Midterm 1 Flashcards
1
Q
The area of central pallor in an RBC should be what fraction of the diameter?
A
1/3
2
Q
What is the difference between ansiocytosis and poikilocytosis?
A
- Ansiocytosis- red cells vary widely in size
- Poikilocytosis- red cells vary widely in shape
3
Q
What is microcytosis (and associated causes)?
A
Red cells that are small
- Iron deficiency
- Thalassemias
- Lead Poisoning
- Sideroblastic anemia
4
Q
What is macroytosis (and associated causes)?
A
Large red cells
- B12/folate deficiency
- Liver or Thyroid disease
- Chemo
- Anti-retrovirals (AZT)
- Aplastic Anemia
- Myelodisplastic Syndroms (MDS)
- Elevated reticulocyte count
5
Q
What is hypochromasia?
A
Red cells that have too little hemoglobin (area of central pallor is increased)
6
Q
What is polychromasia?
A
Red cells that have a bluish tinge (larger and most likely reticulocytes)
7
Q
What are target cells (and associated diseases)?
A
Look like bulls-eyes
- Liver disease
- Thalassemias
- Hemoglobin C
- After splenectomy
8
Q
What are spherocytes (and associated diseases)?
A
RBC with loss of central pallor
- Hereditary spherocytosis
- Autoimmune hemolysis (also smaller)
9
Q
What are schistocytes?
A
Red cell fragments with sharp edges
Hallmark of Microangiopathic Hemolytic Anemia (MAHA)
10
Q
What is the difference between Echinocytes and Acanthocytes?
A
- Echinocytes (Burr cells)- small, regular projections seen in renal disease
- Acanthocytes (Spur cells)- large, irregular projections seen in liver disease
11
Q
When are teardrop cells seen in RBC?
A
- Myelophthisic processes (diseases of bone marrow infiltration) like myelofibrosis and tumors in marrow
- Granulomatous diseases
- Leukemias and lymphomas
- Massive splenomegaly
12
Q
What are Howell-Jolly bodies?
A
- Peripheral, small, round, purple inclusions within red cells (nuclear remnants)
- Seen after splenectomy or splenic hypofunction
13
Q
What are rouleaux?
A
A linear arrangement of RBC (“coins on a plate”)
- Increased levels of immunoglobulin (Multiple Myeloma or Waldenstrom’s macroglobulinemia)
- Severe hypo-albuminemia
14
Q
What does agglutination occur when RBC are coated with IgM?
A
Because IgM is large enough to bridge two red cells and cause the clumping to occur in non-linear fashion
15
Q
What is the classic cell dysfunction associated with lead poisoning?
A
Basophilic stippling
16
Q
What are the two main physiological roles of hemoglobin?
A
- Bind oxygen and deliver to tissues
- Assist in maintaining acid-base balance in the body (binding CO2)
*These depend on PO2 and PCO2*
17
Q
What are the main differences between myoglobin and hemoglobin?
A
- Myoglobin- synthesized in muscle cells, stores oxygen, single polypeptide chain, 80% alpha-helical, binds one O2 molecule
- Hemoglobin- 4 polypeptide cahins (2 alpha and 2 beta), can bind 4 O2 molecules
18
Q
What are the major types of hemoglobin, their subunits, and their presence?
A
- HbA- alpha2+beta2, 97-98% in adults
- HbA2- alpha2+delta2, 1-3% in adults
- HbF- alpha2+gamma2, major Hb in womb (40% at birth)
- HbS- seen in sickle cell trait or anemia, mutation in Beta
19
Q
On which chromosome are the alpha, beta, delta, and gamma hemoglobin genes located?
A
- Alpha- chromosome 16
- Beta, delta, gamma- chromosome 11
20
Q
What is thalassemias?
A
Imbalance in globin chain synthesis (beta or alpha deletion)
21
Q
What makes up a heme group?
A
An iron (Fe) ion held in a heterocyclic ring, known as a porphyrin
22
Q
What is responsible for binding the oxygen in heme?
A
The iron molecule (must be +2)
23
Q
What is the difference in O2 affinity between myoglobin and hemoglobin?
A
- Myoglobin has a single constant affinity for O2 with a P50 of 2.8 torr (high affinity)
- Hemoglobin has a changing affinity for O2 with a P50 of 26 torr (low affinity)
24
Q
How does the binding of O2 in heme affect its affinity for more O2 binding?
A
- The T conformation favors the deoxy form (release)
- The R conformation favors the oxy form (bind)
- O2 is a positive allosteric regulator of Hb O2 binding and changes the conformation of the other subunits
25
What is 2,3 di-phosphoglycerate (2,3-DPG) and its role in Hb?
* 2,3-DPG is produced in RBCs when glucose is abundant and stabilizes the T (deoxy) state of Hb.
* Can supply O2 to tissues operating a high metabolic rate (in response to hypoxia)
26
What are some common cases when 2,3-DPG would increase?
* Chronic Obstructive Pulmonary Edema
* High altitude
* Chronic anemia
* Pregnancy
27
What is the Haldane effect?
* The favored synthesis of CO2 and H2O from H2CO3 in the lungs
* Due to the high pO2 (drives binding of O2 to Hb and release of H+)
28
What is the Bohr Effect?
* Protons bind to Hb and favor the T state, favoring O2 release in RBCs
* Caused by dissociation of H2CO3 -\> H+ + HCO3-
29
What is the effect of pH on O2 binding by Hb?
* Increase pH favors O2 binding
* Decrease pH favors O2 release
30
What is the importance of fetal hemoglobin (HbF)?
