CR II - Coagulation Flashcards
What are 4 major components that interact to promote and inhibit clot formation? What do each do?
Endothelial cells - inhibit clot formation
Sub endothelial tissues - form clots when in contact with platelets
Platelets - activated, release factors for activation of coagulation - soft plug
Clotting factors - in plasma, platelets, and subendothelial activate to form hard clot
What 2 things do endothelial cells produce/express to inhibit coagulation? What 1 thing does it produce to inhibit platelet activation? What 1 thing does it produce to stimulate clot dissolution?
Inhibit coagulation - heparin sulfate proteoglycan and thrombomodulin
Inhibit platelet activation - prostacyclin PGI2
Stimulate clot dissolution - tissue plasminogen activator (tPA)
What are the three phases of hemostasis? Do they occur in sequence or simultaneously?
Pro-coagulation
Anti-coagulation
Fibrinolysis
Simultaneously
What are two receptors expressed by platelets to directly and indirectly bind to collagen?
GPIb/IX/V - indirect, binds to vWF which then binds to collagen
GPIa/IIa - direct, binds directly to collagen
What 6 additional compounds that are released in hemostasis? What do each do?
ADP - stimulates further platelet activation by binds to G-Protein coupled P2Y receptors
Serotonin - vasoconstrictor (around damaged endothelium)
Fibrinogen
Factors V, VII, and Ca
VWF
Platelet derived growth factor (PDGF) - for improved wound healing
Thrombocytes A2 (TXA2) - stimulates further platelet activation
Which factor overcomes the excretion by the endothelium to prevent coagulation?
Thromboxane A2
What membrane receptor on platelets is the most abundant? Once the platelet is activated, what does this receptor bind? Aggregates what?
GPIIb/IIIa
Binds fibrinogen
Aggregates activated platelets
How to platelets change once they are bound to collagen? What do they form?
Change shape
Form physical plug
How does the platelet surface change to provide place for coagulation?
Phosphatidylserine (PS) moves from inner leaflet to outer leaflet
What pathway initiates coagulation? When what is exposed to plasma?
Extrinsic pathway
When tissue factor is exposed to plasma
Where is tissue factor found? What does it bind to to initiate the extrinsic pathway? What is required to do this?
Transmembrane in subendothelium
Finds to FVII
Only in presence of Ca2+
After FVII is activated by binding to tissue factor, what two things is it further activated by?
FXa or thrombin
What complex is formed what tissue factor binds to FVII with CA? What else is this called? What does it activate?
tissuefactor-FVIIa-Ca complex
X-are complex
Activates FX to FXa and FIX to FIXa
Why is it ok that FVIIa has a long half-life?
Because it is only active when bound to tissue factor
What is the first step in the final common pathway?
Formation of FXa from FX
What forms a platelet membrane bound complex with FXa? What does this complex do? What is needed?
FV (from platelets)
Cleaves prothrombin to thrombin
Ca is required for prothrombin to bind to membrane
What are two things that thrombin does?
Converts fibrinogen to fibrin monomers
Promotes further coagulation by activating factors in intrinsic, extrinsic, and common pathways
What 5 factors can thrombin activate?
FVIII and XI - intrinsic
FV and FXIII - common
FVII of extrinsic
What pathway is coagulation initiated through?
Intrinsic pathway
What is required for initiation of the intrinsic pathway?
Exposure to anionic surface
Where do proteins of the intrinsic pathway come from? Which binds first to anionic surface? What does it undergo?
Plasma
FXII - undergoes conformational change to increase activity
What two factors are brought close to FXII by complexing with HMWK? Where does HMWK also bind?
FXI and prekallikrein
HMWK also binds to anionic surfaces
What activates prekallikrein to kallikrein? What are the next 4 steps in the intrinsic pathway?
FXII Kallikrein activates FXII to TXIIa FXIIa activates FXI to FXIa FXIa activates FIX to FIXa FIXa and FVIIa activates FX to FXa (Ca dependent)
What protects FVIII from proteolytic destruction prematurely?
