Anemia diseases Flashcards
What are general findings in anemia (6)?
Fatigue
Weakness
Dyspnea
Lightheadedness
Pale conjunctiva
Headache
How, generally, is anemia diagnosed?
Hematocrit and hemoglobin
Anemias are divided into 3 general categories. What are they?
Microcytic anemia (<80 fL)
Normocytic anemia (80-100 fL)
Macrocytic anemia (>100 fL)
What causes microcytic anemia?
extra division in erythrocyte to maintain MCHC, as hemoglobin synthesis is impaired
What are the 5 causes of microcytic anemia?
Sideroblastic anemia
Anemia of chronic disease (Late)
lead poisoning
Thalassemia (alpha and beta)
Iron deficiency (Late)
(SALTI)
What is sideroblastic anemia?
Deficiency in protoporphyrin synthesis resulting in anemia
What causes sideroblastic anemia? (2 causes)
ALA synthase mutation or vitamin B6 deficiency
What is the pathophysiology of sideroblastic anemia?
Fe is pumped into mitochondria located in the erythroblast. Because there is a deficiency in ALA sythase, porphyrin is never made and Fe never binds to porphyrin in the mitochondria. This results in a build up of iron in the mitochondria causing the formation of free radicals. These free radicals eventually destroy the cell and release all of the iron into the blood. As a result, transferrin binds the massive spillage of iron and brings it to storage tissue.
What are the lab findings in Sideroblastic anemia? (serum iron, TIBC, % saturation, ferratin)
Increased ferratin
Decreased TIBC
Increased serum iron
Increased iron saturation on transferrin
hypochromic RBCs
What is anemia of chronic disease?
Chronic inflammation resulting in anemia
What is the pathophysiology of anemia of chronic disease?
Chronic inflammation results in the increased synthesis of hepcidin, which inhibits ferroportin preventing the release of iron from storage sites (duodenal enterocytes, liver, and bone marrow macrophages), and suppresses Epo synthesis. This decreases the amount of Hb synthesis, resulting in an extra division of erythrocytes resulting in microcytic RBCs and anemia
What are lab findings of anemia of chronic disease? (serum iron, TIBC, % saturation, ferratin, FEP)
decreased serum iron
Decreased TIBC (cells sense that there is plenty of iron so it decreases the amount)
decreased iron saturation % on transferrin
increased ferratin
increased free erythrocyte protoporphyrin (FEP)
Hypochromic RBCs
What is the treatment for anemia of chronic disease?
treat the underlying cause
Some patients will benefit from recombinant Epo, since chronic inflammation can suppress natural synthesis of Epo
What is anemia from lead poisoning? How does it present?
lead inhibits ALAD and ferrochetolase, which inhibits Hb synthesis
Similar to sideroblastic anemia
What is thalassemia? What are the two types?
A decrease in SYNTHESIS of globin chains
alpha and beta thalassemia
What are the 3 normal types of hemoglobin?
HbF (α2γ2)
HbA (α2β2)
HbA2 (α2δ2)
How many alpha genes do we have?
- 2 alleles for each chromosome
What are the 4 types of alpha thalassemia and indicate their genotype and severity
Silent carrier:
- -α/αα
- Asymptomatic
α-thalassemia trait
- -α/-α (more common in Africans) or –/αα (more common in Asians)
- Mild anemia
HbH disease
- –/-α
- Severe anemia
- Formation of HbH (β4 tetramer), which damages RBCs
Hydrops fetalis
- –/–
- Incompatible with life
- Formation of Hb Bart’s (γ4 tetramer)
How many beta genes do we have?
- 1 allele on each chromosome
When does beta thalassemia typically present. Why?
6-9 months of age
This is the transition period from HbF to HbA
What are the types of mutations that can occur in a beta allele?
absent (β0) or diminished (β+) production of β-globin
What are the types of beta thalassemia? Indicate the geneotype and its severity
β thalassemia minor
- β/β+ or β/β0
- Mild form of anemia
β thalassemia major
- β/β+ or β0/β0
- Severe anemia
- Typically presents around 6-9 months when beta chains replace γ chains
What are the lab findings of thalassemias?
target cells
Electrophoresis
- Decreased HbA
- Increased HbA2
- Increased HbF
What is the treatment for thalassemias?
blood transfusions with iron chelator to prevent iron overload
Decribe iron homeostasis (how it is absorbed and delivered into tissues). What is hepcidin?
