Red Blood disorders Flashcards
Anemia
Decreased in RBC mass
Anemia
Decreased in RBC mass
Anemia in males vs females
Males
Microcytic anemia
MCV
Heme
Iron and protoporphyrin
Hemoglobin made of
Hene and globin
Microcytic anemia caused by deficiencies in what 4 things
Heme, globin, iron, protoporphyrin (sideroblastic anemia)
What are the 4 microcytic anemias
Iron deficiency anemia
Anemia of chronic dz
Sideroblastic anemia
Thalassemia
Anemia in males vs females
Microcytic anemia
MCV
Heme
Iron and protoporphyrin
Hemoglobin made of
Hene and globin
Microcytic anemia caused by deficiencies in what 4 things
Heme, globin, iron, protoporphyrin (sideroblastic anemia)
What are the 4 microcytic anemias
Iron deficiency anemia
Anemia of chronic dz
Sideroblastic anemia
Thalassemia
Iron deficiency anemia
Decreased iron = decreased heme = decreased Hb = microcytic anemia
How is iron absorbed
Heme/non-heme forms
Duodenum
Enterocytes have DMT1 transporters
(heme form more readily absorbed) and transport iron across cell membrane into blood via ferroportin
Transferrin stores iron in blood & delivers it to liver & bone marrow macrophages for storage
Stored intracellularly bound to ferritin
Lab iron status measurements
Serum iron
TIBC
% saturation
Serum ferritin
Iron in body
Iron in blood bound to transferrin
Every 3 transferrin - 1 will be carrying iron
In macrophages iron bound to ferritin
Serum iron
Iron in blood
Transferrin molecules
TIBC - total iron binding capacity
% saturation
How many transferring bound to iron
Serum ferritin
How much iron present in liver and bone marrow macrophages
Dietary deficiency or blood loss
Breast feeding infants
Poor diet in children
Adults: PUD - males, pregnancy/menorrhagia (females)
Elderly - Western world - colon polyps, carcinoma vs developing world - hook worm (necator and ancylostoma)
Other causes of iron deficiency
malnutrition
malabsorption (acid aids in iron absorption)
gastrectomy
Fe2+ or Fe3+ absorbed by body?
Fe2+ goes into the body and acid keeps it the Fe2+ state.
Stages of iron deficiency
Storage iron depleted (ferritin) - TIBC will go up
Serum iron depleted
Normocytic anemia
Microcytic, hypochromic anemia
If ferritin is down - liver and macrophages will pump out more transferring molecules out to find iron
Ferritin down
TIBC will go up
What type of anemia is in the very early stage of iron deficiency?
Normocytic anemia
Lab findings of microcytic anemia
MCV
Tx of microcytic anemia
ferrous sulfate
Plummer-Vinson syndrome
Iron deficiency anemia with esophageal web/atrophic glossitis
Anemia, dysphagia, beefy-red tongue
Anemia of chronic disease
Chronic inflammation/cancer
Most common anemia in hospitalized patients
ACD anemia
increase in acute phase reactants - Hepcidin which locks iron in storage sites so it can’t be used
Limits iron transfer from macrophages to erythroid precursors
Hepcidin Suppresses EPO production
Lab findings in ACD
Increases ferritin, Decreased TIBC
Decreased serum, decreased % saturation
Increased FEP (not a problem with protoporphyrin)
Tx of ACD
Addressing underlying cause
Exogenous epo - especially cancer patients
Sideroblastic anemia due to
defective protoporphyrin synthesis - resulting in low heme - low Hb - microcytic anemia
Protoporphyrin synthesized via series of reactions
Final reaction attaches protoprphyrin to iron to make heme (7-8 reactions)
(ferrochelotase)
*Occurs in mitochondria
Steps of protoporphyrin production
Succinyl CoA converted to aminolevulinic acid by Aminolevulinic acid synthetase S CoA (ALAS) ALA (rate limiting step) - VIT B6 is cofactor
ALA to prophobilinogen by Aminolevulinic acid dehydrogenase
ALA (ALAD) Prophobilinogen
Final reaction - protoporphyrin + iron = heme by ferrocheletase in mitochondria
Iron transferred to precursor
Iron from bone marrow macrophages to erythoblasts - iron and protoporphyin meet in macrophage to make heme
What happens if protoporphyrin is deficient?
Iron gets trapped in mitochondria
Iron laden mitochondria form ring around nucleus of erythroid precursors - cells called sideroblasts
What stain marks iron?
prussian blue stain
What enzyme is involved most commonly in congenital sideroblastic anemia?
