Pathology - S2B2 - Blood 2

Front 1

Define Hemoglobinopathy

Back 1

STRUCTURAL defects in Hemoglobin resulting in an abnormal Hb molecule that can precipitate out/polymerize and lead to hemolysis

Front 2

What is HbA?

Back 2

Normal Hemoglobin with 2 Alpha & 2 Beta chains

Front 3

What is HbA2?

Back 3

Hb with 2 Alpha and 2 Delta chains

Front 4

What is HbF?

Back 4

Hb with 2 Alpha and 2 Gamma chains

HbF-AG (FAG)

Front 5

Hemoglobin whose gene is on Chromosome 16

Back 5

Alpha

**you have 4 copies of Alpha genes

Front 6

Hemoglobin whose gene is on Chromosome 11

Back 6

Beta, Gamma, Delta

**have 2 copies of each

Front 7

What is the abnormality in Sickle Cell Disease?

Back 7

Point mutation in which Valine is substituted for Glutamate at position 6 of the BETA chain of Hemoglobin

Front 8

Describe the Pathogenesis of Sickle Cell disease

Back 8

1. Deoxygenation
2. Aggregation and polymerizatoin of HbS
3. Reversible sickling
4. Irreversible sickling
5. Hemolysis

Front 9

What type of hereditary disease is Sickle Cell Disease?

Back 9

Autosomal Recessive = must have both recessive alleles to be diseased = HbS/HbS

Front 10

What group of people have 8% of their population with the Sickle Cell trait (heterozygous = carry trait but are asymptomatic)?

Back 10

African Americans

Front 11

Describe the polymerization of Hb in Sickle Cell Disease

Back 11

HbS polymerize only with other HbS and do so only in the Deoxy state

Front 12

What conditions make Sickle Cell Disease worse?

Back 12

1. Dehydration = increased concentration of RBC's with HbS
2. Low pH (acidic) = decreases Oxygen affinity for RBC --> causes Deoxy

Front 13

Describe the Sickle Cell Trait

Back 13

Patients are Heterozygotes and only a portion of the hemoglobin is HbS and the remainder is normal HbA. RBC sickling and possibly hemolysis occur in hypoxia

Front 14

List the pathologic findings in Sickle Cell Disease

Back 14

1. Sickle Cells
2. Microvascular occlusion -> thrombosis and infarction due to Sickle cells stuck in small vessels
3. Autosplenectomy = due to repeated bouts of infarction
4. Bone Marrow Hyperplasia = due to hemolytic anemia
5. Extramedullary hematopoiesis = when BM cannot keep up with need
6. Gallstones = due to increased Bilirubin from breakdown of Heme from Hb

Front 15

Sickle Cell Disease

Back 15

What disease is this?

Front 16

Why is there pain in Sickle Cell Anemia?

Back 16

Vaso-occlusive crises in the back or limbs due to microvasculature blockage by sickled cells

Front 17

What would cause an Aplastic Crisis in Sickle Cell Anemia?

Back 17

Parvovirus B19

Front 18

What is the most common cause of death in Sickle Cell Anemia? Propose a possible mechanism

Back 18

Infections

Mechanism: Autosplenectomy results in increased incidence of encapsulated organism infections
-Strep pneumo & Hib
-Salmonella -> Osteomyelitis

Front 19

What is the treatment for Sickle Cell Anemia? Explain the reasoning

Back 19

Hydroxyurea

Increases the levels of HbF (gamma2 + delta2) while decreasing the levels of HbS

Front 20

What does Sickle Cell Trait protect against?

Back 20

Falciparum malaria

Front 21

Describe the distribution of normal adult hemoglobin

Back 21

1. HbA = 96%
2. HbA2 = 3% (alpha2/delta2)
3. HbF = 1% (alpha2/gamma2)

Front 22

Define Thalassemias

Back 22

Lack of or decreased synthesis of structurally normal hemoblogin chains

Front 23

Describe the pathogenesis of Thalassemias

Back 23

-

Front 24

What ethnicities is Alpha-thalassemia most prevalent in?

