Week 1 - Monday Flashcards
Can you name some diseases associated with target cells on peripheral smear? (Try to name 6)
Target cells are associated with:
- Thalassemia
- Iron deficiency anemia
- Structurally aberrant hemoglobin disease: HbS, HbC – which also characteristically have the HbC crystal
- Splenectomy
- Liver disease
- Hereditary LCAT (lecithin-cholesterol acyl transferase) deficiency
HbC patients have mild hemolytic anemia
What is the rate limiting step for the HMP shunt (Pentose Phosphate Pathway)? What does the enzyme generate?
The key enzyme is G6P dehydrogenase (G6PD), the rate-limiting enzyme; all steps of the oxidative phase are irreversible and are used to generate NADPH for reductive biosynthetic pathways
NADPH is used to reduce glutathione, a coenzyme for glutathione peroxidase which prevents oxidative damage by converting H2O2 → H2O. This is especially important in RBCs
Increased in tissues that consume NADPH in reductive pathways like adipose tissue for fatty acid synthesis, gonads and adrenal cortex for steroid synthesis, liver for fatty acid and cholesterol synthesis, and glutathione reduction inside RBCs
Where does erythropoiesis take place?
Takes place in myeloid tissue (bone marrow).
Clinical Correlate: The presence of precursor cells, which normally reside in the bone marrow, in the peripheral blood is a useful marker for disease states.
Reticulocyte count can be used to gauge the ability of the marrow to respond to anemic states. It is particularly useful for differentiating anemia caused by increased destruction of RBCs from anemia caused by decreased production of RBCs.
For example, in cases of hemolytic anemia, the bone marrow responds by increasingRBC production, as such reticulocytes are released at a higher rate into the peripheral blood. Thus, reticulocyte count is increased in states of RBC destruction.
In contrast, in cases of decreased production, such as iron or B12 deficiency or aplastic anemia, the marrow is not able to adequately respond by releasing reticulocytes into the blood, thus reticulocyte count will be decreased.
What enzyme acts on CO2 in the bloodstream? What is the final product?
CO2 transport: CO2 is converted to H2CO3 by carbonic anhydrase
H2CO3 (carbonic acid) dissociates to bicarbonate and a proton; the H+ binds to hemoglobin and thus has no effect on serum pH
Allosteric inhibition: CO2 also binds at the hemoglobin chain N terminus, favoring the deoxy Hb form
Which nucleic acids require folate for synthesis?
Folate: needed for thymine and purine synthesis, especially in states of rapid cell division (pregnancy, erythropoiesis)
Deficiency → neural tube defects & megaloblastic anemia
Some conditions/actions result in an increased need for folate:
- pregnancy and lactation
- smoking
- malabsorption, e.g., celiac disease, alcoholism
Numerous medications can interfere with folate utilization, including the following:
Metformin (sometimes prescribed to control blood sugar in type 2 diabetes)
Sulfasalazine (used to control inflammation associated with Crohn’s disease, ulcerative colitis and rheumatoid arthritis)
Triamterene (a diuretic)
Anti-cancer drugs: 5-fluorouracil, methotrexate
What is a schistocyte and when is it seen?
Schistocyte (“helmet cell”): RBC fragment, seen in any hemolytic anemia, formed in cases of mechanical trauma, can be an intrinsic abnormality of erythrocytes
Describe the process behind the formation of RBC bite cells.
Bite cells are formed when the spleen removes a Heinz body from an RBC
Heinz bodies form in G6PD deficiency
Why can the indirect Coombs test be used to cross-match blood?
Indirect Coombs Test: detects free-floating antibodies in serum
A serum sample is incubated with RBCs with known antigens
RBC agglutination = positive Indirect Coombs Test
Used to cross-match blood for transfusion and in antenatal antibody screening (anti-Rh antibodies against a RH+ fetus)
Why does a deficiency of G6PD cause hemolytic anemia?
G6PD deficiency: hemolytic anemia when RBCs are exposed to oxidative stress because of inadequate NADPH production leading to less anti-oxidant activity of glutathione
Causes of oxidizing stress: infections, fava beans, drugs (e.g. sulfonamides, dapsone, primaquine)
Transmitted in X-linked recessive fashion with a predominance in Asia, the Mediterranean, and Africa (disease provides protection against Plasmodium falciparummalaria)
On a peripheral smear look for Heinz bodies (inclusions in RBCs composed of denatured Hemoglobin) and degmacytes (bite cells) (result of splenic macrophages removing Heinz bodies)
Define the MCV cutoffs of macrocytosis and microcytosis.
MCV (mean corpuscular volume): One of the best lab values used for categorizing anemias.
<80 = microcytic, >100 = macrocytic. 80-100 = normocytic
In heme degradation, which molecule is intermediate between heme and unconjugated bilirubin?
Heme Degradation: Heme → biliverdin → unconjugated bilirubin, transported to liver
Which hormone controls the production of red blood cells?
Controlled by erythropoietin (EPO), a glycoprotein hormone produced in kidneys and liver.
How does carbon monoxide compete with oxygen for hemoglobin?
Carbon monoxide: CO is a competitive inhibitor with 200x affinity for heme compared to O2
Carboxyhemoglobin is bright red and poisoned patients are commonly described as having a cherry-red appearance to their skin
What is a dacrocyte? What are the 2 major conditions associated with these cells?
