HAEMOLYTIC ANAEMIA Dr. 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, (thrombocytosis and neutrophilia, if marked immature granulocytes in the blood, producing leucoerythroblastic blood picture)

• Intravascular haemolysis, decrease haptoglobin, increased methaemalbumin, positive urinary haemoglobinuria and haemosiderin

• Compensatory erythroid hyperplasia may give rise to folate deficiency with 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 occurs 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 Hb. is oxidized to form methaemoglobin which binds with albumin to form methaemalbumin, if all protective mechanisms are saturated Hb. appear in the urine(haemoglobinuria), when fulminant this gives rise to black urine. Haemosiderinuria can occur if amount of Hb. is small and reabsorbed by tubular cells.

RBC membrane defect Hereditary Spherocytosis

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

• Inherited as autosomal dominant 75%, the most common deficiency is of beta spectrin 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 normal

internal environment and cell volume. ATP is produced by glycolysis.

• Hexose monophosphate shunt produce nicotinamide adenine dinucleotide phosphate NADPH and glutathione to protect against oxidative stress.

• Defects in hexose monophosphate shunt pathway result in periodic haemolysis precipitated by episodic oxidative stress, while those in the glycolysis pathway result in shortened RBC survival and chronic haemolysis.

G6PDD

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

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

Autoimmune haemolytic anaemia

• This result from RBC destruction due to RBC autoantibodies, causing intravascular haemolysis, but if the complement is weak, the haemolysis will be extravascular. Antibody coated red cells will lose membrane to macrophages in the spleen and hence Spherocytes are present in the peripheral blood.

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

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

Warm Autoimmune Haemolysis

• Incidence 1/100000 population per annum, more common in middle age and in females. SLE, Ra, CLL, Multiple myeloma, Lymphoma, and drugs. No cause is found in 50% of cases.

• Blood film – haemolysis, spherocytes, polychromasia, and Coombs test is positive, which can 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 under

low temperature and cause them to agglutinate. It can be chronic when the antibody is monoclonal, or acute or transient when the antibody is polyclonal.

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

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

• It can occur with mycoplasma pneumoniae or with infectious mononucleosis.

Alloimmune haemolytic anaemia • Unmatched blood transfusion

Non – immune haemolytic anaemia

• Endothelial damage - blood film shows disruption of red cells membrane, and RBC fragments, and markers of intravascular haemolysis.

• 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 called black water fever. Clostridium perfringens, usually in the context of ascending 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, most noticeable in early morning urine, which has a characteristic red brown colour.

• It is associated with an increased risk of venous and arterial thrombosis 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 B chains,

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

• When Hb. is deoxygenated the molecules polymerise to produce pseudocrystaline structures(tactoids), these distort the RBC cell membrane 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 the microcirculation, 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, at best, produce very little), heterozygous – minor

Frontal Bossing and Prominent Maxilla