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Hemat/Onc EXAM 1
Hemat/Onc EXAM 1 - Schober
110
Pharmacology
Graduate
01/03/2012

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Term
hematopoietic stem cell
Definition
precursor that gives rise to other blood cell types

includes myeloid, lymphoid, and pluripotent stem cells
Term
hemoglobin
Definition
protein tetramer that transports oxygen

aldult tetramer comprised of 2 alpha, 2 beta chains and heme moieties
Term
coagulation cascade
Definition
fibrin production through local amplified activation of proteases

composed of intrinsic, extrinsic, and common pathways

results in generation of fibrin clot from fibrinogen
Term
Gla domain
Definition
calcium binding domain found in vitamin K dependent coagulation factors

requires vitamin K for production
Term
anemia
Definition
below normal red blood cell mass

below normal blood hemoglobin concentration

can result from decreased production of or increased loss of hemoglobin
Term
iron deficiency anemia
Definition
anemia caused by insufficient bone marrow iron

hemoglobin and red cell production limited by insufficient iron in the bone marrow

increased loss of iron, increased demand of iron, decreased absorption of iron
Term
sickle cell anemia
Definition
anemia caused by presence of hemoglobin S or other "sickling" hemoglobin

characterized by hemoglobin polymerization and RBC sickle shape

caused by a point mutation (single amino acid change) in hemoglobin
Term
Von Willebrand factor
Definition
large multi-domain, glycosylated protein found in blood vessel wall

binds platelets

important component of platelet adhesion and aggregation
Term
where does hematopoiesis occur?
Definition
[image]

initial fetal production of RBCs occurs in what are called "blood islands" located in the yolk sac

yolk sac production rapidly declines and then hematopoiesis begins to occur in the liver and spleen

liver/spleen production peaks at about 4.5 months

thereafter, marrow of most bones begins to produce blood cells

after birth, proportion of bone marrow production declines in tibias and femurs

later in life production in vertebrae, pelvis, and sternum dominates
Term
properties of hematopoietic stem cells
Definition
stem cells exist in the bone marrow representing a very low percent of the total marrow population (1 stem cell out of every 10,000-100,000 total cells) and even fewer in circulation

SELF RENEWAL
undergo division WITHOUT differentiation

ABILITY TO DIFFERENTIATE
when certain hematopoietic factors are present the stem cell can differentiate into any of the mature types of blood cells (neutrophils, lymphocytes, megakaryocytes, eosinophils, basophils, red cells)

HOMING
stem cells introduced in peripheral circulation can reconstitute the bone marrow after irradiation or drug exposure

MOBILIZATION
in response to certain growth factors, number of stem cells found in circulation increases resulting from a process termed moblization

HOMING and MOBILIZATION are exploited for therapeutic purposes
Term
homing and mobilization of stem cells
Definition
[image]

when there is increased demand for production of blood cells then more stem cells will be found in the peripheral blood (although they still remain a very small fraction of the total cells in the circulation)

administration of colony stimulating factors can increase mobilization of stem cells which can then be harvested from the peripheral blood by apheresis (selective harvesting of a component of the blood)

during mobilization, stem cells are released from stromal cells and matrix proteins in the bone marrow cortex, migrate through the basal lamina, attach to endothelial cells, and enter circulation

the process of homing is the reverse of mobilization

homing is important especially during stem cell transplantation (stem cells infused into circulation find their way to the bone marrow)
Term
blood cell development (hematopoiesis)
Definition
[image]

all blood cells develop from a common precursor called a PLURIPOTENT STEM CELL (top center)

the pluripotent stem cell can differentiate into other stem cells that are common either to all myeloid cells (left: granulocytes, monocytes, megakaryocytes, red blood cells) or all lymphoid cells (right: plasma cells, natural killer cells, T lymphocytes)

certain growth factors or combination of growth factors are required for maturation of stem cells into committed progenitor cells, recognizable precursor cells, and finally mature blood cells found in circulation

these critical hematopoietic growth factors are shown above

some of the factors act on more than one lineage (multi-lineage growth factors) and others act on a single lineage (lineage-specific growth factors)

progenitor cells can self renew

cells above the dashed line are normally found in the bone marrow

later we'll discuss therapeutic use of recombinant growth factors
Term
characteristics of red blood cell development (erythropoiesis)
Definition
like all other blood cells, RBCs begin their development in the bone marrow

the precursor cells have a functioning nucleus and relatively large overall cell size (compared to mature RBC)

DECLINE IN RNA AND PROTEIN PRODUCTION
as the RBC precursor matures in the bone marrow the RNA content, DNA content, and protein production declines

DECLINE IN SIZE

LOSS OF NUCLEUS
finally, the non-functioning nucleus is removed and the mature RBC enters circulation and performs oxygen carrying function

REQUIRES ERYTHROPOIETIN
RBC maturation process requires presence of erythropoietin

[image]

top of figure are images of red cells in different stages of maturation and at bottom of figure are their respective names

A-D describes characteristic changes during maturation of red cells in bone marrow:
A. the diameter of the cell declines
B. the volume also declines
C. the rate of RNA synthesis declines (solid line) and the total RNA content (dashed line) of the cell declines
D. DNA synthesis rate (solid line) and DNA content (dashed line) declines

the nonfunctioning nucleus is removed by a macrophage forming a reticulocyte; reticulocytes are identified by staining of residual RNA content

reticulocyte counts can be elevated in chronic GI bleeding (the body is trying to compensate by making more RBCs and starts making reticulocytes)
Term
erythropoietin
Definition
major growth factor in erythropoiesis

regulated by oxygen tension

produced in kidney

important action in bone marrow

decreased oxygen -> increased HIF-1-alpha -> increased EPO -> increased erythropoiesis

EPO is the major growth factor that controls development and maturation of RBCs

this hormone has little effect on other cell lineages

production of EPO by the peritubular cells in the kidney is regulated by oxygen tension

the oxygen sensor is a heme-containing enzyme which controls the levels of hypoxia inducible factor (HIF-1-alpha)

EPO is produced in the kidney but the main site of action is on red cell precursors in the bone marrow (erythorpoiesis)
Term
normal oxygen tension and low oxygen tension
Definition
DURING NORMAL OXYGEN TENSION HIF-1-ALPHA IS DEGRADED

[image]

1. NORMAL OXYGEN

2. PHD (PROLYL HYDROXYLASE) ACTIVE
during normal (or high) oxygen the PHD enzyme is in active state (the heme iron in PHD is bound to oxygen)
the active PHD hydroxylates

3. HIF-1-ALPHA UBIQUITINATED
HIF-1-alpha which is a substrate for ubiquitination by the VHL (Von Hippel-Lindau) complex

4. HIF-1-ALPHA DEGRADED
the ubiquitinated HIF-1-alpha is degraded in the cell proteosome

HIF-1-alpha is a factor needed for transcription of the erythropoietin gene

DURING LOW OXYGEN TENSION HIF-1-ALPHA IS NOT DEGRADED (EPO GENE IS TRANSCRIBED)

