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87 Cards in this Set

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What are key characteristics of intravascular hemolysis found?
Dec/absent haptoglobin
2+ hemosiderin in urine
2+ Urine Hgb
neg. direct DAT
inc. LDH
What are the key charcteristics of extravascular hemolysis found?
mild dec. haptoglobin
neg. urinary hemosiderin and Hgb
4+ direct DAT
Inc. LDH
Describe Hereditary spherocytosis
1 extravascular hemolysis
*dec. spectrin in RBC memb=dec. attach of protein lattice to lipid bi
*dec. memb-osmotic fragility
*trapped in spleen
*Gene: AD, and some AR
Clinic: normo amenia, spleeno, most common Caucasians-hemo, aplastic with B19, inc. risk gallstones
*Tx: spleenoctomy PRN
DX: Spherocytes with neg DAT, mild inc. indirect bili, elev. retic count
Describe Hereditary Elliptocytosis
*defect self assembly spectrin
*Gene: AD
*Clinic: asx or mild normo anemia, hemo 10-20%
Tx: none or spleenectomy
Describe Glucose 6-Phosphate dehydrogenase deficinecy
Extravascular and Intracascular hemolysis
*H202 accululates b/c of too little glutathionone dep on nl G6PD
*Gene: sex-linked, 10%AA, most common B, all white and 70% AA. More serious Mediterranean
*Oxid. damage to Hgb causes: Heinz bodies
*See Bite cells b/c spleen removes part of memb.
DX: inc. retic, ghost cels, blister cells, dec. HCT, inc. serum bili, and inc. urobili, Heinz bodies, dec. G6PD on assay
Describe Pyruvate Kinase deficiency
*Not enought ATP for Na/K pump and to phosph. spectrin
*rare, AR=northern europe
*many mutant forms
DX: enzyme screen, fluro spot test, inc. retic count,
Describe Sickle Cell Trait
*Gene f: highest central Africa
*DX: CBC/PBS: nl
40-45% Hb S and 55-60% Hb A
*Clinic: can develop crisis in severe hypoxia, to develop impaired renal concentrating ability and painless hematuria
Describe Hb C trait
No Sx
Only impt for kids
Describe Sickle Cell Anemia
*0.14% AA kids, rare Euro-Amer
*Etio: substitute valine for glutamic acid at 6th residue of Beta globin chain.
*DX: protein seperation technique and no HbA detected, 2-205 Hb F, 1-3% Hb A2 and rest HbS
*PBS: normochromic, normocytic RBC with sickle form; Howell-Jolly bodies with absence of spleen function
Describe Sickle/B thalassemia
*central africa, Med and west india
*10% of SCD in US
*Sx: same as SCD
*DX: birth, HbS>HbA c/w B+thal, if HbS c B0 thal if MCV below normal for age; confirm with inc. HbA2
*PBS: HbS/B+thal: micro RBC with polychromatophilia, target cells, basophilic stippling and few sickle
HbS/ B0thal more sickle and less target
Describe HbSC disease
Life expect. NL
*Dx: mild-mod anemia, target cells, RBC normocytic and chromioc, 50% HbS and 50% HbC
*Clinic: mild-mod hemolytic anemia; splenomegaly c sequestration; mild pain infreq; inc. infx; ocular complications, stroke and ACS; avascular necrossi, renal papillary necrosis; preg problems
Describe HgbE
beta globin mutation that has 2 effects: change AA, and activate a cryptic mRNA splice site--to dec. RNA stability and dec. production of beta globin.
*SE asian ancestary, 2nd most common mutation world
*DX: on seperation with cellulose acetate same as A2, but on citrate seperated by IEF and HPLC
*PBS: mostly microcytic and hypochromic with targeting some stippling (less severe if AE)
Describe a thalassemia
Silent carrier
a thal trait
HbH disease
Hydrops fetalis
a-/a- or --/aa dz
Describe the silent carrier of a thal
1 in 4 genes affected
No heme abn;
Hb Barts (4gamma chains) in first 10d of life
20-30% AA have this gene
Describe the a thal trait of thal
2/4 genes abnl/deleted
Clinic: anemia, mild, RBC: microcytic hypochromic
Epid: 3%AA carry (a-/a-) and south asians (--/aa)
Hb Barts in first 10 days of life
Describe HbH disease
--/a- ; deletion or mutation
dx: Rbc mod micro/hypo c some targets; intracellular inclusions=Heinz bodies of precipitation of HbH tetramer
Clinic: well compensated hemolytic state
*Diff mutations; get more severe anemia, earlier onset, larger spleen
*Rare in AA ancestary
Describe Hydrops fetalis
incompatible with life
not reported in African ancestary
Describe B thal major
"Cooley's anemia"
*most severe congenital hemolytic anemia
*usu. homo b0thal; inc. med, south asian and AA.
