1. HEREDITARY/ACQUIRED HEMOLYTIC ANEMIA

2. HEMOLYTIC ANEMIAS Hemolytic anemias = reduced red-cell life span

3. Classification of Hemolytic anemias I
Classification of Hemolytic anemias I. Red cell abnormality (Intracorpuscular factors) A. Hereditary Membrane defect (spherocytosis, elliptocytosis) Metabolic defect (Glucoze-6-Phosphate Dehydrogenaze (G6PD) deficiency, Pyruvate kinase (PK) deficiency) Hemoglobinopathies (unstable hemoglobins, thalassemias, sickle cell anemia ) B. Acquired Membrane abnormality-paroxysmal nocturnal hemoglobinuria (PNH)

4. II. Extracorpuscular factors A. Immune hemolytic anemias 1
II. Extracorpuscular factors A. Immune hemolytic anemias Autoimmune hemolytic anemia caused by warm-reactive antibodies caused by cold-reactive antibodies Transfusion of incompatible blood B. Nonimmune hemolytic anemias Chemicals Bacterial infections, parasitic infections (malaria), venons Hemolysis due to physical trauma hemolytic - uremic syndrome (HUS) thrombotic thrombocytopenic purpura (TTP) prosthetic heart valves Hypersplenism

5. SOME TYPES OF HHA eg. SICKLE CELL DISEASE THALASSEMIAS G6PD DEFICIENCY
HEREDITARY SPHEROCYTOSIS

6. THALASSEMIAS MICROCYTIC, HYPOCHROMIC, HEMOLYTIC ANEMIA
MOST COMMON IN AFRICAN, MEDITERRANEAN, MIDDLE EASTERN, & SOUTHEAST ASIAN DESCENT
MULTIPLE VARIANTS

7. THALASSEMIAS
CHARACTERIZED BY DEFECTIVE SYNTHESIS OF GLOBIN CHAINS, UNABLE TO PRODUCE NORMAL ADULT HEMOGLOBIN
TRAIT THOUGHT TO BE PROTECTIVE AGAINST MALARIA AS WELL

8. HEMOGLOBIN
NORMAL ADULT RBC CONSISTS OF 3 FORMS OF Hb: HbA - 2 α and 2 β globin chains HbA2 – 2 α and 2 δ globin chains HbF - 2 α and 2 γ globin chains
THALASSEMIAS α and β

9. THALASSEMIAS TYPES OF DZ CHARACTERIZED BY DEFFERING EXTREMES OF ANEMIA
DEPENDS ON AMOUNT OF INEFFECTIVE ERYTHROPOIESIS AND PREMATURE DESTRUCTION OF CIRCULATING RBC’S
HYPOXIA IN SEVERE CASES

10. G6PD DEFICIENCY MOST COMMON HUMAN ENZYME DEFECT X-LINKED DISORDER
AFFECTS 15% OF U.S. BLACK MALES
DECREASE IN GLUTATHIONE LEVELS

11. G6PD DEFICIENCY HEINZ BODIES SEEN ON PERIPHERAL BLOOD SMEAR
NEONATAL JAUNDICE 1-4 DAYS AFTER BIRTH IN SEVERE VARIANTS
INCREASE INCIDENCE OF PIDMENTED GALLSTONES AND SPLENOMEGALY

12. G6PD DEFICIENCY
ACUTE HEMOLYTIC CRISIS DUE TO: BACTERIAL/VIRAL INFECTION OXIDANT DRUGS (SULFAMETHOXAZOLE) METABOLIC ACIDOSIS (DKA) RENAL FAILURE INGESTION OF FAVA BEANS

13. G6PD DEFICIENCY DIAGNOSIS – QUANTITATIVE ASSAY DETECTING LOW ENZYME
TREATMENT – SUPPORTIVE AND PREVENTATIVE

14. HEREDITARY SPHEROCYTOSIS
RBS MEMBRANE DEFECT
MOST COMMON HEREDITARY ANEMIA FROM PTS OF NORTHERN EUROPEAN DESCENT
AUTOSOMAL DOMINANT
MUTATIONS IN SPECTRIN AND ANKYRIN (MEMBRANE PROTEINS)

15. HEREDITARY SPHEROCYTOSIS
SPHEROCYTES – IN PERIPHERAL BLOOD SMEAR
SPHEROCYTES UNABLE TO PASS THROUGH THE SPLEEN
SEVERE CASES REQUIRE A SPLENECTOMY