[image]

1. LOW OXYGEN

2. PHD INACTIVE
during low oxygen tension less PHD (prolyl hydroxylase) is active (less enzyme in the oxygen bound state)

3. ACCUMULATION OF HIF-1-ALPHA
HIF-1-alpha is not hydroxylated and therefore, does not enter the ubiquitination proteosome degradation pathway described in the previous slide
the HIF-1-alpha accumulates and enters the nucleus and dimerizes with HIF-1-beta forming an active transcription complex

4. TRANSCRIPTIONAL ACTIVATION OF EPO
the EPO gene (and others) are transcribed

chronic renal disease is associated with insufficient red blood cell production because EPO is not made
Term
EPO signal tranduction in bone marrow cells
Definition
[image]

1. LIGAND BINDING AND DIMERIZATION
the action of EPO is on red blood cell precursors in the bone marrow
upon EPO binding, the receptor (EPOR) dimerizes and JAK2 kinase (triangle) binds to the cytoplasmic domain of the receptor
JAK2, while bound to the cytoplasmic domain of the receptor is phophorylated (activated)

2. ACTIVATION OF STAT PATHWAY
JAK2 kinase activates the STAT pathway through phosphorylation

3. TRANSCRIPTIONAL ACTIVATION
STAT dimerizes (through SH2 domain binding) and enters the nucleus and activates transcription of genes needed for erythropoiesis (red cell maturation)

activating mutations in JAK2 = increased RBC production

JAK inhibitors have promise for treatment of polycythemia vera; an activating mutation in JAK is associated with polycythemia vera and other myeloproliferative disorders

4. CELL MATURATION
Term
conditions and mechanisms that STIMULATE erythropoiesis
Definition
certain conditions can stimulate the process of erythropoiesis such as bleeding, increased red cell destruction (hemolysis), mountain climbing (high altitude), or pulmonary disease

in these conditions the kidneys sense hypoxia and respond by increasing the production of erythropoietin through the mechanism shown previously

mutations in the JAK-STAT pathway that cause high constitutive activity (the pathway is always "on" even without EPO) in the pathway result in increased red cell production by the bone marrow

bleeding: induce tissue hypoxia

hemolysis: induce tissue hypoxia

high altitude: induce tissue hypoxia

pulmonary disease: induce tissue hypoxia

JAK2-activating mutations in myeloproliferative disorders: increase intracellular JAK-STAT signalling
Term
conditions and mechanisms that INHIBIT erhytopoiesis
Definition
other conditions can inhibit the process of erythropoiesis

chronic kidney disease: decreases EPO synthesis in kidney
in chronic renal disease the peritubular cells may not be able to produce enough erythropoietin

iron, folate, or vitamin B12 deficiency: decreased erythroblast differentiation and decreased erythrocyte production
interfere with maturation of red blood cells b/c of deficient substrates for hemoglobin synthesis

chronic inflammatory conditions: decreased erythroblast differentiation and decreased erythrocyte production

sideroblastic anemia: decreased erythroblast differentiation and decreased erythrocyte production

thalassemia: decreased erythroblast differentiation and decreased erythrocyte production

malignant infiltration of bone marrow: decreased erythroblast differentiation and decreased erythrocyte production

aplastic anemia: decreased erhythroblast differentiation and decreased erythrocyte production

drug-induced bone marrow toxicity: decreased erythroblast differentiation and decreased erythrocyte production
Term
relationship between EPO and hemoglobin (response to anemia)
Definition
[image]

triangle indicate patients with normal blood hemoglobin concentration and squares indicate anemia without any complications such as renal disease, chronic inflammatory disease, or chronic infection

the kidney will respond to anemia by increasing production of EPO

the EPO plasma concentration correlates inversely with hemoglobin concentration
Term
development of platelets
Definition
PRECURSORS MATURE INTO MEGAKARYOCYTES
MEGAKARYOCYTES ARE LARGE (8-128N)
REQUIRES THROMBOPOIETIN
CELL FRAGMENTS (PLATELETS) ARE RELEASED

precursors in the myeloid lineage mature into committed megakaryocytes which requires thrombopoietin and other factors

in later stages the cell becomes large and polyploid (having more than 46 (2N) chromosomes)

cytoplasmic fragments (platelets) from megakaryocytes are released which enter peripheral circulation and function during hemostasis
Term
thrombopoietin (TPO) receptor
Definition
[image]

the receptor for TPO is very similar to the EPO receptor

they both signal through the JAK-STAT pathway

certain mutations have been identified that cause constitutive activity of the TPO receptor which can cause elevated platelet count (called thrombocythemia or thrombocytosis)

details of STAT pathway are not shown in the above figure

the signalling is occurring on platelet precursors (megakaryocytes)
Term
development of platelets
Definition
[image]

the hematopoietic stem cells mature into myeloid lineage cells and then committed precursor cells and then finally into megakaryoblasts

the megakaryoblast undergoes endomitosis (duplication of chromosomes and cytoplasmic growth without division into daughter cells) resulting in a large polyploid (8-128N) cell

the polyploid megakaryocyte sheds cytoplasmic fragments (platelets) which then enter the blood stream and function in hemostasis

thrombopoietin is required for the above process
Term
regulation of thrombopoietin activity
Definition
TPO is produced at a CONSTANT rate by the liver and kidneys

the total pool of TPO is made of free fraction and a fraction bound mainly to platelets (less to megakaryocytes)

only free is active and can stimulate maturation of precursor cells in marrow

the activity (free fraction) of TPO is regulated primarily by amount of platelets in circulation

[image]

NORMAL
no decrease or increase in platelets; free TPO constant

THROMBOCYTOPENIA
decrease in platelets causes increase in free TPO
when platelets are decreased in the plasma more free TPO is available to stimulate platelet output by the bone marrow

THROMBOCYTOSIS
increase in platelets causes decrease in free TPO
high platelet count provides more binding sites for TPO and thus causes lower free fraction of TPO
Term
hemoglobin and oxygen transport
Definition
fetal - 2alpha, 2gamma chains
adult - 2alpha, 2beta chains

one heme in each chain

oxygen binds in cooperative manner

affinity of oxygen affected by pH, pCO2, and 2,3-BPG

the hemoglobin protein is comprised of 4 subunits (polypeptide chains)

fetal hemoglobin has 2 alpha and 2 gamma subunits

adult hemoglobin has 2 alpha subunits and 2 beta subunits

each subunit coordinates a single heme molecule

oxygen binds hemoglobin is a cooperative manner such that oxygen affinity is increased with successive occupation of neighboring heme with oxygen

hemoglobin affinity for oxygen is altered by hydrogen ion concentration, partial pressure of CO2, and concentration of 2,3-biphosphoglycerate (BPG) which is an allosteric effector of oxygen binding to hemoglobin
Term
hemoglobin
Definition
[image]

each subunit contains one heme (iron + protoporphyrin IX)

there are other types of heme and remember that heme is found in other enzymes and proteins

oxygen binds iron in ferrous state (Fe+2) which is coordinated by 4 nitrogen atoms in protoporphyrin IX
Term
normal change (switching) in hemoglobin gene expression
Definition
[image]

this graph plots relative expression of different hemoglobin genes during different developmental stages

