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Pathoma- Red blood cell disorders

Terms in this set (69)

Anemia
-reduction in circulating RBC mass present with signs and symptoms of hypoxia
-weakness, fatigue, and dyspnea
-pale conjunctiva and skin
-HA and lightheadedness
-angina, esp with preexisting CAD
-RBC's = carry oxygen within blood - within Hb
RBC mass measurements
-Hb, Hct, and RBC count are used as surrogates for RBC mass
-each of these is concentration dependent - sometimes may not be good estimate

-ex = woman pregnant - normal RBC mass - but Hb and hCt go down due to more blood volume (dilution)
-ex = gunshot wound - bleed out RBCs and fluid - Hb and HCt normal --> give them fluid, Hb and hct will dec
Def of anemia
-Hb < 13.5 g/dl in males
-Hb < 12.5 g/dl in females
-lower in females due to loss of blood during menstruation
classification of anemias
-microcytic (MCV < 80)
-Normocytic (MCV = 80-100)
-Macrocytic (MCV > 100)

-MCV = mean corpuscular volume - gives estimate of size of RBC
Microcytic anemias
*MCV < 80

*Formation of RBC
-comes from erythroblast - relatively large cell - continuously divides ---> produces small RBCs
-Microcytosis is due to an "extra" division* of the erythroblast
-Microcytosis = always due to dec production of Hb - this is why it divides extra time - trying to make up for this and maintain its pink color
Hemoglobin
-made of heme and globin

*heme = iron and protoporphyrin
-ex = low iron - low heme = low Hb = microcytic anemia (iron def)
-ex = anemia of chronic disease = chronic inflamm - iron locked away in macrophages and not avail for use = microcytic anemia
-ex = any cause that dec protoporphyrin = Sideroblastic anemia = microcytic anemia

-globin =
-Thalessemia = dec prod of globin chain'
4 major causes of microcytic anemia
-iron def anemia
-anemia of chronic disease
-sideroblastic anemia
-Thalassemia
Iron def anemia
-due to dec levels of iron
-MC type of anemia
-lack of iron is MC nutritional def in world
Iron biochem
-consumed in heme (meat-derived) and non-heme (vegetable derived) forms
-heme form = more readily absorbed
-absorption occurs in the duodenum***
-enterocytes transports iron into blood via ferroportin
-body doesn't have a way to get rid of iron from body
-why enterocytes regulates how much comes in
-once in blood, iron binds to transferrin
-transferrin transports iron and delivers it to liver and bone marrow macrophages for storage
-stored intracellular iron is bound to ferritin (prev iron from gen free radicals)
Lab measurements of iron status
-serum iron = how much iron in blood

-TIBC = how many transferrin molecules in the blood (whether bound to iron or not)

-% saturation = how many transferrin molecules are actually bound to iron

-serum ferritin = how much iron present in storage sites (bone marrow macrophages and liver)
iron def can be caused by
-dietary lack or blood loss
-infants = breast feeding (breast milk has little to no iron)
-children = poor diet
-adults - peptic ulcer disease (males); menorrhagia or preg (females)
-elderly - colon polyps/carcinoma (western world); hookworm- Necator and Ancelostoma (developing world)

*Other causes =
-malnutrition
-malabsorption - celiac dz (villi of duodenum destroyed)
-Gastrectomy*** - iron can be present in Fe2+ or Fe3+; Fe2+ is more easily absorbed by body (Fe2 goes in2 the body)
-acid maintains the Fe2+ state --> more readily absorbed
Stages of iron def
-storage iron is depleted - serum ferritin DECREASES + TIBC INCREASES (these are always opp)
-serum iron is depleted - serum iron DECREASES + % saturation DEC
-normal % sat = 33%

-normocytic anemia*** (know this happens first- initial stage)
-as iron depleted from storage and serum - bone marrow trying to make RBCs - tries to make normal size, just less

-microcytic, hypochromic anemia
-eventually, iron def so severe - no more normal RBCs can be made - so bone marrow prod smaller than norm + less Hb (color) RBCs (greater pale area in mid)
CM and labs in iron def anemia
*CM
-anemia
-koilonychia = spoon shaped nails
-Pica = craving/chewing - dirt and ice

