HAEMOLYTIC ANAEMIADr. Hasan Fahmawi, MRCP(London), FRCP(Edin)

Consultant Physician

Haemolysis

• Definition – shortening of the normal red blood lifespan of 120 days• Increase in unconjugated bilirubin, increased urinary urobilinogen,• Increased LDH, reticulocytes, leucoerythroblastic blood film,

(thrombocytosis and neutrophilia, if marked immature granulocytesin the in the blood, producing leucoerythroblastic blood picture)

• Intravascular haemolysis, decrease haptoglobin, increasedmethaemalbumin, positive urine , haemoglobinuria and haemosiderin

• Compensatory erythroid hyperplasia may give rise to folate deficiencywith megaloblastic blood picture.

Clinically

• Pallor• Jaundice• Splenomegaly• We have to suspect haemolysis

Differential diagnosis of haemolysis

• Clinical scenario, family history.• Blood film• Coombs test for antibodies• Spherocytes are small dark red cells that suggest autoimmune

haemolysis or spherocytosis• Sickle cells• Red cell fragments indicate microangiopathic haemolysis• Bite cells suggests oxidative disorder

Intravascular and Extravascular haemolysis

• Extravascular – physiological haemolysis occur in the liver or spleen,avoiding Hb in the serum (predominant)

• Intravascular – less common, RBC wall damage due to complement• Free Hb. is toxic to cells, so haptoglobin is produced by the liver and

bind with free Hb. resulting in fall in it’s levels and when finished it isoxidized to form methaemoglobin which binds with albumin to formmethaemalbumin, if all protective mechanisms are saturated Hb.appear in the urine(haemoglobinuria), when fulminant this gives riseto black urine. Haemosiderinuria can occur if amount of Hb. is smalland reabsorbed by tubular cells.

RBC membrane defectHereditary Spherocytosis

• Abnormality in the cytoskeleton of the RBC, it loses elasticity and take abnormalshape, which is smaller more red cell, but shorter survival.

• Inherited as autosomal dominant 75%, the most common deficiency is of betaspectrin or Ankyrin, prevalence is 1:5000 and may be more, may be at any age.Severity of spontaneous haemolysis vary,

• Pigmented gall stones present in 50% and may cause symptomatic cholecystitis.• A heamolytic crisis, infection.• A megaloblastic crisis, due to folate deficiency, which might present in pregnancy• An aplastic crisis, parvovirus infection (erythrovirus).Patient present with severe

anaemia and low reticulocyte.• Diagnosis flow cytometry tests detecting binding of oesin-5-maleimide to red

cells.• Management – folic acid 5mg daily• Splenectomy which improves , but doesn’t normalize red cell survival.(above• 6 years ,Sepsis) .• Coombs –ve, as spherocytosis are present in haemolytic anaemia.

Red cell enzymopathy

• Mature RBC must produce energy via ATP to maintain a normalinternal environment and cell volume. ATP is produced by glycolysis.

• Hexose monophosphate shunt produce nicotinamide adeninedinucleotide phosphate NADPH and glutathione to protect againstoxidative stress.

• Defects in hexose monophosphate shunt pathway result in periodichaemolysis precipitated by episodic oxidative stress, while those inthe glycolysis pathway result in shortened RBC survival and chronichaemolysis.

G6PDD

• It is important in hexose monophosphate shunt, it affects 10% of thepopulation . Inheritance is X-linked, therefore it affects males andrare homozygous female, but it is carried by female. Heterozygousfemales are affected in the presence of skewed X-inactivation as well.

• Avoid drugs and Fava beans. Acute transfusion support might be lifesaving.

Autoimmune haemolytic anaemia

• This result from RBC destruction due to RBC autoantibodies, causingintravascular haemolysis, but if the complement is weak, thehaemolysis will be extravascular. Antibody coated red cells will losemembrane to macrophages in the spleen and hence Spherocytes arepresent in the peripheral blood.

• Warm antibodies – bind best at 37 C, account for 80% and majorityare IgG.

• Cold antibodies – binds best at 4 C, but can bind at 37 C. They areusually IgM, they account for 20% of cases.

