haemolytic anaemia
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Haemolytic Anaemia
Prof Preethika Angunawela
www.usmlemcq.com
*Haemolysis ?
The destruction of red cells
*Mean life span of a red cell
120 days
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Aged red cell-*Changes on the surface membrane
*Decrease in enzyme activity
• Signals it’s incapacity to the RE system
• Macrophages of the RE system remove it (bone marrow, liver ,spleen)
• 1% of the red cells are destroyed & replaced by new cells each day
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Breakdown of normal red cells Haemoglobin
Haem Globin
Iron Protoporphyrin Amino acids
Transferrin CO Bilirubin (free)
Erythroblast conjugation (liver)
secreted in bile www.usmlemcq.com
Haemolytic Anaemia-
Those anaemias which result from an increase in the rate of red cell destruction
*Haemolytic state can exist without anaemia (compensated haemolytic disease)
*normal adult marrow can produce 6-8 times the normal rate.
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1.Erythroid hyperplasia- Increase in the proportion of cells committed to erythropoeisis in the marrow (brings out immature cells-reticulocytes)
2.Expansion of the volume of active marrow
When the haemolysis exceeds the compensatory capacity of the marrow
Haemolytic anaemiawww.usmlemcq.com
Haemolytic anaemias
1.Extra vascular- breakdown of red cells in the RE system (commoner than 2.)
2.Intra vascular- breakdown of red cells within the circulatory system (liberation of haemoglobin)
Causes of IV haemolysis
• Oxidant stress (G6PD)• Cold auto immune• Red cell fragmentation synromes MAHA• Drug induced• Infections• ABO,Rh incompatibility
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Haemolytic anaemias1.Intra corpuscular breakdown of red cells due to a defect in the cell. (almost all are Congenital. except-PNH)
2.Extra corpuscular- breakdown of red cells due to an external cause. (Acquired)
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Anaemic patient
Haemolytic?
Extravascular or Intravascular?
Cause?
Clinical history
Examination
Investigations
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Clinical signs & symptoms of haemolysis
Anaemia Jaundice Dark urine (urobilinogen/haemoglobinuria) Abdominal pain Leg ulcers Precipitating factors-
drugs,infections,warm,cold Family history Hepatosplenomegaly
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Investigating a haemolytic anaemia
1.Increased red cell breakdown
*Haemoglobinaemia*Haemoglobinuria*reduced plasma haptoglobins*reduced plasma haemopexin*Methaemalbuminaemia*Haemosiderinuria*Increased plasma LDH*Increased unconjugated bilirubin*Increased urinary urobilinogen*51Cr labelled red cell survival
Hb
Haptoglobin kidney methaemoglobin
HbHp Hburia Ferrihaem
Hsuria haemopexin albumin
liver HbHpx Mth- alb
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Investigating a haemolytic anaemia
1.Increased red cell breakdown
*Haemoglobinaemia*Haemoglobinuria*reduced plasma haptoglobins*reduced plasma haemopexin*Methaemalbuminaemia*Haemosiderinuria*Increased plasma LDH*Increased unconjugated bilirubin*Increased urinary urobilinogen*51Cr labelled red cell survival(gold standard)
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2.Increased red cell production
*Reticulocytosis (if severe, normoblasts also +)
*Erythroid hyperplasia in bone marrow
3.Abnormal red cells in blood picture
*Spherocytes*Sickle cells*Fragmented cells
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Classification of Haemolytic anaemias
Inherited
Membrane defect1.Hereditary spherocytosis 2.Hereditary elliptocytosis Enzyme defect1.G6PD deficiency2.Pyruvate kinase def
Haemoglobin defects1.Thalassaemias2.Haemoglobinopathies-HbS,HbC
Acquired
Immune1.Autoimmune*warm Ab*cold Ab2.Alloimmune*Transfusion rn
*HDN
3.Drug induced*Quinine *M.dopa cont.
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Classification of Haemolytic anaemias cont.
Acquired
Non Immune1.Mechanical -March haemoglobinuria -Prosthetic heart valves
2.Micro-angiopathic haemolytic anaemia
3.Infections -Malaria -Clostridium welchii4.Burns5.Drugs -Dapsone6.PNH
-DIC-TTP-HUS
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14 year old boy
C/O - fever, yellow discolourationof eyes and abdominal pain – 2 weeks
O/E – Pale ++ , Icteric +, Spleen – 1cm
What are the first line investigations?