*Lab findings
-microcytic, hypochromic anemia with inc RDW (broad spectrum of sizes)
RDW= spectrum of size
-dec ferritin, inc TIBC
-dec serum iron + dec % saturation
-inc FEP (free erythrocyte protoporphyin)***
-heme = Fe + proto
-in iron def = dec Fe + proto normal
-not enough iron to bind to proto so FEP increases
Blood smear of iron def anemia
-RBCs should be size of nucleus of lymphocyte
-note small RBCs
tx of iron def anemia
-supplemental iron = ferrous sulfate
-treat underlying cause
Plummer vinson syndrome
-iron def anemia with esophageal webs and atrophic glossitis
-presents with anemia, dysphagia, and beefy red tongue
Anemia of chronic disease
-a/w chronic inflamm or cancer
-MC type of anemia in hosp patients
-chronic dz results in acute phase reactants
-ex = Hepcidin = sequesters iron in storage sites (trying to hide it from bacteria, which thrive off iron even though there is no bact, body thinks there is in chronic dz)
-limits iron transfer from macrophages to erythroid precursors
-suppresses EPO prod
**both lead to less heme
-dec available iron leads to microcytic anemia
Lab findings and tx of anemia of chronic dz
-Lab findings
-inc ferritin, dec TIBC
-dec serum iron, dec % saturation
-inc FEP
-Seq = normocytic anemia first, then microcytic anemia

-Treatment
-address underlying cause
-exogenous EPO is useful in a subset of patients, esp those with cancer
Sideroblastic anemia
-due to defective protoporphyrin synthesis = microcytic anemia

-protoporphyrin is syn via a series of reactions
-final reaction attaches protoporphyrin to iron to make heme
-some occur in mitochondria, some in cytosol

-1st step = SuccinylCoA --> aminolevalunic acid (ALA)
-NX = ALA synthase (ALAS)
-RATE LIM STEP****
-Vit B6 = cofactor for NZ***
-2nd step = ALA porphobilinogen
-NZ = ALA dehydrogenase (ALAD)**
-next series of reactions
-final reaction = protoporphyrin + Fe --> Heme
-NZ = Ferrochelatase**
-occurs within mitochondria**
more about protoporhyrin
*iron is transferred to erythroid precursor as protoporphyrin is made
-enters mito to form heme
-if protoporphyrin is def = iron remains trapped in mitochondria --> creates ring of iron loaded mitochondria around nucleus in cell = RINGED SIDEROBLAST (PIC**)
-Prussian blue stain
-HY ? = give pic, where is iron located = MITOCHONDRIA
cause of sideroblastic anemia
-MC congenital = defect in ALAS***

-acquired =
-Alcoholism - mito poison
-Lead poisoning - can denature ALAD and ferrochelatase
-Vit B6 def - MC occurs in INH treatment
Lab findings in sideroblastic anemia
-gen = iron overloaded state (excess iron cause cell to die -iron leaks out - macrophages eat it + leaks out into blood)
-inc ferritin, dec TIBC
-inc serum iron, inc % saturation
Thalassemia
-dec synthesis of globin chains of Hb
-dec globin leads to dec Hb, resulting in microcytic anemia
-due to inherited mutation - carriers are protected against Plasmodium falciparum malaria

*divided into alpha and beta
-based on dec prod of alpha or beta globin chains
-normal types of Hb are HbF (alpha2gamma2), HbA (alpha2beta2), HbA2 (alpha2delta2)
-consistent use of alpha - most imp chain
Alpha thalassemia
-usu due to gene deletion
-normally 4 alpha alleles are present on chromosome 16

-Possibilities
-1 gene deleted = asymptomatic

-2 genes deleted with slightly inc RBC count
-if on same on chromosome = cis deletion*
-Cis is worse
-a/w inc risk of severe thalassemia in offspring
-seen in Asians inc rate of spont abortion due to this
-if on opposite chromosomes = trans deletion*
-MC in Africa

-3 genes deleted = severe anemia
-B chains form tetramers (HbH**) that damage RBCs
-HbH is seen on electrophoresis