16. HEREDITARY SPHEROCYTOSIS
NEONATAL JAUNDICE IN 1ST WEEK OCCURS IN 30-50% OF HS PTS
ANEMIA, SPLENOMEGALY, JAUNDICE, AND TRANSFUSIONS NEEDED VARY DEPENDING ON SEVERITY OF DZ

17. Hereditary microspherocytosis 1
Hereditary microspherocytosis 1. Pathophysiology - red cell membrane protein defects (spectrin deficiency) resulting cytoskeleton instability 2. Familly history 3. Clinical features - splenomegaly 4. Laboratory features - hemolytic anemia - blood smear-microspherocytes abnormal osmotic fragility test positive autohemolysis test prevention of increased autohemolysis by including glucose in incubation medium 5. Treatment splenectomy

18. Sickle-Cell Anemia

19. Hemoglobin Composed of: 1 Heme and 4 Globin Chains
4 Types of Globin Chains:
Alpha, Beta, Delta, Gamma

20. Sickle Cell Disease Cannot make Beta Chains
Valine substituted for glutamate in 6th position of beta chain

21. Sickle Cell Disease Affects people of African descent
Affects 72,000 people in the US
2 million people are carriers
Occurs once in every 375 African American births

22. Sickle Cell Anemia
Sickle Cell anemia is an inherited red blood cell disorder. Normal red blood cells are round like doughnuts, and they move through small blood tubes in the body to deliver oxygen.
Sickle red blood cells become hard, sticky and shaped like sickles used to cut wheat. When these hard and pointed red cells go through the small blood tube, they clog the flow and break apart. This can cause pain, damage and a low blood count, or anemia.

23. The origin of the disease is a small change in the protein hemoglobin
The change in cell structure arises from a change in
the structure of hemoglobin.
A single change in an amino acid causes hemoglobin
to aggregate.

24. Hemoglobin is a carrier protein
HbO2
CO2
deoxy Hb (CO2)
Tissues
Lungs

25. Hemoglobin changes structure for efficient oxygen uptake and delivery
HbO2
deoxy Hb (CO2)
Strong binding state
R state
Weak binding state
T state

26. The small change in hemoglobin structure leads to aggregation
Subunits
Normal hemoglobin (Hb A)
Sickle cell hemoglobin (Hb S)

27. Genetic Inheritance

28. Symptoms in Children Start to appear at 6 months
Dactylitis (swelling of hands and feet)
Heart Enlargement
Growth Retardation
Delayed Sexual Development

29. Dactylitis

30. Sickle Cell Crisis Severe pain caused by blocked blood flow
Triggered by Infection, Dehydration, Fatigue, or Emotional Stress
Can last up to 5 days

31. Splenic Sequestration
Spleen tried to remove abnormal cells
Becomes enlarged and causes pain
Autosplenectomy occurs
Usually not seen in adults

32. Symptoms of Anemia Tiredness Headaches Dizziness Faintness
Shortness of breath

33. Other Symptoms Chronic, low-level pain in joints and bones
Abdominal pain
Retina Damage
Gallstones
Leg Ulcers (adults)
Chest pain

34. Leg Ulcers

35. Blood Picture Sickle, Target and/or nRBCs Decreased Hemoglobin
Increased retic count
White cell count increased
WBC shift to the left

37. Hgb Electrophoresis
Amino acids in globin chains have different charges
Separates hemoglobin according to charge
90% Hgb S, 10% Hgb F, small fraction of Hgb A2

39. Prognosis No cure Life expectancy: 42 years men 48 years women
85% reach the age of 20
50% reach age 50
Causes of death:
Infection, heart failure

40. Treatment Pain Medication Increase fluids Blood Transfusion
Bone Marrow Transplant

41. Acquired Hemolytic Anemia

42. Introduction Increased RBC Destruction –
Short RBC life span <120 days.
Normocytic normochromic, reticulocytosis
Anemia, Jaundice, marrow hyperplasia
Splenomegaly, bilirubin gall stones
Unconjugated “acholuric” (pale urine)
Common types - AIHA, MAHA

43. Types of acquired HA AutoImmune Haemolytic Anemias (+ve DAT)
Alloimmune haemolytic anemias
Drug-induced immune haemolytic anemias
Red cell fragmentation syndromes
Infections
Chemical & physical agents
Secondary Haemolytic anemias
Paroxysmal Nocturnal Haemoglobinuria (PNH)

44. Pathogenesis of Jaundice:
Hb Globin-Iron-Haem Bilirubin 
Glucoronide–Conjugation  Bile  Gut
Stercobilinogen & Stercobilin (ex.in stool)
Urobilinogen & Urobilin (ex. In urine)

45. Ketabolism of Hb:

46. Classification : Auto Immune AIHA - Alloimmune Non-Immune
Warm antibody type
Cold antibody type
Alloimmune
Transfusion reactions
Hemolytic disease of new born
Non-Immune
Microangiopathic hemolytic anemia
Infections – Malaria, clostridia,
Burns, Toxins, snake & spider bites.

