Flashcards in Module 1: G6PD deficiency; Sickle Cell and Paroxysmal Nocturnal Hemo Deck (42):
What kind of anemia is G6PD deficiency?
Normocytic Anemia with predominant Intravascular hemolysis with also Extravascular hemolysis (only case where its both)
--periodic not chronic
What inheritance pattern is G6PD?
X linked recessive
--mediterranean, asian and African
--all men because its x linked
What are the two main type of G6PD deficiency mutation?
G6PD A: African Variant: milder version (only older RBCs are affected)
G6PD B: Mediterranean Variant: More severe ( even younger RBCs are affected)
What is the pathogenesis for G6PD deficiency mutation?
Defect in the hexose monophosphate shunt
G6PD dehydrogenase reduces NAD to NADPH
--NADPH keeps glutathione in the reduced form and therefore keeping glutathione in the reduced form is a protection mechanism from oxidative stress which happens all the time
---In G6DP deficiency there is a decreased half life of G6PD therefore decreased NADPH and decreased reduced glutathione so cells are prone to oxidative stress by H202 (intravascular hemolysis part)
G6PD deficiency is considered episodic not chronic why?
only happens when the cell undergoes oxidative stress
1. Infection (particularly pneumonia)
2. Fava beans (aka diet)
3. Sulfa Drugs
---oxidative stress in intravascular hemolysis
G6PD deficiency is considered intravascular as well as extravascular hemolysis.Explain the two mechanisms
Oxidative stress -------- oxidation of SH groups on globin chains of Hb ---- Hb precipitate as Heinz Bodies ---- intravascular hemolysis (predominant) --- Hemoglobinuria and Hemoglobinemia
---splenic macrophages pick up the Heinz bodies and literally take a bite out of the RBC and eat the Heinz bodies ---- extravascular hemolysis
What is the presentation for G6PD deficiency?
Dark Urine (due to free Hb in the intravascular hemolysis)
What are the two stains for G6PD deficiency?
Crystal Violet or Supra Vital Stain (aka green): allows you to see oxidize globin chains aka heinz bodies
Wright-Giemsa Stain: see bite cells directly from the spleen consequence of extravascular hemolysis
What is seen on peripheral blood smear in a patient with G6PD deficiency?
No spherocytes seen on peripheral smear
--do see reticulocytes, heinz bodies and bite cells
What do you see in the bone marrow of a patient with G6PD deficiency?
Erythroid Hyperplasia: bone marrow compensating by forming lots of RBCs
What is the best investigation for G6PD deficiency?
G6PD assay also called enzyme assay
---have to wait a few weeks after hemolytic crisis to do this test because reticulocytes have a normal half life but as they mature into erythrocytes the half life decreases
What do you see as far as lab values in patients with G6PD deficiency?
1. Increased LDH
2. Unconjugated Bilirubin
4. Hemoglobinemia (due to increased free Hb due to destruction of RBC in the intravascular space)
5. Increased Reticulocytes
6. Decreased heptoglobin (protein produced by the liver and this protein mops up free hemoglobin in the blood. the levels are reduced because they are getting used up trying to mop up the mess aka free Hb)
7. In urine: free Hb ---- hemoglobinuria and hemosiderin = hemosiderinuria
What is the complication of patients with G6PD deficiency?
None --- self limiting so complete resolution
--note no splenomegaly
If a patient with G6PD gets involved in a car accident and needs his spleen taken out and does not get the needed yearly vaccines and therefore keeps getting infections, what could be a complication?
Acute tubular necrosis (Excess hemoglobin is damaging the renal tubules aka nephrotoxic)
What type of anemia is sickle cell?
Normocytic anemia with predominant extravascular hemolysis
What is the inheritance pattern of sickle cell anemia?
Autosomal recessive point mutation (also called missense mutation) at position 6 of Beta Chain
--glutamic acid replaced by valine
--happens in Africans
Explain the bands seen in normal individuals?
HbA2: alpha 2 and delta 2 (Everyone has this no function at all -- like 1-2%)
HbF (after 6 months of age expires)
HbA (we all have this in large quanities)
Explain the bands of a carrier/trait (heterozygote carrier)
HbA, HbS (asymptomatic)
RBCs with less than 50% HbS don't sickle in vivo except in renal medulla during extreme hypoxia/hypertonicity of the medulla
Explain the bands of a sickle cell patient (homozygous)
HbS & HbS (again extravascular)
A crisis is due to an increase of sickling of the RBC's, what are these crisis events caused by?
1. Hypoxia (long flights)
Explain the 4 different sickle cell crisis's
1. Aplastic crisis: caused by parvo virus B19
2. Vaso-occlusive Crisis: bone and joint pain due to ischemia due to sickeled RBC sticking together in the vessels
3. Splenic Crisis (splenic sequestration): formation of a white infarction leading to coagulative necrosis of the spleen
4. Hemolytic Crisis: Happens in the spleen (Spleen is actually destroying the sickle cells aka splenic macrophages)
What is the pathogenesis for sickle cell anemia?
