WBC and RBC - RBC.pdf

Anemias = reduction of total circulating red cell mass, hematocrit (ratio of packed RBCs:total blood volume) -> MCV: average volume of RBC -> Mean cell hemoglobin: average content of Hgb per red cell -> Mean cell hemoglobin concentration (MCHC): average concentration of Hgb in given volume of pack...

Anemias = reduction of total circulating red cell mass, hematocrit (ratio of packed RBCs:total blood volume) -> MCV: average volume of RBC -> Mean cell hemoglobin: average content of Hgb per red cell -> Mean cell hemoglobin concentration (MCHC): average concentration of Hgb in given volume of packed RBCs -> Red cell distribution width (RDW): coefficient of variation of red cell volume Disease Name Cause of Dx MOA Key Features Associated Diseases Tx for Disease Prognosis Picture Anemia Loss of intravascular volume -> acute blood loss -> massive Presentation: Pale, weakness, malaise, fatigue, dyspnea on mild exertion loss: CV collapse, shock, and death ex) gun shot wound, external (vomiting blood), internal Hypoxia -> fatty change in liver, myocardium, and kidney (hematoma rupture) Myocardial hypoxia => angina pectoris Renal hypoperfusion -> acute blood loss and shock, oliguria (abnormally small amount of urine), and anuria (lack of pee) CNS hypoxia => headache, dimness of vision, and faintness Rate of hemorrhage, if bleeding is internal or external -> determines clinical features Blood volume is rapidly restored by movement of water from interstitial fluid compartment -> intravascular compartment -> leads to hemodilution and lower hematocrit Outside of body into body to replenish, because you are bringing in a lot of volume and diluting it and therefore lowering the ratio of RBCs to volume of fluid = lower hct Decr oxygenation in tissues (hypoxia) -> increases secretion of EPO from kidney -> stimulates proliferation of committed erythroid progenitors If RBCs extravasate into tissue (aka move from blood vessels -> tissues) -> iron is recaptured If bleeding happens outside -> iron is lost -> possible iron deficiency Bleeding -> decrease BP -> compensatory release of adrenergic hormones -> mobilizes granulocytes from intravascular marginal pool -> leukocytosis Increased marrow production -> increase reticulocyte count Reticulocytes = larger than normal RBCs with blue-red polychromatophilic cytoplasm (b/c of presence of RNA) Early recovery from blood loss -> increased platelet production -> thrombocytosis Hemolytic Anemia Features: - Shortened RBC life span ( RBC recognition - Compensatory increase in erythropoiesis and removal by phagocytes = - RBC hemolysis -> accumulation of Hgb degradation products physiologic destruction of senescent - Reticulocytosis in peripheral blood RBCs that takes place in - Extramedullary hematopoiesis = liver, spleen, lymph nodes macrophages (abundant in spleen, - Accumulation of hemosidering = spleen, liver, bone marrow liver, bone marrow) Clinical Features: - Anemia -> leads to erythroid differentiation -> increased # of erythroid precursors in marrow - Splenomegaly - Jaundice (unconjugated bilirubin because takes place prior to liver conjugation) **IN ALL uncomplicated hemolytic anemia = excess serum bilirubin is unconjugated - Liver -> excretes excessive bilirubin -> into biliary tract -> gallstones (derived from heme pigments) Extravascular Hemolysis of RBCs Alterations that make RBCs less deformable (reduced deformability -> makes passing through the spleen difficult => leading to sequestration and phagocytosis by macrophages) -> Extravascular hemolysis = premature desctruction of RBCs (destruction can also happen with phagocytes) -> hyperplasia of phagocytes -> splenomegaly **RBC eaten by macrophage -> go to spleen -> spleen eats macrophages => splenomegaly [patients can benefit from splenectomy] Some Hgb escapes from phagocytes -> plasma: free Hgb binds to the haptoglobin and alpha2 proteins -> decreased levels of plasma haptoglobin because it is being bound -> therefore decrease in plasma haptoglobin and alpha2 globulin -> remaining free Hgb is floating around still and can be filtered by kidney -> causes potential damage Intravascular Hemolysis of RBCs -> anemia, hemoglobinemia (DIFFERENT FROM EXTRAVASCULAR), hemoglobinuria, hemosiderinuria (iron in pee), and jaundice --> hemoglobinemia = Hgb in blood -> goes to urine = hemoglobinuria = RBCs chopped up inside the blood vessel - Mechanical injury: ex- trauma from cardiac valves, narrowing of microcirculation by thrombi, or repetitive physical truma like marathon running - Complement fixation: infections/inflammation -> ABs recognize and bind RBC Ags - Intracellular parasites: ex- falciparum malaria, exogenous toxic factors - clostridial sepsis => release of enzymes that digest RBC membrane - NO splenomegaly Lysed RBCs -> free Hgb => binds to haptoglobin = forms complex, that is cleared by phagocytes -> serum haptoglobin is depleted -> free hemoglobin oxidizes to methmeglobin (BAD because unable to bind O2) = brown in color Hemoglobin-Haptoglobin complexes -> have heme groups => within phagocytes: metabolized to bilirubin -> jaundice Renal proximal tubular cells reabsorb and break down filtered Hgb and methemoglobin -> BUT some passes in urine = red brown color Hemolytic Anemia Hereditary Spherocytosis (HS) Intrinsic defects from RBC membrane skeleton -> renders NORMAL RBC Cytoskeleton: RBC lifespan decreased to 10-20 days (vs normal 120) RBC = spheroid -> therefore: less deformable and vulnerable - durable, lie close to surface plasma membrane to splenic destructions - spectrin = 2 polypeptide chains (alpha and beta) -> form Spherocytosis -> not pathogonomic and seen in other RBC disorders flexible heterodimers AD Inheritance -> worse for heterozygotes = compound -> head region: self associates -> forms tetramers Features: heterozygosity -> tail region: associates with actin oligomers - reticulocytosis - Proteins: ankyrin and band 4.2 -> bind spectrin to the - marrow erythryoid hyperplasia Diverse mutations affecting ankyrin, band 3, Spectrin or transmembrane ion transporter band 3 - hemosiderosis band 4.2 -> cause frameshifts or introduce premature - Protein 4.1 binds spectrin to transmembrane protein - jaundice (because RBCs not going to spleen to die) stop codons => failure to produce any protein -> glycophorin A - cholethiasis insufficiency of membrane skeletal and destabilizes **if any alterations to proteins -> alters cytoskeleton -> - moderate splenomegaly -> splenectomy will treat the anemia overlying plasma membrane (lipid bilayer) components - therefore RBCs are not able to hold their shape => > as RBCs age in circulation = sheds membrane spherical - red cells are abnormally sensitive to osmotic lysis when incubated in hypotonic salt solutions = osmotic fragments -> less membrane relative to cytoplasm = fragility test smaller cell = sphere! -> reduced deformability => - dehydration by loss of K+ and H20 -> increased mean cell Hgb concentration trapped in splenic cords + eaten by macrophages Parvovirus acute infection -> infection in killing of RBC progenitors -> cause all RBC production to stop until an immune response clears virus in 1-2 weeks => if not cleared: aplastic crisis (lack of RBC production) Hemolytic Anemia G6PD Deficiency Deficient or impaired enzyme function -> abnormalities in G6PD reduces NADP -> NADPH, while oxidizing G6P Features: G6PD- and G6PD hexose monophosphate shunt OR glutathione metabolism -> NADPH -> provides reducing equivalents needed for oxidized - Exposure to oxidative stress -> episodic hemolysis Mediterranean provide **Hereditary, X linked recessive, males reduce ability of RBCs to protect themselves against glutathione --> reduced glutathione = protects against oxidant **Because only older RBCs are at risk for lysis => episode is self limited protection against **Variants: oxidative injuries -> hemolysis injury - Common trigger: Infection -> activates leukocytes -> produces O2-derived free radicals -> episodic Plasmodium falciparum = = with Hemolysis -> protein misfolding hemolysis malaria -> more suspectible to proteolytic G6PD deficiency: => Common infections that can cause this: viral hepatitis, pneumonia, typhoid fever degradation -> mature red cells do not synthesize new proteins -> G6PD- = AA, -> as RBCs age = variant enzyme activities fall to levels that Triggers to G6PD deficiency: -> G6PD