-4 genes deleted = lethal in utero (hydrops fetalis**)
-gamma chains form tetramers (Hb Barts**) that damage RBCs
-Hb Barts are seen on electrophoresis
Beta Thalassemia
-due to gene mutations** (NOT DELETIONS)
-2 Beta genes on chrom 11
-mutations result in absent (B0-null) or diminished (B+) production of Beta-globin
-wide spectrum of disease - B0B+, B+B+, etc
Beta Thalassemia Minor
-B-Thalassemia Minor (B/B+)
-mildest form of disease
-usu asymptomatic with inc RBC count
-microcytic, hypochromic RBCS and target cells on blood smear**
-PIC of target cell**

-Hb electrophoresis findings
-slghtly dec HbA
-inc HbA2 to 5% (normal 2.5%)***
-inc HbF to 2%
Beta thalassemia Major
-B-Thalassemia Major (B0/B0)
-most severe form of dz
-presents with severe anemia a few months after birth
-HbF (a2g2) at birth temporarily protective
-takes a few months for symptoms to develop
-alpha tetramers aggregate and damage RBC
-ineffective erythropoiesis
-extravascular hemolysis

-massive erythroid hyperplasia
-expansion of hematopoiesis into marrow of skull and facial bones --> crew cut appearance on xray* + chipmunk-like face*
-PIC- xray with crew cut skull**
-extramedullary hematopoiesis with HSM
-risk of aplastic crisis with parvovirus B19

-tx = chronic transfusions are often necessary
-leads to risk for secondary hemochromatosis (excess iron in tissues)
Blood smear and electrophoresis in B-thal major
-Blood smear
-microcytic, hypochromic target cells and nucleated red blood cells
-nucleated RBCs - when RBCs are made in abn place - liver, kidney

-Electrophoresis
-NO or little HbA
-inc HbA2 and HbF
Macrocytic anemia
*Anemia with MCV > 100
-MC due to folate or Vitamin B12 deficiency (megaloblastic anemia)
-megaloblastic = all cells that rapidly divide become large
-Review biochem
-THF is methylated when comes into body
-must be unmethylated to produce DNA precursors
-Vit B12 will take methyl group then passes methyl group to homocysteine produces methionine
Causes of macrocytic anemia
-impairs syn of DNA precursors
-megaloblastic anemia - macroovalocytes
-hypersegmented neutrophils - greater than 5 lobes
-megalobalstic change in rapidly dividing epithelial cells (ex = intestine)

*PIC OF HYPERSEGMENTED NEUTROPHIL
Other causes of macrocytic anemia
-alcoholism
-liver disease
-drugs (5-FU)
-large RBCs but NO hypersegmented neutrophils or megaloblastic change in other rapidly dividing cells
Folate
- obtained from green vegetables and some fruits
-absorbed in jejunum**
-folate def - develops within months
-b/c body stores are minimal

-Causes of def
-poor diet = alcoholics and elderly
-inc demand (preg, cancer, hemolytic anemia)
-folate antagonists (ex = methotrexate)
CM and lab findings in folate def
-macrocytic RBCs and hypersegmented neutrophils
-glossitis
-dec serum folate
-inc serum homocysteine
-normal methylmalonic acid**
-Vit B12 - converts this to succinylcholine
-imp neg finding - how you know its not Vit B12 def
Vit B12 def
-complexed to animal-derived proteins (meat, eggs)
-once in body, Vit B12 cleaved from proteins - becomes bound by R binder (prod by salivary gland) this complex travels thru esophagus + stomach to reach small bowel then R binder cleaved away (via proteases prod by pancreas) Vit B12 then binds intrinsic factor (prod parietal cells in body of stomach*) this complex goes to ileum where it is absorbed
-less common than folate def
-takes years to develop due to large hepatic stores* of Vit B12

-MC cause = Pernicious anemia
-AI destruction of parietal cells (body of stomach) - intrinsic factor def
others causes of VIT B12 def
-pancreatic insuff = pancreas creates NZs that cleave R binder
-damage to terminal ileum due to Crohns dz or Diphyllobothrium latum
-dietary deficiency is rare, except in vegans
CM and lab findings in B12 def
-macrocytic anemia with hypersegmented neutrophils
-glossitis
-subacute combined degeneration of spinal cord (methylmalonic acid builds up in myelin of spinal cord)***
-dec serum Vit B12
-inc serum homocysteine
-inc methylmalonic acid**
Normocytic anemia
*Anemia with normal sized RBCs (MCV 80-100)
-due to inc peripheral destruction or underproduction
-reticulocyte count helps distinguish btwn these 2 etiologies
reticulocytes
-young RBCs released from bone marrow
-identified on blood smear as larger cells with bluish cytoplasm (blue due to residual RNA**)
-PIC***
-normal count = 1-2%
-RBC lifespan is 120 days
-each day - roughly 1-2% of cells are removed from circulation and replaced by reticulocytes
-properly functioning marrow should respond to anemia by increasing RC to >3%
-RC, however, is falsely elevated with anemia
-measured as percentage of total RBCs
-decreased in total RBCs falsely elevates percentage of reticulocytes

