RBC disorders Flashcards
1
Q
RBC indices: What do they mean?
A
- hemoglobin : concentration of Hb in blood
*less : anemia
*More: polycythemia
2. Mean corpuscular volume(MCV) : average size of the RBC - smaller: microcytic
- Larger: macrocytic
3. Red cell distribution width (RDW) : how similar or different the RBCs are in size: more the variation, higher the RDW
4. mean corpuscular hemogolbin concentraiton : concentration of hb in each RBC:
Normal: normochromic - reduced: hypochromic
5. Hematocrit, or packed cell volume(PCV) : volume %of RBCs in blood
2
Q
anemia: reduction in the total …… of the blood
A
oxygen -carrying capacity
3
Q
Consequenes and clinical features for anemia
A
- patients appear pale - conjunctiva, palms, and face
- weakness , malaise, easy fatigability, and dyspnea on mild exertion
- hypoxia: fatty change in the liver, myocardium, and kidney
- CNS hypoxia: headache, dimness of vision and faintness
4
Q
Classification of anemia : based on morphology- ?
A
normocytic, microcytic, macrocytic
5
Q
Morphological classification:normal RBC
A
- biconcave in shape the central pallor
: to make space for all the hb - to have more surface area for favorable hb -oxygen interaction
makes RBC deformable like fleible enough to faicilitate passage through small capilaries and sinuosids
Normal RBC is roughly the same size as the nucleus of a small lymphocyte -
6
Q
Microcytic:
A
Hb synthesis has been affected- less Hb production - smaller size of RBC
- Iron+ protoporphyrin = heme +globin chains= hemoglobin
7
Q
cause of microcytic:
A
- Iron is deficient in the body
- Unavailable to RBC precursors to make Hb (Iron is there but RBC can’t get it)
- synthesis or incoorporation with iron defective
- Qauality or quantitity of globin chain produced is defective or not enough
8
Q
RBC will be smaller in size as there is less hb to occupy the cell
A
= microcytic
9
Q
Less hb means colors of RBC will be less
A
= hypochromic central pallor will increase
10
Q
If problem #3-
A
iron will be in excess and express as hemosiderin deposit in RBC and precursors- siderocytes and sideroblasts
11
Q
Macrocytic:
A
Imparied Dna synthesis but normal RNa synthesis and translation
12
Q
Normocytic:
A
signal for erythropoiesis reduced or there is not enough space for erythropoiesis in the bone marrow.
- can also be seen in early stages of anemia due to iron deficiency or unavailability
13
Q
Morphology of RBCs in anemias:
change in shape of RBC -
A
poikilocytosis
14
Q
- Spherocyte:
A
- any damage or defect in RBC membranes- reduced surface area to volume ratio - has to accommodate same hb - takes the most economical shape- spherical
- reduced deformabiliy - become easy targerts for splenic macrophages
- Can be seen in inherited defects in RBC membrane protein or acquired causes of damage to RBC membrane
15
Q
- Tear drop: dacrocyte
A
- marrow fibrosis: RBC distored on its way out of the bone marrow
- abnormal inclusion in RBC: splenic macrophages try to take them out- shape distorted
16
Q
- Target cell/ codocyte
A
: RBCs having a surface that is disproportionately large compared with their volume
- seen in condtions with defective hemoglobinization, reduced Hb, membrane lipid imbalance.
17
Q
- Sickle cell/ drepanocyte:
A
- a specific genetic defect in beta globin chain of hb makes it less soluble- in deoxygenated state it forms polymers- distorts the shape of RBC
- obstructs small capilaries and can cause ischemia
18
Q
5.Fragmented RBC/ Schistocyte
A
- physical damage to RBCs within the vessels- triangular fragments or looking like helmets
19
Q
- Bite cell
A
- a specific genetic defect causing deficiency in an enzyme of hexose monophosphate shunt or gluthathione metabolism - makes it less protected against oxidative damage.
