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PHGY 313 > Pincez Pathophysiologies of RBCs (L7) > Flashcards

Pincez Pathophysiologies of RBCs (L7) Flashcards

1
Q

What informations do automated blood cell counters provide us with?
(ex: flow cytometry?)

What is the good old alternative?

A
  1. Count for each cell type: RBC, platelets white blood cells
  2. Differential of wbc (i.e. subtypes: neutrophils, lymphocytes)
  3. Several erythrocytes parameters:
    - Hemoglobin concentration (g/L)
    - Mean corpuscular volume (MCV) = hematocrit/rbc count (fL)
    - Reticulocytes (g/L) = rbc precursors → marker of RBC production

Good old method = let the blood sediment in a tube and measure the hematocrit

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2
Q

How do reticulocytes appear in the microscope?

A

They appear more blue/purple because they still have RNA
- center is less pale

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3
Q

What different part of RBC morphology can be indicative of disorders?

A
  1. Size variations
  2. Hemoglobin distribution (very thin outside)
  3. Shape variation (Sickle cell, Burr cell/dehydrated, elongated, spheric)
  4. Inclusions of other organelles
  5. Agglutination/Rouleaux
  6. Crystal formation
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4
Q

What is the difference between looking at normal bone marrow vs peripheral blood?

A

Bone marrow → different blood cell precursors
Peripheral blood → only mature forms of the cells (mostly RBCs)

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5
Q

How does Hemoglobin concentration in the blood vary throughout life?
What is the normal range for male vs females?

A

Very high in neonates → goes down quickly in first 3 months → gradually ramps back up to reach steady state ~20 years old

Hemoglobin (Hb) concentration:
120 – 155 g/L (adult females)
140 – 175 g/L (adult males)

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6
Q

What is the normal hematocrit (Ht) range for male vs female adults?

A

Total volume of rbc/total blood volume:
34.9-44.5% (adult females)
38.8-50.0% (adult males)

*Ht and Hb are highly correlated

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7
Q

What are the 2 main sites of destruction of erythrocytes?

A

Liver and Kidney

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8
Q

Which diseases are related with bone marrow failure (aplastic anemia)?

A

Constitutional (genetic):
- Fanconi anemia (susceptibility to DNA damage) → lack of DNA replication due to the damage
- Dyskeratosis congenita (telomere maintenance failure) → quickly children can’t produce enough blood cells because the telomeres are too short

Acquired:
- Immune (idiopathic)
- Toxic (drug or radiation-induced)
- Infection

Tumoral bone marrow (Leukemia) → tumor cells take up all the space, noe more space for normal hematopoietic cells (see a lack of diversity un the microscope)

*Not specific to erythrocytes, all hematopoiesis is affected

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9
Q

What are the 3 main phases of erythrocyte synthesis?

A
  1. Ribosome synthesis
  2. Hemoglobin synthesis
  3. Nuclear and organelles extrusion

2e6 RBCs produced/second
- main component of mature erythrocytes = hemoglobin

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10
Q

What factor can be the cause of anemia at the different levels listed below:
1. DNA
2. Ribosomes
3. Globin chains
4. Fe2+
5. Porphyrin
6. Heme
7. EPO (hormonal stimulus)

A

the different levels listed below:
1. DNA → B9/B12 vitamine deficiency impairs replication
2. Ribosomes → Diamond-Blackfan anemia (can’t translate enough GATA1 or globin chains)
3. Globin chains → Thalassemia
4. Fe2+ → Inflammation or Iron deficiency
5. Porphyrin → Porphyria
6. Heme → Sideroblastic anemias
7. EPO → Chronic kidney disease

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11
Q

What part of erythrocyte synthesis can explain polycythemia/erythrocytosis?

A

Increase in EPO secretion from the kidney

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12
Q

What is primary vs secondary polycythemia?

A

Primary = Defect in the bone marrow (EPO-independent)

Secondary = Defect in the kidney → secrete higher levels of EPO

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13
Q

What can be the different causes of Secondary polycythemia?