47. Laboratory Diagnosis:
RBC Breakdown:
Hyperbilirubinemia
Urobilinogen, stercobilinogen
serum haptoglobins
RBC Production:
Reticulocytosis, *MCV
Marrow hyperplasia*
Damaged RBC
Morphology, fragility, survival

48. Laboratory Diagnosis:
Additional features of Intravascular Hemolysis:
Hb-naemia and Hb-nuria
Haemosiderinuria
Methaemoglobinemia

49. DRUG RELATED HA ALPHA-METHYLDOPA LEVODOPA PROCAINAMIDE SULFA DRUGS
PENICILLIN
CEFTRIAXONE
CEFOTETAN
QUINIDINE

50. MICROANGIOPATHIC SYNDROMES
THROMBOCYTOPENIC PURPURA
HEMOLYTIC UREMIC SYNDROME

51. TTP & HUS - PATHOPHYS
PLATELET AGGREGATION IN THE MICROVASCULATURE CIRCULATION VIA MEDIATION OF von WILLEBRAND’S FACTOR LEADS TO THROMBOCYTOPENIA AND FRAGMENTATION OF RBC’S AS THEY PASS THROUGH THESE OCCLUDED ARTERIOLES AND CAPILLARIES

52. THROMBOCYTOPENIC PURPURA (TTP)
PLATLET COUNTS < 20,000
MORE COMMON IN WOMEN AGES 10-60
FEVER, NEUROLOGIC DEFICITS, HEMORRAGE, AND RENAL INSUFFICIENCY
UNTREATED – 80-90% MORTALITY

53. TTP SCHISTOCYTES OR HELMET CELLS SEEN OF PERIPHERAL SMEAR
INCREASED BUN/Cr LEVELS

54. TTP PREGNANCY IS THE MOST COMMON PRECIPITATING EVENT FOR TTP
PREECLAMPSIA SIMILAR TO TTP; DELIVERY TX FOR PREECLAMPSIA, NOT CURE TTP

55. TTP – ER TREATMENT PREDNISONE 1-2mg/kg/day INITIALLY
PLASMA EXCHANGE TRANSFUSION IS FOUNDATION FOR TX (INFUSE FRESH FROZEN PLASMA IF TRANSFUSION UNAVAILABLE
AVOID PLATELET TRANSFUSION
NEVER USE ASPIRIN

56. TTP – ER TREATMENT PT MAY NEED SPLENECTOMY
AZATHIOPRINE AND CYCLOPHOSPHAMIDE FOR THOSE WHO FAIL OR CANNOT TOLERATE STEROIDS

57. HUS DZ OF EARLY CHILDHOOD PEAK INCIDENCE BETWEEN 6mo-4yr
OFTEN FOLLOWS BACTERIAL/VIRAL ILLNESS
MORTALILY 5-15%, WORSE IN OLDER CHILDREN & ADULTS

58. HUS
CHARACTERIZED BY ACUTE RENAL FAILURE MICROANGIOPATHIC HA FEVER THROMBOCYTOPENIA (NOT AS SEVERE AS TTP)

59. HUS THE MOST COMMON CAUSE OF ACUTE RENAL FAILURE IN CHILDHOOD
E.Coli O157:H7 COMMON CAUSE
MICROTHORMBI ARE CONFINED MAINLY TO KIDENYS, WHERE TTP MORE WIDESPREAD

60. HUS – ER TREATMENT
MILD HUS < 24hr OF URINARY SX NEELS ONLY FLUID/ELECTROLYTE CORRECTION AND SUPPORT CARE
STEROID THERAPY
HEMODIAYLSIS IF ACUTE RENAL FAILURE PRESENT
ABX TX CONTROVERSIAL WHEN E.Coli PRESNENT; DO NOT USE ANTIMOLITY DRUG, INCREASE RISK OF DEVELOP HUS

61. HELLP SYNDROME
HEMOLYSIS
ELEVATED LIVER ENZYMES
LOW PLATLET COUNTS

62. HELLP SYNDROME 1 IN 1OOO PREGNANCIES
SEEN IN PRESENCE OF ECLAMPSIA, PREECLAMPSIA, AND PLACENTAL ABRUPTION
MAY EXTEND UP TO 6 DAYS POSTPARTUM

