Coagulation

Initiation

Vessel injury exposes bare collagen and tissue factor.

FVII \(\stackrel{\text{Tissue factor}}{\to}\) FVIIa

FX \(\stackrel{\text{FVIIa}}{\to}\) FXa

Meanwhile, platelets undergo

• Adhesion to the denuded collagen via vWF
• Aggregation by binding to each other via GPIIb/IIIa-fibrinogen complex
• Activation, which releases

1. Serotonin \(\to\) vasoconstriction
2. Thromboxane and ADP \(\to\) activate more platelets
3. Lots of FV

Vasoconstriction + platelet plug formation produces primary haemostasis

$$FV \xrightarrow{\text{FXa (slow)}} FV_a$$

$$\text{Prothrombin} \xrightarrow{\text{FXa+FVa+activated plt membrane+iCa}} \text{Thrombin}$$

Amplification

Thrombin...

• Activates more platelets
• Activates FV (from platelet granules)
• Activates FXI, which activates FIX
• Cleaves vWF off factor VIII and activates it; FIX+FVIII activates more FX
• FXa + FVa + plt membrane + iCa \(\to\) more thrombin \(\to\) positive feedback

Propagation

$$\text{Fibrinogen} \xrightarrow{\text{Thrombin}} {\text{Fibrin}}$$

$$\text{FXIII} \xrightarrow{\text{Thrombin}} {XIIIa} \to \text{Crosslinks fibrin strands}$$

Negative feedback

Protein C \(\xrightarrow{\text{thrombin}}\) Protein Ca (with protein S) \(\to\) inactivates thrombin, indirectly initiates thrombolysis

Antithrombin III: circulating serine protease that inactivates thrombin, FXa, FIXa, FXIa. Potentiated by heparin.

Intact endothelium express anticoagulants that prevent clot propogation out of area of injury

• Tissue factor pathway inhibitor (TFPI) \(\to\) inhibits TF-VIIa complex
• Thrombomodulin \(\to \ \uparrow\)activation of protein C by thrombin

Process

1. Plasminogen binds to thrombin at lysine residues (N.B. TXA resembles lysine and diverts plasminogen)
2. tPA (produced by endothelial cells) binds to plasminogen-thrombin complex
3. tPA converts plasminogen to plasmin, which cleaves fibrin into degradation products
4. These products...

• Bind to GPIIb/IIIa on platelets without crosslinking \(\to\) impaired aggregation
• Compete with fibrinogen for thrombin binding \(\to\) anticoagulation

Factors decreasing tPA activity

• Plasminogen Activator Inhibitor 1 (PAI1): produced by liver, direct tPA inhibitor
• \(\alpha\)-2 antiplasmin: binds plasmin

Factors increasing tPA activity

• Protein C cleaves PAI1 and promotes lysis