Test 1 Flashcards
1
Q
Where is red marrow in adults? in kids?
A
Adult red marrow only in epiphysis and metaphysis of trabeculae’s osteons
Kids: everywhere in bones, all of their marrow
2
Q
Where is hemoatopoetic activity in first month of fetal life?
months 2-6?months 8-9?
Which month does hematopoeisis start in the marrow?
A
First month of fetal life hematopoeisis: yolk sac
Months 2-6: liver and spleen
months 8-9: marrow… starts month 4
3
Q
Where is yellow marrow in adults? in kids?
A
Yellow marrow in adults: diaphysis’s medullary cavity, middle of long bones
Kids: nowhere
4
Q
Differentiate totipotent, pluripotent, multipotent, and unipotent stem cells
A
- Totipotent –differentiate into all tissues of embryo plus extra-embryonic tissue, Present very early in fertilized egg
- Pluripotent – differentiate into all tissues of embryo
- Multipotent – differentiate into cells of a given germ layer, Most “adult” stem cells, Like Hematopoietic stem cells
- Unipotent – differentiate into a single cell type, Like lymphoid progenerators that can generate into B/T/K lymphocytes
5
Q
what are the 3 factors involved in maintaining hematopoietic stem cell pool?
A
3 factors needed to maintain Hematopoietic Stem Cells:
SCF
IL-3
BM stroma (Bone marrow stroma)
6
Q
What causes differentiation of Hematopoietic stem cells to myeloid vs lymphoid precursor cells?
A
Hematopoitetic stem cell differentiation into Myeloid progenitor: SCF, IL3, GM-CSF
Hematopoitetic stem cell differentiation into Lymphoid progenitor: SCF, IL3, IL-7
7
Q
What are the defects that can occur in hematopoiesis?
A
Hematopoietic stem cells are killed, replaced, or become malignant
8
Q
What are the 3 types of Colony Stimulating Factors involved w/Hematopoietic Stem Cell differentiation? What do they bind to?
A
○ GM CSF = granulocyte macrophage colony stimulating factor
○ G CSF = granulocyte colony stimulating factor
○ M CSF = monocyte colony stimulating factor
They all bind to Kit receptor on the HSCs
9
Q
What is Kit receptor? and what type of receptor is it? what does it do?
A
CD 117 = Kit receptor
Tyrosine kinase Type III receptor, sends signal to nucleus to activate HSC to survive, proliferate, and differentiate
receptor for stem cell growth factors (SCF) and colony stimulating factors (CSF)
10
Q
What causes differentiation of Hematopoietic stem cells to erythrocytes vs megakaryocytes?
A
HSC to erythrocytes: EPO (erythropoietin)
HSC to megakaryocytes: TPO (thrombopoietin)
11
Q
What are the 3 types of transient (acquired) defects in hematopoiesis?
A
Transient (acquired) hematopoietic defects
1) infection
2) maternal isoimmunization
3) premature birth, low # of RBCs
12
Q
What is Fanconi anemia? inheritance? how does it present?
A
Fanconi anemia = aplastic anemia, affects all cell lines
Autosomal recessive
Chromosmal repair and stability proteins mutated
Presentation: short, strabismus, low set ears w/frequent infections +/- deafness, abnormal/absent thumbs
13
Q
What is Diamond-Blackfan anemia? inheritance? how does it present?
A
Diamond Blackfan anemia = Erythrocyte mutation
Autosomal Dominant, and sporadic pedigrees
Defect in ribosome fx
Presentation: 50% have skeletal abnormalities, RBC aplasia, macrocytic anemia w/reticulocytopenia, snub nose
14
Q
What is Kostmann syndrome? inheritance? how does it present?
A
Kostmann syndrome = neutrophil mutations
Autosomal Recessive
Mutation in G_CSF receptor
Presentation: predisposition to luekemia development and recurrent infections
15
Q
What is Amegakaryocytic thrombocytopenia? inheritance?
A
Amegakaryocytic thrombocytopenia = megakarycyte mutation
Autosomal recessive and x-linked
16
Q
What is Thrombocytopenia-absent radius (TAR) syndrome? how does it present?
A
Thrombocytopenia-absent radius (TAR) syndrome
presentation: Thrombocytopenia at birth, skeletal anomalies
17
Q
What is the congenital hematopoietic defect that affects Erythrocyte development?
A
Diamond-Blackfan anemia
18
Q
What is the congenital hematopoietic defect that affects Megakaryocyte development?
A
Amegakarocytic thrombocytopenia and Thrombocytopenia-absent Radius (TAR) syndrome
19
Q
Order the WBCs from most numerous to least numerous
A
Never Let Monkeys Eat Bananas
Neutrophils > Lymphocytes»_space; Monocytes > Eosinophils > Basophils
20
Q
Describe the order of development from hematopoeitc stem cell to erythrocyte
Which stage kicks out the mitochondria? the nucleus?
Which stage starts chromatin clumping?
