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02. Red Blood Cell Disorders > 3. Normocytic anemia > Flashcards

3. Normocytic anemia Flashcards

1
Q

Definition of normocytic anemia

A

Anemia with normal-sized RBCs (MCV = 80 - 100 fL)

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2
Q

Mechanism of normocytic anemia

A

Decreased blood volume and/or decreased erythropoiesis

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3
Q

Disease that can present with normocytic anemia

A
  1. Hemolytic anemia
    a. Intrinsic defects:
    i. Hemoglobinopathies
    - Sickle cell anemia
    - HbC disease
    ii. Enzyme deficiencies
    - Pyruvate kinase deficiency
    - G6PD deficiency
    iii. Membrane defects
    - Paroxysmal nocturnal hemoglobinuria
    - Hereditary spherocytosis
    b. Extrinsic defects:
    i. Autoimmune hemolytic anemia
    ii. Microangiopathic hemolytic anemia
    iii. Macroangiopathic hemolytic anemia
    iv. Infections
    v. Mechanical destruction
  2. Nonhemolytic anemia
    a. Blood loss
    b. Aplastic anemia
    c. Anemia of chronic kidney disease
    d. Iron deficiency anemia (early phase)
    e. Anemia of chronic disease (early phase)
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4
Q

Epidemiology of Sickle cell anemia

A
  1. Predominantly affects individuals of African and East Mediterranean descent
  2. Sickle cell anemia is the most common form of intrinsic hemolytic anemia worldwide.
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5
Q

Pathophysiology of Sickle cell anemia (genetics)

A
  1. Heterozygotes (HbSA): carry one sickle allele and one other (usually normal) → sickle cell trait
  2. Homozygotes (HbSS): carry two sickle alleles → sickle cell anemia
  3. Point mutation in the β-globin gene (chromosome 11) → glutamic acid replaced with valine (single amino acid substitution) → 2 α-globin and 2 mutated β-globin subunits create pathological hemoglobin S (HbS).
  4. Glutamic acid can also be replaced with a lysine, creating hemoglobin C.
    a. Hemoglobin SC disease
    - Heterozygosity for hemoglobin S and hemoglobin C
    - Results in a phenotype more severe than sickle cell trait but not as severe as sickle cell disease (e.g., fewer acute sickling events)
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6
Q

Pathomechanism of Sickle cell anemia

A
  1. HbS polymerizes when deoxygenated, causing deformation of erythrocytes (“sickling”). This can be triggered by any event associated with reduced oxygen tension.
    a. Hypoxia (e.g., at high altitudes)
    b. Infections
    c. Dehydration
    d. Acidosis
    e. Sudden changes in temperature
    f. Stress
    g. Pregnancy
  2. Sickle cells lack elasticity and adhere to vascular endothelium, which disrupts microcirculation and causes vascular occlusion and subsequent tissue infarction.
  3. Extravascular hemolysis and intravascular hemolysis are common and result in anemia.
  4. Hemolysis and the subsequent increased turnover of erythrocytes may increase the demand for folate, causing folate deficiency.
  5. The body increases the production of fetal hemoglobin (HbF) to compensate for low levels of HbA in sickle cell disease.
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7
Q

Hemoglobin composition in sickle cell trait

A

HbA (60%)
HbS (40%)
HbF (<2%)

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8
Q

Hemoglobin composition in sickle cell disease

A

HbA (0%)
HbS (75-95%)
HbF (5-25%)

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9
Q

Hemoglobin composition in normal

A

HbA (95-98%)
HbS (0%)
HbF (<2%)

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10
Q

Clinical presentation of sickle cell trait

A
  1. Often asymptomatic
  2. Painless gross hematuria due to renal papillary necrosis: often the only symptom
  3. Hyposthenuria: nocturia, enuresis
  4. Recurrent urinary tract infections
  5. Renal medullary carcinoma
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11
Q