ALAS (rate limiting enzyme)
Common causes of acquired sideroblastic anemia?
Alcoholism (mito poisoning) Lead poisoning (LAD/ferrochelatase) Vit B6 deficiency (for ALAS) - common in isoniazid deficiency
Lab findings in sideroblastic anemia
Iron overloaded state
increased ferritin, decreased TIBC
Increased serum iron, increased % saturation
Iron - damages cells/death by free radicals - so iron leaks out and bone marrow eats iron, some can leak into blood
Thalassemia
decreased synthesis of globin chains - decreasing Hb
Thalasemmia is decrease in synthesis!
Inherited mutation
What kind of malaria are people with thalassemia protected against?
Plasmodium falciparum malaria
What are the three normal types of Hb?
HbF (alpha2,gamma2)
HbA (alpha2,beta2)
HbA2 (alpha2,delta2)
alpha common - most important in all globin chains
How many copies of alpha allele?
4 on chromosome 16
Alpha thalassemia - is due to
Gene deletion
What happens when one alpha is deleted?
Asymptomatic
What happens when 2 alpha genes are deleted?
Mild anemia with slightly increased RBC count
What are the possibilities for 2 alpha gene deletions
Cis - worse than trans - increased risk of severe thalassemia in offspring (seen in Asians)
Trans - one deletion of gene on each chromosome (Africa)
What about when 3 alpha genes are deleted?
Severe anemia
Beta chains form tetramers (HbH) that damage RBCs
What is HbH
beta chain tetramer
What happens when 4 alpha genes deleted?
Lethal in utero - hydrops fetalis
Gamma chains form tetramers (Hb Barts) that damage RBCs
Hb Barts seen on electrophoresis
Beta thalassemia due to
Gene mutations
2 genes present on chromosome 11
Mutations in absent (Betanull) or diminished (Beta+) production of beta globin chain
Mildest form of beta thalassemia
B/B+
Beta thalassemia minor
Usually asymptomatic with increased RBC count
Microcytic, hypochromic RBCs and target cells on smear
Increased HbA2
Target cell
decreased cytoplasm or increased membrane
Most severe form of beta thalassemia
Beta(null)/Beta(null) - beta thalassemia major
Severe anemia few months after birth
HbF (alpha2gamma2) at birth is temporarily protective
form alpha tetramers that damage RBC - ineffective erythropoiesis/extravascular hemolysis
Beta thalassemia - massive erythroid hyperplasia
Expansion of hematopoeisis into marrow of skull/facial bones
(EPO released by kidney) - skull - crew cut appearnace on x-ray, facial bones thickened “chipmunk like face”
Extramedullary hematopoiesis with HSM
Risk of aplastic crisis with parvovirus B19
Tx for beta thalassemia
Chronic transfusion
At risk for secondary hemochromatosis
Beta thalassemia blood smear
Microcytis, hypochromic target cells, nucleated RBC
Beta thalassemia
No HbA
Increased HbA2 and HbF
Macrocytic anemia
MCV>100
larger than normal
d/t most commonly - folate/VitB12 deficiency
one less division than normal (DNA precursor deficiency)
THF
comes in and quickly gets mehtylated - VIT B12 takes methyl group
VIT B12 passes methyl group to homocysteine and becomes methionine - transfers methyl groups
Lack of VIT B12 or folate
Megaloblastic anemia Hypersegmented neutrophils (greater than 5 lobes) Megaloblastic change in all rapidly dividing epithelial cells
Other causes of macrocytic anemia
Alcoholism
Liver dz
Drugs (5-FU)
Where is folate absorbed?