A

ELEVATED EPO LEVELS

  1. Constitutional (germline) genetic variants leading to augmented hypoxia sensing => Inappropriate activation of EPO transcription (i.e. even in normoxia)
    - Variants in VHL, EPAS1 (HIF-1a), EGLN1 (PHD2, which degrades HIF-1α)
  2. Chronic hypoxia due to high altitude => Appropriate activation of EPO transcription (physiological)
  3. Chronic hypoxia due to cardiopulmonary disease or smoking => Appropriate activation of EPO transcription
    - Chronic pulmonary disease, Sleep apnea, Smoking
    - Cyanotic heart disease
  4. Local chronic hypoxia due to kidney disease => Appropriate activation of EPO transcription
    - Arterial stenosis, Kidney disease (hydronephrosis, cysts)
  5. Secretion of EPO by tumors (hepatocellular carcinoma, renal cell carcinoma, hemangioblastoma…) => Ectopic activation of EPO transcription (non-regulated)
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14
Q

What is the main cause of Primary polycythemia?

A

Polycythemia vera

Polycythemia vera (PV), the most frequent type of myeloproliferative neoplasm (MPN). Somatic mutation in JAK2 kinase (V617F) most common
Result in constitutive (EPO-insensitive) activation of downstream STAT (promotes differentiation)
=> Polycythemia

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15
Q

What are the 2 main/general types of anemias?

A

Non-regenerative (low RET):
- Problem in the production of RBCs
1) Microcytic (low MCV)
2) Normo/Macro-cytic

Regenerative (high RET)
- Problem in the destruction of RBCs
1) Non-hemolytic
2) Hemolytic → Intracorpuscular or Extracorpuscular

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16
Q

What can be causes of Non-regenerative Microcytic anemias?
How do these cell appear in the microscope?

A

Microcytic = low MCV + low RET

  1. Iron deficiency (poïkylocytosis = abnormal shape)
  2. Thalassemia (globin chains) → normal iron, target cells (Hb small circle in the center)
  3. Sideroblastic anemia → normal iron, cells have dark spots of iron in them as it is not incorporated into heme

Can diagnose in the microscope seing low hemoglobin content → thick edges get very thin

17
Q

What can be causes of Non-regenerative Normo or macrocytic anemias?

A

Normal or high MCV, low RET

  1. Chronic kidney disease
  2. Blackfan Diamond anemia
  3. B9/B12 deficiency
    Other causes…
18
Q

What can be causes of Regenerative Non-hemolytic anemias?

A

*high RET
Non-hemolytic = not related to destructions of RBCs

Cause = Acute Bleeding

19
Q

What can be causes of Regenerative Hemolytic Intrcorpuscular anemias?

A

High RET, High RBC destruction

  1. Membranopathies
  2. Hemoglobinopathies
  3. Enzymopathies
20
Q

What can be causes of Regenerative Hemolytic Extracorpuscular anemias?

A

High RET, High RBC destruction

  1. Autoimmune hemolytic anemia
  2. Mechanical
  3. Infection
21
Q

What are the 2 mechanisms of erythrocyte destruction?

A

Extravascular (physiological, but pathological when too much):
Physiological < 1% of RBCs
1. RBC is phagocytosed by macrophage in the kidney/liver and broken back in 1 of the 3 main components
2. Protoporphyrin turned into bilirubin → liver and excreted in urine

Intravascular (pathological):
- Contents are released in the bloodstream → Hb goes to the kidney → urine (change in color)

22
Q

What are clinical indicators of hemolysis?

A
  1. Icterus (jaundice)
  2. Splenomegaly if extravascular (macrophages destroying the RBCs are mainly in the spleen → spleen gets really big
  3. Red urine if intravascular
23
Q

What are biological consequences of hemolysis?

A

*Regenerative anemia (high RET)

  • Increased unconjugated bilirubin
  • Increased lactate dehydrogenase
24
Q

What are the intracorpuscular hemolysis mechanisms?

A

*Defect of the RBC

Membrane:
- Congenital membrane defects
- Paroxysmal nocturnal hemoglobinuria

Hemoglobin: (acquired)
- Thalassemia
- Sickle Cell Disease

Enzymes:
- G6PD deficiency
- Pyruvate kinase deficiency

25
Q

What are the extracorpuscular hemolysis mechanisms?

A

Immune:
- Autoimmune hemolytic anemia

Mechanic:
- Thrombotic microangiopathy
- Cardiac valves
- Thermal injury

Infection:
- Malaria

26
Q

What is hereditary spherocytosis?

A

A membranopathie → intracorpuscular hemolysis

Membrane → phospholipid bilayer closely linked to cytoskeleton
Problem: lack of link between cytoskeleton and membrane → loss of pieces of membranes

Spherocytes have lost a small volume and a large surface → decreased surface/volume ratio → more spherical shape → splenic sequestration → increase contact with macrophages → phagocytosis

*Cytoskeleton made of a-spectrin and b-spectrin

27
Q

What confers deformability to RBCs?