Warm Autoimmune Haemolysis

• Incidence 1/100000 population per annum, more common in middleage and in females. No cause is found in 50% of cases.

• Blood film – haemolysis, Spherocytes, and polychromasia, andCoombs test is positive, which cab be negative in brisk haemolysis.

• Treatment – treat underlying cause, stop any underlying drug,

Cold Agglutinin Disease

• This is usually mediated by IgM antibodies, which bind to the RBC underlow temperature and cause them to agglutinate. It can be chronic when theantibody is monoclonal, or acute or transient when the antibody ispolyclonal.

• Chronic cold agglutinin disease – affects elderly patients and may beassociated with underlying low grade B- cell lymphoma.

• It cause a low-grade intravascular haemolysis with cold, painful and oftenblue fingers, toes, ears, or nose (acrocyanosis), the latter is due to RBCagglutination in the small vessels in these cold exposed areas .

• It can occur with mycoplasma pneumoniae or with infectiousmononucleosis.

Alloimmune haemolytic anaemia

• Unmatched blood transfusion

Non – immune haemolytic anaemia

• Endothelial damage - blood film shows disruption of red cellsmembrane, and RBC fragments, and markers of intravascularhaemolysis.

• Mechanical heart valve• March haemoglobinuria• Thermal injury• Microangiopathic haemolytic anaemia, disseminated carcinomatosis,• Malignant or pregnancy induced hypertension, haemolytic uraemic• syndrome, thrombotic thrombocytopenic purpura, and DIC.

• Infections - plasmodium falciparum malaria when severe it is calledblack water fever. Clostridium perfringens, usually in the context ofascending cholangitis or necrotizing fasciitis,

• Chemicals and drugs – Dapsone and sulfasalazine, arsenic gas, copper,chlorate, nitrites and nitrobenzene.

Paroxysmal Nocturnal Haemoglobinuria

• Episodes of intravascular haemolysis result in haemoglobinuria, mostnoticeable in early morning urine, which has a characteristic redbrown colour.

• It is associated with an increased risk of venous and arterialthrombosis in unusual sites, such as the liver or abdomen.

Haemoglobinopathies

• Affect the globin chains.• Two alpha globin chains, produced throughout life.• Two non-alpha globin chains.• Hb-A , Adult Hb, two Beta chains• Hb-F, Fetal Hb, two Gamma chains• Hb-A2 (constant, about 2%) is made from birth, two delta chains.• Qualitative abnormality - Hb S• Quantitative abnormality -Thalassemia

Sickle Cell Anaemia

• Single glutamic acid to valine substitution at position 6 of the beta globin(polypeptide chain).

• Inheritance autosomal recessive, homozygous produce abnormal B chain,Hb SS (Sickle cell disease), heterozygous produce normal and abnormal Bchains,

• Hb. AS (Sickle cell trait),which may result in sudden and cardiovasculardeath.

• When Hb. is deoxygenated the molecules polymerise to producepseudocrystaline structures(tactoids), these distort the RBC cellmembrane and produce sickle-shaped cells.

• Hb. C participates in the polymerisation, Hb. F strongly inhibit it.

Clinical features

• Sickling is precipitated by hypoxia, acidosis, dehydration and infection.Irreversible sickled cell has a shortened survival and plug themicrocirculation, sickle cell crises and organ damage.

• Painful vaso-occlusive crises, bone pain, infarcts, fat embolism,systemic response with tachycardia, sweating and fever.

• Stroke, children• Sickle chest syndrome, adult• Sequestration crisis, spleen, liver and priapism,• Aplastic crises, parvovirus B 19• Pregnancy

Management

• Analgesics• IV fluid• Transfusion, top-up transfusion and exchange transfusion• Oxygen.• Prognosis• 20% dead by age 20 years• 50% dead by age 40 years• SCA and surgery

Thalassaemias, B Thalassaemia

• Partial or complete failure to synthesise a specific type of globin chain• The most common is failure to synthesise B chain, B thalassaemia,

Homozygous - thalassaemia major, (failure to synthesise Hb A or, atbest, produce very little), heterozygous – minor

Frontal Bossing and Prominent Maxilla