Benign Flashcards
1
Q
Draw out the lineage of hematopoetic system, starting with HSC (stem cell) and ending with mature classes of myeloid, lymphoid cells.
A
see notes
2
Q
What cells are next in line after the common myeloid progenitor? What do they diff to?
A
Common myeloid –> granulocyte-macrophage progenitor + megakaryocyte-erythroid progenitor.
Each of these progenitor cells forms colony-forming units (CFUs) which then mature, via several stages, into mature cells.
3
Q
What are the classes of mature cells that we have to know? Give general fxn and indicate if they are of myeloid or lymphoid lineage.
A
Myeloid (from common myeloid progenitor)
- Granulocytes (G)
- neutrophils
- eosinophils
- basophils
- Macrophages (M)
- Erythrocytes (E)
- Platelets (P)
Lymphoid (from common lymphoid progenitor)
- Bc
- Tc
4
Q
Hematopoetic stem cells (HSC)
- Division mechanism
- Key cell surface Ag
A
- Asymetric division –> daughter cell that diff’s + daughter cell that self-renews
- CD34+
5
Q
Hematopoetic progenitor cells
- Family of cells that diff to
- Ability for self-renewal
- Cytokines/GF role
A
- Prog cells –> CFU (defined by ability to form CFU’s)
- Cannot self-renew
- Require and respond to cytokinds/GF’s
6
Q
What are the two most important myeloid growth factors? Function, release factor, etc?
A
- Epo: true hormone, secreted by mesangial cells of glom in response to hypoxemia –> Epo release –> ++poeisis in bone marrow –> ++RBCs
- Tpo (thrombopoetin): Released constant level by liver , stimulates MK to create platelets.
7
Q
What type of cell surface receptor-messenger system used by myeloid growth factors?
A
Epo/Tpo bind –> dimerization –> activation of JAK2 (tyr. kinase) –> cascade
8
Q
What are the four terminal cells of the GMP (granulocyte-macrophage progenitor)? Give the lineage from GMP to terminal cell.
A
GMP –> CFU-G –> G
GMP –> CFU-M –> M
Granulocytes
- Neutrophils
- Eosins
- Basos
plus 4. MP’s!
9
Q
Give brief desciption of each granulocyte (function + histology) to help compare/contrast
A
- Neuts: most common, innate, light-staning nuc. w/ polymorphic nuc.
- Eosins: red-staining, allergic rxns, acute infx
- Basophils: dark-staining (basophilic)
NB: eosins and basos both have prominent granules
10
Q
Familial cyclic neutropenia
- Etiology
- Time needed to create neut from HSC
- Typical blood result
A
- INH mut neut elastase
- 21 days
- B/c of 21 day cycle, get cyclical rise/fall of neuts.
11
Q
What is the general blood smear result for reduced prod’n?
A
Low cellular levels with LOW reticulocyte count (high reticulocytes would indicate increased destruction with increased production - body getting immature cells out quicker)
12
Q
What would a pancytopenia manifest as in blood smear?
A
low counts (anemia - E, leukpenia - Bc, Tc, thrombocytopenia - P) + low retics
13
Q
Common causes of pancytopenia
A
- Aplastic anemia (stem cell failure)
- Marrow disorder (leukemia, etc.)
- Deficiency (B12, folate)
- Infx
- Myelodysplastic synd
14
Q
In cases of pancytopenia what labs/diag’s are done?
A
smear, bone marrow biopsy
15
Q
Where are BM biopsies done?
A
Posterior iliac crest
16
Q
What is a major diff b/t BM aspiration/biopsy and core biopsy?
A
aspiration: live cells
core: dead cells
17
Q
What tests/labs can be done on bone marrow aspiration (mention five)?
A
- cell morphoogy
- diff’l count
- histochem. staining
- take cells for flow cyto
- culture
(basically, all the things you can do with LIVE cells)s
18
Q
What are the two normal values we shoudl know from a myelogram from aspirate?
A
Blasts should be 0-5%
Myel:Eryth ratio shoudl be 2:1-4:1
19
Q
what are BM core biopsies good for?
A
- architecture
- staining
- cell popns and patterns
remember cells are DEAD so can’t take samples, do cytology, cytometry, etc.
20
Q
Fanconi anemia
- Lab diagnosis?
A
- Dicentric xsomes in karyotype (induced)
21
Q
What are two drugs that can cause acquired aplastic anemia?
A
- methotrexate
- chloramphenicol (antibiotic, most notorious)
22
Q
Paroxysmal nocturnal hemoglobinuria (PNH)
- Def
- Etiology
- Pathophys
A
- A type of acquired BM failure + hemolysis –> aplastic anemia, lysis
- Mutated CD55 & CD59 –> poorly modulated complement
- Unusual sensitivity to complement leads to lysis and dmg to HSC’s.
23
Q
What are the two main approaches to Rx of aplastic anemias?
A
- Immune suppression (cort’s, cyclosporine)
- HSC replacement (xplantation, allogenic)
24
Q
Anemia lab def
A
- decreased Hg >2 SD below mean
- Decrease HCT
25
Anemia pathopys def.
Low RBC's means **inadequate delivery of O2 to tissues.**
26
HCT def
% of RBC's / volume
27
Reticulocyte
youngest normal RBC entering circ. from BM (large purplish cell on smear w RNA remnants visualized on vital stain)
28
What is the key/standard measure of reticulocytes?