- free radical dmage to hb - become denatured
- Form membrane- bound precipitates HEINZ bodies
- splenic macrophages eat these precipitates - cell looks like bite
20
Q
How can we visualize the Heinz bodies:
A
supravital stains
21
Q
How can we visualize the Heinz bodies:
A
supravital stains : light the cells
22
Q
- Polychromatophilic cells/ reticulocyte
A
- juvenile immature red cells larger in size than normal
- contain remnants of the ribosomal rna present in the cytoplasm. (RNA stains blue)
- if increased : reflects increased erythropoietic activity like compensatory hyperplasia etc = increased meaning bone marrow making so much RBC
- if decreased: reflects decreased erythropoietic activity like lack of space or raw materials, defects in stem cells in bone marrow = decrease meaning less RBC making from bone marrow
- On routine stain - Hb stains the cell pink +remnant RNA stains the cell blue - polychromatophilic cell
- On supravital stain: RNA remnants can be seen making a mesh - reticulocyte - if we want to see RNA
23
Q
- Howell Jolly Bodies
A
- Remnant of dna
- Usually removed by spleen - if present indicates decreased function or absence of spleen .
- Heinz bodies: on supravital stain
- Howell jolly bodies- on routine stains.
24
Q
- Howell Jolly Bodies
A
- Remnant of dna (dna stains blue)
- Usually removed by spleen - if present indicates decreased function or absence of spleen .
- Heinz bodies: on supravital stain
- Howell jolly bodies- on routine stains.
25
9. pappenheimer bodies:
- composed of hemosiderin
- positive for perl's stain - prussian blue positive
- small peripherally sited basophilic erythrocyte inclusion
- soderb;asts.
- excess hemosiderin
26
Blood loss:
Rate of blood is an important determinant of the changes seen in peripheral blood and bone marrow - acute or chronic.
27
What is acute blood loss?
- effects mainly due to loss of intravascular volume due to tramua
if massive= cardiovascular collapse, shock and death
if survives- movement of water from interstitial fluid compartment to the intravascular compartment - blood volume is rapidly restored like compensatory mechanisms
- But this produces hemodilution!! and lowers the hematocrit - reduces the tissue oxygenation ischemia!!
- triggers increased secretion of erythropoietin from the kidney. - stimulates the proliferation of erythroid precursors in bone marrow - takes about 5 days for them to appear as reticulocytes in blood .
If bleeding internal into tissue- iron recaptured rom hb by macrophages
- if bleeding into gut or outside- iron lost- can hamper restoration of normal RBC counts
28
Peripheral smear finding in acute blood loss:
- Initially red cells appear normal in size and color
, as bone marrow production increases- reticulocytosis-
- increased platelet production - thrombocytosis
- mobilization of marginal pool of neutrophils- increased total leucocyte count.
29
Chronic blood loss:
- presents with anemia only
- when the rate of loss exceeds the regenerative capacity of the marrow
- when the iron reverse are depleted and iron deficiency anemia appears
common in gastric bleeds as in peptic ulcer disese
30
WHat is hemolytic anemias? three features
1. RBCs life span less than 120 days
2. elevated erythropoietin levels like compensatory mechanism
3. accumulation of hemoglobin degradation products that are created as part of the process of hemolytic
31
Causes of hemolytic anemias: 6 different causes
1. Hereditary spherocytosis: membrane defects
2. Glucose 6 phosphate dehydrogenase deficiency- enzyme defect
3. Sickle cell anemia, thalassemia- hemoglobin defects
4. paroxysmal nocturnal hemoglobinuria - complement mediated lysis
5. autoimmune hemolytic anemias - autoantibodies against RBC antigens
6. Micro and macroangiopathic hemolytic anemias- mechanical damage to RBCs
32
What is extravascular hemolysis?
outside blood vessel RBC destruction
- When can RBCS become more prone to destruction by splenic macrophages?
1. They are less flexible - change in shape
2. They have been made tasty by opsonization by complement proteins like C3b or immunoglobulin like IgG
33
What does less deformable mean?
They don't change shape that easily when moving through sinusoids - biconcavity lost
2. passages through splectic sinusoids difficult- chronic condition cause splenomegaly.
splenectomy can be possible
34
Intravascular hemolysis?
inside blood vessel red destruction
What causes RBC to die within the vessel itself?