* Different beta chain, has a higher affinity for oxygen that adult hemoglobin
* Binds 2,3-DPG very poorly
31
What are the two genotypes that can cause sickle cell disease?
* Homozygous mutations for the Bs mutation
* Heterozygous for the Bs mutation and the B-thalassemia allele (B+ is mild)
* Heterozygous for the Bs mutation and hemoglobin C (more mild to sickle cell anemia form- HbC disease)
32
What else can bind to iron in HbA and alter oxygen binding?
* Cyanide
* Carbon Monoxide (very stable and forms more rapidly)
* Nitroden Dioxide
* Hydrogen Sulfide
33
What is methemoglobinemia?
* Increased amounts of Fe3+ in the blood (cannot bind O2) due to a mutation
* Cyanosis and brown color to blood
34
What are some of the main causes of methemoglobinemia?
* Mutation to 3 AA on distal side of heme
* Mutations in PPP
* Glutathione malfunction (increases reactive oxygen species)
* **Mutation in cytochrome b5 reductase**
* Gastrectomy (lack of stomach acid to keep in Fe2+ state)
35
At age 4, what changes in hematopoiesis?
Bone marrow outgrows needs for hematopoiesis and mainly occurs in axial skeleton and proximal long bones
36
What constitutes the stroma of bone marrow?
* Fat cells
* Macrophages
* Endothelial Cells
* Fibroblasts
37
What are the non-specific growth factors in hematopoiesis?
* IL-3
* GM-CSF (granulocyte-monocyte colony stimulating factor)
38
What are the lineage specific growth factors in hematopoiesis?
* G-CSF (granulocyte)
* M-CSF (monocyte)
* IL-5
* EPO (erythropoietin)
* TPO (thrombopoietin)
39
What are the two main functions of pluripotent stem cells (PPSC)?
* Self-renewal: proliferate to produce more SC
* Differentiation: produce specialized mature cell types and more developmentally restricted cells (progenitor)
40
What can a multipotent hematopoietic stem cell differentiate into?
Common lymphoid or common myeloid progenitor
41
What is the major cell type in the bone marrow?
Fat cells consist of 50% of the bone marrow
42
What are the two methods for bone marrow examination?
* Aspiration (liquid sample taken with needle)
* Biopsy (solid core examined)
43
What is the first granulocyte precursor to enter the blood stream?
Band (stab) cell
44
How do megakaryocytes make platelets?
From the cell membrane and protein
45
What are some characteristics and examples of pyrimidines?
* 6 membered heterocyclic with 2 nitogens in ring
* Insoluble in water
* Cytosine, Thymine, Uracil (RNA)
46
What are some characteristics and examples of Purines?
* Pyrimidine rind fused with imidazole
* Almost all have DB oxygen (not Adenine)
* Water soluble
* Adenine, Guanine, Xanthine, Hypoxanthine, Inosine, Uric acid
47
What is the difference between nucleoside and nucleotide?
* Nucleoside= base + sugar
* Nucleotide= base + sugar +phosphate group
48
What are the 2 main differences between RNA and DNA structure?
* RNA= OH at 2'C of sugar, less table
* DNA= H at 2'C of sugar (deoxy)
49
What are the 3 main sources of nucleotides?
* Dietary- only 5% enter circulation
* De novo synthesis- mostly occurs in the liver
* Salvage pathay- uses turnover from RNA/DNA
50
What is the common precursor in Purine and Pyrimidine synthesis?
Ribose 5-Phosphate (from the Pentose Phosphate Pathway) becomes PRPP *(PRPP Synthetase*)
51
How is PRPP Synthetase regulated?
* Activated by high phosphate (indicates low NT)
* Inhibitied by purines (feedback)
52
What is Arts Syndrome?
* Rare genetic disorder in PRPP synthetase
* X-linked; sever nervous system abnormalities
* Reduced purine levels, uric acid in serum
53
What is gout?
* Most cases are due to underexcretion of uric acid
* Less common is overproduction of uric acid
* High levels of uric acid (hyperuricemia)
* Urate crystals in joints (inflammation)
* Uric acid kidney stones
54
What is the committed step of Purine synthesis?
* The addition of initial amine to PRPP
* Catalzyed by *glutamine phosphoribosyl amidotransferase*
* Activated by PRPP
* Inhibited by nucleotides
55
How do AMP and GMP inhibit *glutamine phosphoribosyl transferase (PRPP amidotransferase)*?
* They cause formation of a dimer (monomer is active)
* Bind via non-competitive binding sites
* Participte in synergistic effect on enzyme
56
How does the body get THF?
* From folate in the diet (vitamin B9)
* Must convert using DHFR (2 reactions)
57
What is the role of THF in Purine metabolism?
Serves as a carbon donor at 2 steps in the formation of Inosine Monophosphate (IMP)
58
What is the common precursor for all purine nucleotides?
Inosine Monophosphate (IMP)
59
What is the mechanism by which methotrexate inhibits DHFR (used in cancer therapy)?
* Mimics folate
* Reduces synthesis of THF (inhibition of DHFR)
* Reduces purine synthesis (and DNA replication)
60
How does the body maintain an AMP/GMP balance?
* Positive Cross-Regulation
* Formation of GMP from IMP requires ATP
* Formation of AMP from IMP requires GTP
61
What are two immunosuppressant drugs that inhibit IMP dehydrogenase?
* Mycophenolic Acid (prevents graft rejection)
* Ribavirin (anti-viral and anti-tumor agent)
62
What enzymes are involved in the conversion of AMP/GMP to final ATP/GTP?
