8/2/2019 Anaemia Presentation MNH
1/75
Anaemia defined as a decrease in circulating RBC mass; theusual criteria being
Hb
8/2/2019 Anaemia Presentation MNH
2/75
1 :Deficiency of nutrients(Iron, Folic acid,
Vitamin B12, Pyridoxine and Vitamin C)necessary for haemopoeisis.
2: Depression of bone marrow:
This is caused by toxins eg drugs used inchemotherapy,radiation therapy, diseases of the
bone marrow of unknown origin( eg idiopathic
aplastic anaemia,leukaemia) reduced production
or responsiveness to erythropoietin ( chronicrenal failure, rheumatoid arthritis, acquired
immunodeficiency disease).
8/2/2019 Anaemia Presentation MNH
3/75
` Direct injury to the blood vessels.
` Acute blood loss most commonly occurs in the
gastrointestinal (GI)tract(gastritis due to alcohol or
NSAIDS,diverticulosis,or peptic or gastric ulcerdisease)and may be accompanied by epigastric
symptoms, nausea and vomiting or diarrhea.
` Worm infestation(hookworm infestation)
8/2/2019 Anaemia Presentation MNH
4/75
This has many causes including
haemoglobinopathies such as sickle cell anaemia,
adverse reactions to drugs and inappropriate
immune reactions.
8/2/2019 Anaemia Presentation MNH
5/75
` A systemic approach to anemiais best at
narrowing down the diagnosis and guiding the
diagnostic workup.
8/2/2019 Anaemia Presentation MNH
6/75
` The history and physical exam play key roles in
approaching anemia.` Patient may be asymptomatic,but at the Hb
level30%) but pt may have
symptoms of fatigue,malaise,dizzness,syncope or
angina.
8/2/2019 Anaemia Presentation MNH
7/75
Common signs & symptoms of anemia
` Pallor
` Tachycardia
` Hypotention
` Dizzness
` Tinnitus
` Headache
` Loss of concentration
` Fatigue
` Weakness
` Atrophic gastritis
` Angular cheilosis` Koilonychias(spoon nails)
` Brittle nails
` Reduced exercise toletance
` Dyspnoea on exertion
` Heart failure in more severe anemia
8/2/2019 Anaemia Presentation MNH
8/75
IRON:
Total body content in a 70kg man is 4gm.Sixty five% of which circulates in blood as haemoglobin.
About half the remainder is stored in the
liver,spleen and bone marrow as ferritin and
haemosiderin.
8/2/2019 Anaemia Presentation MNH
9/75
The iron in these molecules is
available for fresh haemoglobinsynthesis.
The rest which is not available for
haemoglobin synthesis is present inmyoglobin, cytochrome and various
enzymes.
8/2/2019 Anaemia Presentation MNH
10/75
Pharmacokinetics:
Daily iron requirement in men is15mg, in growing children and
menstruating women is 15mg.
In pregnancy it is two to ten times thisamount.
8/2/2019 Anaemia Presentation MNH
11/75
Iron in meat is present as haem
which is absorbable, and about 20-40% of haem iron is available for
absorption.
Non haem iron in food is mainly inferric state and this needs to be
converted to ferrous iron for
absorption.
8/2/2019 Anaemia Presentation MNH
12/75
Ascorbic acid stimulates iron
absorption partly by forming solubleiron ascorbate chelates and partly
reducing ferric iron to the more
soluble ferrous form.Tetracycline forms an insoluble iron
chelate resulting in impaired uptake
of both substances.
8/2/2019 Anaemia Presentation MNH
13/75
8/2/2019 Anaemia Presentation MNH
14/75
Iron stores:
Iron is stored in two forms thesoluble ferritin and insoluble
haemosiderin.
The precursor of ferritin is apoferritin.Apoferritn takes up ferrous iron,
oxidises it and deposits the ferric iron
in its core. In this form it constitutes ferritin.
8/2/2019 Anaemia Presentation MNH
15/75
Excretion:
Small amounts of iron leave the bodythrough desquamation (peeling off )
of the mucosal cells containing
ferritin.Even smaller amounts leave in the
bile, sweat and urine.
A total of about 1mg is lost daily.
