What is the role of Thrombin Activatable Fibrinolysis Inhibitor (TAFI) in coagulation?

Role of TAFI in Coagulation

TAFI (Thrombin Activatable Fibrinolysis Inhibitor) suppresses fibrinolysis by eliminating the fibrin-binding sites for plasminogen through removal of C-terminal lysine residues on fibrin. 1

Mechanism of Action

TAFI serves as a critical molecular link between coagulation and fibrinolysis systems. The protein functions through the following mechanism:

1. Activation process:

   • TAFI circulates in plasma as an inactive precursor (zymogen)
   • It is activated by proteolytic cleavage by:
     • Thrombin
     • Plasmin
     • Thrombin-thrombomodulin (TM) complex (most efficient activator) 1, 2
   • This cleavage removes the activation peptide and liberates the carboxypeptidase catalytic domain (TAFIa)

2. Antifibrinolytic function:

   • TAFIa removes C-terminal lysine and arginine residues on:
     • Partially degraded fibrin
     • Fibrin degradation products (FDPs) 1
   • This leads to two key effects:
     • Decreased cofactor function of fibrin in the activation of plasminogen by tPA
     • Increased dissociation of plasmin from fibrin (decreased protection of plasmin), promoting its rapid inhibition by α2AP 1, 3

Clinical Significance

The role of TAFI in regulating fibrinolysis has important clinical implications:

• Thrombotic disorders: Increased thrombin generation (as seen in thrombophilia) may enhance TAFI activation, potentially leading to a hypofibrinolytic state that contributes to thrombotic tendency 2

• Bleeding disorders: Patients with factor XI deficiency are prone to bleeding from tissues with high local fibrinolytic activity (urinary tract, nose, oral cavity, tonsils), which may be explained by decreased thrombin-mediated TAFI activation 4

• Venous thromboembolism: Recent murine models suggest TAFI promotes venous thrombus stability and reduces embolization 1

Measurement Challenges

Measuring TAFI activity presents several challenges:

• TAFIa is intrinsically unstable at physiologic conditions with a half-life of around 7 minutes
• Carboxypeptidase activity measurement is complicated by the presence of constitutively active carboxypeptidase N
• Limited availability of specific functional assays for TAFIa activity in plasma 1

Key Distinction

It's important to note that contrary to its name, TAFIa functions more as a fibrinolysis attenuator rather than a true inhibitor 1. It does not directly inhibit plasminogen activators (option B), but rather removes binding sites that would facilitate plasminogen activation.

TAFIa is not a receptor for activated protein C (option A), nor does it bind thrombin to convert it from procoagulant to anticoagulant (option D).