EXAM #1: REVIEW Flashcards
What cells produce endogenous G-CSF? What is their normal role?
Macrophages secrete G-CSF from sites of inflammation, which circulates to the bone marrow and stimulates the production of granulocytes
List the morphological, structural, and staining changes that happen to RBCs as they mature.
1) Cell size decreases
2) N:C ratio decreases
3) Nucleoli decrease in number and disappear
4) Cytoplasmic staining goes from dark blue to light blue
What is the normal percentage of “bands?”
3-5%
List the four major purposes of RBC metabolism. What is required to accomplish these purposes?
1) Reduce iron–NADH for methemoglobin reductase
2) Maintain ion gradients (K+/Ca++)– ATP
3) Reduce protein SH-goups–NADPH
4) Maintain cell shape–ATP
What are the two regulated steps of glycolysis in RBCs? What inhibits these enzymes?
1) Hexokinase
2) Phosphofructokinase-1
Both are inhibited by lowered pH
Draw and label the pertinent metabolic pathways in a RBC.
N/A
What is the effect of 2,3 BPG on Hb’s oxygen affinity?
2,3 BPG will lower Hb’s affinity for oxygen
When cells are acidotic, 2,3 BPG synthesis is inhibited. What is the effect on Hb’s oxygen affinity?
Increased oxygen affinity
What is the Bohr effect?
Decreased Hb oxygen affinity in acidotic conditions
What activates Glucose 6-phophate dehydrogenase?
Low NADPH
Draw the role of glutathione peroxidase and glutathione reductase in antioxidant defense.
N/A
What are two enzyme defects that cause non-spherocytic anemia? What is the mode of inheritance?
- G6PD= X-linked recessive–>lack of NADPH
- Pyruvate Kinase Deficiency= autosomal dominant and recessive–>lack of NADH/ATP
List the four cytoskeletal protein components of a RBC.
1) Spectrin= filamentous scaffold
2) Ankryin= peripheral membrane protein*
3) Band 3= integral membrane protein
4) Glycophorin= integral membrane protein
*Most common cause of Hereditary Spherocytosis (autosomal dominant)
What enzyme reduces Fe+++ to Fe++ for absorption?
Cytochrome p450
Outline how iron gets from the plasma to the cytoplasm of the cell.
1) Clathrin-mediated endocytosis of Transferrin-Fe++
2) ATPase acidifies the endosome (forming lysosome)
3) Conformational change in Transferrin releases Fe++
4) Fe++ –>Fe+++
5) Fe+++ reduced back to Fe++
6) DMT-1 transports Fe++ into the cytoplasm
Describe the post-transcriptional regulation of ferretin translation.
1) 5’ UTR contains the Iron Response Element
2) Iron Regulatory Proteins bind the IRE to block translation
3) Free iron in the cytoplasm binds to IRPs and displaces them; thus, translation begins quickly
What is the effect of free iron on ALA synthetase?
Increased translation of ALA synthetase
What is the effect of free iron on transferrin receptor transcription?
Free iron DECREASES the synthesis of the transferrin receptor by binding to IRPs and STABILIZING the mRNA
Note that this is opposite of the case for Ferretin and AlA Synthetase–likely test question
List the most common causes of iron deficiency in the following age groups: infants, children, adults, and the elderly.
Infants= breast-feeding Children= poor diet Adults= PUD in males and menorrhagia in females Elderly= - Western= colon polyps/ carcinoma - Developing= hookworm
What are the three stages of iron deficiency anemia?
1) Iron depletion
2) Deficient erythropoesis with normal Hb
3) Inadequate Hb
What are the common causes of iron overload?
1) Chronic blood transfusion
2) Inappropriate parenteral transfusion
3) Ineffective hematopoiesis
4) Hereditary uptake disorder e.g. hemochromatosis
What is the genetic defect in Hemochromatosis?
Mutation in the HFE gene that codes for Hepcidin; thus, Ferroportin is NOT inhibited and increased iron is released from enterocytes into the plasma
Draw the heme synthesis pathway. Label the enzymes that are associated with pathology.
N/A
What is X-Linked Sideroblastic anemia?
- X-Linked disorder caused by defective protoporphyrin synthesis, which leads to a microcytic anemia
- Specifically, caused by mutant ALA synthase encoded by the on ALAS2 gene on the X-Chromosome
What products of heme synthesis accumulate in AIP? What is the clinical consequence?
ALA and PBG, which cause the urine to turn a dark red color
What are the three classifications of anemia based on etiology?
1) Under production
2) Destruction
3) Blood loss
What is the normal distribution of leukocytes?
1) Neutrophils
2) Lymphocytes
3) Monocytes
4) Eosinophils
5) Basophils
How is a reticulocyte count corrected?
