Rebalancing is a non-factor approach to hemostasis for people with hemophilia. The rebalancing approach targets key anticoagulants and affects their inhibitory functions. One anticoagulant that can be targeted is called TFPI, or tissue factor pathway inhibitor.¹

TFPI plays a key role on the anticoagulation side of the equation, inhibiting procoagulant activity at an early stage of the clotting process.² 

Because deficiencies in factor VIII or factor IX, both procoagulation elements, are the pathological basis for hemophilia A and B, limiting the action of an anticoagulant may “rebalance” the process.^2-4 

Rebalancing through TFPI inhibition has the potential to block TFPI’s normal anticoagulation properties, even when factor VIII or factor IX are absent or deficient.⁴ 

This approach is currently being explored across hemophilia A and B regardless of a patient’s inhibitor status.⁴

The coagulation cascade is a sequence of events that leads to hemostasis. Within the cascade, procoagulant and anticoagulant proteins balance each other to produce a stable blood clot.^1,5 

The cascade begins when a blood vessel is injured and starts bleeding^2,6:

• Platelets aggregate at the site of injury and cause sequential activation of components, including multiple clotting factors
• This ultimately leads to the production of thrombin,* which then activates the production of fibrinogen; this results in production of fibrin^† adequate for forming a stable clot and stopping the bleeding

Rebalancing through TFPI inhibition begins with the coagulation cascade. The coagulation cascade consists of the extrinsic and intrinsic pathways, both of which lead into the common pathway.^2,5

Activation of these pathways results in the production of thrombin, a component required for the subsequent production of fibrin. The formation of a fibrin mesh stabilizes the blood clot.⁵

In the early phase of the cascade, the activated extrinsic pathway produces an initial, limited production of thrombin. TFPI limits the activity of the extrinsic pathway and dampens thrombin production.^7,8

In patients without hemophilia, the initial thrombin produced is enough to trigger a rapid up-regulation of the intrinsic pathway.^1,9 Multiple clotting factors (including factor VIII and factor IX) are further activated, leading to the common pathway and ultimately producing a “thrombin burst” substantial enough to produce the fibrin needed to form a reinforced secure clot.¹

In patients with hemophilia, the lack of adequate factor VIII or factor IX within the intrinsic pathway prevents adequate activation of the common pathway, ultimately resulting in insufficient clot formation.¹⁰

When TFPI inhibition is introduced, TFPI’s activity within the extrinsic pathway is limited or prevented.^2,4

TFPI inhibition does not interfere with the regulation of other downstream coagulation processes.¹¹

The extrinsic pathway may no longer be limited and may continue to initiate the common pathway—despite limitations in the intrinsic pathway. Adequate thrombin and then fibrin may be produced to form a reinforced, secure clot.^1,6

The specific binding site (or sites) on the TFPI protein that is targeted in order to block TFPI’s natural inhibition activity in the coagulation cascade is one or more Kunitz (K) domains.⁴

• TFPI isoforms exhibit 3 distinct K domains⁷:
  • K1 binds to the active site of factor VII while it is bound to the tissue factor-factor VII complex, forming a larger complex that further inhibits factor X activation
  • K2 binds to the active site of factor X, resulting in direct inhibition of the TFPI-factor X complex
  • K3 is thought to enhance the inhibitory effects of K2
    
• Because activation of factor X is the convergence point of both the intrinsic and extrinsic pathways, inhibition of K2 could increase coagulation activity initiated by either pathway^4,7,9
  
• Thrombosis may be a consideration with the use of procoagulant agents⁴

Because TFPI inhibition aims to enable the extrinsic and common pathways, the rebalancing approach may allow adequate thrombin production without factor VIII or factor IX. Therefore, research is being conducted in hemophilia A and B.^1,4,14,15

Further, rebalancing through TFPI inhibition is currently being explored for patients regardless of inhibitor status, including for those who have developed inhibitors.^4,14