Mediterranean = Middle East are inadequate to protect against oxidant stress - antimalarials **Older RBCs are more prone to hemolysis than young ones - sulfonamides - nirofurantoins - fava beans Intravascular and Extravascular Hemolysis G6PD deficient RBCs exposed to high levels of oxidants -> cross linking of reactive sulfhydrl groups on globin chains => become denatured and -> form Heinz Bodies = membrane-bound precipitates -> dark inclusions within red cells stained with crystal violet -> damage membrane => intravascular hemolsysis -> as inclusion-bearing RBCs pass through the splenic cords -> macrophages select/pluck out Heinz bodies -> due to membrane damage: partially devoured cells = have abnormal shape ~ bite taken out of them Acute Intravascular Hemolysis => anemia, hemoglobinemia, hemoglobinuria Hemolysis stops when only younger G6PD-replete RBCs remain -> this is true even if the trigger persists Recovery phase marked by reticulocytosis Sickle Cell Disease Missense mutation in B-globin -> replacement of charged HbS polymers grow and herniate through skeleton -> project Hallmarks: irreversibly sickled cells, reticulocytosis, severe hemolytic anemia, hyperbilirubinemia glutamate --> hydrophobic valine from cell only covered by the lipid bilayer Asplenia -> Howell-Jolly bodies in RBCs [b/c not removed by spleen] (Howell-Jolly bodies are small, round, **8-10% AA are heterozygous for HbS basophilic inclusions found in red blood cells. They are remnants of nuclear material, typically seen when the spleen is (Sickle Cell Trait) Normal adult RBCs: HbA (a2, B2) with small amounts of Repeated sickling episodes: RBCs -> dehydrated, dense, rigid not functioning properly or is absent. In a healthy spleen, these remnants are usually removed from red blood cells.) HbA2 (a2, σ2), and fetal Hgb HbF (a2, y2) Most severely damaged cells -> irreversibly sickled = retain Features In affected individuals: Hgb in RBCs are HbS (a2, B^s2) sickle shape EVEN when fully oxygenated - Compensatory erythroid hyperplasia occurs in the bone marrow (reciprocal increase in number of RBCs in -> Severity of hemolysis ~ percentage of irreversibly sickled bone marrow due to sickling) cells = rapidly removed by phagocytes via extravascular - Bone marrow expansion -> changes in bone -> crewcut changes on radiology hemolysis - Hyperbilinrubinemia and pigment stones - Red pulp congestion -> splenomegaly [auto splenectomy in adolescence = gradually shrinks and becomes Mechanically fragile sickle RBCs -> intravascular hemolysis nonfunctional] - Vascular occlusion -> infarction in bones, brain, kidney, liver, retina, pulmonary vessels - Stagnation in subcutaneous tissue -> leg ulcers - Stunted growth, hyposthenuria (cannot concentrate urine) - Altered spleen function -> increased suspectibility to infection with encapsulated organisms Crises Vaso-occlusive pain crisis: dehydration or acidosis -> hypoxic injury and infarction -> severe pain in bones, lungs, liver, brain, spleen, or penis - acute chest syndrome: vaso-occlusive crisis = lungs -> fever, cough, chest pain, pulmonary infilrates - priapism: 45% males post-puberty -> hypoxic damage and erectile dysfunction - stroke, retinopathy: loss of visual acuity and blindness Sequestration crisis: massive entrapment of sickled RBCs -> rapid spleen enlargement with hypovolemia and shock -> fatal Aplastic crisis: parvovirus B19 -> infects RBC progenitors -> transient cessation of erythropoiesis and worsening anemia Sickle Cell Anemia Continued deoxygenation -> HbS molecules assemble into Features due to HbS molecules stacking into polymers when deoxygenated: Protective effects against long needle-like fibers within RBCs => sickle shape - Chronic hemolysis falciparum malaria for AA - Microvascular occulsions Variances in Rate and Degree of Sickling: - Tissue damage G6PD Deficiency and Interactions between HbS + other Hb types: Thalassemia => also - HbAs: 40% = HbS, 60% = HbA => RBCs in heterozygotes protect against malaria: only sickle if exposed to prolonged, relatively severe Raise levels of oxidant hypoxia stress -> membrane - Heredtiary persistence of HbF = high HbF expression damage in the parasite inhibits polymerization