2 epsilon and 2 zeta are expressed in early embryonic development

during fetal development when hematopoiesis occurs mainly in the liver 2 gamma and 2 alpha subunits make up the hemoglobin tetramer with little beta subunit

in adults about 97% of the hemoglobin is comprised of 2 beta and 2 alpha chains (called hemoglobin A) and very little is fetal hemoglobin

hemoglobin A2 is 2 delta and 2 alpha subunits (also a minor fraction of hemoglobin in adults
Term
oxygen binding to hemoglobin as a function of pO2
Definition
COOPERATIVITY enhances oxygen delivery by hemoglobin

[image]

the graph shows percent of maximal oxygen binding to hemoglobin (Y, fractional binding) as a function of partial pressure of oxygen (pO2) in torr

the hemoglobin oxygen binding curve is very steep b/c of cooperativity between the 4 subunits

the cooperative manner of oxygen binding to hemoglobin has very important implications for oxygen transport

the pO2 in the lungs is 100 torr which results in near 100% occupancy of the binding sites on hemoglobin

the hemoglobin is then transported through circulation to tissues where the pO2 is 20 torr which results in 66% release of the oxygen

comopare the hemoglobin curve to the curve with no cooperativity

the oxygen delivery is much less, only 38% of the binding sites are emptied with the same drop (100 to 20 torr) in partial pressure

one oxygen unbinds and that decreases the affinity for the next site; the affinity of one occupied site is much higher when there is just one unoccupied space as opposed to 3 unoccupied sites
Term
fetal hemoglobin has higher oxygen affinity
Definition
2,3 BPG decreases oxygen affinity for hemoglobin

fetal hemoglobin has lower 2,3 BPG affinity

[image]

the plot compares fetal hemoglobin to adult hemoglobin

the affinity of fetal hemoglobin is higher (a left shift, higher oxygen binding at same partial pressure of O2)

an important consequence of this difference in affinity is transport of oxygen from maternal circulation to fetal circulation

the difference in affinity can be attributed to binding of 2,3-BPG to hemoglobin

BINDING OF 2,3-BPG TO HEMOGLOBIN DECREASES THE AFFINITY OF OXYGEN FOR HEMOGLOBIN

fetal hemoglobin has lower affinity for 2,3-BPG compared to adult hemoglobin

assuming equal concentration of 2,3-BPG in the fetal and adult red blood cell, the adult hemoglobin will have more 2,3-BPG bound resulting in lower oxygen affinity
Term
factors affecting oxygen affinity for hemoglobin
Definition
[image]

A = HIGHER AFFINITY OF OXYGEN FOR HEMOGLOBIN
hemoglobin variants
hemoglobinopathies
increased pH
decreased pCO2
decreased 2,3-BPG
inherited hemoglobin variants and hemoglobinopathies can have higher or lower affinity for oxygen

B = LOWER AFFINITY OF OXYGEN FOR HEMOGLOBIN
hemoglobin variants
hemoglobinopathies
decreased pH
increased pCO2
increased 2,3-BPH
in the tissues where pCO2 may be high, there will be a drop in pH due to resultant production of carbonic acid
2,3-BPG binds to deoxyhemoglobin with higher affinity compared to oxyhemoglobin, so as hemoglobin unloads oxygen in the periphery (converts to deoxyhemoglobin) 2,3-BPG will bind and decrease affinity of oxygen for hemoglobin resulting further unloading of oxygen to tissues

pO2 50 is the partial pressure of oxygen which results in 50% saturation (higher affinity = lower pO2 50)
Term
optimal hematocrit for oxygen transport
Definition
[image]

oxygen transport depends on RBCs, thus a low hematocrit results in insufficient oxygen transport

if hematocrit is too high oxygen transport will also be insufficient

the effect of high hematocrit on oxygen transport is related to blood viscosity

as viscosity increases b/c of high hematocrit, oxygen transport declines

this is b/c of the relationship between cardiac output and blood viscosity
increased viscosity = decreased cardiac output (more resistance to blood flow, heart has to work harder)
Term
iron metabolism
Definition
body distribution
dietary requirements
iron cycle
transferrin
ferritin

transferrin functions to transport iron in plasma

ferritin functions as iron storage protein
Term
iron body distribution
Definition
[image]

body iron can be divided into functional and storage form

most of the body iron is performing some function with oxygen transport being the largest and myoglobin second

storage form (mainly ferritin) is a significant portion of total body iron

storage form is the first to be depleted during sustained negative iron balance

myoglobin serves as oxygen storage in muscle and gives raw meet a red color

hemosiderin is found inside cells
Term
minimum dietary iron requirements
Definition
[image]

above table shows amounts of iron that must be absorbed to meet average daily iron loss

these demands vary in different groups

dietary intake must be correspondingly 10-fold higher to supply enough absorption (not all iron ingested is absorbed and table assumed typical combination of meat and vegetable iron intake)

about 20% of consumed heme iron is absorbed

dietary heme iron comes from myoglobin in red meats

vegetables have non-heme iron which is poorly absorbed
Term
intestinal absorption of iron
Definition
[image]
dietary iron can be absorbed as non-heme or heme forms:

1. apical membrane
there are specific transporters for iron
one for heme iron (heme transporter) and one for free iron (DMT1, divalent metal transporter-1)
iron in ferric state must be reduced to ferrous state by membrane bound cytochrome B before transport by DMT1

2. ferritin bound
inside the epithelial cell Fe can be stored by binding to ferritin (mucosal ferritin)

3. loss in epithelial cells
a major source of iron loss from the body is shedding of GI epithelial cells

4. basolateral membrane
iron is transported across the basolateral membrane by specific transporters (ferrous iron by ferroportin-1) and then oxidized by hephaestin

