anemias Flashcards
Adult ment and postmenopausal women with evidence of iron deficiency
must be attributed to GI blood loss until proven otherwise
disappearance of stainable iron from macs in the bone marrow
diagnostically significant finding in iron deficiency anemia (hypochromic microcytic)
accumulation of hemoglobin degregation productions, increased levels of erythropoietin, short RBC life < 120 day
hemolytic anemias- all of these feature in common
extravascular hemolysis
destruction of RBCs inside MOs
- How does red cell sequestration occur?
- principle clinical features of extravascular hemolysis
RBCs lose their shape and cannot move through the sinusoids of splenic cords
- jaundice
- splenomegaly
- anemia
intravascular hemolysis: causes
- mechanical injury
- complement fixation
- intracellular parasites
- exogenous toxic factors
clinical features of intravascular hemolysis
- jaundice
- anemia
- HEMOglobinURIA
- HEMOsiderinURIA
- large amounts of free hemoglobin taken up by MOs and then released as–>
-
methoglobin (brown)–>
- collects in kidney tubules –>
- RENAL hemosiderosis
- collects in kidney tubules –>
-
methoglobin (brown)–>
what kind of bilirubin is seen in intravascular hemolysis
unconjugated
haptoglobin-hemoglobin complex
Splenomegaly: intra vs extra - vascular
extravascular
not seen in intravascular hemolysis
morphology: hemolytic anemia (generalized)
- O2 goes down–> erythropoietin goes up–> CFU-E stimulates increase in erythroid precursor NORMOBLASTs –> increase in prominent RETICULOCYTES -
- increased phagocytosis –> hemosiderosis
- severe anemia –> extramedullary hematopoiesis
- elevated biliary excretion —> pigmented gallstones
red cell membrane protein defects causing them to be less deformable, autosomal recessive
hereditary spherocytosis: spheroid shaped, cause splenic sequestration because they can’t move out
hereditary spherocytosis –> ethinic groups?
northern europeans the worst
life span of the RBC in hereditary spherocytosis
10-20 days in length usually
small, dark staining (hyperchromic) red cells. lack central zone of pallor. patient complains of cholic-like pain and shows sign of splenomegaly
hereditary spherocytosis: cholelithiasis in 40/50%, congestion of cords of billroth–> increased # of phagocytes
increased mean cell hemoglobin concentration
RBC osmotic lysis abnormally sensitive
What crisis-scenario might this patient be prone to developing?
hereditary spherocytosis: increased MCHC caused by loss of K and H20 (relative hemoglobin measurement)
aplastic crisis with any infection that reduces hematopoiesis: biggie is the PARVOVIRUS B19
a man with an inherited blood disorder that has been well contained comes into the hospital complaining of dyspnea and weakness. PMH indicates hospitalization for an infection two weeks earlier
hereditary spherocytosis- parvovirus b19 may cause aplastic anemia 1-2 weeks afterward
recessive X linked trait
periods of jaundice and fatigue followed by recovery
- G6PD
- G6P –> reduces NADP+–>NADPH
- NADPH+Glutathione–> NADP+ + Reduced Glutathione
- Reduced glutathione –> reduced RO2 to ROH
Hexose monophosphate shunt also abnormal in this condition…
Heinz Bodies
G6PD: high oxident levels cause sulfylhydral groups to be added to globin chains–> denatures globin and forms membrane bound precipitates
- heinz bodies–> damage membranes
- MOs take a bit out of damaged cells in the splenic cords = bite cells
most common triggers in G6PD
- infections (#1)
- drugs
a point mutation causing glutamate –> valine replacement
sickle cell disease
common hereditary hemoglobinopathy causing point mutations in the beta globin chain
sickle cell anemia
chronic hemolysis, tissue damage, microvascular occlusion. clinical symptoms caused by tednecy for this protein to polymerize when deoxygenated
sickle cell anemia
Sickle Cell Trait
only 40% of hemoglobin has the mutation, and polymerization only occurs under conditions of extreme hypoxia/deoxygenation
HbSC Disease
HbSC Disease
caused by the hemoglobin variant HbC: the SC heterozygosity causes sickling but is usually milder than sickle cell disease
Characteristics of RBCs and travel in Sickle Cell Disease and their relationship to microvasculature, and their consequences
Slower velocity: polymerization occurs under periods of protracted deoxygenation, so any vasculature that requires more time to traverss will be a site for increased sickling-accuulation- bone marrow/spleen.