* *Adenylate kinase* (AMP -\> ADP)
* *Guanylate kinase* (GMP -\> GDP)
* *Nucloeside disphosphate kinase* (ADP/GDP -\> ATP/GTP)
\*\*All of these rxns require ATP\*\*
63
What is the difference between pyrimidine and purine nucleotides after degregation?
* Pyrimidines are soluble and can be used in other metabolic pathways
* Purines are not soluble and lead to production of uric acid
64
Where does purine degredation mainly occur?
In the liver
65
What is the the main product of purine degredation before uric acid?
* Xanthine (made by the degredation of both AMP and GMP)
* Enzyme is *Xanthine Oxidase (*can be inhibited by Allopurinol)
66
Why does a deficiency of Adenosine Deaminase (ADA) lead to SCID?
* ADA catalzyes adenosine -\> inosine in purine degredation
* Exists at high levels in lymphocytes
* Inability to breakdown dAMP increases dATP
* High levels of dATP reduce DNA synthesis
* Lymphocytes die
67
Why is AMP Deaminase deficiency not as deleterious as Adenosine Deaminase deficiency?
* AMP deaminase is mainly in the skeletal muscle (converts AMP -\> IMP)
* Can lead to some myopathy, fatigue, or camps
68
Which values in a CBC are directly measured?
* Hemoglobin (concentration of Hb)
* RBC (number x1012/L)
* MCV (RBC volume)
69
Which values in CBC are calculated?
* Hematocrit (volume of RBC per total volume)
* MCH (Hb dvided by RBC)
* MCHC (Hb divided by MCVxRBC)
* RDW (varation in MCV)
70
What is the definition of anemia?
* Decreased hemoglobin/hematocrit below the normal range for gender and age
* A manifestationof disease (not the final diagnosis)
71
How do changes in blood volume relate to anemia?
* Acute blood loss can lead to low blood volume (anemia)
* Chrnoic anemia can lead to fluid retention and increased blood volume
72
What is the effect of quick vs. slow changes in hemoglobin count?
* Quick drops in hemoglobin leads to more dramatic symptoms
* Slow drops in hemoglobin actually lead to cardiopulmonary compensation
73
What are the 4 main symptoms of hypovolemia?
* Hypotension (low BP)
* Orthostatic changes (sit vs stand)
* Syncope (faint)
* Shock (don't deliver O2 to tissues)
74
What are the 4 main sypmtoms of tissue hypoxia?
* Fatigue
* Shortness of breath
* Cognitive difficulties
* Ischemic pain (angina or clardication)
75
What are the 2 main acute responses to anemia?
1. Increased heart rate (stroke volume)
2. Vasoconstriction (from blood loss)
76
What are some of the chronic responses to anemia?
* Kidneys retain salt and water, expan intravascular volume
* Increased 2,3-DPG (cuases more O2 release)
* Increase erythropoietin synthesis (renal signal)
77
What do you need to consider when transfusin a patient with chronic anemia?
Need to be aware that a transfusion could lead to volume overload, so need to administer a diuretic during treatment
78
What are the 3 main causes of anemia?
1. Hemorrhage (blood loss)
2. Decreased RBC survival (hemolysis)
3. Decreased RBC production
79
How do we classify anemia by erythropoietic response (reticulocyte count)?
1. **Hyperproliferative** (plenty of reticulocytes)- retic index above 2% of retic count above 100,000
2. **Hypoproliferative** (not enough reticulocytes)- retic index below 2% or retic count below 75,000
80
How do we classify anemia by the RBC size (MCV) and Hb concentration?
1. **Microcytic, hypochromic** (MCV below 80)- problem with Hb synthesis
2. **Macrocytic** (MCV above 100)- Megaloblastic or non
3. **Normocytic, normochromic**- indicates marrow or acute problem
81
What is the absolute volume at which hemoglobin is deemed to low and need for transfusion is immediate?
There is no value, a patient can have a Hb value to high for transfusion but not too low
82
When is a transfusion necessary in anemic patient?
* Cardiovascular compromise (failure, shock, angina)
* Hypopoliferative anemia with no/long recovery
* Anemic patient going into surgery
83
What can you say about patient 1?
The patient has a large amount of HbS which indicates either:
1. Heterozygous for B-thalassemia and a Bs mutation
2. Homozygous for Bs mutation withrecent transfusion
84
What can you say about patient 2?
Most prominent band is HbS with some HbF and HbA2. The patient is most likely sickle cell anemia with elevated HbF (homozygous Bs mutation)
85
What can you say about patient 3?
Equal amounts of HbA and HbS, most likely a sickle cell trait patient (BaBs heterozygote)
86
What can you say about patients 4 and 5?
Both are most likely normal, with 4 being a newborn and 5 being an adult
87
When is HbS at risk for sickling (and why)?
The deoxy form (T state) of HbS partcipates in sickling because the open valine residues cause nucleation events that continue to grow exponentially after forming a critical nucleus.
88
Why does a higher HbS concentration cause more sickling (like during dehydration)?
Because there are more HbS molecules which can participate in nucleation
89
Does an acidic environment cause more or less sickling for HbS?
A drop in pH (acidosis) causes more sickling because the acidic environment favors the deoxy form.
90
How does temperature affect sickling in HbS?
A rise in temperature sharply increases the rate of sickling (however, in acidosis this effect is attenuated)
91
Why does a drop in PO2 cause more sickling by HbS?
Becuase a drop in PO2 indicates there is less O2 present, which means that Hb will want to release any bound oxygen. The doexy form of HbS will then begin to nucleate (and eventually sickle)
92
What are the 3 molecular mechanisms of hemoglobinopathies?
1. Loss of function (thalassemia)
2. Novel property mutation (sickle cell disease)
3. Heterochronic or ectropic expression (fetal hemoglobin persistence)
93
What is the equation for the Hardy Weinberg Principle?
