Exam 6 - Coagulation Cascade Flashcards
Factor I
Fibrinogen
Factor II
Prothrombin
Factor III
Tissue thromboplastin
Factor IV
Calcium
Factor V
Proaccelerin
Factor VII
Proconvertin
Factor VIII
Antihemophilic factor A
Factor IX
Plasma thromboplastin component
Factor X
Stuart factor
Factor XI
Plasma thromboplastin antecedent
Factor XII
Hageman factor
Factor XIII
Fibrin stabilizing factor
PC
Protein C
PS
Protein S
HMWK
High molecular weight kininogen
TF
Tissue factor (thromboplastin)
Prothrombinase complex
Xa bound to Va+Ca on PL
Xa + Va
Extrinsic tenase complex
VIIa + TF
Intrinsic Tenase Complex
- Platelet tenase complex
- IXa + VIIIa
Hemostasis
- circulatory homeostasis
- keep blood liquid…but stop from bleeding
How hemostasis is maintained
Anticoagulant factors: - from endothelial cells Procoagulant factors: - platelets - plasma proteins in inactive states (zymogens...most are)
Arterial circulation
- high flow, high pressure
- smaller vessels
- platelets are big player
- anti-platelet agents used to treat thrombosis
Venous circulation
- low flow, low pressure
- bigger vessels
- rate of thrombin formation big player
- antithrombin agents for DVT
What happens when arterial blood vessel damaged
- constriction
- platelet adhesion
- platelet activation (plug forms)
- coagulation and fibrin clot formation
- clot retraction
- fibrinolytic cascade
- vessel repair
End point of activation stage
- fibrin clot formation
Platelet role in coagulation
- needed for quick clot formation
- provide surface to take place on
- receptor site for coagulation factors
- release some factors
- not just # important…but need to be activated at site of injury
Normal platelet count
150,000 - 350,000 / uL
Two types of coagulation factors
Proenzymes
- become enzymes when activated
Procofactors
- become cofactors but not actual enzymatic activity
Which part of cascade model is no Ca necessary
- interaction of thrombin with fibrinogen
Intrinsic pathway
- contact activation / blood itself contacts activation agent
- aPTT
Extrinsic pathway
- release of TF from damaged tissue
- PT
Common pathway
- thrombin production
- thrombin cleaves fibrinogen to fibrin
- PT
Factor XIIa activates
- intrinsic pathway
- neutrophils
- platelets
- fibrinolytic system (starts right away)
- form kallikrein (activator of fibrinolysis)
- compliment cascade
- w/ HMWK forms bradykinin
Heparin effect on coagulation
- Amplifies antithrombin (ATIII)…stops coagulation
How does XIIIa strengthen fibrin
- protects fibrin from plasmin mediated breakdown
Low thrombin [ ] effect on fibrin clot
- lead to loose fibrin plug
- fibrin broken down more easily
- weak clot…may not form or do job
- opposite is true as well
Pro’s of Cascade model
- How enzymatic steps work and cofactors
- showed Ca dependence
- development of aptt/ PT
Ca chelating anticoagulants
- bind to Ca which stops cascade
- Citrate is example
Cons of Cascade model
- Only works in-vitro
- only applies if blood is NOT moving and not interacting with other cells / linings
- Shows intrinsic and extrinsic can activate factor X separately
- in vivo they can’t (extrinsic needed)
3 phases of cell based model
initiation phase - occurs on TF bearing cells amplification phase - platelets and cofactors activated - recruiting phase propagation phase - thrombin burst - clot formation - takes place on platelets
Initiation phase step 1
- Cell damage exposes TF on cell
- TF binds with VII
- VII is converted to VIIa
- extrinsic tenase complex forms
- TF + VIIa
Initiation phase step 2
- Extrinsic tenase complex converts:
- IX to IXa
- X to Xa
- IXa inhibited by TFPI and ATIII
- Tissue factor pathway inhibitor
- If ACTIVATED platelets close…IXa (w/ help of VIIIa) will convert more X to Xa
Initiation phase step 3
- Prothrombinase complex formed
- this complex makes small amount of prime thrombin
- factor II into factor IIa
- not enough to clot….just recruit platelets
Amplification phase
