Lectures 41 and 42 Hemolytic Anemias

Question 1

What is the definition of Hemolytic Anemia? What are characteristic cellular/lab findings?

Answer 1

Increased RBC Destruction

Premature Destruction of RBC (anything less than the normal 100-120 days)
Elevated EPO
Increased Hemoglobin degradation products

Question 2

Intravascular VS Extravascular Hemolysis:

• What is the difference?
• what are some differentiating characteristics?

Answer 2

Extravascular – Destruction of the RBC outside of the vasculature, such as in the Phagocytes of the Spleen.
Splenomegaly and jaundice

Intravascular – hemolysis in the vasculature due to complement fixation, parasites, or injury
Findings: Hemoglobinemia, Hemoglobunuria, Hemosiderinuria
Jaundice
No splenomegaly

Question 3

What are some etiologies of Hemolysis?

Answer 3

Red Cell Membrane Disorders – Hereditary Spherocytosis

Enzyme Deficiencies: G6P DHG Deficiency

Acquired Genetic Defects: Paroxysmal Nocturnal Hemoglobinuria

Antibody mediate Destruction

Mechanical Hemolysis

Infections: Malaria, Babesia Microti

Question 4

What are 2 Red Cell Membrane Disorders?

Answer 4

Hereditary Spherocytosis

Hereditary Elliptocytosis (not tested)

Question 5

hereditary Spherocytosis:

• Pathophsyiology
• manifestations

Answer 5

Mutations in Spectrin and Ankyrin proteins
Leads to defect in binding of lipid bilayer to the cytoskeleton

Low of Membrane integrity; more rigid; loss of biconcave shape

Cannot escape spleen == Splenomegaly (congestions of the cords of Billroth)

Manifestations – Splenomegaly, low level Chronic Hemolytic Anemia, Pigment Gall Stones

Question 6

hereditary Spherocytosis:
- Diagnosis
Specific Diagnostic Test
- Treatment

Answer 6

• Osmotic Fragility – cells more susceptible to lysis due to hypotonicity

Treat:
Folate
Splenectomy

Question 7

Enzyme Deficiencies: Glucose 6 Phosphate Dehydrogenase Deficiency: G6PD –

Pathophysiology:

Answer 7

XLR
Defective Enzyme of Glycolysis

Episodic Intra and Extra Vascular Hemolysis:
Hemolysis caused by anything that causes oxidant stress

Inclusions in the RBCs
Some Destroyed by the Spleen
Some lose membrane integrity —- spherocytosis

Question 8

What are some examples of exposures that can lead to increased oxidatant stress leading to episodic hemolysis in G6P DHG Deficiency?

Answer 8

Infection – most commonly

Drugs – anti-malarials; sulfa drugs

Foods – Fava beans in the Mediterranean Variant

Question 9

Acquired Genetic Defect: Paraoxysmal Nocturnal Hemoglobinuria:

• pathophysiology

Answer 9

• Defect In PIG A enzyme; which makes GPI (a complement regulator)
• GPI prevents break down of complement regulators (DAF and CD59) (?)
• Therefore there is unregulated Complement Activity leading to Thrombosis, platelet dysfunction,

5-10% of patients will go on to devleop AML (leukemia)

Question 10

Paraoxysmal Nocturnal Hemoglobinuria:

- specificic test

Answer 10

Flow Cytometry of GPI Linked Proteins that regulate Complement – CD55 (DAF), CD59, C8 binding protein

Sucrose Hemolysis Testing –

Question 11

Antibody Mediate Destruction: Hemolytic disease of the New Born

• Pathophysiology -
• Treatment

Answer 11

Rh Antigen Negative Mom becomes sensitized to Rh Antigen Positive Fetus
Exposure either due to Fetomaternal hemorrhage vs Previous Pregnancy

Mom’s antibodies cross the placenta and cause fetal Anemia

Treatment:
Prophylaxis of Rh negative Moms with Rh Positive Fetus with RhoGAM (RhD Ig)

