Quiz 1 Flashcards
Define anemia:
A decrease in the body’s ability to carry oxygen
What are some symptoms an anemic patient might notice?
Symptoms related to oxygen carrying capacity; like shortness of breath, palpitations and fatigue
About how long will a RBC remain in circulation? Where does it go to be destroyed?
3 months; the spleen
Hgb levels in an adult male below what level may be indicative of anemia?
13.5 g/dL
Hgb levels in an adult female below what level may be indicative of anemia?
12.0 g/dL
A nutritional deficiency may be indicated by what finding on a CBC?
A high RDW
A B12 or folate deficiency may be indicated by a CBC finding of an MCV above what level?
110
A CBC finding of an MCV below 70 may suggest what condition?
Thalassemia
What product is made in the first step in heme synthesis?
Delta- aminolevulinic acid (delta-ALA)
What enzyme is responsible for creating CO?
Heme oxygenase
What is the main goal of secondary hemostasis?
Make fibrin
What is the most important ECM component for platelet adhesion?
Collagen
What effect do ADP and TxA2 have after binding platelet surface receptors?
Promotion of granule release from platelets
What is the goal of primary hemostasis?
Formation of a platelet plug
What is a factor inhibitor (in context of a mixing study)?
An antibody directed against a clotting factor
Coagulation: Short & Lucky
Extrinsic pathway: 7 activates X
Coagulation: TENET
Intrinsic pathway: Twelve -> Eleven -> Nine -> Eight -> Ten
What cofactor is used by factor X in the coagulation cascade?
Factor V
What is the primary purpose of thrombin?
To convert fibrinogen to fibrin
Approximately how small of a deletion can be detected by FISH?
1Mb
aCGH or array CGH can provide how small of a resolution for genetic testing?
50-100 kb, sometimes less
What does the acronym SpPin stand for?
Specificity in a Positive test result help to rule IN a test
What does the acronym SnNout stand for?
Sensitivity in a Negative test result helps to rule OUT a test
delta-ALA synthase synthesizes delta-ALA from what two substrates?
succinyl-CoA and glycine
Why can X-linked sideroblastic anemia often be cured by high doses of vitamin B6?
High levels of vitamin B6 encourage high levels of pyridoxal phosphate, which can stabilize the active site of delta-ALA synthase
What is the name of the enzyme that catalyzes the last step in heme synthesis?
ferrochelatase
If a 1 day old neonate is found to have a fever of 38.5 C, they are at risk for hypoglycemia. Why?
On average, humans can experience a 12% increase in metabolic rate per increase of 1C, placing neonates especially at higher risk for hypoglycemia
Where do enzymes bind substrates?
the active site
Of Vmax Km and kcat, which vary with enzyme concentration?
Vmax only
What are the two common mechanisms for enzyme regulation?
post-translational modification and binding of activators/inhibitors
What are the most common primary causes of hypercoagulability?
Favtor V Leiden, Prothrombin mutations, or increased levels of clotting factors
What are the components of the Virchow triad?
Endothelial injury, abnormal blood flow, and hypercoagulability
How do you calculate the likelihood ratio +?
Sensitivity / 1- specificity
How do you calculate the likelihood ratio -?
Specificity / 1 - sensitivity
Why is double-stranded DNA more soluble than single stranded DNA?
The hydrophobic bases are paired and not as exposed to a hydrophillic environment
How can PCR help detect translocations of a DNA sequence?
PCR will only give product if the left and right primer are on the same chromsome; thus two primers on different chromsomes will only produce product if a translocation occurs
What are the four most common microcytic anemias?
iron deficiency anemia (IDA), anemia of chronic disease (ACD), thalassemias, and sideroblastic anemia
What is the expected MCV for a microcytic anemia?
less than 80
What chief issue underlies a sideroblastic anemia?
Deficiency in protoporphyrin
What is the most common nutritional deficiency in the world?
iron deficiency
Where does absorption of iron occur?
the duodenum
What transporter do enterocytes use to move absorbed iron into the blood?
ferroportin
Where does transferrin principally transport iron?
the liver as well as bone marrow macrophages
What 4 lab tests provide the best measurements of iron status?
serum iron, serum ferritin, TIBC, and % saturation
What is a normal % saturation level for transferrin?
about 33%
Rank ferric iron (Fe3+), ferrous iron (Fe2+) and heme iron from most to least bioavailable
Heme iron > ferrous iron > ferric iron
When ferritin in the body decreases, what will increase to compensate?