A
HSC > myeloid precursor cell > Hemocytoblast > Proerythroblast > basophilic Erythroblast > Polychromatic erythroblast > Orthochromic erythroblast/Normoblast > Reticulocyte > Erythrocyte
Polychromatophilic erythroblast kicks out mitochondria
Orthochromic erythroblast/Normoblast kicks out nucleus to turn into Reticulocyte
Basophilic Erythroblasts start chromatin clumping
21
Q
What is clinically significant about Basophilic Stippling of Erythrocytes?
What if there’s Howell-Jolly bodies?
A
Basophilic Stippling = toxic bone marrow injury IE megaloblastic anemia or lead poisoning (leads to lots of dots=condensed ribosomes/RNA)
Howell Jolly bodies = 1 or 2 dots, significant of spleen dysfunction or absence
22
Q
What are Neutrophils significant for? why? (what do they do?) What interleukins are required for their differentiation?
What is a Left Shift in Neutrophils significant for? (what do they do?)
Where are most Neutrophils?
A
Neutrophils = acute bacterial infection, bc they phagocytize bacteria, debris, and dead tissue (collects and dies as pus) and degranulate
Need *IL6, GM-CSF, and *G-CSF to differentiate
Left shift = very sick person, marrow’s releasing immature neutrophils
Most neutrophils are in tissue
23
Q
What are Eosinophils significant for? What do they do?What interleukins are required for their differentiation?
A
Eosinophils = allergies, parasite, cancer, bc they’re phagocytic for Ag-Ab complexes and neutrophils, attracted to inflammation sites by basophil/mast cell cytokines
Need *IL5, GM-CSF
Make inflammatory cytokines and granules, some break down our own tissue
24
Q
What are basophils significant for? What do they do? What interleukins are required for their differentiation?
A
Basophils = maybe myeloproliferative disorders, inflammation, parasites, allergies… least common leukocyte
Need IL3, *IL4, GM-CSF to differentiate
Basophils enhance inflammation by arachidonic acid metabolite release, and release granules
25
What are mast cells significant for? What interleukin does it require for differentiation and growth? What is it blocked by?
What do receptor do they have and what do they bind?
Mast cells = allergies and Type I Hypersensitivity, requires SCF and *IL-4 to mature and grow
Mast cells blocked by anti-H1 (Diphenhydramine) or H2 (Cimetidine or Ranitidine)
Possess Fcε receptor, and bind IgE w/it
26
Differentiate mast cells vs basophils
Mast cells mature in the tissue site, as fixed in tissues, bigger than basophils, have 1000 granules/cell, granules 6x smaller than basophil's, round nucleus
Basophils mature in bone marrow, aren't fixed in tissues, smaller than mast cells, have only 80granules/cell, granules 6xbigger than mast cell's, and bilobar nucleus
27
What are lymphocytes significant for?
Lympocytes = viral infection or lymph system disease
28
What are Monocytes significant for? Where do they differentiate, and what do they differentiate into? What do they do?
Monocytes = end of acute infection, some chronic infections (TB, endocarditis), Cronh's and ulcerative Colitis, and Hodgkin's
Circulating phagocytes then
They differentiate into macrophages in tissue
29
What do plasma cells do? What's it significant for?
```
Mature lymphocytes (develop from Bcells), make and secrete Abs
Significant for Multiple Myeloma
```
30
Describe what Fixation, Heat, and Storage artifacts look like of peripheral blood smears
Fixation: water contamination in methanol fixation -> refractile rings in erythrocytes
Heat: erythrocytes bud off and microspherocytes appear, get counted as platelets, can occur in burn victims
Storage: WBCs are fragile, forming smear cells (mushed), Neutrophil nuclei 'round up' and form homogenous round mass, RBCs undergo echnicytic change, making Burr cell
31
What is Hemotocrit? Why does it fall during pregnancy?
Hct = (RBC volume) / (plasma volume)
| Pregnancy causes RBC mass to increase, but plasma volume increases more
32
Walk through Iron absorption steps from good ingestion to getting into an macrophage
1) Iron gets reduced by a reductase on the brush-border membrane of enterocytes to Fe2+
2) Iron enters enterocyte via DMT1 (aka DCT1)
3) In enterocyte, Fe2+ can get oxidized to Fe3+ by ferroxidase and stored on Ferritin OR can get out through Ferroportin, helped by Hephaestin that oxides it
4) in blood, Fe3+ travels around on Transferrin
5) Transferrin can dock on TransferrinReceptor1 on RBC and endocytosed, getting out via DMT1
6) RBCs can get ingested by macrophage
Fe2+ gets out via DMT1, and either stays in macrophage on Ferritin, OR gets out via Ferroportin, helped by Ceruloplasmin that oxidizes it
33
Walk through VitB12 absorption steps from ingestion to liver
1) B12 freed from food proteins by low pH (needs low pH)
2) B12 binds to R-factor, that's in saliva
some B12 binds to IF that's in gastric juices but bond isn't as strong as w/R-factor
3) B12-Rfactor moved into small intestin
4) Pancreatic enzymes release B12 from Rfactor
5) B12 binds to IF
6) B12-IF gets absorbed into enterocyte brush border
7) Inside, B12 is freed and binds to Transcobalamin II
8) B12-transcobalamin II moves into blood
9) B12 stored in liver, released as needed by bone marrow
34
Walk through folic acid absorption, from ingestion to enterocyte
1) Folic acid in leafy greens, liver, some fruits (easily destroyed in cooking)
2) Folic acid broken down from pteromonoglutamic acid to pteromonoglutamate by brush border enzyme
3) Folic acid absorbed through carrier protein
4) Folic acid converted to THF (tetrahydrofolate), needed for purine and thymidine synthesis
35
VitB12 deficiency and Folic acid deficiency both show a build up in what?