HbS polymerizes (or crystalizes) when deoxygenated --- polymers aggregate into needle like structures --- sickle cells
(note: prone to small vessel thrombosis)
What do you find in the blood of patients with sickle cell?
Increased unconjugated bilirubin
Increased free Hb (dark urine)
Decreased haptoglobin (cleaning up all the free Hb, getting used up super fast)
What do you see on a blood smear in patients with sickle cell?
Target cells (hemoglobin settling in center of RBCs --- looks like an actual target)
What is the best investigation for sickle cell?
Hemoglobin Electrophoresis (no HbA and lots of HbS)
What symptoms do you see in children with sickle cell anemia?
1. Crew Cut appearance and chipmunk face (prominent maxillary bones due to expansion of medullary cavity aka hematopoeisis in the skull) (Adults and kids) (more thalassemia then sickle cell)
2. Failure to thrive
3. Dactylitis: swollen hands and feet due to vaso-occlusive infarcts seen in the bones (note only see this in kids due to tiny capillaries so its easy for sickle cells to occlude these capillaries)
4. Autosplenectomy due to fibrosis --- leads to recurrent encapsulated bacterial infections: most common cause of death in kids
5. Frontal bossing (children and adults): prominent frontal skull bone
In adults what are the two most common causes of death in patients with sickle cell anemia?
1. Acute chest crisis: necrotizing pneumonia aka red infarct in the lung due to vaso-occlusion (patients do not respond to abx)
2. Chronic Renal failure
What are the complications for patients with sickle cell anemia?
1. LE: ulcers due to ischemia ---can get secondary infection via Staph Aureus ---sepsis and gangrene
2. Bone: Salmonella Osteomyelitis (infection of the bone)
(note only patients with sickle cell get this type of bone infection)
3. Hip Bone: Avascular necrosis of the head of the femur
4. Penis Priapism: painful sustained erection this is b/c they have a problem draining blood from the penis
5. Hepatomegaly: liver takes over from the spleen and liver starts to do extravascular hemolysis and extramedullary hematopoeisis
6. Chololithiasis and Jaundice due to damage to the liver
7. Acute inflammation of the spleen (big) then chronic inflammation and fibrosis = atrophy
8. Encapsulated bacterial infection due to no spleen
9. Megaloblastic Anemia due to no folate (needed for DNA maturation)
10. Heart Failure
11. Eyes Retinopathy due to acute ischemia
12. Brain they get ischemic strokes due to vaso-occlusion aka red infarct
What are some treatments for sickle cell?
1. Hydroxyurea (stimulates HbF, increased NO and decreased platelet aggregation)
2. Folic Acid
3. Vaccines after splenectomy
4. Bone marrow transplant (Definite solution)
What is hemoglobin C?
Patient will have both hemoglobin C and S: C is very similar to S in that C is a point mutation: lysin replaces glutamic acid on position 6.
---less sickling in C
--so patients with HbSC actually do better than patients with HbSS
---they do get more vascular retinopathy and avascular necrosis of the head of the femur but less sickling
What type of anemia is paroxysmal nocturnal hemoglobinuria?
Normocytic anemia with predominant intravascular hemolysis
---episodic or periodic (Same thing)
What is the etiology for paroxysmal nocturnal hemoglobinuria?
Acquired defect in myeloid stem cells --- mutation of X linked gene PIGA --- absent GPI (Cell membrane glycolipid anchor) ----cells become susceptible to complement
What binding proteins are absent in PNH?
Absence of CD55, CD59 and C8 binding proteins ---- susceptibility to hemolysis
CD55 (Also called DAF--decay activating factor)
CD59 (Also called MURHLE)
--normally located on the RBC and these protect the cell from complement (most complement activity is at night)
Intravascular hemolysis leads to what?
What is the presentation for PNH?
See dark urine the 1st time you pee in the morning
Spleenomegaly: splenic vein thrombosis because PNH patients get platelet dysfunction (venous thrombosis a lot)
What are the two investigations for PNH?
Screening: sucrose hemolysis test and Ham's acid Test
Flow cytometry: absence of CD55 and CD59 on WBC's ; Flaer test
What are the complications of PNH?
Venous Thrombosis (Hepatic, portal, or cerebral vein): DVT to PE
--can lead to hepatic vein thrombosis --- Budd Chiari --- Cirrhosis
Iron Deficiency Anemia (Due to chronic loss of Hb in urine)
AML (acute myeloid leukemia) or MDs in 10% of patients
---note PE from DVT is the most common cause of death
What are treatments for PNH?
What is the half life of a RBC in a sickle cell patient?
About 20 days (due to splenic hemolysis)
Paroxysmal Nocturnal Hemoglobinuria, means what? and why is the pee dark first thing in the AM?
At night (nocturnal)
Blood in urine (hemoglobinuria) hence why pee is dark the dark indicates blood
---pH of blood is lower than usual and this usually happens at night so hence pH drops and the RBCs start lysing
What is the pathogenesis for PNH?
Sleep --- resp depression -- increased CO2 levels so hypercapnia ---- resp acidosis --- complement --- however no CD55 or CD59 so you get intravascular hemolysis that causes hemoglobinuria