of HbS -> sickle cell disease is much RBCs => are removed less severe from bloodstream -> - HbSC: HbS = 50%, HbAS = 40% => With aging, HbSC cells therefore: increasing tend to lose salt and water -> become dehydrated -> increases clearance and decreasing intracellular concentration of HbS => increases tendency to adherence of infected polymerize -> HbSC disease = HbSC heterozygotes with RBCs symptomatic sickling disorders **milder TLDR: Fs > As (40% S, 60% normal) > Cs > Ss = FACS Mean Cell Hgb Concentration (MCHC) - Higher HbS concentrations -> increase polymerization during deoxygenation - Intracellular dehydration increases MCHC => facilitates sickling - Homozygous HbS and Alpha Thalassemia -> decreases Hbg synthesis -> milder disease TLDR: Increase in MCHC => increase sickling => worse prognosis Intracellular pH - Decrease in pH -> reduces Hgb oxygen affinity => increases fraction of deoxygenated HbS at any given oxygen tension => increases sickling TLDR: decrease pH => worse sickling symptoms Transit Time of RBCs through Microvascular Beds - normal: blood flow is too fast for significant deoxygenated HbS aggregation -> sickling is confined to microvascular beds - inflamed vascular beds are prone to sickling and occlusion TLDR: decrease transit times -> more likely for occlusions to occur => increases chance of sickling Thalassemia Disease Name Cause of Dx MOA Key Features Associated Diseases Tx for Disease Prognosis Picture Thalassemia Genetically heterogenous germline mutations -> decrease Identical pair of alpha globin chains on Chromosome 16 -> 2 Endemic in Mediterrean basin, Middle East, Tropical Africa, India, Asia -> most common inherited Dz synthesis of A-globin or B-globin -> anemia, tissue alpha chains in HbA hypoxia, and RBC hemolysis [due to lack of globin chain synthesis] Single B-globin gene on chromosome 11 -> 2 beta chains in HbA Heterozygous carrier = **A: 2->16, B: 1->11 protected against malaria B-Thalassemia B chain synthesis deficiency -> B thalassemia Impaired B globin synthesis -> deficient HbA synthesis -> Clinical classification is based on severity of anemia, depending on genetic defect -> B+, B0 & gene underhemoglobinized, hypochromic microcytic RBCs with dosage (homozygous or heterozygous) subnormal O2 transport capacity (when RBCs are microcytic => no iron -> no heme -> no hemoglobin -> nothing holding RBC as a whole => smaller) Impaired B globin synthesis -> Imbalance in A globin and B globin synthesis -> unpaired Alpha chains precipitate within RBC precursors -> forms insoluble inclusions -> membrane damage -> RBCs undergo apoptosis (due to damage) = diminished survival of RBCs and their precursors -> ineffective erythropoiesis Marrow -> membrane damaged red cells with inclusions -> splenic sequestration + extravascular hemolysis Massive erythroid hyperplasia in marrow (expanding mass of RBC precursors) -> erodes bony cortex -> impairs bone growth -> skeletal abnormalities Metabolically active erythroid progenitors steal nutrients from O2-deprived tissues -> severe cachexia (in untreated patients) Expansion of erythroid precursors -> increased absorption of iron from the gut Repeated blood transfusions -> severe iron accumulation -> secondary hemochromatosis Extramed hemato -> expanding lots of RBC precursors = need IRON -> thereofre incr iron absorption from gut ---> blood transfusions as part of Tx will cause severe iron accumulation because you are ALREADY re-absorbing iron -> secondary hemochromatosis Mechanism Overview: 1. Expansion of Erythroid Precursors: Stimulus: The body experiences a condition where there is a demand for increased red blood cell (RBC) production, such as in chronic anemia. Effect: The bone marrow responds by expanding the number of erythroid precursors (immature RBCs) in an attempt to produce more RBCs. 2. Increased Absorption of Iron from the Gut: Mechanism: The expansion of erythroid precursors signals the body to increase the absorption of dietary iron from the gut. This is because iron is a critical component of hemoglobin, the oxygen-carrying protein in RBCs. Outcome: The body absorbs more iron than usual, even if the iron stores are already sufficient. 