8/2/2019 Anaemia Presentation MNH
16/75
Preparations:
Several salts are available for oral use. Ferroussulphate the main one but also Ferroussulphate, ferrous gluconate and Ferrous fumerate.
Parenteral preparations: Iron dextran for i.m. & i.v.Iron sorbitol for i.m. only.
These are used in malabsorption syndromes andin patients who have undergone surgicalprocedures or those who have inflammatoryconditions involving the gastrointestinal tract.
8/2/2019 Anaemia Presentation MNH
17/75
Clinical uses:
To treat iron deficiency anaemia which can be
caused by:-
Chronic blood loss (menorrhagia,hookworm or
colon cancer).
Increased demand (pregnancy and early infancy).
Inadequate dietary intake.
Inadequate absorption (following gastrectomy).
8/2/2019 Anaemia Presentation MNH
18/75
Unwanted effects:
Nausea abdominal cramps and diarrhoea.Acute toxicity:
Severe necrotising gastritis,withvomiting,haemorrhage followed by circulatorycollapse.
Chronic iron toxicity:
Iron overload is caused by chronic haemolyticanaemia(eg thalassaemia,repeated bloodtransfusions.
8/2/2019 Anaemia Presentation MNH
19/75
Treatment:
This involves use of chelators eg
desferrioxamine which forms a
complex with ferric iron.
The complex is excreted in urine.
Deferipone is a new orally absorbed
iron chelator for thalassaemia where
desferrioxamine is contraindicated.
8/2/2019 Anaemia Presentation MNH
20/75
Folic acid and Vitamin B12:
These are necessary for DNA
synthesis and cell proliferation.
Their actions are inter dependent.
Deficiency of either vit.B12 or Folicacid results in Megaloblastic
anaemia.
8/2/2019 Anaemia Presentation MNH
21/75
The deficiency of these two vitamins
affects tissues with a rapid cellturnover particullary bone marrow.
Vitamin B12 deficiency also causes
important disorders of nerves(peripheral neuropathy, dementia as
well as subacute combined
degeneration of the spinal cord).
8/2/2019 Anaemia Presentation MNH
22/75
Folic acid deficiency:
This occurs in dietary deficiency,during
pregnancy,increased demand as it occurs inchronic haemolysis (haemoglobinopathies).
Vitamin B12 deficiency:
Occurs in decreased absorption caused by a lack
of intrinsic factor ( in patients with pernicious
anaemia, resection of diseased ileum eg Crohns
disease ).
8/2/2019 Anaemia Presentation MNH
23/75
Folic acid:
Sources: Liver,green vegetables.
Daily requirements: 200mcg.
Actions: Dihydrofolate (FH2) and tetrahydrofolate
(FH4) act as carriers and donors of methylgroups
(1 carbon transfers )in a number of metabolic
pathways.
FH4 is essential for DNA synthesis as a cofactor in
the synthesis of purines and pyrimidines.
8/2/2019 Anaemia Presentation MNH
24/75
Folates are important for the
conversion of deoxyuridylatemonophosphate to deoxythymidylate
monophosphate- the rate limiting in
mammalian DNA synthesis andcatalysed by thymidylate synthetase.
8/2/2019 Anaemia Presentation MNH
25/75
Pharmacokinetics:
Folate in food is in the form ofpolyglutamate.
It is converted to monoglutamate for
absorption and reconverted topolyglutamate the more active form in
the tissues.
Folate is absorbed in the ileum.
8/2/2019 Anaemia Presentation MNH
26/75
Methyl-FH4 is the form in which folateis usually carried in blood and which
enters the cell. It is functionally inactive until it is
demethylated in a vitamin B12
dependent reaction.Methyl- FH4 is a poor substrate for
polyglutamate formation.
Adverse effects: There is a theoreticalrisk of precipitating neuropathy in anundiagnosed anaemia.
8/2/2019 Anaemia Presentation MNH
27/75
Vitamin B12 ( Hydroxocobalamin )
Source: Meat,liver,eggs and diaryproducts.
All cobalamins must be converted to
methylcobalamin (methyl vit.B12 ) or 5-deoxydenosylcobalamin for activity.
Daily requirement of vit B12 is 2 3
mcg.
