ANEMIA

1
Definition
• Anemia precisely defined as the absolute reduction in the number of
circulating RBC or reduction in RBC volume as determined by
measuring RBC volume or mass.
• RCM study & the above definition has the following shortcomings
• Not practical
• Not cost effective
• Not available

• Alternative definitions are designed.

2
• Anemia has been defined as a reduction in one or more of the major
red blood cell (RBC) measurements:
• Hemoglobin concentration
• Hematocrit, or
• RBC count

3
• Hemoglobin concentration (HGB)
• The concentration of the major oxygen-carrying pigment in whole blood.
• Values may be expressed as grams of hemoglobin per 100 mL of whole blood
(g/dL) or per liter of blood (g/L)
• Hematocrit (HCT)
• The percent of a sample of whole blood occupied by intact red blood cells.
• RBC count
• The number of red blood cells contained in a specified volume of whole
blood.
• Usually expressed as millions of red blood cells per microL of whole blood.

4
Normal Values for RBC Parameters in Men &
Women

5
• WHO criteria for anemia
• Men HGB < 13g/dL
• Women HGB < 12g/dL

• Limitations
• 2.5% in two tailed & 5% in one tail distribution are labelled anemic
• Volume status (RCM, plasma volume) – subject for variation in certain
physiologic and pathologic conditions
• Special population

6
• Special population
• High altitude
• Smokers
• Environmental pollution
• High prevalence of chronic diseases
• Race
• Athletes
• Elderly
• Lower HGB in general
• The difference between the genders becomes non-significant
7
Hematopoiesis
• The process by which the formed elements of blood are produced.
• Tightly controlled process; regulated through a series of steps
beginning with the hematopoietic stem cell.
• Requirements
• Sufficient nutrients
• Stromal framework
• Cytokines
• Erythropoietin
• A defect in any of these key components can lead to anemia.

8
• STEPS
• Lineage commitment (Pluripotent stem cells differentiate into primitive
erythroid progenitors).
• Erythroid cells come from a common erythroid/megakaryocyte
progenitor
• Hematopoietic progenitor and precursor cells come increasingly under
the regulatory influence of growth factors and hormones.
• Erythropoietin (EPO) is required for the maintenance of committed
erythroid progenitor cells.

9
• Erythropoietin
• Produced largely in the kidney (>90%) and to a lesser extent in the liver
(<10%).
• Produced by cells that sense adequacy of tissue oxygenation relative to
the metabolic need.
• Interstitial fibroblasts in renal cortex
• Proximal tubules
• Hypoxia is the main stimulus.
• Affects the growth and differentiation of RBC progenitors especially the
terminal events (CFU-E).

10
• Others cytokines and growth factors besides EPO involved
• Steel factor (SF)
• IL-3
• GM-CSF
• IGF-1 & Insulin
• Activin
• Hepatocyte growth factor

11
12
RBC life cycle
• Under steady condition
• Production = Destruction
• The survival of RBC in the circulation
• 110 – 120 days
• 100 days for practical purposes
• The Bone Marrow
• Produces 1% of RBC/day
• Vast potential to increase production by >5 fold
• RBC survival of around 20 days can be tolerated

13
• Reticulocytes
• Survive for 4 days totally (3 days in BM and 1 day in the circulation)
• Stay in the BM can be shorter
• Last phase before turning in to mature RBC
• Contain ribosomes and the nucleus is already extruded
• Need special stain in the blood smear

14
Clinical Manifestations
• Most often recognized by abnormal screening laboratory tests.
• Clinical Features of anemia per se depend on
• Degree of anemia
• Rate of the decline in HGB
• Oxygen demands of the patient
• Other features
• Manifestation of acute blood loss
• Sn & Sx of the underlying diseases
• Associated presentation of specific anemias

15
• Acute blood loss
• When 10–15% of the total blood volume lost
• Hypotension
• Decreased organ perfusion
• When >30% of the blood volume is lost
• The patient prefers to remain supine
• Postural hypotension and tachycardia
• When >40% of the blood volume is lost (>2 L in the average-sized adult)
• Signs of hypovolemic shock (confusion, dyspnea, diaphoresis,
hypotension, and tachycardia)