**absolute reticulocyte count:** retic % x total red cell #
29
# Define the following lab values:
* RBC
* MCV
* MCH
* MCHC
* RDW
* RBC: # RBCs/uL blood
* MCV: mean corp. vol.
* MCH: Hg in single cell
* MCHC: Hg conc in given vol. of RBCs
* RDW: size distribution of RBCs
30
S/S of anemia
* fatigue
* pallor
* SOB esp exertion
* Tachy
* Orthostatic hypoTN
31
Reticulocyte index
* Def
* Expected value in anemic pt who has adequate BM response
* rectic count x (Hct/40)
* \>2
32
Hypoprolif anemia (def and lab value)
* Anemia caused by not making enuf RBC's (inadequate BM response to degree of anemia)
* Low ret index (\<2) and/or count
NB: note that although megaloblastic anemias do have poor production, they are not considered classically hypoproliferative b/c the reticulocytes are killed before leaving the BM. So the reticulocyte count can be normal or low.
33
Hyperprolif anemia (def, lab value)
* Anemia showing robust BM response, as evidenced by....
* ...increased ret index (\>2) +/or count
34
What is the most common anemia ? is it hypo- or hyperprolif? Micro- or macrocytic?
Fe def; hypoprolif.; microcytic.
35
Common macrocytic (hi MCV) anemias (4)
* B12 def.
* Folate def.
* EtOH
* Liver dz
36
Common etiologies of microcytic anemias (4)
1. Fe def. (most common by far)
2. Toxins/Pb
3. Chronic dz (anemia of chronic dz)
4. Thalassemia
37
Normocytic anemias are generally a problem of \_\_\_\_\_\_
Hemolysis (destruction) - either intra- or extra-vascular
38
In addition to fatigue and pallor, what are three (3) clinical signs of Fe def ?
1. Hair loss
2. PICA
3. Spoon-shaped nails
39
Three common causes of Fe def?
* Blood loss
* Malabsorption (due to cel. dz, gastric bypass, etc.)
* Poor diet
40
# Define the following Fe-related proteins
* Ferritin
* Ferroportin
* Hepcidin
* Hemosiderin
* Ferritin: Water-soluble Fe storage in liver/heart; lo Fe stores = lo ferritin
* Ferroportin: xports Fe out of basolateral membrane --\> circulation.
* Hepcidin: triggers degradation of ferroportin on the surface of enterocytes and macrophages. This _decreases iron absorption from the intestine_ and _inhibits iron release from macrophages_, leading to hypoferremia
* Hemosiderin: water-insoluble Fe storage
41
What are the distignuishing lab findings (smear, blood assays) of Fe def. anemia (IDA)?
* Smear: Microcytosis, Hypochromia (low MCH), Low RBC count, Low Retic (hypoprolif)
* Assays; Low ferritin, high TIBC
42
What does image show?
Fe def anemia w/ wide central pallor = hypochromia
43
What will ferritin levels be in Fe def anemia?
Low (depeletion Fe stores)
44
What lab findings woud you find in anemia of chronic dz?
* A defining feature of ACD = higher than nl Ferritin i(Hepcidin causes Fe sequestration)
* Decreased TIBC (not sure why, but remember than in Fe-Def anemia, TIBC will be elevated reflecting a true deficiency)
45
What are the 2 primary causes of Fe overload?
* Hereditary hemochrom. (Fe overload)
* Tranfusional
46
How much Fe (in mg) in 1 cc packed RBCs
1 mg
47
Sources of folate? Where absorbed?
* Vitamin found in leafy green veg's, foritfied foods, some fruits/vegs
* Jejunum (proximal)
48
B12
* Source
* Absorbtion site
* Most animal (liver, meat, some dairy)
* Terminal ileum
49
Pernicious anemia
B12 def. caused by lack of intrinsic factor from stomach parietal cells.
50
Primary cuases of B12 def?
* Malabsorption (gastrectomy, pern. anemia, no intrinsic factor)
* GI probs
51
Smear findings in pernicious anemia? Include any special cells you might find.
macrocytic cells w/ some teardrop cells
52
subacute combined degen
chronic B12 deficiency-related neuropathy (irreversible if damages spinal cord)
53
* Example of two megaloblastic anemias
* What does this refer to?
* B12 def and folate def anemias = megaloblastic anemias
* Megaloblastic: **Megaloblastic red cell precursors** (seem in BM aspiraton) are larger than normal and have more cytoplasm relative to the size of the nucleus. Promegaloblasts show a blue granule-free cytoplasm and a "salt and pepper" granular chromatin that contrasts with the ground-glass texture of its normal counterpart.
54
Common causes Folate def
* Dietary
* Malbsorption/GI
* Drugs (folate antagonists like methotrexate)
55
Def hyperprolif anemia
Anemia w/ increased destruction (hemolysis) of RBCs and increased reiculocyte count/index.
56
Hereditary spherocytosis
* Def
* Etiology
* Hemolytic anemia (most common)
* Congenital, w/ membrane protein defects
57
Lab diagnosis of hered. spherocytosis
* Smear
* Special test
* Smear:
Increased retic
Increased MCHC (mean corpuscular Hg conc.)
Spherocytes on smear
* Abnormal **osmostic fragil. test**
58
Hereditary elliptocytosis
* Def
* How does it comparie to hereditary spherocytosis (HS)?
* Also a membrane disorder of RBC's --\> hemolytic anemia
* Milder than HS
59
What is the difference b/t intra- and extravascular hemolysis?
Examples of each?
This just refers to where the RBC's are being destroyed. Extravascular refers to the spleen.