Clinical presentation of sickle cell disease

A
  1. Onset
    a. 30% develop symptoms in the first year of life; > 90% by age 6 years
    b. Manifests after 6 months of age as the production of HbF decreases and HbS levels increase
  2. Acute symptoms:
    a. Acute hemolytic crisis (severe anemia):
    i. Splenic sequestration crisis:
    - Splenic vaso-occlusion → entrapment and pooling of large amounts of blood in the spleen → acute left upper quadrant pain, anemia, reticulocytosis, and signs of intravascular volume depletion (e.g., hypotension)
    ii. Aplastic crisis:
    - Red blood cell aplasia with an acute, severe drop in hemoglobin and associated reticulocytopenia due to an infection with parvovirus B19
    - Dysmorphic erythrocytes in sickle cell disease and hereditary spherocytosis are susceptible to parvovirus B19 infection, which can temporarily suppress bone marrow erythropoiesis.
    iii. Hyperhemolysis: intravascular and extravascular hemolysis triggered by mild oxygen deficiency (rare)

b. Infection:
i. Pneumonia
ii. Meningitis
iii. Osteomyelitis (most common cause: Salmonella spp., Staphylococcus aureus)
iv. Sepsis (most common cause: Streptococcus pneumoniae)

c. Vaso-occlusive events:
i. Vaso-occlusive crises (painful episodes, painful crisis): recurrent episodes of severe deep bone pain and dactylitis → most common symptom in children and adolescents
ii. Acute chest syndrome
iii. Priapism
iv. Stroke (common in children)
v. Acute sickle hepatic crisis (manifests with RUQ pain, jaundice, nausea, fever, hepatomegaly, and elevated transaminase levels)
vi. Infarctions of virtually any organ (particularly spleen) and avascular necrosis with corresponding symptoms

  1. Chronic symptoms:
    a. Chronic hemolytic anemia: fatigue, weakness, pallor; usually well-tolerated
    b. Chronic pain
    c. Cholelithiasis (pigmented stones)
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12
Q

Lab studies for sickle cell anemia

A
  1. Liquid chromatography and isoelectric focusing to quantify hemoglobin subtypes
  2. Sickle cell test: detects sickle cells in blood smear under anaerobic conditions
  3. Peripheral blood smear:
    a. Sickle cells (drepanocytes) crescent-shaped RBCs
    b. Target cells
    c. Possibly Howell-Jolly bodies
    d. Reticulocytosis
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13
Q

Imaging studies for sickle cell anemia

A

X-ray of the skull shows hair-on-end (“crew cut”) sign due to periosteal reaction to erythropoietic bone marrow hyperplasia

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14
Q

Complications of sickle cell anemia

A

Recurrent vascular occlusion and disseminated infarctions lead to progressive organ damage and loss of function.

  1. Spleen
    a. Functional asplenia
    - Increased risk of infection with encapsulated bacteria (Streptococcus pneumoniae (most common), Neisseria meningitis, Haemophilus influenzae type b, Salmonella typhi)
    - Appearance of Howell-Jolly bodies in RBCs
  2. Kidney
    a. Renal papillary necrosis
    Countercurrent microcirculation of kidney → hypoxic environment of renal medulla → sickling of RBCs → vaso-occlusion → renal papillary necrosis
    Manifests as hematuria
  3. Skeletal: Avascular osteonecrosis
  4. CNS: Recurrent strokes
  5. Male genitals: Priapism
  6. Lungs: Acute chest syndrome
  7. Heart: Heart failure, MI
  8. Eye: Retinal vessel infarction
  9. Liver: Hepatic sequestration, Acute sickle hepatic crisis
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15
Q

Definition of Hemoglobin C disease

A

Occurs in individuals who are homozygous for the hemoglobin C mutation (HbCC)

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16
Q

Definition of Hemoglobin C trait

A

Occurs in individuals who are heterozygous carriers of the hemoglobin C mutation (HbAC)

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17
Q

Pathophysiology of Hemoglobin C

A

Glutamic acid can also be replaced with a lysine, creating hemoglobin C.