16
• Acute hemolysis
• The signs and symptoms depend on the mechanism that leads to red
cell destruction
• Intravascular hemolysis (with release of free hemoglobin)
• Acute back pain
• Free hemoglobin in the plasma and urine, and
• Renal failure

17
• Chronic or progressive anemia
• Symptoms depend on
• The age of the patient
• The adequacy of blood supply to critical organs
• Moderate anemia
• Fatigue, Loss of stamina, Breathlessness, and Tachycardia
(particularly with physical exertion)

18
• Progressive anemia (over a period of days or weeks)
• The total blood volume is normal to slightly increased
• Changes in cardiac output and regional blood flow
• Chronic anemia
• Shunting of blood away from organs that are relatively rich in blood
supply (kidney, gut, and skin)

19
• Chronic inflammatory states (infection, rheumatoid arthritis, cancer)
• Mild to moderate anemia
• Lymphoproliferative disorders (chronic lymphocytic leukemia, other B
cell neoplasms)
• Autoimmune hemolysis

20
Classification of Anemia
• The functional classification of anemia has three major categories.
1) Marrow production defects (hypoproliferation)
2) Red cell maturation defects (ineffective erythropoiesis)
3) Decreased red cell survival (blood loss/hemolysis)

• Based on RBC size anemia has three major categories

21
• A hypoproliferative anemia
• Low reticulocyte production index
• Normocytic, normochromic anemia
• Maturation disorders
• Slight to moderately elevated reticulocyte production index
• Macrocytic or microcytic red cell indices
• Hemolysis
• Increase in the reticulocyte production index (at least 3 times normal)
• Hemorrhagic anemia
• Doesn’t result in production indices of more than 2.0–2.5 times normal
22
23
Approach to the anemic patient
• Principles • Questions to answer
• Anemia is just a major sign of • Is the patient bleeding
disease (anytime)?
• Any degree of anemia is Never • Is the BM suppressed?
Normal • Is there evidence of
• Hx, P/E & Laboratory destruction?
• Is there deficiency state? Why?

24
History
• Acute or chronic onset (fatigue, dizziness, dyspena, palpitation,
syncope, tinnitus, virtigo, throbbing headache, irritability, difficulty to
concentrate)
• Dietary Hx, alchol ingestion Hx
• Hx of drug expose
• Hx of blood loss
• Family Hx of anemia
• Blood in the feces
• Abnormal urine color change
25
• Sore mouth and difficulty swallowing are expressed by pts with
vitamin B12 and iron deficiency
• Menstrual Hx
• Neurologic Sx
• Hx of jaundice; gall stone
• Craving for ice, clay (picophagia)

26
• Symptoms related to other disorders commonly associated with
anemia – Sx of underling ds (cardiac, hepatic, renal, Chronic infection
or malignacy)
• Sickle cell anemia patient will have a lifelong history of episodic
bone and joint pains

27
Physical Examination
• Aim • Important examinations & Sns to
• Severity look for
• Cause • Vital signs & signs of infection
• Other related hematologic or • Pallor
medical conditions • Jaundice
• LAP
• Hepatosplenomegaly
• Per rectum examination
• Bone tenderness
• Integumentary system

28
• Clues to the mechanisms of anemia
• Infection
• Blood in the stool
• Lymphadenopathy, Splenomegaly – underlying lymphoproliferative
disease
• Petechiae – platelet dysfunction
• Forceful heartbeat, strong peripheral pulses, a systolic "flow"
murmur
• Palmar creases lighter in color than the surrounding skin
• The hemoglobin level is usually <8 g/dL
29
30
IRON DEFICIENCY ANEMIA
(IDA)
11/02/2015

31
Introduction
• The development & the rapidity of IDA is dependent upon the body’s
iron store.
• Iron store in turn depends on
• Age
• Sex
• Rate of growth
• Balance b/n loss & absorption
• Generally lower Iron values for women because of menstrual loss,
pregnancy, lactation.