- 1. mechanical injury- trauma caused by cardiac valves, narrowing of the microcirculation by thrombi, or repetitive physical trauma
2. Complement fixation - antibodies recognize and bind red cell antigens - membrane attack complex activated (MAC) activation
3. toxic injury- best exemplified by clostridial sepsis
4. intracellular parasites like plasmodium falciparum
like malaria
35
Meet haptoglobin :
a2- globulin that binds free hemoglobin and prevents its exertion in the urine. There is difference between hematuria and hemogluria
36
mechanism of haptoglobin:
- RBC breaking within the vessels- lots of free hemoglobin released- bound by haptoglobin - serum levels of haptoglobin reduced
- free Hb - brown methemolgobin- some passes out in urine- red brown color
- hemosiderin accumulating within tubular cells - renal hemosiderosis
37
How will we know that our patient has hemolytic anemIA AND WHICH TYPE?(4 reasons)
1. Patient presents with anemia (pallor) and jaundice(icterus) - and lab reports
2. If splenomegaly present- think of extravascular hemolysis
3. If hemoglobin emia and uria - think of intravascular hemolysis
4. Look for evidence of increased RBC breakdown and compensatory erythropoiesis
38
Evidence of increased RBC breakdown
1. Increased bilirubin
2. Chronic cases: may even precipitate formation of gall bladder pigment stones
3. Increased lactate dehydrogenase
4. decreased serum haptoglobin
39
Evidence of compensatory erythropoiesis:
1. Reticulocyte count increase
2. in a hurry nucleated RBCs may get released into circulation
3. Bone marrow will be hyperplastic - can cause bone changes.
40
Bone marrow examination to dertime type of hemolytic anemia?
NOPE not helpful
41
What is hereditary spherocytosis?
- Inherited cause extravascular hemolysis
- vulnerable to splenic sequestration and destruction
- Etiology: Commonly autosomal dominant mutation in genes coding for membrane protein of RBC- most commonly ankyrin!
42
clinical features of hereditary spherocytosis?
1. anemia:
2. splenomegaly: evidence of extravascular hemolysis
3. Unconjugated hyperbilirubinemia due to continuous hemolysis- gallstone (abdominal pain)
4. Increased LDH(evidence of increased breakdown of RBC)
43
Pathogenesis of hereidtary spherocytosis
Reduced RBC membrane stability- loss of small fragments during normal shearing stresses on blood circulation- become spherical- unable to transverse the splenic sinusoids - phagocytosis by splenic macrophages
Cells also become dehydrated in spleen +loss of surface area = MCHC increases
44
Hematological finding regarding hereditary spherocytosis?
1. Normocytic normochromic RBC
2. Spherocytes( lack of central pallor)
3. Polychromatophilic cells +nucleated RBC
4. If splenectomy - Howell Jolly bodies
5. MCHC high ( concentration of hb within the cell increases bc loss of water )
45
What is for osmotic fragility test?
To confirm the presence of spherocytes
1. Spherocytic RBCs lyse prematurely compared to normal RBCs , when exposed to increasingly hypotonic salt solution - less space for expansion. (hypotonic meaning water enters but membrane damge so less space for expansion)
46
Splenectomy can correct the anemia but the
spherocyosis will persist
47
What is micro/ macroangiopathic hemolytic anemias?
1. Macroanigiopathic hemolytic anemia- hemolysis stems from shear forces produced by turbulent blood flow and pressure gradients across damaged / prosthetic valves
2. Microangiopathic hemolytic anemia- microvascular lesion - luminal narrowing (often due to the deposition of thrombi) - producing shear stresses that mechanically inure compassing red cells
48
Most commonly seen with ? * microangiopathic hemolytic anemias
Disseminated intravascular coagulation. (DIC)
coagulation
- Peripheral blood- schistocytes/ fragmented RBCs
THnk of fragmented RBC. Schistocyte
49
What is parxysmal nocturnal hemoglobinuria ?
- sudden attacks at night intravascular hemolysis.
Definition: hemolytic anemia with an acquired genetic cause- result in complement mediated intravascular lysis precipitated sudden attacks by acidosis.
Normally PIGA gene codes for GPI anchoring proteins normally- act as structural support for complement regulatory proteins- protect cells from complement mediated damage.
Ex) C8 binding protein, CD 55, CD 59.
50
What happened to mutation in PIGA gene?
- No GPI anchored proteins formed normally
- no structural support for complement regulatory proteins.
- complement mediated intravascular damage to RBCs and even other blood cells.
51
The tendency for red cells to lyse at night is explained by a..........
- slight decrease in blood pH during sleep, which increases the activity of complement - lysis and urine looks dark coloured in the morning.