What builds up only in VitB12 deficiency?
Lack of B12 and Folic Acid both lead to Homocysteine buildup
B12 deficiency also leads to MMA (methylmalmonic acid) buildup
no folic acid -> lots of homocysteine, no methionine
no B12 -> lots of homocysteine and MMA, no methionin or Succinyl CoA
36
What are the 2 Integral proteins in the erythrocyte membrane, and what do they do?
RBC Integral membrane proteins
1) Band 3: major integral protein, anion (Cl-) transport, links lipid bilayer to Ankyrin and protein 4.2 making vertical interactions
2) Glyphorin: provides (-) charge to cell surface
37
What are the 3 peripheral proteins of erythrocyte membrane?
RBC Peripheral Proteins
1) Spectrin: makes repeating 6unit lattice just below lipid bilayer surface, foundation of membrane skeleton making horizontal interactions
2) Ankyrin: couples spectrin lattice to Band 3 proteins making vertical interactions
3) Actin/Protein 4.1/Spectrin complex: more binding proteins
38
where in the erythrocyte lipid bilayer are the charged vs uncharged phospholipids more concentrated?
RBC lipid bilayer
more charged phospholipids in inner monolayer vs
more uncharged phospholipids outer monolayer
39
What stimulates kidneys to produce EPO?
Hypoxia stimulates kidneys to produce EPO
40
which haemopoetic cell lacks CD markers? why?
Lymphoid progenitor cells lack CD markers bc pre-Tcells migrate to thymus to mature, and pre-Bcells migrate to bone marrow to mature
41
Walk through lymphocyte proliferation from lymphoid progenitor cell to mature B/T cells
1) lymphoid progenitor cells divide into pre B/T cells after interacting w/ IL3+IL7/IL7
2) pre B/T cells must express heavy/beta chains, otherwise they're destroyed
3) Pre B/T cells must complete their antigen receptor by expression the Light/Alpha chains
4) If their complete antigen receptor binds self too strong, destroyed through negative selection
If no self antigen recognized destroyed by failure of positive selection
If there's weak self antigen recognition, B/T cell matures through positive selection!
42
T/F? B and T cells develop their antigen specificity in the absence of antigen
True! B and T cells develop their antigen specificity in the absence of antigen bc their -/+ selection is against self antigen
43
What are the gene coding regions on Bcell heavy (H) and light (kappa/lambda) chains?
After activation, Bcells only express what Ig on its surface?
Heavy: V, D, J
Light: V, J
Activated Bcells express only IgM as membrane molecule
44
What are the gene coding regions on Tcell beta and alpha chains?
Beta: V, D, J
Alpha: V, J
45
From what do NK lymphocytes differentiate from? What do NK lymphocyte recognize, and what do they do to the invaders?
NK lymphocytes differentiate from T lymphocyte precursors, but don't require thymus for maturation
NK recognize the absence of HLA molecules like tumor cells or cells infected by viruses
NK lymphocytes have lysing granules or Fc receptors that help them participate in Ab dependent cell mediated cytotoxicity
46
What do the 5 types of CD4+ lymphocytes do?
Th1: helps CD8+
Th2: helps Bcells switch from IgM to IgE
Thf: helps Bcells switch from IgM > IgG + IgA
Th17: activates inflammation via cytokine secretion
Treg: down regulates other lymphocytes via IL10 and TGFbeta
47
What do Monocytes divide into?
Monocytes divide into Macrophages and Dendritic cells
48
What types of anemias cause an RDW increase?
```
nutritional deficiencies (b12, folate) cause elevated RDW
Thalassemias cause elevated RDWs, but not as much
```
49
what's the preferred site of bone marrow aspiration biopsy? additional options for adults or kids?
Preferred site = posterior iliac crest
Adults: sternum, or anterior iliac crest
infants: tibia
50
What's the normal Erythroid:Granulocyte precursor ratio in bone marrow?
normal Erythroid:granulocyte 1:3
51
What are the key, regulatory enzymes for the pentose phosphate pathway, glycogen synthesis, and glycolysis?
Pentose phosphate pathway: G6PD
Glycogen synthesis: Glycogen synthase
Glycolysis: Phosphofructokinase
52
What moves glucose into erythrocytes? is it regulated by insulin?