32
Epidemiology
• IDA is supposed to be one of the commonest forms in our country
• 1 - 2% even in the Western countries
• Iron deficiency without anemia 11% in women (men 4%)
• Prevalence
• Young children – 48%
• Pregnant women – 51%
• Non-pregnant women – 35%
• Adult men – 18%

33
• IDA
• Commonest among the nutritional anemias
• More prevalent in developing countries (36% vs 8%)
• Local data show similar pictures
• North Western Ethiopia
• General population – 40.5%
• Children – 47.2%
• Jimma
• 57% has been reported in pregnant women

34
Iron Metabolism
• Regulation of iron balance
• Interaction of various proteins
• Interplay b/n iron absorption & loss

35
• Proteins involved
• Transferrin (Tf) & its receptors (TfR)
• Ferritin
• Iron responsive element-binding protein( IRE-BP), IRP/IRF
• HFE
• Divalent Metal Transporter (DMT1)
• Stimulator of iron transport (SFT)
• Ferroportin & Hephaestin
• Hepcidin

36
• Transferrin (Tf)
• Transports Fe3+ through plasma
• Synthesized in the liver
• Increased production in deficiency states
• Measured as Tf or TIBC
• 1/3rd saturated normally
• Fe/Tf = 33%

37
• States with decreased Tf saturation or increased TIBC
• IDA
• ACD (occasionally)
• Ferroportin mutation
• States with increased Tf saturation or decreased TIBC
• Aplastic anemia
• Sideroblastic anemia
• Ineffective erythropoiesis
• Hemochromatosis

38
• Ferritin
• Huge molecule for cellular storage of Fe (4500 atoms of iron)
• Acute phase reactant
• Accessible for metabolic needs
• Excess is changed to Hemosiderin
• Hemosiderin is not easy accessible for metabolism
• Measured as apoferritin in the plasma
• Plasma level reflects body iron store
• 1ng of ferritin = 10mg of total iron store

39
• Iron balance
• Normal body content = 3 - 4gm
• HGB = 2.5gm
• Other Fe containing proteins = 400mg
• Tf bound in the plasma = 3 - 7mg
• The rest as ferritin/hemosiderin = body Fe store
• Adult men = 1gm
• Adult women = much less than men
• Daily iron loss = 1mg

40
• Intestinal absorption
• Diet contains heme & non-heme Fe
• 30% vs 10% absorbed
• Released in the acidic environment and is sent with mucin to the
doudenum for absorption
• Enhancers vs Inhibitors
• Ferric vs ferrous

41
Causes of Iron Deficiency
• Blood loss (major cause) • Others causes
• Obvious or occult • Pulmonary hemosiderosis
• GI loss the main, including Hook • Intravascular hemolysis
worm • Hemoglobinuria &
• Decreased absorption hemosiderinuria
(uncommon) • Increased demand
• Part of generalized • Rx with EPO, folate or Vitamin
malabsorption like Celiac & B12
Tropical Sprue

42
Stages of development of IDA
• Stage 1 • Stage 3
• Depleted iron store without • Typical character
anemia • In the face severe Fe deficiency
• High risk of anemia with slightest • Microcytic hypochromic
bleeding
• Imbalance b/n heme & globulin
• Iron from daily RBC turn over synthesis
• Stage 2 • High EPO
• Normocytic • Low retic count
• Normal reticulocyte count
• Common in developed countries

43
Clinical Manifestations
• General features of anemia
• Typical of IDA
• Koilonychia (spoon nails)
• Blue sclera
• Pica & pagophagia
• Beeturia
• Paterson-Kelly/Plummer-Vinson Syndrome
• Dysphagia
• Oesophageal web
• Atrophic glossitis
44
Lab Features
• Low HGB, HCT, RBC counts • Low serum iron & ferritin
• Microcytic-hypochromic • High Tf level
• Low MCV, MCH & MCHC • Low saturation (≤2.5%)
• Increased central pallor
• High TIBC
• High platelet count (reactive
• Absent iron stores
thrombocytosis)
• Brisk response to therapeutic
• Normal WBC Count &
trail
Morphology

45
46
Diagnosis
• The Dx of IDA has 2 components
• Confirmation of iron deficiency
• Identify the cause

