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Platelet Structure and Function
October 17 Lecture
57
Immunology
Graduate
10/20/2011

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Term
Hemostasis involves 3 processes
Definition
1) of platelet adhesion (mediated by von Willebrand factor, collagen and specific platelet receptors)
2) platelet aggregation (mediated by fibrinogen or von Willebrand factor and platelet receptor glycoprotein IIb,IIIa (alpha2b,beta3),
3)and fibrin formation mediated by the coagulation cascade
Term
what is platelet adhesion mediated by
Definition
von Willebrand factor, collagen and specific platelet receptors
Term
what is platelet aggregation mediated by
Definition
fibrinogen or von Willebrand factor and platelet receptor glycoprotein IIb,IIIa (alpha2b,beta3),
Term
what is fibrin formation mediated by
Definition
coagulation cascade. This results in the formation of a “plug” comprised of platelets, insoluble fibrin and cellular elements of the blood (WBC and RBC) “trapped” in the clot
Term
Active processes mediated by _______ cause degradation of the blood clot.
Definition
proteolytic enzymes
Term
There is ordinarily a delicate balance between ______ and ________ factors in the blood such that vessel integrity and flow is maintained.
Definition
procoagulant and anticoagulant
Term
The endothelium plays an active role by
Definition
1) providing a barrier between the flowing blood and the subendothelium
2) synthesizing a number of factors that that can inhibit or activate platelets, inhibit or activate blood coagulation, inhibit or activate fibrinolysis; or
3) effect vascular tone.
Term
platelets
Definition
small (2um) anucleate cytoplasmic fragments derived from bone marrow megakaryocytes that mediate the process known as primary hemostasis; these circulate in an 'inactive'state and their interactions with the endothelium and blood proteins does not cause disruption of normal blood flow.
Term
The platelet surface expresses many receptors, some of which are linked to ________ and others are surface receptors acting as ____________
Definition
g proteins

adhesion molecules
Term
Protease activated receptors (PARs)
Definition
a class of receptors that exist of the surface of platelets that are g protein coupled.
Term
Granules in platelets contains substances such as these that upon release can aid in platelet activation
Definition
ADP, vWF, fibrinogen
Term
Phospholipid metabolism is critical to normal platelet function fore what two reasons
Definition
1) thromboxane synthesis and release
2) phosphatidyl serine exposure
Term
upon injury to endothelium, platelets stick to exposed collagen by 2 different mechanisms:
Definition
1) via collagen receptors on the platelet surface (there are several)
by the action of von Willebrand factor (vWF) binding to collagen and the platelet surface glycoprotein Ib,IX,V complex.
Term
VWF (von Willebrand factor)
Definition
large, circulating, adhesive glycoprotein critical for platelet adhesion (defined as platelets sticking to collagen and other non platelet surfaces) especially in conditions of high shear stress
Term
Activating a platelet leads to:
Definition
mediated receptor engagement, second messenger generation followed by platelet shape change, thromboxane synthesis from membrane lipids, granule secretion, surface phospholipid exposure (to support coagulation reactions) and exposure of the integrin, glycoprotein IIb,IIIa (alpha2b,beta3). Exposure of this integrin in a form that allows interaction with plasma proteins (fibrinogen and vWF) causes platelet aggregation to occur. This is the process of platelets sticking to one another.
Term
platelet cytoskeleton
Definition
places an important function in platelet activation allowing rapid platelet shape change
Term
glycoprotein alpha2bbeta3
Definition
an integrin, that when exposed in a certain form, allows interaction with plasma proteins (fibrinogen and vWF) causing platelet aggregation to occur.
Term
once in the cell, iron can do two things
Definition
1) be stored in ferritin (globular protein can hold thousands of iron molecules)
2) can transport iron out of cell and into blood
Term
in an enterocyte, what is the port that inron exits the cell through
Definition
ferroportin
Term
in the enterocyte, this is the protein that oxidizes iron once it exits the cell
Definition
hephaestin
Term
Transferrin (TF)
Definition
in the blood, iron is bound to this when it wants to enter the cell
Term
the three types of transferrin
Definition
1) mono-
2) di-
3) apo-
Term
out of the 3 transferrins, whuch one does the transferrin receptor have the highest affinity for?
Definition
di-transferrin
Term
ceruloplasmin
Definition
this oxidizes iron when it is leaving the macrophage cells; contains a copper molecule
Term
What are the three things that regulate iron transfer
Definition
1) if RBC is deficient in iron it then makes more TFr's
2) cells at bottom of crypt
3) protein hepcidin
Term
Iron Response Elements (IRE)
Definition
short stem loop bound by iron response protein (IRP) found in UTRs (untranslated regions of mRNA) whose products are involved in iron metabolism
Term
Explain how IRE for ferritin works
Definition
mRNA of ferritin (iron storage) has IRE in 5' UTR ; when iron is low, IRP binds to IRE in ferritin mRNA leading to reduced translation rate
Term
Explain how IRE for transferrin receptor works
Definition
mRNA of transferrin receptor (iron acquisition) has IRE bind to 3' UTR and this leads to increased mRNA stability
Term
Iron Response Proteins exist in 2 forms
Definition
1) if lots of iron is in the cell, it occupies that space
2) if there is not a lot of iron in the cell, then space is unoccupied.