Back 24

Africa & SE ASIA

Front 25

What ethnicities is Beta-thalassemia most prevalent in?

Back 25

Africa
Asia
MEDITERRANEAN

Front 26

In Thalassemias, What 2 things does Free globin chain aggregates result in?

Back 26

1. Destruction in the spleen

2. Ineffective erythropoiesis = premature destruction of maturing erythroblasts within the BM

Front 27

What is Beta-Thalassemia and what is the cause?

Back 27

1. Decreased synthesis of Beta chains

2. Point mutations causing:
-Splicing errors (most common)
-Promoter region (β+)
-Chain termination (β0)

**unlike Alpha-thalassemia, gene deletions are uncommon

Front 28

Resulting anemia in Beta-Thalassemia

Back 28

Hypochormic, microcytic anemia

**b/c there is less Hb = less heme = less iron in RBC

Front 29

What Hb's are elevated in Beta-Thalassemia?

Back 29

HbF (a2g2)

HbA2 (a2d2)

Front 30

Pathological findings of Beta-thalassemia

Back 30

1. Bone Marrow Hyperplasia
-cortical thinning = "crewcut" skull x-ray
=increased size of maxilla

2. Hepatosplenomegaly

3. Hemosiderosis
- hemolysis is taking place in BM and Spleen where Fe+ is recoverable
-Severe Thalassemias require blood transfusions

Front 31

Beta-Thalassemia

Target cells

Back 31

What disease?

What are the cells called?

Front 32

Beta-thalassemia

Back 32

What disease causes "crewcut" skull on x-ray?

Front 33

List the clinical features of Beta-Thalassemia Major

Back 33

1. β0/β0 or β+/β+ = no functional Beta-globin
2. Severe anemia, ↑↑↑ HbF, ↑ HbA2
3. Transfusion dependent
4. Hemosiderosis
5. Treatment: BM transplant
6. Develops at 6 months of age when HbF levels decline

β0/β0 = do not produce β-chains at all

β+/β+ = reduced β-chain synthesis

Front 34

What is the genotype for β-Thalassemia intermedia

Back 34

β0/β, β+/β+

**severe anemia, but not enough to require regular blood transfusions

Front 35

List the clinical features of β-Thalassemia minor

Back 35

1. β0/β or β+/β = there is one normal Beta-globin gene
2. Asymptomatic
3. Mild anemia, ↑ HbF, ↑ HbA2
4. Protects against Falciparum malaria

Front 36

What is the Etiology of Alpha-Thalassemias?

Back 36

GENE DELETIONS of alpha chains

**there are 2 alpha genes on each of our Chr. 16 = 4 total
**can be various combos of deletions

Front 37

What is the silent carrier state of Alpha-Thalassemia?

Back 37

1 out of 4 alpha genes is deleted (-a/aa)
- completely asymptomatic

Front 38

Describe the Alpha-Thalassemia Trait

Back 38

2 deletions of the Alpha gene:
- (--/aa) or (-a/-a)

Front 39

What is the concern with individuals with the Alpha-Thalassemia Trait?

Back 39

If 2 individuals with the genotype (--/aa) mate, they can produce a child with Hydrops Fetalis = Genetic Counseling

*25% chance of offspring with Hydrops fetalis

Front 40

Describe the HbH disease in Alpha-Thalassemia

Back 40

3 deletions of Alpha chain (--/-a) causes increased HbH = tetramer of Beta chains (β4)

Front 41

What is the result when there are 4 deletions of the Alpha gene in an individual?

Back 41

Hydrops fetalis

Front 42

Type of anemia in Alpha-Thalassemias

Back 42

Hypochromic, microcytic anemia

Front 43

What are the pathologic findings associated with Alpha-Thalassemia?

Back 43

1. Hypochromic, microcytic anemia of variable severity
2. HbH disease
3. Bone Marrow Hyperplasia
4. Hepatosplenomegaly

Front 44

What is Barts Hemoglobin (Gamma4) associated with?