TIBC (transferrin)
Is the very early stage of IDA normocytic or microcytic?
Normocytic
What are three clinical features of IDA?
Anemia, koilonychia, and pica
What condition is indicated by the following lab findings?
Iron deficiency anemia
What is FEP?
Free erythrocyte protoporphyrin
Why would FEP be elevated in IDA?
Inability to produce sufficient heme groups results in an excess of protoporphyrin rings floating freely
How is IDA treated?
Treating the cause of the iron deficiency (hookworm, cancer, etc) or supplemental iron (ferrous sulfate)
What is Plummer-Vinson syndrome?
IDA additionally associated with esophageal web and atrophic glossitis; pt presents with anemia, dysphagia and a beefy-red tongue
What condition is described by chronic inflammation causing Hepcidin to sequester iron in storage sites, limiting iron transfer from macrophages to erythroid precursors?
Anemia of chronic disease
Why is Hepcidin upregulated in ACD?
The body responds to chronic inflammation by hiding the iron from perceived pathogen invasion
What condition would be associated with the following lab findings?
Anemia of chronic disease
How would ACD be treated?
Treat the underlying cause of disease, occasionally EPO treatment can be helpful (like in cancer patients)
Defects in production of heme (Fe or protoporphyrin) will lead to what type of anemia?
microcytic
What enzyme catalyzes the first step of heme synthesis?
ALA synthase
What is the substrate and product of the reaction with ALA synthase?
succinyl CoA; ALA
What cofactor is especially necessary for ALA synthase function?
vitamin B6
What enzyme is responsible for catalyzing the reaction between protopoyrphyrin and Fe?
ferrochelatase
Where does the final step of heme synthesis occur in the cell?
the mitochondria
How does protoporphyrin deficiency lead to ringed sideroblasts?
Iron is brought into the mitochondria, and deficient protoporphyrin leads to trapped excess iron, which accumlates in the mitochondria (which surround the nucleus) leading to a ring structure
What is the most common form of congenital sideroblastic anemia?
A congenital defect in ALA synthase
What are the most common causes of acquired sideroblastic anemia?
alcoholism, lead poisoning, and vitamin B6 deficiency
What condition would be associated with the following lab findings?
Sideroblastic anemia
Why is ferritin found to be high in sideroblastic anemia?
Iron overloaded cells will lyse, and macrophages will eat the excess iron, and store it as ferritin; these findings are SIMILAR in hemochromatosis
What condition would be associated with the following lab findings?
Thalassemia (need more information to specify which)
What specific type of disease are thalassemia carriers protected against?
Plasmodium falciparum malaria
Which subunits comprise fetal hemoglobin (HbF)?
Which subunits comprise HbA?
Which subunits comprise HbA2?
What are the three normal types of hemoglobin?
HbF, HbA, HbA2
How many alleles of alpha hemoglobin exist in a normal genome? Where are they located?
4 (two per chromsome); chromsome 16
What is the most common genetic mutation causing alpha-thalassemia?
gene deletion
What is a cis deletion in alpha-thalassemia?
When 2 copies of the alpha HgB allele that are knocked out are on the same chromosome
What is a trans deletion in alpha-thalassemia?
When 2 copies of the alpha HgB allele that are knocked out are on opposite chromosomes
In what geographic population are cis deletions in alpha-thalassemia seen?
Asians
In what geographic population are trans deletions in alpha-thalassemia seen?
Africa
Is the cis or trans deletion in alpha thalassemia associated with a more severe risk of anemia in offspring? why?
Cis deletion; because both deletions are on one chromsome, and that chromsome could pass both deletions on to offspring
What characteristics would be seen in alpha thalassemia with a 3 gene deletion?
What comprises HbH? What is the pathology?
a tetramer of beta-chain HgB; defective alpha chains/lack of alpha chains leads to tetramerization of beta-chain dimers
What occurs in a 4 gene deletion of the alpha thalassemia alleles?
What is Hb Barts?
a tetramer of gamma HgB chains
How many beta hemoblogin alleles exist in the normal human genome? Where are they located?
two (one on each chromsome); chromsome 11
What are characteristics of beta thalassemia minor (B/B+)?