if in 5', it prevents translation
if in 3', it stabilizes message from being degraded
Term
crypt theory
Definition
this explains that intestinal cells have vili and crypts; intestine cells are born in crypt and move up to vilus tip and then die/slough off
the base of the crypt is bathed in blood (gives nutrients to cells)
iron gets into these cells (either will make DMT-1 or not)
if there is no iron, mRNA for DMT-1 stabilized and makes lots of DMT-1 so iron can be absorbed
Term
all the things that regulate the amount of hepcidin produced in the liver
Definition
1) 2 TFr's on cell membrane
2) HFE protein
3) BMP
4) HJ (hemojuvelin)
Term
if iron is low, how will this effect:
1) hepcidin
2) DMT-1
3) ferroportin
4) ferritin
Definition
1) decrease
2) increase
3) won't be degraded
4) you will make less
Term
the ______ senses the amount of iron in blood, and this controls the amount of hepcidin made in the cell
Definition
Liver
Term
does hepcidin increase or decrease during inflammation?
Definition
increases

(inflammatory cytokines (IL-6) creases this increase)
Term
two ways to decrease iron levels in body
Definition
1) Proton pump inhibitor- (decreases person's ability to absorb iron (bc your body's acid is decreased)
2) increased hepcidin production from inflammation (iron trapped in macrophages and iron doesnt get absorbed; iron can't go to RBC's and creates anemia
Term
after an injury, what is the general process that occurs?
Definition
1) platelet receptor, glycoprotein 1b95 sticks to collagen by circular protein vWF secreted in blood and made by megakaryocytes, then firm adhesion occurs (when PLT binds to receptors and then PLTs aggregate (express integrin on cell surface) and circulate plasma protein Fibrinogen binding dependent on alpha2bbeta3
Term
explain glycoprotein 1b95
Definition
Platelet glycoprotein IX (GP9) is a small membrane glycoprotein found on the surface of human platelets. It forms a 1-to-1 noncovalent complex with glycoprotein Ib (GP Ib), a platelet surface membrane glycoprotein complex that functions as a receptor for von Willebrand factor (VWF). The main portion of the receptor is a heterodimer composed of 2 polypeptide chains, an alpha chain and a beta chain, that are linked by disulfide bonds. The complete receptor complex includes noncovalent association of the alpha and beta subunits with GP9 and platelet glycoprotein V .
Term
firm adhesion
Definition
when platelet binds to receptors (VWF must bind collagen first before PLT's)
Term
when PLT's aggregate:
Definition
they express integrins on cell surface
(in resting state, they can't bind to ligand)
-circulating plasma protein involved is fibrinogen (binding is dependent on alpha2bbeta3
Term
General short hand summary of PLT activation
Definition
1) shape change
2) ADP
3) TXA2
4) PL(theta) exposure
5) alpha2bbeta3
Term
phospholipase A2
Definition
this is in the dense tubular system
-if intercellular calcium increases, then this is released and coverted to thromboxane A2
cyclo-oxygenase1 targets
Term
receptors on surface of platelet that bind collagen directly
Definition
alpha2beta1
glycoprotein 6
Term
True or false: platelet activation involves tyrosine inositol phosphate reaction
