What are is the role of thrombin activatable fibrinolytic inhibitor in the pathophysiology of factor IX (FIX) deficiency (hemophilia B)?

Updated: Mar 09, 2021
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Srikanth Nagalla, MD, MS, FACP  more...
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The demonstration that thrombi generated in plasmas obtained from patients with hemophilia A or B underwent premature lysis generated the hypothesis that bleeding in patients with hemophilia may be due not only to failure of adequate thrombin generation and clot formation, but also to a failure of adequate suppression of fibrinolysis leading to accelerated clot removal.

Proof of the concept of the latter has been provided for decades in patients with hemophilia, long before the role of thrombin activatable fibrinolytic inhibitor (TAFI) was even suspected, by the amply proven hemostatic adequacy of a single dose of replacement factor when combined with prolonged inhibition of fibrinolysis in patients with severe hemophilia undergoing dental or other mucocutaneous procedures. The demonstration in vitro of rapid clot lysis in hemophilic plasmas was followed by a demonstration of rapid clot lysis in plasmas deficient in FXI or factor XII (FXII), with prolongation of clot lysis by restitution of the missing factor.

Recently, a large amount of information has accrued regarding the pathophysiologic role of TAFI in thrombohemorrhagic disorders. TAFI, a single-chain carboxypeptidase B–like zymogen, is activated by thrombin to generate activated TAFI (TAFIa). Thrombin, plasmin, and trypsin all can activate TAFI, but thrombin bound to thrombomodulin has an approximate 1250-fold greater catalytic rate than thrombin alone; however, thrombin alone is sufficient to achieve significant TAFI activation.

The importance of TAFIa in influencing fibrinolysis is emphasized by the fact that conversion of only 1% of the zymogen to TAFIa is sufficient to suppress normal fibrinolysis by approximately 60%. TAFIa suppresses fibrinolysis by removing C-terminal lysine and arginine residues in a fibrin clot that has been partially degraded by plasmin. Removal of C-terminal lysine residues reduces the rate of plasminogen activation by a number of mechanisms, attenuating fibrinolysis. This effect is counterbalanced in normal plasma by the activation of protein C, which has profibrinolytic properties due to its ability to suppress thrombin generation by its major effect in degrading FVa and, to a lesser extent, FVIIIa.

In normal plasma, a balance exists between the effects of activated protein C on the one hand (profibrinolytic) and TAFIa on the other (antifibrinolytic). Thrombin secures survival of the thrombus created by its action on fibrinogen by activating TAFI, thereby inhibiting fibrinolysis. In this context, note that cross-linking of fibrin induced by activated factor XIII (FXIIIa, activated by thrombin) also renders the clot insoluble (for more information, see Factor XIII). Thus, thrombin uses multiple prongs to assure survival of its creation, fibrin, and affects the normal delicate balance between thrombus formation and thrombus resolution.

A reduction in the level of FIX via reduction of thrombin generation reduces TAFI activation and increases fibrinolysis, whereas persistence of FVa (as is the case with co-inheritance of factor V [FV] Leiden) leads to increased (persistent) thrombin production and TAFI activation, thereby inhibiting fibrinolysis.

These data, along with the known effects of epsilon-aminocaproic acid (EACA; Amicar) certainly raise the question of the efficacy of prolonged fibrinolytic inhibition in individuals with hemophilia as a possible mechanism with which not only to reduce the frequency of spontaneous bleeding but also to provide reduction in product usage in surgically induced bleeding in which fibrinolytic inhibitors currently are not used as adjuvant therapy. An expansion in the role of fibrinolytic inhibitors to control all types of bleeding in individuals with hemophilia could be explored in properly designed prospective clinical trials. Such trials could provide the first objective data on the true frequency of thromboembolic and other complications involved in the use of fibrinolytic inhibitors with replacement therapy.

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