94
What are the 2 rules for biallelic sites in the Hardy-Weinberg Principle?
p + q = 1
p2 + 2pq + q2 = 1
95
What approximations can you make with the Hardy-Weinberg Principle for recessive conditions that are rare?
* q = sqrt (prevalence)
* p = 1
* carrier frequence = 2q
96
What are the main assumptions of the Hardy-Weinberg Principle?
* Population is large
* Random mating
* Allele frequencies remain constant over time
97
What are the effects of small populations on allelic frequency?
* Genetic drift- fluctuations in allele frequency resulting from chance occurrences
* Founder (bottleneck) effect- nonrandom distribution of alleles by those who founded subpopulation
98
What are some examples of non-random mating?
* Stratification (subgroups)
* Assortative mating (deaf mate with deaf)
* Consanguinity (relation)
99
What are some exceptions to a constant allele frequency?
* Selection against or for alleles (fitness)
* Mutation
* Migration
100
Can a couple with cis or trans alpha-thalassemia minor (trait) have a baby with hydrops fetalis?
Cis
101
What are the difference in causes between Alpha and Beta thalassemias?
* Alpha- most are caused by gene deletions
* Beta- most are caused by missense, nonsense, or frameshift mutations
102
What is Factor V Leiden?
* Gain of function mutation in gene for Factor V
* Increases production of thrombin
* Increased risk for DVT (up to 5 fold for hetero, up to 80 fold for homo)
* Expression of phenotype is influenced by environemental factors
103
What is haploinsufficiency?
* Normal physiology requires more than 50% of fully active gene product to prevent disease
* Refers to dominant phenotypes
* Transcription factors, structural proteins, cell surface receptors
104
What is a dominant negative effect?
* Abnormal protein causes abnormal phenotype by intereferring with normal allele product
* Osteogenesis imperfecta
105
What are some common factors that complicate pedigree analysis?
* Environmental factors
* Heterogeneity (allelic and locus)
* Mosaicism
* New mutations
* Penetrance
* Pleiotropy
* Variable expressivity
106
Why does the body use nucleotide salvage pathways?
* Energetically advantageous
* Reutilize nucleotides and free bases from degredative processes
* Used in lymphocytes as major source of nucleotides
107
What are the two pathways for nucleotide salvage?
* Nucleoside -\> Nucleotide (phosphorylation by kinases)
* Free Base -\> Nucleotide (Use PRPP)
108
Nucleotide salvage pathways involving PRPP utilize which enzymes?
* IMP and GMP use hypoxanthine guanine phosphoribosyltransferase (HGPRT)
* AMP uses adenine phosphoribosyltransferase (APRT)
\*These reactions are irreversible, due to PPi cleavage\*\*
109
Why are purine compounds so useful in the salvage pathway?
Because they are easily interconvertible
110
What does a deficiency in purine nucleoside phosphorylase lead to?
* Nucleosides accumulate
* Responsibel for Inosine -\> hypoxanthine and guanosine -\> guanine
* T-cell immunodeficiency
111
What are some of the main causes of overproduction of uric acid?
* Loss of regulation at committed step of purine nucleotide synthesis (increased PRPP)
* **Lesch-Nyhan Syndrome**- decreased salvage of hypoxanthine and guanine (increased PRPP)
* **Chemotherapy**- high cell death causes excess purine degredation products
112
What is Von Gierke Disease and its relation to gout?
* G6PD deficiciency
* Excess G6P is shunted to the PPP
* More R5P -\> More PRPP -\> More nucleotide synthesis
113
What is Lesch-Nyhan syndrome?
* X-linked recessive disorder
* Deficiency of HGPRT
* Increased PRPP -\> low AMP, GMP, IMP
* Excess uric acid
* Neurological and behavioral abnormalities, gout
114
What are some common treatments for acute gout?
* Anti-inflammatory agents
* Colchicine
115
What are some common treatments for chronic gout?
* **Probenecid**- affects renal excretion of uric acid
* **Allopurinol**- Inhibits uric acid synthesis (structural analog of hypoxanthine)
* **Febuxostat**- inhibitor of xanthine oxidase
116
Why does tumor lysis lead to hyperuricemia?
* Large tumors have high levels of serum and uric acid
* Destruction of tumor leads to this release
* Treat with allopurinol or rasburicase
117
What is different about pyrimidine synthesis from purine synthesis?
* Synthesis does not start with ribose 5-phosphate backbone (added later)
* Also a simpler ring than purine
118
What is the committed step in pyrimidine synthesis (and its enzyme)?
* Conversion of glutamine and CO2 -\> carbamoyl phosphate
* *Carbamoyl Phosphate Synthetease II (CPS-II)*
* Inhibited by UTP, activated by PRPP
119
What is CAD and its role in pyrimidine synthesis?
* **_C**_arbamoyl phsophate synthetase II, _**A**_spartate transcarbamoylase, _**D_**ihydroorotase
* Huge multisubunit protein carries out the first 3 reactions of the pyrimidine synthesis pathway
* Glutamine -\> orotic acid
120
Hereditary Orotic Aciduria is caused by a mutation in which enzyme?
* *UMP Synthase (either subunit)*
* Leads to poor growth, anemia, high levels of orotic acid in urine
* Treat with addition or uridine (becomes UTP and inhibits CSPII, reducing de novo synthesis)
121
How is pyrimidine nucleotide synthesis regulated?
* PRPP activates CPS II (allosteric activator)
* ATP is required forfirst step (helps balance)
* UTP and UDP are feedback inhibitors (CPS II)
122
How are UTP and CTP made?