Teardrop cells (Dacrocytes): found in myelofibrosis (replacement of bone marrow by fibrous tissue aka myelophthistic anemia) and thalassemia major
What happens to serum ferritin levels in iron deficiency anemia?
Labs: ↓ serum iron, ↓ ferritin, and ↑ TIBC
Serum ferritin is correlated to intracellular iron stores → serves as an excellent way to differentiate iron deficiency anemia (↓ ferritin) from anemia of chronic disease (↑ ferritin)
The increase of TIBC is due to a decrease in the total number of binding sites occupied by iron. Remember that TIBC and Transferrin always change in the same direction!
The change in transferrin is due to a negative feedback process. When the body senses a decrease in total iron → upregulation of Tf synthesis
↓ MCV (microcytic)
The day after a physically intensive match, a 17-year-old soccer player develops an abscess. Cultures grow S. aureus but are also notable for extensive neutrophils. From which precursor are these cells differentiated?
Neutrophils, eosinophils, and basophils differentiate from myeloblasts. Monoblasts differentiate into monocytes. Lymphoblasts differentiate into B-cells/plasma cells, T-cells and NK cells.
Disruption of heme synthesis results in which clinical diseases?
Disruption at 4 points in the pathway leads to accumulation of intermediates → porphyrias
Explain how a direct coombs test works.
Direct Coombs Test
The direct Coombs test (aka direct antiglobulin test) is used to detect antibodies that are bound directly to the surface of RBCs.
RBCs are exposed to anti-human globulin. If anti-RBC antibodies are present on the surface of RBCs, the anti-human globulin will cause agglutination, thus constituting a positive test.
A positive Direct Coombs Test suggests autoimmune hemolysis.
A 38-year-old female with gastroparesis that is treated with metoclopramide is prescribed sulfamethoxazole-trimethoprim for a urinary tract infection. After taking the first dose, she develops dyspnea, fatigue, and confusion. You note that her lips are blue.
Pulse oximetry shows an oxygen saturation of 91%. An arterial blood gas on room air returns the following:
pH 7.48
pCO2 30 mm Hg
pO2 100 mm Hg
What is the likely diagnosis?
Methemoglobinemia: oxidation to the Fe3+ (ferric) state leads to decreased affinity of O2 at these heme sites; however, at other non-oxidized heme sites, there is a compensatory increase in affinity → leading to a left shift of the oxygen-dissociation curve
Normally, oxidation is prevented via a reductive enzyme pathway (HMP shunt) in RBCs
Drugs that cause methemoglobinemia: Metoclopramide, Procaine, Nitrites, Antimalarials, Sulfonamides, Dapsone.
Can be easily remembered with mnemonic: A Methemoglobinemic Patient is Not Always Something Deadly.
In a centrifuged blood sample, what components of blood will be in each fraction?
In a centrifuged blood sample, plasma is the top layer, leukocytes and platelets are in the middle layer, and RBCs are in the bottom layer.
What is the main treatment for anemia of chronic disease?
Treatment of underlying inflammatory condition is paramount. Do NOT give iron!
Aside from iron deficiency, name 3 diseases that cause microcytic anemia.
Microcytic Anemias: Thalassemias, Anemia of chronic disease, Iron deficiency, Lead poisoning.
Can be remembered with mnemonic TAIL
Thalassemias will also show target cells, basophilic stippling
Sideroblastic anemia is associated with myelodysplastic syndrome (“pre-leukemia”) as well as chronic alcoholism and lead poisoning.
Anemia of Chronic disease commonly presents as microcytic anemia
The best way to differentiate microcytic anemias is by serum ferritin levels.
Thalassemia: Normal iron studies. (There is no deficiency of iron.)
Anemia of Chronic disease: ↑ Ferritin, ↓ % saturation of transferrin, ↓ serum iron.
Why?
- Inflammatory state (from chronic infection, immune disorders or neoplasms) → IL-6 production → ↓ release of iron from iron stores.
- Because iron stores are normal or elevated, ferritin is increased.
- However, circulating iron in the blood is low → ↓ % saturation of transferrin and serum iron.
Iron Deficiency Anemia: ↓ Ferritin because of deficient iron stores.
TIBC can also be used to differentiate iron deficiency anemia from anemia of chronic disease.
Recall that TIBC is inversely proportional to the body’s iron stores —
- When iron stores are low (as in iron deficiency) → TIBC is increased
- When iron stores are adequate (as in anemia of chronic disease) → TIBC is decreased.
What is plasma?
Plasma: Fluid portion of blood, contains proteins.
Albumin: maintains oncotic pressure of the blood.
Clinical Correlate: Burn victims and patients with nephrotic syndrome lose albumin (through their skin and urine, respectively), resulting in edema due to loss of oncotic pressure.
Gamma and beta globulins: transport hormones, metal ions, and lipids.
Blood coagulation proteins, including fibrinogen → fibrin is the reaction that forms the fibrin clot.
Plasma without fibrinogen is serum.
List 4 factors that encourage oxygen dissociation from hemoglobin.
1) ↓ pH: relative acidic environment, like peripheral tissues
2) CO2: produced by cellular metabolism
3) 2,3-DPG (diphosphoglycerate, the same as bisphosphoglycerate): stabilizes the *taut *conformation, produced by glycolysis
4) ↑ temperature
These factors shift the O2 dissociation curve to the right – a higher O2 pressure is needed to maintain the same level of hemoglobin saturation
