic hemolytic anemia – RBC damage because trying to squeeze through abnormally narrowed vessels Malaria ~ One of 4 types of protozoa: ~ 3 benign forms: Plasmodium vivax, P. malariae, P. ovale ~ P. falciparum – fatal!  causes “Black Water Fever” ~ all forms transmitted by anopheles mosquitoes (female) ~ saliva from mosquitoes introduce sporozites which infect LV cells ~ sporozites replicate in LV and form schizont with lots of merozoites and these are released ~ merozoites infect RBC and body has no immune reaction to it because they are hiding in RBC and immune cells can’t get to it ~ they reproduce in there until RBC lysis  all released into bloodstream  huge infection  see ss/sxs of malaria Anemias of Diminished Erythropoiesis Fe deficiency Anemia ~ m/c form of nutritional deficiency ~ storage pool represented by hemosiderin and ferriten bound iron ~ iron transported by transferring ~ shed iron through mucosal and skin cells ~ iron balance maintained by regulating absorption of dietary iron ~ negative iron balance (excrete more than absorb) w/ consequent anemia d/t: ~ 1) decrease intake ~ 2) malabsorption ~ 3) increased demands ~ 4) chronic blood loss (most important cause in western world, GI loss or menses) ~ microcytic hypochromic ~ develops insidiously (slow depletion of stored hemosiderin) ~ at first, see decrease in stored iron (measure by decline in serum ferritin and depletion of iron in bone marrow) ~ then see decrease in circulation iron, low level serum iron, rise in serum transferring Fe-binding capacity ~ in the end: affects Hg, myoglobin, and other iron compounds ~ impaired work and brain performance and reduce immunocompetence Anemia of Chronic Disease ~ m/c form of anemia in hospitalized patients ~ stem from inflammation induced iron sequestration w/in reticuloendothelial cells

~ variety of chronic inflammatory disorders: ~ 1) chronic microbial infections ~ 2) chronic immune disorders ~ 3) neoplasm (Hodgkin disease), carcinomas (LU and breast) Megaloblastic Anemias ~ two types: folate deficiency and B12 deficiency ~ both these, plus B6, recycles homocysteine ~ both folate and B12 needed for DNA synthesis ~ cell continues to grow until DNA is complete before separation through cytokinesis ~ so if DNA is lagging behind in transcription and translation because of B12 and folate deficiency, the cell will continue to grow  hence megaloblastic ~ see enlargement of erythroid precursors (megaloblasts) and see abnormally large RBC (macrocytes) ~ also see hypersegmented neutrophils ~ why anemia? B/c cellular apoptosis (ineffective hematopoiesis), decreased total RBC output, premature destruction by mononuclear phagocyte system Folate Deficiency Anemia ~ poor diet and increased metabolic needs ~ active form (tetrahydrofolate) is reduced ~ active form is supposed to act as an acceptor and donor of 1Carbon units to make purins and thymidylate in DNA Vitamin B12 deficiency: Pernicious Anemia ~ decrease vitamin B12 (cobalamin) ~ demyelinating disorder  first peripheral nerves and then spinal cord ~ long term B12 deficiency leads to posterolateral sclerosis ~ causes: malabsorption and dietary deficiency ~ pernicious anemia = inadequate or defective gastric production or function of intrinsic factor ~ B12 absorbed in distal ileum and deliver to LV and other cells using transcobalamin ~ B12 stored in LV and reabsorbed from bile but takes 5-20 years to deplete stored sources, so takes vegetarians many years to show symptoms ~ deficiency of B12 implies pernicious anemia secondary to inadequate production or function of intrinsic factor (in western world) ~ 3 potential causes: ~ 1) autoimmune to intrinsic factor or parietal cells ~ 2) gastrectomy or resection of ileum ~ 3) gastric atrophy and achlorhydria ~ B12 is needed to recycle tetrahydrofolate and therefore decrease B12 equals decrease availability to use activated folate and therefore leads to DNA synthesis problems ~ see demyelination of posterior and lateral columns of spinal cord Aplastic Anemia ~ aplasia = lack of growth

~ suppression of multipotent myeloid stem cells with resultant anemia, thrombocytopenia, and neutropenia (pancytopenia) ~ penia = decrease number of cells ~ mainly idiopathic or expose to myelotoxic agents or viral infections Polycythemia (aka erythrocytosis) ~ increase concentration of RBC and increase in Hb level ~ 1) relative polycythemia = decrease fluid mass therefore relative increase or RBC ~ basically dehydration ~ 2) absolute polycythemia = actual increase in RBC ~ primary = increase myeloid stem cells = increase RBC ~ secondary = increase EPO = increase RBC White Cell Disorders – Non-neoplastic disorders Leukopenia ~ decrease WBC count ~ usually involves neutrophils (neutropenia) ~ lymphopenias is less common Neutropenia / Agranulocytosis ~ decrease number of granulocytes (neutropenia) ~ or when severe – agranulocytosis ~ it’s a type of leukopenia ~ two categories: ~ 1) make too little (bone marrow problem) ~ 2) kill them off too quickly  specific immune response to neutrophils ~ or you can use them too much because there’s a huge infection Reactive Leukocytosis ~ increase number of WBC ~ inflammatory state caused by microbial and nonmicrobial stimuli ~ may mimic leukemia = leukemoid reactions (NOT LEUKEMIA) Infectious Mononucleosis ~ acute, self limiting disease of adolescents and young adults ~ caused by EBV, part of herpes virus family (characterization of infection not on exam) ~ caused by intimate oral contact ~ normal immune response is really important to control proliferation of EBV-infected B cells ~ usually IgM and IgG formed against the viral capsid antigens ~ need to control polyclonal B cell proliferation, cytotoxic CD8 T cells, and natural killer cells ~ see atypical lymphocytes, virus specific cytotoxic T cells, in circulation  very characteristic of this disease!