* UMP -\> UDP -\> UTP
* UTP -\> CTP
123
What is the significance of *Ribonucleotide Reductase*?
* Enzyme required for synthesis of deoxyribonucleotides (DNA)
* Replaces the 2' OH with H
* Requires thioredoxin as cofactor (supplies H)
124
How does hydroxyurea inhibit *ribonucleotide reductase*?
* Degrades R2 tyrosyl free radical
* Reduces dNDPs (and dNTPs)
* Reduces DNA synthesis
* Useful as anti-tumor compound
125
How is the activity or ribonucleotide reductase regulated?
* Activity site: activated by ATP and inhibited by dATP
* Substrate Specificity Site: cross-regulation by dNTPs (helps balance correct amounts of each)
126
What is the MoA of 5-Fluorouracil as an Anti-Tumor Drug?
* Converts to 5-fluorodeoxyuridine monophosphate, binds thymidylate synthase
* Inactivates the enzyme and reduces conversion of dUMP -\> dTMP
127
What is the MoA of methotrexate as an anti-tumor drug?
* Competitive inhibitor of DHFR and reduces levels of THF, reduces conversion of dUMP -\> dTMP
128
What is the MoA of 6-mercaptopurine as an anti-tumor drug?
* Competes with guanine and hypoxanthine, converts to 6-MMP by HGPRT + PPRP
* Negatively regulates PRPP amidotransferase (reduces nucleotides)
* Inhibits IMP -\> AMP and IMP -\> GMP pathways
129
What is the MoA of Leflunomide as an anti-tumor drug?
* Inhibits dihydroorotate dehydrogenase
* Blocks orotate and pyrimidine production
130
What are the general features of Hemolytic Anemia?
* Jaundice
* Dark Urine
* Pigmented gallstones
* Ankle ulcers
* Splenomegaly
* Aplastic crises (Parvovirus B19)
* Increased need for folate
131
What is bilirubin?
A yellow compound that occurs in the normal catabolic pathway that breaks down heme
132
Why is splenomectomy used to treat disorders?
* Used when there is uncontrolled splenic destruction of RBC or platelets
* Need to vaccinate against encapsulated organisms
* Howell-Jolly bodies form afterwards
133
What is parvovirus B19?
* Non-encapsulated DNA virus
* Infects and lyses RBC precurors in marrow, 7-10 day cessation of erythropoiesis
* Causes aplastic crisis in hemolytic anemias because hemoglobin plummets
134
How do we classify hemolytic anemias?
* Sites of RBC destruction
* Acquired vs. congenital
* Mechanism of RBC damage
135
What are some key differences between extravascular and intravascular hemolytic anemias?
* **Extravascular**- macrophages in spleen, liver, marrow remove cells
* **Intravascular**- cells rupture within vascular and release free Hb into circular (kidney damage)
136
What are some indicators that there is increased RBC production?
* Elevated reticulocyte count in blood
* Eryhtroid hyperplasia in BM
* Deforming changes in the bones (frontal bossing)
137
What are some indicators that there is increased RBC destruction?
* Elevated LDH (released after lysis)
* Elevated bilirubin (byproduct of heme breakdown)
* Reduced serum haptoglobin (binds free Hb)
138
What is the only disorder in which MCHC will be referenced (and increased)?
* **Hereditary Spherocytosis** (defect in ankyrin)
* Autosomal dominant
* Inreased osmotic fragility
* Treat with folate supplement and splenectomy
139
What is an osmotic fragility test?
* Used to diagnose thalassemias or hereditary spherocytosis
* Add RBC to different salt concentrations
* Unhealthy RBC start to lyse at higher tonicity than normal
140
Why does G6PD deficiency cause anemia?
* Low G6PD = low levels of NADPH and glutathione (protect Hb from oxidative damage)
* Oxidizing agents convert hemoglobin to methemoglobin -\> Heinz bodies
* "bite cell" or "blister cell"
141
What is the hallmark of autoimmune hemolytic anemia?
* A positive Coomb's test
* **Direct Coomb's** (Direct Antiglobulin Test) tests for IgG or C3 directly on RBC
142
What are some key clinical features of Warm-Antibody hemolytic anemias?
* Increased reticulocytes, bilirubin, and LDH
* Low haptoglobin
* Positive Coomb's test
* Spherocytes on peripheral smear
143
Why does cold agglutination disease lead to RBC agglutination and clumping?
* Because IgM is so large
* Cyanosis and ischemia occurs in extremities
* Need to keep patient warm
144
What is the hallmark presence in Microangiopathic Hemolytic Anemia?
Schistocytes on peripheral blood smear
145
Hwo are beta-globin mutations annotated?
* Absent beta globin synthesis B0
* Decreased beta globin synthesis B+
* Can be heterozygous, homozygous, or compounded with another mutation of beta globin gene (BS)
146
What are some classic symptoms of iron overload?
* Bronze skin
* Liver failure
* Endocrine failure
147
What are some unique findings about beta thalassemia minor (trait)?
* Usually asymptomatic
* Very microcytic cells (MCV around 70)
* May or may not have mild anemia
* RBC count is very elevated
* RDW is normal (all are small)
* Synthesis of delta chains upregulated (high HbA2)
148
Which alpha thalassemias have normal Hemoglobin electrophoresis?
* One gene deletion and two gene deletion
* Exception is that newborns with two gene deletions will show Hemoglobin barts (gamma tetramer)
149
Are all people with three alpha globin gene deletions subject to severe Hemoglobin H disease?
* No, some are barely affected and others are severely affected
* Depends on presence of beta tetramers (HbH) which are unstable and form Heinz bodies
* Most have splenomegaly
150
How can you save a baby with 4 alpha globin deletions (hydrops fetalis)?