the rest of the vasculature is too short for deoxygenation to induce major sickling with one exception:
Inflamed vascular bed: sites of decreased oxygen, so this will cause sickling/accumulation
Sticky cells: express high levels of adhesion molecules making them “sticky”
sickling/clogging microvasculature causes the most serious complications. extravascular hemolysis is another complication
reticulocytosis
hyperplastic bone marrow
new bone formation on cheeks and skull
cholethiasis potentially
autosplenectomy
vasoocclusive crises
howell jowel bodies
sickle cell anemia
the dick will not go down
priapism, seen in sickle cell anemia
cough, chest pain, pulmonary infiltrates
vaso occlusive crises possible in sickle cell anemia
stroke, loss of visual acuity, sequestration
sickle cell complications: sequestration in the spleen causes massive hypovoluemia –> shock
why are older cells more prone to hemolysis in G6PD?
erythrocytes do not synthesize new proteins. G6PD (The two variants) misfold and resistant proteolytic breakdown, permitting ROS to accumulate and wear down the cell.
most common causes of G6P.
1 cause = infections. Viral hepatitis, pneumonia, typhoid fever are among most likely.
Others: drugs - sulfonamides, nitrofurantoins, antimalarials.
favaism: most common countries
endemic to the mediterranean, middle east, parts of africa
clinical description of G6PD
acute intravascular hemolysis—>
followed by anemia —>
hemoglobinuria, hemoglobinemia.
Usually begins 2-3 days after the initial exposure
why is G6PD episodic?
only older cells are at risk for increases lysis, the younger ones are ok.
why are the RBCs damaged so sevely in G6PD
- the G6PD misfolds–> resists degredation –> damages membrane –> intravascular hemolysis.
- the remainder are spherocytes and bite cells, both trapped and removed by phagocytes
reticulocytosis in G6PD
heralds recovery phase
small hyperchromic cells lacking a central zone of pallor
hereditary spherocytes
a crystal violet stain reveals inclusions along the lipid bilayer. debris reveals hemolyzed rbcs. what will likely occur to the ones remaining?
DECREASED membrane deformability.
the inclusions are heinz bodies consisting of denatured G6PD
alpha 2 beta 2
normal adult hemoglobin
alpha 2 delta 2
normal adult HbA2 (present to a lesser degree than Hb alpha 2 beta 2)
alpha 2 gamma 2
HbF (fetal hemoglobin)
heterozygosity for HbS is _____
asymptomatic
PfEMP-1
sickling prevents the formation of PfEMP-1 proteins produced by the plasmodium falcipurium virus, which causes the cell to adhere to the endothelium
40% of the Hb is HbS; 50% of the Hb is HbS; 100 % of Hb is HbS
1) Heterozygosity for HbS
2) HbSC Disease
3) Sicle Cell Disease
- Valine –> glutamate
- lysine –> glutamate
- HbS
- HbC
these cells tend to lose salt and water and become dehydrated, increasing the intracellular concentration of HbS
HbSC disease: HbSC cells
what can the increase or decrease of MCHC tell us in sickling disorders?
HbS tends to cause dehydration of cells, increasing the mean corpuscular hemoglobin concentration. An increased value would tell us there is more hemoglobin polymerization.
what does a decreasing MCHC tell us?
decreased HbS polymerization: conditions like alpha-Thalsemmia reduce Hb synthesis and thus leads to a milder disease if co-existant with HbS mutation.
how does sickling actually damage membranes?
it forms crystals (that induce the sickle shape) and puncture through the membrane causing hemolysis. severity of hemolysis directly correlates to % of irreversibly (old) sickled cells.
important concept in Robbins about microvasculature and sickle cells
microvasculature damage is not in fact caused by the number of irreversible sickled cells but
“subtle red cell membrane damage and local factors, such as inflammation or vasoconstriction, that tend to slow or arrest the movement of red ells through microvascular beds.”
sticky cells
cytokine/inflammation induced mediators cause erythrocytes to express adhesion molecules that make them sticky to the endothelium and accumulate
NO depletion may contribute to process: hemoglobin released from cells can bind/inactivate NO (vasodilator) allowing for further vasoconstriction, further enhancing platelet aggregation. result- stasis, sickling, thombosis
morphology sickle cell dz
peripheral blood: irreversibly sickled cells, increased reticulocytosis, and target cells produced by dehydration. Howell Jolly Bodies (nuclear remnants) seen in some RBCs dur to asplenia.
extramedullary hematopoiesis may occur.
increased hemoglobin breakdown –> hyperbilirubinemia/gallstones
pain crisis: what it’s other name is, what causes it, tissues effected by it, and one of the most common ones
vaso-occlusive crisis: causes hypoxic injury (pain) and infarctino of tissues/organs
- bones
- brain
- lungs
- liver
- spleen
- penis
- eyes
- bones- extremely common in children, hard to distingusish from osteomyelitis
- priapism: effects 45% of males after puberty–> may lead to erectile dysfunction
- retinopathy
- strokes
sequestration crisis: what is it, and in whom does it most likely occur
children: common in sickle cell patients (kids)
spleen grows so large that is leads to hypovolemia secondary to sequestration of blood.