- other activators of complement - surgery, infection, alcohol, stress
- Therefore,EPISODIC hemolysis- chronic symptoms do not develop.
< PNH needs trigger like surgery, infection, alcohol and stress it is not like constant hemolysis.
52
Defect in PIGA gene of hematopoietic stem cell (affects all blood cells not just RBC) .
- this is somatic mutation not inherited.
-So, it affects RBC leading to anemia due to intravasuclar hemolysis
- affects WBC leading to leukopenia (low WBC) leading to fever and infection.
- affects thrombocytopenia - leading to mucosal beledings, petechiae, ecchymosis (bruseis) = Pancytopenia (all cell decreases)
= penia meaning decrease
53
Clonal stem cell defect leads to two things?
1. risk of aplastic anemia( bone marrow failure)
| 2. risk of malignancy- acture myeloid leukemia , and myelodysplastic syndrome.
54
Even though in PNH there are less platelet, they still cause///
increased risk of thrombosis
1. platelet activation due to complement system
2. free Hb binds to NO and inactivates it - NO lost- nothing to prevent platelet aggregation leading to thromosis
55
So if thrombosis happend in hepatic vein because of pnh
Budd chiari syndrome- hepatomegaly, abdominal pain, jaundice,
- mesenteric vein - abdominal pain, rectal bleeding
- cerebral vein - seizure, headache, vomiting
56
In PNH, triad of.....
pancytopenia, thromobiss, hemolytic anemia= PNH
57
Investigation for PNH?
- CBC: Anemia, leukopenia, thromboycytoppenia
- increased reticulocyte count during the episode
2. Urine anyalysis: hemoglobinemia, hemosiderinuria (intravascular hemolysis)
- early morning urine samples will be darker because of hemosidernuria/
3. Seroloy: Indirect hyperbilirubinemia; low haptoglobin; high LDH, and low serum iron (state of iron deficiency due to hemosiderinuria)
When urinary hemoglobin is reabsorbed by renal tubular cells, it is processed to hemosiderin. Therefore, urinary hemosiderin reflects hemoglobinuria and suggests severe or intravascular hemolysis.
4. Coomb's test: negative (differentiate from autoimmune hemolytic anemia- AIHA - antibody mediated destruction of RBC)
5. flow cytometry: techniques to detect CD markers on cells - RBCs negative for CD 55 and CD 59
58
What is G6PD deficicency?
Deficient or impaired enzyme function - abnormalities in the hexose monophosphate shunt or glutathione metabolism- reduce the ability of red cells to protect themselves against oxidative injuries - lead to hemolysis.
59
Pathogenesis of G6PD deficiency?
- glucose 6 phosphate dehydrogenase (G6PD) deficiency.
- X linked recessive inhereience = male patients more likely.
- Triggers of oxidative damage like infections, drugs like sulfonamides or ingestion of fava beans- no protection from free radicals
- free radicals attacks Cross linkage of reactive sulfhydryl groups on globin chains- become denatured and form membrane- bound precipitates known as Heinz bodies.
60
Heinz body--- cause significant membrane damage in RBCs leading to
intravascular hemolysis & extravascular
we can see heinz body on supravital statin.
- 1. Heinz body causes significant membrane damage in RBCs - intravascular hemolysis
2. Heinz body can cause less membrane damage in RBCs - no lysis but change in shape to accommodate (membrane rearragne themseleves form spherocytes.
3. Splenic macrophages attempt to pluck the Heinz bodies out - bite cells
Less deformable RBCs (because of spherocytes) leading to extravascular hemolysis.
61
3 things to remember about G6PD deficiency.
1. Both intravascular and extravascular
2. Episodic after a trigger
3. Because it happened (trigger) it does not cause chronic symptoms of hemolysis seen.
62
Regarding G6PD deficiency, older RBCs are not protected against oxidant stresses, so .... to test G6PD deficiency, we need to .........
- if we do a G6PD assay immediately after an episode, cells with no G6PD would have been lysed. Only younger cells with enzyme activity will remail. REsult will say no deficiency present- false negative.
Hence, we wait at least 3 months after the hemolytic episode. .
63
Hematological findings for G6PD deficiency?
1. Normocytic normochromic RBCS
2. Bite cells and SPherocytes
3. Heinz bodies on supravital stain
4. Polychromatiphilic cells (plus minus) of nucleated RBCS
5. during hemolytic episode- other finding of hemolysis
64
CLinical features of G6PD deficiency?
