JP / EN

TECHNOLOGY / SERVICE

Thrombo Translational Research Lab Inc.

TECHNOLOGY

image

Our technology for dissecting the distinct mechanisms for the active form of factor (F)X generation in an initiation phase of blood coagulation

To provide the innovative research and diagnostic products for improving prevention and treatment of thrombotic and hemorrhagic complications, we are creating the technology for dissecting the distinct mechanisms for the active form of FX (FXa) generation in an initiation phase of blood coagulation.

Blood coagulation is a key for hemostasis in response to tissue injury, but also contributes to thrombosis. FXa has a crucial role in blood coagulation: FXa forms prothrombinase complex by binding to its active cofactor FVa and the complex activates prothrombin to an active enzyme thrombin. Thrombin produces stable clots and plugs by activation of platelets and fibrin formation. To date, direct oral anticoagulants (DOACs) targeting FXa are widely used for treating patients with stroke and venous thrombosis. Despite the excellent antithrombotic profile, there still remain unmet needs for reducing bleeding complications. Safer therapy with DOACs requires more understanding of the mechanisms of the FXa generation that contribute to thrombosis but have lesser impact on hemostasis.

In the current concept, the tissue factor (TF) complex with the active form of FVII (FVIIa) converts FX to FXa by the proteolytic activation of FX. After being released from the FVIIa-TF complex, FXa functions as a proteolytic enzyme such as prothrombin activation. The recent study has provided a novel insight into the activity of FXa: the nascent product FXa of FVIIa-TF, which is in the ternary complex of FXa-FVIIa-TF albeit the temporary complex, has a proteolytic activity since FXa still bound to FVIIa-TF activates protease-activated receptor 2 (PAR-2) expressed on a cell membrane by a limited proteolysis (Blood 130:1604-1605, 2017).

【 Schematic illustration of the activation of FX by the FVIIa-TF complex 】

Schematic illustration of the activation of FX by the FVIIa-TF complex

FXa is also generated by the proteolytic activation of FX with the active form of FIX (FIXa). The FIXa activation of FX requires the active form of FVIII (FVIIIa), a cofactor of FIXa. In the current schema on blood coagulation, it is believed that FVIIIa is generated by the thrombin activation of FVIII and that the FXa generation by FIXa-FVIIIa contributes to the amplification of blood coagulation not to initiation, leading to thrombin burst. More recently performed studies, however, have indicated involvement of the TF pathway products in the activation of FVIII. Given evidence that the FVIIa-TF complex generates FIXa , it is highly likely that the FXa generation by FIXa-FVIIIa occurs in an initiation phase of coagulation.

Our discovery of the previously unrecognized mechanism of the FVIII activation by the TF pathway product FXa-FVIIa-TF complex

Selective factor VIII activation by the tissue factor-factor VIIa-factor Xa complex. Blood.130(14):1661-1670, 2017

Schematic illustration of the activation of FVIII by FXa still bound to the FVIIa-TF complex and the generation of FXa by FIXa-FVIIIa

FVIIIの活性化図解
blood(R)

SERVICE

image

Development of the highly sensitive blood coagulation test “SMAT” kits

The novel thrombin production assays

What is the SMAT?

Based on the discovery of the novel coagulation mechanism, we have established the assays with very high sensitivity for determining the initial small amounts of thrombin that are here indicated as "SMAT": SMAT-FVIII is for the thrombin production via the FIXa-FVIIIa mechanism by which FVIII is activated by the FXa-FVIIa-TF complex; SMAT-TF is for the thrombin production via the FVIIa-TF pathway.

The potential applications and perspectives of the SMAT kits
  • ●For study aiming at the evaluation of abnormality and alteration in blood coagulation in patients with thrombotic and hemorrhagic complications
  • ●For development of research and diagnostic products for assessing the relationship of serious and dangerous illnesses including cancer and COVID-19 with blood clots
  • ●For development of prevention and treatment of serious and dangerous illnesses that are associated with blood clots
  • ●For development of extracorporeal circulation devices and analysis equipment for blood tests
         

● SMAT kit lineup ●

Research use only, not for use in diagnostic procedures.

SERVICE 01
The SMAT-TF kit

The SMAT-TF kit is utilized for specifically determining the TF-driven thrombin production independently of FVIII activation. The kit includes anti-FVIII antibody blocking the FVIIIa activity. The kit may provide an excellent approach for accessing hypercoagulable state and thrombosis caused by the FVIIa-TF pathway.


【 The SMAT-TF kit for determining the TF-driven thrombin production in an initiation phase of blood coagulation independently of FVIII activation 】
FVIIIに依存しないSMAT検査試薬キット原理図解
SERVICE 02
The SMAT-FVIII/IX kit
               

The abnormal function and defect of FVIII leads to severe, sometime life-threatening bleeding episode as reported in hemophilia patients.
In contrast, increased levels of FVIII in blood cause prothrombotic hypercoagulability in the venous and arterial systems. Thus, FVIII exerts a crucial function in the blood clot formation.
The SMAT-FVIII kit is utilized for specifically determining the thrombin production via the FIXa-FVIIIa mechanism by which FVIII is activated by the FXa-FVIIa-TF complex. The kit may provide excellent approaches for accessing bleeding and thrombosis risks caused by the defect and increase in FVIII, respectively.



This product is currently under development.
【 The SMAT-FVIII kit for determining FVIII-dependent thrombin production in an initiation phase of blood coagulation 】
FVIIIに依存するSMAT検査試薬キット原理図解
We also will be able to provide customized kits and contract service for supporting your research and development. Please feel free to contact to us.