transent cessation of erythropoiesis and worsening of anemia
aplastic crisis: caused by parvovirus B19 in sickle cell patients because progenitor cells are killed off
which kind of sickle celled patients are more likely to develop infections from encapsulated bacteria?
children- they still have their spleen but its function is reduced.
adults may have no response because of autosplenectomy.
hypothenuria
inability to concnetrate urine because of damage to the renal system in sickle cell pts
two organisms most often infecting sickle celled patients
pneumococcus penumonia and haemophilus influenza
diagnosis of SSD
evidence of irreversibly sickled cells and +tests for sickled hemoglobin: accomplished by mixing blood w/metabisulfate. if sickling induced, +
tests for sickle cell dz
metabisulfate and electrophoresis
most common cause of B*
most common cause of B null
B*: splicing erros–> siMRNA mutations cause splicing to occur mostly in exons, but if they occur in the intron then it create on site of defective DNA and another VIABLE strand, so one functional: unfunctional
B null: most common cause is a chain termination via mutation in the promoter region- creates a stop condon (UAA, UAG, and UGA); less common is frameshift mutations- both block translation and synthesis of beta globin
Beta thalassemia causes anemia by two mechanisms
- reduced beta globin reduces oxygen binding capacity, so reduced oxygen delivery
- dysfunctional beta globin forms of tetramers, inducing extravascular hemolysis via apoptosis (membrane damage turns it on)
morphology of beta thalassemia
erthypoietic drive in setting of severe uncompensated anemia–> massive erythroid hyperplasia in marrow + extensive extramedullary hematopoiesis (spleen, liver, LNs)
complications of beta thalassemia
- extramedullary hematopoiesis –> cortical bone destruction
- metabolically active erythroid progenitors–> steal nutrients –> wasting/cachexia
- excessive Fe absorption from diet (or transfusions)–> secondary hemachromatosis
- dysfunctional (decreased) erythropoiesis –> decreased hepcidin (negative Fe regulator)–> excessive absorption of iron due to low hepcidin
- iron accumulation in liver and skin
more prevalent in South Asian and West African populations.
α-Thalassemias are more prevalent in South Asian and West African populations.
more prevalent in Mediterranean populations.
beta thalassemias
- When both parents carry ______ offspring may be completely devoid of α-hemoglobin: instead they have
- This is called
- leads to
When both parents carry cis-deletions–> offspring may be completely devoid of α-hemoglobin: instead they have four γ-chains
This is called Hb Barts disease
leads to hydrops fetalis and fetal loss.
which thalassemia is most common among the beta’s?
beta thalassemia minor
what do we expect to find in beta thalassemia mino lab wise?
why do we care?
MCV: Decreased
RDW: Normal
differentiates β-thalassemia minor from iron deficiency anemia)
deletion of the beta globins and overproduction of the alpha globins: what are possible genotypes
beta thalassemia major: B+/B+, Bnull/Bnull, Bnull/B+
- marked variation in size
- marked variation in shape
- smaller than normal
- hypochromia
- condocytes
- fragmented red cells, small dots at the periphery of the RBC showing ribosomes
- normoblast RBCs in peripheral blood
- poorly hemoglobinized red cell precursors
what age group do we expect this condition to begin exhibiting signs of anemia?
what is an important cause of death in these patients?
morphology seen in beta thalassemia. in order
- aniscytosis
- poikilocytosis
- microcytosis
- hypochromia
- target cells
- basophilis stippling,
- same as other side
- nucleaed red blood cells
6-9 months after birth- so children
secondary hemachromatosis–> cardiac disease
Individuals with sickle cell-beta thalassemia
compound heterozygotes:
-
one mutant allele that encodes HbS (sickle cell allele) + second mutant allele:
- diminished (β+) or
- absent (β0) β chain synthesis.
- The severity of anemia in individuals with sickle cell-beta thalassemia depends on the amount of β chain produced (β+ vs. β0).
alpha thalassemia:
three deleted alleles
three deleted alleles: HbH disease
causes more severe anemia due to formation of β-globin tetramers inside red cells in a manner similar to α-globin tetramers in β-thalassemia major. However, the timing and location of tetramer formation differs in these two disorders:
In β-thalassemia major, α-globin tetramers precipitate inside developing erythroid precursors in the bone marrow (directly interfering with red cell maturation)
In α-thalassemia, β-globin tetramers precipitate inside mature red cells in the circulation (forming Heinz bodies that are destroyed by splenic macrophages)
what lab finding confirms beta thal?
Elevated HbA2 (α2δ2) >3.5% on gel electrophoresis- a confirmatory diagnostic test for β-thalassemia minor.