  1. HbC precipitates as crystals → ↑ RBC rigidity and ↓ deformability → extravascular hemolysis
  2. β-globin mutation (glutamate replaced by lysine)
  3. HbC is less soluble than HbA and tends to form hexagonal crystals, which lead to RBC dehydration (↑ MCHC).
  4. RBCs have reduced oxygen-binding capacity and a shorter lifespan.
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18
Q

Clinical presentation of Hemoglobin C

A
  1. Hemolytic anemia (usually mild)
  2. Cholelithiasis
  3. Jaundice
  4. Splenomegaly
  5. Patients with HbSC gene mutation (one HbC and one HbS trait) have milder symptoms than HbSS patients.
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19
Q

Lab studies for Hemoglobin C disease

A
  1. CBC
    a. ↓ MCV, ↑ MCHC
    b. Mild anemia
    c. ↑ Reticulocytes
  2. PBS
    a. Anisopoikilocytosis
    b. Target cells and microspherocytes
    c. Rod-shaped RBCs containing precipitated hemoglobin C crystals
  3. Hb electrophoresis
    a. Hemoglobin C: > 95%
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20
Q

Lab studies for Hemoglobin C trait

A
  1. CBC
    a. ↓ MCV, ↑ MCHC
    b. Usually no anemia or reticulocytosis
  2. PBS
    Usually normal
  3. Hb electrophoresis
    a. Hemoglobin C: ∼ 50%
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21
Q

Definition of Paroxysmal nocturnal hemoglobinuria

A

An acquired genetic defect of the hematopoietic stem cell characterized by a triad of hemolytic anemia, pancytopenia, and thrombosis

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22
Q

Epidemiology of Paroxysmal nocturnal hemoglobinuria

A
  1. Median age of onset: approx. 35–40 years.

2. ♀ = ♂

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23
Q

Pathophysiology of Paroxysmal nocturnal hemoglobinuria

A
  1. Physiologically, a membrane-bound glycosylphosphatidylinositol (GPI) anchor protects RBCs against complement-mediated hemolysis.
  2. Acquired mutation on the PIGA gene located on the X chromosome → GPI anchor loses its protective effect → RBC destruction by complement and reticuloendothelial system → intravascular and extravascular hemolysis
  3. The GPI anchor proteins involved in PNH are:
    - CD55/DAF (Decay accelerating factor)
    - CD59/MIRL (Membrane inhibitor of reactive lysis)
  4. PNH can also occur in patients with aplastic anemia and myelodysplastic syndrome.
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24
Q

Clinical presentations in Paroxysmal nocturnal hemoglobinuria

A
  1. Pallor, excessive fatigue, weakness
  2. Intermittent jaundice
  3. Episodes of hemoglobinuria causing pink/red/dark urine which usually occurs in the morning due to the concentration of urine overnight.
  4. Vasoconstriction
    a. Headache, pulmonary hypertension
    b. Abdominal pain, dysphagia, erectile dysfunction
  5. Venous thrombosis in unusual locations (e.g., hepatic, cerebral, and/or abdominal veins)
  6. Increased risk of infections (in case of pancytopenia)
25
Q

Lab studies for Paroxysmal nocturnal hemoglobinuria

A
  1. CBC: anemia, thrombocytopenia, and/or pancytopenia ; usually ↑ reticulocytes
  2. Hemolysis workup: ↓ haptoglobin, hemosiderinuria, hemoglobinuria
  3. Direct Coombs test: negative
  4. Flow cytometry of peripheral blood (confirmatory test for PNH): can show deficiency of GPI-linked proteins on the surface of RBCs and WBCs (e.g., CD55, CD59)
CATCH 
C - Cytopenias 
A - Aplastic anemia / Myelodysplastic syndrome
T - Thrombosis 
C - Coombs-negative hemolysis 
H - Hemoglobinuria
26
Q