1. X linked disease- males affected more commonly
2. Acute hemolysis- marked by anemia, hemolgobinemia, and hemoglobinuria
3. Usually begins 2 to 3 days following exposure of G6PD deficient individuals to environmental triggers
4. Only older red cells are at risk for lysis- episode is self limited
5. Recovery phase- reticulocytosis
6. Intermittent hemolytic episodes and not chronic- so no splenomegaly and cholelithiasis are absent ( gall bladder stone)
65
Intro to hemoglobinopathies?
we have normal 2 alpha and 2 beta gamma chins.
- alpha globin - pair of genes (4 alleles) on chromosome 16
- beta globin - a single gene (2 alleles) on chromosome 11
66
two types of hemoglobinopathies?
1. Quantitative hemoglobinopathy- deficient production of alpha or Beta globin chains- Thalassemia and microccytic RBCs
2. Qualitative hemoglobinopathy- change in structure of globin chain - sickle cell disease. (defect in beta globin chain)
67
What is sickle cell disease?
- hereditary qualitative hemoglobinopathy caused by a point mutation in beta globin that promotes the polymerization of deoxygenated hemoglobin, leading to have sickle shaped RBC, hemolytic anemia, microvascular obstruction and ischemic tissue damage.
68
Sickle cell disease is auto......
recessive.
There is also sickle cell traits heterozygotes
and sickle cell anemia called homozygotes
69
Pathogenesis of Sickle cell anemia :
Missence point mutation in beta globin leads to replacement from glutamate to hydrophobic valine)
- mutatnt HbS = less soluble- polyermises in deoxygenated states, in acidosis, or high altitude
- cycle of deoxygenation and oxygenation leading to membrane damage leading to have irreversibly sickle shaped RBC leading to have hemolysis and microvascular occlusion.
- dehydration (cell membrane damage so water is out) - increased HbS concentration leading to have more sickling.
70
What are the factors that affecting sickling?
HbA: asymptomatic. protective
HBC: Sickling increases if a cell has both HbS and HbC
HbF: protective (for Rx-hydroxyurea- increases the amount of HbF- inhibits the polymerization of HbS. )
- Anything increases HbS(MCHC - concentration of membrane damage) like dehydration - increases HbS concentration - increases sickling.
- Alpha thalassemia: less alpha for mutated globin to bind to - decreased MCHC - sickling decreases.
- Decreases pH- reduces O2 affinity of Hb- increases deoxygenated Hb - sickling increases
- Increased transit time through microvascular beds- like in spleen, bone, and inflamed tissue
71
CLinical features of sickle cell anemia?
1. due to hemolysis (intra and extravscular hemolysis)
- moderately severe hemolytic anemia
- early childhood - splenomegaly
- bone marrow compensatory erythroid hyperplasia
- producing prominent cheeckbones and changes in the skull that resembles crewcut ( bc of osteoclast to osteoblast cycle)
- hyperbilirubinemia and formation of gallbladder
2. auto splenectomy
- chronic microvascular occulsion - splenic infarction, fibrosis, and progressive shrinkage
- increased susceptibility to infection with encapsulated organisms - vaccine.
- peripheral smear findings of absence of spleen = howell jolly bodies
3. Chronic hypoxia - generalized impairment of growth and development
4. Sequestration crises= children with intact spleen - massive entrapment of sickled red cells leads to rapid splenic enlargement, hypovolemia, and sometimes shock.
5. Aplastic crises: Bone marrow is full of erythroid precursors. infection by parvobirus B19 - transient cessation of erythropoiesis- sudden worsening of the anemia- sudden drop in reticulocyte count
(aplastic crisies can be seen with other inherited hemolytic anemia. )
6. Episodes of hypoxic injury and infarction causes sevrere pain
Hand foot syndrome, acute chest pain, stroke,blindness,
renal infarction , papillary necrosis
Osteomyelitis especially due to Salmonella species.
72
Investigation for sickle cell anemia?
1. peripheral smear
2. screening
3. Hb electrophoresis: HbA fartherest- HbF- HbS- HbC
On CBC: bilirubin levels are normal for sickle cell trait whereas indirect bilirubin raised for sickle cell anemia.
73
what is Thalseemias?