Jejunum
Folate deficiency
poor diet (minimal stores) - alcoholics, elderly Increased demand (pregnancy, cancer, hemolytic anemia) Folate antagonists (MTX)
Lab findings of macrocytic anemia
Macrocytic RBC and hypersegmented neutrophils Glossitis Decreased serum folate Increased serum homocysteine Normal methylmalonic acid
B12
complexed to animal derived proteins
Cleaved then bound to R-binder from salivary gland
Then goes to small bowel - R binder cleaved by pancreatic proteases
VITB12 bound by IF (parietal cells of stomach) and absorbed by ileum
Most common cause of B12 deficiency
AI destruction of parietal cells leading to intrinsic factor deficiency
Parietal cell
proton pumps
pink - upon staining
Pernicious anemia
“P”
Other causes of VIT B12 deficiency
Pancreatic insufficiency (can't cleave from R-binder) Damage to terminal ileum d/t Chron's dz or diphyllobthrium latum Dietary deficiency (rare execpt in vegans)
Clincal findngs B12 deficiency
Macrocytic anemia with hypersegmented neutrophils
Glossitis
Subacute combinded degeneration of spinal cord (from methylmalonic acid building up - can’t be converted to succinyl-CoA - builds up in myelin)
Lab findings in B12 deficiency anemia
Decreased serum vit B12
Increased serum homocysteine
Increased methylmalonic acid (can’t be converted to succinyl CoA)
Normocytic anemia definition/cause
RBC are normal size but decreased amount
d/t peripheral destruction or underproduction
How do you determine normocytic anemia is peripheral destruction or underproduction
Reticulocyte count - young RBC from bone marrow
Bluish cytoplasm from residual RNA
Reticulocyte count falsely elevated in
macrocytic anemia
Decreased in total RBC falsely elevated % reticulocytes
Corrected reticulocyte count
Multiply reticulocyte count by Hct/45
> 3% = good marrow response and suggests peripheral destruction
Extravascular hemolysis invovles RBC destruction by
RE system: macrophages of spleen, liver, lymph nodes - break down Hb
Break down of Hb
Globin - amino acids
Heme - iron and protoporphyrin
Protoporphyrin - unconjugated bilirubin
Clinical findings of extravascular hemolysis
Anemia with splenomegaly
Jaundice - unconjugated bilirubin
Increased risk for bilirubin gallstones
Marrow hyperplasia w/ corrected reticulocyte count >3%
Intravascular hemolysis and findings
Hb binds haptoglobin - (complex) - so free haptoglobin levels decrease
Hemoglobinemia
Hemoglobinuria
Hemosiderinuria
Decreased serum haptoglobin
Normocytic anemia with predominant extravascular hemolysis
Hereditary spherocytosis
Sickle cell anemia
Hemoglobin C
Hereditary spherocytosis
Inherited defect in RBC cytoskeleton membrane tethering proteins
*ankryin, spectrin, band 3.1
Membrane blebs formed and lost over time - so cells round
Spherocytes less able to maneuver thru
splenic sinuses so they’re consumed
Clinical and lab findings hereditary spherocytosis
Spherocytes w/ loss of central pallor
Increased RDW
Increased MCHC
Splenomegaly, jaudice w/ unconjugated bilirubin - increased risk for bilirubin gallstones
Increased risk for aplastic crisis (parvo B19) - erythroid precursor
Dx of hereditary spherocytosis
osmotic fragility test: increased spherocyte fragility in hypotonic soln
Tx of hereditary spherocytosis
Splenectomy - anemia resolves but spherocytes persist
Howell Jolly bodies
Sickle Cell anemia
AR mutation in Beta chain in hemoglobin
Glutamic acid (hydrophilic) replaced with valine (hydrophobic)
What malaria is protected against in SCD?
Falciparum malaria
Sickle cell dz vs trait
SCD:
2 abnormal beta genes present
>90% HbS in RBC
SCT:
one mutated and one normal beta chain
HbS polymerizes when
deoxygenated
Aggregates into needle like structures resulting in Sickle cells
(hypoxemia, dehydrogration, acidosis)
Protective factor against sickling
HbF
Tx: hydroxyurea increases levels of HbF
Extravascular hemolysis symptoms SCD
Anemia
Jaundice with unconjugated hyperbilirubinemia
Increased risk for bilirubin gallstones
Intravascular hemolysis with SCD
decreased haptoglobin
Target cells on blood smear
SCD - massive erythroid hyperplasia
Expansion of hematopoiesis into skull/facial bones
Extramedullary hematopoiesis with hepatomegaly
Aplastic anemia crisis (Parvo B19)
Dactylitis
Common in infants
Swollen hands/feet d/t vao-occlusive infarct of bone (irreversible sickling)
Autosplenectomy
Irreversible sickling
Increased risk of infection with encapsulated organisms (most common cause of death in children)
Increased risk of salmonella osteomyelitis
Howell Jolly bodies
What is the most common cause of death in children w/ SCD?
Encapsulated organsims
Acute chest syndrome
Vaso-occlusive in pulm microcirculation
Chest pain, SOB, lung infiltrates, often precipitated by pneumonia
Most common cause od death in adults (SCD)
Most common cause of death in adults w/ SCD?