- When consumed, heme is broken down via heme oxygenase, which releases Fe3+.
- Ferroreductase converts iron into its ferrous form at the duodenum
- Fe3+ —-ferroreductase—-> Fe2+ (ferrous iron)
- Fe2+ moves through the divalent metal transporter DMT1
- Some of the ferrous iron is stored in a protein cage, which together is called ferritin
- Fe2+ moves through the enterocyte via the ferroportin channel located on the basolateral side of the enterocyte
- This channel can be inhibited by hepcidin
- Once, out of the enterocyte, Fe2+ is oxidized to Fe3+ via ferrous oxidase
- Fe3+ binds to transferrin, a protein responsible for iron transport in the blood
- Transferrin is important as free iron creates free radicals
- Transferrin delivers Fe3+ to liver and bone marrow macrophages for storage
What are some clinical presentations of iron deficiency anemia?
Koilonychia (spoon nails; concaved nail beds)
Pica (chewing on things)
What are the lab findings in iron deficieny anemia? (serum iron, TIBC, % saturation, ferratin, FEP)
Serum iron decreases
Total iron binding capacity (TIBC) increases (increase to try and find more iron)
% saturation decreases
Ferritin is decreased
Free erythrocyte protoporphyrin (FEP) increases
Hypochromic RBCs
What is the treatment for iron deficiency?
ferrous sulfate
What are the two subcategories of normocytic anemia?
non hemolytic (underproduction)
hemolytic (immune mediated and non-immune)
What are the causes of non-hemolytic anemia?
Aplastic anemia
myelophthisic processes
iron deficiency (early)
anemia of chromic disease (early)
Fanconi anemia
What is aplastic anemia?
an insult to HSCs, which results in pancytopenia
What is the pathophysiology to aplastic anemia?
Alteration to the stem cell can either 1) result in expression of a neoantigen that results in immune destruction of the HSC via CD8s, or 2) reduce the HSC’s ability to proliferate
Can drugs and chemicals cause aplastic anemia?
yes
Can viral infections cause aplastic anemia?
yes
Can autoimmune damage cause aplastic anemia?
yes
Name a genetic disease that causes aplastic anemia
fanconi anemia
What would CBC show in aplastic anemia? bone marrow biopsy?
pancytpoenia (all cells from meyloid lineage)
decreased cellularity and increased adipose tissue
What is the treatment for aplastic anemia (think about the different causes)?
Cessation of drug or prevent exposeure to chemical
corticosteroids to suppress immune system
Transfusion
marrow stimulating factors
HSCT
What is a myelophthisic process?
Process that replaces the bone marrow, which impairs hematopoiesis.
(cancer, fibrosis, etc)
What are causes of immune mediated and non-immune hemolytic anemia?
Immune:
- Paroxysmal nocturnal hematuria
- Immune hemolytic anemia
- Warm
- Cold
Non-immune:
- Intrinsic:
- Glucose-6-Phosphate Dehydrogenase Deficiency
- Hereditary spherocytosis
- Sickle cell anemia
- Extrinsic:
-
Microangiopathic hemolytic anemia
- TTP, HUS, DIC
-
Macroangiopathic hemolytic anemia
- Defective heart valve
-
Microangiopathic hemolytic anemia
What is the pathophysiology of Paroxysmal nocturnal hematuria? Why does it occur at night?
Acquired defect of the GPI linkage protein in myeloid cell lineage (all myeloid cells), resulting in absent GPI. GPI is needed for CD59 and CD53 (Decay accelerating factor) linkage. This leaves RBCs and other cells vulnerable to complement system, which is in the blood serum, leading to cell destruction.
The reason for increased destruction at night is due to our bodies breathing shallow when we sleep, making us retain more CO2. This decreases blood pH, which increases activity of complement. Therefore, the decrease in pH causes increased destruction.
Will Paroxysmal nocturnal hematuria have a positive coombs test?
Yes!
GPI deficiency results in no CD59 or CD53 (DAF). This means Ig mediated complement activation can occur
What test is used to definitively diagnose Paroxysmal nocturnal hematuria?
acid lysis test
(decrease pH which increases activity of complement system)
What are the two types of immune hemolytic anemias? What are the Igs involved?
Warm Autoantibodies (IgG)
Cold Autoantibodies (IgM)
WAG CAM
What is the pathophysiology of warm and cold immune hemolytic anemia?