Genetically heterogeneous autosomal recessive disorder caused by germline mutation that decreases the synthesis of either alpha or beta globin , leading to anemia, tissue hypoxia, and red cell hemolysis related to the imbalandce in globin chain reaction.
74
Beta thalassemia0 heterogenous genetics?
1. Beta globin has 2 alleles,
splicing mutation and promoter region mutation- reduced globin from that allele and called B+ allele
- reduced production of beta globin.
2. Chain terminator mutation - nonglobin from that allele0 called B0 allele- no beta gene at all
75
What type of beta thalamssemias?
1. Beta thalassemia major/ cooley's anemia: homogygous : one plus or one zero, one zero/ the other zero, one plus/another plus : severe anemia. Depend on transfusion : hemosiderin probelm casued (hemochromatosis- harmful iron level)
2. Beta thalassemia intereiate
3. Beta thassemia minor/ trait- less severe bc of heterzygous : Asymptomatic at least normal gene to protect your body.
76
Pathogenesis of beta thalassemias:
- Beta globin chains very less- leading to microcytic hypochromic cells,
- less globin and more membrane - having target cells
- Alpha globin in excess - excess unpaired alpha globins form unstable tetramers- can precipitate in erythroid precursors - apoptosis of precursors- ineffective eryhropoiesis- basophillic stippling.
- can precipitate in mature RBCs - splenic macrophages tries to take them out - can form tear drop cells and extravascular hemolysis. = chronic condition: splenomegaly and conmpensatory erythropoiesis.
77
One major thing differentiate between beta thalassemia major and beta thalassemia minor is :
Hb types:
Major- Beta is very very low, HbA very less, HbF is high
Minor: Beta is slightly low, HbA is slightly less, HbA2
78
alpha thalassemias are caused by
genetic deletion.
- Alpha globin chains are coded by a pair of alpha genes ( 4 alleles)
- (one allele can be deleted , two alleles can be deleted= asymptomatic)
( Three or four deletion: symptomatic:
All allels: lethal!!
79
Malaria endemic areas :
1. Point mutation in globin gene- sickle cell
2. Mutation leading to globin deficiency: A , B thalassemia
3. Mutation affecting red cell enzyme - glucose 6 phosphate dehydrogenase deficicency
4. Mutation causing red cell membrane defects - band 3 , spectrin.
80
What is autoimmune hemolytic anemia?
- hemolytic anemia with a defect extrinsic to RBC caused by antibodies that recognize red cells and lead to their premature destruction
81
What is etipathogenesis of AIHA?
1. formation of autoantibodies that can be idiopathic or following infections, drugs, lymphomas
2. Antibodies can either opsonize the RBC themselves or initiate a complement activation- can form opsonins or membrane attack complex- hemolysis
82
Diagnosis of AIHA?
Test done is Coombs antiglobulin test- direct and indirect
- direct: demonsstrate the presence of antibodies or complement on RBCs
- indirect: in the sera of the patient
- reagent used is commbs reagent- anti human globulin - antibody against human antibodies/ complement.
83
Warm antibody?
Cold antibody?
Cold Antibody?
1. Warm antibody: IgG antibodies, normal temperature (37)
- IgG opsonize - Splenic macrophages0 extravascular hemolysis
2. Cold antibody- IgM antbodies- lower than 37
- IgM binds to RBCs in exposed fingers, toes, ears etc- fixes complement- C3b forms blood recirculates to warmer areas- IgM falls off before MAC is formed. C3b opsonizes RBCs - splenic macrophages- extravascular hemolysis (bc of C3b)
= cold agglutinin disease(pentamer structure of IgM)
3. Cold antibody- IgG antibody- bind to RBCs at lower than 38
- IgG binds to RBCs in exposed fingers, toes, ear,etc
- fixes complement - doesn't fall off when blood recirculates to warmer areas- MAC formed- intravascular hemolysis
= cold hemolysin diseases/ paroxysmal cold hemoglobinuria
84
Warm hemolysin?
- most common AIHA, associated with systemic lupus eryhematous, drugs like alpha methyl dopa, B-cell neoplasms like chronic lymphocytic leukemia
- target antigen - most commonly Rh IgG coated RBCs bind to Fc receptor on phagocytes - remove a bit of membrane- spherocytes formed- lysed in spleen.