8/2/2019 Anaemia Presentation MNH
28/75
Pharmacokinetics:
Absorption requires an intrisic factor. The stomach secretes large amounts
of intrisic factor.
The vitamin is stored in the liver(4mg).
Def. symptoms will occur only 2- 4
years after total gastrectomy.
8/2/2019 Anaemia Presentation MNH
29/75
Actions:
1 Conversion of methyl- FH4 to FH4.
2 Isomerisation of methylmalonyl-CoA to succinylCoA.
Conversion of methyl-FH4 to FH4:
The reaction involves both conversion of 5-methyltetrahydrofolate (methyl-FH4) to FH4 andhomocysteine to methionine, and the enzymewhich accomplishes this is homocysteine-
methionine methyl-transferase; the reactionrequires B12 as a cofactor and 5-methyltetrahydrofolate as a methyl donor.
8/2/2019 Anaemia Presentation MNH
30/75
It is thought that the 5-mehtyltetrahydrofolate
donates the methyl group to B12, the cofactor.
The methyl group is then transferred to
homocysteine to form methionine.
This vitamin B12 dependent reaction thus has a
significant role in the generation of tetrahydrofolate
from methyltetrahydrofolate.
8/2/2019 Anaemia Presentation MNH
31/75
Vitamin B12 deficiency results in the
trapping of the inactive
methyltetrahydrofolate form and the
consequent depletion of all intracellular
folate polyglutamate coenzymes (which
are necessary for early stages of DNAsynthesis) since methyltetrahydrofolate
is not converted to the polyglutamate
form which is the active form of thecoenzyme.
8/2/2019 Anaemia Presentation MNH
32/75
The preferred substrate for
polyglutamate synthesis isformyltetrahydrofolate, and the
conversion of tetrahydrofolate to
formyltetrahydrofolate requires aformate donor such as methionine.
8/2/2019 Anaemia Presentation MNH
33/75
Isomerization of methylmalonyl-CoA to succinyl-CoA
Propionate is converted to succinate.
Through this pathway cholesterol, odd chain fatty
acids, some aminoacids and thymine may be usedfor energy production via the tricarboxylic acid
cycle,or for gluconeogenesis.
Vitamin B12 in the form of deoxyadenosyl cobalamin
(ado-B12) is a cofactor in the reaction. In vitamin B12 def. states the reaction cannot occur
and methylmalonylCoA accumulates.
This distorts fatty fatty acid in neural tissue and may
be the basis of neuropathy which occurs in vit. B12deficency.
8/2/2019 Anaemia Presentation MNH
34/75
Haematopoietic growth factors:
1.Erythropoietin: Produced in juxtatubular cells inthe kidney and also in macrophages.
Action:Erythropoietin stimulates committed erythroid
progenitor cells to proliferate and generateerythrocytes.
Two forms of recombinant human erythropoietin Epoetin alpha and Epoetin beta are available.
These are clinically indistinguishable and arereferred to as Epoetin.
8/2/2019 Anaemia Presentation MNH
35/75
Pharmacokinetics:
Epoietin can be given i.v., s.c. or i.p.,
the response is greater after s.c.injection and fastest after i.v. injection.
Clinical uses of epoetin:
Anaemia of chronic renal failure.Anaemia during chemotherapy for
cancer.
Prevention of anaemia that occurs inpremature infants.
8/2/2019 Anaemia Presentation MNH
36/75
To increase the yield of autolgous
blood before donation.Anaemia of AIDS (which is
exacerbated by Zidovudine
treatment).Anaemia of chronic inflammatory
conditions such as rheumatoid
arthritis(investigational).
8/2/2019 Anaemia Presentation MNH
37/75
Unwanted effects:
Transient influenza-like symptoms. Hypertension is common and can
cause encephalopathy and headache,
disorientation and sometimesconvulsions also occur.
Iron deficiency can be induced as
more iron is required for enhancederythropoiesis.
8/2/2019 Anaemia Presentation MNH
38/75
Blood viscosity increases as the
haematocrit of the blood rises andincreasing the risk of thrombosis
especially during dialysis.
2 Colony stimulating factors:These stimulate the formation of
maturing colonies of leucocytes in
semi solid medium in vitro.