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Hereditary spherocytosis
Commonest hereditary haemolytic anaemia
Auto. Dominant Defect in structural protein – Spectrin Red cells lose membrane as they
circulate through the spleen & RE system – spherocytes
Die prematurely as they circulate through spleen
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H.S cont. Anaemia may present from infancy to old
age. may suddenly increase- Aplastic crisis Jaundice is typically fluctuating Splenomegaly + in most cases Pigment gallstones are frequent
Reticulocytosis + Microspherocytes in the blood picture
i
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Spherocytes
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H.S cont.Special tests *Coombs test negative (D/D autoimmune haemolysis) *Osmotic fragility increased + *autohaemolysis increased, corrected by glucose
Treatment *Splenectomy treatment of choice (avoided in early childhood- pneumococcal infection)
i
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Hereditary Elliptocytosis Auto. Dominant
Defective membrane glycoproteins
Clinically milder than HS
Elliptocytes in blood picture
Splenectomy needed occasionally
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G6PD deficiency Deficiency or functional inadequacy of
glucose 6 phosphate dehydrogenase enzyme.
Sex linked recessive
GSH GSSGGlucose
G6P 6PG
NADP NADPH
G6PD
Oxidantstress
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G6PD cont. Oxidant stress- primaquin, sulphonamides,
infections fava beans. Rapid intravascular haemolysis with
Hburia.Usually self limiting within 7 days. May present as neonatal jaundice High frequency in Mediterranean countries
and in South east Asia Blister and bite cells in the blood picture
with reticulocytosis Heinz bodies – 2nd to 10 th day
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Heinz bodies
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G6PD cont.Brewer test Nitrite oxidizes Hb to methHb, methylene
blue reduces it to oxyHb if HMP is intact
Enzyme assay
Treatment *Avoid precipitating factors *Symptomatic – blood transfusions *Good hydration
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Pyruvate kinase deficiency Auto. Recessive Red cells are rigid due to reduced ATP
formation Prickle cells in blood film Auto haemolysis increased but not
corrected with glucose Enzyme assay to diagnose Splenectomy may alleviate the anaemia
but does not cure it
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Thalassaemias Reduced synthesis of normal globin chains Adult blood has- *HbA (2 alpha ,2 beta globin chains) *HbA2 (2 alpha ,2 delta) *HbF (2 alpha ,2 gamma) Alpha globins are coded by 4 genes (2 genes for
each globin chain)
alpha alpha alpha - (Thal)
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Thal cont.Beta globins are coded by 2 genes
beta beta beta - - -
normal Thal minor Thal major Thal inter.
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Thal cont. Reduction of alpha chains – alpha thal Haemolysis, Hb H (beta 4), Hb Barts
(gamma 4)
Reduction in beta chains – beta thal
Precipitation of alpha chains – ineffective erythropoeisis.
Excess alpha chains are mopped up by producing more gamma chains.Therefore increase in HbF (Thal major)
increase in HbA2 (Thal minor) www.usmlemcq.com
Hb Barts
Thal. minor
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Thal cont. Reduction of alpha chains – alpha thal Haemolysis, Hb H (beta 4), Hb Barts
(gamma 4)
Reduction in beta chains – beta thal
Precipitation of alpha chains – ineffective erythropoeisis.
Excess alpha chains are mopped up by producing more gamma chains.Therefore increase in HbF (Thal major)
increase in HbA2 (Thal minor) www.usmlemcq.com
Thal majorClinical features *severe anaemia at 3- 6 months after birth
*hepatosplenomegaly due to red cell destruction and extra medullary haematopoeisis
*expansion of bones –skull
*Iron overload –liver, pancreas, myocardium, thyroid, parathyroid, skin
*susceptibility to infection
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Thal major cont. Investigations
*blood film- hypochromic microcytic red cells, target cells, reticulocytes, normoblasts
*haemoglobin electrophoresis – almost complete absence of HbA, over 90% HbF.
*serum ferritin increased
*skull x-ray – hair on end appearance
i
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Thal major cont.