-in order to adjust for anemia, correct Reticulocyte count
-multiplying by Hct/45
-if lower than normal (<3%) - indicates poor bone marrow response; suggest underproduction of RBCs
-if >3% = good bone marrow response - suggest peripheral destruction
Peripheral RBC destruction (hemolysis)
-divided into extravascular and intravascular
-extravascular - destroyed by reticuloendothelial system (macrophages) - outside RBCs
-intravascular - destroyed within blood vessel
-both result in anemia with good marrow response
Extravascular hemolysis
-involves RBC destruction by the reticuloendothelial system - macrophages of spleen, liver, and LNs
-macrophages consume RBCs and break down the hemoglobin
-globin AAs
-heme iron and protoporhyrin
-iron recycled
-protoporphyrin unconjugated bilirubin (bound to serum albumin; delivered to liver for conjugation and excretion into bile)
CM and lab findings in extravascular
-anemia with splenomegaly
-jaundice due to unconjugated bilirubin
-inc risk for bilirubin gallstones
-marrow hyperplasia with corrected reticulocyte count >3%
Intravascular hemolysis
-destruction of RBC within vessels
-Hb passed directly into blood - response of body - to bind Hb with Haptoglobin - takes it to spleen to be reprocessed

*-Clinical and lab findings
-Hb builds up in blood - hemoglobinemia - leaks out into urine - hemoglobinuria
-hemosiderinuria - hemosiderin in tubular cells of kidney - takes up Hb and excretes Hb in urine***
-dec serum haptoglobin
Hereditary Spherocytosis
-inherited defect of RBC cytoskeleton - membrane tethering proteins
-MC involves spectrin, ankyrin, or band 3.1
-membrane blebs are formed and lost over time
-loss of membrane renders cells round (spherocytes) instead of disc shaped
-PIC**
-creates a high RDW - older cells have lost more membrane than newer cells creating diff shapes
-spherocytes are less able to maneuver thru splenic sinusoids - so they are consumed by splenic macrophages resulting in anemia
CM and labs in spherocytosis
-spherocytes with loss of central pallor
-inc RDW
-Inc MCHC (mean corpuscular hemoglobin conc)***
-splenomegaly, jaundice with unconjugated bilirubin, and inc risk of bilirubin gallstones
-macrophages hypertrophy*
-inc risk of aplastic crisis with parvovirus B19 infection of erythroid precursors
Dx and tx of spherocytosis
-Diagnosis
-osmotic fragility test - inc fragility in hypotonic solution

-Treatment
-splenectomy
-anemia resolves, spherocytes persist
-Howell-Jolly bodies emerge on blood smear*
-spleen must remove fragments of DNA within RBCs
-in this case, no spleen = fragments of DNA remain in RBC - H-J body
-PIC*** - indicates splenic dysfunction


PIC = The RBC in the center of the field contains several Howell-Jolly bodies, or inclusions of nuclear chromatin remnants
Sickle cell anemia
-AR mutation in Beta chain of hemoglobin
-normal glutamic acid (hydrophilic) replaced with valine (hydrophobic)
-gene carried by 10% of individuals of African descent - likely due to protective role against falciparum malaria
sickle cell dz
-arises when 2 abn B genes are present
-results in >90% HbS in RBCS
-HbS polymerizes* when deoxygenated
-polymers aggregate into needle-like structure resulting in sickle cell (banana shaped)
-not covalently bonded
-polymerization = reversible
-PIC**
-inc risk of sickling with
-hypoxemia, dehydration, acidosis
-HbF protects against sickling
-high HbF at birth is protective for first few months of life (no symptoms til 6 months of age)
-treatment with hydroxyurea increases levels of HbF