47
• Establishing IDA • Search for the source
• CBC & ESR • History is vital
• RBC indices • Gynecologic
• Peripheral smear • History of surgery
• Iron studies • Dietary habit
• Serum iron • Stool exam
• Serum ferritin • Occult blood
• Serum Tf, TIBC • Ova of parasites
• BM study • Endoscopy
• Therapeutic trail & others • Colonoscopy
48
Differential Diagnosis
• When anemia is mild with normal indices (Stage 2 IDA)
• ACD
• Anemia due to CRF
• Anemia due to endocrine disorders
• Classic (microcytic- hypochromic)
• Thalassemia
• Sideroblastic anemia
• ACD
• Lead poisoning

49
Treatment
• Two aspects
• Treatment of the underlying cause
• Administration of iron

50
• General principles of iron treatment
• Iron is absorbed in the duodenum & proximal jejunem
• Shouldn’t be given with food
• Best absorbed in a mildly acidic media
• Give ascorbic acid
• 2hrs before or 4hrs after antacids
• Cost and effectiveness
• UGI discomfort is directly related to the amount of iron
• Try the elixir

51
• Oral preparation
• Ferrous sulfate 65mg of elemental iron
• Ferrous fumarate 106mg of elemental iron
• Ferrous gluconate 28 - 36mg of elemental iron
• Ferrous sulfate elixir 44mg/5ml
• Side effect
• GI upset

52
• 150 - 200mg of elemental iron
• Response to treatment
• Reticulocytosis in 7 days
• Rise in HGB 2gm over 3 weeks
• Reasons for failure
• Duration of treatment
• Continue after normalization of HGB to replenish the iron stores
• 3 – 6 months after normalization of HGB

53
• Parenteral iron
• IV or IM
• Preparations
• Iron dextran
• Ferric gluconate
• Iron sucrose
• Major side effects
• Local & systemic

54
ANEMIA OF CHRONIC
DISEASE (ACD)
11/02/2015

55
Introduction
• ACD can be associated with
• Inflammation
• Infection
• Malignancy
• Severe trauma
• Heart disease
• Diabetes
• Acute or chronic immune reactivation
• Typically
• NCNC, Hypoproliferative
56
Pathogenesis
• Primarily reflect a reduction in RBC production but there may be a
component of RBC reduced survival.
• Three factors for hypoproliferative state
1) Trapping of iron in macrophages
2) Reduced sensitivity of BM to EPO
• Normal marrow
• Increase apoptosis of RBC precursors
3) Relative reduction in EPO

57
• Acute variant
• “Anemia of critical illness”
• Acute event related
• Major surgery
• MI
• Sepsis
• Major trauma

58
Laboratory Findings
• Anemia in ACD is of variable • 1/4th of patients are iron
severity deficient
• Many 10 - 11gm HGB • Serum ferritin normal or
• Some (20%) will have HGB of elevated
8gm or less
• Bone marrow
• Low absolute reticulocyte count • Macrophages increased or
• High acute phase reactants & normal iron content
cytokines • Erythroid precursers –
• Low serum iron & Tf level (TIBC) decreased or absent

59
Differential Diagnosis
• ACD is usually NCNC & hypoproliferative
• CRF
• Severe endocrine disorders
• Some patients with severe anemia & microcytic hypochromic picture
• IDA
• Thalassemia
• Sideroblastic anemia

60
61
Treatment
• Usually mild & may not interfere with quality of life
• Correction of underlying problem
• Erythropoietin
• After measuring the level
• ?Survival
• Darbepoetin
• Supplemental iron
• To maintain 20% or above saturation of Tf

62
MEGALOBLASTIC ANEMIAS
11/2/2015

63
Introduction
• It’s nuclear maturation defect which leads to defect in DNA synthesis.
• Megaloblasts
• Nucleated RBC precursors in the BM which may be seen in rarely in
severe deficiency states [deficiencies of Vitamin B12 (cobalamin, Cbl) or
Folic Acid (FA)]
• The morphologic hallmark of the syndrome
• Other causes of impaired DNA or RNA formation, such as
antimetabolite drugs and myelodysplastic syndrome, can also lead to
megaloblastic anemia.
• Macrocytic anemia is more appropriate

64
Vitamin B12 deficiency
• General consideration
• It belongs to family of Cobalamin
• It serves as cofactor for two rxn
1. For conversion of homocystein to methionin (as methylcobalamin)
• A critical step in DNA synthesis
2. For conversion of methylmalonyl coA to succinyl coA
• Important in myelin formation and in the neurologic
abnormalities seen with B12