3. Repeated Blood Transfusions: Context: Patients with conditions like chronic anemia often require repeated blood transfusions to maintain adequate hemoglobin levels. Effect: Each transfusion introduces additional iron into the body, as donated blood contains iron within the hemoglobin of RBCs. 4. Severe Iron Accumulation: Cumulative Effect: Over time, the combination of increased dietary iron absorption and the additional iron from transfusions leads to an excessive accumulation of iron in the body. Result: This excess iron is deposited in various organs, including the liver, heart, and endocrine glands. 5. Secondary Hemochromatosis: Condition: The excessive iron deposition results in secondary hemochromatosis, a condition characterized by organ damage due to iron overload. Outcome: If left untreated, secondary hemochromatosis can lead to severe complications, such as liver cirrhosis, heart disease, diabetes, and other organ dysfunctions. Summary: The expansion of erythroid precursors drives the body to absorb more iron from the gut, while repeated blood transfusions add even more iron to the system. This leads to severe iron accumulation, which can cause secondary hemochromatosis, a dangerous condition characterized by iron overload and subsequent organ damage. B-Thalassemia Major Homozygous: B0/B0, B+/B+, or B0/B+ Severe and requires blood transufsions Common in Meditteranean countries, parts of Afirca, and South East Asia 6-9months after birth: HbF -> HbA -> anemia will appear at this point (because fetal hemoglobin has a higher O2 affinity, so when it goes away, it causes anemia) Severe RBC abnormlatiies = anisocytosis, poikilocytosis, microcytosis, and hypochromia [low heme + low hgb -> microcytic and hypochromic] Target cells (bulls-eye appearance, central zone of Hgb surrounded by clear zonea nd outer ring of Hgb) , basophilic stippling (fine, dark-blue granules dispered through RBC cytoplasm: immature RBCs -> ribosomal RNA accumulations), and fragmented RBCs Extramedullary Hematopoiesis: -> increased reticulocyte count -> expanding marrow -> erosion of cortical bone -> crewcut appearance of bone (radiology scan picture) -> enlarged spleen, liver, lymph nodes Hemosiderosis and secondary hemochromatosis -> heart, liver, pancreas damage B-Thalassemia Minor Heterozygotes: B+/B or B0/B -> mild asymptomatic microcytic Blood smear: hypochromia, microcytosis, basophilic stippling, and target cells [NO DIFFERENT anemia SHAPES/SIZES] More common, affects Meditteranean countries, parts of Bone marrow: mild erythroid hyperplasia Afirca, and South East Asia Increased HbA2 (a2, sigma2) [embryonic] = 2-5% -> 4-8% => elevated ratio of sigma chain to B chain synthesis HbF: normal or slightly increased  A-Thalassemia Inherited deletions -> reduced or absent synthesis of A- A chain synthesis deficiency -> A thalassemia globin chains -> remove 1-4 a-globin genes = unpaired B, y, sigma globin chains -> can combine to form tetramers Severity ~ dependent on how many a-globin chains are (Barts/HbH) affected Inadequate hemoglobin synthesis and presence of excess, unpaired B, y, & sigma globin chains -> anemia Hgb Barts: newborn y4 tetramers HbH: B4 tetramers in older children & adults with excess B- globin chains A thalassemia HbH Deletion of 3 alpha-globin genes Deletion -> only 1 normal a-globin gene = because reduced Common in Asian populations by synthesis AND B globin tetramers = HbH HbH (not useful for O2 delivery) -> high O2 affinity -> tissue hypoxia (because doesn't want to give up O2), that is disproportionate to Hgb level Oxidation of HbH -> causes it to precipitate to form intracellular inclusions -> promotes RBC sequestration and phagocytosis in spleen -> moderately severe anemia that resembles B-thalassemia intermedia A thalassemia Hydrops fetalis Deletion of all 4 alpha globin chain -> most severe form of Deletions -> excess gamma globin chains that form tetramers Fetus (~similar to hemolytic disease of newborn) Tx: lifelong dependence alpha-thalassemia = hydrops fetalis in the fetus => HgB Barts = high O2 affinity and deliver little to - severe pallor of blood transfusions most severe A-thalassemia tissues -> fetal distress - generalized edema WITH RISK of iron - massive hepatosplenomegaly overload Tx: to cure -> hematopoietic stem cell transplantation Paroxysmal Nocturnal Hemoglobinuria Acquired mutations in PIGA gene (phophatidylinositol glycan PIGA mutation: deficiency in recognition system -> deficiencies Typical PNH: chronic hemolysis without dramatic hemoglobinuria => only 25% have hemolysis Tx: Eculizumab -> complementation group A gene) = enzyme essential for in proteins that are being synthesized -> therefore: complement monoclonal AB = **only acquired one** synthesis of membrane-associated complement regulatory system can bind and attack Sleep: Slight decrease in blood pH -> increases complement activity -> tendency for RBCs to lyse at night prevents conversion proteins of C5 to C5a [C5 RBCs are deficient in GPI linked proteins that normally regulate Mild-moderate anemia Inhibitor] -> reduces complement activity: hemolysis, transfusion -> Decay-accelerating factor: CD55 Hemosiderinuria = loss of heme iron in urine -> iron deficiency => exacerbates anemia (if untreated) requirements, and -> Membrane inhibitor of reactive lysis CD59 => normal: potent lowers risk of inhibitor of MAC (C5b-C9) complex that prevents intravascular Thrombosis => leading cause of PNH related death thrombosis hemolysis of RBCs by complement) -> 40% of patients have venous thrombosis, involving the hepatic, portal, or cerebral veins -> C8 binding protein Drawbacks of this Tx: Some develop: acute myeloid leukemia (AML) OR myelodysplastic syndrome -> PNH => means that PNH -> high cost Normal PIGA: enzyme -> membrane-associated complement can arise from genetic damage to hematopoietic stem cells -> incr risk of regulatory proteins = go on membranes of RBC so meningococcal infection complements don't EAT It Dx: flow cytometry -> CD55 negative and CD59 negative = PNH Tx option for marrow aplasia -> immunosuppressive drugs Tx that cures!: HSC transplantation Immunohemolytic Anemia ABs that recognize RBCs -> premature RBC destruction Dx: Detection of ABs or complement on RBCs -> Direct Coombs antiglobulin test: patients RBCs mixed with sera+ABs specific for human Ig => directly on RBC itself, if positive: will agglutinate DIRECT: testing to see if AB is on RBC surfaces -> if positive: agglutination -> Indirect Coombs antiglobulin test: patients serum tested for its ability to agglutinate commercially available RBCs with particular defined AGs INDIRECT: testing to see if AG on commercial RBCs -> if positive: agglutination Immunohemolytic Anemia Warm AB Type IgG class RBCs antibodies -> bind stably to RBCs at 37*C -> Induced by: extravascular hemolysis = The red blood cells coated with - Idiopathic: IgG (RBC ABs) = bind RBCs IgG = HOT 80% of immunohemolytic anemia IgG are usually removed by macrophages in the spleen Idiopathic: unknown cause -> IgG: more significant/severe cases and liver, leading to their destruction outside of the bloodstream (extravascular). - Drug Induced: IgM = COLD -> Antigenic drugs: These include drugs like penicillin and -> IgM: Insignificant/self limiting therefore goes away by cephalosporins. They can bind to red blood cells and act as itself antigens, causing the immune system to produce antibodies against the red blood cells. -> Tolerance-breaking drugs: An example is methyl-dopa. These drugs can disrupt the immune system's tolerance, leading to the production of autoantibodies against red blood cells. = Methyldopa can alter the immune system’s ability to distinguish between the body’s own cells and foreign invaders. The drug may modify red blood cell proteins, or it might change the way these proteins are presented to the immune system. This alteration can break the immune tolerance, leading to the production of autoantibodies. Immunohemolytic Anemia Cold Agglutinin Type IgM ABs -> bind to RBCs at 0-4*C [low] Mycoplasma pneumoniae, EBV, CMV, Influenza virus, HIV -> Self limiting (because dealing with IgM) -> NO intravascular hemolysis, NO clinically significant extravascular Tx: avoid cold cold agglutinin type hemolysis temperatures IgG = HOT 15-20% of immunohemolytic anemia Mycoplasma pneumoniae, EBV, CMV, Influenza virus, HIV -> -> IgG: more