5. plasma transport
iron (bound to transferrin) can be transported to liver for storage or incorporated into hemoglobin in the bone marrow
Term
iron cycle
Definition
[image]

most of the iron in the body is recycled

the dietary absorption is not enough to meet the demands of red blood cell turnover (25 mg/day is needed for erythropoiesis)

the recycling of iron is indicated by the large, bold arrows in the above figure

begin in the bone marrow; red blood cells are produced in the bone marrow and have a limited life time (average 120 days) in circulation

red blood cells are removed from circulation by the reticuloendothelial system (RES, primarily in the spleen)

iron is recovered by the macrophase (in the RES) and then transported in plasma bound to transferrin (Fe2-Tf, transferrin carries two ferric irons) and transported back to bone marrow for hemoglobin synthesis

excess iron can be stored in liver bound to ferritin

small amounts of iron are absorbed to balance iron loss from the body (shedding of epithelial cells in the GI tract, bleeding

free iron is toxic
Term
hemostasis
Definition
coagulation + platelet aggregation

hemostasis is the process by which bleeding is stopped after disruption of vascular integrity

this process involves both the coagulation cascade and platelet aggregation

vascular injury -> activation of coagulation cascade and activation of platelets -> fibrin formation and platelet aggregation -> hemostasis

after vascular injury, tissue factor and von Willebrand factor are exposed to blood flow which activates the coagulation cascade and platelets, respectively

platelets adhere to von Willebrand factor and fibrin is formed from fibrinogen

these two major processes lead to hemostasis
Term
the coagulation cascade
Definition
[image]

intrinsic, extrinsic, common pathways

TF, VII, VIII, IX

all the factors in the coagulation cascade circulate in the plasma in an inactive, pro-enzyme state

for activation the factors must be cleaved by proteolysis

a single factor can activate many factors in the next step of the cascade resulting in rapid amplification

lower case "a" denotes activated factors

calcium is a cofactor in many of the steps

the cascade is divided into the intrinsic and extrinsic pathways for historical reasons

it is the extrinsic pathway that is more important for coagulation initiation after vessel injury

the 2 pathways converge onto the common pathway

at the end of the cascade fibrinogen is converted to fibrin polymer which is then further stabilized by crosslinking
Term
Gla domains in coagulation factors bind calcium
Definition
Gla domain containing: II, VII, IX, X

vitamin K dependent: II, VII, IX, X

Gla = gamma-carboxyglutamyl

[image]

CALCIUM ION BINDING TO THE GLA DOMAIN ALTERS THE CONFORMATION OF PROTHROMBIN

in the absence of calcium, the negatively charged Gla residues are exposed to the solution, and the hydrophobic residues are buried

calcium ion binding to Gla residues provides sufficient energy to alter the overall conformation of the Gla domain and expose the hydrophobic residues

insertion of the hydrophobic residues into a membrane is illustrated shcematically

the Gla domain is found in vitamin K dependent coagulation factors

the Gla domain is composed of clusters of gamma carboxy glutamyl residues as indicated in the above figure (in this example factor II (prothrombin) is shown)

calcium binding induces a conformational change exposing hydrophobic residues which mediate membrane binding

this is the mechanism for cell (especially platelets) membrane binding of the vitamin K dependent coagulation factors and explains why calcium is essential for the coagulation cascade

lipid membrane binding is important b/c it localizes the effect
the factors are circulating in the blood; when they are activated, it causes the factors to bind to lipid membranes and localizes the activity of the coagulation activity
Term
the importance of vitamin K in Gla production
Definition
[image]

glutamate is converted to Gla (gamma-carboxy-glutamate) by action of carboxylase which requires oxygen and carbon dioxide

another essential cofactor is vitamin K in hydroquinone form

vitamin K hydroquinone is oxidized to vitamin K epoxide

note the site of action of warfarin (it prevents regeneration of vitamin K hydroquinone through inhibition of the epoxide reductase)

warfarin inhibits production of the viatmin K dependent coagulation factors (II, VII, IX, X)
Term
activation of the extrinsic pathway
Definition
[image]

the cell can be smooth muscle cells, fibroblasts, damaged endothelial cells

EXPOSURE OF TISSUE FACTOR ACTIVATES THE EXTRINSIC COAGULATION PATHWAY

tissue factor binds VIIa and the tissue factor-VIIa complex activates IX and X

after vascular injury, activation of the extrinsic coagulation pathway plays an important role

cells under endothelium express tissue factor on their surface (these cells include smooth muscle cells and fibroblasts)

damaged endothelial cells also express tissue factor

a key role of tissue factor is binding of activated factor VII

the tissue factor-VIIa complex activates factors IX and X
Term
platelet aggregation and von Willebrand (vWF) factor
Definition
[image]

1. endothelial injury and removal
2. vWF exposure
3. platelet binding and activation
4. platelet aggregation

also, vWF stabilizes VIII

vWF is synthesized by endothelial cells

vWF is stored in Weibel-Palade bodies in endothelial cells

vWF is released from endothelial cells and becomes bound to the collagen below endothelial cells

1. removal of endothelial cells (vasulcar injury) is the initiating factor not only for activation of the extrinsic coagulation pathway, but also activation of circulating platelets

2. damage and removal of endothelial cells exposes vWF bound to the subendothelial matrix

3. vWF binds the glycoprotein Ib (GpIb) receptor on platelets mediating platelet adhesion and activation

4. activated platelets bind fibrinogen through glycoprotein IIb-IIIa (also known as integrin alpha-IIb beta-3) causing platelet aggregation

another important function of vWF is prolonging the plasma t1/2 of factor VIII

[image]

this figure is more focused on the platelet-ligand interactions

exposure of vWF is an important event for the initiation of platelet adhesion to the injured vessel wall

a functional (qualitative) or quantitative deficit in vWF is called von Willebrand disease

platelet-platelet interaction is mediated by binding of 2 glycoprotein IIb-IIIa receptors to one fibrinogen protein

a functional or quantitative deficit in IIb-IIIa is called Glanzmann's thrombasthenia

deficit in GpIb is called Bernard-Soulier syndrome

release of ADP from damaged tissue and activated platelets induces a conformational change in glycoprotein IIb-IIIa on the platelet surface increasing fibrinogen binding (plavix is an antagonist of ADP formation)
Term
clinical laboratory evaluation of blood
Definition
CBC (complete blood count):
red cell indices - red blood cell volume (MCV), red blood cell hemoglobin concentration (MCHC), red cell distribution width (RDW)

prothrombin time (PT)

activated partiatl thromboplastin time (APTT)

peripheral blood smear
Term
what is normal (reference) range?
Definition
[image]

if we sampled blood from healthy individuals and measured hematocrit we would obtain a normal distribution

+/- 2 standard deviations from the mean is considered the normal range

the cut-offs of 2 SDs on the edge are about 5% of the population
some healthy people will fall outside of the normal range
Term
what is a CBC?
Definition
complete blood count is compromised of many different parameters (both directly measured and calculated)

a CBC is obtained from a flow cytometer in a clinical hematology lab
Term
the principle of flow cytometry
Definition
[image]

flow cytometry is an automated laboratory method used for evaluation of blood cells

a patient sample is aspirated into a machine

the flow cell separates blood into individual cells

single cells pass through laser

the side scatter (granularity) and forward scatter (size) are measured

the flow cytometery can count cells, identify cell types, determine cell size, and provide red cell indices (MCV, MCHC, RDW)

the essential component of a flow cytometer is a flow cell
Term
red blood cell indices: MCV (mean corpuscular volume)
Definition
MCV = hematocrit (%)/red blood cell count

microcytic = low MCV, smaller than 80 fL

normocytic = normal, 80-100 fL

macrocytic = high MCV, larger than 100 fL

MCV is one of the red blood cell indices (calculated parameter) included in a CBC

