Pathology Chapter 9 (Lesson 2) PDF

# Red Blood Cells 9 - **Blood amounts** - Average adult: 5 liters - Men: 12 pints - Women: 9 pints - **Function:** Carries oxygen, nutrients, platelets, and cells of the immune system. Removes waste - **Blood layers** - Plasma: (52-62%) - White blood cells and platelets: < 2%...

# Red Blood Cells 9 - **Blood amounts** - Average adult: 5 liters - Men: 12 pints - Women: 9 pints - **Function:** Carries oxygen, nutrients, platelets, and cells of the immune system. Removes waste - **Blood layers** - Plasma: (52-62%) - White blood cells and platelets: < 2% - Red blood cells: (38-48%) **Plasma** - **Solvent**: Suspends components of blood in absorption of molecules & their transport & transport of thermal energy - **90% water**: With sugar, protein, fat and salt - **7% proteins**: With specific function & make colloid osmotic pressure - Ex: Albumin, globulins (including antibodies), fibrinogen - **Other**: Electrolytes, nutrients, gases (O2, CO2, N2), regulatory substances (enzymes, & hormones), waste products (urea, uric acid) **Hematopoiesis** - **Production of blood cells** - Starts in embryonic development in yolk sac - Taken over by liver and lymphatic organs - Red bone marrow (adults) - **Precursor of new blood cells**: Pool of undifferentiated pluripotent stem cells * **Stem cell**: Precursor of new blood cells is a pool of undifferentiated pluripotent stem cells. ## Erythrocytes - **Places nucleus so it can carry more oxygen.** - **Appearance**: Deformable, non-nucleated, biconcave disks (Large SA for oxygen diffusion). - **Function**: Carries O2 from lungs to body & CO2 from body to lungs. - **Most abundant blood cell** - **Hematocrit**: Packed RBC after it has been centrifuged. - **Oxygen carrying cell**: Rich in hemoglobin. - **Hemoglobin**: Iron containing biomolecule & complex metalloprotein. Releases O2 & carries waste. - **Gives red color of cells.** **Mature erythrocyte has no nuclear material** - **Stimulates bone marrow to make RBC.** - **Embryo, liver is where it's made by hormone erythropoietin made by the kidney.** - **RBC live for 100-120 days, removed from circulation at the end.** - **Appear as uniform round cells with central pallor (concavity) under a microscope.** - **Recycled by macrophages in the spleen.** ## Variation in RBC - **Anisocytosis**: Variation in size of RBC. - **Normocytic RBC**: Normal size. - **Macroptosis**: Larger RBC (elevated MCV). - **Microcytosis**: Smaller RBC (decreased MCV). - **Mean Corpuscular Volume (MCV)**: Measure of average volume or size of RBC. ## Erythropoiesis - **Formation and life cycle of RBC (make RBC in 7 days)** - **Normochromic**: Cells are all the same color. - **Hypochromic**: Decreased hemoglobin, pale. - **Hyperchromic**: Increased hemoglobin, more red. ## RBC Count - **Counts # of circulating RBC in 1 mm³ of peripheral venous blood.** - **Anemia**: Value is decreased below range of expected value. - **Low RBC caused by**: Hemorrhage, hemolysis, dietary deficiencies, genetic aberrations, drug ingestion, marrow failure, etc. - **Greater count is caused by**: Body's need for more oxygen carrying, causes: Diseases that product hypoxia - **Polycythemia Vera**: Neoplastic condition causing uncontrolled production of RBCs. - **Drugs that inc RBC**: Erythropoietin & gentamicin. - **Drugs that dec RBC**: Decrease marrow production or cause hemolysis. - **Blood collected in EDTA & tube inverted 7 times after collection to mix blood & anticoagulant.** - **Release ATP when they undergo shear stress in constricted blood vessels, ATP dilutes it.** ## Polychromatic Erythrocyte - **3rd stage of erythropoiesis**. - **Where cell division ceases (1% of cells).** - **Appearance**: Round nucleus with mature chromatin, no nucleoli, cytoplasm has hemoglobin synthesis. - **Purple due to residual RNA.