65
• All Vit B12 comes from diet & is present in all foods of animal origin.
• After being ingested
• Vit B12 is bounded to IF (protein secreted by gastric parietal cells)
• Vit B12–IF complex
• Travels through the intestine & absorbed in the terminal ileum
• Transported through plasma & stored in liver

66
• Daily absorption is 5 µg.
• Liver contain 2000 – 5000µg of stored Vit B12.
• The body has sufficient store of Vit B12
• Vit B12 deficiency develops more than 3 yrs after Vit B 12 absorption
ceases

67
Causes of Vitamin B12 deficiency
• Dietary deficiency
• Rare – except strict vegetarians
• Decreased production of IF
• Pernicious Anemia (immunological destruction of parietal cells in
stomach which produce IF)
• Most common cause
• Gasterectomy

68
• Competition for Vit B12 in gut
• Blind loop syndrome (bacterial over growth)
• Fish tape worm (rare) – Diphyllobotherium latum
• Pancreatic Insufficiency
• Cobolamin initially combined with salivary glycoprotein which is
digested by pancreatic trypsin & transferred to IF
• Decreased ileac absorption
• Surgical resection
• Crohn’s disease

69
Clinical Features
• General features of anemia
• Specific to Vitamin B12 deficiency
• Anorexia
• Diarrhea
• Glossitis
• Neurologic Sx
• Paresthesia
• Next Posterior column impaired (difficulty in balance)
• Loss of position & vibration sense
• Progressive spastic & ataxic weakness (SCD)
70
Lab Features
• Classic Presentation • Neurologic Presentation
• Anemia with MCV > 100fL • Cyanobalamin deficiency
(usually >115) without anemia
• Low – normal or low ARC • Only hypersegemented
• Macro-ovalocytes neutrophils
• ?megaloblasts
• Hypersegemented neutrophils
Oval macrocytes, usually with considerable anisocytosis and poikilocytosis,
are the main feature

71
• Peripheral blood smear
• Hyper segmented neutrophils
• >5% of peripheral neutrophils have ≥5 lobes of nucleus
• Macrocytosis
• BM morphology
• Cytoplasm maturation with retarded nuclear development

72
• Coalmine serum level (N >240pg/ml)
• Low-normal or normal
• Serum levels of homocysteine & methylmalonic acid
• Schilling test (3 stages)
• Antibodies to IF and parietal cells

73
Treatment of Vitamin B12 deficiency
• Identify the underlying cause
• Cobalamine 1000µg (1 mg)/daily; IM
• Given every 3–7 days (twice weekly) for 6 doses then monthly OR
• 1000µg (1mg) daily for 1wk
• 1mg/wk for 1month
• 1mg/month then after
• Cause not known or PA → give for life monthly
• Folic acid 5 mg daily; Po; for 3–4 months

74
• Response
• Reticulocytosis occur (5–7 days)
• Hematology picture normalize 2 months
• CNS Sx reversible if it’s short duration (< 6 month)

75
Folic Acid Deficiency
• General consideration
• It’s present in most fruits & vegetables
• Daily requirement - 50–100µg/day
• Total body store ~5000µg; enough to supply for 2–3months

76
Causes of Folic Acid deficiency
• Dietary: by far the most common cause
• Alcoholic person who don`t eat fresh fruits & vegetable
• Those over cooks there food are candidate for folate deficiency
• Decreased absorption - rare b/c absorption occur from entire GIT
• Tropical sprue
• Drugs like phenytoin, cotrimoxazol, sulfasalazine
• Increase requirement
• Pregnancy
• Chronic hemolytic anemia
• Exfolative skin diseases
77
Clinical Features
• Similar to vitamin B12 except
• Neurologic abnormalities
• Can develop in relatively short duration
• Pregnancy
• Acute & severe infection
• Severe hemolysis

78
Lab Features
• Similar to Vitamin B12
• Serum Vitamin B12 level normal
• RBC folate level <150 ng/ml is diagnostic

79
Treatment of Folic Acid deficiency
• Folic acid 1–5 mg/d orally; For 1–4 months
• Response
• Rapid improvement & sense of wellbeing
• Reduction in LDH in 2days
• Reticulocytosis in 3–4days (peak in 1wk)
• Total correction of hematologic abn. (rise in HBG & reduction in MCV) in
8wks
• Delay in cases of iron deficiency