- characterized by Chronic anemia, splenomegaly
- cold aggulutinin- Associated with mycoplasma, EBV, CMV,HIV
: Clumped/ agglutinated RBCs seen in peripheral smear with some spherocytes
- Raynaud phenomenon when exposed to cold
-cold hemolysin- associated with viral infection in children. : normocytic RBC
-
85
Decreased production: hypo proliferative anemias
1. defective stem cells affecting production o all types of blood cells
2. No space in bone marrow due to tumor cells, metastasis
3. Lack of raw material needed for RBC production
86
Megalobastic anemia? what is it ?
- impairment of DNA synthesis that leads to ineffective hematopoiesiss and distinctive morphologic changes, including vitamin B12, folic acid are coenzymes required for the synthesis of thymidine. so Dna affected not RNA.
87
causes of vitamin B12 deficiency?
1. Decreased of intake- inadequate diet, strict vegan
2. impaired absorption- pernicious anemia, gastrectomy, malabsorption, any diffuse intestinal disease, fish tapeworm infestation
88
Causes of folic acid deficiency?
1. decreased intake of green vegetables like in alcoholics
2. impaired absorption
3. preganancy demand (reduce brain and spinal cord defect)
4. Folic acid antagonist drugs like methotrexate
89
Vitamin B12 absorption?
1. Ingestion problem
2. pancreatic proteases problem
3. intrinsic factor
4. distal ileum ,
- The B12- IF complexes pass to the distal ileum and get absorbed via a receptor IF into the enterocytes
!. Decreased intake - deficiency
- pancreatic insufficiency and distal ileal diseases-
- autoantibodies against intrinsic factor/ pernicious cells- pernicious anemia
90
if vitamin B12 is deficient- folate will remain in this form " folate trap"
- Methyl malonyl coenzyme A: if vitamin B12 is deficient- increased levels in urine and serum- formation and incorporation of abnormal fatty acids into neuronal lips
- myelin prone to breakdown- subacute combined degeneration methyl malonyl coenzyme A is increased,
91
Findings in megaloblastic anemia
1. Drangement in DNA synthesis affects all types of cells - causes most precursors to undergo apoptosis in the bone marrow- ineffective hematopoiesis - pancytopenia
2. Due to ineffective eryhropoiesis- reticulocyte count is low
3. As a result to make more cells- precursors increase- bone marrow becomes hypercellular
- (it is busy yet ineffective-pancytopenia in blood but bone marrow is hypercellular)
In allcells- delayed nuclear maturation +normal cytoplasmic maturation and Hb accumulation leading to nuclear cytoplasmic asynchrony
An-iso-poikilo cytosis(variation in shape and size of RBCs)
4. Erythroid family- large precursors in bone marrow called Megaloblasts making mature RBCs called macrocytes - highly characteristic
5. Granulocyte family - large precursors in bone marrow called giant metamyelocytes making mature neutrophils that are larger and show nuclear hypersegmentation
- there are more than 5 nuclear lobes instead of normal 3-4 lobes
92
Findings in megalobalstic anemia?
- signs and symptoms of anemia
- Bc of the ineffective eryhropoiesis, itramedullary hemolysis might occur-mild jaundice
- Beefy tongue- due to megaloblastic changes in the oropharyngeal epithelium
- neurological symptoms in vitamin B12 deficiency
- start with serum vitamin B12 and folic levels
- If serum homocysteine levels- elevated
- Serum methylmalonic acid- elevated (only in B12)
- Red cell folate level- low (only in folate deficiency)
- Schilling test- not done anymore -
93
very important to exclude B12 deficiency before starting treatment for folate deficiency . IT might transiently correct the anemia, but
While depleting the little remaining B12 and lead to worsening of the neurological symptoms
94
What is pernicious anemia?
autoantibodies to their partietal cells- destroyed- less intrinsic factor is produced
- it is chronoic- a prominent infiltrate of lymphocytes and plasma cells
Diagnosis: all the same symptoms of B12 defificiency
Serum antibodies to intrinsic factor are highly specfic for pernicious anemia
95
What is iron deficiency anemia?