*Clinic: after 4 months; severe anemia because of ineffective erythropoiesis and RBC destruction in bone marrow, shortened life span of RBCs because unstable a-globin monomers damage membrane
*failure to thrive and impaired develop; skeletal abnl; massive spleenomeg; death before 5
*DX: PBS: microcyt, marked variation in size and shape: targets, teardrops, cigar; nucleated RBC seen
*Hb electro: large amts of HbF, variable HbA, HbA2 is inc.
*Tx: supportive therapy keep Hb >9; watch for tissue hemosiderosis; life span till 30; can do BM transplant
Describe B thal intermedia
moderate severity regardless of genotype which require less transfusion and have nl growth
*Usu. coinheritance of a thal and b thal genes
similar to B thal major but milder
Describe B thal minor
*B thal trait, hetero Bthal and HbA
Clinic: 20% Spleno; mean Hgb 15% less than Nl
DX: PBS: microcyt, hyprochrom, occn'l target cells, cigar shape and basophilic stippling
**If iron def w/dz A2 looks nl, after replacement will rise
50%mod elevation of Hb F
Tx: none counseling
What is a DAT?
*The DAT detects antibodies attached to the patient's RBCs.
*The DAT is also known as the direct Coombs test.
What is an indirect Coomb's test?
Detection of free antibodies against a pt's RBCs in the serum.
What is Warm autoimmune hemolytic anemia?
*Most common, is autoantibodies IgG against RBC surface antigens that are active at 37C.
*Assoc. with Dz: Non-Hodgkin's Iymphomas, Hodgkin's disease, and autoimmune disorders (rheumatoid arthritis; SLE), and drugs (methyl dopa) are common causes of warm AIHA; however, most cases are idiopathic.
*DX: Sx of hemolytic anemia; Spherocytosis; + DAT
What is Cold autoimmune hemolytic anemia or cold agglutinin disease?
*Caused by IgM complement fixing antibody that binds at <30C.
*hemolytic anemia characterized by RBC agglutination and hemolysis in acral cold exposed areas of the body.
*The fixed complement causes intravascular hemolysis. As RBCs are warmed in the central organs the bound IgM is lost leaving only bound C3 (DAT positive only for C3).
*associated with Iymphoma (antibodies against anti-i), Mycoplasma pneumonia (antibodies against anti-I), and rarely infectious mononucleosis (antibodies against anti-i).
*Chronic hemolytic anemia with episodes of hemoglobinuria and jaundice.
*DX: signs of hemolytic anemia, +DAT to C3 only, less spherocytes.
What is Evan's syndrome?
What is the treatment of AIHA?
1) treatment of the underlying disease, 2) discontinue offending drugs, and 3) corticosteroids (Prednisone
What are the two defined mechanisms of drug induced hemolytic anemia? (what is the third?)
1. 1)HAPTEN FORMATION (EXTRAVASCULAR): antibody against a drug-RBC membrane complex (penicillin),
2) IMMUNE COMPLEX (INTRAVASCULAR): complement activation following a drug-protein complex on the RBC (quinidine).
3)AUTOIMMUNE (EXTRAVASCULAR); drug induces a warm AIHA, possibly by drug (Methyldopa) induced inhibition of T-suppressor allowing uninhibited autoantibody production by B cells.
What induces microangiopathic hemolytic anemia (majorones)?
1.Infections in the presence of G6PD def.
2. Meningiocoocal or pneumococcal septicemia
3. Malaria-intravascular and extravascular hemolysis
What happens when a drug damages an RBC membrane?
Cause intravascular hemolysis through formation of Heinz bodies that damage the membrane of the cells.
*EX: lead and arsenic poisening
***causes nonspecific binding of plasma proteins
What are other ways that the RBC membrane can be damaged besides drugs?
1.severe thermal burns: acanthocytes, schistocytes, and spherocytes.