* Treat in utero by exchange transfusions
* Give bone marrow transplant after birth
151
What is Hemoglobin C?
* Sixth AA in beta chain is changed from glutamate to lysine
* Increases cellular dehydration
* Presence of target cells and Hemoglobin C crystals (homozygous CC disease)
152
What are the rates of:
* African Americans carrying sickle cell trait
* African Americans with sickle cell disease
* Hispanic-Americans with sickle cell disease
* 1 in 12 African Americans carry sickle cell trait
* 1 in 500 African Americans have sickle cell disease
* 1 in 1000-5000 Hispanic-Americans have sickle cell disease
153
What are the 3 causes of sickle cell crises?
* **Splenic sequestration**- rapid and extensive trapping of RBC in spleen, typically in children (occurs quickly)
* **Aplastic crisis**- parvovirus B19 leads to bone marrow supression, rapid anemia
* Painful (**vaso-occlusive**) crisis- most common
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What are some common treatments for painful crisis of sickle cell anemia?
* Treat underlying infection (if any)
* Treat pain adequately
* Supplemental oxygen
* Folate replacement
* Replace fluid if dehydrated (but watch for pulmonary edema)
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What are some common infection problems for sickle cell patients?
* Increased susceptibility to encapsulated organisms ("autosplenectomy")
* Spesis from encasulated organisms, *Yersinia* or *Vibrio* (if chelation therapy)
* Pneumonia can worsen acute chest syndrome
* Salmonella osteomyelitis
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What are the respiratory complications in sickle cell patients?
* Acute Chest Syndrome- most common cause of death
* Pulmonary hypertension- one third of SCD adults (death within 2 years)
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What is acute chest syndrome?
* Hypoxemia (infiltrate on CXR and fever, pain, dypsnea, or cough)
* Infections with atypical organisms- chlamydia and mycoplasma
* Fat embolism from necrotic bone marrow
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How is acute chest syndrome treated?
* Antibiotics
* Oxygen
* Transfusion to lower HbS concentration (simple or exchange)
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What leads to stoke in SCD patients?
* Disorderd blood vessels (not atherosclerosis)
* Median age of occurence is 5 yo
* Treat acutely with exchange transfusion
* Chronically with regular transfusions
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How can you prevent stroke from occuring in a young SCD patient?
* Transcranial doppler shows narrowing of circle of Willis
* Chronic regular transfusion can prevent!
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Why are transfusions complicated in SCD patients?
* Iron overload (treat with chelation)
* Allo-immunization (fewer RBC antigens; transfuse with C, E, Kell negative blood)
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What are some unique complications in SCD patients?
* Renal papillary necrosis (Isothenuria) and renal failure (dialysis)
* Leg ulcers
* AVN = avascular necrosis (shoulders and hips)
* Episodic or chronic priapism (erections)
* Proliferative retinopathy (SC or SB)
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What is the use of hydroxyurea in SCD patients?
* **Increases amount of HbF** (decrease concentration of HbS)
* Increases Hb values
* Reduces sickle crises
* Reduces episodes of acute chest syndrome
* Prevents pulmonary hypertension
* Reduces mortality
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What are the health risks with sickle cell trait?
* May have renal manifestations (isothenuria or microscopic hematuria)
* Prone to heat stoke and rhabdomyolosis (need frequent breaks)
* Pregnancy will lead to symptoms (HTN, pain crises, UTIs, clotting, renal/pulmonary complications)
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What is unique about iron kinetics and regulation?
1. Majority of iron is recycled (RBC \<-\> storage)
2. There is no physiological way to get rid of iron overload
3. Iron regulation is at the level of gut epithelium
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What is the difference between heme and nonheme iron sources?
* **Heme**- easily absorbed from meat, 2/3 of iron stores
* **Nonheme-** absorption relies on stomach acid and other substances
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What is the role of ferric reductase, ferroportin and transferrin?
* **Ferric reductase**- reduces dietary iron to ferrous state (transported into enterocyte)
* **Ferroportin**- transporter that allows iron to leave enterocyte and enter blood (general iron release)
* **Transferrin**- binds iron in blood steam and transports to cells
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What is the role hepcidin?
* Blocks the action of ferroportin
* Blocks release of iron from enterocyte, hepatocyte, and macrophages
* Upregulated with inflammatory cytokine expression
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What is the difference between TIBC and transferrin saturation?
* **TIBC**= total iron binding capacity, increases with iron deficiency
* **Transferrin saturation**= fraction available for Fe-binding, decreases with iron deficiency
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What is the predominant storage place for iron?
* Stored in protein ferritin, in the liver.
* There is no regular excretion of iron, lost when RBC are lost
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What are some common means of iron loss?
* Menstruation
* Pregnancy
* Blood donation
* GI blood loss
* GU loss
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How many units of blood transfusion are needed to raise the hemoglobin of an adult by 1g/dL?
One unit of blood transfusion per 1g/dL of hemoglobin
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What is the most common cause of iron deficiency?
* Almost always due to blood loss
* Can be component of malnutrition or dietary insufficiency
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What are the stages of iron deficiency?
1. **Storage iron is depleted** (ferritin low)
2. **Serum iron is depleted** (% serum down, TIBC up)
3. **Normocytic anemia** (BM makes low amounts of normal sized RBCs)
4. **Microcytic, hypochromic anemia** (inability to make normal RBCs)
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What are some key signs/symptoms of iron deficiency?
* Glossitis
* Koilonychia
* **Pica**
* **Thrombocytosis**
* Restless leg syndrome
* Hair loss
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What findings are present in CBC acutely, then later during iron deficiency?