What are normal hemoglobin concentrations in an adult?
HbA- 96.5%
HbA2- 2.5%
HbF- 1%
What electrophoresis findings would be significant in beta-thalassemia minor?
HbA2 increased to about 5%
What are common characteristics of beta-thalassemia major (Bo/Bo)?
Lack of beta HgB will lead to a tetramer of what type of HgB?
an alpha tetramer
What are two significant effects of alpha HgB tetramerization?
ineffective erythropoiesis and and extravascular hemolysis (destruction by spleen)
What is Massive erythroid hyperplasia?
expansion of hematopoeisis into marrow of skull and facial bones (extramedullary hematopoeisis) clinical appearance is nicknamed “chipmonk face”
What is parvovirus B19?
a virus that infects and shuts down erythroid precursors (usually lasts 1-2 weeks)
How is parvovirus B19 different with thalassemic patients (especially beta thalassemia major)?
It may cause an aplastic crisis (there is extra dependence on RBC product)
How is thalassemia treated?
Chronic transfusions are often necessary (which has a secondary risk of hemochromatosis)
In addition to the blood smear findings for beta thalassemia minor, what else is notable for a blood smear from a beta thalassemia major patient?
nucleated RBCs
On average how long does it take to replete human iron stores?
6-12 months
How do cells that need iron get it into the cytosol?
They upregulate transferrin receptors for transferrin to bind and pull iron into the cell
What is aconitase?
A protein that responds to Fe to regulate mRNAs with an iron regulatory element (IRE)
What affinity does aconitase have in a low iron environment?
What role does aconitase have on ferritin production in a low iron environment?
What affinity does aconitase have in a high iron environment?
What role does aconitase have on ferritin production in a high iron environment?
What role does aconitase have on transferrin receptor production in a low iron environment?
What role does aconitase have on transferrin receptor production in a high iron environment?
Mutations in what gene make up the majority of hereditary hemochromatosis cases?
HFE
By what principal cytokine does inflammation lead to an upregulation of hepcidin?
Interleukin 6 (IL-6)
What effect would hypoxia or erythropoeisis have on hepcidin levels?
They would downregulate hepcidin production
How does methotrexate affect folate useage by the body?
What is leucovorin?
An exogenous form of activated folate that can be administered as a drug
Which common cause of vitamin B12 deficiency is responsible for pernicious anemia?
Autoimmune destruction of gastric parietal cells
Where in the body is vitamin b12 absorbed? What must it be bound to?
the ileum; intrinsic factor
What effect does kidney disease have on EPO production?
Reduced production of EPO
Once RBC precursors are bound by EPO, what transcription factor is recruited by the JAKs (kinases)?
STAT5
What lab results would be consistant with hemolysis?
What are Heinz bodies as found in G6PD?
precipitated denatured globin chains
What effect do prolyl and asparagine hydroxylases have on HIF-alpha?
They trigger its degradation
In hypoxic conditions, what is the action of HIF-alpha?
HIF-alpha is not degraded, enters the nucleus, finds HIF-beta and binds HRE, upregulating EPO production
What effect will a substrate analog (competitive inhibitor) have on an enzyme’s Vmax and Km?
Vmax- no effect
Km- increase
What are the best dietary sources for folate and vitamin B12?
folate: leafy greens
Vit B12: animal proteins
What four lab tests can best assist in diagnosing a folate or vitamin B12 deficiency?
Folate, B12, MMA, and homocysteine
How large is the human body’s liver stores of vitamin B12?
3-5 years supply
In order to participate in DNA synthesis methyl-THF passes its methyl group to what molecule?
Cobalamin (B12)
After being methylated by THF, where does methyl-cobalamin pass the methyl group?
to homocysteine (creating methionine)
How does 5-FU inhibit DNA synthesis?
By binding to 5,10-methylene-THF and permanently inactivating Thymidylate synthase
How does Vitamin B12 affect methyl-malonic acid?
Vitamin B12 catalyzes a reaction converting methyl-malonyl CoA to succinyl CoA
What information can be gathered by high serum levels of MMA?
Vitamin B12 deficiency
What problems are caused by a build up of methyl-malonic acid?
