Lecture 2a Flashcards
What makes someone anemic?
Hgb <12 female, <13.6 male
Hct <35% female, <41% male
What are the causes of microcytic anemia?
Iron deficiency
Lead toxicity
Zinc deficiency
Thalassemia
Chronic anemia
What are the causes of macrocytic(megaloblastic) anemia?
Vitamin B12 deficiency
Folate deficiency
DNA synthesis inhibitors
Define intravascular hemolysis.
RBCs lyse within blood vessels
Note: decrease in haptoglobin, possible hemoglobinuria
What types of RBCs appear in intravascular hemolysis?
Schistocyte
Define extravascular hemolysis.
RBCs are destroyed within organs (spleen, liver)
Note: haptoglobin may not decrease
Why do sphereocytes form in extravascular hemolysis?
A little piece of RBC gets bitten off but the RBC snaps back into a normal form
How is iron in the cells affected between intravascular and extravascular hemolysis?
Intravascular: decrease in iron over time
Extravascular: iron is recovered and stored
When do we see spleen enlargement?
Extravascular hemolysis
When do we see red-brown urine?
Intravascular hemolysis
Why would MCV be elevated in hemolysis?
Because of the increase of reticulocyte count
Why would reticulocyte not increase?
Bone marrow may run out of resources to make more
What is a type of structural anemia?
Hereditary spherocytosis
What are types of hemoglobinopathies?
Thalassemias
Sickle Cell disease
What is a type of metabolic anemia?
G6PD deficiency
What is a type of immune-related anemia?
Autoimmune hemolytic anemia
Paroxysmal nocturnal hemoglobinuria
Hemolytic disease of the newborn
Who often inherits hereditary spherocytosis?
1 in 5000 northern Europeans
Autosomal dominant
What is the pathology behind hereditary spherocytosis?
Round instead of flexible biconcave disk
In small red pulp fenestrations which leads to phagocytic destruction
What are some symptoms of hereditary spherocytosis?
Mild to severe anemia
Can be undetected for years
Jaundice
Enlarged spleen
Gallstones (50% of pts)
What are possible treatments for hereditary spherocytosis?
Folic acid 1mg daily
Transfusion (EPO may reduce the need in infants)
Splenectomy only >5yo or until puberty (need antipneumococcal vaccination)
What tests should we order to help determine hereditary spherocytosis?
Blood smear
Coombs testing(should be negative)
What are the types of Hgbs and how prevalent they are?
HgbA 97-99% in RBC (2alpha, 2 beta subunits)
HgbA2 1-3% in RBC (2alpha, 2 delta)
HgbF <1% in RBC (2alpha, 2 gamma)
HgbS (2 alpha, 2 betaS)
What chromosomes are important for creating Hgb? What do they code for?
Chromosome 16: 2 copies of alpha-globing gene (4 total)
Chromosome 11: 1 copy of beta-globulin gene (2 total), as well as delta and gamma
What causes alpha thalassemias?
Gene deletions that reduce alpha-chain synthesis
What shows up on a Hgb electrophoresis for alpha thalassemia?
Equal proportions of HgbA, HgbA2, HgbF
What is the pathology behind alpha thalassemias?
Increased number of small “pale” RBCs
Excess beta chains precipitate which causes damage to RBC membranes leading to hemolysis in marrow and splenic vessels
Who are likely to have alpha thalassemia?
Southeast asian and Chinese descent
Mediterranean or African descent
What is the alpha thalassemia syndrome called when they have 3 normal a-globulin genes? 2,1,0?
3: silent carrier (alpha thalassemia minima)
2: alpha thalassemia minor
1: hemoglobin H Disease (no use for O2 transport)
0: Hydrops fetalis
What labs do we use to find alpha thalassemia?
Hgb electrophoresis (normal in minima and minor, HgbH band in HgbH disease)
Inclusion bodies (in HgbH disease)
What appears on a peripheral smear for alpha thalassemia trait/minor?
Hypochromic microcytic cells
Target cells
What appears on a peripheral smear for a Hgb H disease?
Hypochromic microcytic cells
Target cells
Poikilocytosis
Normal RBC if had transfusion
What treatment do you need for alpha thalassemia minima?
No treatment needed
Check of iron overload from transfusion
What treatment do you need for Hgb H disease?
Folic acid supplementation 1 mg/day
Splenectomy
Regular transfusion
What do you avoid taking when you have Hgb H disease?
Iron supplements
Oxidative drugs…
Sulfa drugs
Antimalarials
Isoniazid
Nitrofurantoin
What causes beta thalassemias?
Gene point mutations that cause reduced beta-chain synthesis
What are the types of mutations in beta thalassemias?
Beta+: reduced, but not absent beta-chain synthesis
Beta0: absent beta-chain synthesis
What shows on on a Hb electrophoresis for beta thalassemia?
Increased HgbA2 and HgbF
Who are likely to have beta Thalassemias?
Mediterranean descent
African and Asian descent
What is the pathology of beta thalassemias?