Definition
true
Term
Platelet maturation process/steps:
Definition
1) early stem cell
2) committed stem cell
3) early megakaryocyte
4) late megakaryocyte
5) platelets
Term
what proteins are involved in platelet maturation?
Definition
-IL3
-thrombopoietin
-KL
-IL-6
Term
overview of platelet activation
Definition
1) resting
2) adhesion
3) activation ( shape change, granule release, TXA2 synthesis, PL exposure, IIBIIIA exposure)
4) aggregation
Term
Glycoprotein Ib,IX,V complex
Definition
binds to vWF
constitutively present on cell surface
Term
glycoprotein IIb,IIIa (alpha2bbeta3)
Definition
a platelet receptor
-present on surface but inaccessible to its ligand
-needs to be converted to state where it can bind to its ligand
-primary ligands are fibrinogen and vWF
Term
types of platelet receptors:
Definition
-Glycoprotein Ib,IX,V complex
-Glycoprotein IIb,IIIa (alpha2bbeta3)
-G protein coupled receptors such as
----Thrombin-protease activated receptor
----Thromboxane A2
----ADP
----Prostacyclin
-Collagen receptors
----GPVI, alpha2beta1
Term
what are the 4 types of g-protein coupled platelet receptors?
Definition
-Thrombin-protease activated receptor
-Thromboxane A2
-ADP (P2Y1 stimulatory g protein and P2Y12 inhibitory g protein that inhibits adenylate cyclase)
-Prostacyclin (stimulates adenylate cyclase)
Term
Protease activated receptors (PAR)
Definition
These receptors are members of the seven transmembrane G-protein-coupled receptor superfamily; these are activated by the action of serine proteases such as thrombin (acts on PARs 1, 3 and 4) and trypsin (PAR 2).[2] These enzymes cleave the N-terminus of the receptor, which in turn acts as a tethered ligand. In the cleaved state, part of the receptor itself acts as the agonist, causing a physiological response. once cleaved, it becomes active.



ex. thrombin
Term
reasons for platelet assymmetry
Definition
-negatively charged Phospholipids are sequestered inside the membrane (PS, PE)
- numerous enzymes responsible for this asymmetry (floppases, flippases, scramblases)
Term
PLT surface receptors include:

and most of these use GTP bind proteins and phospholipase C (converting PIP into IP3 and DAG)
Definition
ADP receptors
Thromboxane receptors
alpha2beta1 receptors
GP6 receptors
thrombin receptors
Term
what is the role of phospholipase C?
Definition
it converts PIP into:
1) IP3--> increasing calcium concentrations
2) DAG --> creating more protein kinase C
Term
when PLT's adhere to collagen receptors, what happens to intracellular
1)calcium levels
2) thromboxane A2 levels
3) phosphliase C levels
Definition
1) increases
2) increases
3) increases

they can act in autocrine or paracrine way
Term
platelet aggregation
Definition
ADP synthesis recruits other PLT's to neighborhood,
enzymes that sequest negative charge are then althered so neg. charge in membrane is exposed. coagulation on surface of PLT as neg. phospholipid gets exposed.
Term
what two things inhibit platelet aggregation?
Definition
1) if ADP is inhibited
2) if there is aspirin present

keep in mind, inhibiting parts of the pathway is not nearly as bad as inhibiting alpha2beta3 (final part of pathway)
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