Exam 1: Hemostasis Flashcards
what are the basic events in normal clot formation after initial blood vessel injury
vasoconstriction platelet adhesion platelets undergo conformation change platelet aggregation clotting (coagulation) pathways activate formation of fibrin meshwork resolution of clot formation through fibrinolysis
vasoconstriction occurs from release of _____
endothelin by endothelial cells
vasoconstriction decreases ______
blood flow (but cant stop blood loss)
vasoconstriction brings _______ to the site of injury
platelets and coagulation factors (tissue factor exposure for clotting activation)
what facilitates the binding of platelet (platelet adhesion)
exposure of subendothelial collagen following injury
binding is greatly enhanced by
von Wellebrand factor (vWF), especially in high flow rate blood vessels
where is vWF stored
in endothelial cells and platelets and circulates in blood stream bound to factor VIII
platelets undergo conformation change and release what?
stored products in their granules such as Ca, ADP, vWF, thromoxane A2, epinephrine, platelet activating factor
what do these products do
activate platelets
the conformation change also exposes ______
fibrinogen binding sites
fibrinogen binding sites are important for what
platelets to bind to other platelets
in the conformation change, there is a change in platelet membranes that expose
specific platelet phospholipids that are important in activation of the clotting cascade
more platelets stick to site of injury by binding to each other via
fibrinogen (important in the platelet plug)
clotting activation ocurs quickly after initial vascular injury by exposure of _____ which activates clotting cascade and eventual formation of thrombin
tissue factor
thrombin, in turn, cleaves _____ which is vital to the formation of this stabilized clot
fibrinogen to fibrin
______ is incorptated into the platelet mass to hold/glue the clot together, forming the ______
fibrin; fibrin meshwork
the process of the fibrin meshwork ______ clot formation
stabilizes
resolution of clot fomration occurs through
fibrinolysis
fibrinolysis is mediated throguh
plasmin following activation from plasminogen
must maintain appropriate balance of clot resolution vs. clot retention or will have
hemorrhage or thrombosis depending on the imbalance
blood vessel endothelium has what kind of properties
anticoagulant and procoagulant properties
what is the lifespan of platelets
about 7-10 days
in high shear blood vessels, platelets bind to
vWF that has adhered to subendothelial collagen in damaged high shear blood vessels
in low shear blood vessles plateelets bind to
directly to collagen or fibronogen that has bound to collagen in the damaged vesssel
after binding to the site of injury, platelets undergo ____
conformational changes
what do these confomration changes do?
enhance platelet to platelt binding by interaction with fibrinogen
expose membrane phospholipids which initiate clooting factor pathways
releases stored products from granules
thromboxane TxA2 causes what
vasoconstriction and platelet aggregation
TxA2 inhibited by
aspirin
Ca increased after _____ release
TxA2
Ca is essential for
clotting factor pathways, contractile elements of platelts
where are the clotting pathways with formation of fibrin and fibrin cross-links essential?
after loose plug is formed, it must become stronger with stronger interactions
are factors numbered in order of activation?
no
is there a factor VI
no
factor I
fibrinogen
factor II
prothrombin
factor III
tissue factor
factor Ia
fibrin
factor IIa
thrombin
factor IV
Ca
factor V through factor
XIII
factor XIII
fibrin stabilizing factor
what factors require vitamin K for synthesis
II, VII, IX, X, protein C and S
where does vitamin K work?
x
most clotting factors are produced by the
liver
what factors are the only ones without enzymatic like activity
V and VIII and IV
what does this mean for these factors that have enzymatic activity
not necessarily consumed in the reaction ot activate the clotting pathway
so factors V and VIII are
consumed and have a risk of depletion if the liver cant keep up production levels
what are the two classical methods of clotting pathways
classical (in-vitro) or Y model
Cell-based or in-vivo model
in secondary hemostasis, what is needed for all stages?
calcium
- after injury to vascular endothelium, the exposure of ____ on cells beneath the endothelium initiates the hemostatic reaction
tissue factor
what is the only relevant activator of hemostatic pathwayss in real life
tissue factor
tissue factor is expressed on what membranes
subendothelial fibroblasts, smooth muscle cells, other stromal cells and monocytes
______ then binds to tissue factor on the membrane of one or more of these cells to allow the formation of the extrinsic tenase complex
factor VIIia
what is the only factor that circulates in the blood in active form
factor VIIa (although only 1% is in active form)
what does the activated factorVIIa/TF complex do
activates more factor VII and VIIa, which will bind more TF and form more extrinsic tenase complexes
extrinsic tenase complexes now promotes _____
circulating factor X to bind and become activated to factor Xa
circulating factor V can now bind to the complex and become
factor Va by factor Xa
this activation is very ______ at this point
slow and inefficient
V to Va is much more dependent on _____ for activation
thrombin
small amounts of circulating _______ can also bind to the complex and become activated to _____
factor IX, IXa
this complex is now composed of
tissue factor, Ca, factors VIIa, Xa, Va, IXa
this complex with these factors is now called
1st prothrombinase complex
1st prothrombinase complex main purpose is to
allow binding and activation of prothrombin to thrombin
thrombin at this point will begin to perform its multitude of functions to include
activating platelets, cleaving circulating factor VIII from vWF that in turn allows activation of factor VII, activataing circulating factor V, activating circulating factor XI and cleaving fibrinogen to fibrin
only a small amount of prothrombin is activated to thrombin at this point, and if the reaction does not proceed to amplification stage of hemostasis, what will happen to the clot
will not form properly
what is the key to amplification step of secondary hemostasis
dissociation of some factor IXa from the 1st prothrombinase complex
why does this dissociation occur?