Question 12

Mechanical Hemolysis:

- etiologies:

Answer 12

Abnormal Heart valves,
Microangiopathic Hemolytic Anemias (MAHAs) = DIC, TTP, HUS,

Bypass/Hemodialysis
Burns
Drowning
Marathons

Question 13

Mechanical Hemolysis: MAHAs – Thrombocytopenic Purpura (TTP)

• pathophysiology
• SEAT (what does this acronym stand for?)
• Treatment

-

Answer 13

SEAT - Shistocytes, Elevated LDH, Altered vWF, Thrombocytopenia

Pathophysiology:
Deficiency of ADAMTS 13 – a Metalloprotease which cleaves vWF before activation by shear stress causes platelet aggregation
Defiency leads to – vWF platelet aggregation and microvascular thrombosis
As RBCs navigate small vessels they are cleaved by Fibrin strands — leading to Schistocytes

Treatment: Plasma Exchange –

Question 14

Infections and Hemolytic Anemia –

- what two infections ?

Answer 14

Malaria – parasitic Infection

Babesia Microti –

Question 15

Differences in presentation and Peripheral blood smear findings between Malaria and Babesia Microti ?

Answer 15

malaria – Paroxysmal Fevers
Smear: Intra-RBC Ring forms
Falciprum – Banana shaped gametocyte

Babesia Microti – Extra-RBC Parasites, ring forms
Destruction of parasites is constant
Therefore fever is not paroxysmal

Question 16

Classifications of Hemoglobin Abnormalities

Answer 16

Deficient Globin Synthesis – Thalassemia Syndromes

Hemaglobinopathies: Structurally abnormal Globins – Sickle Cell Disease, Unstable Hemoglobins

Question 17

what globin subunits make up the following hemoglobin types?

• Embryonic HGB
• Fetal HGB
• HGB A-
• HGB A2

Answer 17

Embryonic Hemoglobin - Zeta and Epsilon

Fetal Hemoglobin – Gamma and Alpha

Hemoglobin A – Alpha and Beta

Hemoglobin A2 – Delta and Alpha

Question 18

Thalassemias — Deficient Globin Synthesis

Answer 18

Pathophysiology:

Loss of production of either 1 of the 4 alpha chains or 1 of 2 beta genes

Question 19

What is alpha thalassemia?

What are some ethnic groups that have higher incidence of the condition?

Answer 19

Missing 1 or 2 of the 4 alpha genes

36% of AA have a mutation in 1 of the alpha genes
RBCs are Low Normal Size
Usually these people are Asymptomtic

4% of AA have 2 Defective Alpha genes (on different chromosomes)
Small RBCs

5% of SE Asians – loss of both alpha globin genes on the same chromosome; loss of A1 and A2 genes

Question 20

What is Alpha Thalassemia Intermedia ?

Describe the pathology

Answer 20

Mixed Alpha I and II Thalassemia
3 Mutant Alpha Globin Genes

With only 1 working Alpha Globin Gene, some Alpha/Beta Tetramers can form but there will be excess Beta Chains

Excess Beta Chains form Beta Tetramers = HGB H
Doesn’t bind O2 very well
Precipitates of Hemoglobin –> Heinz Bodies –> Spleen tries to remove –> Spherocytosis –> Splenic Sequestration/Phagocytosis

Question 21

Alpha Thalassemia Major

Answer 21

Mutations in all 4 alpha genes
1/1600 SE Asians

Severe Fetal anemia; Hydrops Fetalis; die in utero

only have Tetramers of Beta chains (hemoglobin H)
or Gamma chains (hemoglobin Barts)

Question 22

What are Beta globin only tetramers called?

What are gamma globin only tetramers called?

Answer 22

Beta - HGB H

Gamma - Hemoglobin Barts

Question 23

What is Beta thalasemia, in general?

ethnic groups?

Answer 23

Partial or full dysfunction of 1 or both of the beta globin genes

Similar geographic/ethnic distribution to alpha thalassemias

Question 24

Beta Thalassemia Minor:

• What is the genetic profile of the beta genes?
• pathophysiology?