80
HEMOLYTIC ANEMIAS
11/04/2015

81
Introduction
• Hemolytic anemia
• Vast group
• Important cause of anemia
• Shorted RBC survival
• Splenomegaly (hypersplenism)
• Hemolysis
• Shorted RBC survival less than 100 days
• Normal RBC survival – 120 days
• Not necessarily HA

82
Classification of causes of HA
I. Extravascular destruction of red blood cells
A. Intrinsic red blood cell defects
• Enzyme deficiencies (eg, G6PD or pyruvate kinase deficiencies)
• Hemoglobinopathies (eg, sickle cell disease, thalassemias, unstable
hemoglobins)
• Membrane defects (eg, hereditary spherocytosis, elliptocytosis)

83
B. Extrinsic red blood cell defects
• Liver disease
• Hypersplenism
• Infections (eg, bartonella, babesia, malaria)
• Oxidant agents (eg, dapsone, nitrites, aniline dyes)
• Other agents (eg, lead, snake and spider bites)
• Microangiopathic (eg, DIC, TTP-HUS)
• Autoimmune hemolytic anemia (warm- or cold-reacting, drugs)
• Intravenous immune globulin infusion
• Large granular lymphocyte leukemia

84
II. Intravascular destruction of red blood cells
• Microangiopathy (eg, aortic stenosis, prosthetic valve leak)
• Transfusion reactions (eg, ABO incompatibility)
• Infection (eg, clostridial sepsis, severe malaria)
• Paroxysmal cold hemoglobinuria
• Paroxysmal nocturnal hemoglobinuria
• Following intravenous infusion of Rho(D) immune globulin
• Following intravenous infusion with hypotonic solutions
• Snake bites

85
Diagnostic Approach
I. Suspecting Hemolysis
• Rapid onset of pallor and anemia
• Jaundice with increased indirect bilirubin concentration
• History of pigmented (bilirubin) gallstones
• Splenomegaly
• Presence of circulating spherocytic red cells
• Increased serum LDH concentration
• Reduced (or absent) level of serum haptoglobin
• A positive direct antiglobulin test (Coombs test)
• Increased reticulocyte percentage or absolute reticulocyte number
86
II. Confirming Hemolysis
• The combination of an increased serum LDH & a reduced haptoglobin
• 90% specific for diagnosing hemolysis
• Combination of a normal serum LDH & haptoglobin >25 mg/dL
• 92% sensitive for ruling out the presence of hemolysis

87
III. Determining the Cause
• A thorough history and physical examination is important
• Drugs
• Toxins
• Systemic disorders (eg, infection, autoimmune disease, malignancy)

88
• Abnormalities on the peripheral • Abnormalities which suggest
blood smear suggesting that the hemolysis is
extravascular hemolysis intravascular
• Spherocytes • Presence of free hemoglobin in
• Fragmented red cells plasma or urine
• "Bite" or blister cells • A urine sediment positive for
• Acanthocytes iron (hemosiderinuria)
• Teardrop red cells • Presence of circulating red cell
"ghosts"

89
• Atypical presentation
• Hemolysis with out anemia
• Hemolysis with out reticulocytosis

90
AUTOIMMUNE HEMOLYTIC
ANEMIA (AIHA)

91
Introduction
• Most common causes of acquired hemolytic anemia.
• Immunologic destruction of RBCs mediated by autoantibodies directed
against antigens on the patient's RBCs.
• Antibodies of two major types are produced in AIHA
1) IgG antibodies
• React with protein antigens on the RBC surface at body temperature
("warm agglutinins“)
2) IgM antibodies
• React with polysaccharide antigens on the RBC surface only at
temperatures below that of the core temperature of the body ("cold
agglutinins“)
92
Etiology
• Most cases of warm agglutinin AIHA are idiopathic.
• Causes or conditions which may be associated with AIHA include
• Infections (Viral infections, Malaria, C. perfringens sepsis, Shiga toxin–
producing E. coli)
• Autoimmune and connective tissue diseases (particularly SLE)
• Malignancies of the immune system (NHL, CLL)
• Prior allogeneic blood transfusion or hematopoietic cell transplantation
• Drugs (Penicillin's, Cephalosporins, Quinine, Methyldopa, NSAIDs)
• Toxins (Snake venom)