Hemoglobin electrophoresis findings in β-thalassemia minor
(mildly) Decreased HbA (α2β2)
(mildly) Elevated HbA2 (α2δ2)
(mildly) Elevated HbF (α2γ2)
–/–, α/α delections: in which population would we expect to find them?
Cis-deletions (deletions which occur on the same chromosome) [–/–, α/α] are associated with increased risk of severe anemia in off-spring. Cis-deletions are more common in South Asian populations.
Trans-deletions (deletions which occur on each chromosome) [α/–, α/–] are associated with mild anemia. Trans-deletions are more common in West African populations.
Hemoglobin electrophoresis findings in β-thalassemia major
Absent (0%)
HbA (α2β2)
Increased HbA2 (α2δ2)
significantly) Increased HbF (α2γ2)
how many alpha genes and beta genes do we inherit?
- we inherit two alpha genes from each parent on chromosome 16 = 4 alpha genes
- we inherit one beta gene from each parent on chromsome 11 = 2 beta genes
in the abscence of beta globin, what happens
alpha globin forms tetramers
alpha thalassemia consequences (name the two big ones)
1) hemoglobin barts- severe infant form of HbH dz (deletion of three alpha genes)
2) HbH Disease- adolescent/childhood form (deletion of three alpha genes)
HbH disease
- most common in asian populations
- occurs due to deletion of three alpha genes
- causes beta tetramers to form
hemoglobin barts
betatetramers form due to deletion of alpha globin genes which induce intracellular stress and cause them to burst
an elevated reticulocyte count but weirdly low for an anemia and variable number of normoblasts. what is the condition and what are normoblasts
beta thalassemia
normoblasts = poorly hemoglobinized nucleated red blood cells
asian alpha thalassemi vs african alpha thalassemia
- asian = two alpha globin genes deleted from a single chromosome
- african = one alpha gene from each of the two chromosomes
ethnicity/geography of thalassemias
beta thal maj - mediterranean countries
alpha thal trait- cis deletions - asian
alpha thal trans deletions- african/ some asian
genotype of hydrops fetalis
- alpha - / alpha - or
- ”-/-“
mutations in PIGA: what it stands for, what it is why its significant
- PIGA = phosphatidylinositol glycan complementation group A
- X linked, subject to lyonization
- only hemolytic anemia caused by an acquired genetic defect
PIGA mutations: what’s it causing and what causes it
- single acquired somatic mutations that inactivate PIGA enough to decrease GPI-linked proteins
- GPI is just a cell surface anchor- without it, your cell cant hold on to CD59 or CD55
- CD59 and CD55 are complement protein regulators
what is the molecular outcome of a somatic mutation in the PEGI gene?
loss of GPI surface anchor–> loss of
- CD55 (also known as decay accelerating factor)
- CD59 [also known as MAC-inhibitory protein and membrane inhibitor of reactive lysis (MIRL)]
CD59
CD59 blocks the binding of C9 and prevents formation of the membrane attack complex (MAC). The absence of CD59 leads to intravascular hemolysis.
CD55 loss
- EXTRVASCULAR HEMOLYSIS
- CD55 prevents the formation of C3 convertase.
- absence of CD55 allows C3 fragments to accumulate on the surface of erythrocytes (opsonization) leading to extravascular hemolysis.
Notable diagnostic/laboratory findings in PNH, main cause of death in PNH, other diseases PNH may progress to
- Anemia
- Hemoglobinuria
- Increased lactate dehydrogenase (LDH)
- Increased indirect (unconjugated) bilirubin
- Decreased serum haptoglobin
- Negative direct antiglobulin (Coombs) test
- Hemosiderinuria–>Fe deficiency
- Thrombosis is the MCC death
- AML or myelodysplastic syndrome
is HCT useful in evaluating blood loss?
no: HCT = blood cells to plasma ratio
Normocytic anemias (generall)
acute blood loss
early iron deficiency
early ACD
aplastic anemia
chronic renal failure
chronic renal failure (burr cells!)
hereditary spherocytosis
phereditary elliptocytosis
paroxysmal nocturnal hemoglobinuria
paroxysmal cold hemoglobinuria
sickle cell anmia
G6PD deficiency
pyruvate kinase defiency
actue blood loss
warm AIHA
cold AIHA
drug induced hemolytic anemia
alloimmune hemoluytic anemia
malaria
microangiopathic/macriangiopathic hemolytic anemia
most important mutation in PNH
CD59- prevents CD3 from spontaneous activation. Manifests as intravasular hemolysis.
tendency for red cells to lyse at night is explained by slight decreases in blood pH during sleep, which increases activity of complement
why does PNH appear at night?
slight tendency for pH to drop at night, increasing activity of complement system