Similar to hereditary spherocytosis, immune hemolytic anemia causes spherocytosis. Immunoglobulins bind to antigens on RBCs, which pass through the spleen and are recognized via splenic macrophages. These macrophages either completely destroy the RBC or remove part of the membrane, decreasing the surface area-to-volume ratio, forming spherocytes. These spherocytes are then destroyed when they pass through the spleen.
will immune hemolytic anemia have a positive coombs test?
yes
What is the treatment for immune hemolytic anemia?
corticosteroids (suppress immune system)
IVIG (attack IVIG which leaves RBCs alone)
splenectomy (gets rid of the Ig secreting plasma cell source)
What are the two categories of non-immune hemolytic anemias and the causes?
Intrinsic:
- Hereditary spherocytosis
- G6PD deficiency
- HbS
Extrinsic
-
Microangiopathic hemolytic anemia
- HUS, TTP, DIC
-
Macroangiopathic hemolytic anemia
- Valve problem
What is the pathophysiology of hereditary spherocytosis?
Defective vertical connections cause blebs in the RBC membrane. Macrophages in the spleen remove the blebs, which causes a spherical shape over time due to the low surface are-to-volume ratio. Ultimately, these spherocytes are not able to maneuver through the spleen and so they are destroyed
What are the 3 common genetic mutations that cause hereditary spherocytosis?
Band 3, Ankyrin, or Beta-spectrin are most common causes
How is hereditary spherocytosis diagnosed?
Osmotic fragility test
What is the treatment for hereditary spherocytosis?
Splenectomy
remember, the spherocytes are viable. The issue is they cannot maneuver through the spleen and are therefore destroyed. Remove the spleen and the RBCs will be fine
What is Glucose-6-Phosphate Dehydrogenase Deficiency?
X-linked recessive mutation in G6PD gene
What is the pathophysiology of G6PD?
Mutation in the G6PD gene results in a reduce half-life of G6PD. G6PD is required for the synthesis of glutathione. Glutathione is responsible for reducing reactive oxidative species that damage the cell. The reduced half-life of G6PD means the cell loses the ability to synthesize glutathione much sooner than a normal cell. Without glutathione, ROS wreak havoc and denature Hb. Denatured Hb form precipitates called Heinz bodies. Splenic macrophages will sometimes remove the precipitates by taking a “bite” of the cell, forming bite cells or it will completely destroy the cell.
What are type of blood cells are found in G6PD deficiency?
Bite cells
What is HbS?
Sickle cell anemia is a autosomal recessive mutation in beta chain of hemoglobin resulting in a defect in Hb
What is the pathophysiology of HbS anemia?
When HbS becomes deoxygenated, the HbS polymers aggregate into “needle-like structures” which forces the RBC to become a sickle shape. This results in extravascular (primary pathology) and intravascular hemolysis. Intravascular lysis can result in vaso-occlusive issues
How does HbF prevent sickling?
HbF (fetal hemoglobin) helps prevent the polymerization of HbS within the RBC. HbF is synthesized even after birth, but at low amounts. However, some individuals synthesize more than others.
What is the treatment for HbS?
Hydroxyurea
Hydroxyurea increases HbF expression, which prevents sickling
What is microangiopathic hemolytic anemia?
Formation of a thrombus that results in the sheering of the RBC
What are the causes of microangiopathic hemolytic anemia?
Thrombotic thrombocytopenia purpura
Hemolytic uremia syndrome
Disseminated intravascular coagulation
What causes macrocytic hemolytic anemia?
typically defective heart valves
What are the causes of macrocytic anemia
megaloblastic anemia
non-megaloblastic anemia
What are the 3 causes of megaloblastic anemia?
folate deficiency
B12 deficiency
orotic aciduria (don’t need to know for the test)
Describe folate homeostasis (absorption and delivery)
What are the 4 major lab findings in folate deficiency?
Hypersegmented PMNs (> 5 lobes)
Decreased serum folate
Increased serum homocysteine
Normal methylmalonyl-CoA levels
Describe B12 homeostasis
What is pernicious anemia?
Pernicious anemia is an autoimmune disorder that destroys the parietal cells in the stomach, which prevents the synthesis of IF. The lack of intrinsic factor prevents the absorption of cobalamin leading to anemia and other complications
Which deficiency, folate or B12, will result in CNS abnormalities?
B12
What are the 4 major lab findings in B12 deficiency?
Hypersegmented PMNs (> 5 lobes)
Decreased B12 levels
Increased serum homocysteine
Increased methylmalonyl-CoA levels
