Lectures 41 and 42 Hemolytic Anemias Flashcards
What is the definition of Hemolytic Anemia? What are characteristic cellular/lab findings?
Increased RBC Destruction
Premature Destruction of RBC (anything less than the normal 100-120 days)
Elevated EPO
Increased Hemoglobin degradation products
Intravascular VS Extravascular Hemolysis:
- What is the difference?
- what are some differentiating characteristics?
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
What are some etiologies of Hemolysis?
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
What are 2 Red Cell Membrane Disorders?
Hereditary Spherocytosis
Hereditary Elliptocytosis (not tested)
hereditary Spherocytosis:
- Pathophsyiology
- manifestations
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
hereditary Spherocytosis:
- Diagnosis
Specific Diagnostic Test
- Treatment
- Osmotic Fragility – cells more susceptible to lysis due to hypotonicity
Treat:
Folate
Splenectomy
Enzyme Deficiencies: Glucose 6 Phosphate Dehydrogenase Deficiency: G6PD –
Pathophysiology:
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
What are some examples of exposures that can lead to increased oxidatant stress leading to episodic hemolysis in G6P DHG Deficiency?
Infection – most commonly
Drugs – anti-malarials; sulfa drugs
Foods – Fava beans in the Mediterranean Variant
Acquired Genetic Defect: Paraoxysmal Nocturnal Hemoglobinuria:
- pathophysiology
- 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)
Paraoxysmal Nocturnal Hemoglobinuria:
- specificic test
Flow Cytometry of GPI Linked Proteins that regulate Complement – CD55 (DAF), CD59, C8 binding protein
Sucrose Hemolysis Testing –
Antibody Mediate Destruction: Hemolytic disease of the New Born
- Pathophysiology -
- Treatment
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)
Mechanical Hemolysis:
- etiologies:
Abnormal Heart valves,
Microangiopathic Hemolytic Anemias (MAHAs) = DIC, TTP, HUS,
Bypass/Hemodialysis
Burns
Drowning
Marathons
Mechanical Hemolysis: MAHAs – Thrombocytopenic Purpura (TTP)
- pathophysiology
- SEAT (what does this acronym stand for?)
- Treatment
-
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 –
Infections and Hemolytic Anemia –
- what two infections ?
Malaria – parasitic Infection
Babesia Microti –
Differences in presentation and Peripheral blood smear findings between Malaria and Babesia Microti ?
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
Classifications of Hemoglobin Abnormalities
Deficient Globin Synthesis – Thalassemia Syndromes
Hemaglobinopathies: Structurally abnormal Globins – Sickle Cell Disease, Unstable Hemoglobins
what globin subunits make up the following hemoglobin types?
- Embryonic HGB
- Fetal HGB
- HGB A-
- HGB A2
Embryonic Hemoglobin - Zeta and Epsilon
Fetal Hemoglobin – Gamma and Alpha
Hemoglobin A – Alpha and Beta
Hemoglobin A2 – Delta and Alpha
Thalassemias — Deficient Globin Synthesis
Pathophysiology:
Loss of production of either 1 of the 4 alpha chains or 1 of 2 beta genes
What is alpha thalassemia?
What are some ethnic groups that have higher incidence of the condition?
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
What is Alpha Thalassemia Intermedia ?
Describe the pathology
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
Alpha Thalassemia Major
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)
What are Beta globin only tetramers called?
What are gamma globin only tetramers called?
Beta - HGB H
Gamma - Hemoglobin Barts
What is Beta thalasemia, in general?
ethnic groups?
Partial or full dysfunction of 1 or both of the beta globin genes
Similar geographic/ethnic distribution to alpha thalassemias
Beta Thalassemia Minor:
- What is the genetic profile of the beta genes?
- pathophysiology?
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
Beta Thalassemia Intermedia/Major:
Genetic profile?
Pathophysiology? Manifestations, Smear?
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
Beta Thalassemia Intermedia/Major:
Treatment?
Side effect of treatment and subsequent management
Dependent on Transfusions
Which can lead to Transfusional Iron Overload
Patients need to be on Chelation therapy to bind excess Iron
What is the major Hemoglobinopathy ?
Describe the mutation and how this leads to a misshapen RBC
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
Sickle Cell Disease –
- Mechanisms of Damage
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
Sickle Cell Disease –
Pathophysiology and Manifestations
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
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 ?
Exercise, dehydration, low pH,
Cold Temperatures
Infections
Encapsulated Organisms: Pneumococcus, H. Flu, Nisseria
Virus: Parvovirus B19 (erythemia Infectiosum aka cheek slapped rash)
What is the most common cause of death in SCD patients?
Infection
Treatment and Management of Sickle Cell Disease
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
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?
Gel Electrophoresis to determine presence of abnormal HGB
Sickle Cell patients: Hemoglobin S; No Hemoglobin A
Sickle Cell Trait: Hemoglobin S; + Hemoglobin A
which two hemoglobin abnormalities are susceptible to aplastic crisis caused by Parvovirus B19?
Beta Thalassemia Major
Sickle Cell Disease