Pt. Hct/45 x Reticulocyte count= corrected reticulocyte count
What is the major difference in lab values that differentiates between IDA and ACD?
IDA= low serum ferretin and high TIBC ACD= high serum ferretin and low TIBC
What are the four lab tests used to diagnose lymphoma? Which of these is the most important?
1) Immunophenotyping=*****
- Immunohistochemistry
- Flow cytometry
2) H&E staining
3) Cytogenetics/FISH
4) Molecular diagnostics
What is Fanconi anemia?
Autosomal recessive genetic disorder caused by defects in DNA repair, which manifests with deficient hematopoiesis
What is normoblastemia?
Presence of nucleated RBCs in PBS; this is a sign of extramedullary hematopoiesis and anemia
What are the two causes of sphercytosis?
1) Hereditary spherocytosis
2) Autoimmune hemolytic anemia
What causes the formation of schistocytes seen on PBS?
Any hemolytic anemia:
- Microangiopathic anemia i.e. TPP/HUS and DIC
- Other hemolytic anemia
List the causes of punctate basophilia.
1) Pb poisoning
2) Severe anemia
3) Severe infection
4) Drugs
5) Alcohol
What causes HJ bodies?
1) Splenectomy
2) Hemolysis
The spleen is unable to rid the body of abnormal RBCs.
What are the causes of macrocytic anemia?
1) Vitamin B12 and/or Folate deficiency
2) Alcoholism
3) Liver disease
4) Drugs
What is a normal Hct in men? Women?
Men= 42-50% Women= 36-44%
What is a normal MCH?
30-34 pg
What is a normal MCHC?
30-36%
What is a normal RDW?
13-15%
Remember that smaller RDW indicates a more uniform cell size
How much iron can be absorbed per day?
1-3 mg
How much iron is circulating in the blood in RBCs?
2,500mg
How much iron is in iron containing proteins?
400mg
How much iron is transferrin bound?
3-7mg
How much iron is stored as ferretin?
1,000mg
According to Dr. Volker, what is the most specific value for ICD?
Low serum iron (less than 10)
**Note that normal is 60-150 mcg/dL
What is a normal TIBC?
300-360 mcg/dL
What is a normal iron saturation?
20-50%
What is a normal serum ferretin?
40-200 mcg/L
How should you go about iron supplementation in a patient with iron deficiency anemia? What is NOT recommended?
PO= max dose of 25mg per day IV= max dose of 500mg per day
IM is NOT recommended b/c of the adverse effects of administration.
List the cytokines that will stimulate hepcidin production.
1) IL-6
2) TNF
3) IF-a
4) IF-g
What is “Rouleaux” formation? What is this characteristic of?
This refers to stacks or aggregations of RBCs on PBS, which is caused by ACD
What is HbH?
Hb composed of a beta tetramer
What is Hb-barts?
Hb composed of a gamma tetramer
What are the hallmark signs of Beta-Thalassemia?
1) Crewcut x-ray and large forehead (b/c of massive erythroid hyperplasia)
2) Chipmunk facies
3) Hepatosplenomegaly b/c of extramedullary hematopoiesis
How is Beta Thalassemia treated? What is the paradox with this treatment?
Transfusion, which can lead to secondary hemochromatosis b/c blood products contain iron
What enzyme is deficient in Hereditary Sideroblastic Anemia?
ALA Synthase
What is the cause of congenital sideroblastic anemia? Acquired?
Congenital= deficiency in ALA synthase
Acquired=
1) Alcoholism–mitochondrial poison
2) Pb poisoning–ALAD and ferrochetolase inhibited
3) B6 deficiency–cofactor for ALA synthase (seen in Isoniazid treatment for TB)
What is a Pappenheimer Body?
RBC with abnormal granules of iron seen on PBS
What is polycythemia?
Abnormal INCREASE in Hb concentration
What is the RBC count in Thalassemia?
HIGH
What are the causes of nonmegaloblastic macrocytic anemia?
1) Alcoholism
2) Liver disease
3) Drugs
5) Hypothyroidism
6) Myelodysplastic syndrome
What are the two PBS hallmarks of megaloblastic anemia?
1) MCV greater than 100 fL
2) Hypersegmented neutrophils
How do you calculate an absolute reticulocyte count?
(RBC x % reticulocytes)/100
If this number is less than 100,000, then reticulocytosis can be EXCLUDED
What is the presentation of Congenital Transcobalamin II Deficiency?
Infant that presents with anemia within the first few weeks of life
What is the presentation of Congenital methylmalonic acidemia and aciduria?
Infants ill from birth
How should you approach B12 supplementation?
Give 1,000micrograms SC or IM for a week for 1 month, then same dose monthly
What lab values are diagnostic for pernicious anemia?
1) Parietal cell and IF antibody positive
2) High serum gastrin
3) Low pepsinogen
What is the clinical manifestations of hemolytic anemia?
