Pathology/immunology

Front 1

Platelets are formed in a process called

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Thrombopoiesis

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Platelets are regulated by a circulating growth factor called

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thrombopoietin (TPO)

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The large, precursor cell to platelets in the bone marrow. They have no nucleus, just a little cytoplasmic RNA, and virtually no ability to synthesize proteins. They do display active metabolism.

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Megakaryocytes

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How do megakaryocytes react to injury or inflammation?

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they change shape, release contents, and form a platelet plug

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Function of open canalicular system of platelets

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increase surface area by 50%
has receptors for IgG and fibrinogen

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platelet membrane contains what?

why is this important?
and how does it stay this way? what if it doesn't stay this way?

Back 6

phosphatidylserine and phosphatidylethanolamine

stays on interior leaflet because of atp translocase

atp pump shuts during release reaction, and scramblase causes PS to relocate to exterior

Front 7

What does glycocalix do?

Back 7

causes net negative charge causing repulsion of platelets from eachother

Front 8

release of platelet granules caused by:

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actin.
profilin relinquishes hold on g actin under influence of DAG, and F actin becomes prominent in filopodia following calcium influx

Front 9

what maintains discoid shape of platelet?

what allows for shape change?

Back 9

tubulin and MAP (microtubule associated protein)
- when calcium influx, these depolymerize allowing platelets to change shape

Front 10

What do dense bodies contain?
(called dense because of electron density from Ca++ and MG++)

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serotonin, ADP, ATP

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what do alpha granules hold?

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large molecules like proteins

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IgG and fibrinogen are taken up by

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endocytosis

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PF4 and beta thromboglobulin are taken up by

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energy dependent concentrations

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thrombospondin and platelet derived growth factor are included through

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biosynthesis

Front 15

What is Adhesion?

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sticking and spreading of discrete platelets on damaged endothelium via binding to collagen in the subendothelial, intimal and medial layers

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what holds platelets to subendothelial collagen?

how is this done?

what happens at high shear rates?

Back 16

vWF

this is accomplished by receptor complex GPIb/IX/V

vWF becomes sticky and hypercoagulable or thrombotic

Front 17

What causes Bernard-Soulier syndrome?

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inherited defects in any of the subunits of GPIb/IX/V
that affect their ability to interact and bind with vWF

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What is Aggregation?

What is it dependent on?

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the sticking of activated platelets to one another in a clump. Dependent on fibrinogen.
receptor for fibrinogen is GPIIb/IIIa

Front 19

What causes Glanzmann's Thrombasthenia?

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damage to GPIIb/IIIa (receptor for fibrinogen)

Front 20

what activates GPIIb/IIIa?

Back 20

agonist of injury like ADP, collagen, thrombin, serotonin, TxA2

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response to injury agonist:

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a)influx of free calcium into cytoplasm
b)shape change into spiny sphere
c)phosphorylation via calcium dependent and independent kinases
d)breakdown of PIP2 to IP3 and DAG
e)liberation of arachidonic acid to TxA2
f)aggregation via fibrinogen to GPIIb/IIIa
g)scrambling of PS to outer leaflet
h)release of alpha granule contents and fusion with outer membrane
i)release of dense granule contents and fusion with outer membrane

Front 22

What is thrombin?

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Thrombin is an agonist that acts on platelets and other cells by binding to and then proteolytically cleaving its own receptors

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production of arachidonic acid:

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hydrolysis of phospholipids , converted by cyclooxygenase to prostaglandin PGH2 which is converted to TxA2 by thromboxane synthetase

NSAIDS target the synthesis of TxA2

NSAIDS do not block thrombin because it can independently relase vWf and phospholipase A2

Front 24

Weak and strong agonists

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ADP (but can potentiate other agonists)
Epinephrine (inhibits adenylyl cyclase and cAMP, increasing platelet aggregation)

Collage is a strong agonisht and acts via GPVI to trigger Ca++

Front 25

Von Willebrand Factor vWf

Back 25

is made in megakaryocytes and endothelial cells

is processed in Weibel-Palade body

platelet vWf is stickier than other forms becasue not proteolytically processed

binds to collagen

binds to GPIb/IX/V (resting and active)
binds to GPIIb/IIIa on activated

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What is plasma?

What is Serum?

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the fluid, non cellular part of blood with its clotting mechanisms intact. clotting tests are always done on plasma.
Serum is clotted plasma

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what do Zymogen factors do?

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are activated to form protease factor a

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clotting enzymes:
clotting proteases:

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serine proteases
trypsin-like enzymes

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contact activation

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factor XIIa + Tissue Factor cofactor, prekallikrein, and HMW-kininogen = activated XI, which activates IX

see chart

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fibrin formation

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fibrinogen has A alpha and B Beta chains cleaved to form fibrin. *starts with A alpha removal, strengthened by loss of B primer

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clotting:
Vitamin K is required for?

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factor VII
factor IX
factor X
prothrombin
Protein C
Protein S

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anticoagulants:

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coumadin and warfarin are antagonists of vitamin K

advantage over heparin because they can be taken orally for years

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Inhibitors of clotting cascade:

antithrombin III

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inhibits factor Xa and thrombin. a partial deficiency of ATIII causes problem because rate of inhibition is decreased in proportion to the concentration.

heparin accelerates rate of action of ATIII

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Tissue Factor Pathway Inhibitor

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**formed in negative feedback

TFPI:Xa inhibits TF:VIIa complex

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Inhibitors:
Protein C

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works with protein S to inactivate cofactors VIIIa and Va


need thrombomodulin (TM) for Protein C activation)

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clotting tests:
Prothrombin Time

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initiated with preparation of TF

extrinsic pathway (VII)

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Partial Thromboplastin Time (PTT)

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involves contact system: (intrinsic pathway)
factor XI which activates IX, which activates X

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Thrombin TIme

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involves adding exogenous thrombin to plasma and timing clot formation

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Fibrin degradation products (FDPs)

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products of fibrinolysis used to measure a thrombotic state

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Fibrinolysis

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part of the repair and restitution of vessel function that follows either normal clotting or deep vein thrombosis.
closely linked to both clotting and inflammation pathways

requires plasmin (which recognizes both lysine and arginine)