_Intravascular_
* Burn
* G-6-PD deficiency
* Malaria
* thrombotic thrombocytopenic purpura
* disseminated intravascular coagulation
* paroxysmal nocturnal hemoglobinuria (PNH)
* Immune hemolytic anemia (warm & cold)
NB: all of the microangiopathic hemolytic anemias are intravascular (HUS, TTP, DIC, etc.)
_Extravasc._
* Sickle cell dz
* Hered. spherocytosis
60
What are the two kinds of autoimmune hemolytic anemias? What differentiates them immunologically?
warm & cold; warm = IgG Ab's (extravascular hemolysis), cold = IgM (intravascular hemolysis)
61
What are examples of non-immune acquired hemolytic disorders?
* Infx
* Burns
* Liver dz
62
Warm autoimmune hemolysis
* Def
* Mechanism of cell destruction
* Location of cell destruction
* IgG-mediated autoimmune lysis of RBC's --\> hyperprolif. anemia
* IgG Abs directed against RBC Ag's --\> hemolysis via complement.
* extravasc
63
Coombs test
* To dx **immune hemolytic anemia**
* Uses agglutination to test for autoAb's and/or complement on RBC surface
* RBCs are incutaed w/ Abs to Ig and C3
* If agglutination takes place then test is positive and RBC's presumed to have IgG/C3 bound to surface.
64
Indirect Coombs test
* Used for ?
Testing for immune hemolysis in newborns and transfusion pts - also an agglutiation test
65
Clin features of hered. spherocytosis (5)
* Jaundice (increased indirect bilirubin)
* splenomegaly (EV hemolysis)
* Hyperhemolytic crises
* Aplastic crises (Parvo B19 infxn)
* Pigment gallstones (due to hemolysis)
66
G6PD Deficiency
* Def
* Two common variants
* Sign in newborn
* hereditary cause of hemolytic anemia
* African (milder), mediterranean (more severe, all RBCs deficient)
* Common cause of neonatal jaundice
67
G6PD Def pathophys
Lack/mutated G6PD --\> impaired prodn of NADPH which is needed to produce **reduced glutathione**, the primary superoxide salvager. This leads to hemolysis via **oxidative dmg**.
68
What are some signs of G6PD deficiency anemia on periph. smear?
* ghost cells, **bite cells** on smear
* **Heinz body** w/ supravital stain (RNA frag)
69
What are the types of abnormal cells? What dz is this?
* bite and ghost cells
* G6PD anemia
70
what cell?
neut: polymorphic nucleus
71
cell type?
eosin
72
cell type?
basophil
73
cell type?
Lc
74
What would increase the number of neuts and bands?
acute bact. infx
75
What are some conditions that would increase eosin's?
"worms, wheezes and wierd diseases": allergies, parasites, TB, sarcoid, etc.
76
What are three causes for increased monocyte count?
Two causes of decreased?
_Increased_
* Chronic infx eg TB
* Chronic INF eg Sarcoid
* Chronic neutropenia
_Decreased_
* BM failure
* Cort's
77
What are factors that can decrease neut count via (1) decreased prod'n or (2) increased destruction
_Dec. production_
* congential
* acquired via viral, meds, aplastic anemica, malignancy
_Increased dest._
* hypersplenism (sequestration)
* immunological
78
def. **toxic granulation**
dark azurophilic granules in neut's, seen in INF states
79
What is a relatively common disease that would show more than 5-10% basophils?
CML
80
Pelger-Huet anomlay
* Cell type & anomaly
* Causes (2)
Bilobed neutrophil nucleus due to benign disorder or myelodysplastic syndrome
81
What is seen in some of these neutrophils? What are two causes?
Pelger-Huet anomaly - caused by "benign" hereditary disorder or myelodysplastic syndrome
82
What does the image show? What generally causes it?
Dohle body: Döhle bodies are discrete, blue-staining nongranular areas found in the periphery of the cytoplasm of the neutrophil in _infections and other toxic states_. They represent aggregates of rough endoplasmic reticulum.
**(The cell is a band, the inclusion is the _Dohle body)_**
83
When are Dohle bodies often seen? What cell type?
In Neuts, during sepsis (chronic INF).
84
What are the two primary ways that phagocytes kill microbes once they are phagocytosed?
Oxygen independent
* lysosome fusion + enzymes
Oxygen dependent
* respiratory burst (superoxides)
85
Def. respiratory burst and give two key enzymes
Burst of activity that creates superoxides. Key enzymes are **superoxide dismutase (SOD)** --\> H2O2 + O2
and
**myeloperoxidase** --\> **.**OCl-
86
Chediak-Higashi syndrome
* Genetics
* Def
* Clinical picture
* Rare, AR
* Failure of phagolysosome formation (ineff. lysosomes)
* recurrent skin and syst. infxs, s. aureus
87
Chronic granulomatous dz (CGD)
* Defect
* Clinical picture
* Defect in resp. burst enzyme complex --\> very lo H2O2 prodn
* Because CGD neut's cannot scavenge H2O2 from catalase + bacteria, these are much more problematic.
* Severe skin, sinopulm. infxs, granulomas, sepsis w/ lymphadenopathy, hepatosplenomegaly
88
Job's syndrome
* Defects
* Clinical picture
* aka **hyperimmunoglobulin E–recurrent infection syndrome**
* HyperIgE + defect in chemotaxis... leads to:
* _recurrent skin and sinopulm. infxs_
89
Myeloperoxidase def
* Def
* most common neutrophil defect
* AR trait
* Isolated myeloperoxidase deficiency is **not associated with clinically compromised defenses**, presumably because other defense systems such as hydrogen peroxide generation are amplified.