Excess alpha chains precipitate which damages RBC membranes causing hemolysis in marrow, spleen, and liver
Alpha chains → inclusion bodies → damaged erythroid precursors
Surviving RBCs → inclusion bodies → shortened lifespan
What are the types of beta thalassemias?
Normal
Minor
Intermedia
Major
What shows up on a Hgb electrophoresis for beta thalassemia?
Abnormal proportions of HgbA, HgbA2, HgbF
What exam findings would appear on a pt with beta Thalassemia?
Chipmunk Faces
Thinning of long bones
Pathologic fracture
Failure to thrive
Why are children not growing when they have beta Thalassemia?
They are not getting enough O2
What appears on a a peripheral smear for beta-thalassemia minor?
Hypochomic microcytic cells
Target cells
Note: same as alpha-thalassemia minor
What appears on a peripheral smear for beta-thalassemia intermedia?
Hypochomic microcytic cells
Target cells
Poikilocytes
Note: Same as Hgb H disease
What appears on a peripheral smear for beta-thalassemia major?
Hypochomic microcytic cells
Target cells
Poikilocytes
Nucleated RBCs
What is the treatment for B-minor?
None
What is the treatment for B-intermedia?
Genetic counseling (usually)
Transfusion
Splenectomy
Avoid Iron supplements
What is the treatment for B-major?
Transfusion-dependent
Splenectomy
Luspatercept - action-A trap drug
Allogenic bone marrow transplant
What is contraindicated for Luspatercept?
Splenectomy
Pregnant
Breastfeeding
What is the MOA for Luspaterecept?
Promotes production of RBCs by interfering with TGF-beta signaling
What is the dosing for Luspatercept?
SC injection every 3 weeks
What are the SE to Luspatercept?
Decreased Creatine clearance
Increase LFTs (liver function test)
MSK pain
GI upset
HTN
Extramedullary hematopoietic masses
Thromboembolisms
Why do we worry about iron overload?
The spleen destroyed RBCs but the heme is still there so careful when taking iron supplements
What is the cause of SCA?
Autosomal recessive inherited disease affecting betaS gene (affects HgbS)
Heterozygous: sickle cell trait (asymptomatic)
Homozygous: sickle cell anemia
Who are most likely to get SCA?
African Americans 1/400 in US
Mediterranean, Latin, Native American Descent
What is the pathology behind SCA?
Unstable HbS causes “sickeled cells” causing vaso-occlusive episodes(block blood flow)
Why do sickle cells cause vasoocclusion?
They are inflexible and stick to endothelium
What can trigger vast-occlusive episodes in SCA?
Hypoxemia
Acidosis
Infection
Excessive exercise
Abrupt temp changes
Anxiety/stress
What shows up on a Hgb electrophoresis in SCA?
Abnormal proportions of HgbA, HgbA2, HgbF
Presence of HgbS band
What appears on a peripheral smear in SCA?
Target cells
Sickled RBCs
Howell-Jolly inclusion body
When do S/S appear in SCA? What are they?
6 month
Jaundice, pallor
Pain
Retinopathy
Splenomegaly
Hepatomegaly
Gallstones
Cardiomegaly
Hyperdynamic precordium
What are the symptoms of SCA on the extremities?
Non healing wound
Dactylitis(swelling and inflammation of digits)
Where are the locations of sickle cell crisis(ischemic injury)?
Abdomen, bones, joints, soft tissue
Less than 18months: hands/feet
Childhood/teens: bones of arms and legs
Adults: vertebrae
What are some complications of sickle cell?
Bone necrosis
Cerebral atropy
CKD
Cardiac enlargement/heart failure
HTN
Hyposplenism
Retinopathy
Hepatomegaly, hepatic failure
Sickle cell crisis
What makes sickle cell anemia so bad compared to other anemias?
To blocks blood vessels and cuts off blood flow to tissues
What can we give to support SCA?
Folic Acid
Vacines (pnuemococcal, covid, influenza)
Ace inhibitors (protect from proteinuria)
Omega-3-fatty acids (reduce crisis)
Transfusion
Pain management
Antibiotics
Why do we give prophylactic antibiotics to SCA pts?
So they dont get sick
What are the disease-modifying medications for SCA?
Hydroxyurea
Crizanlizumab
L-glutamine
How does hydroxyurea work?
Increase HgbF levels
Reduces vasoocclusive episodes
What is the major SE of hydroxyruea?
Bone marrow suppression
Vasculitis skin ulcer
Increase cancer risk
Teratogenic (don’t use if pregnant)
What medications do we give to SCA if they cannot tolerate hydroxyurea?
Crizanlizumab
L-glutamine
How does crizanlizumab work?
Monoclonal antibody against P-selectin proteins on endothelial cells and platelets
Reduces vasoocclusive episodes by reducing interactions between RBCs and endothelium
What are the SE and dosage of crizanlizumab?
Some joint pain
IV every 2-4 weeks, expensive
How does L-glutamine work?
Decreases vasoocclusive episodes by reducing oxidative stress that promotes sickling
What are the SE and dosage for L-glutamine?
