Haemolytic Anaemia

Prof Preethika Angunawela

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*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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