93
Clinical Features
• The clinical manifestations of warm agglutinin AIHA varies greatly
with the amount and effectiveness of the causative antibody.
• Asymptomatic even if slightly anemic – when the amount is small or the
antibody is inefficient
• Shortness of breath and dyspnea on exertion (common presentation)
• Severe degrees of cardiac decompensation (heart failure, arrhythmia,
and/or chest pain) – if the hemolysis is severe and of sudden onset
• Physical examination usually reveals
• Pallor and jaundice
• Spleen is usually enlarged to a moderate degree

94
Diagnosis
• Accurate diagnosis requires
• Documentation of the presence of hemolysis
• Demonstration of the presence of a warm-reacting autoantibody on the
surface of the patient's red cells

95
• The MCHC is increased
• The absolute reticulocyte count will be elevated
• Elevated levels of indirect bilirubin and LDH
• Reduced levels of haptoglobin
• The peripheral blood smear
• Spherocytes
• Increased number of reticulocytes
• Direct Coombs' test
• 99 % of patients will exhibit a positive result with anti-IgG &/or anti-C3

96
Complications
• Two potential complications of warm AIHA are
• Lymphoproliferative disorder
• Venous thromboembolic disease

97
Treatment
• Transfusion of red cells
• If the antibody involved is unspecific, all the blood units cross-
matched will be incompatible → Transfuse incompatible blood
• Corticosteroids
• Prednisone 1 mg/kg per day then taper the dose
• In one-half of the cases, it will produce a remission
• In some patients who are apparently cured, relapses can occur
• Cessation of any possible offending drug
• Treatment of any underlying disease, such as SLE or CLL

98
• Other treatment options include
• Immunosuppressive drugs
• Monoclonal antibodies – monoclonal anti-CD 20 antibody (rituximab)
• Danazol
• Reduction in antibody effectiveness
• Splenctomy
• IVIG

99
Monitoring Response
• Serial laboratory tests
• LDH
• Haptoglobin
• Indirect bilirubin
• Coombs test

100
APLASTIC ANEMIA
11/04/2015

101
Epidemiology
• In general, men and women are affected with equal frequency.
• Aplastic anemia is a disease of the young.
• The age distribution is biphasic
• The major peak in the teens & twenties
• A second rise in the elderly

102
Etiology
• Aplastic anemia can be constitutional or acquired (idiopathic or
secondary).
• Constitutional disorders
• Fanconi's anemia
• Dyskeratosis congenita
• Shwachman-Diamond syndrome
• Most cases of acquired aplastic anemia are idiopathic.

103
• Secondary causes of acquired aplastic anemia include
• Radiation – marrow aplasia is a major acute sequela
• Chemicals – benzene
• Drugs
• Dose-dependent – chemotherapeutic drugs
• Idiosyncratic reactions – chloramphenicol
• Infections
• Seronegative hepatitis (non-A, non-B, non-C, non-G)
• Epstein-Barr Virus
• Parvovirus B19
104
• Immunologic diseases
• Transfusion-associated graft-versus-host disease (GVDH)
• Eosinophilic fasciitis
• SLE
• Pregnancy
• Paroxysmal nocturnal hemoglobinuria (PNH)

105
Pathophysiology
• Bone marrow failure results from severe damage to the
hematopoietic cell compartment.
• Mechanism
• Extrinsic damage
• Massive physical or chemical insults (high doses of radiation and
toxic chemicals)
• Altered drug metabolism (idiosyncratic reaction)
• Immune-mediated injury

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• Replacement of the bone marrow by fat is apparent in the
morphology of the biopsy specimen and MRI of the spine.
• Stem cell pool is reduced to 1% of normal in severe disease at the
time of presentation.
• Aplastic anemia does not appear to result from defective stroma or
growth factor production.