63. HELLP SYNDROME
RUQ AND EPIGASTRIC PAIN – SEEN IN 90% OF PTS (POSSIBLE HEPATIC RUPTURE)
DX BASED ON LAB DATA
DECREASED SERUM HAPTOGLOBIN LEVEL MOST SENSITIVE

64. HELLP SYNDROME - TX PROMPT DELIVERY OF INFANT
SUPPORTIVE CARE FOR SEIZURES AND HTN CRISIS
STEROIDS MAY HELP FETAL LUNGS, BUT NO BENEFIT TO HELLP SYNDROME

65. Warm AIHA Cold Idiopathic Secondary Spherocytes IgG antibody, C3d
Autoimmune lymphoma, drugs
Spherocytes
IgG antibody, C3d
Direct Coombs - 37°
Anti c / anti e
Idiopathic
Secondary
Infections
Lymphoma
RBC clumps
IgM antibody
Cold Ag. Titre 4°
DAT +ve compl*
Anti I / i

66. Warm AIHA Cold Idiopathic Secondary Idiopathic Secondary PCH (anti-P)
SLE, Autoimmune disorders.
CLL
Lymphoma
Drugs – Mdopa.
Idiopathic
Secondary
Infections
Lymphoma
PCH (anti-P)

67. Warm AIHA IgG, C3d, rarely other Ab. Destruction in Spleen & RES
Loss of partial membrane – spherocytes
Clinical Features:
Spleenomegaly

68. Autoimmune hemolytic anemia caused by warm-reactive antibodies: I
Autoimmune hemolytic anemia caused by warm-reactive antibodies: I. Primary II. Secondary acute viral infections drugs ( -Methyldopa, Penicillin, Quinine,Quinidine) chronic rheumatoid arthritis, systemic lupus erythemat lymphoproliferative disorders (chronic lymphocytic leukemia, lymphomas, WaldenstrÖm’s macroglobulinemia) miscellaneous (thyroid disease, malignancy )

69. Autoimmune hemolytic anemia caused by cold-reactive antibodies: I
Autoimmune hemolytic anemia caused by cold-reactive antibodies: I. Primary cold agglutinin disease II. Secondary hemolysis: mycoplasma infections viral infections lymphoproliferative disorders III. Paroxysmal cold hemoglobinuria

70. Alloimmune Haemolysis:
Antibody from another person.
Transfusion reactions
Haemolytic disease of Newborn (HDN)
RH-D, RH neg mother, + father, 2nd baby Kleihauer test HbF,
ABO – IgG in O mother, mild*, 1st baby- agglutination & spherocytes, DAT neg/mild +
Post transplantation induced.

71. Paroxysmal nocturnal hemoglobinuria 1
Paroxysmal nocturnal hemoglobinuria Pathogenesis an acquired clonal disease, arising from a somatic mutation in a single abnormal stem cell - glycosyl-phosphatidyl- inositol (GPI) anchor abnormality - deficiency of the GPI anchored membrane proteins (decay-accelerating factor =CD55 and a membrane inhibitor of reactive lysis =CD59) - red cells are more sensitive to the lytic effect of complement intravascular hemolysis Symptoms - passage of dark brown urine in the morning

72. 3. PNH –laboratory features: - pancytopenia - chronic urinary iron loss serum iron concentration decreased hemoglobinuria - hemosiderinuria - positive Ham’s test (acid hemolysis test) - positive sugar-water test specific immunophenotype of erytrocytes (CD59, CD55) 4. Treatment: - washed RBC transfusion - iron therapy allogenic bone marrow transplantation

73. Microangiopathy:

74. Spherocytes:

75. AIHA Cold ab type: Clumping.

76. Assesment of HA Clinical features: - pallor - jaundice - splenomegaly

77. Laboratory features: 1. Laboratory features normocytic/macrocytic, hyperchromic anemia reticulocytosis increased serum iron antiglobulin Coombs’ test is positive 2. Blood smear anisopoikilocytosis, spherocytes erythroblasts schistocytes 3. Bone marrow smear erythroid hyperplasia

78. Diagnosis of hemolytic syndrome: 1. Anemia 2. Reticulocytosis 3
Diagnosis of hemolytic syndrome: Anemia Reticulocytosis Indirect hyperbilirubinemia

79. Autoimmune hemolytic anemia - diagnosis positive Coombs’ test Treatment: steroids splenectomy immunosupressive agents transfusion