Complications of Paroxysmal nocturnal hemoglobinuria

A
  1. Vasoconstriction and thrombotic emboli leading to thrombotic complications, e.g., infarction, Budd-Chiari syndrome
  2. Development of acute leukemia
27
Q

Epidemiology of Hereditary spherocytosis

A

Most common inherited hemolytic disease among individuals of Northern European descent

28
Q

Etiology of Hereditary spherocytosis

A
  1. Congenital RBC membrane protein defect
  2. Inheritance pattern
    a. Autosomal dominant (∼ 75% of cases)
    b. Autosomal recessive (∼ 25% of cases)
    c. Family history often positive for relatives who required splenectomy and/or developed cholelithiasis at a young age
  3. Frequently affected proteins
    a. Spectrin
    b. Ankyrin
    c. Band 3
    d. Protein 4.2
29
Q

Pathophysiology of Hereditary spherocytosis

A

Genetic mutation → defects in RBC membrane proteins (especially spectrin and/or ankyrin) responsible for tying the inner membrane skeleton with the outer lipid bilayer → continuous loss of lipid bilayer components → decreased surface area of RBCs in relation to volume → sphere-shaped RBCs with decreased membrane stability → inability to change form while going through narrowed vessels →

  1. Entrapment within splenic vasculature → splenomegaly
  2. Destruction via splenic macrophages → extravascular hemolysis
30
Q

Clinical presentation in Hereditary spherocytosis

A
  1. Anemia and pallor
  2. Jaundice (due to ↑ unconjugated bilirubin)
  3. Splenomegaly with left upper quadrant pain
  4. Black pigment gallstones (made of calcium bilirubinate), may lead to cholecystitis

Presentation is based on the severity of the disease

31
Q

Lab studies for Hereditary spherocytosis

A
  1. Laboratory findings
    a. Normocytic anemia
    b. ↑ Red blood cell distribution width (↑ RDW)
    c. ↑ Reticulocytes (normal range: 0.5%–1.5% of total RBC count)
    d. Findings of hemolytic anemia:
    ↑ Unconjugated bilirubin
    ↓ Haptoglobin
    ↑ LDH
  2. Laboratory tests
    a. Eosin-5-maleimide binding test (EMA)
    b. Negative Coombs test
    c. Positive osmotic fragility test
  3. Blood smear
    a. Characteristic spherocytes
32
Q

Complications of Hereditary spherocytosis

A
  1. Hemolytic crisis: esp. as a result of viral infection
  2. Aplastic crisis: following infection with parvovirus B19 (erythema infectiosum); characterized by a low reticulocyte count (< 0.1% of total RBC count)
  3. Megaloblastic anemia: folate and vitamin B12 deficiency may develop due to chronic hemolysis and high RBC turnover
  4. Megaloblastic crisis: due to folate deficiency (although uncommon in developed countries, it might still be seen among pregnant women)
  5. Other:
    a. Bilirubinate gallstone formation, possibly leading to cholecystitis, cholangitis, and pancreatitis
    b. Growth retardation and skeletal abnormalities due to bone marrow expansion
33
Q

What are the 2 types of Autoimmune hemolytic anemia?

A
  1. Cold AIHA

2. Warm AIHA

34
Q

Definition of cold agglutinin hemolytic anemia

A

Cold agglutinin hemolytic anemia (cold AIHA) refers to a group of autoimmune disorders characterized by hemolysis that is caused by the binding of cold-sensitive autoantibodies to RBCs

  1. Cold agglutinin disease (CAD): primary (idiopathic) form of cold AIHA in which hemolysis is mediated by monoclonal cold-sensitive IgM autoantibodies produced by a low-grade clonal B-cell lymphoproliferative disorder of the bone marrow
  2. Cold agglutinin syndrome (CAS): a rare form of cold AIHA in which cold-sensitive autoantibody-mediated hemolysis occurs secondary to another condition (e.g., infection, lymphoma)
35
Q