** ## Reticulocyte Count - **Increased bone marrow release of RBC as response to anemia.** - **Index should be 1.0** - **When elevated**: Noticeable in Wright Stain peripheral blood smear - **Reticulocyte**: Intermediate position between nucleated RBC & mature RBC. - **Large, polychromatic RBC.** ## Shift / Stress Reticulocytes - **Shifted to circulation earlier than 2-3 day maturity, has residual RNA.** ## Abnormal RBC Morphology - **Blood cell count and normal ranges:** - Adult/Elder: - Male: 4.7-6.1 x 10⁶ /µL or 4.7-6.1 x 10¹² / L - Female: 4.2-5.4 x 10⁶ /µL or 4.2-5.4 x 10¹² / L - Children: - 2-8 weeks: 1.0-6.0 x 10⁶ /µL - 2-6 months: 3.5-5.5 x 10⁶ /µL - 6 months-1 year: 3.5-5.2 x 10⁶ /µL - 1-6 years: 1.0-5.5 x 10⁶ /µL - 6-18 years: 4.0-5.5 x 10⁶ / µL - Newborns: 4.8-7.1 x 10⁶ / µL ## What prevents normal count of blood? - Improper anticoagulant - Hemodilution - Hemoconcentration - High WBC - Bad shape RBC - Hemolysis ## Hematocrit - **Indirect measurement of RBC # & volume (Hct).** - **Mainly used for**: Pt with bleeding, anemia, or need rapid treatment. - **Measures % of total blood volume made up by RBC.** - **Measures height of RBC column that is centrifuged and compare it to column of total whole blood, ratio x100.** - **Altered by**: Abnormal RBC size (larger = higher Hct), hemodilution, dehydration, pregnancy (decreased), high altitude (increased). ## Hemoglobin (Hgb) - **Measure of Hgb in peripheral blood.** - **Determines ability of blood to carry O2.** - **Adults**: - Male: 14-18 g/dL - Female: 12-16 g/dL - Pregnant Female: > 11 g/dL - **Children**: - Newborns: 14-24 g/dL - 0-2 weeks: 12-20 g/dL - 2-6 months: 10-17 g/dL - 6 months - 1 year: 9.5-14 g/dL - 1-6 years: 9.5-14 g/dL - 6-18 years: 10-15 g/dL - **Elderly values decrease.** - **In pregnant pt**: Decrease due to dilution effect of expanded blood volume and slight diurnal variation in Hb. - **High altitude inc Hgb**: Since less O2 is available. ## Hemoglobin Synthesis - **2 pairs of globulin chains form tetramer with heme compound at each chain.** - **Newborn Hgb**: 2 alpha globins & 2 gamma globin (higher affinity for O2) - **At 12 months**: Gamma is replaced by delta & forms hemoglobin A. - **Hemoglobin A**: 2 alpha globin chain with 2 beta globin. Makes up most Hb. - **Hemoglobin A2 & F**: Made of pair of alpha & pair of delta globin. Makes up remaining Hb. ## Breaking Down Hemoglobin - **Removed by macrophages in spleen & liver.** - **Broken into**: - **Heme**: Iron is conserved & reused for more Hgb. - During metabolism, it's turned to bilirubin, taken to liver by albumin to make bile. - **Globin**: Protein recycled or broken for amino acids. ## Mean Corpuscular Volume (MCV) - **Measures average volume/size of RBC and classifies anemias.** - **MCV = hematocrit ( %) x 10 / RBC (million/mm³)** - Adult/Elder/Child: 80-95 fL - Newborn: 96-108 fL ## Mean Corpuscular Hemoglobin (MCH) - **Measures average amount of hemoglobin in RBC.** - **MCH = Hemoglobin (g/dL) x 10 / RBC (million/mm³)** - Adult/Elder/Child: 27-31 pg - Newborn: 32-34 pg ## Mean Corpuscular Hemoglobin Concentration (MCHC) - **Measure of average concentration or % of hemoglobin in RBC.** - **MCHC = Hemoglobin (g/dL) x 100 / Hematocrit (%)** - **Hypochromic**: Deficiency of hemoglobin (less MCHC). - **Normochromic**: Normal MCHC. - **Can't be hyperchromic**: Since max value is 37 g/dL. - Adult/Elder/Child: 32-36 g/dL (32%-36%) - Newborn: 32-33 g/dL (32%-33%) ## Red Blood Cell Distribution Width (RDW) - **Indicates variation in RBC size** - **Calculate using MCV & RBC values** - **Anisocytosis**: Blood condition where RBC abnormal size. - Adult: 11.9 - 14.5 % ## Anemia - **State of RBC deficiency that lowers ability to carry O2.** - **Classified by size (MCV) & hemoglobin (MCH) of RBC.