Path-Rbc Disorders

Front 1

What are key characteristics of intravascular hemolysis found?

Back 1

Schistocytes
Dec/absent haptoglobin
2+ hemosiderin in urine
2+ Urine Hgb
neg. direct DAT
inc. LDH

Front 2

What are the key charcteristics of extravascular hemolysis found?

Back 2

spherocytes
mild dec. haptoglobin
neg. urinary hemosiderin and Hgb
4+ direct DAT
Inc. LDH

Front 3

Describe Hereditary spherocytosis

Back 3

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

Front 4

Describe Hereditary Elliptocytosis

Back 4

*defect self assembly spectrin
*Gene: AD
*Clinic: asx or mild normo anemia, hemo 10-20%
Tx: none or spleenectomy

Front 5

Describe Glucose 6-Phosphate dehydrogenase deficinecy

Back 5

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

Front 6

Describe Pyruvate Kinase deficiency

Back 6

*Not enought ATP for Na/K pump and to phosph. spectrin
*rare, AR=northern europe
*many mutant forms
Severe=spleenectomy
DX: enzyme screen, fluro spot test, inc. retic count,

Front 7

Describe Sickle Cell Trait

Back 7

Hb AS
*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

Front 8

Describe Hb C trait

Back 8

No Sx
Hb AC
Only impt for kids

Front 9

Describe Sickle Cell Anemia

Back 9

Hb SS
*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

Front 10

Describe Sickle/B thalassemia

Back 10

*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

Front 11

Describe HbSC disease

Back 11

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

Front 12

Describe HgbE

Back 12

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)

Front 13

Describe a thalassemia

Back 13

Silent carrier
a thal trait
HbH disease
Hydrops fetalis
a-/a- or --/aa dz

Front 14

Describe the silent carrier of a thal

Back 14

1 in 4 genes affected
No heme abn;
Hb Barts (4gamma chains) in first 10d of life
20-30% AA have this gene

Front 15

Describe the a thal trait of thal

Back 15

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

Front 16

Describe HbH disease

Back 16

--/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

Front 17

Describe Hydrops fetalis

Back 17

--/--
incompatible with life
not reported in African ancestary

Front 18

Describe B thal major

Back 18

"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

Front 19

Describe B thal intermedia

Back 19

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

Front 20

Describe B thal minor

Back 20

*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

Front 21

What is a DAT?

Back 21

*The DAT detects antibodies attached to the patient's RBCs.
*The DAT is also known as the direct Coombs test.
Direct

Front 22

What is an indirect Coomb's test?

Back 22

Detection of free antibodies against a pt's RBCs in the serum.

Front 23

What is Warm autoimmune hemolytic anemia?

Back 23

EXTRAVASCULAR HEMOLYSIS
*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

Front 24

What is Cold autoimmune hemolytic anemia or cold agglutinin disease?

Back 24

INTRAVASCULAR HEMOLYSIS
*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.

Front 25

What is Evan's syndrome?

Back 25

AIHA + ITP

Front 26

What is the treatment of AIHA?

Back 26

1) treatment of the underlying disease, 2) discontinue offending drugs, and 3) corticosteroids (Prednisone

Front 27

What are the two defined mechanisms of drug induced hemolytic anemia? (what is the third?)

Back 27

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.

Front 28

What induces microangiopathic hemolytic anemia (majorones)?

Back 28

1.Infections in the presence of G6PD def.
2. Meningiocoocal or pneumococcal septicemia
3. Malaria-intravascular and extravascular hemolysis

Front 29

What happens when a drug damages an RBC membrane?

Back 29

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

Front 30

What are other ways that the RBC membrane can be damaged besides drugs?

Back 30

1.severe thermal burns: acanthocytes, schistocytes, and spherocytes.
2. Renal failure and Liver disease can shorten RBC lifespan and cause burr cells

Front 31

name the major microangiopathic processes.

Back 31

1. thrombotic thrombocytopenic purpura
2. hemolytic uremic syndrome
3. DIC
4. Malignant HTN
5. Pre-eclampsia
6. Vascular neoplasms

Front 32

What is hemolytic disease of the newborn (erythroblastosis fetalis)?

Back 32

**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.

Front 33

What is paroxysmal cold hemaglobinuria?

Back 33

INTRAVASCULAR HEMOLYSIS
*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
body

Front 34

What is Postinfectious Cold Agglutinin-Induced Hemolysis?

Back 34

INTRAVASCULAR 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

Front 35

What is microangiopathic hemolysis?

Back 35

*caused by RBCs torn apart on fibrin strands strung across small vessels or on damaged endothelial surfaces of small vessels

Front 36

What is Thrombotic Thrombocytopenia Purpura?

Back 36

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

Front 37

What is hemolytic uremic syndrome?

Back 37

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.

Front 38

What is "jogger" or March hemoglobinuria?

Back 38

from trauma to red cells occuring in the feet, usually secondary to jogging, running, or marching. No RBC changes are seen on the PBS.

Front 39

What is paraoysmal nocturnal hemoglobinura?

Back 39

*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

Front 40

What is the ddx list for a microcytic/hypochromic anemia?

Back 40

# iron deficiency anemia
# thalassemia
# anemia of chronic disease
# sideroblastic anemia

Front 41

What are the potential causes of microcytic/hypochromic anemia?

Back 41

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)

Front 42

What are the causes of FE deficiency anemia?

Back 42

1. Blood loss
2. Lack of dietary Fe
3. malabsorption

Front 43

What does ferritin do?

Back 43

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

Front 44

How does Ferritin change with certain conditions (3 impt)?

Back 44

1) ferritin increases in chronic inflammation;
2) ferritin is increased in hepatocellular disease; and
3) ferritin may be increased in malignancy.