Permanent neurological defects
What are common causes of B12 and folate deficiencies?
folate: diet
vitamin B12: loss of IF or resection of bowel involving ileum
How is heme synthesis primarily regulated?
negative feedback
What is the broad name of inherited or aquired disorders affecting heme biosynthesis?
Porphyrias
In the heme biosynthetic pathway, which two enzymes are vulnerable to inhibition by lead poisoning?
ALA dehydratase and ferrochelatase
How does increased acidity (decrease in pH) and increased levels of 2,3-BPG affect HgB affinity for oxygen?
Oxygen affinity decreases (favoring release of O2), causing a right shift in the oxygen saturation curve
How do increased CO levels affect HgB affinity for O2?
They increase affinity, with a left shift curve (note that HgB is permanently bound to CO and oxygen carrying capacity rapidly decreases as levels of CO increase)
What is the meaning of the aPTT in coagulation testing?
Time to fibrin clot involving the intrinsic coagulation pathway
What is the meaning of the PT in coagulation testing?
Time to fibrin clot involving the extrinsic coagulation pathway
Is plasma or serum used for the aPTT/PT testing?
plasma
What is indicated by a CORRECTS result from a mixing study?
A clotting factor deficiency
What is indicated by a FAILS TO CORRECT result from a mixing study?
Inhibition of a clotting factor(s)
What are three contact factors than can cause aPTT prolongation without bleeding diathesis?
Factor VII, prekallikrein, and HMWK
What PT/aPTT would you expect with a Hemophilia A/B diagnosis?
Prolonged aPTT
normal PT and platelets
(Factor VIII/IX impaired activity)
Which coagulation factor is NOT made by hepatocytes?
Factor VIII
What is the aPTT/PT status for von Willebrand disease?
Normal (usually)
What are chief differential dx for elevated PT alone?
F VII deficiency/inhibitor, therapeutic levels of warfarin, vitamin K deficiency
What are chief differential dx for elevated PT/aPTT together?
Warfarin/vitamin K (high levels), common pathway inhibitor/deficiency
What should be on the differential dx for elevated PT/aPTT with reduced platelets?
DIC, severe liver disease
Which coagulation factors are vitamin K dependent?
Factors II, VII, IX, and X
How does heparin act as an anticoagulant?
heparin potentiates antithrombin
What active enzyme dissolves a fibrin clot?
plasmin
What factors are inactivated by antithrombin?
What factors are inactivated by proteins C and S?
What are the three risk factors for thrombosis of Virchow’s Triad?
endothelial injury
abnormal blood flow
hypercoagulability
What is the pathophysiology of Factor V Leiden?
An autosomal dominant point mutation in factor V makes it resistant to cleavage by protein C
What is the essence of disseminated intravascular coagulation?
a massive systemic intravascular activation of coagulation
What is meant by the fact that DIC is not a primary disease?
It is associated with many diseases that cause release of tissue factor or endothelial injury
What symptoms are significant in a dx of DIC?
elevated D dimer, decreased fibrinogen. prolonged PT/aPTT, and decreased platelets
What is the meaning of the pneumonic “CADET, face right” pertaining to the HgB saturation curve?
CO2, Altitude, 2,3-DPG (or BPG), Exercise, Temperature all involve right shift with increases
Acute intermittent porphyria may present with what unique symptoms?
Diffuse abdominal pain and dark colored urine, without any focal findings
What is the main pathology of Bernard-Soulier syndrome?
A deficiency in GP Ib in the primary hemostasis pathway that prevents effective platelet plug formation
Is bleeding time more related to primary or secondary hemostasis?
primary hemostasis
What characterizes an Acute Hemolytic Transfusion Reaction? (mechanism, timing, other facts)
What characterizes an Allergic Transfusion Reaction? (mechanism, timing, other facts)
What characterizes a Delayed Hemolytic Transfusion Reaction? (mechanism, timing, other facts)
What characterizes a Febrile Non-Hemolytic Transfusion Reaction? (mechanism, timing, other facts)
What characterizes a Septic Transfusion Reaction? (mechanism, timing, other facts)
What characterizes a Transfusion Associated Circulatory Overload (TACO)? (mechanism, timing, other facts)
What characterizes a Transfusion-Related Acute Lung Injury (TRALI)? (mechanism, timing, other facts)
Does Rh factor matter in plasma donations?