Treatment
*Regular transfusions Hb > 10g/dl (leucocyte
depleted washed packed cells)
* Folic acid
*Iron chelation (after 10-15 units of blood. Serum ferritin maintained
<1000micrograms/l Desferioxamine, Deferiprone
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Thal major cont.
Treatment
*Splenectomy may be required to reduce blood transfusions but delayed until 6
years of age
*Bone marrow transplant
*Gene therapy www.usmlemcq.com
Sickle cell anaemia
Synthesis of an abnormal Hb, HbS (alpha 2, betas 2) Substitution of valine for glutamic acid at
position 6 on the beta chain Hb forms insoluble crystals at low oxygen
tens. Red cells sickle and block the
microcirculation causing infarcts in various organs
Homozygous disease-severe haemolytic anaemia punctuated by criseswww.usmlemcq.com
Sickle cell anaemia cont.
Clinical features
*Painful crises- frequent, due to ischaemia.
Precipitated by infections, acidosis, dehydration.
Infarcts of bones, lungs, spleen(small spleen),
brain
*Haemolytic crises- fall in Hb, rise in retic count www.usmlemcq.com
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Sickle cell anaemia cont. Clinical features
*Aplastic crises- fall in Hb, fall in retic count (parvo virus or folate def)
*Visceral sequestration- severe chest syndrome, commonest cause of death
*leg ulcers
*pigment gall stones
*priapism www.usmlemcq.com
Sickle cell anaemia cont. Investigations
*Hb 6-9g/dl.low in comparisson to symptoms of anaemia as HbS shifts the dissociation curve to the right.
*Sikcle cells & targets in the blood film
*positive sickling test
*HbS band on elecrophoresis
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Sickle cell anaemia cont. Investigations
*Hb 6-9g/dl.low in comparisson to symptoms of anaemia as HbS shifts the dissociation curve to the right.
*Sikcle cells & targets in the blood film
*positive sickling test
*HbS band on elecrophoresis
i
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Sickle cell anaemia cont. Treatment
*Avoid precipitating factors
*Hydration
*good nutrition & hygiene
*Blood transfusions
*drugs to enhance HbF (hydroxyurea,Azactydine)
*Bone marrow transplantwww.usmlemcq.com
Haemoglobin ECommonest Hb variant in South east
asia
Alpha 2, beta26glu—lys 2.
Microcytic hypochromic anaemia with targets.
HbE band on electrophoresis
May remain undetected www.usmlemcq.com
Warm autoimmune haemolytic anaemia
Antibodies optimally active at 370. IgG
Causes*Idiopathic*secondary
SLECLLLymphomasDrugs- Methyl dopa
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Warm autoimmune haemolytic anaemia cont.
Pathogenesis IgG antibodies are present on the red
cells, some of them also bind complement(C3)
Red cells are destroyed mainly in the RE system (preferentially spleen)
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Warm autoimmune haemolytic anaemia cont.
Clinical featuresHaemolytic anaemia JaundiceSplenomegaly
InvestigationsReticulocytosisSpherocytes Increased serum bilirubinPositive direct coomb test
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Warm autoimmune haemolytic anaemia cont.
TreatmentCorticosteroids
Splenectomy
Immunosuppresives- Azathioprine
Folic acid
Treat underlying causewww.usmlemcq.com
Cold autoimmune haemolytic anaemia Auto antibodies (IgM) that react best
at temp. <370 (0-40)
Causes*Idiopathic (CHAD)*secondary
MycoplasmaInfectious mononucleosisLymphomaSLE
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Cold autoimmune haemolytic anaemia cont.
Clinical featuresSome have acute IV haemolysis &
Hburia in cold weather but maintain a normal Hb in warm weather
Others have a compensated chronic haemolysis with a mild to moderate reduction of Hb.
Acrocyanosis, Raynauds phenomenon due to agglutinates.
Spleen may not be enlarged www.usmlemcq.com
Cold autoimmune haemolytic anaemia cont.
Investigations
Anaemia with red cell agglutinatesMacrocytosisReticulocytosisPositive direct coomb testFeatures of IV haemolysis
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Cold autoimmune haemolytic anaemia cont.