MCV is the average volume of red blood cells

normal value is about 80-100 femtoliters

the MCV is useful in anemia diagnosis and treatment monitoring

in iron deficiency anemia, the MCV is low = microcytic

in folate and vitamin B12 deficiency the MCV is high = macrocytic anemia
Term
red blood cell indices: MCHC (mean corpuscular hemoglobin concentration)
Definition
MCHC = hemoglobin (g/dL)/hematocrit (%)

hypochromic = low MCHC

normochromic = normal MCHC

hyperchromic = high MCHC

MCHC is another red blood cell indice calculated from other directly measured parameter in the CBC

MCHC is the average hemoglobin concentration in a volume of red blood cells (calculated as shown above)

MCHC is useful in diagnosis of anemia and treatment monitoring
Term
red blood cell indices: RDW (red cell distribution width)
Definition
RDW = standard deviation of size x 100/mean size

above normal = anisocytosis (size variation)

RDW is measure of size variability of red blood cells and is calculated by dividing the standard deviation of red cell size by the average red cell size (MCV) and multiplying by 100

the RDW is like CV (coefficient of variation) used in statistics

some types of anemia have increased RDW (iron deficiency anemia, megaloblastic anemia, microangiopathic anemia)
Term
bleeding time
Definition
not routinely used

bleeding time measures PLATELET FUNCTION (does not depend on coagulation factors)
Term
PT (prothrombin time)
Definition
for the prothrombin time (PT) a sample of patient plasma is mixed with tissue factor and excess calcium to overcome the anti-coagulant in the test tube

the time required to form a fibrin clot is measured

PT will detect deficiencies in the EXTRINSIC AND COMMON PATHWAYS (I, II, V, VII, and X)

warfarin inhibits production of vitamin K dependent coagulation factors (II, VII, IX, and X)
*PT is used to monitor warfarin therapy

PROLONGED PT: heparin, warfarin, liver disease, vitamin K deficiency
Term
activated partial thromboplastic time (APTT)
Definition
a sample of the patient plasma is mixed with tissue factor and lipids

APTT is sensitive to deficiencies in the INTRINSIC AND COMMON PATHWAYS

measures all factor deficiencies EXCEPT VII and XIII

PROLONGED APTT: heparin*, liver disease, vitamin K deficiency, hemophilia A and B, von Willebrand disease

therapeutic warfarin levels do not significantly prolong APTT

APTT is more sensitive to warfarin compared to PT

*APTT is used to monitor heparin therapy

for von Willebrand disease, the PT is normal but the APTT is abnormal because vWF is a binding partner with factor VIII
without vWF factor VIII will not work
factor VIII is in the INTRINSIC PATHWAY
Term
intrinsic and extrinsic pathways with APTT and PT
Definition
[image]

extrinsic = I, II, V, VII, and X

APTT is dependent on all the coagulation factors except VII and XIII (factor XIII functions to stabilize the fibrin clot through cross linking, the end point of the instruments that measure coagulation time is formation of fibrin, not cross linked fibrin)

PT is dependent on factor VII and factors in the common pathway (I, II, V, VII, X)
Term
peripheral blood smears
Definition
blood smears are routinely performed in clinical labs

much information can be gained through blood smear evaluation

a drop of patient blood is placed onto glass slide and "smeared" to produce a thin layer of cells

the smear is stained and cells are evaluated by microscopy
Term
[image]
Definition
normal blood smear

the image shows RBCs, platelets, a lymphocyte, and a mature neutrophil

the shape of a normal RBC is bi-concave disc
Term
[image]
Definition
severe iron deficiency anemia

[image]

severe hypochromia (low MCHC) and microcytosis (low MCV) in iron deficiency anemia.
small lymphocyte in field

normal

[image]

normal erythrocytes
small lymphocyte in center of field

we can see that the RBCs in the iron deficient patient are pale (low MCHC, hypochromic) and small (low MCV, microcytic)
Term
[image]
Definition
iron deficiency anemia + transfusion

[image]

the cells are pale with an enlarged central pallor, in sharp contrast to the transfused normochromic cells
Term
[image]
Definition
sickle cell anemia

low and high magnification of a peripheral blood smear from a patient with sickle cell disease

large variation in cell shape is observed = poikilocytosis
Term
[image]
Definition
megaloblastic anemia

[image]

macrocytosis and a circulating megaloblast with abnormal, binucleated nucleus

megaloblastic anemia is characterized by large RBCs (increased MCV), presence of nucleated RBCs, and binucleated RBCs

the nuclei of neutrophils are hypersegmented (not shown)

mainly caused by a deficiency in folate and/or vitamin B12 (DNA synthesis is impaired)
Term
iron deficiency anemia: general causes
Definition
dietary deficiency
impaired absorption
increased requirement
increased loss

healthy adults lose iron from shedding of GI and skin epithelial cells, and menstruation

1-2 mg must be absorbed from diet to maintain iron stores which requires 10-20 mg consumption (~10% dietary intake is absorbed)

any condition that causes a negative iron balance can cause iron deficiency anemia

iron in heme form (from meats) is more readily absorbed compared to non-heme iron

strict vegetarian diet increases risk of iron deficiency

intestinal disease and inflammation can interfere with absorption

young children and pregnant women have higher iron demand

increased loss from chronic bleeding is a common cause in the US
Term
changes in iron storage and distribution over time during negative iron balance
Definition
[image]

most of the total body iron can be divided into 3 compartments: storage iron, transport iron, and erythron (RBCs and precursors) iron

the time course begins with normal body iron

changes in iron storage and distribution are shown over persistent negative iron balance

the storage pool is first to be depleted followed by transport pool, then erythron pool

notice that plasma ferritin is first to decline followed by total plasma iron and transferrin saturation

microcytic and hypochromic red cells appear last
Term
MCV values in iron deficiency anemia
Definition
[image]

correlation between venous blood hemoglobin concentrations and mean corpuscular volume (MCV)

nearly 70% of cases exhibited distinct microcytosis

however, at least 30% of cases of iron deficiency anemia will be misdiabnosed if physicians rely on the erythrocyte MCV

mean corpuscular volume (MCV) will be lower in most patients with iron deficiency anemia, but MCV is not 100% sensitive as illustrated above

all of the points plotted above are hemoglobin values in patients diagnosed with iron deficiency anemia

note all hemoglobin values are <12 g/dl (anemia), but some (30%) of the patients have normal MCV
Term
sickle cell anemia
Definition
sickle cell anemia is commonly characterized as anemia associated with presence of hemoglobin S which is mutation (glutamic acid replaced by valine) of the 6th amino acid position in the beta chain of hemoglobin (other hemoglobin mutations can cause cells to sickle)

the highest incidence of this disease in US is in African-American population

in heterozygotes about 40% of the total body hemoglobin is S

in homozygotes almost all hemoglobin is S

interestingly, heterozygotes are protected against malaria (mechanism uncertain, proposed that infected RBCs may be preferentially removed by spleen)