No
How are plasma donations different from blood donations?
Donating plasma results in opposite H protein protocols; i.e. type B+ can only RECEIVE blood from B or AB groups
What is the incidence of a disease?
The # of new cases in a time period
What is the prevalence of a disease?
The # of cases at any point in time
What is the function of an independent T test?
To compare the means of two numerical variables
What is the function of a paired T test?
to compare the mean of the same group at different points in time
What is the function of a chi squared test?
To compare two categorical variables (i.e. survey responses)
What pathology might these lab results indicate?
What is the first step when hemolytic anemia is suspected?
A DAT
Which proteins are most commonly affected in Hereditary spherocytosis?
Spectrin, Ankyrin, Band3
What disease is indicated by these findings?
Hereditary Spherocytosis
How can an osmotic fragility test help diagnose hereditary spherocytosis?
The test places cells in a hypotonic solution, where extra membrane is required to absorb water. Spherocytes lack this and will lyse
What is the preferred treatment for hereditary spherocytosis?
splenectomy
What are Howell-Jolly bodies?
extra fragments of RBC nuclear materieal normally removed by the spleen
What is the genetic mutation that causes sickle cell anemia?
An autosomal mutation where a glutamic acid is replaced with valine
How is sickle cell disease characterized?
Two abnormal beta genes resulting in > 90% HbS in RBCs
When RBCs are deoxygenated, or in the T state, what takes place with a person with sickle cell disease?
The HbS molecules polymerize into a rigid sickle-shape
What 3 main physiological environments can increase sickling risk in SCD?
Hypoxemia
Dehydration
Acidosis
What treatment helps to increase HbF levels in patients with SCD?
hydroxyurea
What is dactylitis?
Swollen hands and feet due to vaso-occlusive infarcts of tissue (common sign in infants)
What are three notable consequences of autospenectomy/splenectomy?
-Increased risk of infection with encapsulated organisms
-Increased risk of Salmonella paratyphi osteomyelitis
-Howell-Jolly bodies
What is acute chest syndrome?
Vaso-occlusion in pulmonary microcirculation; presents with chest pain, SOB, and often precipitated by pneumonia Most common cause of SCD death in adults
What is the difference between sickle cell disease and sickle cell trait?
Sickle cell trait involves only one mutated gene; they will have less than 50% HbS (sickling only occurs at > 50%)
What is the major exception where someone with sickle cell trait may experience sickling?
The renal medulla, where extreme hypoxia and hypertonicity cause sickling, which can lead to microinfarctions
What is the purpsoe of metabisulfite?
It will cause cells with any amount of HbS to sickle
Results from this gel electrophoresis would be indicative of what pathology?
Sickle Cell Disease
Results from this gel electrophoresis would be indicative of what pathology?
Sickle Cell Trait
What is the condition Hemoglobin C?
AR mutation in beta chain converting glutamic acid to lysine (SCD is valine)
What is the object highlighted in the picture?
A hemoglobin C crystal
What is Paroxysmal Nocturnal Hemoglobinuria?
An aquired defect in myeloid stem cells resulting in absent GPI, which holds DAF and MIRL to the RBC membrane (which protect from complement) *platelets and leukocytes also at risk
Why is PNH exacerbated/triggered at night?
Shallow breathing at night -> mild respiratory acidosis 0> activates complement which lyses RBCs, WBCs, and platelets
What are major signs of intravascular hemolysis?
hemobloginemia, hemoblinuria
What are two tests that can be used to diagnose PNH?
acidified serum test, or flow cytometry to detect lack of CD55 (DAF)
What is the main danger of PNH?
Thrombosis, due to destroyed platelets releasing cytoplasmic contents to induce thrombotic events
What is G6PD deficiency?
Deficiency of G6PD -> less NADPH to regenerate Glutathione -> more oxidative stress on RBCs
What are the two clinical variants of G6PD?
African variant (mild)
Mediterranean variant (severe)
What sources of oxidative stress may induce intravasuclar hemolysis in G6PD deficient patients?
Infections
Drugs (primaquine, sulfa drugs, dapsone)
Fava beans
How do you screen for G6PD?
a Heinz preparation (used to see Heinz bodies); afterwards an enzyme study can confirm deficency (can’t be done til after hemolytic episode)
What are the two types of autommune hemolytic anemia?