Treatment
Avoid coldMay need blood transfusionsPlasmapheresis has been usedCorticosteroids and splenectomy are
rarely of any benefit
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ABO & Rh incompatibiltyHaemolytic transfusion reactions may
be immediate or delayed.
Immediate life threatening reactions associated with massive IV haemolysis is seen with complement activating antibodies of IgM & IgG classes(ABO antibodies)
Severity of the reaction depends on the recipient’s titre of antibody
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ABO & Rh incompatibilty cont.
Extra vascular haemolytic transfusion reactions are seen with the immune antibodies( IgG, unable to bind complement).
The only feature may be unexplained anaemia with jaundice
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14 year old boyC/O - fever, yellow discolourationof eyes and abdominal pain – 2 weeks
O/E – Pale ++ , Icteric +, Spleen – 1cm
What are the first line investigations?
Hb- 9g/dl, Retic count- 6%,S.Bilirubin – 2.5mg/dl Urine urobilinogen – normalCoombs test – NegativeWhat is the D/D, What further investigations toConfirm the diagnosis?
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Mechanical haemolytic anaemiaRed cells may be injured by excess
physical trauma as they circulate through the vascular system.
Cardiac – Occasional complication of open heart surgical procedures eg. valve prostheses.In severe cases marked anaemia with intravascular haemolysis.
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Mechanical haemolytic anaemiaMarch haemoglobinuria – Hbnaemia &
Hburia following strenuous exercise in healthy young adult males.
soldiers,athletes,karatekas. Traumatic effect on the blood within
vessels of sole.
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Microangiopathic haemolytic anaemiaMechanical haemolytic anaemia in
which the red cell fragmentation is due to contact between red cells & abnormal intima of partly thrombosed, narrowed, or necrotic small vessels.
1.Disseminated intravascular coagulation2.Haemolytic uraemic syndrome3.Thrombotic thrombocytopaenic purpura
Associated thrombocytopaeniawww.usmlemcq.com
DICDue to widespread intra vascular
coagulation induced by pro coagulants that overcome the natural anti coagulant mechanisms with formation of thrombin.
These pro coagulants may be produced in the blood or introduced from out side the circulatory system.
This results in-www.usmlemcq.com
DIC cont.Formation of micro thrombi
Ischaemia
Consumption of platelets & clotting factors
BleedingCauses
*Trauma*Cancers*Bacteraemia*Haemorrhage*Obstetric & surgical events
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DIC cont.InvestigationsFragmented red cells
Low platelet count
Prolongation of PT, aPTT, TT,
Elevated FDP, D dimerswww.usmlemcq.com
HUS-TTP Initially described as two distinct
entities but now thought to be two points in the same spectrum
Formation of platelet thrombi (hyaline thrombi) in terminal arterioles & capillaries.
Microangiopathic haemolytic anaemia with Thrombocytopaenia
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HUS-TTPPathogenesisPresence of abnormal vwf (platelet
adhesion)Deficiency of vwf cleaving proteases Increase in vwf activity, platelet
aggregationMicrothrombi formation
Clinical featuresFeverNeurological symptomsRenal failure www.usmlemcq.com
HUS-TTPInvestigationsRed cell fragmentationLow platelets Increase in indirect bilirubin Increase in LDHNo alteration of clotting profile
CausesE.Coli o157 toxinShigella dysenteriaeDrugs- Quinine, Cyclosporine A
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HUS-TTPTreatmentPlasma exchange
Glucocorticoids
Antiplatelet drugs- Dextran
Platelets not given
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InfectionsMalaria – anaemia is often only mild
*can be severe esp.with falciparum infections
*Blackwater fever rare but serious complication, seen in endemic areas & in those who have repeated attacks. Pptd by antimalarial drugs.
*Diagnosis by demonstrating the parasite
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InfectionsClostridium welchii – due to direct action
of toxin*mostly post abortal or puerperal infections
*Intra vascular spherocytic anaemia, retic count
not very high
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DrugsDue to direct toxic effects in normal
subjects*Sulphasalazine
Haemolysis in subjects with metabolic abnormality G6PD def*primaquine, nitrofurantoin
Due to a immune mechanism*Quinine, Penicillin, Sulphonamides
Toxins – Snake bite www.usmlemcq.com
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