8/2/2019 Anaemia Presentation MNH
39/75
Colony stimulating factors not only stimulate
particular committed progenitor cells to proliferate,
but also cause irriversible differentiation. (a) Granulocyte colony stimulating factor(G-CSF)
eg Filgrastim, Lenograstim.
(b) Granulocyte-macrophage colony stimulating
factor (GM-CSF) eg Molgrasmostim is available foruse clinically.
8/2/2019 Anaemia Presentation MNH
40/75
Actions.
GM-CSF stimulates the development
of progenitors of neutrophils,monocytes, eosinophils and (undersome circumstances) megakaryocytesand erythrocytes.
It also enhances the functional activityand survival of the mature cells.
GM-CSF may increase the production
of other cytokines.
8/2/2019 Anaemia Presentation MNH
41/75
G-CSF acts only on the neutrophil line
increasing the proliferation and
maturation of neutrophils.
It also stimulates their release from
bone marrow storage pools and
enhancing their function.
8/2/2019 Anaemia Presentation MNH
42/75
Pharmacokinetics:
GM-CSF and G-CSF are given s.c. ori.v. and both are well tolerated butbone pain occurs in 10-20% of pts.
GM-CSF frequently produces fever,skin rashes, muscle pain and lethargy.There may be pain and reddening at
the site of injection.
8/2/2019 Anaemia Presentation MNH
43/75
G-CSF has produced mild dysuria(rare) and
reversible abnormalities in liver function tests.
Vasculitis has been reported with long term use.With i.v. infusion a syndrome of flushing,
hypotension, tachycardia, breathlessness, nausea
and vomiting and arterial oxygen desaturation has
occurred but can be reversed by oxygen and i.v.fluid administrtion.
8/2/2019 Anaemia Presentation MNH
44/75
Clinical uses of the colony-stimulating factors:
CSFs are used in specialist centres.
1. To reduce the severity and duration of
neutropenia induced by cytotoxic drgs during:-
-conventional anticancer chemotherapy
-intensive courses of chemotherapy that
damage haemopoietic tissue, necessitating
autologous bone marrow rescue
-following bone marrow transplant
8/2/2019 Anaemia Presentation MNH
45/75
2. To stimulate release into the
circulation of progenitor cells, whichcan then be harvested and infused
with, or instead of bone marrow cells
after high-dose, intensivechemotherapy.
3. To expand the number of harvested
progenitor cells ex vivo before re-infusing them.
8/2/2019 Anaemia Presentation MNH
46/75
4. For persistent neutropenia in
advanced HIV infection.5. They may have a role in treatment
of aplastic anaemia.
8/2/2019 Anaemia Presentation MNH
47/75
8/2/2019 Anaemia Presentation MNH
48/75
THE MOST USEFULL INDICES ARE
1.MCV-mean volume of the red cells & normal range 80-96fl
` Microcytic ifMCV96fL
` Normocytic 80-96fL
2.RDW -is reflection of availability in the size of RBC and
with the proportional to the standard deviation of the
MCV.
` An elevated RDWindicate increased variability of RBC
size.3.MCH-describe the concetration of Hb in each cell.
` Elevation level indicate_spherocytes or
hemoglobinopathy.
8/2/2019 Anaemia Presentation MNH
49/75
4.RETICULOCYTECOUNT-measures the % of
immature RBC in the blood and reflect the bonemarrow(BM)response to anemia.(i.e.bone marrow
response to anemia is to increase production of
RBC there fore the R is increased).
` Normal R is ~1%` In anemia or blood loss BM should increse
production ofRBC in proportion to loss of
RBC,there fore 1% R count in anemia is
inappropiate.
8/2/2019 Anaemia Presentation MNH
50/75
5. RETICULOCYTE INDEX(RI)
Calculated as R% actual Hct/normal Hct,and is
important in determining if patients BM isresponding appropiately to the level of anemia.
` Normal 1.0-2.0
` RI2 with anemia-indicate hemolysis or loss of
RBCs-laeding to inreased compeensatory
production ofR(hypoproliferative anemia)
6.PERIPHERAL SMEAR-Necessary part of innitial
hematologic evaluation.shape,size,presence of
inclusions,orientation of cells to each other.
