The Healthy Circulation and Physiologic Hemostasis Flashcards Preview

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Flashcards in The Healthy Circulation and Physiologic Hemostasis Deck (70)
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Blood is

A complex liquid flowing under pressure
Normally, blood will not interact with each other


What happens to blood under injury?

Blood is stopped by clot formation and normal flow is restored


Physiologic Clot is

Just right in size and strength and persists just long enough


influences on blood flow

Blood itself
Virchow's triad


Blood flow normally

Denser RBCs in the middle with laminar flow....platelets and plasma at periphery


Blood flow in anemia

Narrower central column, less viscous, flows faster, and thicker outer sleeve with more opportunities for endothelial interaction...more prone to excess bleeding


Polycythemia affects on blood flow

More viscous so thicker central column...more opportunities for endothelial interaction so more likely to thrombosis


Healthy endothelium

Keep flow moving and avoid interaction with passing bloodstream components except for purpose of promoting normal flow...if endothelium activate, it can secrete procoagulant substances (normally held in reserve)


Endothelial cells and NO

Endothelium forms NO from L-arginine via NOS...diffuses across cell membranes and causes vasodilation while inhibiting platelet adhesion and aggregation
NO destroyed by hemoglobin and short half life (local interactions)


Intravascular hemolysis effecto n NO

Causes local depletion of NO


What is normally bound to endothelial surface

Heparans and thrombomodulin - part of natural anti-coag system



Expressed on endothelial surface bound to glypican and syndecan glycoproteins
Similar to heparin
Bind and activate antithrombin, enable anticoagulant effect confined to normal endothelial surface

Effect is to inhibit unwanted clotting in the intact circulation



Expressed on intact endothelium, cooperates with thrombin to activate protein C

Effect is to confine clot formation to the site of the injury by inhibiting the spread to adjacent normal endothelium



INtact endothelial cells adjacent to disrupted endothelium enzymatically release arachidonic acid
COX2 converts to prostacyclin
COX2 predominates on endothelium, induced by laminar blood flow

Effect of PGI2 is vasodilation and maintenance of healthy blood flow



COX1 converts AA into thromboxane A2 in platelets
Stimulator of platelet activation and aggregation and produces vasoconstriction
Endothelial COX2 generates PGI2 which blocks [platelet aggeregation and antagonizes TxA2 mediated vasoconstriction

NET effect is an adjustable tension between vasodilatory of PGI2 and vasoconstrictive of TxA2



Tissue plasminogen activator is secreted by endothelium under stress or vascular occlusion...initiates fibrinolyis

Helps limit clot size



Endothelium secretes vasoconstrictive peptides called endothelins...immediate but temportary


In healthy flow vs. acute bleeding

Healthy - vasodilatory of NO predominantes
Acute bleeding - endothelin mediated vasoconstriction precomes predominant

Out of balance in fascular dz


vWF, ADAMTS-13, FV8, Tissue factor

All help to clot (pro-coagulants)

vWF - primary hemostasis
ADAMTS-13 - cleaves vWF
F8 - secondary hemostasis
TF - not normally expressed but exposed with endothelial acitivation to begin secondary hemostatic process


Primary and secondary hemostasis

Primary - platelet interactions with vWF and each other (platelet plug)
Secondary - interactions of procoagulant proteins with cell surfaces, platelet plug, and each other (fibrin clot)

Occur at same time

Modulated by natural anticoagulant and fibrinolytic systems


Overview of primary hemostasis formation

Damage exposes vWF...circulating platelets bind to vWF, collagen activates platelets...platelets release substances ot recruit other platelets...activated platelets sitck together via fibrinogen bridges


Enhancing the platelet plug

Damaged or activated endothelial cells release additional high weight vWF factors that are cleaved by ADAMTS-13 protease


Key structures of a platelet

Phospholipid bilayer
Contractile proteins that flex into its activated form
Dense bodies - contain smaller molecules and ions like ADP, serotonin and calcium
Alpha granules - contain 300 proteins and peptides with various functions