* **Microbicidal activity of neutrophils is delayed but not absent**. Myeloperoxidase deficiency may make other acquired host defense defects more serious.
90
Leuk. adhesion defect
* Genetics
* Defect
* Clinical
* Very rare AR
* Defect in ICAM1, problem w/ phagocytosis
* Delayed loss umb. cord, poor would healing, bact. infxs
91
What are two specific tests for CGD? What is result when pt has dz?
* Nitroble-trarazolium (NBT) test (measures activity of resp. burst pathway) **negative** in CGD
* Measured level of superoxides & H2O2 s/p stimulus.
92
To what types of microbes are CGD patients especially susc to?
catalase +
93
What characterizes **leukemoid reaction?**
* Increased neuts, bands and other young leukocytes...
...reflecting heightened BM response.
94
What is a "left shift" on smear?
Increase in bands on perip. blood smear, a normal resp. to infx or hemorrhage.
95
Draw out the factors in the intrinsic pathway. What is the relationship b/t these factors?
The factors become activated factors for the next in the cascade:
Factor XII --\> XI --\> IX --\> VIII (VIII helps to activated IX which feeds into cmoon pathway)
96
What is the instrinc pathway?
Factor VII (VIIa feeds into the common pathway by helping to form Xa)
97
Sketch out the common pathway
Factor X is activated by IXa (instrinsic) and VIIa (extrinsic). Xa activates thrombin from prothrombin.
fibrinogen ---(thrombin)---\> fibrin --\> crosslinked fibrin
98
How does quiescent endothelium act to prevent clots? Mention four mediators and their fxn.
* **Prostacyclin** prevents platelet activation
* **Antrithrombin III** lowers thrombin
* **tPA** increases fibrinolysis
* **NO** reduces adherence, etc.
99
How does activated endothelium create a procoagulatory milieu?
* Upregulation of adhesion
* Opsonization --\> neut. recruit
* **Upreg. of thrombin**
* Upreg of **endothelin** (vasoconst)
100
F XIII
XIII: activated by thrombin, crosslinks fibrin monomers
101
What is characteristic of FXIII def? Why?
* Late/delayed bleeding b/c it's a late step in clotting cascade.
* Not reflected in screening assays.
102
Vit K role in clotting, and med that counteracts
* Needed for synth of F's 2,7,9 and 10
* **warfarin** inhibits K-dependent pathway
103
PTT
* What part of pathway does it test?
The **partial thromboplastin time** **(PTT)** tests the **instrinsic system**.
104
vWF function (2)
Released in resp to vessel injury, it
* Leukocyte adhesion (binds collagen, then binds platelet via Gp Ib)
* Interacts positively w/ f8
105
PT - what part of pathway does it test?
extrinsic
106
TT (thrombin time) - what does it measure? what part of pathway?
measures time for conversion of fibrinogen to fibrin clot (late steps). Part of common pathway.
107
What are two importnat coag. mediators NOT reflected in PTT or PT?
vWF & f13
108
Describe the key parts of the **fibrinolytic pathway**
endothel. release of tPA
Plasminogen --(tPA)---\>plasmin
fibrin ---(plasmin)---\> fibrin degradation products
109
What are some things that could slow down clotting NOT in TT, PT or PTT (6)?
* vWF
* fXIII
* platelet problem
* bleeding
* DIC
* vit K
110
How does a fXII def usually present?
Longer PTT but no abnormal bleeding
111
What is the general pattern for coagulation tests (PT, PTT, TT) for vit K def?
* Prolonged PT, PTT
* Normal TT
112
HbF (fetal Hb)
2 alpha, 2 gamma (begins to decline at 6 mos.)
113
HbA
2 alpha, 2 beta
114
HbA2
2 alpha, 2 delta
115
Def. thalassema
a *quantitative* disorder of Hb synth --\> S/S
116
def. Beta thal & alpha thal
* B-thal: decreased or absent B chain synth
* A-thal: decreased/abset A chain synth
117
Alpha thalassemia minor
* Genetics
* Clinical
* deletion of 2 alpha globin genes (cis or trans)
* mild anemia
118
Pathophys of alpha thal's?
* Def in alpha chains leads to...
* ...B tetramers
* These precipitate causing hemolysis.
119
Hydrops fetalis
* Genetics
* Outcome
* 4 alpha chain deletions
* incompat. w/ life
120
HbH dz
* def
* genetic abnormality
* abnormal Hb?
* phenotype
* type of alpha thal
* deletion of 3 alpha globin genes
* HbH: these become common in HbH - they are **beta tetramers**.
* can be severe
121
alpha thal trait
* def
* clinical
* deletion of 1 alpha gene
* no anemia
122
Hb Constant Spring
* Describe the abnormal Hb - which globin locus is affected - alpha or beta?
* What type of mutation is this?
* Describe the clinical picture of hetero- and homozygous.
* A substition in the a2 termination codon leads to abnormal a2 Hb (a non-deletional alpha thal, much less common)
* As above - non-deletional in alpha chain
* Hetero: No abnormality
* Homo: mild thalassemic changes with normal-size red cells. The hemoglobin consists of approximately 5 to 6 percent hemoglobin Constant Spring, normal hemoglobin A2 levels, and trace amounts of hemoglobin Bart's. The remainder is hemoglobin A.