Front 45

What is transferrin?

Back 45

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
**

Front 46

What is ferritin without Fe called?

Back 46

Apoferritin, it is an accute phase reactant

Front 47

What is hemosiderin?

Back 47

insoluble iron protein complex derived from partially degraded ferritin aggregates, most commonly seen in macrophages

Front 48

What is the tranferrin receptor?

Back 48

CD71, binds 2 transferrin molecules and is then endocytosed.
**In RBCs, the vesicle fuses with lysozome, and acid pH causes transferrin to release Fe+++

Front 49

What happens to Fe+++ after it is released from transferrin in the lysosome of the RBC?

Back 49

It travels to the mitochondria where it is incorportated into heme to become protoporphyrin IX

Front 50

What are the sources of Iron?

Back 50

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

Front 51

How is heme Fe absorbed in the gut?

Back 51

heme broken down from hgb in the gut,then passively transferred across the enterocyte surface and iron seperated by heme oxygenase

Front 52

How is ferric iron absorbed int he gut?

Back 52

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)

Front 53

How does the Fe get out of the enterocyte?

Back 53

Ferroportin with Hephaestin transport Fe++ across the basolateral membran and hand it to transferrin

Front 54

What is Fe used for in the body?

Back 54

1. forming [2Fe-2S] clusters
2. mitochondrial ferritin
3. hemoglobin

Front 55

What is the crypt programming model of plasma iron regulation?

Back 55

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

Front 56

What is the Hepcidin model of plasma iron regulation?

Back 56

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

Front 57

What is hepcidin?

Back 57

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

Front 58

How is iron catabolised?

Back 58

1. Macrophages catabolize heme with heme-oxygenase-1 and release ferrous iron to a Fe-ATPase transporter for intracellular transmembrane iron transport

Front 59

What is ceruloplasmin?

Back 59

important role in mobilizing iron from macrophages and for its oxidation and incorporation into ferric transferrin.

Front 60

How much Fe is stored in the macrophage after breakdown of the RBCs?

Back 60

20-30% as ferritin

Front 61

Where are most of the macrophages found that are storing the iron?

Back 61

Liver, Spleen and bone marrow

Front 62

How does the mitochondria regulate iron?

Back 62

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)

Front 63

How does mitochondria use the iron?

Back 63

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

Front 64

What are Iron regulatory proteins?

Back 64

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!

Front 65

How do the Iron regulatory proteins work at high cellular iron levels?

Back 65

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

Front 66

What happens to the Iron regulatory proteins when cellular Fe is low?

Back 66

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

Sooooo...inc Transferrin R and dec. ferritin

Front 67

What are the lab values to asses the level of Fe in the body?

Back 67

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

Front 68

What is the best measure of the body's iron load?

Back 68

Use the Serum ferritin. Only a problem if there is malignancy/inflammation/or thyroid dz

Front 69

What is anemia of inflammation?

Back 69

Also, anemia of chronic disease.
**Iron is unavailable for heme synthesis, because of an underlying dz.

Front 70

What does the AI look like labs?

Back 70

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.

Front 71

What is the mechanism of AI?

Back 71

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.

Front 72

What is Anemia of Renal failure?

Back 72

*hypoproliferative anemia, because of decresed erythropoitin production and decreased RBC survival.
**normocytic, normochromic

Front 73

What does anemia of renal failure look like-labs?

Back 73

Burr cells
normocytic, normochromic

Front 74

What is sideroblastic anemia?

Back 74

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"

Front 75

Why do people get sideroblastic anemia?

Back 75

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

Front 76

What does Hereditary sideroblastic anemia look like?

Back 76

micro/normocytic; basophilic stippling; anisocytosis;
Transferrin saturation inc. >80%; serum LDH inc (ineffective erythropoeisis)

Front 77

How do you treated hereditary sideroblastic anemia?

Back 77

Can treat with pyridoxin=B6

Front 78

What are acquired sideroblastic anemias associated with?

Back 78

1.MDS
2. Drugs (EtOH, isoniazid, chloramphenicol, cytotoxic agents, Vit B6 antag)
3. heavy metals (lead)
4.hematologic, neoplastic and inflammatory dz

Front 79

What does lead poisening do?

Back 79

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

Front 80

What do the FE labs look like in thalessemia?

Back 80

Serum Fe: Nl/inc
Transferrin: N
% Saturation: N/inc
Ferritin: N/inc
BM Fe store: N

Front 81

What do the Fe labs look like in AI?

Back 81

Serum Fe: dec
transferrinL N/dec
% saturation: dec
Ferritin: N/inc
BM fe store: inc

Front 82

What do the Fe labs look like in Fe deficiency?

Back 82

Serum Fe: dec
Transferrin: inc
% saturaton: dec
Ferritin: dec
BM Fe stor: dec

Front 83

What do the Fe labs look like for sideroblastic anemia?

Back 83

Serum Fe: N/inc
Transferrin: N
%Saturation: N/inc
Ferritin: N/inc
BM Fe storage: inc or dec

Front 84

In Fe overload what happens to the extra iron?

Back 84

iron is deposited in parenchymal cells in the liver, heart and other tissues.

Front 85

What happens if Fe overload is from hemolysis?

Back 85

It accumulates in the macrophages first and only later in the parenchymal cells. Reitculoendothelial macrophages sequester the iron preventing the parenchymal deposition

Front 86

What is Hereditary hemochromatosis?

Back 86

-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

Front 87

What are the clinical findings of Herediatry hemochromatosis?

Back 87

liver-cirrhotic
skin-50%pigmented
pancreas-diabetes
heat-CHF->death
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