Regulatory mechanisms and fibrolysis

Hemostatic System

The process of blood clot formation involving initiation and propagation phases, which are interdependent and involve cells expressing tissue factor and platelets.

Initiation

The phase of blood clotting initiated by the extrinsic tenase complex (VIIa, TF, Ca++, phospholipids, leading to the activation of platelets and factors like V, VIII, XI, and fibrinogen cleavage.

Propagation

The phase where most thrombin is generated on activated platelets, leading to the formation of COAT platelets and the amplification of coagulation complexes.

What are COAT platelets?

Collagen and thrombin platelets

COAT platelets

• Higher levels of procoagulant activity

• Surface for formation and amplification of complexes

• Both platelets and TF-bearing cells essential for coagulation

Regulatory Mechanisms

Systems that balance procoagulant and anticoagulant activities to control the coagulation process and prevent excessive clotting.

Principle regulators

• Tissue factor pathway inhibitor (TFPI)

• Antithrombin (AT)

• Activated protein C (APC)

Tissue Factor Pathway Inhibitor (TFPI)

A regulator that binds to and inhibits factor Xa and the VIIa:TF complex, crucial for controlling thrombin generation.

What is the TFPI 2 step process?

• TFPI binds factor Xa and inactivates it

• TFPI:Xa complex binds and inactivates TF:VIIa in the TF:VIIa:Xa complex

Activated Protein C (APC)

A key regulator that, with protein S, inactivates factors Va and VIIIa to slow down or block thrombin generation.

Protein S

Cofactor that binds and stabilizes APC

• Synthesized in liver

• 40% circulates plasma freely and can serve as the APC

• 60% is covalently bound to complement control protein C4b-binding protein (bound form cannot participate in protein C anticoagulant

Antithrombin (AT)

A serine protease inhibitor that binds and neutralizes several serine proteases, requiring heparin for effective anticoagulant activity.

Which serine proteases does antithrombin bind and neutralize?

• thrombin

• IXa

• Xa

• XIa

• XIIa

• Prekallikrein

• Plasmin

What does heparin do?

• AT’s are amplified 2000-fold by binding to heparin

• Induces conformational change in AT molecule

  • allows binding of activated coag factors → inactivation

What is the inhibition of thrombin, factor X, and other serine proteases by AT dependent on?

• the length of the heparin chain

  • longer heparin chains able to bind both molecules → inhibition of thrombin

Fibrinolysis

The process of breaking down fibrin clots through activators like tissue plasminogen activator (TPA) and urokinase plasminogen activator (UPA).

Plasminogen

The precursor to plasmin, a serine protease that digests fibrin, activated by TPA, urokinase, or other endogenous activators.

Tissue Plasminogen Activator (TPA)

An enzyme that hydrolyzes fibrin-bound plasminogen to initiate fibrinolysis, bound to inhibitors like PAI-1 in circulation.