2. Renal failure and Liver disease can shorten RBC lifespan and cause burr cells
name the major microangiopathic processes.
1. thrombotic thrombocytopenic purpura
2. hemolytic uremic syndrome
3. DIC
4. Malignant HTN
5. Pre-eclampsia
6. Vascular neoplasms
What is hemolytic disease of the newborn (erythroblastosis fetalis)?
**secondary to maternal alloimmunization to fetal RBC antigens (maternal antibodies cross the placenta; react with fetal RBCs and cause a fetal hemolytic anemia).
**Most commonly from the Rh factor but can because of differnt blood groups
*Sx in the infant: stillbirth, fetal heart failure, and
kernicterus (bilirubin staining of basal ganglia and other CNS structures) leading to neurologic damage.
What is paroxysmal cold hemaglobinuria?
*IgG antibodies=Donath Landsteiner Ab against the P blood group
*Usually associated with viral infections=measles and mumps or from tertiary syphilis, and in kids go away without further problems
*Acute hemolysis occurs after warming from a cold exposure; lysis is complement mediated after the Ab have come off in the warm parts of the
What is Postinfectious Cold Agglutinin-Induced Hemolysis?
*Acute and severe intravascular hemolysis after an infx.
*Assoc: mycoplasma pneumonia, EBV.
*Transient and disappears in 2-3 wks
**Antibodies are heterogensous
DX: sudden severe anemia, hemoglobinuria, +DAT with broad spectrum and complement, agglutinated RBCs on PBS, elevated cold agglutinin titer with high thermal amplitude
**Tx: keep warm and transfusion but only warm blood
What is microangiopathic hemolysis?
*caused by RBCs torn apart on fibrin strands strung across small vessels or on damaged endothelial surfaces of small vessels
What is Thrombotic Thrombocytopenia Purpura?
Fibrin and platelet deposited on the walls of small vessels causes shearing of RBCS.
*usually adults with neurologic and mild renal abnormalities. There may be fever.
*Schistocytes and severe thrombocytopenia are classic.
PT/PTT normal
What is hemolytic uremic syndrome?
Similar to TTP except fibrin and platelets are mainly in the microvasculature of the kidney.
*More common in kids and primarily involves the kidney
**Schistocytes and severe thrombocytopenia are classic. PT/PTT normal.
**Prognosis better than TTP
***associated with infection, especially E. coli which produces verocytotoxin.
What is "jogger" or March hemoglobinuria?
from trauma to red cells occuring in the feet, usually secondary to jogging, running, or marching. No RBC changes are seen on the PBS.
What is paraoysmal nocturnal hemoglobinura?
*clonal disorder with an abnormality in the gene involved in the synthesis of the glycosyl-phosphatidylinositol (GPI) anchor in the RBC membrane.
**Hemoglobinura is from Chronic INTRAVASCULAR HEMOLYSIS
**Can get Fe deficiency from Fe loss in urine
**DX: PBS: mild/moderate macrocytosis x if FE deficeint; CBC dec. WBC and platelet counts because of complement activation
**BM often hyperplasia but can see the opposite
What is the ddx list for a microcytic/hypochromic anemia?
# iron deficiency anemia
# thalassemia
# anemia of chronic disease
# sideroblastic anemia
What are the potential causes of microcytic/hypochromic anemia?
This inadequacy of structural matter may be due to:
1) an inadequate supply of nutrients (Fe deficiency)
2) a diverting of nutrients (? trapping by macrophages in anemia of chronic disease)
3) a failure of appropiate mechanisms (sideroblastic; Pb toxicity)
4) inadequate production quantity (thalassemia)
What are the causes of FE deficiency anemia?
1. Blood loss
2. Lack of dietary Fe
3. malabsorption
What does ferritin do?
It is an "iron buffer" and stores iron to either release or hold as needed.
**Closely reflects serum storage of Fe
***It carries it as Fe+3
How does Ferritin change with certain conditions (3 impt)?
1) ferritin increases in chronic inflammation;
2) ferritin is increased in hepatocellular disease; and
3) ferritin may be increased in malignancy.
What is transferrin?
It is an Fe transporter protein created by the liver and macrophages.
**Each molecule can bind 2 atoms of Fe, usus. about 1/3 of transferrin is bound to Fe
What is ferritin without Fe called?
