Test 1 Flashcards
What are the major clinical manifestations of Hemochromatosis?
Cirrhosis, DM, arhtritis, cardiomyopathy, hypogonadotrophic hypogonadism
Hemochromatosis & Porphyria
At 10,000 feet, explain hemochromatosis
Innapropriate intestinal absorption of iron d/t decreased hepatic production of Hepcidin
Hemochromatosis & Porphyria
What gene is associated w/ hereditary hemochromatosis?
HFE gene located on HLA-A locus on chromosome 6P
A 20 yo patient presents with classic Hemochromatosis symptoms. What type of the disease does he have?
Non-HFE associated. HFE associated hemochromatosis presents in the 50’s or 60’s.
Where in the GI tract is iron absorbed?
In the duodenum through DMT1 transporters or through the reduction of Fe3+ (ferric) into Fe2+ (ferrous) iron by duodenal cytochrome B (DcytB)
What type of iron molecule is absorbable?
Fe2+, FerrOUS iron
What acts as the regulator of iron traffic in the body?
Hepcidin – its presence decreases iron absorption by binding to ferroportin molecules in basolateral membranes and macrophages
What is the first symptomatic organ in patients w/ Hemochromatosis?
The liver – hepatomegaly, spider angiomas, splenomegaly, ascites are all results of liver damage
What is the best lab value to rule in/out hemochromatosis?
Serum ferritin concentration
What is a porphyria?
A disease in which one or more specific enzymes in the heme synthesis pathway is either inhibited or increased
What is the primary manifestation of a hepatic porphyria?
Neurological deficits
There are 8 enzymes which encode for heme. Where are each found?
1 & 6-8 are located in the mitochondria. #2-5 are in the cytosol of erythroid precursor cells
What are the two types of porphyrias?
Hepatic and erythropoetic, depending on whether the heme intermediate that accumulates arise from the liver or from developing erythrocytes
Are erythropoeitic or hepatic porphyrias more common?
Hepatic! Erythropoetic porphyrias are characterized by elevations of porphyrins in the bone marrow and erythrocytes
Is Acute Intermittent Porphyria (AIP) hepatic or erythropoeitic?
AIP is a hepatic, autosomal dominant condition
Which is the most common porphyria?
Porphyria Cutanea Tarda
What are the primary clinical features of Porphyria Cutanea Tarda?
Blistering skin lesions on the backs of hands, forearms, face, legs, feet. Neuro symptoms are absent.
What is the indicated treatment for PCT?
Weekly phlebotomy or (Hydroxy)Chloroquine
What is the primary treatment for an attack of AIP?
Cessation of the offending inciting factor, and IV Hemin.
Name each WBC type
What is the order of erythropoeisis?
Proerythroblast –> Basophilic Erythroblast –> Polychromatophilic Erythroblast –> Orthochromatophilic Erythroblast –> Reticulocyte –> Erythrocyte
As RBCs mature, what happens to their size?
They get smaller as they lose organelles and concentrate only hemoglobin
What are the three stages of megakaryocytosis?
Megakaryoblast –> Promegakaryocyte –> Megakaryocyte
During which step of RBC production does the immature RBC lose its nucleus?
From Orthochromatic erythroblast –> Reticulocyte
Where do RBCs get their source of energy from?
Anaerobic glycolysis – They have no organelles!
Which cell type is more specialized, CFU or BFU?
CFU comes after BFU, therefore is more specialized and is more sensitive to Erythropoietin
At what point in the Hematopoiesis process do the cells enter circulation?
About 24 hrs after enucleation, as a Reticulocyte
Where is Erythropoietin primarily produced?
In the kidneys by peritubular cells
What two molecules determine our oxygen carrying capacity in the blood?
Hepcidin – DECREASED Hepcidin = INCREASED iron absorption in the gut, resulting in INCREASED hemoglobin
Hypoxia-inducible factor (HIF-2) – Increases Erythropoietin releases, results in INCREASED RBC synthesis
What is a risk of exogenous Erythropoietin?