Platelet receptors

Throbin, epinephrine, ADP, and collagen
AA released from platelet membrane and converted to TXA2
GPIb/9/5 receptor - platelet adhesion to GPIb binding domain on vWF molecule (always exposed)
GP2b/3a recepotr - binding platelets into aggregated platelet plugs (concelaed on quiescent platelet but exposed on activated)

Can also make NO


Activation of platelets causes

Granule release, shape change, recruitment, and aggregation



Produced in endothelial cells and megakaryocytes
Linear monomer that dimerize via disulfide bonds...dimers form multimers
Circulating ADAMTS-13 cleaves into smaller ones


vWf binding sites

FV8, collagen, GB1b and GB2b/3a

Cleavage site of ADAMTS-13 q


3 pools of vWF

Circulating - rolled up to conceal GPIb binding domain...binds F8 and prevents prevents degradation by protein C (chaperone function)

Subendothelial deposit fomr - stretched out by collagen binding...poised for action if injury occurs (by binding platelets)

Endothelial storage granule form - ultra large monomers unroled that can be extruded for rapid hemostasis...cleaved by ADAMTS-13


Once adherent to subendothelial vWF via GPIb interaction

Platelet also comes in contact with subendothelial collagen which activates platelet...platelet undergoes shape change and exposes GP2b/3a receptors, release of granule contents


How is ADP imprtant in platelet recruiting process

Interacts with P2Y12 ADP receptor on nearby resting platelet



Occurs once Gp2a/3b is exposed and ready to engage with a fibrinogen many as six platelets can engage with a fibrinogen molecule


PLatelet plug function

Initially stops bleeding and serves as scaffolding for secondary hemostasis

Disorders = thrombosis and bledding


Secondary hemostasis

Fromation of fibrin strands on and witin the platelet plug which knit plug together int oa fibrin clot


Activation of fibrin forming coagulation cascade

Begins with exposure of TF...on all cells but RBCs


TF location

Subendothelial, not on actual with damage...heavy in the brain and placental villi


Tissue factor and F7

Factor 7 wraps around TF...activated to become protease (F7a)...cleaves and activates factor X...factor X cleaves prothombin into thrombin


Coagulation facotrs

Made in liver
F8 made in endothelium
Most are serine proteases that cleave
Factors 5 and 8 are cofactors for Fx and FIX


Secondary hemostasis general process

Latent but poised (coag factors criculate as zymogens)
Multistep cascade that is amplified
Localized to site of injury

Requires platelet and cell membrane surfaces for efficient factor interaction


Coordinated choreography

Cell membranes (including platelet plug) is where secondary hemostasis takes place


Sticking to the stage (secondary)

Factors 7 and other serine proteases employ carboxylated glutamates to bind calcium ions

Calcium helps bind factors to cell membvranes so they can function properly


Vitamin K role

Factors 7, 9, 10, prothrombin dependent and also anticoagulant proteins C and S
Glutamic acid rich tdomains in 3 structure
Gamma carboxy glutamic acids needed for interaction with membranes and calcium


Vit K dependent protein creation

Gamma carbons of glutamate residues are carboxylated by Vit K dependent enzyme...needed to make functional prothrombin as well


Vit K dependent protein structure

Gamma carboxylation permits interactions with calcium and cell/platelet membranes

No vitamin K---- no gamma carboxylation ---- no membrane bound factor complexes


Vit K

Dietary sources
VK2 made by gut bacteria
Def with diet or AB use
Replacement given orally
Subq - poor absorption in obese
IM - hematoma risk
IV - anaphylaxis risk


Recycling of VK2

VK2 catalyzes gamma carboxylase and in process oxidized to VKO...VKO restored to normal form beginning with VK epoxide reductase (VKOR)



Inhibits VKOR the VK2 recylcing function


In vivo cascade

Factor 7a activates factor X which cleaves prothrombin into thrombin...these are on the phospholipid bilyaer ot TF cells