ONSET 5-6 MONTHS
onset appears with gene expression of beta chain
up until this point fetal hemoglobin is still being produced

DEOXYHEMOGLOBIN S is polymerizable
in the oxygen bound state, it doesn't polymerize
Term
factors that effect Hgb S polymerization
Definition
1. HEMOGLOBIN S CONCENTRATION (RELATIVE AND ABSOLUTE)

the most important factor determining cell sickling is concentration of Hbg S in the cell

heterozygotes have about 40% Hbg S and the rest is primarily Hgb A (2 alpha and 2 normal beta)

heterozygotes (called sickle trait) only sickle under conditions of severe hypoxia

absolute Hgb concentration is an important factors

higher MCHC increases probability of Hgb S polymerization

for example, compare 2 cells with the same percent Hgb S in a red cell, but different MCHC; the cell with higher MCHC will be more prone to Hgb S polymerization

2. PH

pH is a factor b/c low pH decreases the affinity of oxygen for hemoglobin, thus producing more deoxyhemoglobin which is the form of Hgb S that polymerizes

inflammed tissue has lower pH

3. DEOXYGENATION (TRANSIT) TIME
spleen, bone marrow, inflammation

transit time of the red cell through microvascular beds is also a factor

in the microvascular system hemoglobin is in the deoxygenated state

in the spleen and bone marrow, red cells require more time to travel through the microvascular beds

sickle cells get trapped in and occlude micro vessels

also, in areas of inflammation red cells adhere to endothelial cells of the microvascular system thus Hgb remains in deoxygenated state for longer periods
Term
polymerization of Hgb S
Definition
[image]

after conditions for polymerization of Hgb S become favorable there is relatively long period (lag phase) before rapid growth of polymers occur

lag phase is characterized by formation of a critical mass of aggregated Hbg S tetramers (about 30)

the time in lag phase is highly dependent on Hgb S concentration

the red cell must return to the lungs for oxygen before critical polymer is reached (this is why transit time is very important and tissues with longer transit time tend to have micro-occlusions)

after lag phase polymerization rate is rapid
Term
pathophysiology of sickle cell disease: microvascular occlusion
Definition
[image]

microvascular occulsion and red cell hemolysis underlie sickel cell "crisis"

the above figure illustrates the point mutation in Hgb S (glutamic acid is replaed by valine in the beta chain)

deoxygenated Hgb can become irreversibly sickled caused by permanent damage to the red cell membrane)

the spleen removes irreversibly sickled cells

the boxes highlight areas of occlusion in bone, spleen, and inflammation (i.e. in lung infection)

occlusion and hemolysis worsen the pathophysiology in a positive feedback manner (occlusion worsens tissue hypoxia thus promoting production of deoxyhemoglobin S and increasing transit time)
Term
megaloblastic anemia
Definition
anemia with HIGH MCV

usually normal MCHC, but elevated MCH

insufficient DNA synthesis

ASYNCHRONOUS red cell maturation

commonly cuased by B12 OR FOLATE DEFICIENCY

PERNICIOUS ANEMIA is a type of megaloblastic anemia = lack of INTRINSIC FACTOR

megaloblastic anemia is characterized by presence of large red blood cells in bone marrow and peripheral blood

although the total average amount of hemoglobin/cell is increased (increased MCH) because the cells are larger (increased MCV), the average concentration of hemoglobin is usually normal (normal MCHC)

the basic cause of megaloblastic anemia is insufficient DNA synthesis in the erythroid lineage

DNA synthesis does not keep up with the rate of cytoplasmic growth (asynchronous red cell maturation in bone marrow) leading to abnormally large red cells

vitamin B12 and folate deficiency are common causes of megaloblastic anemia

pernicious anemia is a specific type of megaloblastic anemia where vitamin B12 deficiency is caused by lack of intrinsic factor production from parietal cells
autoimmune process where parietal cells are destroyed and there is decreased production of intrinsic factor
intrinsic factor is needed for the metabolism of B12
Term
[image]
Definition
megaloblastic anemia

increased MCV

[image]

a peripheral blood smear shows a HYPERSEGMENTED NEUTORPHIL with a 6 lobed nucleus

bi nucleated or nucleated RBCs are not shown in the image
Term
interaction between B12 and folate metabolism
Definition
[image]

relationship of N5-methyl FH4, methionine synthase, and thymidylate synthetase

in cobalamin (Cbl, vitamin B12) deficiency, folate is sequestered as N5-methyl FH4. this ultimately deprives thymidylate synthetase of its folate coenzyme (N5,10-methylene FH4), thereby impairing DNA synthesis

1. the proximal cause of megaloblastic anemia is decreased cofactor (methylene-tetrahydrofolate (-FH4)) production for thymidylate synthetase which in turn interferes with production of dTMP and thus, DNA causing megaloblastic anemia

2. cobalamin (Cbl, vitamin B12) deficiency can also cause megaloblastic anemia because B12 is needed for production of FH4 and thus, mehtylene-FH4

3. megaloblastic anemia cuased by B12 deficiency can be treated with folate (folate is converted to FH4 in liver); however the neurological symptoms of B12 deficiency are not relieved with folate administration
Term
von Willebrand disease
Definition
deficit in vWF (1% incidence) - quantitative or qualitiative

> 20 genetic variants causing disease

subendothelial matrix-vWF-platelet

platelet-vWF-platelet

von Willebrand disease is characterized by a deficit in vWF

the incidence is about 1% in the general population

the deficit may be quantitative in nature which means the patient has a reduced quantity of plasma vWF

a qualitative deficit means the level of plasma vWF in the patient is within normal range but the vWF does not function properly

more than 20 different variants (genetic mutations) in vWF have been characterized

vWF is released by the endothelial cells and binds subendothelial matrix such as collagen

when vascular integrity is compromised vWF is exposed to blood flow

platelets adhere to exposed vWF through the GpIb receptor

vWF also binds GpIIb-IIIa (integrin alpha IIb-beta3) which promotes platelet aggregation
Term
types of von willebrand disease
Definition
type 1: variable quantitative deficit; usually mild
characterized by variable quantitative deficiency of vWF and accounts for 70% of vWD cases
most cases are mild symptoms
it is inherited through autosomal dominant pattern

type 2: qualitative defect
caused by a functional defect in the vWF protein
plasma concentration is usually normal

type 3: severe quantitative deficit
very low or sometimes undetectable plasma levels of vWF
autosomal recessive inheritance
Term
lab findings for von Willebrand disease
Definition
normal platelet count
platelet count is normal or slightly low

prolonged APTT
the APTT is high because of low factor VIII
recall that factor VIII is stabilized in the plasma through binding to vWF

prolonged bleeding time
bleeding time is dependent on platelet function
although platelet count is normal bleeding time is prolonged in vWD because platelet function depends on vWF

low plasma VIII
Term
clinical presentation of von Willebrand disease
Definition
spontaneous mucosal bleeding

excessive and prlonged bleeding from wounds

bruising

symptoms can be attributed to poor platelet function and are similar to symptoms observed with thrombocytopenia

epistaxis

gingival bleeding
Term
hemophilia A
Definition
[image]

factor VIII deficiency (qualitative or quantitative)