Erythropoietin can cause tumor angiogenesis, providing them with the blood they need to grow
What is the role of Ankyrin and Spectrin in the RBC?
These peripheral cell membrane proteins provide for stability. Ankyrin binds Alpha and Beta Spectrin proteins to the cell wall.
What are the roles of Horizontal and Vertical interactions?
Horizontal: Mostly Spectrin-Spectrin interactions, allowing for stretching and distortion of the RBC membrane
Vertical: Stabilize the interaction of the Spectrin lattice to the lipid bi-layer
What are the defective proteins in Hereditary Spherocytosis?
HE is an Autosomal Dominant mutation in the Ankyrin complex, resulting in spherical RBCs
What is the defective protein in Hereditary Elliptocytosis?
HE is an Autosomal Dominant mutation in Spectrin, not allowing the RBC to “rebound” its shape after malformation, resulting in a progressively elongated RBC
Which hemoglobin type is present in a fetus, but not in an adult?
γ (gamma) chain disappears shortly after birth, leaving only α (alpha), β (beta) and δ (delta) hemoglobin types.
What are the three types of Hemoglobin?
HbA - Most common (96%). Two alpha, two beta chains
HbA2 - Two alpha, two delta
HbAf - Fetal hemoglobin. Two alpha, two gamma
What is the difference between oxyhemoglobin and methemoglobin?
Methemoglobin contains iron in the FERRIC (non-absorbable) state, Oxyhemoglobin has iron in the FERROUS state
What are the different platelet granules, and what do they contain?
Alpha granule - Clotting and growth factors
Dense (delta) granule - Ca2+, ADP, Serotonin (These are to recruit more platelets & to vasoconstrict)
What 2 mechanisms result in platelet adhesion?
Glycoprotein 1a (GP1a) binds directly to exposed subendothelial collagen
Glycoprotein 1b (GP1b) binds to Von Willebrand factor on exposed collagen
What clotting factor binds to Von Willebrand Factor to increase it’s t1/2, and sometimes results in a concomittant coagulopathy in a patient w/ Von Willebrand disease?
Factor VIII
Which platelet secretions result in platelet recruitment?
ADP and TXA2
Which platelet receptor is exposed during the conformational change of the activation step of the platelet plug is used for Fibrinogen binding and platelet to platelet adhesion?
Glycoprotein 2b/3a
What enzyme produces Thromboxane A2 within platelets?
COX enzyme – This is why Aspirin is an effective anticoagulant!
Which factors are at play in the Common pathway?
The money pathway!
Factor 10
Factor 5
Factor 2
Factor 1
Where do the Extrinsic and Intrinsic pathways combine?
At the activation of Factor X
What is the goal of the clotting cascade?
Turn Fibrinogen (Factor 1) into Fibrin (Factor 1a) by Thrombin (Factor IIa)
What are the two beginning factors in the clotting cascade, and what activates them?
Intrinsic: Factor XII
Extrinsic: Factor III
They are both activated by damage to the subendothelial matrix
What is the role of Factor VIII in the clotting cascade?
Factor VIIIa + IXa + Ca2+ = Tenase, which increases the rate of X –> Xa by A LOT
What electrolyte is the most important co-factor in the clotting cascade?
Calcium (Factor IV)!!! Required for activation of Prothrombinase and Tenase, the two positive feedback loops
Which factor covalently links Glutamine and Lysine residues together to form a final, stable blood clot?
Factor XIII which is activated by Thrombin
What clotting factors are deficient in Hemophilia A, B and C, and which is most severe?
A - Factor VIII
B - Factor IX
C - Factor IX (Least severe)
Which clotting factors require Vitamin K for synthesis and production?
Factors: II (Prothrombin), VII, IX and X
What is the result of activation of Thrombomodulin?
Thrombomodulin binds Thrombin, this new complex activates Protein C, which activates Protein S.