** - **Causes**: Blood loss, hemolysis, less RBC made. - **Hemolysis**: RBC destruction. - **Symptoms**: Pallor, fatigue, dyspnea, poor O2, chest pain, AMS. - **Body response**: Try to make more, exchanging gases (tachypnea) & circulating more volume (tachycardia). ### Causes of Hemolysis (in bloodstream only) - **Intravascular Hemolysis**: Mechanical RBC trauma, mechanic heart valve, ABO incompatible, PCH, Infection, Snakes, etc. - **Extravascular Hemolysis**: Inherited or acquired (not always present in early childhood). ## Hemolytic Anemia - **Symptoms**: Jaundice, fatigue, tachycardia, pallor (pigmented gallstones if chronic), leg ulcers, splenomegaly, dark urine. ## Polycythemia - **Diseases characterized by surplus RBC and inc viscosity of blood causing symptoms.** - **Hemolytic transfusion reaction**: Destruction of RBC after a transfusion mediated by host antibodies. ## 3 Ways to Classify Anemia - **Production Defect**: Anemia (chronic disease), renal disease, Fanconi anemia, Blackfan-Diamond syndrome, parvovirus infection, drug toxins. - **Survival Defect**: Hemoglobinopathies, immune hemolytic anemia, hemolysis, membrane & metabolic abnormalities. - **Maturation Defect**: Vitamin B12 deficiency, folate dec, iron dec, sideroblastic anemia, lead poisoning, hemorrhage, hyposplenism. ## Anemia of Blood Loss ### Acute Blood Loss - **Rapid loss of 10% or more blood thru hemorrhage, result in shock.** - **Caused by**: Loss of intraovascular volume (can cause cardiovascular collapse, shock & death if massive) - **Blood volume restored by**: Intravascular shift of water from interstitial fluid compartment. - **Results in**: Hemodilution & lowers hematocrit. - **Symptoms of acute blood loss**: Tachycardia, intravascular volume. - **Treatment**: Intravenous fluid resuscitation with normal saline. ### Chronic Blood Loss - **Induces anemia when loss > regeneration of marrow or when iron low.** - **Iron deficiency anemia**: Most common, when dietary intake/absorb nutrition, hemoglobin can't be made. ## Hemolytic Anemia - **Cause**: Hereditary defect of RBC or damage by extrinsic factors that inc RBC destruction by phagocytes. - **Symptoms**: RBC< 120 days, inc erythropoietin level, inc erythropoiesis. - **Physiological destruction of RBC takes place in macrophages (in the spleen, liver, bone marrow).** - **Accumulation of hemoglobin degradation products created as part of the process of red cell hemolysis.** - **Caused by**: Age changes in RBC surface protein - recognition by phagocytes - **Extravascular hemolysis**: Premature destruction of RBC in phagocytes. Caused by alterations that render RBC less deformable. - **Reticular endothelial system (ex: spleen)** ### Pathogenesis of Hemolytic Anemia - **Hyperbilirubinemia, jaundice**: From degradation of hemoglobin by macrophages. - **Splenomegaly**: From hyperplasia of phagocytes in spleen. - **Bilirubin-rich gallstones & pigmented stones**: Bilirubin is a product of broken hemoglobin, it also inc cholecystitis secondary to bile duct blockage. ## Intravascular Hemolysis - **Cause**: Mechanical injury (microcirculation, bad cardiac valve, physical trauma, RBC burst). - **Can also be caused by**: Intracellular parasites (malaria & clostridicium release enzymes and digest RBC membrane). - **Complement fixation**: Antibody recognize & bind RBC antigen. ### Membrane Defects - **Hereditary Spherocytosis (HS)**: Inherited disorder (autosomal dominant) defect in spectrin a membrane protein. - **Cause**: Inherited defects in RBC membrane skeleton proteins, cause membrane loss & deform spherocytes that lose deformability. - **Biconcave RBC released from marrow become sphere, due to loss of membrane.** - **Small, dark, no central pallor.** - **RBC life span**: 10-20 days (compared to normal 120) - **Cell takes in too much water.** - **RBC sensitive to osmotic lysis in hypotonic solution**: Water in RBC. - **RBC have inc MCHC**: From dehydration. - **Spleen overworked.