123
Alpha thal's are caused *mostly* by _______ whereas B thal mutations are often \_\_\_\_\_\_.
deletions; point mutations
124
Clinical picture of B thal major (5)
* severe anemia w/ hemolysis
* bone deformities (chipmunk facies, crewcut appearance on head x-ray due to expansion of marrow compartment)
* splenomegaly
* Fe overload (why?)
* Hi output heart failure (secondary to chronic anemia)
125
Rx for B thal major
* RBC xfusion (birth --\> life-long)
* Fe chelation
* BM xplant
126
What will be typical labs in Thal's?
* Low Hb, HCT
* Microcytosis (abs. requirement)
* High RBC disproportionate w/ Hb value
* NORMAL Fe studies
127
How will Fe studies look in Thal?
Normal
128
Typical periph blood smear, thal?
* microcytic
* hemolytic
* variable shapes (poikilocytosis)
* target cells
* hi retic
129
Gel results for the following
* Alpha thal trait
* HbH
* Beta thal
* Normal, w/ HbA only
* fast migrating band formed by B tetramers
* Increased HbA2 & HbF levels
130
How can HPLC pick up Thal? Which one?
Can detect B thal by reliably quantifying HbA2 & HbF fractions in **B thal**.
131
HbE
* Def
* Features
* Variant Hb
* Mutation causes reduced synth of Beta chain and a **mild B-thal phenotype**.
132
Pathophys of SS dz
* HbS easily polymerized in deoxy conformation
* Dec. solubiity --\> precipitates --\> aggregation --\> membrane distortion --\> sickling
* Sickle cells cause occlusion --\> ischemia, pain
* Precipitation --\> hemolysis
133
SS dz genetics (HbSS)
AR mutatation in B globin allele; 2 abnormal Beta alleles = Sickle dz; HbS = Alpha2,B**s**2
134
Genotype of sickle trait; what is the mix of Hb's?
HbAS (heterozygous); gives a mix of A2/Bs2 (HbS) and HbA (so the name sort of reflects this mix of Hb's) ... however, in sickle trait, generally have \<50% HbS.
135
Diagnosis of Sickle dz
* Smear
* Gel electrophoresis
* HPLC
* Specific test for Sickle
* anemia w/ hi retic, normal MCV unless sickle thal, sickled RBCs
* Gel: distinctive migration pattern
* HPLC: HbS has distinctive retention time, can quantify HbS proportion (SS will be 100%)
* Sickle solubility: Positive if pt has *any* HbS.
136
Explain four (4) types of crises in Sickle cell
1. **Vasooclusive crisis:** acute pain epidose w/ hypoxia (most common)
2. **Hemolytic**
3. **Aplastic:** erythroid aplasia due to Parvo B19 infx
4. **Sequestration:** pooling in spleen --\> splenomeg + shock-like state (more common children)
137
What are some of the organ manifestations of SS dz?
1. Blood: Chronic hemolytic anemia + chronic pain (vasooclusion)
2. Skin: Chronic leg ulcers
3. Endo: growth retardation, hypogonadism
4. Ocular: sickle retinopathy
138
Selected complications of SS dz (5)
* Heart failure
* Pulm. HTN
* Stroke
* Renal failure
* Infections
139
Acute chest syndrome def.
fat embolus from marrow infarction (or other etiology) causing lung necrosis, pulmonary hypertension/infiltrate, cor pulmonale, pleuritic pain; risk death; treat supportively for symptoms.
140
Two primary indications for RBC transfusion in SS dz
1. Acute chest
2. Stroke prophylaxis
141
Two primary complications of RBC xfusion in SS dz
1. Ab's to RBC Ag's
2. Fe overload
142
How is it believed that **hydroxyurea** helps pts w/ SS dz?
* Increased HbF which leads to....
* ...improvement in S/S.
143
Mixing study
* def
* interpretation/results
* In pt w/ prolonged PT and/or PTT, mix blood 1:1 w/ pooled plasma, then repeat PT/PTT at 2 hours.
* **Correction** = clotting factor def.
* **Failure** = INH protein
144
vWD S/S (2)
* Mild mucosal & skin bleeding
* Epistaxis
145
2 major fxns of vWF
* **Mediates platelet adhesion**
* **Stabilizes factor VIII** in circulation
146
Type I vWD
* Most common
* Mild
* **Deficient vWF**
147
Type 2 vWD
* Qualitative defect in vWF
* Similar to others... low f8 etc
148
Type 3 vWD
* Severe def/absence of vWF w/ lo levels FVIII (cannot stabilized FVIII --\> lo levels)
* AR, very rare
149
Etiologies (3) of acquired vWD
1. Autoimmune: Ab's bind to vWF
2. Hypothyr: lo synth
3. Cardiac: destruction of vWF (Ao stenosis, cong. heart dz, etc.)
150
Lab evaluation for vWD
* PTT/PT
* Bleeding time
* Special test?
* Increased PTT (vWF stabilizes f8) but overall secondary hemostasis works pretty well
* Increased bleeding time
* Ristocetin test will be abnormal, hwoing deficiency of vWF
151
What dz can be treated w/ DDAVP (desmopressin)?
How does it work?
vWD
* promotes release of stroed vWF ffrom endoth. cells.
152
Rx of type 2 & 3 vWD often requires ?
VWF-containing factor VIII concentrate
153
How to Rx acquired vWD?
Most important - Rx underlying condition & use immunosupression
154
Hemophilia
* Genetics of A & B types
* Etiology of A & B
* both x-linked recessive
* **A**: F VIII def; **B**: F IX def.