X-linked recessive inheritance

the level of activity of VIII correlates with severity of disease (less than 1% of normal activity correlates with severe disease, 2-5% of normal activity moderate disease, and 6-50% of normal activity mild)

VIIIa is a cofactor for IXa

the VIIIa-IXa complex is required for activation of X

calcium binding induces proper conformation for factor activity

lipid surface provided by platelets catalyzes the reactions
Term
hemophilia A inheritance
Definition
Xh = presence of hemophilia gene

[image]

the gene for factor VIII is located on the X chromosome

a number of mutations in the VIII gene can cause hemophilia A

hemophilia A is a recessive trait

in the top example a normal (no hemophilia gene, XX) female produces offspring with hemophilic male (one hemophilia gene, XhY)

all of the offspring will be normal b/c the disease is recessive

in the bottom example a carrier female produces offspring with a normal male

50% female offspring are carrier and 50% male are hemophilic
Term
hemophilia A - lab findings
Definition
NORMAL BLEEDING TIME

platelet count normal

normal PT

prolonged APTT

patients with hemophilia A usually have normal bleeding time, platelet count, and PT

the APTT (measures the intrinsic pathway) is prolonged

direct measurements of factor VIII in patient plasma must be part of the diagnostic workup
Term
clinical presentation of hemophilia A
Definition
patients have excessive bleeding after trquma or surgery, and have spontaneous HEMARTHROSES (internal bleeding around joints)

normal lab bleeding time and excessive bleeding after trauma or surgery appears to be an inconsistency
Term
hemophilia B (Christmas disease)
Definition
factor IX deficiency

lab findings and clinical presentation same as hemophilia A
Term
idiopathic (immune) thrombocytopenia purpura (ITP)
Definition
most cases autoimmune

low platelet count

bruising, bleeding

idiopathic means of unknown cause

"immune" is replacing "idiopathic" in the acronym ITP b/c most cases are now known to be caused by an autoimmune mechanism

auto-antibodies (mainly IgG) directed against platelet surface glycoproteins (Ib and IIb-IIIa) may be present causing increased platelet removal from circulation

clinical manifestations depend on platelet count; include easy bruising and spontaneous mucosal bleeding

purpura: small breaks in vessels underneath the skin; little bumps
Term
hydroxyurea for sickle cell disease
Definition
increases expression of hemoglobin gamma chain

however, weak correlation between expression and clinical benefit

other mechanisms proposed (NO production)

hydroxyurea increases expression of fetal hemoglobin (2 alpha and 2 gamma chains) replacing expression of adult form (2 alpha and 2 beta chains)

originally the re-expression of fetal hemoglobin was thought to be the primary anti-sickling mechanism of hydroxyurea

however, studies found poor temporal correlation between expression of fetal hemoglobin and beneficial effect of hydroxyurea

other mechanisms have been proposed including changes in blood rheology, decreased adhesion of red cells to endothelial cells and increased production of nitric oxide
Term
hydroxyurea-induced expression of gamma chain requires guanylyl cyclase (GC)
Definition
[image]

inhibition of gamma globin induction by sGC inhibitors

before incubation with hydroxyurea, erythroid proenitor cells were pretreated with the sCG inhibitors for 30 minutes, 15 minutes, and 12 hours

hydroxyurea was added on day 4, and gamma globin mRNA levels were measured after 48 hours

this experiment shows the effect of hydroxyurea on gamma chain gene expression is DEPENTENT ON SGC (SOLUBLE GUANYLYL CYCLASE)

the second bar shows a 2 fold increase in expression of gamma chain caused by hydroxyurea

bars 3-5 show the effect of 3 different inhibitors of GC (the level is reduced to baseline)

the conclusion from this data is hydroxyurea increases gamma chain through the guanylyl cyclase signaling pathway.
Term
proposed mechanism of hydroxyurea
Definition
[image]

how hydroxyurea induces expression of fetal hemoglobin

metabolism of hydroxyurea produces NO which activates sGC or alternatively hydroxyurea directly activates sGC

active sGC converts GTP to cyclic GMP (cGMP)

cGMP activates transcription of the gamma chain gene

this mechanism requires a functional nucleus, thus it can only work on a red cell precursor, not a fully mature RBC

NO production is beneficial since it causes vasodilation and decreased adhesion of RBCs to endothelial cells
Term
keratinocyte growth factor
Definition
palifermin
Term
disease treated by palifermin
Definition
palifermin is a keratinocyte growth factor used to treat chemotherapy induced oral mucositis

palifermin is indicated for leukemia and lymphoma patients undergoing chemotherapy where rapidly dividing cells (epithelial) are adversely effected
Term
MOA of palifermin
Definition
recombinant protein

promotes epithelial cell growth and survival

palifermin is a recombinant growth factor produced in E. coli

the polypeptide is a recombinant form of keratinocyte growth factor

it stimulates division and survival of epithelial cells

palifermin is used for treatment of oral mucositis in patients receiving chemotherapy
Term
ADRs of palifermin
Definition
concern of STIMULATING TUMOR GROWTH

the safety of drug in patients with solid tumors has not been assessed

there is concern that palifermin could promote growth of solid tumors, in particular, carinomas
Term
recombinant erythropoietins
Definition
epoetin alpha

darbepoetin alpha

methoxy-PEG-epoetin (pegylated)
Term
MOA of recombinant erythropoietins (epoetin alpha, darbepoetin alpha, and methoxy-PEG-epoetin)
Definition
epoetin alpha - same amino acid sequence as endogenous EPO

darbepoetin alpha - additional glycosylation sites; longer plasma t1/2

methoxy-PEG-epoetin - pegylated

first increases RETICULOCYTE COUNT then hematocrit/hemoglobin

the DNA of erythropoietin was cloned and purified (the same must occur for production of any recombinant protein)