** - **(Enlarged spleen)** - **Symptoms**: Anemia (chronic hemolytic), splenomegaly, jaundice, no erythropoiesis. - **(Can also be asymptomatic) & (can also be asymptomatic)** - **Spherocytosis shape**: Smear as small dark stain (hyperchromic), lack central pallor, polychromatic reticulocytes. - **Parvovirus infects and kills RBC progenitors**: Causing no making of RBC. - **(Remove the spleen).** - **Treatment**: Transfusion, splenectomy (to treat anemia, but can also damage spleen, at risk for sepsis). - **(Through taking in of microorganisms).** - **Hereditary Elliptocytosis (HE)**: Autosomal dominant disorder. - **Oval in shape**. - **Membrane protein not correct.** - **Cause**: Defective tetramerization of cytoskeletal spectrin causing elliptocytes (ovalocytes). - **Hereditary Pyropoikilocytosis**: Variant of HE where RBC are sensitive to damage from heat. - **Variation in shape.** - **Peripheral blood smear shows RBCs of every shape and size.** - **HE manifests as lifelong hemolytic anemia.** - **Long, thin, oval shape** ## Glucose-6-Phosphate Dehydrogenase Deficiency (G6PD) - **Causes**: Impaired reduction of glutathione, infection (O2-derived free radicals from WBC), hemolysis infections, drug initiators. - **Reduce RBC to protect themselves from oxidative injuries & hemolysis.** - **Abnormal hexose monophosphate shunt or glutathione metabolism**: From impaired enzyme function. - **Reduced glutathione protects hemoglobin & RBC membrane from oxidative damage.** - **When not enough G6PD enzyme**: Hemolytic anemia, RBC break faster than they are made. - **Genetically X-linked trait (male at higher risk)** & hundreds of variations. - **Some variants cause mis-folding of protein making proteolytic degradation** - **Cell looks like a blister cell, literally has a bitemark in it.** - **Drugs**: Antimalarial, sulfonamide, nitrofurantoin. ## Sickle Cell Disease - **Autosomal recessive disorder caused by single point mutation in amino acid.** - **6th codon of B-globin**: Glutamate replaced with valine residue -> Sickle hemoglobin (HbS). - **Normal hemoglobins**: Hemoglobin A (a2b2) and fetal hemoglobin (HbF) (a2b2). ### Effects: 4 Types - **Hemoglobin crystallizes at low O2 tension**: HbS cause hemolysis & microvascular occlusion. - **Unstable hemoglobin**: Chronic hemolysis with Heinz bodies. - **Heinz bodies**: RBC inclusion composed of denatured hemoglobin. - **Hemoglobin inc O2 affinity**: Polycythemia (from high pH). - **Hemoglobin won't be oxidized**: Cyanosis - **Changes shape & function of hemoglobin**: Inc the chance of blockages. ## Symptoms - **Vascular occlusion**: Resultant ischemia: Severe pain in long bones, abdomen, chest. - **Pain crisis**: Caused by localized obstruction of microvasculature by sickled cells: Block vessels since they're sticky. - **Major pathological manifestations**: Chronic hemolysis, microvascular occlusions, tissue damage, hematuria, jaundice, stroke. - **MCHC inc**: From higher HbS & intracellular dehydration. - **Morphology**: Peripheral blood has sickled cells, reticulocytes, target cells. - **Spleen no function right.** - **Howell-Jolly Bodies**: Small nuclear remnants from asplenia. - **Bone marrow is hyperplastic**: (From compensation, erythroid hyperplasia). ## Thalassemia - **Hemoglobinopathy**: Caused by mutations in genes can cause abnormal globin chains, causing disease. - **Has reduced production of normal globin chain.** - **Hemoglobin structure**: - **4 polypeptide chains** - **Major adult hemoglobin A (HbA)**: Made of 2 alpha & 2 beta chains. - **1 gene per cell** - **2 alpha chains in HbA made by a pair of alpha globin genes on chromosome 16, beta chains made by single B-globin gene on chromosome 11.