* First, you will see an elevation of RDW followed by falling MCV
* Lastly, hemoglobin and hematocrit will fall
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What is a key finding in iron deficiency (and some things to be careful of)?
* Ferritin levels below 15 indicate iron deficiency (best test)
* However, these can be normal levels if there is an infection (cytokines increase ferritin)
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What do iron studies include?
* Serum iron
* TIBC
* Transferrin levels
* Transferrin saturation
179
Why is oral iron replacement difficult?
* It can cause nausea, constipation, and black stools
* IV iron has risk of anaphylaxis but used with IBD and gastric bypass patients
180
What is placental transfusion?
* The placenta passes blood to the baby
* Takes a few minutes after the initial birth
* Should hold the baby lower than the placenta and delay clamping/cutting
181
At what point is RBC production highest during pregnancy and why?
* Last trimester (3-5 times more production than adults)
* Hypoxia in utero drives erythropoiesis
* Preparing iron storage during last month for birth
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What is physiologic anemia of infancy?
* Hemoglobin and reticulocyte counts drop after birth (drop in epo production with oxygen)
* Premature infants affected, shorter RBC survival
183
Why is iron deficiency a problem during puberty for boys and girls?
* Boys- myoglobin increases and causes even higher need for iron (muscle)
* Girls- menstruation begins
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What are risk factors for iron deficiency in children?
* Perinatal- maternal iron deficiency, prematurity, fetal-maternal hemorrhage
* Insufficient iron intake
* Cow's milk given at \<12 months
185
What are ways to prevent iron deficiency in children?
* Treat iron deficiency in pregnant and breast-feeding women
* Use only iron fortified formulas
* Avoid feeding cow's milk until 1 yo
* Children under 5 should limit cow's milk consumption
186
What are some effects on iron deficiency in children?
* Neuropsychiatric manifestations (ADHD)
* Increased risk for thrombosis in infants
* Increased risk for lead toxicity (pica for paint chips)
187
What are the global health risks with iron supplementation?
* Malaria related interactions with iron supplemented children
* Iron overload possibility with thalassemias (increased iron absorption)
188
What are the key differences between Iron deficiency and anemia of chronic disease?
* **Iron Deficiency**- very high TIBC and very low ferritin
* **Anemia of chronic disease**- low TIBC and normal/high ferritin
189
When should hydroxyurea be avoided for SCD patients?
* Pregnancy (dangerous to fetus)
* If patient will not return (can cause problems and need to be monitored)
190
Where does absorption of iron into enterocytes occur?
In the duodenum of the small intestine
191
Why does free erythrocyte protoporphyrin (FEP) increase in iron deficiency anemia?
Because there is less heme (due to lack of Fe), the protoporphyrin has nothing to bind to form hemoglobin. As a result, it floats freely in the blood.
192
What is Plummer Vinson Syndrome?
* Iron deficiency anemia with esophageal web and atrophic glossitis
* Classic Triad: anemia, esophageal web (beefy tongue), dysphagia
193
What is the difference between Hemoglobin Barts (HbB) and Hemoglobin H (HbH)?
* **HbB**- excess gamma-chains form tetramers, present in hydrops fetalis (death) and alpha-thalassemia trait (early life)
* **HbH**- excess beta-chains form tetramers, present in 3 deletion alpha-thalassemia
194
In which type of anemia can hypersegmented PMNs occur?
Only in megaloblastic anemias (still rare)
195
What can cause a low reticulocyte count (hypoproliferative anemia)?
* Acute blood loss or destruction
* Nutritional anemias
* Bone marrow depression/failure (aplastic anemia)
* Defective RBC production (myelodysplasia)
* Destruction of RBC precursors (parvovirus)
* Replacement of BM with something else
196
What is unique about B12 deficiencies?
Present rare neuro/psychiatric features that are reversible
197
What is a megaloblastic anemia?
* Defect in DNA synthesis within the bone marrow cells
* Nucleus usually appears immature (present and big)
198
What do you measure to check for folate or B12 deficiency?
* Folate- High homocysteine
* B12- High homocystein and methylmalonic acid
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What is the role of the following in B12 absorption:
* Animal products
* R protein
* Intrinsic Factor
* Distal ileum
* Animal products- only source of B12
* R protein- salivary protein that binds B12 for pancreatic enzymes
* Intrinsic Factor- secreted by parietal cells to bind B12
* Distal ileum- main place of absorption (B12-IF complex)
200
What is pernicious anemia?
A form of B12 anemia in which parietal cells (which secrete IF) have been picked off by antibodies.
201
Why is folate an important supplement during pregnancy?
Essential for closing the neural tube and preventing birth defects.
202
What is pancytopenia?
A decrease in all of the 3 parts of blood (RBC, WBC, platelets)
203
What is the genetic significance of Franconi's anemia?
* 1:300 gene frequency
* 1:100 in Ashkenazi Jews
* Autosomal recessive or X-linked
* A form of aplastic anemia
204
What are some key clinical features of Franconi's anemia?
* Short stature
* Abnormalities of the thumb
* Lymphocytes cultured with DEB show chromsomal breakage
* Need to reduce intensity pre-transplant (allogeneic)
205
What are some characteristics of Dyskeratosis congenita?
* Inherited form of aplastic anemia
* Telomere shortening
* BM failure, predisposed to acute leukemia or other solid tumors
* Triad: hyperpigmentation, abnormal nails, mucosal leukoplakia
* Pulmonary fibrosis, premature gray hair, cirrhosis
* Allogeneic transplant (reduced intensity)
206
What are the criteria for required screen tests?
