Pincez Pathophysiologies of RBCs (L7) Flashcards
What informations do automated blood cell counters provide us with?
(ex: flow cytometry?)
What is the good old alternative?
- Count for each cell type: RBC, platelets white blood cells
- Differential of wbc (i.e. subtypes: neutrophils, lymphocytes)
- 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
How do reticulocytes appear in the microscope?
They appear more blue/purple because they still have RNA
- center is less pale
What different part of RBC morphology can be indicative of disorders?
- Size variations
- Hemoglobin distribution (very thin outside)
- Shape variation (Sickle cell, Burr cell/dehydrated, elongated, spheric)
- Inclusions of other organelles
- Agglutination/Rouleaux
- Crystal formation
What is the difference between looking at normal bone marrow vs peripheral blood?
Bone marrow → different blood cell precursors
Peripheral blood → only mature forms of the cells (mostly RBCs)
How does Hemoglobin concentration in the blood vary throughout life?
What is the normal range for male vs females?
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)
What is the normal hematocrit (Ht) range for male vs female adults?
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
What are the 2 main sites of destruction of erythrocytes?
Liver and Kidney
Which diseases are related with bone marrow failure (aplastic anemia)?
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
What are the 3 main phases of erythrocyte synthesis?
- Ribosome synthesis
- Hemoglobin synthesis
- Nuclear and organelles extrusion
2e6 RBCs produced/second
- main component of mature erythrocytes = hemoglobin
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)
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
What part of erythrocyte synthesis can explain polycythemia/erythrocytosis?
Increase in EPO secretion from the kidney
What is primary vs secondary polycythemia?
Primary = Defect in the bone marrow (EPO-independent)
Secondary = Defect in the kidney → secrete higher levels of EPO
What can be the different causes of Secondary polycythemia?
ELEVATED EPO LEVELS
- 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) - Chronic hypoxia due to high altitude => Appropriate activation of EPO transcription (physiological)
- Chronic hypoxia due to cardiopulmonary disease or smoking => Appropriate activation of EPO transcription
- Chronic pulmonary disease, Sleep apnea, Smoking
- Cyanotic heart disease - Local chronic hypoxia due to kidney disease => Appropriate activation of EPO transcription
- Arterial stenosis, Kidney disease (hydronephrosis, cysts) - Secretion of EPO by tumors (hepatocellular carcinoma, renal cell carcinoma, hemangioblastoma…) => Ectopic activation of EPO transcription (non-regulated)
What is the main cause of Primary polycythemia?
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
What are the 2 main/general types of anemias?
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
What can be causes of Non-regenerative Microcytic anemias?
How do these cell appear in the microscope?
Microcytic = low MCV + low RET
- Iron deficiency (poïkylocytosis = abnormal shape)
- Thalassemia (globin chains) → normal iron, target cells (Hb small circle in the center)
- 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
What can be causes of Non-regenerative Normo or macrocytic anemias?
Normal or high MCV, low RET
- Chronic kidney disease
- Blackfan Diamond anemia (ribosome protein synthesis)
- B9/B12 deficiency
Other causes…
What can be causes of Regenerative Non-hemolytic anemias?
*high RET
Non-hemolytic = not related to destructions of RBCs
Cause = Acute Bleeding
What can be causes of Regenerative Hemolytic Intrcorpuscular anemias?
High RET, High RBC destruction
- Membranopathies
- Hemoglobinopathies
- Enzymopathies
What can be causes of Regenerative Hemolytic Extracorpuscular anemias?
High RET, High RBC destruction
- Autoimmune hemolytic anemia
- Mechanical
- Infection
What are the 2 mechanisms of erythrocyte destruction?
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)
What are clinical indicators of hemolysis?
- Icterus (jaundice)
- Splenomegaly if extravascular (macrophages destroying the RBCs are mainly in the spleen → spleen gets really big
- Red urine if intravascular
What are biological consequences of hemolysis?
*Regenerative anemia (high RET)
- Increased unconjugated bilirubin (heme is converted into biliverdin, then into unconjugated bilirubin (insoluble), needs to bind to albumin for transport to the liver to be conjugated and excreted as bile, liver has limited capacity of bilirubin)
- Increased lactate dehydrogenase (LDH is an enzyme found in RBCs)
What are the intracorpuscular hemolysis mechanisms?
*Defect of the RBC
Membrane:
- Congenital membrane defects
- Paroxysmal nocturnal hemoglobinuria
Hemoglobin: (acquired)
- Thalassemia
- Sickle Cell Disease
Enzymes:
- G6PD deficiency → more sensitive to oxidative stress
- Pyruvate kinase deficiency → impaired glycolytic pathway → less ATP → hemolysis