Chinese hamster ovary cells are genetically programmed to produce the human EPO

epoetin alpha has the same amino acid sequence as endogenous EPO

in darbepoetin, four of the amino acids have been changed to asparagine (Asn) which is a site of glycosylation

the rationale for adding more glycosylation sites was to increase the plasma t1/2

addition of polyethylene glycol also increases plasma t1/2
Term
ADRs of recombinant erythropoietins (epoetin alpha, darbepoetin alpha, methoxy-PEG-epoetin)
Definition
antibody production

induces IRON DEFICIENCY (RELATIVE AND ABSOLUTE)

thrombotic events, hypertension

a sudden burst in erythropoiesis after administration can cause relative or absolute iron deficiency

relative meaning insufficient mobilization of iron from storage (ferritin)

absolute meaning depletion of iron storage

the mechanism underlying thrombotic events and hypertension are uncertain (recommended that dosage adjusted to gradual rise in hematocrit)
Term
effects of pegylation
Definition
[image]

increases the size of the protein; this could decrease the filtration in the kidney = increased t1/2

PEG blocks antibody binding - helps immune system from getting to the drug

blocks immunogenic sites

PEG can block the activity of proteolytic enzymes
Term
trombopoietin (TPO) and other factors involved in platelet production
Definition
[image]

the above figure shows maturation of megakaryoblasts and production of platelets

TPO is not the only growth factor involved in megakaryocytopoiesis

others including IL-11, IL-3, stem cell factor (SCF) and granulocyte-megakaryocyte colony stimulating factor (GM-CSF)

IL-11 is more important in the earlier stages whereas TPO acts in the later stages of platelet production
Term
recombinant thrombopoietin examples
Definition
PEG-rhMGDF - pegylated recombinant human megakaryocyte growth and differentiation factor

romiplostim
Term
ADRs PEG-rhMGDF
Definition
the pegylated recombinant human megakaryocyte growth and differentiation factor trail was stopped b/c of cases of thrombocytopenia which was attributed to patient production of antibodies against endogenous TPO
Term
MOA of romiplostim
Definition
recombinant thrombopoietin

[image]

FUSION of Fc and receptor binding domains

romiplostim was developed by Amgen and is currently approved for ITP (an autoimmune disease resulting in low platelet count)

Fc domain prolongs plasma t1/2, and the peptide domain binds and activates the TPO receptor
Term
what disease is romiplostim approved for?
Definition
romiplostim is approved for idiopathic (immune) thrombocytopenia purpura (ITP)
Term
small molecule TPO receptor agonist
Definition
eltromobopag
Term
ADRs of eltromobopag
Definition
risk of hepatic toxicity

restricted use through the Promacta Cares program for ITP treatment
Term
recombinant human interleukin-11 (IL-11)
Definition
oprelvekin
Term
MOA of oprelvekin
Definition
recombinant human interleukin-11 (IL-11)

increases platelet production during chemotherapy

oprelvekin is human recombinant IL-11 produced in E. coli

IL-11 enhances production of megakaryocytes and platelets and is used for prevention of thrombocytopenia during chemotherapy
Term
ADRs of oprelvekin
Definition
hypersensitivity

FLUID RETENTION - peripheral and pulmonary edema, effusion exacerbation

cardiac arrhythmias

dilution anemia

a major problem with IL-11 is fluid retention which can be manifested as edema, plasma expansion, and exacerbation of effusions

cardiac arrhythmias can be caused by plasma volume expansion (increased plasma volume causes cardiac muscle stretching (increased preload) which, in turn, causes arrhythmias)

dilutional anemia result of plasma volume increase
Term
colony stimulating factors
Definition
GM-SCF (sargramostim) - granulocyte-macrophage colony stimulation factor

G-CSF (filgrastim and PEG-filgrastim) - granulocyte colony stimulating factor
Term
uses of sargramostim
Definition
neutropenia recovery after chemotherapy

after stem cell transplantation

mobilize precursor cells from bone marrow

accelerates recovery from neutropenia after chemotherapy regimen, facilitates bone marrow transplantation and mobilizes precursor cells for harvest by apheresis

the effect of sargramostim is greater on neutrophil production probably b/c other factors are needed for complete maturation and production of macrophages

the antimicrobial activity of neutrophils is also increased (beneficial for preventing infection)
Term
MOA of sargramostim
Definition
granulocyte-macrophage colony stimulating factor

produced in yeast

very similar to endogenous factor except one amino acid substitution and extent of glycosylation
Term
ADRs of sargramostim
Definition
bone pain

high doses cause neutrophilia

lung infiltration

edema
Term
uses of filgrastim and PEG-filgrastim
Definition
uses SIMILAR to sargramostim (neutropenia recovery, transplantation, mobilization)
Term
MOA of filgrastim and PEG-filgrastim
Definition
granulocyte colony stimulating factor

in contrast to sargramostim, filgrastim is produced in bacteria (E. coli)

the recombinant protein is not glycosylated

rationale for pegylated form is to increase plasma t1/2 and increase dosage interval
Term
ADRs of filgrastim and PEG-filgrastim
Definition
high neutorphil count (neutophilia)

bone pain
Term
coagulation factors and vWF
Definition
VIIa:
used for bleeding episodes (hemophilia A and B, VII deficiency)
factor VIIa binds to tissue factor and the VIIa-TF complex can convert X to Xa and IX to IXa thus activating the common coagulation pathway and generating fibrin and promoting hemostasis

VIII:
RECOMBINANT AND ANTIBODY PURIFIED FORMS
used for hemophilia A
there are many different preparations of factor VIII (recombinant and purified from plasma using monoclonal antibodies specific for factor VIII)

IX:
partially purified
used for hemophilia B (Christmas disease)
factor IX is available in partially purified preparations (IX concentrate)

vWF-VIII combination:
used for hemophilia A and vWD
vWF is currently available in combination with factor VIII
remember that vWF also stabilizes circulation factor VIII
vWD patients can also have low VIII

before the mid-1980s many hemophilia patients were infected with HIV b/c of the use of plasma products and factor concentrates derived from plasma

challenge is to retain factor activity while inactivating viruses through detergent and chemical treatment
Term
use of desmopressin
Definition
for mild to moderate hemophilia A and vWD
Term
MOA of desmopressin
Definition
vasopressin (ADH) analog

activates TYPE 2 vasopressin receptor

VIII and vWF release

desmopressin is a close analog of naturally occurring nonapeptide vasopressin (anti-diuretic hormone, ADH)

desmopressin is more specific for type 2 vasopressin receptor (compared to type 1)

type 1 receptor mediates vasoconstriction

stimulation of type 2 receptor causes release of vWF and VIII from storage sites in endothelial cells

desmopressin increases plasma concentration of vWF and VIII

[image]

modifications of the vasopressin peptide have resulted in less activity at type 1 receptor and greater activity at type 2 receptor:
1) deamination increases anti-diuretic activity
2) replacement with D-arginine decreases vasopressor activity

desmopressin has much higher anti-diuretic:vasopressor ratio compared to vasopressin (ADH)
Term
ADRs of desmopressin
Definition
water retention

hyponatremia

unstable blood pressure

desmopressin stimulation of the type 2 receptor in renal tubule cells mobilizes water channels and increases water re-absorption

hyponatremia is result of dilution effect and hypertension likely results from vasoconstriction action
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