155
Classic S/S of hemophilia
1. hemarthroses, often spontaneous
2. Other bleeds
156
What level factor measured in **severe** hemophlia A/B?
\<1%
157
Three (3) lab studies that would correspond to hemophilia diagnosis.
* Prolonged PTT
* Correction w/ mixing study
* Factor assay (VIII or IX) w/ low result.
158
Rx hemophilia
* 1st line
* adjunctive
* Plasma derived (rare) or recombinant factor.
* Adjuntive: Ortopedic, R**I**CE, narcotics (pain - avoid NSAIDS), DDAVP (mucosal bleeds)
159
Acquired hemophilia
* Etiology
* Clinical
* Rx
* AutoAb to FVIII
* Severe soft tissue bleeds
* Immunosupp., FVIII conc.
160
DIC
* Def
* Etiology
* Pathophys
* Labs
* Rx
* Bleeding disorder caused by pathological activation of coag. cascade
* Generally secondary to sepsis, obstetric complication, venom. These cause a **consumptive coagulopathy** --\> hemorrhage, thrombosis
* Labs**: lo platelets**, **prolonged PT/PTT,** lo coag factors, low fibrinogen, **hi d-dimer, schistocytes** (microangiopathic hemolysis).
* Rx: platelet xfusion, factor replacement, _correct underlying cause_
161
How can liver failure --\> bleeding disorder?
* impaired synth of clotting factors --\> coagulopathy
* vitK deficiency (due to lo bile) --\> clotting problems
162
Alpha granules in platelets contain substances that act in aggregation/adhesion, coagulation, and late stage healing. Give examples from each category.
* _Aggregation & adhesion factors_
- **ADP** (released on activation, induces Pt to express Gp IIb/IIIa which binds fibrinogen b/t two receptors to help Pt's aggregate)
- **TXA2** (pro-aggregation also by upregulating expression of IIb/IIIa)
* _Coagulation_
- **Factor V** (released by alpha granules but also in circulation)
* _Healing_
- **PDGF**
- **P-selectin** (adhesion of activated platelets to phagocytes; also released from _Weibel-Palade bodies_ of endothelial cells which also contain vWF)
163
Content of dense granules (3), w/ functions
* **ATP, ADP**: platelet activation & recruitment
* **5-HT** (serotonin): vascoconst.
* **Ca**: cofactor for forming fibrin clot
164
Discuss the function of the following receptors on the *platelet* cell membrane:
* **Gp 1b**
* **Gp 1a/2b**
* **Gp 2b/3a**
* ** ** **Gp 1b:** Binds vWF which is bound to collagen in damaged endothelium, *adhesion*.
* **Gp 1a/2b:** Can bind collagen directly, *adhesion.*
* ** Gp 2b/3a:** Binds _fibrinogen_, forming bridge b/t platelets, *aggregation*.
165
What is the role of **thrombin** WRT platelets?
Binds to receptor on platelets and and activates them.
166
Along w/ thrombin, what is another potent platelet activator? How is it synthesized?
TXA2: ptent activator, binds to platelet receptor. ARA derivative formed via COX.
167
Name the primary mediators for these activities of platelets:
* Adhesion
* Activation
* Aggregation
* Clot retraction/healing
* Adhesion: vWF, collagen (bind to receptors on platelet)
* Activation: TXA2, thrombin
* Aggregation: fibrinogen (via Gp IIb/IIIa)
* Clot retraction/healing: PDGF
168
Explain the following tests for platelet disorders:
* Bleeding time
* Platelet aggregation
* PFA-100
* Bleeding time: not as commonly done, increased time could indicate platelet dys.
* Platelet aggregation: self-explanatory
* PFA-100: tests adhesion & aggregation, EZ screening w/ small amount whole blood
169
Make note of the image and learn it!
170
Bernard-Soulier Dz
* Def
* What receptor affected
* Results in?
* Congenital platelet disorder (cytopathy)
* Gp Ib (vWF receptor - vWF bound to collagen)
* Results in poor adhesion --\> prolonged bleeding time.
171
Glanzmann's thombasthenia
* Def
* Receptor affected
* Results in ?
* Congenital thrombocytopathy
* **Gp IIb/IIIa** (fibrinogen receptor)
* Abnormal aggreg., PFA 100 and bleeding time
172
What is the most common acquired thrombocytopathy? What is the etiology?
* ASA/NSAID induced
* COX inhibition --\> deficiency in TXA2 which is needed to activate platelets.
173
DIC
* Def
* Etiology
* Most common causes
DIC
* Consumptive coagulopathy w/ cytopenia - over-coagulation leads to depletion of platelets.
* Most commonly cuased by release of tissue factor from...
* ...inflammed tissues (commonly due to endotoxin/sepsis, tissue injury, infections)
174
ITP
* Def
* Etiology of primary ITP
* Common conditions that can present w/ secondary ITP
* common acquired autoimmune disorder defined by a low platelet count
* autoimmune: Ab's against platelets --\> removal/destruction
* SLE, pregnancy
175
What are some acquired conditions/stimuli that can lead to decreated prod'n of platelets (4)?
* Malignicancy
* Infectious (Parvo)
* Drugs
* Radiation
176
What are some acquired causes of increased dest. of platelets?
* HIT (heparin)
* hypersplenism
* ITP
* HUS
* APLA (antiphospholipid Ab synd)
177
HELLP syndrome
**H**emolysis, **EL**evated liver enzymes, **L**ow **P**latelets; a complication of pregnancy. The hemolysis is secondary to formation of thromboses which shear the RBCs and consume Pt's.