Apoferritin, it is an accute phase reactant
What is hemosiderin?
insoluble iron protein complex derived from partially degraded ferritin aggregates, most commonly seen in macrophages
What is the tranferrin receptor?
CD71, binds 2 transferrin molecules and is then endocytosed.
**In RBCs, the vesicle fuses with lysozome, and acid pH causes transferrin to release Fe+++
What happens to Fe+++ after it is released from transferrin in the lysosome of the RBC?
It travels to the mitochondria where it is incorportated into heme to become protoporphyrin IX
What are the sources of Iron?
1. Placenta
2. Intestinal absorption, diet and physiologic regulation of Fe
-Heme iron better than non-heme, most done in the duodenum and proximal jejunum
How is heme Fe absorbed in the gut?
heme broken down from hgb in the gut,then passively transferred across the enterocyte surface and iron seperated by heme oxygenase
How is ferric iron absorbed int he gut?
Ferric iron is reduced to ferrous iron (fe+++) by a membrane-bound reductase and transported across the apical membrane of the enterocyte by the divalent metal transporter (DMT1)
How does the Fe get out of the enterocyte?
Ferroportin with Hephaestin transport Fe++ across the basolateral membran and hand it to transferrin
What is Fe used for in the body?
1. forming [2Fe-2S] clusters
2. mitochondrial ferritin
3. hemoglobin
What is the crypt programming model of plasma iron regulation?
1. Iron absorption is programmed in the crypt region by interaction of the transferrin receptro with the HFE complex on undifferentiated duodenal crypt cels when they take up plasma iron.
2. When the crypt cells mature iron uptake by the crypt cellsis modulated by the ealrier interaction of the TfR1 with HFE
What is the Hepcidin model of plasma iron regulation?
1.High plasma iron: inc. synthesis of hepcidin, which decreases the release of iron from the enterocytes and macrophagest
2. Low plasma iron level: decreases synthesis of hepcidin, which allows increased release of iron
What is hepcidin?
It is made in the liver, and is the primary regulator for the absorption of dietary iron and of release of iron from macrophages.
**Synthesis is induced by sinusoidal endothelial and Kupffer cells exposed to iron-saturated transferrin, bacteria or inflammatory cytokins that induce the hepaotcytes it synthesize and secrete hepcidin
How is iron catabolised?
1. Macrophages catabolize heme with heme-oxygenase-1 and release ferrous iron to a Fe-ATPase transporter for intracellular transmembrane iron transport
What is ceruloplasmin?
important role in mobilizing iron from macrophages and for its oxidation and incorporation into ferric transferrin.
How much Fe is stored in the macrophage after breakdown of the RBCs?
20-30% as ferritin
Where are most of the macrophages found that are storing the iron?
Liver, Spleen and bone marrow
How does the mitochondria regulate iron?
1. Uptake of Fe is regulated by [2Fe-2S] and [4Fe-4S] cluster proteins synthesized in the Mito.
2.These clusters include respiratory chain enzymes, ferrocheltase, citric acid cycle enzymes (aconitase)
How does mitochondria use the iron?
1. To synthesize the Fe-S clusters it begins with elemental sulfur , the cofactor pyridoxal-5-phosphate and a scaffold protein and it builds up the clusters
2. or it can be storred as mitochondrial ferritin
What are Iron regulatory proteins?
IRP-1 and IRP-2 are cytoplasmic RNA binding Fe-S cluster proteins.
**control translation of ferritin and Transferritin receptor synthesis by binding to "iron-responsive-elements in the RNA!
How do the Iron regulatory proteins work at high cellular iron levels?
1.[4Fe-4S] clusters form in IRP-1 (low affinity) which:
-blocks binding to the 3'IRE of the transferritin receptor mRNA, decreasing its stability and decresing the translation of it
-binding to the 5'IRE of ferritin mRNA and allowing translaiton of ferritin

SOOOOO....dec. transferritin R and inc. ferritin
What happens to the Iron regulatory proteins when cellular Fe is low?
1. the Fe-S clusters fail to form and IRP-1 (high affinity) bind:
-to 3'IRE in the tranferritin receptor mRNA and stabilizes the IRE and increases its translation
-binds to 5'IRE of ferritin mRNA blocking translation and decreasing synthesis of ferritin Transferrin R and dec. ferritin
What are the lab values to asses the level of Fe in the body?