A
  1. High surface/volume ratio
  2. Low intracellular viscosity
  3. Healthy membrane

*Disk shape, not spheric

28
Q

What is the best treatment for hereditary spherocytosis?

A

Splenectomy
But increase risk of encapsulated bacteria fatal infections, thrombosis and possibility cancer

Because spherical RBCs get seuqestered in the spleen

29
Q

What are the 3 membranopathies?

A

membranopathie → regenerative anemia (hemolysis)

  1. Spherocytosis → loss of vertical interactions
  2. Elliptocytosis → loss of horizontal interactions
    - Defect inside the cytoskeleton → RBC is elongated
  3. RBC hydration is maintained through ionic channels and pumps
    - Intracellular Ca2+ (by activating GARDOS channel) is the main parameter of H2O flux regulation
    - Overhydrated hereditary stomatocytosis
    - Dehydrated hereditary stomatocytosis (xerocytosis)

*Can see all in the microscope with a blood smear

30
Q

What causes paroxysmal nocturnal hemoglobinuria?

A

Somatic (acquired) variant (mutation) in PIGA gene (coding for GPI)
GPI is an anchor for CD55 and CD59 proteins that prevent complement activation

=> Acquired loss of CD55 and CD59 => Complement mediated hemolysis

*Encoded by PIGA locus on the X chromosome

Can be diagnosed by treating the samples in flow cytometry (CD55-CD59-)

31
Q

What are clinical implications and treatment of paroxysmal nocturnal hemoglobinuria?

A

1) Acute hemolytic anemia Classically at night
2) Thrombosis
3) Bone marrow failure

Treatment:
Complement blocker (eculizumab)

32
Q

Which enzymopathies cause regenerative anemia?

A
  1. G6PD deficiency
    RBC are highly vulnerable to oxidative stress due to:
    - High oxygen content
    - Presence of only one defensive mechanism against free radicals: G6PD/NADPH pathway that produces reduced glutathione

*X-linked autosomal disease

  1. Pyruvate kinase deficiency
    RBC do not have nucleus nor mitochondria, Energy supply rely on Glycolysis (Amount of pyruvate kinase already synthetized)

Without enough ATP, Na+ K+ ATPase pumps are the first to stop => Dehydration secondary to K+ leak

*Autosomal recessive disorder

33
Q

What are the different classes of G6PD deficiencies?

A

Increased sensitivity to oxidative stress
- Class 2-3: Only while increased oxidative stress
(some drugs, ingestion of fava beans, infection) - Class 1: At baseline (permanent)

Hemolytic regenerative anemia
- Intermittent (class 2-3)
- Chronic (class 1)

34
Q

What are 2 types of Autoimmune hemolytic anemia (AIHA)?

A

Autoimmune destruction of RBC, by:

  1. IgG → produced mainly in B-cells, most frequent
    - Leads to macrophage phagocytosis → they remove small parts and end up with microspherocyte
  2. IgM → bigger immunoglobulin, hemolysis in the liver and by complement activation
35
Q

What are causes/test/features of Autoimmune hemolytic anemia (AIHA) by IgG?

A

Causes:
Primary (no underlying cause)
Secondary to
- Immunodeficiency
- Autoimmune disorder
- Leukemia/lymphoma
- Drugs

Direct antiglobin test (coombs test)
Agglutination at 37 degrees
=> Warm AIHA
- In a dish, put an Ab against IgG at the surface of RBC → will bind and agglutinate in the dish
- If no agglutination, it means the RBCs have no IgGs at their surface

Clinically classified as regenerative hemolytic anemia

36
Q

What are features of Autoimmune hemolytic anemia (AIHA) by IgG?

A

Direct antiglobin test (coombs test) Agglutination at 3-4 degrees
=> Cold AIHA

Causes:
Primary
Secondary to
- Infection
- Lymphoma

37
Q

What are clinical symptoms of Mechanic-caused Extracorpuscular Hemolytic Regenerative anemia?

And the dysfunction of organ implicated?

A

Mechanic

Clinically:
- Regenerative hemolytic anemia
- Thrombocytopenia (low blood platelet count)
- Schistocytes (fragmented red cells)

Dysfunction of the organ downstream of thrombi:
- Kidney (hemolytic and uremic syndrome)
- Brain (thrombotic thrombocytopenic purpura)

38
Q

What are Infection-causes Extracorpuscular Hemolytic Regenerative anemia?

A

Malaria → RBC destruction
*regenerative hemolytic anemia

PHGY 313 (4 decks)

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