GLUT1 moves glucose into erythrocytes... not regulated by insulin
53
What are the 4 essential products from glucose metabolism in erythrocytes, and what do they do?
4 essential products from glucose metabolism
1) NADPH: decreases ROS, from pentose phosphate pathway by reducing glutathione to recycle it
2) NADH: reduces methemoglobin's Fe3+ to Fe2+, from glycolysis pathway
3) NAD+: needed to glycolysis cycle going, made by converting pyruvate + NADH → lactate + NAD(+)
4) 2,3-bisphosphoglycerate (2,3-BPG): allosterically regulates O2 binding to Hg from glycolysis offshoot pathway
54
```
What are the consequences of having a
Pyruvate kinase deficiency
G6PD deficiency*
for erythrocytes?
*most prevalent human genetic enzyme deficiency in world, confers malaria resistance
```
Pyruvate kinase deficiency means erythrocytes can't make pyruvate, losing 50% of its ATP making ability (plus can't convert pyruvate to lactate, so can't make NAD+ and glycolysis grinds to halt)
G6PD deficiency means pentose phosphate pathway can't occur, so buildup of ROS bc lack of glutathione destroys erythrocytes
55
What can tip people off to their G6PD deficiency?
```
G6PD can be brought to surface when:
taking oxidant drugs
infection (malaria)
fava bean consumption
at birth, jaundiced, can lead to kernicterus = bilirubin accumulation in brain
```
56
How does Hepcidin gene translation get upregulated?
Hepcidin upregulation pathway:
1) When there's lots of iron, there's lots of holotransferrin that competes with HFE's bond w/Transferrin receptor 1
2) HFE will go bind w/Transferrin receptor 2 when Holotransferring bumps it off
3) Transferrin receptor 2 will signal hepcidin upregulation when HFE binds and activates it
57
```
Where do the following proteins have their Iron Regulating Proteins (IREs)? at the 5' or 3' end or mRNA?
Transferrin
Ferroportin
DMT1
Ferritin
ALAS (aminolaevulinic acid synthase)
```
5' IREs:
Ferritin
Ferroportin
ALAS1
3' IREs:
Transferrin
DMT1
58
Differentiate hereditary spherocytosis vs elliptocytosis
| what type of linking is disrupted? what's mutated?
Spherocytosis: most prevalent RBC membrane mutations, disrupted VERTICAL linking of proteins, mostly ankyrin, protein 4.2 and band 3 affected
Elliptocytosis: disrupted HORIZONTAL linking of proteins, mostly protein 4.1 and spectrin affected
59
```
Differentiate these top 5 Hemoglobinopathies:
alpha thalassemia
beta thalassemia
Sickle cell
HbC disease
HbE disease
```
Alpha thalassemia: decreased synthesis alpha globin, accumulates beta globin
Beta thalassemia: decreased synthesis beta globin, accumulates alpha globins
Sickle cell: mutated globins, HbSS aggregates under hypoxic states and sickles the cell, v bad
HbC: crystalized HbCC aggregates under high oxygen states, where homozygote has mild microcytic anemia and maybe splenomegaly but the HbSC is bad
HbE: beta globin decreased, HbSE is bad
60
What's the genetic etiology and pathophysiology of sickle cell anemia?
PBS?
Genetics:HbAS = sickle trait, HbSS = sickle cell anemia
HbS (Glu to Val) contort in LOW oxygen state d/t decreased solubility
Sickled cells
61
What's the genetic etiology and pathophysiology of HbC disease?
PBS?
Genetics: HbAC = trait, HbCC = disease
HbC (Glu to Lys) crystalizes in LOW oxygen state d/t decreased solubility
PBS: target cells
62
What's the genetic etiology and pathophysiology of spherocytosis? Describe the 4 forms
PBS?
Genetics: AD, common in northern Europeans
Ankyrin mutation creates an abnormally stiff membrane and interrupts vertical bonds, commonly ruptures
1 mild
2 moderate: anemia, jaundice, splenomegaly, gall stones
3 moderate/severe
4 severe needs frequent transfusions, short, delayed sex develop, skeletal problems
Spherocytes
63
What's the genetic etiology and pathophysiology of elliptocytosis?
Genetics: AD, alpha/beta spectrin mutations interrupts horizontal bonds, creating elongated ellipisoid cells, but mostly asymptomatic/mild hemolytic anemia
64
What's the genetic etiology and pathophysiology of G6PD deficiency? When do sxs appear?
PBS?
Genetics: X-linked recessive, accumulation of disulfide bridges leads to rigid RBC and increased membrane
Sxs appear after infection, exposure to oxidative drugs, or ingestion of fava beans
PBS: Heinz bodies, Degmacytes aka bite cells, blister cells, and spherocytes
65
What's the genetic etiology and pathophysiology of pyruvate kinase deficiency? Sxs?
Genetics: autosomal recessive, mutations in Pyruvate kinase in RBCs (liver is fine)
Sxs: aysmptomatic to fetal anemia
66
```
What are the PBS of
sickle cell
HbC
spherocytosis
elliptocytosis
G6PD deficiency?