Back 44

Hydrops fetalis Alpha-Thalassemia (lacks all 4 alpha-globin chains)

Front 45

Alpha-Thalassemia (HbH disease = 3 deletions)

Target cells in upper
Heinz bodies = HbH (β4)

Back 45

What disease is this?

How do you know?

Front 46

What ethnicity typically carries the cis genotype (--/αα)of the Alpha-Thalassemia trait?

Back 46

Asians = if both partners have it there is a 25% chance of having child with intrauterine death

Front 47

What ethnicity typically carries the trans genotype (a-/a-) of the Alpha Thalassemia trait?

Back 47

African-Americans

Front 48

Disease caused by an acquired deficiency of Glycosyl Phosphatidyl Inositol (GPI)-linked proteins due to mutations in Phosphatidylinositol Glycan A (PIGA)

Back 48

Paroxysmal Nocturnal Hemoglobinuria

Front 49

Describe the pathogenesis of Paroxysmal Nocturnal Hemoglobinuria

Back 49

1. ↓ GPI anchored proteins (CD55, CD59, C8-binding protein, Decay Accelerating Factor)
2. ↑ complement sensitivity
3. Intravascular Hemolysis

Front 50

How do you diagnose Paroxysmal Nocturnal Hemoglobinuria?

Back 50

Look for the presence of cell surface proteins, if missing it means PNH

Front 51

What are the clinical findings of Paroxysmal Nocturnal Hemoglobinuria?

Back 51

1. Anemia
2. Hemosiderinuria --> leads to iron deficiency
3. Venous thrombi which may be fatal

Front 52

What complications does Paroxysmal Nocturnal Hemoglobinuria cause an increased risk of? (3)

Back 52

1. Aplastic anemia
2. Acute Leukemia
3. Venous thrombosis

Front 53

What cell type has the acquired defect in Paroxysmal Nocturnal Hemoglobinuria?

Back 53

Multipotent Myeloid Stem Cell

Front 54

Why would Paroxysmal Nocturnal Hemoglobinuria occur at night?

Back 54

Respiratory acidosis, which occurs during slow breathing that causes retention of CO2, causes activation of Complement

Front 55

What Screening test and what Confirmatory tests are used in Paroxysmal Noctural Hemoglobinuria?

Back 55

Screening = Sucrose Hemolysis
- sucrose enhances complement destruction of RBC's

Confirmatory = Acidified Serum Test (Ham test)
- acidified serum activates the Alternative complement pathway

Front 56

What type of Anemias are Immunohemolytic anemias?

Back 56

Extrinsic = environment is causing RBC destruction

Front 57

Type of Antibody that causes Warm Autoimmune Hemolytic Anemia

Back 57

IgG, active at 37' C

Front 58

Describe the pathogenesis of Warm AIHA

Back 58

1. IgG coated RBC
2. Fc receptor binds to Splenic Macrophages
3. Spherocytes
4. Destruction in the spleen = Extravascular

Front 59

What are the Secondary causes of Warm AIMA?

Back 59

1. Lymphoproliferative disorders = Lymphoma = B cell neoplasm making Ab's against RBCs
2. Autoimmune diseases = SLE
3. Drugs
-Haptens
-Autoantibodies

Front 60

What drugs can act as Haptens and cause Warm AIHA?

Back 60

1. Quinidine
2. Penicillin
3. Cephalosporin

Front 61

What drug can cause the production of an Autoantibody to RBC's causing Warm AIHA?

Back 61

Methyldopa

**causes production of an Ab that cross-reacts with RBC

Front 62

What 2 disorders are characterized by Spherocytes and how do you differentiate?