significant/severe cases cold agglutinin type IgM binds to RBCs in vascular beds -> temperature falls before 30*C in exposed fingers, toes, and ears IgM = COLD Temperature falls before 30*C in exposed fingers, toes, ears -> allows IgM to bind to RBCs in these vascular -> IgM: Insignificant/self limiting therefore goes away by beds -> RBC agglutination -> vascular obstruction => pallor, cyanois, and Raynauds phenomenon itself Megaloblastic anemia Vitamin B12 and Folic Acid coenzymes = normally required Increased numbers of hematopoietic precursors -> RBCs: macro-ovalocytes = macrocytic and oval, lack central pallor (not white in middle = red in middle, and Assoc with other autoimm: for thymidine synthesis (nucleotide bases of DNA) hypercellular marrow white around) - Thyroiditis Older adults - Adrenalitis Autoimm attack on gastric mucosa Deficiency in Vitamin B12 and Folic Acid -> impaired DNA To overcome anemia: Increase levels of growth factors => Low reticulocyte count Hallmark of chronic atrophic gastritis synthesis -> defective nuclear maturation -> ineffective increase number of hematopoetic precursors => produce more Large neutrophils => loss of parietal cells hematopoiesis -> abnormally large erythroid precursors -> RBCs = But RBCs are defective due to faulty DNA synthesis Neutrophils are hypersegmented = 5+ nuclear lobes (normal: 3 lobes) abnormally large RBCs = Megaloblasts => ineffective hematopoesis => marrow hyperplasia Other causes: Marrow hyperplasia - Achlorohydria (no chlorine in Vitamin B12: organometallic compound in animal products Dysmaturation of granulocyte precursors (aka granulocytes are not maturing) stomach) & loss of pepsin secretion (in (fish, meat, milk, eggs) => daily requirement: 2-3 micrograms older adults) Normal: stomach fundic mucosa => parietal cells -> secrete Dx based on: - Gastrectomy IF = needed for Vit B12 absorption from gut - moderate to severe megaloblastic anemia with leukopenia and hypersegmented granulocytes - Insufficiency of exocrine pancreas IF and B12 Complex = endocytosed by ileal (ileum) - low serum Vit B12 - Ileal resection or diffuse ileal disease enterocytes via IF receptors - elevated serum levels of homocysteine and methylmalonic acid - Eating raw fish -> tape worm Vit B12 -> secreted into plasma -> Vit B12 carrier protein - Increased demand causing relative transcobalamin II -> delivers to liver, bone marrow Atrophic Glossitis deficiencies => pregnancy, proliferating cells, and GI tract MOA: fundic gland atrophy and intestinal metaplasia -> beefy shined glazed tongue = atrophic glossitis hyperthyroidism, disseminated cancer, chronic infection Demyelination of dorsal and lateral spinal tracts -> spastic paraparesis, sensory ataxia, and severe parathesia in lower limbs Megaloblastic anemia Pernicious anemia Autoimmune gastritis -> impairs production of intrinsic factor - > pernicious anemia has everything that is written above with megaloblastic + additional related ** Serum ABs to IF => pernicious anemia MOA with Intrinsic Factor Pernicious anemia -> gastric mucosa atrophy and metaplasia -> increased risk for gastric carcinoma Vitamin B12 Function & Deficiency FUNCTION 1: Cofactor Methyl Cobalamin needed for: Homocysteine -> Methionine Cofactor Methyl Coabalmin also: N5-methyl FH4 [inactive folate] -> tetrahydrofolic acid (FH4) => used for DNA synthesis (because it helps to form thymidine) Vit B12 Deficiency -> impairs methionine synthase from converting N5-methyl FH4 to FH4, therefore: it traps the folate in its inactive form and it accumulates -> and due to no FH4, there is no thymidine production -> impairing DNA synthesis Vitamin B12 deficiency -> lack of folate -> anemia THEREFORE: Supplementing patient with folic acid -> treats anemia FUNCTION 2: ISOMERIZATION: (Propionate) -> Methylmalonyl CoA (via methylmalonyl CoA mutase and B12 cofactor) succinyl CoA **THIS REQUIRES VIT B12 AS A COFACTOR -> Absence of Vit B12 = not enough cofactor for this isomeratization reaction = isomerization rxn does not take place = build up of methylmalonic acid in plasma and urine -> Build up of Propionate and Methylmalonate -> formation of abnormal FFAs into neuronal lipids -> myelin