```
sickle cell = sickles
HbC = target cells
spherocytosis = spherocytes, round and dark
elliptocytosis = elliptocytes
G6PD deficiency = Heinz bodies and Dacrocytes aka bite cells
67
What parts of the RBC membrane-cytoskeletan contribute to spherocytosis and elliptocytosis?
```
Spherocytosis = ankyrin, vertical bonds
Elliptocytosis = alpha/beta spectrin, horizontal bonds
```
68
What is a compound heterozygosity of HbSC lead to?
HbSC = less severe form of sickle cell, leads to
Vascular retinopathy
AVN of fem head
69
What type of hypersensitivity is immune mediated anemia?
Immune mediated anemia = Type 2 hypersensitivity, cytotoxic, complement activated, IgM and IgG response to Ags on RBCs, NK cells
70
Differentiate warm and cold Abs responses
type of antigen on RBC
which Ig induced?
what's the immune response?
Warm: Rh antigen, IgG, hemolysis d/t opsonization and ADCC
Cold: A/B/O antigen, IgM, hemolysis d/t complement activation
71
Why do glycoproteins induce IgG response and carbs induce IgM?
Glycoproteins processed by APCs and presented to CD4+ Tcells that mature into Tfh cells that activate Bcells to facilitate IgM switch to IgG
Carbs are recognized by Bells as T-independent antigens and produce an IgM response to them
72
What are the 2 types of warm and cold immune mediated hemolysis? What are the assoc disease populations?
Warm:
Autoimmune hemolysis: infections, SLE, CLL
Drug induced: methyldopa, penicillin
Cold:
Cold agglutinin disease: anti-l or anti-i after EBV, mycoplasma, CMV
Paroxysmal cold hemoglobinuria: IgG anti-P after MeaslesMumps, syphilis
73
```
Define MAHA (microangiopathic hemolytic anemia)
what do you see in labs
PBS?
```
```
MAHA = non-immune hemolytic anemia from intravascular RBC fragmentation that makes schistocytes
Labs:
normocytic
low RBCs
high reticulocyte
high bilirubin
high LDH
low haptoglobin
increased RDW
PBS: schistocytes
```
74
Differentiate Thrombotic thrombocytopenic purpura (TTP) with Shiga Toxin mediated Hemolytic Uremic Syndrome (ST-HUS), and with HELLP
clinical
pathophys
definitive tx?
TTP:
sxs: purpura, CNS organ involvement, NO renal failure
Loss of degrading enzyme of vWF, leads to platelet thrombosis and shears RBCs, creates petechiae and ecchymoses
Tx: Plasmapheresis w/plasma replacement
ST-HUS: Kids <5yo
Bloody diarrhea, CNS alterations, black urin to oliguria to anuria to renal failure
Shiga toxin binds to platelets, glomerular capillary, endothelial cells
Tx: supportive, may need dialysis and electrolyte correction
HELLP:
Hemolysis, elevated liver fx tests, low platelets
Sxs: RUQ pain, proteinuria
Tx: delivery
75
Artemisinin Combo drugs
*MOA
ADEs
(artesunate/artemether amodiauine/lumefantrine/mefloquine)
MOA: makes free radicals by combining w/iron
*used in combination bc short 1/2 life, standard tx in areas of endemic Falciparum
ADEs: N/V diarrhea, dizziness
76
```
Chloroquine
MOA
*TI
*ADEs
CI
```
Chloroquine
MOA: prevents heme detox, building up toxic heme to kill plasmodium
TI: *drug of choice tx and prophylaxis for blood schizonts
ADEs: *high fever
CI: psoriasis, porphyria
77
```
Quinine and Quinidine
MOA
TI
PK
*ADEs
```
```
Quinidine/Quinine
MOA UNK
TI plasmodium Falciparum, Babesiosis
PK IV is cardiotoxic, oral
ADEs: *tinnitus, HA, nausea, dizziness, *flushing, *visual disturbances
```
78
```
Primaquine
MOA
*TI
PK
*ADEs
*CI
```
Primaquine
MOA: UNK
*drug of choice for liver dormant forms of malaria
TI: radical cure of acute plasmodium Vivax and Ovale (+Chloroquine), terminal prophylaxis of Vivax and Ovale
ADEs: GI, *Hemolysis if G6PD deficiency
CI: G6PD deficiency and pregnancy
79
```
Atovaquone/Progaunil (Malarone)
MOA
TI
PK
ADEs
```
Malarone (Atovaquone-Proguanil)
Atovaquone MOA: blocks DHOD in electron transport chain
Proguanil MOA: blocks dihydroflate reductase in electron transport chain
TI plasmodium Falciparum
ADEs N/V, diarrhea, HA, *insomnia
CI : pregnancy
80
Doxycycline
MOA
What do you combine it w/for malaria tx?
Doxycycline
MOA: blocks 30S ribosome
+Atovauone, Quinine, or artesunate
81
Which malaria drugs are seeing drug resistance?