** - **Cause**: Genetic abnormality in either alpha or beta globin chain synthesis. - **Imbalance in hemoglobin synthesis**: Causes reduced hemoglobin & hemolysis. ## Symptoms - **Microcytic & hypochromic blood picture**: Damages developing and mature RCs, anemia, hypoxia. - **3/4 or 4/4 genes deleted (syndrome)**, but if it's only 2 or 1 it's a trait. ### Beta Thalassemia (Mediterranean / Cooley's anemia) #### Major - **Symptoms**: Severe, transfusion-dependent anemia from infancy, splenomegaly, marrow expansion and bony deformities and premature death. - **Cause**: Be deficient synthesis of B-chain from inheritance of 2 genes. - **Blood picture**: Microcytic, hypochromic anemia (beta chain not get replaced by gamma). - **Both are same symptoms.** - **Symptoms**: Severe anemia, growth retardation, iron overload, splenomegaly, bony deformities, premature death, severe. - **Morphology**: RBC abnormalities, anisocytosis, poikilocytosis, microcytosis, hypochromia. Inc reticulocytes purple target. #### Polychromasia - **Disorder where abnormal, high, immature RBC in bloodstream.** - **Codocytes**: "Target cells", RBC that look like a bullseye. ### B-Thalassemia Minor - **More common than B-Thalassemia major.** - **Still inherited but less severe than major.** - **Pt heterozygous carriers of Bt or Bo allele.** - **Symptoms**: Mild anemia, pt usually asymptomatic, milder erythroid hyperplasia in bone marrow. - **Blood smear**: RBC abnormal, hypochromia, microcytosis, basophilic stippling, target cells. ### a-Thalassemia - **Cause**: Inherited deletions that result in absent synthesis of a-globin chains. (Normally 4 a-globin chains). - **Severity depends on how many genes are affected.** #### Silent Carrier State - **Deletion of single a-globin gene**: Barely detectable reduction in a globin chain synthesis. - **Mostly asymptomatic.** ### Thalassemia Trait - **Deletion of 2 a-globin genes from 1 chromosome (a/a/-1) or deletion of 1 a-globin from 2 chromosomes.** - **Clinically identical but have different implications for children of infected individuals.** ### Hemoglobin H Disease - **Cause**: Deletion of 3 a-globin genes. - **1 normal a-globin gene**: Alpha chain reduced & tetramers of B-globin. - **Symptoms**: Hypoxia (High 02 affinity), RBC sequestration & phagocytosis in spleen, severe anemia. ### Hydrops Fetalis - **Most severe form of a-thalassemia.** - **Extra y-globin chains form tetramers.** - **Cause**: Deletion of all a-goloin genes. - **Extra y-globin chains in fetus deliver little O2.** - **Symptoms**: Severe pallor, generalized edema (shown in 3rd trimester of pregnancy), enlarged liver & spleen. ### Paroxysmal Nocturnal Hemoglobinuria (PNH) - **Cause**: Acquired mutations in phosphatidylinositol glycan complementation group A gene (PIGA) - enzyme essential for membrane protein. - **Hemolytic anemia caused by genetic defect.** - **PNH is RBC membrane defect (DAF)**: Inc susceptibility to complement mediated lysis. - **X-linked, inactivates X chromosome in F.** ### Immunohemolytic Anemia - **Cause**: Antibodies bind to antigen on RBC membrane & cause premature destruction. - **Direct Coombs Anti-Globulin Test**: RBC mixed with antibodies/sera that are specific for human immunoglobulin or complement. ## Hemolytic Anemia Causes ### Trauma - **Mainly in people with cardiac valve prostheses and microangiopathic disorders.** - **Microangiopathic hemolytic anemia**: Most common with DIC, TTD, HUS. - Disseminated intravascular coagulation: Micro clots & breaks it. ### Mechanical - **Intravascular hemolysis of RBC from abnormal forces**. - **Traumatic hemolysis from cardiac valves.** - **Microangiopathic hemolytic anemia**: Occurs when small vessels become narrowed by thrombi. - **DIC.** - **Aggressive clotting.