- Jaundice b/c of a serum increase in unconjugated/ indirect bilirubin
- Pallor
- Dyspnea
- Discoloration of urine
- Gallstones
- Splenomegaly
List the labs necessary to diagnose hemolytic anemia and what you expect to find.
1) Decreased Haptoglobin
2) Elevated LDH
3) Elevated RC count
4) Elevated indirect bilirubin
5) Hemosidinuria
What is the most common enzyme defect that causes hemolytic anemia?
G6PD- X-linked recessive
What are the abnormal PBS cell types that are seen in G6PD?
Heinz bodies
Bite cells
List the consequences of vaso-occlusion in Sickle Cell Anemia.
1) Dactylitis
2) Autosplenectomy
3) Acute Chest Syndrome
4) Pain crisis
5) Renal papillary necrosis
How is Hereditary Spherocytosis treated?
- Folate supplementation
- Splenectomy
What is the initial treatment for autoimmune hemolytic anemia?
Corticosteroids
List the drugs associated with hemolysis.
- PCN
- Quinine
- Methyldopa
- Cephalosporin antibiotics
List the contents of platelet alpha granules.
Fibrinogen Fibronectin vWF Factor V PDGF
What is the extrinsic Xase complex?
TF + VIIa + X
- This Factor VIIa of this complex cleaves Factor X to Xa
What factors are inhibited by the protein C/S complex?
Factor Va
Factor VIIIa
What is the specific mutation seen in Factor V Leiden Deficiency?
Arginine–>Glutamine at aa position #506
What factors are inhibited by TFPI?
VIIa and Xa
What is Desmopressin indicated for? What is its mechanism of action?
- vWF Disease*
- Induces release of vWF and VIII from endothelial stores
What are the autoantibodies in ITP specifically directed towards? What happens to platelets that are bound to antibody?
GpIIb/GpIIIa –>phagocytosis in the spleen
What is the specific target of autoantibodies in HIT?
Heparin and Platelet Factor 4
What are the anticoagulant properties of the endothelium?
1) Heparin like molecule that activates antithrombin III
2) Thrombomodulin, which binds Thrombin to activate proteins C/S
What are the three prothrombic properties of the endothelium?
1) Tissue Factor (TF)
2) vWF
3) Plasminogen activator inhibitors (PAI)
List the combined effects of blood turbulence and stasis?
Turbulence= increased injury
- Endothelial activation
- Clotting factors accumulate
- Blockade of clotting factor inhibitors
Stasis=
- Platelet brought close to endothelium
What is the most common primary cause of hypercoaguability?
Factor V Leiden Deficiency
List some of the common secondary causes of hypercoaguability.
- Stasis
- Oral contraceptives
- Smoking
- Cancer
- Nephrotic Syndrome
- Lupus
- Anti-phospholipid Syndrome
How much does oral contraception alone increase the risk for thrombosis?
3.7x
How much does oral contraception AND Factor V Leiden Deficiency increase the risk for thrombosis?
34.7x
What are the indications for further evaluation of a potential clotting disorder when a patient presents with thrombosis?
1) Young patient
2) Patient’s w/ a family history of a coagulopathy
3) Thrombosis WITHOUT risk factors
4) Recurrent miscarriage
5) Patient with warfarin induced skin necrosis
6) Neonatal purpura fulminans
What is the effect of 2,3-BPG on Hb and oxygen binding?
2,3-BPG favors dissociation i.e. decreases oxygen affinity
What subunits compose Hb Gower 1?
2x zeta and 2x epsilon
What subunits compose Hb Gower 2?
2x alpha and 2x epsilon
What subunits compose Hb Portland?
2x zeta and 2x gamma
What subunits compose Hb F?
2x alpha and 2x gamma
What are Heinz bodies?
Aggregates of hemichrome
- Hemichrome is formed from methemoglobin
- Methemoglobin is the product of unstable Hb that has been oxidized
How does hydroxyurea prevent Sickle Cell Disease?
Though an antineoplastic agent, it increase HbF and promotes Hb solubility/prevent sickling
What is Hb-constant spring? How is it formed and what does it lead to?
- Point mutation leading to alpha-thalassemia
- Stop codon–>Glutamine
- Read through occurs and increases the alpha globin chain
This is relatively asymptomatic b/c the mRNA is very unstable and behaves like alpha+ thalassemia
What is unique about Hb-lepore? How is it formed?
- Alpha and delta fusion protein
- Recombination events delete part of beta and delta globin
What reaction is the source of most of the carbon in the one carbon pool?
Serine hydroxymethyltransferase
Serine + THF = Glycine + N5,N10 methylene-THF
List the four metabolic processes that require folate.
1) Methionine synthesis
2) Thymidlate synthesis
3) Purine synthesis
4) Histidine catabolism