Warm AIHA
Cold AIHA
What characterizes Warm AIHA?
IgG binds RBCs in warm central body, and part of membrane is consumed by splenic macrophages, this leads to less membrane > spherocytes
What characterizes Cold AIHA?
RBCs are bound in colder temperatures (fingers/toes) are complement is fixed, and results in hemolysis
What is the treatment for AIHA?
cessation of offending drug, steroids, IVIG (distracts spleen), spenectomy (last resort)
Patients with mycoplasma pneumoniae or mononucleosis are at risk for developing what type of AIHA?
Cold AIHA
How does the DAT (Coombs) determine AIHA?
An anti-IgG antibody is added to patient RBC, and agglutination will occur if RBCs are coated with IgG (positive test)
How is Microgangiopathic hemolytic anemia characterized?
A vascular pathology causes RBC destruction as they pass through circulation; this produces schistocytes
What are the 3 major conditions that fall under microangiopathic hemolytic anemia?
TTP
HUS
DIC
How is Thrombotic Thrombocytopenic Purpura characterized?
ADAMTS13 levels are greatly decreased (<10%) causing vWF multimers to be undegraded
What are major signs or symptoms of TTP?
RBC fragments in blood, ADAMTS13 levels <10%, presenting with thrombocytopenia, fever, neuro sx
What are major symptoms of HUS?
RBC fragments in blood, renal failure, bloody diarrhea
What is the name of the highlighted molecule in the picture?
a schistocyte
What proteins are most involved in Alzheimer’s disease?
beta-amyloid and Tau
What proteins are most involved in Parkinsons disease?
alpha-synuclein
T/F: Hemoglobin bound to no oxygen is said to be in the R-state or relaxed conformation
False; it is the T-state or tight conformation
Does fetal hemoglobin have a low or high affinity for 2,3 DPG (BPG)? Why is this?
very low affinity; this encourages materal delivery of oxygen to the fetus
What are two similarities between sickle cell disease and amyloid?
They are both diseases of protein folding
They are both diseases of specific protein aggregation
What are two differences between sickle cell disease and amyloid?
HbS tetramer still maintains native structure and alpha-helical fold, while amyloid involves polymerization of beta-sheets.
HbS occurs in hemoglobin, while amyloid can occur in many protein types, mutated or not
What is pictured in this histology slide? What stain is being used?
A ringed sideroblast (prussian blue stain)
What treatment is often viable for x-linked sideroblastic anemia?
High-doses of vitamin B6
SCD is most often caused by what type of mutation in what gene?
a missense mutation (E->V) in the beta-globin gene
If hemolytic anemia is suspected, what is the first step to be taken?
DAT (Coombs test)
In suspected hemolytic anemia with a negative DAT, what is the next step in diagnoses?
Blood smear
What causes paroxysmal nocturnal hemoglobinuria (PNH)?
Mutation in PIGA gene causes faulty synthesis of GPI anchor, in whose absence complement is activated against RBCs
What lab indications might be indicative of PNH?
Extremely high (1000s) ALT and AST
Lack of CD 55 and CD 59 on RBCs
What are the major differences in symptoms between TTP and HUS?
TTP: ‘Pentad” Fever, thrombocytopenia, MAHA, neurologic symptoms, renal insufficiency
HUS: preceding bloody diarrhea, renal failure (more prominant than TTP)
What are the differences in treatment of HUS and TTP?
TTP: excellent response to plasma exchange
HUS: treatment other than plasma exchange usually required
Since hemoglobinopathies (like SCD) are difficult to detect with FISH, what other molecular methods can be used to detect deletions or point mutations?
HPLC; which can detect globin changes
What a major effect of chronic kindey disease on RBC production?
CKD can lead to underproduction of EPO
Who can a B+ bloodtype patient receive plasma from?
B, AB
What is the most common transfusion reaction? What is the etiology?
Allergic reations; preformed IgE antibodies directed against plasma proteins in donor; severity ranges from hives to anaphylaxis
What is the biggest worry in transfusion medicine (TM)? What is the etiology?
Hemolytic event; IgM activation of complement against RBC surfaces due to mistyping