Malaria's developed Chloroquine resistance
82
What's the drug of choice for
Blood schizonts?
liver dormant forms of malaria?
What's the standard Falciparum therapy in endemic areas?
What can't you give to G6PD deficiency pts for malaria?
preggos?
Drug of choice for blood schizonts: Chloroquine
Liver dormant tx: Primaquine
Standard Falciparum tx: Artemisinin + ___
G6PD deficiency avoids Primaquine (and others?)
Preggos avoid Primaquine and Malarone
83
What is a ringed sideroblast? Why does it form?
Ringed sideroblasts are erythroblasts w/1+ mitochondria filled w/so much iron-ferritin that it shows up on stain.
Defective heme synthesis causes iron build up
84
What are the 2 types of ALAS that causes sideroblastic anemia, where are the gene and protein mutations, and what are these ALAS regulated by?
1) ALAS1, housekeeping (hALAS) in all cells, mutation in Chromosome 3, regulated by product inhibition = heme
2) ALAS2, erythroid (eALAS) cells, mutation in X-chromosome, regulated by iron availability
85
What's a way to treat sideroblastic anemia?
Sideroblastic Anemia Tx:
| Vit B6 = pyridoxine, gets converted to Pyridoxine5-phosphate (PLP) that forces more binding w/ALAS via chaperonins
86
what are the 4 ways to acquire sideroblastic anemia?
1) alcohol (adults)
2) lead (kids)
3) Isoniazid
4) chloramphenicol
87
Genetics, pathophys, clinical, PBS for 2 types of beta-thalassemias?
Beta-thal-minor: 50% reduction in beta globin synthesis w/very little alpha chain accumulation, mostly asymptomatic
Beta-thal-major: no beta globin copies, accumulates alpha chains, creates inclusion bodies creates ROS destroys RBC membrane, immature erythroblasts destroyed, mature erythrocytes lysed
Sxs: HSM, jaundice, gallstones, heart failure, FTT, extramedullary hematopoiesis
PBS: microcytic, hypochromic RBCs, target cells, poikilocytes, anisocytosis, Schitzocyte (dumpling)
88
Genetics, pathophys, and clinical for 4 types of alpha-thalassemias
* α+-thalassemia trait: 1 α-globin gone , silent
* α°-thalassemia trait: 2 α-globins gone , Typical, usually referred to as the "typical trait"
* Hb H disease: 3 α-globins gone, accumulates gamma chains as fetus and beta chains after birth, but beta chains precipitate slowly
* Hydrops fetalis with Hb Bart: 4 α-globins gone, gamma tetramer accumulations incompatible w/life extremely high O2 affinity lead sto severe hypoxia, edema, and CHF
89
What's the Hg make up of HbH and HbBarts
HbH: some Hb beta tetramer precipitates, but mostly normal HbA
HbBarts: gamma tetramer accumulations
90
Why don't sxs of beta-thalassemia major appear until 6mo?
| What's the leading cause of death, and how do we extend life?
beta-thal-major appears when beta-globin takes over for fetal gamma globin
Leading cause of death: secondary hemochromatosis d/t transfusions, death by 30yo from cirrhosis and cardiomyopathy
Can use iron chelating agents to extend life
91
What's the most common deletion pattern of alpha-globin genes b/w African vs Asian populations?
Africa: trans
Asian: cis
92
ESAs Epoetin alfa, Darbepoetin alfa
TI
*PK
*ADEs
ESA (EPO Stimulating Agents) Epoetin/Darbepoetin alfa
TI: secondary anemia CKD, prevent transfusions, cancer pts myelosuppressive therapy, HIV pts
PK: Darbepoetin's half-life >> epoetin's half life
ADEs: HTN, **thrombotic complications like stroke and MI, cancer progression/recurrence
93
Ferrous Sulfate/Iron Dextran
* PK
* ADEs
* CI
Ferrous Sulfate/Iron Dextran
PK *Iron dextran can be given parenterally, ferrous drugs given IV only
ADEs *fatal child poisoning, *hypersensitivity by anaphylaxis, black stool, GI problems
CI: *hypersensitivity, extensive chronic anemia, unable to tolerate/absorb oral iron
94
Deferoxamine
TI
ADEs
Deferoxamine
TI iron toxicity, potent iron-chelating drug
ADEs: N/V, orange/red urine
95
What are the PKs differences of Vit B12 and Vit B9?
Vit B12 can give parenteraly, Folic acid you must give orally
96
How can you partially correct a B12 deficiency w/folic acid?
1-cobalamin (B12) deficiency, can't convert Methyltetrahydrofolate into tetrahydrofolate
2-means you can't convert dUMP to dTMP, means you can't synthesize DNA
3-Can add Folic Acid to be converted to Diydrofolate, to be converted to tetrahydrofolate
*still won't be able to convert MMA to succinyl CoA
97
Extramedullary hematopoesis
what causes it?
where?
