COAG Cascade & Chp. 35

Primary Hemostasis, Secondary Hemostasis, Fibrinolysis

1*: list the three stages of PLT activation in Primary Hemostasis

adhesion, aggregation, and secreation

1*: define adhesion in 1* Hemostasis

PLT stick to exposed collagen at the site of injury

1*: define aggregation in 1* Hemostasis

PLT stick to each other forming the PLT plug

1*: define secreation in 1* Hemostasis

Granular contents released, Phosphytidlyserine flips out, and bridges to 2* Hemostasis

1*: What is the key glycoprotein (GP) receptor involved in PLT Adhesion

GPIb/IX/V

1*: in PLT Adhesion what does GPIb/IX/V do

binds the PLT to VWF, which is bound to exposed collagen

1*: What is the key glycoprotein (GP) receptor involved in Platelet Aggregation?

GPIIbIIIa

1*: in PLT aggregation what does GPIIbIIIa do

binds PLT to fibrinogen (bridge between PLT)

1*: during the PLT Plug formation what GP binds PLT to Collagen after the Adhesion step

GP VI

1*: What are the contents released during Platelet Secretion (Degranulation)? (Remember PUG)

P: P-selection (adhesion molecule)

U: Up-regulation of GP IIbIIIa (activation)

G: Granular contents including Alpha granules and Dense granules

1*: List the Alpha Granules

vWF, Fibrinogen, PDGF, P-selectin, Factor V, Factor VIII

1*: List the Dense granules

ADP, ATP, Serotonin, Calcium, Epinephrine

1*: What 2 Granule contents amplify aggregation

ADP & TXA2

1*: What is the role of Phosphatidylserine (PS) exposure in Primary Hemostasis?

During platelet activation, PS flips from the inner to the outer leaflet of the platelet membrane

2*: What are the 3 main pathways of the Coagulation Cascade?

1. Intrinsic Pathway (Contact Activation Pathway)

2. Extrinsic Pathway (Tissue Factor Pathway)

3. Common Pathway

2*: Define the Intrinsic (Contact Activation Pathway) Activation

Endothelial rupture exposes collagen

2*: Define the Extrinsic Pathway (Tissue Factor Pathway) Activation

Tissue injury outside of vessel, damaged cells release TF

2*: List the Factors in the Intrinsic pathway

XII, XI, IX, VIII

2*: List the Factors in the Extrinsic pathway

Factor VII and III

2*: List the Factors in the Common pathway

Factors X, V, II (Prothrombin), I (Fibrinogen)

2*: State what makes up the Int-X-ase complex

IXa, VIIIa, Ca²+, PL (Phosphatidylserine)

2*: State what makes up the Ext-X-ase complex

III, VIIa, Ca²+, PL (Phosphatidylserine)

2*: State what makes up the Prothrombinase complex

Xa, Va, Ca²+, PL (Phosphatidylserine)

2* Procoagulant: What complex’s can the Ext-X-ase complex Activate

Int-X-ase complex and Prothrombinase complex

2* Procoagulant: What complex can the Int-X-ase complex Activate

Prothrombinase complex

2*: What complex is considered the rate limiting step of the entire cascade and why

Prothrombinase complex as it converts Prothrombin into Thrombin

2*: What is the final step of Secondary Hemostasis?

Fibrinogen (Factor I) → Fibrin (Factor Ia)

2*: what does factor XIII do

cross-links with Fibrin (Ia) forming a stable insoluble clot

2* Anticoagulant/Regulator: What are the 3 major Natural Anticoagulants (Down-regulators)?

1. Antithrombin (AT)

2. Protein C + Protein S

3. Tissue Factor Pathway Inhibitor (TFPI)

2* Procoagulant: What does PK and HMWK do

Activate the Intrinsic pathway Factor XII

2* Procoagulant: What does IIa (Thrombin) activate

XI, VIII, V, XIII, Thrombomodulin, and converts I to Ia

2* Procoagulant: What does Thrombomodulin activate after being activated by IIa

EPCR (Endothelial Protein C Receptor)

2* Procoagulant: What Pathway is the first to be activated/turned on

Extrinsic Pathway

2* Anticoagulant/Regulator: What Factors does AT inhibit

XI, IX, XII, II, PK, but mainly IIa and X

2* Anticoagulant/Regulator: what does AT and TFPI require

Protein S cofactor

2* Anticoagulant/Regulator: What is the up regulator of AT

Heparin Sulfate

2* Anticoagulant/Regulator: What does TFPI turn off

Ext-X-ase complex and X

2* Anticoagulant/Regulator: What does Activated Protein C (APC) turn off

V and VIII

2* Fibrinolysis: What initiates Fibrinolysis (Clot Breakdown)?

tPA (Tissue Plasminogen Activator) and uPA (Urokinase)

2* Fibrinolysis: What does tPA and uPA do

convert inactive Plasminogen into active Plasmin

2* Fibrinolysis: where is tPA released from? and what targets it?

released from damaged endothelium and is targeted by drugs (Alteplase)

2* Fibrinolysis: what role does Plasmin play

a serine protease that degrades Fibrin

2* Fibrinolysis: What does Plasmin degrade Fibrin into

Fibrin Degradation Products (FDPs)

2* Fibrinolysis: What is the specific fragment produced from cross-linked Fibrin? and why is it important?