Protein C + S degrade factor V & VIII
Remember - Factor V increases speed of clotting w/ Prothrombinase
What is the pathophysiology of Factor V Leiden disease?
A single mutation in Factor V in the clotting cascade, making it resistant to proteolytic cleavage from the Protein C/S complex.
What is the MOA of Dabigatran?
Dabigatran is a direct thrombin inhibitor
What is the role of Plasminogen within a stable clot?
Plasminogen is the inactive form of Plasmin, which breaks stable fibrin and fibrinogen bonds, breaking the clot down and releasing D-Dimer.
What is the defect in Thrombotic Thrombocytopenic Purpura?
ADAMTS13 autoantibodies destroy this metalloproteinase, resulting in over-expression of vWF, which creates thousands of micro-thrombi w/ adhered platelets. These platelets damage passing RBCs, which are removed by the spleen.
What are the typical presenting symptoms of hereditary methemoglobinemia?
It is largely asymptomatic except for a cyanotic appearance.
Acquired methemoglobinemia presents w/ cyanosis, headache, giddiness, altered mental state and fatigue
Is a left shift a higher or lower O2 affinity for hemoglobin?
Higher affinity, usually associated w/ increased pH
A right shift is a lower affinity, less likely to hold onto the O2. Usually associated w/ decreased pH
What does 2-3 BPG do to hemoglobin’s oxygen carrying capacity?
It is a rightward shift. Decreased affinity to O2 to dump it off quicker at peripheral tissues d/t decreased PO2, high altitudes, intense exercise, ischemia, etc.
At what point in erythropoiesis does heme synthesis begin and end?
Begins at Proerythroblast CFU stage
Ends when the enucleation occurs at Reticulocyte stage
What is the rate-limiting step in heme synthesis?
The first reaction! Glycine –> Delta-aminolevulinic acid mediated by ALA-Synthase
What three enzymes in the heme synthesis pathway are inhibited by lead?
ALA Dehydratase
Ferrochelatase
Corproporphyrinogen Oxidase
Iron must be oxidized from Fe3+ (Ferric) state into the Fe2+ (Ferrous) state to be absorbed, then back to the Fe3+ state to be transported in the blood. What enzymes perform these tasks?
In the lumen – Duodenal Cytochrome B removes a H+ ion, then on the basolateral side of the cell, Hephaestin reduces that back to Fe3+ to be transported.
What transports circulating iron?
Transferrin
Where is Bilirubin excreted, and where is it conjugated?
Bilirubin is excreted from Macrophages, and conjugated in the liver.
What type of genetic disease is Sickle Cell Anemia?
Autosomal recessive. It is d/t a single point mutation in Beta-Hb gene that causes a glycine (hydrophilic) to be replaced by a Valine (Extremely hydrophobic)
What is a classic imaging sign on Beta Thalassemia?
Fuzzy skull d/t the body attempting to compensate for decreased Hb by increasing amount of bone marrow
Which of the adult hemoglobin types CAN bind to one another and form a homotetramer?
Beta-Hb can form a homotetramer when alpha subunits are not available, such as in alpha-Thalassemia
Which type of Bilirubin is able to enter the brain?
Unconjugated Bilirubin is INSOLUBLE, but is the only type that will enter the CNS by being carried by a carrier protein (usually albumin), causing kernicterus
What will be seen on blood smear for a patient with beta thalassemia?
Microcytic, hypochromic RBCs and Target cells
On what chromosome is the Beta-Globin gene found that is responsible for Beta-Thalassemia?
The Beta-Globin gene is found on chromosome 11
In what state does iron circulate in the blood?
Bound to transferrin proteins as either monoferric (one Fe3+ atom) or diferric (two Fe3+ atoms)
As they circulate, they look for transferrin receptors, primarily on erythroblast cells
In what state is iron stored within the cell outside of heme?
Bound to a storage protein, apoferritin. Apoferritin + Iron = Ferritin