Extramedullary hematopoeisis
caused by crowding out like myelofibrosis
move to liver and spleen
98
aplastic anemia's BM and PBS findings?
BM only has fat cells and fibroblasts
| PBS has pancytopenia
99
Anemia of Chronic Disease
PBS:
labs:
Mostly normocytic, hypochromic
increased iron in BM bc macrophages have iron buildup
serum labs:
low iron, low TIBC, low transferrin
100
Hemolytic anemia 3 major features
| differentiate intravascular and extravascular
Hemolytic anemia's 3 major features:
1 premature RBC destruction
2 accumulation of Hg catabolism
3 increased erythropoiesis in bone marrow
Intravascular has hemoglobinuria, hemosiderinuria
Extravascular has splenomegaly
both: increased EPO. decreased haptoglobin, extramedullary hematopoesis, increased reticulocytes, jaundice, billirubin and gallstones
101
alpha-thalassemia's globin chains and clinical presentation:
HbH
Barts
Barts = 4 gamma globin chains that combine, only in kids
HbH = 4 beta globin chains
clinical: HbH looks like beta-thalasemia intermediate,
hydrops is fetal fatal
102
beta-thalassemia
pathophys:
clinical:
Can't make normal HbA bc there aren't beta chains
ineffective erythropoesis
increased hemolysis
splenomegaly
crew cut xrays
systemic iron overload bc body's trying to compensate = secondary hemochromatosis from excess hemosiderin
extramedullary hematopoesis
103
iron deficiency anemia labs
| PBS
```
Labs: low Hg
low serum Fe
low transferrin saturation
increased TIBC
PBS: microcytic, hypochromic anemia (know picture)
```
104
iron deficiency anemia in adult men or post-menopausal women, what do you look for??
GI bleed and carcinoma!
105
alcohol induced anemia
PBS?
liver fx test yes or no?
PBS:macrocytc anemia, w/leukopenia and thrombocytopenia
| can't use liver fx tests as indication of alcoholism
106
hereditary spherocytosis
pathophys?
clinical?
what are the 2 types of crisis that can happen?
```
ankyrin deficiency, creates round dark cells
clinical
reticulocytosis
splenomegaly
jaundice
hemolytic anemia
*can have aplastic crisis (can occur in other anemias too), esp after parvovirus, where bone marrow isn't making anything!
*can also have hemolytic crisis
```
107
```
sickle cell disease
clinical?
what's common clinical in kids?
dx test?
lab results?
```
clinical: increased infection susceptibility, initial splenomegaly then autoinfarction, Salmonella-osteomyelitis (although most common cause still staph aureus osteomyelitis)
Kids: painful bone crisis d/t sickeld cells sticking and causing microinfarctions; lung crisis; CNS likes seizures and strokes
Test: electrophoresis for HgS
Labs: low Hct, high reticulocytes
108
Megaloblastic anemia
PBS?
what's the myeloid:erythroid ratio?
problems w/maturation so they get too big
why? nutrient deficiency
mostly B12 and folate
PBS: multilobular neutrophils and pancytopenia (low #s of cells), but they're all big
normal M:E is 3:1, megaloblastic is 1:1
*know picture of hypersegmented neutrophil
109
3 Sxs of Pernicious anemia
| PBS?
```
Pernicious Anemia
1) beefy red tongue = atrophic glossitis
2) chronic gastritis
3) megaloblastic anemia
PBS: anisocytosis, macrocytosis, hypersemgented neutrophils
```
110
G6PD deficiency
PBS?
what causes it?
PBS:Heinz bodies, bite cells Degmacyte, starts to look like spherocytes w/enough membrane removed
Etiology: antimalarias, sulfonamides, nitrofurantoins, infections, fava beans
111
What's the order of where erythropoesis occurs?
```
Young Livers Synthesize Blood
Yolk sac (mesenchyme derived)
Liver
Spleen
Bone Marrow
```
112
Differentiate Diffuse vs Nodular lymphatic tissue
Diffuse: loose aggregates
Nodular: dense, organized, w/Light central region (Germinal Center) of Large Lymphocytes/blasts; and dark peripheral cap of small tightly packed lymphocytes
113
In primary lymphoid organs, what makes up the stroma? what makes up the parenchyma?
Primary lymphoid organs
stroma: no reticular fibers
parenchyma: diffuse lymphoid tissue, no nodules
114
What do Tonsil tissues contain? How do they react to antigens? what kind of antigens
Tonsil tissues have Bcell nodules w/a large germinal center surrounded by diffuse lymphoid aggregates
Tonsils form lymphocytes in presence of airborne and ingested antigens
115
What does the Thymus generate, where is it, and describe its morphology
Thymus is paired organ beneath sternum
Generates Tcells
surrounded by thin connective tissue capsule that has trabeculae extending from it, separating the thymus into partial lobules (lobule = peripheral cortex + central medulla, NO fibers)
116
What's in the Thymic Corpuscle, and why?
Thymic Corpuscles = Hassal's corpuscles
| Maybe site of Tcell death bc lots of macrophages and granulocytes
117
What stimulates thymus proliferation, and what stimulates involution?