Joint pain
Powder, mixed with food and water, expensive
What are the treatments for SCA?
HOP
Hydration
Oxygenation
Pain control
Transfusion
Allogenic hematopoietic stem cell transplant
What is a splenic sequestration crisis?
Disproportionate amount of blood being sequestered in spleen leading to shock
Enlarges spleen and and Hgb drops >2 baseline
10-15% mortality rate
What causes G6PD deficiency?
X-linked recessive genetic defect
Who are likely to be G6PD deficient?
African-American males
Asian and Mediterranean descent
Rarely seen in females
What is the pathology behind G6PD deficiency?
Oxidative stress → Hb denatures, forms precipitate (Heinz bodies)
Heinz bodies damage RBC membrane → destruction by spleen
Cells can also rupture spontaneously (intravascular)
What are some S/S of G6PD deficiency?
Usually asymptomatic
Episodic hemolytic anemia
Jaundice in newborns
What symptoms appear in an acute episode in G6PD deficiency?
Malaise
Weakness
Abdominal
Lumbar pain
Jaundice
Dark urine
What shows on a peripheral smear for a G6PD deficiency?
Bite cells
Blister cells
Polychromataphils/Reticulocytes
Heinz bodies if special stained
What are some preventive measures for G6PD?
Avoiding oxidant drugs, trigger foods
Genetic counseling
What are some therapeutic measures for G6PD?
Removing offending agent
Folic acid supplementation
Transfusion
Do we monitor for iron overload in G6PD deficiency?
No, they hardly need transfusions
What can cause autoimmune hemolytic anemia?
50% idiopathic
Lupus
Lymphocytic leukemia
Lymphoma
Drugs: Antibiotics, methyldopa, levodopa, NSAIDs
What are some symptoms that present in an autoimmune hemolytic anemia pt?
Abrupt, rapid onset with fatigue, jaundice, splenomegaly
10% mortality
What types of RBCs are formed in autoimmune hemolytic anemia?
Spherocytes
What is the pathology for autoimmune hemolytic anemia?
Tags RBCs for destruction by immune system
Complements can also tag to be destroyed by Kupffer cells in liver
IGM help facilitate MAC
What are the two types of autoimmune hemolytic anemia?
Warm: happens at normal body temp
Cold: happens at colder temp
What is the difference between a direct and indirect Coombs test?
Direct: a pts own blood is tested with reagent
Indirect: we take pts serum(has Ig’s) and combine with donors blood and then add reagent
What diagnostic test do we give to determine if a pt has autoimmune hemolytic anemia?
Antiglobulin (Coombs) test
What shows up on a peripheral smear in autoimmune hemolytic anemia?
Marked microsphereocytes
Polychromataphils/reticulocytes
What are the possible treatments for autoimmune hemolytic anemia?
Immunosuppressants (Prednisone, rituximab)
Treat underlying diseases
Transfusion
How does hemolytic disease of the newborn occur?
Mother develops antibodies(IgG) and tags the fetal RBCs which causes the own baby’s immune system to attack and hemolysis their own RBCS
Who are likely to cause hemolytic disease for the newborn?
Rh- mother
Rh+ father/fetus
What are some symptoms for the newborn with hemolytic disease?
Jaundice
Anemia
Hepatomegaly
Splenomegaly
Edema
HF
Which Coombs test is positive for hemolytic disease of the newborn?
Direct Coombs is positive for the newborn
Indirect Coombs is positive for mother
What are some treatments for hemolytic disease of newborn?
Before birth: fetal transfusion, early labor, maternal plasma exchange(reduces Ig levels)
After birth: transfusion, supportive care
Preventative care: RhoGAM
Who are likely to have Paroxysmal Nocturnal Hemoglobinuria?
Young adults
Equal in any gender at any age
What causes paroxysmal nocturnal hemoglobinuria?
Acquired genetic defect that causes RBCs lysis
CD55 and CD59 (regulates MAC)
What substance helps get rid of Hgb?
NO
What are some symptoms of low NO?
Esophageal spasms
Erectile dysfunction
Renal Damage
Thrombosis
Why does paroxysmal nocturnal hemoglobinuria tend to occur at night?
Blood pH drops at night which helps in the process of RBC hemolysis
What are some symptoms of of Paroxysmal Nocturnal Hemoglobinuria?
Thrombosis on veins of mesentery, liver, skin and CNS
Anemia
What diagnostic tests do we give to check for paroxysmal nocturnal hemoglobinuria? Which is gold standard?
Urine hemosiderin
Flow cytometry (gold standard)
What treatments are there for paroxysmal nocturnal hemoglobinuria?
Allogenic hematopoietic stem cell transplant
Eculizumab
Transfusion
Iron replacement therapy
Corticosteroids (short-term)
What is the difference between the acute and chronic blood loss?
Acute is direct loss of RBC
Chronic is depletion of iron stores
What are some symptoms of blood loss?
Hypovolemia: can lead to hypoperfusion
What are some symptoms of blood loss?
Hypovolemia: can lead to hypoperfusion