-cells continuously sickle and de-sickle while passing thru microcirculation
-results in complications related to RBC membrane damage
Major problems in sickle cell dz
1) 1 major problem = membrane damage = becomes less flexible, spleen removes them = extravascular hemolysis
-anemia, jaundice with unconj hyperbilirubinemia, inc risk for bilirubin gallstones
-cells lyse - intravascular hemolysis (minimal amount)
-dec haptoglobin
-target cells on blood smear
-conseq of both hemolysis = massive erythroid hyperplasia
-expansion of hematopoiesis into skull and facial bones - crew cut xray and chipmunk facies
-extramedullary hematopoiesis with hepatomegaly
-risk of aplastic crisis with parvo B19 infection of erythroid precursors

2) 2nd major problem= irreversible sickling
-leas to complications of vaso-occlusion infarction of tissues
-ex = Dactylitis (very HY)
-swelling of hands and feet due to vaso-occlusive infarcts of bones
-common presenting sign in infants***
-PIC***
-ex= autosplenectomy leads to shrunken, fibrotic spleen
-inc risk of infection with encapsulated orgs (MC death in kids**)
-H. influ, S. pneumo (vaccinate against these)
-inc risk of Salmonella paratyphi osteomyelitis
-Howell-Jolly bodies on blood smear
-ex = acute chest syndrome
-vaso-occlusion in pulmonary microcirculation
-presents with chest pain, SOB, and lung infiltrates; often preceipitated by pneumonia
-MC cause of death in adults**
-ex = pain crisis
-ex= renal papillary necrosis
-results in gross hematuria and proteinuria
PIc of dactylitis
Sickle cell trait
-only one mutated beta gene
-prod HbA + HbS**
-HbA is more efficiently produced than HbS (55% to 45%)
-JK <50% HbS** - not enough HbS to sickle = ASYMPTOMATIC
-exception = renal medulla*

-Renal medulla
-extreme hypoxia and hypertonicity cause sickling
-results in microinfarctions
-leads to microscopic hematuria and eventually, dec ability to conc urine**
Labs in sickle cell anemia and sickle cell trait
-Sickle cells and target cells seen on blood smear in sickle cell dz but not in sickle cell trait
-Metabisulfite screen = causes cells with any amount of HbS to sickle
-pos in both disease and trait**
-Hb electrophoresis
-confirms presence and amount of HbS
-Disease = 90% HbS, 8% HbF, 2%HbA2 (NO HbA**)
-Trait = 55% HbA, 43% HbS, 2% HbA2
hemoglobin C
-AR mutation in Beta chain of hemoglobin
-normal glutamic acid is replaced by lysine** (call it lyC)
-less common than sickle cell dz
-presents with mid anemia due to extravascular hemolysis
-see hemoglobin C crystals in RBCs - HISTO PIC***** (C = crystals - appear rectangular shaped)
Paraoxysmal nocturnal hemoglobinuria
-acquired* defect myeloid stem cell - GPI will not be present in RBCs, WBCs, and platelets*
-no GPI = no DAF and no MIRL - cells susceptible to complement destruction**
-DAF - accelerate degradation of C3 converatase
-MIRL + DAF connected to RBC via GPI
-patients most susceptible at night* - get intravascular hemolysis - wake up in morning with very dark urine
-mild resp acidosis develops with shallow breathing during sleep and activates complement
-RBCs, WBCs, and platelets are lysed
Labs and screening in PNH
-Lab findings
-hemoglobinemia
-hemoglobinuria
-hemosiderinuria is seen days after hemolysis

-Screen test = sucrose test
-Confirmatory test = acidified serum test or flow cytometry to detect lack of CD55 (DAF) on surface of RBCs
COD and comp in PNH
-Main COD = thrombosis of hepatic, portal, or cerebral veins**
-destroyed platelets release cytoplasmic contents into circulation inducing thrombosis

-Complications
-iron def anemia = lose iron in urine as they lose Hb
-AML in 10% of patients**
G6PD def
-X-linked recessive disorder resulting in reduced half-life of G6PD
-RBCs live in environment of oxidative stress - to protect themselves, they use glutathione
-NADPH needed to re-produce glutathione once it's used
-must have G6PD to produce NADPH