Acute chest syndrome
Pain crisis in SCD
vaso-occlusion crisis
Renal papillary necrosis
Gross hematuria and proteinuria
Vaso-occlusive crisis
Sickle cell trait
One normal beta gene
One mutated beta gene
HbA and HbS
More HbA than HbS
50% S to sickle so these patients asymptomatic
Sickle cell trait doesn’t sickle except for…
Renal medulla
Extreme hypoxia and hypertonicity cause sickling
Microinfarctions that lead to microscopic hematuria and decreased ability to conc urine
Sickle cell trait
Metabisulfite screen: causes HbS to sickle
No sickle cell dz or target cells
HbC
Ar - Beta chain
Glutamic acid replaced by lysine
Less common than SCD
Mild anemia d/t extravascular hemolysis
HbC crystals
Normocytic anemia with predominant intravascular hemolysis
Paroxysmal nocturnal hemoglobinuria (PNH)
G6PD deficiency
Immune Hemolytic anemia
Microangiopathic hemolytic anemia
Malaria
Paroxysmal nocturnal hemoglobinuria (PNH)
DAF on surface
MIRL on surface
by GPI anchoring protein in normal cells *acquired defect in myeloid stem cell so GPI not present
In PNH - no GPI so no DAF/MIRL so susceptible to complement (intravascular hemolysis at night)
Retain carbon dioxide causing acidosis activating complement when we sleep
Dark urine in morning
Intravascular hemolysis - PNH
Hemoglobinermia
Hemoglobinuria
Hemosiderinuria seen days after hemolysis
Screen for PNH
Sucrose test
Confirmatory test: acidified serum test of flow cytometry to detect lack of CD55 (DAF)
Most common cause of death in PNH
Thrombosis
Platelet fragments activated coagulation cascade - hepatic, portal, cerebral veins
Complications of PHN
Iron deficiency Anemia
Myeloid stem cell mutation - can result in AML
G6PD deficiency
X linked R
Cells susceptible to oxidative stress (glutathione antioxidant neutralizes H2O2 + GSH - GS-SG) - needs to get back to GSH by NADPH which is produced by G6PD
If no G6PH - don’t make reduced glutathione so increased oxidative stress to red blood cells
2 major variants G6PD variants
African - mildly reduced half like g6pD
Mediterranean variant - markedly reduced half life G6PD
G6PD deficiency protective against
Falciparum malaria
What are the oxidative stress inducers of Heinz bodies
Infections, drugs, (primaquine, sulfa drugs, dapsone, fava beans)
Screen for G6PD deficiency
Heinz prep - do this after resolved acute hemolytic episode resolved
What mediates extravascular hemolysis
Immune mediated anemia
Immune mediated anemia
IgG (extravascular hemolysis - warm) or IgM (intravascular - cold)
Results in spherocytes
Immune mediated anemia associated with
SLE, CLL,certain drugs
TX: immune mediated anemia
Cessation of offending drug
IVIG
Steroid
Splenectomy
IgM mediated intravascular hemolysis (immune mediated anemia) associated with what to infections
Mycoplasma pneumoniae
Infectious mono
What test to dx IHA
Direct/Indirect coombs test
Direct: do I have RBC already bound by IgG - anti IgG added
Indirect: Does pt have antibodies in the serum?
Microangiopathic hemolytic anemia
Intravascular hemolysis from vascular pathology
Iron deficiency anemia occurs with chronic hemolysis
Occurs with mircothrombi: TTP-HUS, DIC, HELLP
microthrombi, prosthetic heart valves, aortic stenosis (calcified valves crushes RBC)
Malaria causes hemolysis
Transmitted by Anopheles mosquito
Infection of RBCs and liver plasmodium
RBC ruptures as part of plasmodium life cycle
Intravascular hemolysis and cyclical fever
Fever cycle P falciuparum
daily
Fever cycle P vivax and ovale
Fever every other day
Anemia d/t underproduction
Decreased production of RBC by bone marrow
Low corrected RC
Microcytic and marcocytic anemia
Renal failure
Damage to bone marrow precursor cells
Parvo virus
Temporary halts erythropoiesis
Significant anemia in preexisting marrow stress
Tx; supportive
Aplastic anemia
Damage to HSC
Pancytopenia w/ low RC
Drugs/chemicals, viral, AI damage
Biopsy reveals empty, fatty marrow
TX aplastic anemia
Cessation of causative drugs Transfusions Marrow stimulating factors (EPO, GM-CST, G-CSF) Immunosuppression BMT (last resport)
Myelophthisic process
pathologic process replaces bone marrow
Pancytopenia