because some factors are not tightly bound to the copmplex and can dissociate
factor xa usually stays associated with the 1st prothrombin complex, but if it dissociates _____ or ______ can quickly break it down
antithrombin or tissue factor pathway inhibitor (TFPI)
once factor ixa dissociates from the 1st prothrombin complex, it is free to bind to
adjacent platelet membrane phospholipid
factor ixa is subject to degradation by
minimally by antithrombin
factor ixa is now available to bind with factor viiia on the surface of
platelet membrane
foactor viia becomes activated when
thrombin that was generated from 1st prothrombinase coplex cleaves circulating ffactor vii from vwf at the site of injury
the combination of factor viia, ixa, ca and platelet membrane is called
intrinsic tenase complex
intrinsic tenase complex is responsible for
binding and accelerating the formation of factor x to xa on the surface of platelets which previously was limited to the tissue factor/viia site
once intrinsic tenase complexs are adequately functioning on the surface of platelets, what happens to the extrinsic tenase complex
become relatively insignificant and are shutdown primarily by TFPI
at this point the reaction is ready to proceed to the second phase of amplification process with the formation of the
2nd prothrombinase complex
once factor xa has been generated, factor _____ must be incorporated into the complex in order for factor xa to optimally function
va
factor va has arlready been generated from
thrombin that was produced by the end product of the 1st prothrombinase complex
incorporation of factor Va, platelet membranes, Ca, factor IXa, factor VIIIa, and factor Xa make up the
2nd prothrombinase complex
this complex is now ready to activate ____ into _____
thrombin into prothrombin
which prothrombinase complex is higher for thrombin generation
2nd
during the course of this entire process, circulating _____ has been incorporated into the platelet mass; as well as
fibrinogen; binding platelets to platelets
high thrombin gneration is now responsible for
cleaving fibrinogen to fibrin and surrounding the clot
to stabilize the clot, thrombin activates what
circulating factor XIII to XIIIa
XIIIa does what
cross-links fibrin within the clot to strengthen it
at this point, thrombin is being generated by 2nd and will continue to be produced until
the reaction is shut down
thrombin strongly activates platelets, causing them to do what
release granules and alter their outer phospholipid membranes to expose phosphatidylserine (PS)
how does thrombin generate VIIIa and free vWF
activates factor V to Va and cleaves the circulating bound proteins factor VIII/vWF
thrombin activates
factor XIII to XIIIa
thrombin is a _____ for leukocytes
chemo-attractant
after the clot has formed, what must be done
clotting pathways must be inactivated
inactivation of the pathays occurs by what methods
tissue factor pathway inhibitor
antithrombin
thrombomodulin
TFPI is produced and stored in
endothelial cells (also stored in plateles)
TFPI primarily does what
inactivates factor VIIa and factor Xa, thrombin to a lesser degree
antithrombin does what
inativates factor IIa and Xa, But also prefers
thrombomodulin
small molecule produced on the endothelial surface combines with thrombin to perform actions
heparin sulfate molecules and exogenous heparin do wha
amplify antithrombin to maximize degradation of actor IIa and factor Xa
thrombomodulin and trhombin active ______ then in conjunctive with proein S. inactivates ncativation factor Va, and VIIIa
exogenous hyperia
lastly, what happens to the clot
it must be broken down to prevent thrombosis and without causing hemorrhage (fibrinolysis)
diruing initial clot formation, endothelial cells release
plasminogen activator inhibitor
PIa-1
PAI-1 does wht
prevents the activation of plasminogen to plasmin
as the clot stablizies and endothelial cells being healing, the endothelium releases
tiue plasminogen activator (t-pa)
t-PA does what
converts plasminogen to plasmin
what is plasminogen
a protein produced by the liver that circulates in the plasma and becomes incorporated with the clot but doesnt have any fibrinolytic activity until activated to plasmin
t-pa does not convert plasminogen to plasmin unless ______ is also present
fibrin or cross-linked fibrin (generally does not occur until clot has stabilized)
certain drugs or compounds can convert plasminogen to plasmin such as
urokinase or streptokinases
if plasmin is released into the plasma
alpha2-anthiplasmin (antip-plasmin) will inactivate it unless the system is overwhelemed
____ cells eventually move into and remove much of the material from the clot and normal resolution, the blood vessel heals normally and restores blood flow
phagocytic cells