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Clinical Features
• History
• Onset – abrupt or a more insidious
• Bleeding is the most common early symptom
• A complaint of days to weeks of easy bruising, oozing from the
gums, nose bleeds, heavy menstrual flow, and sometimes petechiae
• Symptoms of anemia are also frequent
• Lassitude, weakness, shortness of breath, and a pounding sensation
in the ears
• Infection is an unusual first symptom in aplastic anemia

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• Systemic complaints and weight loss should point to other etiologies of
pancytopenia.
• Prior drug use, chemical exposure, and preceding viral illnesses must
often be elicited with repeated questioning.
• A family history of hematologic diseases or blood abnormalities may
indicate a constitutional etiology of marrow failure.

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• Physical Examination
• Petechiae and ecchymoses are typical, and retinal hemorrhages may be
present.
• Pelvic and rectal examinations are best deferred to avoid trauma but,
when performed show bleeding from the cervical os and blood in the
stool.
• Pallor of the skin and mucous membranes is common.
• Lymphadenopathy and splenomegaly are highly atypical of aplastic
anemia.
• Café au lait spots and short stature suggest Fanconi's anemia.
• Peculiar nails and leukoplakia suggest Dyskeratosis congenita.
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• Laboratory Studies
• Peripheral blood smear
• Large erythrocytes and a paucity of platelets & granulocytes
• MCV is commonly increased
• Reticulocytes are absent or few
• Lymphocyte numbers may be normal or reduced

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• Bone marrow aspirate – dilute on smear
• Fatty biopsy specimen may be grossly pale on withdrawal
• A "dry tap" instead suggests fibrosis or myelophthisis
• Bone marrow biopsy (which should be >1 cm in length)
• Fat under the microscope
• In the most serious cases the biopsy is virtually 100% fat
• Hematopoietic cells occupy <25% of the marrow space

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• Ancillary Studies
• Chromosome breakage studies of peripheral blood to exclude fanconi's
anemia
• Chromosome studies of bone marrow cells
• Negative in typical aplastic anemia
• Flow cytometric assays for the diagnosis of PNH
• Serologic studies
• Epstein-barr virus, HIV, post-hepatitis aplastic anemia
• CT scanning or ultrasound to determine spleen size
• MRI to assess the fat content of vertebrae

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Diagnosis
• Based on the combination of
• Pancytopenia
• A fatty, empty bone marrow
• Diagnostic problems occur with
• Atypical presentations
• Related hematologic diseases (MDS)
• Megakaryocytes & myeloid precursor cells
• Typical cytogenetic abnormalities

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Prognosis
• The natural history of severe aplastic anemia is rapid deterioration
and death.
• Few patients show spontaneous recovery.
• The major prognostic determinant is the blood count.

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• SEVERE DISEASE is defined by the presence of two of three
parameters
1) Absolute neutrophil count <500/μL
2) Platelet count <20,000/μL
3) Corrected reticulocyte count <1% (or ARC <60,000/μL)
• Survival of patients who fulfill these criteria
• 20% at 1 year after diagnosis with only supportive care
• VERY SEVERE DISEASE
• Defined by an absolute neutrophil count <200/µL
• Treatment has markedly improved survival in this disease
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Treatment
• Hematopoietic stem cell transplantation
• Curative therapy for aplastic anemia
• Best therapy for the young patient
• Allogeneic transplant from fully matched siblings
• Long-term survival rates for children are 80–90%.
• Transplant morbidity and mortality are increased among adults
• Due to the higher risk of chronic GVHD and serious infections

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• Immunosuppression
• Antileucocyte globulin (ALG) or Antithymocyte globulin (ATG)
• Induces hematologic recovery (independence from transfusion and
a leukocyte count adequate to prevent infection) in about 50% of
patients
• Combined treatment (adding cyclosporine to either ALG or ATG)
• Increased response rates to about 70%
• Standard for patients with severe disease
• Improvement in granulocyte number is generally apparent within 2
months of treatment

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• Supportive care
• Transfusion
• Infection in the presence of severe neutropenia
• Parenteral, broad-spectrum antibiotics
• Ceftazidime or a combination of an aminoglycoside, cephalosporin, and
semisynthetic penicillin
• When indwelling plastic catheters become contaminated, vancomycin
should be added
• Persistent or recrudescent fever implies fungal disease
• PCP prophylaxis with monthly inhaled pentamidine
• Suspect exposures to drugs or chemicals should be discontinued
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