HEREDITARY HAEMOLYTIC ANAEMIAS

1. HEREDITARY SPHEROCYTOSIS HEREDITARY HAEMOLYTIC ANAEMIAS BY DR. KAMAL E. HIGGY CONSULTANT HAEMATOLOGIST

3. HEREDITARY HAEMOLYTIC ANAEMIA • MEMBRANE DEFECTS * Hereditary Spherocytosis * Hereditary Elliptocytosis * Hereditary Stomatocytosis etc….

4. HEREDITARY HAEMOLYTIC ANAEMIA • METABOLIC DEFECTS: Deficiency of: * Glucose-6-phosphate dehydrogenase * Pyruvate kinase * Triose phosphate isomerase * Pyrimidine-5-nucleotidase * Glutathione synthetase etc….

5. HEREDITARY HAEMOLYTIC ANAEMIA • HAEMOGLOBIN DEFECTS: * Defective synthesis e.g. Thalassaemia (Alpha or Beta) * Abnormal variants e.g. Hb S, Hb C, Unstable Hb

6. GENETIC ABNORMALITIESOFTHE RED CELL MEMBRANE • Hereditary Spherocytosis • Hereditary Elliptocytosis • Hereditary Stomatocytosis • Hydrocytosis (high MCV, low MCHC) • Xerocytosis (low MCV, high MCHC shrunken RBCs due to K loss) • Acanthocytosis–Abeta-lipoproteinaemia

8. GENETIC ABNORMALITIESOFTHE RED CELL MEMBRANEHEREDITARY SPHEROCYTOSIS (HS) IMP = integral membrane proteinCS = cytoskeleton* as currently numbered on SDS – gels

9. PATHOGENESIS OFHEREDITARY SPHEROCYTOSIS (HS) Spherocytes Abnormal spectrin OF ? Spectrin genes Decreased spectrin in membrane Decreased Synthesis of spectrin Glucose requirement ? Gene for other membrane protein Decreased binding of spectrin Decreased deformability

10. HEREDITARY SPHEROCYTOSIS (HS) • DEFINITION: A congenital disorder which is characterized by: * spherocytes * increased osmotic fragility * autosomal dominant inheritance ( ! recessive ) * beneficial response to splenectomy

11. HEREDITARY SPHEROCYTOSIS (HS) The diagnosis of HS is not always easy since: * The degree of spherocytosis is variable * The changes in osmotic fragility are not always clear cut * Sporadic cases can occur * Other haemolyticanaemias may respond to splenectomy

12. HEREDITARY SPHEROCYTOSIS (HS) • Role of spleen: * Results post splenectomy - Decrease in the rate of haemolysis (ameliorates the degree of anaemia) - Decrease in the number of spherocytes (but can not cure the red cell abnormality) * Spleen is the major site of red cell destruction * RBCs retained for long time in the splenic pulp as a result of decreased deformability + Unfavorable environmental conditions in the splenic pulp (acid pH & decreased glucose) Failure of the cation pump Loss of water Loss of RBCs discoid shape Vicious circle

13. HEREDITARY SPHEROCYTOSIS (HS) Clinical Manifestations: • Most of the cases present in childhood or as teenagers • HS has been rarely diagnosed at: *Neonatal period (persistent jaundice) * The age of 60 (asymptomatic) • The disease has a wide spectrum of severity • The most consistent findings according to frequency are: * Jaundice * Splenomegaly * Anaemia

14. HEREDITARY SPHEROCYTOSIS (HS) Clinical Manifestations (cont…): • Haemolysis can be compensated for, with normal haemoglobin in about 1/3 of the patients • Patients may be more yellow than sick • Cholelithiasis is a complication of HS • HS as any other congenital haemolyticanaemia has a STEADY STATE andEPISODIC CHANGES

15. HEREDITARY SPHEROCYTOSIS (HS) Laboratory Tests and Findings: * Peripheral blood film\ > 1-2% spherocytes in significant * MCHC is increased or in the upper limit of normal range (due to decreased water content) * Increased osmatic fragility (O.F) Shift to the right of the entire curve or only part of it Draw backs of this test: - Laborious test - Needs fresh defibrinated blood - Not specific for HS (can be increased in AIHA) -Insufficiently sensitive (10-25%) of patients genetically proven to have HS have normal O.F) * Acidified glycerol lysis time. The rate of haemolysis (The time required for 50% lysis). Normal values > 1800 seconds) * Auto haemolysis (Screening test). 48 hours incubation under sterile conditions

16. HEREDITARY SPHEROCYTOSIS (HS) Spherocytes

17. HEREDITARY ELLIPTOCYTOSIS (HE) Elliptocytes

18. HEREDITARY STOMATOCYTOSIS (HST) Stomatocytes

19. HEREDITARY SPHEROCYTOSIS

20. HEREDITARY SPHEROCYTOSIS (HS)Autohaemolysis Test * In the more common forms of G6PD deficiency without chronic non spherocytichaemolyticanaemia (CNSHA) the autohaemolysis test is normal

21. HEREDITARY SPHEROCYTOSIS (HS) Differential diagnosis • IF SPHEROCYTOSIS is prominent: Acquired haemolyticanaemia DAT FAMILY DATA Red cell fragmentationfavours poikilocytosis microangiopathic process Fever may favor rare infectious cause for haemolysis (Clostridium welchii) • IF SPHEROCYTOSIS is not prominent with chronic course: PNH ---- Ham test – flowcytometry – molecular genetic Enzymopatheis ---- O.F. usually normal or decreased Autohaemolysis not corrected by glucose

22. HEREDITARY SPHEROCYTOSIS (HS) Complications • Leg ulcers • Gall stones (Often asymptomatic) • Aplastic crises

23. HEREDITARY SPHEROCYTOSIS (HS) Management • No cure • The aim is to minimize the consequences of the genetic abnormality • Splenectomy Avoid below the age of 5 years unless haemolytic anaemia is very severe (rare is HS) • Pneumococcal vaccination – (regular penicillin for at least 2 years) • Treatment of complication’s as arises

24. Different forms of elliptocytosis