178
Rx for ITP?
* Immunomodulation: steroids, IVIG, rituximab.
* adjunctive: control bleeding, anti-fibrinolytics, FVIIa
179
Explain how vessel injury can create a pro-thrombotic state
Vessel injury --\> platelet activation via vWF & collagen
Vessel injury --\> release of tissue factor --\> activaton of coagulation cascade
180
Explain how quiescent endothelium is normally antithrobmotic
* **Prostacyclin** INH platelets
* **Thrombomodulin & antithrombin III** downregulate thrombin
* **tPA** upregulates fibrinolysis
* **NO** reduced adherence overall
181
Virchow's Triad
* stasis
* thrombophilia
* vessel injury...
...lead to **thrombosis**.
182
What are four (4) key inhibotorsy of thrombosis (bloodborne factors)?
* **TFPI:** neutralizes factors Xa and VIIa
* **Proteins C and S**: INH fV and fVIII
* **Antithrombin III**: binds/INH's thrombin
183
Clinical features assoc. w/ thrombosis (and the disease/condition that causes it)
* acute chest pain (PE)
* swelling of extremeties (DVT)
* SOB (PE)
* Ill pt. w/ skin necrosis (DIC)
* Stroke (DVT/ other thrombosis)
* Frequent miscarriages/fetal loss (placental thrombosis)
184
What are some key acquired prothrombotic states (3)
1. age
2. surg
3. estrogens (OCPs)
185
Factor V Leiden
* Def
* Etiology/pathophys
* Most common inherited hypercoag
* Mutant **Factor V** resistant to deg. by **Protein C**
186
Prothrombin gene mutation
* Def
* Pathophys
* Inh. hypercoag.
* Mutation --\> increased prod'n of prothrombin --\> increased plasma levels and venous clots
187
Antithrombin def.
* Def
* Pathophys
* Inherited hypercoag.
* Lack of antithrombin
188
Protein C or S def.
* Def
* What factors affected?
* Hypercoag., inherited
* **Proteins C and S inhibit V and VIII**
189
Antiphospholipid Ab Syndrome
* Def
* Pathophys
* Epidem.
* Clinical (4)
* Acquired hypercoag.
* Immune-mediated, with IgX against proteins on endothel. & platelet membranes.
* F\>M
* thrombosis (venous or arterial), recurrent fetal loss, livido reticularis, thombocytopenia
190
What does this show? Whas is a hypercoag. syndrome assoc. with it?
Livido reticularis - assoc. w/ antiphospholipid Ab syndrome (acquired hypercoag.)
191
Antithrombin III
* Function
* What it inhibits
* Drug that potentiates
* Inhibits coag via...
* ...inh of thrombin (IIa), Xa
* **Heparin** potentiates ATIII 1000x
192
**Unfractionated heparin**
* Administration
* t1/2
* Activity (2)
* IV
* Very short (1-2 h.)
* Augments **anthithrombin** inhibition of thormbin, Xa
* Impairs platelet fxn
193
What are the two major complications of heparin?
* Bleeding
* Hep. induced thrombocytopenia (HIT): body develops Ab's to heparin ---\> T-penia.
194
HIT (hep induced cytopenia)
* Pathophys
* Overall concern in HIT
* What type of heparin has 10x greater incidence of HIT?
* Immune-mediated (Ab against heparin)
* Altho platelets LOW, major concern is thrombosis **because of endothelial cell activation**
* 10x greater w/ unfractionated heparin (vs. LMWH)
195
Rx for HIT?
* Stop heparin
* Thrombin inh's
* Bridge to warfarin when platelets nl
196
what is a key advantage of low mol weight heparin (LMWH) over unfractionated hep?
Less incidence of HIT
197
Warfarin
* Use
* Route admin.
* t1/2
* MOA
* Anticoag.
* Oral
* 36 h.
* INH's Vit. K formation (***Vit K reductase***) --\> **lower amounts of fII, VII, IX, X** b/c the active form of Vit K not able to gamma-carobxylate them to active forms.
198
Key complications of warfarin therapy (2)
* bleeding
* avoid in pregnancy - teratogenic
199
What are the most common thrombolytic agents? Where do they affect thrombosis?
tPA derivs
tPA activates plasminogen which converts to plasmin. Plansim breaks down fibrin to subunits/deriv's.
200
Indications for thrombolytic (tPA) therapy
In general, a *life or limb threatening situation*
* Acute MI (alternative is stenting)
* PE
* DVT
* Thrombotic stroke
201
Some key contraIND's of tPA (4)
* Major bleeding past 6 mos.
* s/p surgery 10 days
* HTN \>200 SYS
* Bleeding disorder
202
Discuss the MOA of these three anti-platelet drugs:
* ASA
* Clopidrogel
* Abciximab
* ASA: COX INH (INH formation of **TXA2** which is pro-aggregator)
* Clop: ADP-R antagonist (INH activation)
* Abciximab: Antibody to GpIIb/IIIa receptor (INH's aggregation)
203
Thymoma
Type of lymphoid malignancy (T cell tumor) - a cause of **acquired aplastic anemia**.
204
What methods are used to remove Lc's from blood products? Why?
Irradiation & Lc depletion; done to avoid _graft vs. host dz (GVH)_
205
What is a compatible transfusion?
Match of ABO + Rh matched.
206
What can result from incompatible transfusion?