D-Dimer, a clinical marker for thrombosis/PE/DIC

2* Fibrinolysis: What are the main inhibitors of Fibrinolysis

1. PAI-1 (Plasminogen Activator Inhibitor -1)

2. TAFI (Thrombin Activatable Fibrinolysis Inhibitor)

3. Alpha-2 Antiplasmin

2* Fibrinolysis: what does PAI-1 (Plasminogen Activator Inhibitor -1) inhibit

tPA and uPA

2* Fibrinolysis: what does TAFI (Thrombin Activatable Fibrinolysis Inhibitor) do and inhibit

cleaves lysine residues on fibrin to prevent plasminogen binding. Stops plasmin once clot is degraded to prevent breakdown of Fibrinogen and Fibrin

2* Fibrinolysis: If Plasmin is not controlled what will it do

will seek out and breakdown Fibrinogen and Fibrin

2* Fibrinolysis: what does Alpha-2 Antiplasmin inhibit

Free plasmin in circulation

2* Fibrinolysis: if Alpha- 2 Antiplasmin does not inhibit free Plasmin in circulation what will happen?

tPA/uPA will continue to convert Free Plasminogen into Free Plasmin which will actively seek out and eat Fibrinogen

How does the Extrinsic Pathway differ from the Intrinsic Pathway in terms of speed?

• Extrinsic Pathway (TF + VIIa): Very fast (seconds). Responsible for initiating the clot.

• Intrinsic Pathway (IXa + VIIIa): Slower amplification loop. Responsible for sustaining the clot and generating massive amounts of thrombin via the "Thrombin Burst."

What is D-Dimer used to determine

the difference between Clot V.S Raw Material Breakdown

What does the Presence of D-Dimer mean

Their is cross linked Fibrin-XIII degradation = Clot Breakdown

What does the lack in Presence of D-Dimer mean

Fibrinogen/Fibrin breakdown BEFORE cross linked Fibrin-XIII degradation

Which factors are vitamin K-dependent and what does vitamin K do?

• Procoagulants: Prothrombin (II), VII, IX, X

• Anticoagulants: Protein C, Protein S, Protein Z

• Function: Vitamin K enables γ-carboxylation of glutamic acid residues → allows calcium binding → enables phospholipid membrane binding

• Sources: Green leafy vegetables, intestinal flora (E. coli, B. fragilis)

• Warfarin inhibits vitamin K recycling

What are the six roles of thrombin in hemostasis?

1. Convert fibrinogen → fibrin (primary function)

2. Amplify platelet activation (direct activator via PAR1/PAR4)

3. Activate Factor XIII (fibrin clot stabilization)

4. Activate cofactors V, VIII, and XI (amplify coagulation cascade)

5. Activate thrombomodulin → Protein C pathway (anticoagulant)

6. Activate TAFI (inhibits fibrinolysis)

How does the Protein C pathway regulate coagulation?

The Protein C pathway acts as a natural brake on blood clotting by turning off key clotting proteins to slow down new clot formation

What does Antithrombin inhibit and what enhances it?

• Inhibits: Thrombin (IIa), IXa, Xa, XIa, XIIa, pre-K, plasmin

• Primary targets: Thrombin (IIa) and Factor Xa

• Enhanced by: Heparan sulfate (physiologic) and therapeutic heparin (2000-fold increase)

• AT is absolutely necessary for heparin's anticoagulant effect

What does Tissue Factor Pathway Inhibitor (TFPI) do?

• Shuts down the extrinsic pathway (TF:VIIa complex)

• Mechanism: Binds and inactivates Xa → TFPI-Xa complex then binds TF:VIIa

• Provides feedback inhibition (activated after coagulation starts)

• Requires Protein S as cofactor

What are the contact factors and do their deficiencies cause bleeding?

• Contact factors: Factor XII, Prekallikrein (PK), High-Molecular-Weight Kininogen (HMWK)

• Activated by negatively charged surfaces (glass, bacterial membranes, stents)

• Activate intrinsic pathway; generate bradykinin (inflammation)

• Deficiencies do NOT cause bleeding (no clinical bleeding disorders)

What role do erythrocytes play in hemostasis?

• Provide bulk and structural integrity to fibrin clot

• Help with marginalization (moving platelets to vessel wall)

• Anemia = increased bleeding tendency

What role do monocytes and lymphocytes play in hemostasis?

• Provide surface-borne tissue factor (in inflammation)

• Membrane integrins and selectins bind adhesion molecules

• Stimulate production of inflammatory cytokines

• Promote wound healing and combat infection