Epidemiology of cold agglutinin hemolytic anemia

A
  1. 10–25% of all AIHAs

2. > 50 years of age

36
Q

Pathophysiology of cold agglutinin hemolytic anemia

A
  1. Cold-sensitive antibodies (cold agglutinins): mostly IgM antibodies cause extravascular hemolysis and acute intravascular hemolysis
    - Stable disease: extravascular hemolysis of complement-coated RBCs by the mononuclear phagocyte system
    - Acute exacerbations: Intravascular hemolysis can occur, mediated through the complement system, which is activated by IgM antibodies bound to RBCs.
  2. The antigen-antibody reaction is triggered by low body temperature and/or cold ambient temperatures
37
Q

Etiology of cold agglutinin hemolytic anemia

A
  1. CAD: idiopathic
  2. CAS occurs secondary to other diseases, including:
    a. Mycoplasma pneumoniae or EBV infection
    b. Malignancy (e.g., non-Hodgkin lymphoma, CLL)
    c. Waldenstrom macroglobulinemia

Cold Weather is MMMMiserable
Cold (IgM), AIHA is seen in Malignancy (CLL), Mycoplasma pneumonia, and Mononucleosis

38
Q

Clinical presentations in cold agglutinin hemolytic anemia

A
  1. Classically associated with cold exposure
  2. Can occur as episodes of acute, severe symptoms
  3. Pallor, fatigue, weakness
  4. Painful cyanosis of the extremities (acrocyanosis)
  5. Livedo reticularis
  6. Raynaud phenomenon
  7. Skin ulcerations
39
Q

Lab studies for cold agglutinin hemolytic anemia

A
  1. Evidence of hemolytic anemia
  2. Direct Coombs Test
    - positive for C3d
    - weakly positive for IgG
  3. Cold agglutinin titer ≥ 64 at 4°C
  4. PBS: agglutination of RBCs; spherocytes may be seen
  5. ↓ C3 and C4 due to complement activation
40
Q

Definition of warm agglutinin hemolytic anemia

A

An autoimmune disease characterized by the binding of heat-sensitive autoantibodies to RBCs, which leads to the phagocytosis and destruction of RBCs in the reticuloendothelial system

41
Q

Epidemiology of warm agglutinin hemolytic anemia

A

Can occur at any age

42
Q

Pathophysiology of warm agglutinin hemolytic anemia

A
  1. Heat-sensitive antibodies: Mostly polyclonal IgG antibodies that first bind to multiple RBC antigens, then to Fc receptors on phagocytes
  2. Binding of the antibodies leads to ↑ extravascular hemolysis mediated by the reticuloendothelial system of the spleen and liver.
  3. The antigen-antibody reaction is triggered by body temperatures of ≥ 37°C

“Warm weather is Great”: Warm AIHA is IgG mediated.

43
Q

Clinical presentations in warm agglutinin hemolytic anemia

A
  1. Symptom onset is typically gradual.
  2. Signs of anemia (pallor, fatigue, weakness)
  3. Mild splenomegaly
44
Q

Lab studies for warm agglutinin hemolytic anemia

A
  1. Laboratory evidence of hemolysis
  2. Direct Coombs Test positive for IgG ± C3d not attributable to another cause (i.e., a recent transfusion or cold agglutinin)
  3. PBS: abundant spherocytes
45
Q

Etiology of Microangiopathic hemolytic anemia

A
  1. Primary MAHA
    a. Thrombotic thrombocytopenic purpura (TTP)
    b. Hemolytic uremic syndrome (HUS)
  2. Secondary MAHA ; causes include:
    a. Autoimmune disease (e.g., SLE)
    b. HELLP syndrome
    c. Hypertensive emergency
    d. Disseminated intravascular coagulation (DIC)
    e. Drug induced (e.g., quinine, trimethoprim/sulfamethoxazole, cyclosporine)
46
Q