- Deficicency of iron is the most common nutritional disorder in the world, related to inadquate hamoglobin synthesis
- 1. dietary lack of iron- breast fed infants and older adults. - teenagers bingeing on junk food
2. Impaired absorption- malabsorptive disorder,s, gastrectomy (decreases acidity of duodenum)
3. Chronic blood loss- in adult men and post menompausal women IDA due to GI bleeding until proven otherwise; menorrhagia
4. Increrased demand- children, pregnant women
96
Normal iron absorption:
There are ferric and ferrous. Ferrous can enter into the cell through heme transporter but ferric has to change to be ferrous through duodenal cytochrome b-ferrieductase and through DMT1- Diavalent metal transporter , it enters into the cell. and To go inside of vessel, they use door for ferrous called ferroportin and enter the blood vessel through changing ferrous to ferric by going through haphaestin.
- liver release the protein called hepcidin which inhibits ferroportin - reduced the iron.
97
Transition from normal to negative iron balance?
Bone marrow iron and ferritin beings to decrease and TIBC begins to rise.
-
98
negatie iron balance to iron deficient eryhropoiesis
- serum iron and transferrin saturation ( how much iron in the blood is bound to transferrin)begin to fall and RBC protoporphhrin begins to rise.
99
iron deficient eryhropoeisis to iron deficiency anemia?
microcytichypochromic RBCs
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Laboratory investigation of IDA?
1. almost absent iron stores in bone marrow (gold standard- Prussian blue absent)
2. Reduced serum ferritin (most sensesitive investigation)
3. reduced transferrin saturation
4. Increased total iron binding capacity(TIBC)
5. Reduced serum iron
6. Increased RBC protoporphyrin
7. Anisocytosis (unequal size of RBC)appears early- RDW increased
8. Microcytic hypochromic RBCs (MCV is low, MCHC is low)
9. Reduced reticulocyte count.
10. Microcytic hypochromic RBCs with anisocytosis and occasional pencil cells.
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CLinical features of IDA?
- due to anemia- faiguabilitly, tiredness, pallor, malaise
- due to the underlying disorders-GI or gynecologic disease, malnutrition, malabsorption,
- due to depletion of iron containing enzymes- koilonychia(spooning shape of nails), alopecia, atrophic changes in tongue and gastric mucosa
- due to depletion of iron from CNS: pica(craving for stuff like clay, flour etc)and periodical movement of limbs during sleep
- Plummer vinson syndrome- esophagel webs+ iron deficiency+ atrophic glossitis
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Treatment of IDA?
1. Oral iron therapy
| 2. Intravenous iron
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What is anemia of chronic disease(ACD)?
- Also called anemia of inflammation
- reduction in the proliferation of erythroid progeonitors and impaired iron utilization leading to anemia in conditions with chronic systemic inflammation
1. Release of inflammatory cytokines like IL-6 from 1. Chronic microbial infection such as osteomyelitis, bacterial endocarditis, and lung abscess
2. Chrnoic immune disorders such as rheumatoid arthritis and inflammatory bowel diseases
3. Neoplasms ,such as carcinomas of the lung and breast, and Hodgkin lymphoma.
(all of those three chronic disorders try to steal iron from the body and causing inflammation)
- proliferation of hepatocytes- hepcidin which inhibits ferroportin (macrophages,duodenal mucosal cells etc(many cells)
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pathogenesis of Anemia of chronic disease?
1. Hepcidin inhibits ferroportin function in macrophages- reduces the transfer of iron from storage pool to developing erythroid precursors in the bone marrow.
2. as a result, the eryhroid precursors are starved for iron : in the midst of plenty
3. Body is trying to hide iron away from whatever started the inflammation - anemia becomes a collateral damage!
4. Iron in storage pool increases- ferritin increases
5. Prussian blue stain in bone marrow - positive
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Pathological findings for ACD?
- serum iron reduced
- TIBC decreased
- transferrin saturation remains almost normal
- cells normocytic , normochromic - later microcyic, hypochromic RBCs
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What is aplastic anemia?
- syndrome of chronic primary hematopoietic failure and teendant pancytopenia(anemia, neutropenia, and thrombocytopenia)
Acquired Causes: - idiopathic
- immune mediaed
- chemical agents (alkylating agents, antimetabolites, benzene, chloramphenicol)- most common
- Physical agents
- paroxysmal nocturnal hemoglobinuria (PNH)
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Aplastic anemia:
- Markedly hypocellular bone marrow is largely devoid of hemtaopoietic cells
- marrow aspirates often yield little material (dry tap)