-G6PD variants
-African variant = mildly reduced half-life of G6PD
-only older cells do not have G6PD
-Mediterranean variant = markedly reduced half-life of G6PD
-young and older cells do not have G6PD
-high gene freq in both population - due to protection against falciparum malaria
G6PD cont
-oxidative stresses
-precipitates Hb as Heinz bodies
-ex = infecitons, drugs (primaquine, sulfa drugs, dapsone) and fava beans
-Heinz bodies are removed by splenic macrophages, resulting in bite cells**
-PIC OF BITE CELL**
-leads to predom intravascular hemolysis

-Presents with hemoglobinuria and back pain
-hours after exposure to oxidative stress

-Heinz preparation
-used to screen for disease - PIC of HEINZ prep - aggregate of Hb
-NZ studies confirm def - only after dz has resolved
Bite cell
Immune hemolytic anemia: IgG
-usu involves extravascular hemolysis
-IgG binds RBCs in relative warm central body - warm agglutination
-membrane of Ab-coated RBC is consumed by splenic macrophages results in spherocytes

-a/w SLE, CLL, and certain drugs
-drug can attach to RBC membrane, and Ab binds drug-memb complex = penicillin
-induce production of autoAbs - ex = methyldopa - Ab bind Ag present already on RBC

-Treatment
-cessation of offending drug
-steroids
-IV Ig
-splenectomy
Immune hemolytic anemia: IgM
-usu involves intravascular hemolysis
-binds RBCs and fixes complement in relative cold temp of extremities (fingers and toes) - cold agglutinin
-a/w Mycoplasma pneumoniae* and infectious mononucleosis*
dx of both immune hemolytic anemias
*Coombs test

-Direct = confirms presence of Ab-caoted RBCs
-Anti-IgG is added to patient RBCs
-agglutination occurs if RBCs are already coated with IgG Ab
-most imp test for IHA

-Indirect = confirms presence of Ab in patient serum
-Anti-IgG and test RBCs are mixed with patient serum
-agglutination occurs if serum Ab are present
Microangiopathic hemolytic anemia
-intravascular hemolysis that results from vascular pathology
-affects small blood vessels - thrombus occurs - blocks vessel partially - RBCs sheared - SCHISTOCYTES** - PIC
-seen in: TTP, HUS, DIC, HELLP
-TTP - platelet thrombi, no ADAMSTP-13
-HUS - platelet microthrombi, due to toxin by E. coli O157:H7
-DIC - platelet+fibrin thrombi
-HELLP - hemolysis, elevated liver NZs, low platelets = pregnant women
-also seen in prosthetic heart valves, aortic stenosis
Malaria
-results in infection of RBCs and liver with Plasmodium
-transmitted by Anopholes mosquito
-PIC** histo
-RBCs rupture as part of Plasmodium lifecycle
-results in intravascular hemolysis and cyclical fever
-P. falciparum = daily fever
-P. vivax and ovale - fever every other day
-spleen also consumes some infected RBCs - splenomegaly
plasmodium vivax
Underproduction
*dec prod of RBCS by bone marrow
-char by low corrected reticulocyte count

*Etiologies
-causes of microcytic and macrocytic anemia
-renal failure
-damage to bone marrow precursor clels
Parvovirus B19
-infects progenitor red cells
-temporarily halts erythropoiesis
-leads to signif anemia in setting of pre-existing marrow stress
-treatment is supportive
Aplastic anemia
damage to hematopoietic stem cells
-results in pancytopenia with low reticulocyte count

-etiologies = drugs or chemicals, viral infections, autoimmune damage

-biopsy reveals = empty marrow (PIC**) - lots of fat present

-treatment
-stop drugs
-transfusions
-marrow stimulating factors (EPO, GM-CSF, G-CSF)
-immunosuppression
-BMT (last resort)
Myelophthisic process
-pathologic process that replaces bone marrow (ex = cancer)
-hematopoiesis is impaired, resulting in pancytopenia
Pelger huet
If most of the neutrophils appear bilobed, this is indicative of an uncommon condition known as Pelger-Huet anomaly, an inherited condition. This is the heterozygous form. The homozygous form is fatal. Just be aware of this condition when you get back a manual differential count with mostly bands, but the WBC count is normal or the patient shows no signs of infection or inflammation.
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