Risk of _fulminant hemolytic reaction_
207
Hemolytic dz of newborn (HDN)
* Mechanism
* Rx
* Rh- mom exposed to Rh Ag ==\> generation of anti-Rh Ab's --\> cross placenta --\> cause ** fetal EV hemolysis**
* Rx: **RhoGam** - hi-dose anti-Rh Ab's --\> bind/sequester Rh Ag's.
208
Neonatal immune thrombocytopenia (NAIT)
* Def
maternal anti-Pt Ab's cross placenta
209
ABO mismatch can cause _______ while Rh mismatch can cause \_\_\_\_\_\_\_\_.
IV hemolysis; EV hemolysis;
210
What characterizes a delayed transfuions rxn? Test used?
Jaundice and anemia 7-10 days s/p xfusion; test: will be Coomb's + at time of reaction.
211
TRALI
* Def
Transfusion-related acute lung injury
* Allergens in Lc's of transfused blood --\> allergic rxn w/ hives & pulm. edema.
* Non-hemolytic
212
Febrile transfusion reaction
* Rxn b/t Lc's (host) and Lc's (xfusion) --\> fever (non-hemolytic)
213
three most common hazards of xfusion? Give brief explanation of each.
* **Fe overload** (can lead to hemochromatosis)
* **Infection:** small chance for viral infx (HIV, hep)
* **Allo-immunization:** sensitization to certain Ag's on RBC's can lead to hemolytic anemias.
214
Where is Fe absorbed?
Duodenum
215
Microangiopathic hemolytic anemia
* Def
* Characteristic lab result (smear)
* Etiologies (6)
* Hemolytic anemia, normocytic, intravascular, caused by shear stress often caused by thrombi, or other things.
* Smear: **schistocytes** aka "helmet cells"
* Etiologies:
TTP
HUS
DIC
HELPP syndrome
Ao stenosis
Prosthetic valves
216
Type III vWD can resemble \_\_\_\_\_\_\_\_\_. How to Rx?
Hemophilia A.... b/c can also present w/ deep bleeding including **joint bleeding**. If DDAVP not sufficient Rx w/ f8 concentrate that has vWF.
217
TTP
* Pathophysiology/etiology of the **congenital form**
* Decrease in **Adam TS13 enzyme** leads to thrombosis which then results in microangiopathic hemolytic anemia & consumptive thrombocytopenia.
* AdamsTS13 is a thrombolytic protein.
218
Two ligands that help to identify a HSC, and one that is **not** present, which also helps to ID.
* CD34+
* c-Kit + (CD 117)
* Lin -
219
What blood product imparts highest risk of bact. infxs? Why?
Pt's b/c they are stored close to room temp.
220
c-kit/CD 117
c-kit is an important HSC marker. it is the _receptor for **stem cell factor**_ and is also referred to as **CD 117.**
221
What are three thrombin INH's to know?
What is a use for them (think heparin)?
* \*Lepirudin
\*Argatroban
\*Dabigatran
* Can use to **Rx heparin-induced TCpenia (HIT)**
222
What are two LMWH's
enoxaparin, dalteparin
223
**Rivaroxaban**
* Def
* MOA
* Uses
* an anticoagulant drug
* f10a INH
* Venous thrombosis
224
Prasugrel
* Type
* MOA
* Indications (2)
Prasugrel
* Antiplatelet drug inhibiting primary hemostasis
* ADP receptor blocker (like _clopidrogel_)
* Indications: treatment of ACS and established peripheral artery disease, as well as for secondary prevention of myocardial infarction and ischemic stroke
225
**Abciximab**
* Drug type
* MOA
**Abciximab**
* Drug type: Antiplatelet (anticoagulant)
* MOA: Mab drug that directly **binds Gp 2a/3b** (fibrinogen receptor) --\> _poor aggregation of Pt's._
226
**Fondaparinux**
* Drug type
* MOA
**Fondaparinux**
* Drug type: A heparin derivative anticoagulant medication.
* MOA: **Factor Xa inhibition** (Heparin INH's Xa & thrombin)
227
**Aminocaproic Acid**
* Type/uses (3)
* MOA
**Aminocaproic Acid**
* Type/use: Procoagulant drug used often (1) post-surgically in cases of heavy bleeding, (2) in situations w/ excess fibrinolysis and (3) as antidote to tPA overdose.
* MOA: **Inhibits plasmin**.
228
**Romiplostim,** Eltrombopag (in devt?)
* Indication
* MOA
* To treat refractory ITP.
* Tpo analog.
229
**Cryoprecipitate**
* What active substances does it have?
* Can be used for which disorders?
* fibrinogen, f8, and vWF.
* **f8**: _hemophilia A_, esp. if recomb. f8 not available.
* **vWF** to patients with _dysfunctional (type II) or absent (type III) **vWD**_
230
Fresh frozen plasma
* Major components (4)
* Indications (3)
Fresh-Frozen Plasma
* FFP contains **stable coagulation factors** (II, V, VII, IX, X, and XI) and plasma proteins: **fibrinogen, antithrombin**, **proteins C and S**.
Indications (3)
* _correction of coagulopathies_ (can be used in place of specifc factors if they are not available not that f8/wVF are from cryoprecipitate not FFP)
* **rapid reversal of warfarin**
* supplying deficient plasma proteins
* treatment of _thrombotic thrombocytopenic purpura_
231
RhoGAM
* Indication
* MOA
* To prevent _hemolytic dz of the newborn_
* Anti-RH-antibody: binds Anti-Rh Ab's from mom to prevent above condition.