TF bearing cells are

Sequestered away from vessel lumen by intact endothelium


Initiation phase

INjury exposes TF...circulating F7 complexes with exposed TF and calcium...converts F7 to F7a...cleaves F10 and F9 into active forms...F10a cleaves prothrombin (F2) into thrombin (F2a)



Tissue factor pathway inhibitor
Modulates early secondary hemostasis by reversibly inhibiting FXa...the FXa-TFPI can then inhibit the F7a-TF complex


Thrombin difference

Not membrane bound and catalyzes a bunch of reactions


Thrombin function

Platelet activating substance that stimulates platelet activation and construction of platelet plug
Activates F11...begins acceleration or porpogation phase of secondary hemostasis
Cleaves fibrinogen to fibrin
Activates F13...F13 cross links fibrin polymers domain E to D


Fibrin monomers

Spontaneuously dimerize and polymerize


F12 does NOT

Participate in secondary hemostasis in vivo...improtant in the test tube


Key events of secondary hemostasis

Interaction of F7 and TF to initiate the process and generation of thrombin to propogate it


2 parts of natural anticoag system

C/S and antithrombin system


C protein

Serine protease activatedby thrombin during secondayr hemostasis...thrombin complexes with thrombomodulin bound to uninjured endothelial membrane adjacent to injury


Protein S

Cofactor for protein C
Activated complex cleaves F5a and F8a


Sequence of C/S systme

F7a-TF complex cleaves F10 into F10a at site of injury
F10a complexes with activated cofactor F5a and cleaving prothrombin into thrombin
Thrombin complexes with TM on uninjured membrane and cleaves protein C to APC...APC complexes with protein S to cleave F5a and F8a (cofactors to F10 and F9) into inactive forms

Inhibition of F5 and F8 slows down the clotting cascade just adjacent to the injury

Basically makes sure clot doesn't spill over


Antithrombin system

Keeps circulation moving by preventing unwanted clot formation from happening in first place

AT is a weak inhibitor of serine proteases but when complexed with heparans, it becomes much more active and can inhibt all of the serine proteases in procoag cascade



Natural ligand for AT
Bound to surface of endothelial cells
Role in inhibiting unwanted coagulation
Circulation is naturally "heparanzed" in vicinity of endothelium


Fibrinolytic system

Limit size of clot formation and lyse the clot when job is done...also role in resolution of pathologic thrombosis



Serine protease that lyses clots by cleaving fibrin molecules...can also cleave fibrinogen
Circulates as plasminogen and activated by tPA (tissue type plasminogen activator) which is made inthe endotheluum



Made by neodthelial cells and Release in response to stress or vascular occlusion

Low affinity for circulating plasminogen but high affinity for fibrin wihtin a thrombus...binds and activates local plasminogen resulting in fibrin spcific physiologic fibrinolysis

Fibrinolysis does not occur diffusely but localized othe clot



Inhibits tPA
PAI-1 def would allow overactivity of tPA leading to pleeding


alpha 2 antiplasmin

Serine protease inhibitor which inactivates circulating plasmin...when complexed with fibrin, helps retard firbrin degradation


Summation of fibrinolysis

Fibrin holds togehter platelet plug with attached plasminogen and plasmin...tPA released andbound to fibrin...cleaves plasminogen to plasmin which in turn cleaves fibrin and releases fibrin degradation products into plasmin escaping clot is captured by alpha 2 antiplasmin and not allowed to float away


How is fibrinolysis modulated

At the beginning by PAI-1 that degrades tPA



Specific cleavage product of cross linked firbin that is normally measured

Fibrinogen made into mesh by thrombin and then crosslinked by factor 13...plasmin then cuts into D dimer


D dimer measurement

Elevation demonstrates PRIOR formation of cross linked fibrin
Expected to be elevated in known VTE, traume, or recent surgery
Negative predictive value - if not elevated, helps rule out VTE in cases of suspected PE