Back 62

1. Warm AIHA
2. Hereditary Spherocytosis

**Warm AIHA will be Direct Coomb's test + = tests for Ab's coated on RBC's

Front 63

Type of Antibody that causes Cold Agglutinin Disease

Back 63

IgM

Front 64

Describe the Pathogenesis of Cold Agglutinin Disease

Back 64

1. IgM coated RBC
2. RBC agglutination
3. Complement fixation
4. Intravascular and Extravascular Hemolysis

Front 65

Why does Cold Agglutinin Disease cause agglutination and complement fixation?

Back 65

IgM is a pentamer so it can latch onto more than one RBC = agglutination

Agglutination causes Complement activation

Front 66

What are 2 acute causes of Cold Agglutinin Disease?

Back 66

recovery from Mycoplasma pneumoniae

recovery from Infectious Mononucleosis

Front 67

What are teh 2 chronic causes of Cold Agglutinin Disease?

Back 67

Idiopathic

Lymphoma

Front 68

Describe the Pathogenesis of Paroxysmal Cold Hemoglobinuria

Back 68

IgG antibodies (cold hemolysins) bind to RBC at low temperature, fix complement, and cause hemolysis at temps above 30 C

Front 69

What is the most important marker of Immune Hemolytic Anemias?

Back 69

Direct Coombs test = direct antiglobulin test (DAT)

Front 70

Warm AIHA
-Spherocytes

**Spherocytes are also caused by Hereditary Spherocytosis

Back 70

Autoimmune hemolytic anemia that would cause this

Front 71

Cold Agglutinin Disease
-IgM causes agglutination of RBC's at temperatures lower than body temp

Back 71

What is this disease?

Front 72

What are the clinical features of Warm AIHA?

Back 72

1. Variably severe anemia -> Splenomegaly
2. Treatment is directed to the underlying cause

Front 73

What are the clinical features of Cold Agglutinin Disease?

Back 73

1. Variably severe anemia
2. Self limited
3. RAYNAUD PHENOMENON

Front 74

What is the clinical feature of Paroxysmal Cold Hemoglobinuria?

Back 74

Intermittent massive hemolysis AFTER exposure to cold

Front 75

Describe Macroangiopathic Hemolytic Anemia

Back 75

RBC is hit against something which causes it to lyse

Front 76

What are 2 possible causes of Macroangiopathic Hemolytic Anemia?

Back 76

1. Aortic Stenosis

2. Prosthetic Heart Valves

Front 77

Describe Microangiopathic Hemolytic Anemia

Back 77

partial occlusion of small vessels is the cause of mechanical disruption of the RBC's

Front 78

Give 6 examples of causes of Microangiopathic Hemolytic Anemia

Back 78

1. DIC
2. Thrombotic Thrombocytopenic Purpura
3. Hemolytic Uremic Syndrome
4. Malignant Hypertension
5. SLE
6. Disseminated Cancer

Front 79

What are the pathologic findings of Traumatic Hemolytic Anemia (Micro- or Macroantiopathic)

Back 79

Schistocytes

Front 80

Schistocytes

Micro- or Macroangiopathic Hemolytic Anemia = Trauma

Back 80

What are these cells called?

What is the cause?

Front 81

An 8-year-old AFRICAN AMERICAN boy presents complaining of SEVERE PAIN IN BOTH LEGS. The pain began after the boy attended a pool party and spent much of the day swimming and reports that he has suffered from severe bouts OF BACK AND CHEST PAIN in the past

Back 81

Sickle Cell Disease
-Swimming and lack of oxygen prompted sickling of HbS
-Back and Extremity pain are due to VASO-OCCLUSIVE crises due to microvasculature blockage by sickled cells

Front 82

What is usually the first clinical manifestation of Sickle Cell Disease?

Back 82

Dactylitis = infarctions in the bones of the digits
= hand-foot syndrome (swelling)

Front 83

Autosplenecomy

Howell-Jolly bodies

Back 83

This is a blood smear from a patient with Sickle Cell Disease. What does it indicate? What is the cell called?

Front 84

B is correct
-Decreased Hemoglobin
-Increased HbA2
-usually asymptomatic

Back 84

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