Pathophysiology of Microangiopathic hemolytic anemia

A
  1. Systemic microthrombi plug small vessels → physical intravascular shearing of RBCs that pass through the small vessels → intravascular hemolysis, schistocytes, and ↑ free Hb
  2. Characteristically accompanied by thrombocytopenia
47
Q

Clinical presentations in Microangiopathic hemolytic anemia

A
  1. Features of anemia (e.g., pallor, fatigue)
  2. Jaundice
  3. Organ dysfunction due to microthrombi formation (e.g., renal dysfunction, altered mental status)
  4. Petechiae due to thrombocytopenia
48
Q

Lab studies for Microangiopathic hemolytic anemia

A
  1. CBC showing anemia and thrombocytopenia
  2. Laboratory evidence of hemolysis with a negative Direct Coombs Test
  3. PBS showing abundant schistocytes
49
Q

Etiology of Macroangiopathic hemolytic anemia

A
  1. Congenital cardiovascular anomalies (e.g., bicuspid aortic valve, coarctation of the aorta)
  2. Moderate and severe aortic stenosis: Heart valve replacement usually resolves the anemia.
  3. In other patient groups: Prosthetic heart valves can cause anemia.
  4. Extracorporeal circulation, dialysis
  5. Exertional hemoglobinuria (“march hemoglobinuria”): RBC destruction in the feet during strenuous exercise (e.g., running on hard surfaces)
50
Q

Pathophysiology of Macroangiopathic hemolytic anemia

A

RBC destruction in the systemic circulation (large vessels) due to mechanical forces applied to RBC membrane → intravascular hemolysis, schistocytes, ↑ free Hb

51
Q

Clinical presentation in Macroangiopathic hemolytic anemia

A
  1. Features of anemia (e.g., pallor, fatigue)

2. Jaundice

52
Q

Lab studies for Macroangiopathic hemolytic anemia

A
  1. Evidence of hemolysis (e.g., ↑ Indirect bilirubin, ↑ LDH, ↓ haptoglobin, reticulocytosis)
  2. DAT: Negative
  3. Blood smear: Schistocytes
  4. Consider echocardiography
53
Q

Definition of Aplastic anemia

A

Pancytopenia caused by bone marrow insufficiency

54
Q

Etiology of Aplastic anemia

A
  1. Idiopathic in > 50% of cases
    a. Possibly immune-mediated
    b. May follow acute hepatitis (hepatitis-associated aplastic anemia)
  2. Medication side effects: carbamazepine, methimazole, NSAIDs, chloramphenicol, propylthiouracil, sulfa drugs, cytostatic drugs (esp. alkylating agents and antimetabolites)
  3. Toxins: benzene, cleaning solvents, insecticides, toluene
  4. Ionizing radiation
  5. Viruses: parvovirus B19, HBV, EBV, CMV, HIV
  6. Fanconi anemia

Can’t Make New Blood Cells Properly = Carbamazepine, Methimazole, NSAIDs, Benzenes, Chloramphenicol, Propylthiouracil

55
Q

Clinical presentation in Aplastic anemia

A
  1. Fatigue, malaise
  2. Pallor
  3. Purpura, petechiae, mucosal bleeding
  4. Infection
56
Q

Lab studies of Aplastic anemia

A
  1. CBC:
    a. Pancytopenia (in contrast to aplastic crisis characterized by anemia only)
    b. Normocytic or macrocytic anemia
  2. Reticulocyte count: low
  3. EPO level: high
  4. Bone marrow biopsy findings
    a. Hypocellular fat-filled marrow (dry bone marrow tap)
    b. RBCs normal morphology
57
Q

Pathophysiology of Anemia of chronic kidney disease

A

↓ synthesis of erythropoietin → ↓ stimulation of RBC production → normocytic, normochromic anemia

58
Q

Lab studies of Anemia of chronic kidney disease

A

↓ hemoglobin, but normal MCV

02. Red Blood Cell Disorders (4 decks)

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