8/2/2019 Anaemia Presentation MNH
51/75
1.A BM BIOPSY
` Indicated in case of normocytic anemias with low
R without identifiable cause or anemia associated
with other cytopenias.` The biopsy may confirm myelophthisic process(i.e.
presence of tear drop or fragmented
cells,normoblasts,or immature WBCs on
peripheral blood smear) in setting of pancytopenia
8/2/2019 Anaemia Presentation MNH
52/75
1.Mng of anemias with derceased RBC production.` Microcytic anemia
` Thalassemia
` Myelodysplastic syndrome
` Sideroblastic anemia` Macrocytic/megaloblastic anemia
` Anemia with chronic renal insuficiency
` Anemia of chronic disease
` Anemia in cancer patients
` Anemia associated with HIV infection
` Aplastic anemia
8/2/2019 Anaemia Presentation MNH
53/75
2.Anemia associated with incresed RBC destruction
The anemia associated with increased
erythropoiesis(elevated reticulocyte count).caused
by bleeding(much more common) orHemolysis,and my exceed the capacity of bone
marrow to correct Hb.
` Sicklecell disease
` G6PD Deficiency` Drug induced hemolytic anemia
` Miroangiopathic hemolytic anemia
8/2/2019 Anaemia Presentation MNH
54/75
3. Approach to transfussion therapy
1.General principles
` Indication/containdication
` Manipulation of blood product` Procedure
2.Special consideration
3.Complications
8/2/2019 Anaemia Presentation MNH
55/75
Indication/contraindicationRBC T is indicated to increase the oxygen-carrying capacity of
blood in anemic patients.
Transfusion threshold in general
-Hb 7-8g/dl with no cardiac risk
-Hb 10g/dl with Hx of coronary artery disease or risk of ischemia-all children with Hct12% or Hb 4g/dl
-less severely anemic children with Hct 13-18% and Hb 4-6g/dl
with ant of the following
*clinical detectable dehydration
*shoch*impared consciousness
*deep and laboured breathing
*Verry high malaria parasitemia>10% of RBC with parasite
8/2/2019 Anaemia Presentation MNH
56/75
1 unit of RBCs increases Hb level by 1g/dl in the average
adult.
If cause of anemia iseasly treatable(e.g iron or folic acid
deficiency) and no CVSor cardiopulmonary compromise
is present,it is preferable to avoid transfusion.
8/2/2019 Anaemia Presentation MNH
57/75
Pretransfusion` dispensed for a pt.Type and screen procedure
tests the recipients RBCs for the A,B & D(Rh)Ag
and also screen the recipients serum for
antibodies against other RBC Ag` Cross matching tests the Pts serum for antibodies
against Ag on the donors RBCs is performed
before specific unit of blood is dispensed for a pt.
8/2/2019 Anaemia Presentation MNH
58/75
Manipulation of blood product
1.Leukoreduced
` Prevent formation of platelet alloantibodies.
2.Irradiation-eliminate immunological
component.used in pt with imminocompromisedBM or organ transplant recipient,pt receiving direct
donation from HLA matched donors or first
degree relatives
3.Washed RBCs .-rare indicated should beconsidered when in patient whom plasmaproteins
may cause serious reaction.(Ig-deficient pt or
other anaphylactic reaction)
8/2/2019 Anaemia Presentation MNH
59/75
1.Long term RBC transfusion therapy
` For >20 unts of RBC-Iron chelation therapy
` To epand RBC antigen pannel to decrease the risk
of RBC alloimmunization and delayed hemolytic
transfusion reaction.2.Emergency RBC therapy used only in situation in
which massive blood loss has resulted in
cardiovascular compromise-
` But volume expansion with NS should attemptedinitially.
` If unmatched blood must be used,should be group
O/Rh ve that have been screened for reactive
antbody.
8/2/2019 Anaemia Presentation MNH
60/75
2.Pt who are unwilling to receive RBC
transfussion(e.g Jehovas Witness)
` Epo is of benefit
`
Use of orl and parenterol Iron
8/2/2019 Anaemia Presentation MNH
61/75
1.Transfusion-transmited infections
` HIV1/2,T-lymphotrophic virus type ,epatitis B&
C,Syphilis and West Nile Virus.