* Disease has substantial burdern of suffering, is common, and has a pre-symptomatic phase
* Treatment is available and works better in presymptomatic phase
* Accurate test
* Does not cause more harm than benefit
207
How long after birth should you wait for new born screening?
24 hours (to avoid false positives)
208
What are some disorders commonly detected by Tandem Mass Spectroscopy?
* Aminoacidopathies
* Organic acidemias
* Fatty acid oxidation disorders
209
What are some rules for carrier screening?
* High frequency of carriers
* High sensitivity and specificity of test
* Cost-effective
* Access to genetic counseling
* Prenatal diagnosis availability
* Acceptance and voluntary participation
210
What are the 5 major causes of malaria?
* *Plasmodium falciparum* (most common & severe)
* *Plasmodium vivax* (South America, Asia)
* *Plasmodium ovale* (relapse)
* *Plasmodium malariae* (relapse)
* *Plasmodium knowlesi* (low diagnosis)
211
Why is *falciparum* the most severe form of malaria?
* Ability to infect nearly every organ (ICAM)
* Ability to stick to placentas (CSA)
* Ability to sequester within vasculature
212
What are the 3 ways malaria kills children?
* Low birthweight (infection during pregnancy)
* Cerebral Malaria (acute febrial illness)
* Severe anemia (chronic infections)
213
What is the difference between prepatent period and paroxysm?
* **Prepatent**- patient is asymptomatic while parasite multiples in the liver (7-14 days)
* **Paroxysm**- chills, fever; as infected RBC burst (release new merozoites)
214
Why does chronic malaria infection have periodic symptoms?
Because when the RBC rupture you have symptoms, but then there is a wait period (48-72 hours)
\*This does not occur acutely\*
215
What is different about areas of low immunity vs. high immunity?
* **Low**- bites are rare, adults are not immune, causes significant disease (Latin America, Asia, urban Africa)
* **High**- bites are common, adults semi-immune w/ continous exposure, children seriously ill (Sub-sahara Africa, Papua New Guinea)
216
What are the forms of genetic resistance to malaria?
* **Inhospitable erythrocyte**- sickle cell trait, thalassemia, G6PDH deficiency
* **Inhibition of invasion**- ovalocytosis (rigid membrane), duffy antigen receptor absence (African populations, vivax malaria)
217
What are zoonoses?
Human diseases with an animal reservoir
218
Whaat is the cycle of vector borne transmission?
219
What are the similarties and differences between Ehrlichia and Analplasma?
* Same- obligate intracellular gram-negative bacteria, rickettsiae family, tick-borne, produce morulae, treat with tetracyclines
* Ehrlichia- infects monocyte, GI symptoms, more severe
* Anaplasmosis- infects granulocytes
220
Why do people often not notice they were bit by a tick with babesiosis?
Because it is a tick in the nymphal stage (too small)
221
Which infection has similar blood smear characteristics to plasmodium (malaria)?
Babesia
222
What increases risk for parvovirus?
When the body is not able to make up for the destruction of RBC by parvovirus:
* Already destroying RBC (hemolysis)
* Underproduction of RBC (hypoproliferative)
223
What do crackles in the base of the lungs indicate?
Heart failure (lungs fill with fluid due to not being pumped properly)
224
What should you do when a paitent has neutropenia and is febrile (neutropenic fever)?
* Give them antibiotics very quickly! (cover pseudomonas)
* They can die quickly from gram negative bacterial infections due to lack of neutrophils that fight infection
225
What is hyperviscosity syndrome?
* Occurs when the blood is too thick (erythrocytosis)
* Headaches
* Visual Changes
* Tinnitus
* Dizziness
* Paresthesias (pins)
* Decreased mental acuity
\*remove blood and replace w/ saline\*
226
What are causes of secondary eythrocytosis?
In general, cause tissue hypoxia and start renal epo production (no risk of blood clots)
* High altitude
* High affinity Hgb
* Cardiopulmonary disease leading to hypoxia
* Obesity-hypoventilation syndrome
* Obstructive sleep apnea
* High carboxyhemoglobin levels
* Tumors secreting epo
* Epo treatments (testosterone)
227
What are the 4 main myeloproliferative disorders?
* Polycythemia vera
* Essential thrombocythemia
* Myelofibrosis
* Chronic Myelogenous Leukemia
228
What is the difference between P. vera and essential thrombocytosis?
* P. vera- all blood cells are elevated
* E.T.- only platelets are elevated
229
What are secondary causes of thrombocytosis?
* Cancer
* Infection
* Inflammation
* Bleeding
* Iron deficiency
230
What is the difference between early and late myelofibrosis?
* Early- high platelets and normal Hgb/WBC
* Late- low platelets and WBC, anemia
231
Which disease has cytopenia and monocytes
Myelodysplastic syndromes
232
What is responsible for the clinical manifestations of porphyria?
Accumulation of toxic porphyrins (deficient enzymes) leads to highly reactive oxydants that damage tissues
233
How can you induce ALAS1?
* Depletion of heme
* Drugs, hormones that induce CYPs
* Caloric and carb restriction
* Metabolic stress
234
What is the classic picture of acute intermittent porphyria?
* Young girl
* Belly pain
* Normal abdominal exam
* Tachycardia
* Hyponatremia
* WBC is fine
235
Why don't we measure porphyrins for acute intermittent porphyria?
Because they are relatively non-specific
236
What is hematin?
* Reduces production of ALA/porphyrins by negative feedback on ALAS
* Used to treat acute intermitten porphyria
237
What is the difference between acute and chronic testing for lead poison?
* Acute- test for physical blood lead levels
* Chronic- Check for elevated FEP and ZPP