** ## Anemias of Diminished Erythropoiesis ### Megaloblastic Anemia - **Macrocytic**. - **Cause**: Impairment of DNA synthesis -> Ineffective hematopoiesis & distinctive morphologic changes. - **Symptom**: Vitamin B12 deficiency & folic acid deficiency. ## Hemolytic Disease of Newborn - **Cytotoxic**: Responsible for tissue damage in hemolytic disease of newborn. - **Cause**: Antigen on PM recognized as foreign, B-cell ready for antibody production from antibody-induced hemolytic anemia. - **Mother & fetus are not blood compatible.** - **Fetus inherit RBC antigenic determinants that are foreign to mother.** ## Type 2 Hypersensitivity Reaction - **Antibody on PM is "foreign"**: Bell ready for antibody production, antibody binds to antigen-> activate complement ## Folate Deficiency - **Cause**: Meagaloblastic anemia. - **Megaloblastic**: Appearance of hematopoietic precursor cells in marrow. - **Appearance**: Nuclei are large & immature. - **Symptoms**: Ineffective erythropoiesis, hypercellular marrow, impairment of DNA synthesis. ## Pernicious Anemia - **A form of megaloblastic anemia**: B12 deficiency (B12 anemia). - **Cause**: Gastritis that impairs production of intrinsic factor (needed for B12 uptake). - **Vitamin B12 (cobalamin)**: Dietary vitamin that needs intrinsic factor to be absorbed. - **Symptoms**: Autosomal attack on gastric mucosa, can't make healthy RBC. - Macrocytic RBC & hyperlobulated WBC. ## Iron Deficiency Anemia - **Most common in chronic bleeding** - **Iron is needed to make hemoglobin.** - **Iron is internalized in RBC cytoplasm and incorporated into protoporphyrin to yield heme**. - **No iron = no hemoglobin.** - **Iron is toxic by itself at high levels.** - **Symptoms**: RBC hypochromic & microcytic, lowered hematocrit. - **Transferrin**: Glycoprotein that binds iron & transports it to the plasma & cells. - **Hepcidin**: Small peptide that regulates iron absorption. ## Sign of Iron Deficiency Anemia - **Low**: RBC, MCV, MCHC - **High**: RDW, platelet # - **Peripheral blood**: Hypochromic, microcytic RBC, scattered elliptocytes. - **Serum ferritin test to confirm iron deficiency**: Below 10 µg/L ## Lead Poisoning (Plumbism) - **Symptoms**: Abdominal pain & cognitive impairment, vomiting, seizures, AMS (altered mental status). - **Presentation**: Microcytic hypochromic anemia. - **Effects**: RBCs, renal epithelium, nervous system. ## Effect of lead - **Inhibition of heme synthesis in maturing erythrocytes.** - **Decreased survival of mature erythrocytes.** ## Sideroblastic Anemia - **Iron incorporated into porphyrin to make heme**. - **Ringed sideroblasts**: Morphological expression of abnormal sequestration of iron in mitochondria (mainly in bone marrow). - **Peripheral blood**: Anemia & dimorphic RBC with normocytic macrocytes & hypochromic microcytes. - **Cause**: Abnormal utilization of iron during erythropoiesis. - **2 forms**: Hereditary & acquired. ## Symptoms of Sideroblastic Anemia - **Physical**: Fatigue, pale skin, conjunctival pallor, bronze-colored skin, malaise, headache, shortness of breath, palpitations ## Anemia of Chronic Disease - **Sustained, systemic inflammation alters iron utilization in marrow and suppresses hematopoiesis.** - **Symptoms**: Mild, refractory, hyporegenerative anemia, normocytic, normochrome. - **Cause**: Impaired RBC production, chronic disease that produce systemic inflammation. ## Aplastic Anemia - **Symptom of chronic primary hematopoietic failure and attendant pancytopenia.** - **Cause**: Suppression of multipotent hematopoietic stem cells. - **Symptoms**: Bone marrow hypocellularity & pancytopenia. - **Acquired**: Idiopathic. ## Pure Red Cell Aplasia - **Primary marrow disorder where only erythrocyte progenitors are suppressed.** ## Polycythemia - **Abnormal high RBC # (mean inc in hemoglobin).** - **Cause**: Dec plasma volume in dehydration causes hemoconcentration. - **Absolute**: Inc in total RBC from abnormal hematopoietic precursors.