- Priming IIa is signal to start this phase
- purpose is to recruit and activate platelets
- still no clot formation
- for clot to form…injury must allow big proteins of amplification/propagation to move out of vessel into tissue where the TF bearing cells are located
Amplification phase step 1
Factor IIa (thrombin) from initiation is busy:
- activates platelets….very important
- V to Va
- Splits VIII+vWF into VIII and VWF
- XI to XIa
Amplification phase step 2
- IIa binds and activates platelet
- platelet shape change
- new shape promotes binding
- release of granules for more platelet activation
- Va / VIIIa / XIa binds to activated platelet
- IXa and VIIIa form Intrinsic Tenase Complex
Propagation phase step 1
- XIa converts IX to IXa
- IXa attaches to VIIIa
- Intrinsic Tenase Complex
- Platelet Tenase Complex
Propagation phase step 2 and 3
- ITC converts X to Xa
- Xa binds to Va to make PTC
- Large number of PTC makes thrombin burst
Clot formation
- happens after thrombin burst
- fibrin clot forms
- majority of thrombin comes AFTER fibrin clot formed
- thrombin also converts XIII to XIIIa to make clot stronger
- additional thrombin is just to make clot stronger
Vascular constriction
- more prominent in crushing injuries
- constriction of smooth muscle (smaller vessels)
Platelet adhesion problem
- area of injury has high shear stress….so low velocity
- hard for platelets to stick
- BUT coaxial migration pushes more platelets to outer vessel
- platelets pushed out to side by larger proteins in middle
Platelet adhesion
- must happen fast
Platelet binds to: - vWF: held by collagen
- GPIb: on platelet…binds to vWF…slows down platelet at injury site
- over time platelet slows enough to actually stop
- interaction of GPIb and vWF causes transmembrane signaling
- signaling AND shear stress activates platelets at injury site
Platelet activation
- loses discoid shape
- GPIb + vWF
- GPIIb/IIIa + vWF (holds platelet)
- GPIa/IIa + collagen (holds platelet)
- GPIV + collagen (signaling)
Goals of platelet activation
- recruit more platelets
- bind platelets to each other to make matrix
- fibrin formation
- protect clot from fibrinolysis
Platelet recruitment
Platelets release 3 agonists:
- Thromboxane (TXA2): vasoconstrictor, made in platelet, released by platelet…aspirin prevents formation of this…recruitment down
- Serotonin: released from granules, vasoconstrictor
- ADP: from granules, no known role
Formation of platelet plug
- GPIIb/IIIa changes via calcium
- complex can bind to vWF or fibrinogen in tight matrix to form plug 1st
- clot formed following plug formation
Termination players
- TFPI
- PC
- PS
- ATIII
TFPI
- made of TF/VIIa/Xa/TFPI
- inhibits priming dose of thrombin
PC and PS
- inactivate Va / VIIIa
- vitamin K dependent
- Va needed for PTC and platelet activation
- VIIIa needed for Xa formation
- PC also activated by thrombin…negative feedback
- PC accelerated by PS…positive feedback
ATIII
- inhibits thrombin
- inhibits 9a to 12a
Fibrinolysis
- plasmin signals start of this phase
Plasmin
- formed from plasminogen
- actively breaks down clots by cleaving fibrin polymers
- cleaved fibrin produced more fibrin degradation products
Endogenous anticoagulants
- keeps blood liquid
- need INTACT endocellular barrier
- release NO and PGI2…prevent platelet adhesion/aggregation
- release ADPase….limits recruitment of platelets
- all overridden by high platelet count at injury site
Bleeding and CPB
- bad outcomes
- more cost
- more infection
- more blood products
CPB and coagulation
- activates intrinsic/extrinsic coagulation pathways
- from suction / negatively charged surface
- activates neutrophils / monocytes
- surgery exposes subendothelium
- activates platelets
- activates endothelial cells
Five causes of bleeding post-op
- surgical leak
- insufficient fibrin formation
- insufficient clot integrity
- insufficient clot adhesion
- fibrinolysis