Answer 24

Beta Thalassemia Minor:
Profile – 1 affected Beta Gene vs 2 partially affected Beta Genes

Some Normal Hemoglobin A
Some Excess Alpha Globin Chains

Precipitate –> Heinz bodies –> spherocytosis –> splenic sequestration

Question 25

Beta Thalassemia Intermedia/Major: Genetic profile? Pathophysiology? Manifestations, Smear?

Answer 25

Genetic Profile -- complete absence of both beta globin genes. Pathophysiology - Beta globin genes are not expressed until infancy. Therefore manifestations only occur after the decline of Fetal Hemoglobin Manifesations -- Skeletal Deformities (of the skull) Smear - Lots of variation of the RBC; Nucleated RBCs

Question 26

Beta Thalassemia Intermedia/Major: Treatment? Side effect of treatment and subsequent management

Answer 26

Dependent on Transfusions Which can lead to Transfusional Iron Overload Patients need to be on Chelation therapy to bind excess Iron

Question 27

What is the major Hemoglobinopathy ? Describe the mutation and how this leads to a misshapen RBC

Answer 27

Sickle Cell Disease Beta Globin Mutation Substitution: Adenine --> thymine, Amino Acid Mutation: Glutamine ---> Valine The Hydrophobic Valine: allows Deoxy HGB to form strands --> Fibers --> Fasicles --> Leading to sickle shape of the RBC and loss of bi-concave shape

Question 28

Sickle Cell Disease -- | - Mechanisms of Damage

Answer 28

Vascular Occlusion: Physical Blocking; sickle cells are rigid and get stuck at bifurcations in small vessels Vascular Adhesions: Damage the Endothelium; adhere to the endothelium; leading to thrombosis and blockage

Question 29

Sickle Cell Disease -- | Pathophysiology and Manifestations

Answer 29

Chronic Hemolytic Anemia -- Sickle cells can only survive for 10 days. The Free HGB Damages Endothelium and Scavenges Nitric Oxide Vascular occlusion and adhesion leads to infarction: - Splenic Infarction: Function Asplenia --- Susceptibility to encapsulated organisms (Nisseria, H Flu, Pneumococcus) - renal Injury -- loss of renal concentrating ability; dehydration; more sickling, crisis - Bone infarct (bone capillaries are rigid and more easily obstructed) - Pulmonary Infarct -- can lead to PNA, infection; exacerbating symptoms - Brain Infarct: - other infarct: hand/food/penile/priapism

Question 30

What Factors increase sickling and therefore risk of sickle cell crisis? To what organisms are persons with Functional asplenia susceptible? What virus is classically associated with onset of aplastic crisis ?

Answer 30

Exercise, dehydration, low pH, Cold Temperatures Infections Encapsulated Organisms: Pneumococcus, H. Flu, Nisseria Virus: Parvovirus B19 (erythemia Infectiosum aka cheek slapped rash)

Question 31

What is the most common cause of death in SCD patients?

Answer 31

Infection

Question 32

Treatment and Management of Sickle Cell Disease

Answer 32

Screen/Rule out/Prevent Infection: - Immunizations for Nisseria and Pneumococcus - CXR, UA Hydrations Transfusion -- shown to prevent stroke Hydroxyurea Treatment: Induce production of fetal HGB (Gamma and Alpha Globin) which is non sickling

Question 33

what is HGB Electrophoresis & Quantification? what is the profile of persons with sickle cell disease? What is the profile of persons with sickle cell trait?

Answer 33

Gel Electrophoresis to determine presence of abnormal HGB Sickle Cell patients: Hemoglobin S; No Hemoglobin A Sickle Cell Trait: Hemoglobin S; + Hemoglobin A

Question 34

which two hemoglobin abnormalities are susceptible to aplastic crisis caused by Parvovirus B19?

Answer 34

Beta Thalassemia Major Sickle Cell Disease