` CMV transmision from RBC and Platelets
transfusion is an important risk in
immunocompromised patients.
2.Hemolytic transfusion reaction
` Acute hemolytic reaction
*Mgm-urine output mintained or equal to 7.5
8/2/2019 Anaemia Presentation MNH
62/75
1.Caused by either a primary or amnestic antibody
response to specific RBC antigen or donor RBC
.pt with IgA deficiency who receive IgA containing
blood productMGN similar as acute.
2.Nonhemolytic febrile transfusion(fevers & chils)
` Decrease incidence with leucoredused product
` The cause is release of cytokines from WBCs
8/2/2019 Anaemia Presentation MNH
63/75
` Mng.
` Acetminophen and Prestorage leucoredused
blood products.
`
Pretretment with glucocorticoids and WBCs orvolume reduced platelets.
8/2/2019 Anaemia Presentation MNH
64/75
` If volume overload is suspected esp in pts with
CHC and cardiovascular overload he IV diuretics
should be used.
` Transfusion related acute lung injury(TRALI)
occurs 4hrs after BT
Cause
Ant-human leucocyte antgen (HLA)or
antgranulocyte antibodyDespite clinical or radiologic findings suggesting
edema data indicate that diuretics have no role
and may be detrimental.
8/2/2019 Anaemia Presentation MNH
65/75
` More common to immunocompromised
patientsdue to result of immunocompetent T
lymphocyte(I pts who share HLA haplotype with
HLA homozygous blood donors(esp close relative
or members of inbred pop)
` Mortality >80%
` Irrariation of blood broduct it prevent the disease
8/2/2019 Anaemia Presentation MNH
66/75
Administration ofblood products >than the normal
blood volume of pt over 24hrs
` Hypothermia
`
Hypocalcemia(mgn calcium gluconate 10ml of10%)
` Hypercalaemia
` Hypokalaemia
` Bleeding complication
8/2/2019 Anaemia Presentation MNH
67/75
` Oral iron therapy
*ferrous sulphate
*ferrous gluconate
*ferrous fumarate
*vit C` Parenterol iron therary
*iron dextran
*sodium ferric gluconate(ferrlecit)
*iron sucrose(venofer)
8/2/2019 Anaemia Presentation MNH
68/75
` No specific rx
` In sevse form of disease RBC transfusion
` Chelation therapy
` Splenectomy(.2units/mo)
8/2/2019 Anaemia Presentation MNH
69/75
` 5-azathitidine
` Decitabine
` Immunosupresive therapy withantthymopacyte
globulin,cyrosporin,glucocoprticoid
8/2/2019 Anaemia Presentation MNH
70/75
` Removal of possible offending agent
` pyridoxine
8/2/2019 Anaemia Presentation MNH
71/75
` Replace the deficient factor
` Potasium suplements
` Folic acid
` Cyanocobalamin for vit B12 deficiency
8/2/2019 Anaemia Presentation MNH
72/75
Erythropoiesis stimulating agents(ESAs)
` Epoetin alfa
` Darbepoetin alfa
The aboe also used in` Chemotherapy induced anemia
` Anemia associated with HIV infection(IV
immunoglobulin G in suspected case of
mycobacterium avium complex Dx established inbone marrow)
` Anemia of chronic dse
8/2/2019 Anaemia Presentation MNH
73/75
` Discontiue suspected offending drug
` Immunosuppessive Rx with
cyclosporin,glucocorticoids,antthymocyte globulin
`
Stem cell transplant` RBC transfussion kept at minimum.But platelet
transfussion recommended.
8/2/2019 Anaemia Presentation MNH
74/75
` Transfusion has no role in RX of uncomplicated
vaso-oclusive crises
` Hydroxyurea therapy(increase level of HbF)
`
Acute chest syndrome-require aggressivetransfusion therapy including red cell exchange.
` Iron chelation therapy
8/2/2019 Anaemia Presentation MNH
75/75
` Glucocorticoids
` IVIG less effective than ITP
` Splenectomy for steroid resistant
` Rituximab` Plasma exchange (for COLD IgM)
` RBC transfusion(for warm IgG) only in decreased
oxygen carryng capacity.,6g/dl
Top Related