1. SI, serum iron: measure of all iron bound to transferrin
2. TIBC, total iron binding capacity: concentration of iron needed to saturate the iron binding sites of transferrin, approximates the amount of transferrin
3. %saturation: calculated as the SI is divided by the TIBC, normal is 25-45%
4. soluble transferrin receptor: reflects the total body mass of cellular transferrin receptor, this is determined by erythroid marrow activity
What is the best measure of the body's iron load?
Use the Serum ferritin. Only a problem if there is malignancy/inflammation/or thyroid dz
What is anemia of inflammation?
Also, anemia of chronic disease.
**Iron is unavailable for heme synthesis, because of an underlying dz.
What does the AI look like labs?
mild anemia, HCT30-40% but can be lower
*RBCS-usus. normocytic, normochromic, but can be less
*Low serum iron; normal or low transferrin; low transferrin saturation; and high serum ferritin; BM stores are usu. increased; Hepcidin Inc.
What is the mechanism of AI?
decreased RBC production because of cytokines that decrease erythropoeises, IL-1 causes release of lactoferrin from neutrophils,theis binds Fe more avidly than transferrin and shunt Fe to macrophages rather than erythroid precursors.
What is Anemia of Renal failure?
*hypoproliferative anemia, because of decresed erythropoitin production and decreased RBC survival.
**normocytic, normochromic
What does anemia of renal failure look like-labs?
Burr cells
normocytic, normochromic
What is sideroblastic anemia?
defective incorporation of Fe into heme. Uptake of iron continues normally, but not able to integrate so it aggregates in the mitochondria ringing the RBC nucleus "ringed sideroblast"
Why do people get sideroblastic anemia?
1. inherited=X-linked recessive trait from decreased activity of ALA syhthesis.
2. Acquired=evidence of Myelodysplastic syndrome, accompany dysplasia of myeloid and megakaryocytic cell lines; also assoc. with drugs, and other conditions
What does Hereditary sideroblastic anemia look like?
micro/normocytic; basophilic stippling; anisocytosis;
Transferrin saturation inc. >80%; serum LDH inc (ineffective erythropoeisis)
How do you treated hereditary sideroblastic anemia?
Can treat with pyridoxin=B6
What are acquired sideroblastic anemias associated with?
2. Drugs (EtOH, isoniazid, chloramphenicol, cytotoxic agents, Vit B6 antag)
3. heavy metals (lead)
4.hematologic, neoplastic and inflammatory dz
What does lead poisening do?
inhibits ALA dehydratase. So Coproporphyrin and ALA spill into the urine. Causes an anemia that is usually microcytic, basophilic stippling, ringed sideroblasts, inc. serum iron, but may be hemolytic
What do the FE labs look like in thalessemia?
Serum Fe: Nl/inc
Transferrin: N
% Saturation: N/inc
Ferritin: N/inc
BM Fe store: N
What do the Fe labs look like in AI?
Serum Fe: dec
transferrinL N/dec
% saturation: dec
Ferritin: N/inc
BM fe store: inc
What do the Fe labs look like in Fe deficiency?
Serum Fe: dec
Transferrin: inc
% saturaton: dec
Ferritin: dec
BM Fe stor: dec
What do the Fe labs look like for sideroblastic anemia?
Serum Fe: N/inc
Transferrin: N
%Saturation: N/inc
Ferritin: N/inc
BM Fe storage: inc or dec
In Fe overload what happens to the extra iron?
iron is deposited in parenchymal cells in the liver, heart and other tissues.
What happens if Fe overload is from hemolysis?
It accumulates in the macrophages first and only later in the parenchymal cells. Reitculoendothelial macrophages sequester the iron preventing the parenchymal deposition
What is Hereditary hemochromatosis?
-body Fe storage is 50x normal
-40-60 yo present
-male:female; 10:1
-AR, mutation in HFE, transferrin receptor 2, ferroportin, hemojuvelin and hecidin have all been found
-only 1in 5 homozygotes get the clinical dz
What are the clinical findings of Herediatry hemochromatosis?
endocrine- pituitary imparied gonadatropins-testicular atropy 1/4pts; loss libido, amenorrhea, impotence, sparse hair
joints-arthropathy- hands and fingers
indolent dz- 1/4 hepatic death/gi bleed; 15%hepatocellular CA