Thymopoietin stimulates thymus proliferative activity of lymphocytes
Adrenocortical and sex hormones at puberty mediate thymus involution
118
Describe clinical features of Gaisboch's syndrome
Gaisboch's:
| Type A middle aged executives w/caffeine and tobacco excess, diuretics for HTN, and a chronic plasma volume reduction
119
What are the clinical sxs and tx for Polycythemia Rubra Vera? What's the crisis that can occur?
Polycythemia Rubra Vera
Low EPO, Jak2 mutation, WBC and platelet elevations, splenomegaly, normal oxygenation
Tx: Therapeutic phlebotomy, and ASA for thrombocytosis
Marrow can burn out
120
Differentiate appropriate vs non-appropriate secondary polycythemia
Appropriate polycythemia: anything that decreases O2 delivery to kidneys -> pulmonary, cardiac, or Hg problems
Inappropriate polycythemia: renal disease, pharm abuse, tumor production of EPO
121
What are microspherocytes indicative of? (3)
microspherocytes
1: spherocytic hemolytic anemia
2: burn victims
3: microangiopathic hemolytic anemia
122
What 4 diseases can target cells indicate?
Target cells:
| Thalassemia, liver disease, HgC, asplenia
123
When has erythrophagocytosis been seen?
Erythrophagocytosis has been reported sporadically following spider bite,[6] quinine administration,[7] and in hemolytic diseases of the newborn.[8] Erythrophagocytosis by cells other than neutrophils has been reported in acute myeloid leukemia,[9] in blast crisis of chronic myeloid leukemia[10] and occasionally in warm autoimmune hemolytic anemia.
124
How does the spleen develop embryologically?
Spleen forms in dorsal mesentery, rotating to the Lt to become posterior pritoneal organ
125
What's the difference b/w an accessory spleen and splenosis?
```
Splenosis = traumatic causes of splenic pieces
Spleniculi = accessory spleen, usually connected to spleen by thin band, found in Gastro-splenic ligament or greater omentum
```
126
Differentiate red pulp vs white pulp of spleen?
Red pulp = vasculature
| White pulp = Tcells
127
What are the splenic ligaments, and what's in them?
Spleno-Renal: Spleen to Posterior abdominal wall (Lienorenal), has main splenic vessels, and tail of pancreas
Phrenico-Colic: Spleen to Anterior abdominal wall, has short gastric vessels and Lt gastro-epiploic branches of splenic artery
Gastro-Splenic: Spleen to stomach
Spleno-Colic: Spleen connected to Lt/Splenic flexure via peritineum
Phrenico-Splenic: Spleen to Thoracic diaphragm
128
What's the most important aberrant branch of the splenic artery/
What's the most common type of splenic artery? what type of surgery is it good for?
What's the other type of splenic artery, and what type of surgery is it good for?
Splenic artery -> Pancreatica magna
Distributed artery most common, short trunk w/ few long branches, easy laproscopic dissection/partial splenectomy, difficult splenectomy
Bundled artery less common, long trunk w/lots of short branches, easier splenectomy, difficult dissection
129
What are the PSNS and SNS innrevations of the spleen?
| What are the primary receptors?
Spleen's PSNS = vagus
Spleen's SNS = celiac ganglion, superior mesenteric ganglion
primarily Noradrenergic receptors
130
What are the vaccines you must give before splenectomy?
Pre-splenectom vaccines:
1) H influenzae
2) Meningicoccal group C
3) Polyvalent pneumococcal
131
If you perform splenectomy, but don't look for accessory spleens, ___ can recur
If you perform splenectomy, but don't look for accessory spleens, _ITP_can recur
132
What receptor do Tcells express, that recognizes chemokines in the spleen? What happens after they bind?
Tcells express CCR7 receptors, and recogonizing chemokines in the spleen the Tcells segregate in periarteriolar sheaths
133
What type of Bcells are T-dependent, and give rise to long-lied plasma cells?
What type of Bcells contribute the most to T-independent Ab response to blood borne antigens? How?
Follicular Bcells are T-dependent, class-switched, high-affinity, give rise to long-lived plasma cells
Marginal Bcells in spleen are major contributors to T-cell independent Ab responses to blood-borne antigens, by responding to polysaccharide Ag
134
What's special about splenic macrophages?
Splenic macrophages in the marginal zone can bind to unopsonized Ags, along w/polysaccharide Ag, mycobacteria, bacteria, viruses, and opsoninzed Ags
135
Walk through splenic clearance of bacteria
Spleen clears bacteria by
coering microorganisms w/opsonins, esp encapsulated polysaccharide ag inducing IgM through T-celll independent mehcanism
IgG responses require protein to interact w/Tcells
136
What are 2 ways Ag can interact w/Bcells w/o Tcells?
Bcells can interact w/antigens through IgM and PRR (pattern recognition receptors)... but Bcell doesn't develop memory and there isn't an isotype switch to IgG