Bound to vWF in plasma
What of fibrinogen prevents its aggregation? What remedies this allowing formation of soft clot?
Amino termini of central globular domain
Thrombin cleaves amino termini, releasing fibrinopeptides allowing aggregation of to form soft clot
What factor acts on fibrin to form hard clot? What is it activated by? What is it classified as? What two residues on fibrin does it link? With what bond?
FXIIIa Activated by thrombin Classified as transflutaminase Transamidination between glutaminyl and lysyl residues on two different fibrin Covalent linkage
What are the 7 enzymes or factors involved in anti-coagulation? Which two are Vitamin K dependent?
Antithrombin Thrombomodulin Protein C - vit K dependent Protein S - vit K dependent Tissue factor pathway inhibitor Other serpins NO
Where is antithrombin synthesized? What 5 things does it inactivate? What greatly enhances its activity?
Synthesized in liver
Inactivated thrombin, FIXa, FX, FXIa, and FXIIa
Glycoasminoglycans - heparin and heparan sulfate
What is thrombomodulin? Where is it found? What binds, forming a complex to reduce activity? What activity does this complex activate?
Plasma membrane receptor protein
Endothelial cells
Thrombin binds, reducing activity of thrombin to bind fibrinogen
Increases activity of protein C
Where is Protein C synthesized? Where is then found? What activates it? What does it then form a complex with?
Liver
Plasma
Activated by thrombin-thrombomodulin complex
forms complex with Protein S (APC)
Where does the APC complex bind? What does it depend on? What two factors does it inactivate?
APC binds to surface of platelet
Depends on Ca
Inactivates FVa and FVIIIa
What protein, bound to lipoproteins, circulates in blood and binds/inactivates tissuefactor-FVIIa-Ca_FXa complex?
Tissue factor pathway inhibitor
What are serpins? Where are they found? What do they bind? What are three examples?
Serine Protease inhibitors
Circulate in plasma
Bind to proteases (coagulation factors) inactivating them
Anti-thrombin, a-macroglobulin, a-antitrypsin
Besides vasodialation, what does NO do?
Inhibits platelet adhesion and aggregation
What are three major compounds that activate plasminogen to plasmin?
Tissue plasminogen activator
Urokinase
Streptokinase
In liquid phase of blood, what rapidly inactivates plasmin?
alpha-antiplasmin
What must tPA be bound to in order to be active? What is excess tPA activity prevented/inhibited by?
Fibrin
Inhibited by PAI-I
What activates urokinase?
Conformationally activated FXII
How does streptokinase activate plasminogen?
By confirmational change
What are the 6 vitamin K dependent factors? What do they contain which is required for Ca binding? Where is this created? What does this process depend on?
Prothrombin (II), FVII, FIX, FX, protein C and protein S
Gamma-carboxyglutamyl residues
Post-translationally in liver
Vitamin K dependent process
What disorder prolongs bleeding time?
Platelet disorders
When will activated partial thromboplastin time (aPTT) be prolonged?
Deficiency in either intrinsic or common pathway
What is added to citrated platelet-poor plasma for aPTT? For Prothrombin time?
aPTT - kaolin (clay providing anionic surface), phospholipids, and excess Ca
Prothrombin time - tissue factor-containing extract and exces Ca
When will prothrombin time be prolonged?
Extrinsic and common
What two things cause prolonged thrombin time?
Persons treated with heparin or who have fibrogen deficiency
What two deficiencies cause hemophilia? Which is more common? Are both genetic?
Hemophilia A - deficiency FVIII - more common
Hemophilia B - deficient FIX
Both x-linked recessive
What deficiency may also be associated with von Willebrand disease?
FVIII deficiency
Is von Willebrand disease consistent? Common? What is treatment?
Highly variable
Very common
Replacement therapy
What is deficient in Bernard-Suulier disease? How does it differ from von Willebrand disease?
GPIb/IX/V receptors deficient
FVIII not affected
What is characterized by Factor V Leiden?
Mutation in FV normal cleavage site
FVa inactivation much slower leading to hyper coagulable state