breakdown -> subacute degeneration of spinal cord While you can overcome B12 deficiency with addition of Folic Acid (re: function 1) -> this can worsen the neurologic symptomology because you are not supplementing actual B12 which is needed in the isomerization reaction -> therefore: no isomerization, and leading to function 2 Anemia of Folate Deficiency Sources of folic acid: green vegetables (lettuce, spinach, asparagus, broccoli), fruits (lemons, bannanas, melons), and animal (liver) FH4 is important in the following: - purine synthesis - conversion of homocysteine -> methionine (cofactor: Vit B12) - dTMP synthesis [-> thymidine] What leads to folic acid deficiency: - nutritionally inadequate diet or lack of intestinal absorption - > decreased intake - increased requirements - impaired utilization folic acid deficiency -> megaloblastic anemia with same features as Vit B12 deficiency folic acid deficiency -> serum homocysteine increased BUT NO EFFECT ON METHYLMALONATE CONCENTRATIONS (=normal) therefore no buildup of propionate/FFAs -> no neurologic changes occur Iron Deficiency Anemia Normal Iron Storage: Due to: Anemia = low serum iron, low ferritin, and low transferrin saturation Important because free iron is toxic -> therefore: must be - dietary lack sequestered into one of the following - impaired absorption Dx: absence of stainable iron in macrophages -> not seeing blue dots -> liver and macrophages: stored by hemosiderin and ferritin - increased requirement -> ferritin: liver -> stored in parenchymal cells, in other - chronic blood loss Normal RBC: sufficient Hgb -> zone of central pallor that is 1/3 of diameter tissues -> found in amcrophages Iron Deficiency: zone of pallor is enlarged & Hgb may be seen as only a narrow peripheral rim **FERRITIN LEVELS CORRELATE WITH BODY IRON Seen with: STORES** - infants => because breast milk only has a small amount of Sx: -> hemosiderin: iron + hemosiderin -> chemically reactive -> iron (not enough) - Pencil cells: small, elongated RBCs -> contributes to poikilocytosis blue-black with K+ ferrocyanide = Prussian Blue Stain - impoverished - Pica: depletion of iron from CNS -> pica = craving of non-food items = ice, clay, flour, paint chips, dirt eater - older adults - Koilonychia (spoon nails) Iron Transport = transferrin - teenagers => b/c they mostly eat junk food - Alopecia -> synthesized in liver - chronic blood loss - Atrophic changes in tongue and gastric mucosa -> major function: transfer iron through plasma -> to deliver - increased requirement: growing infants, children, adolescents, - Intestinal malabsorption to cells = ex) erythroid precurosors (these require iron to pregnancy synthesize Hgb) Plummer-Vinson Syndrome Iron deficiency -> inadequate Hgb production -> hypochromic TRIAD: Esophageal webs + microcytic hypochromic anemia + atrophic glossitis THERE IS NO REGULATED PATH FOR IRON microcytic anemia = low serum iron, low ferritin, and low EXCRETION -> usually lost through mucosal and skin transferrin saturation Lab Dx: epithelial cell shedding - Hgb: low As body iron stores increased -> absorption decreases - Hct: low - Serum Iron: low Liver produces -> hepcidin = regulates iron storage in - Serum ferrotin: low duodenum and binds to ferroportin -> inhibits iron transfer - Total iron binding capacity: HIGH => trying to find iron (so has high capacity to bind), but unable to bind from enterocyte to plasma => therefore: iron is endocytosed (therefore more empty) and degraded - Transferrin saturation: low - Hepcidin levels: low => b/c want to maximize the absoprtion of the iron that is available (so low levels of High levels of hepcidin -> iron becomes trapped within hepcidin => if there were higher, then the iron that was found would be taken to be degraded/storage) duodenal cells in mucosal ferritin -> slough off cells = lose - RDW: high => broader distribution because smaller cells (microcytic) iron Too much iron in body = high levels of hepcidin -> inhibit iron absorption into blood Low iron in body = low levels of hepcidin -> facilitates iron absorption Explanation: Ferroportin = helps transport iron from storage into blood Too much iron: hepcidin binds to ferroporti