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Coagulation Pathway Studies In Vitro

Coagulation Pathway Studies In Vitro

The drug development of anticoagulants and procoagulant agents are the most important for the treatment of thrombotic and hemorrhagic disorders, including cardiovascular diseases. So the in vitro screening platform for anticoagulants and procoagulant drugs plays a crucial role in the early stage of drug discovery. Medicilon provides studies of coagulation pathways, offering clients high-quality screening data to support further drug structure-activity relationship studies.

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  • The normal functioning of the coagulation mechanism requires the intricate interaction of multiple proteins, collectively referred to as coagulation factors. Currently, there are 15 known coagulation factors, including 12 factors from the classical coagulation pathway (Factors I to XIII, excluding VI), two factors from the kinin system and vwf. The ultimate outcome of the coagulation process is to convert fibrinogen into fibrin, and most of the coagulation factors are serine proteases.
    Specifically, the coagulation factors are as follows: Factor I: Fibrinogen; Factor II: Prothrombin; Factor III: Tissue Factor; Factor IV: Calcium Ion; Factor V: Labile Factor; Factor VII: Proconvertin; Factor VIII: Antihemophilic Factor A; Factor IX: Antihemophilic Factor B; Factor X: Stuart Factor; Factor XI: Plasma Thromboplastin Antecedent; Factor XII: Hageman Factor; Factor XIII: Fibrin-Stabilizing Factor.
    The traditional view of the coagulation cascade is that the blood clotting process is composed of three parts: the intrinsic pathway, the extrinsic pathway and the common pathway.
    The intrinsic pathway refers to that part of the process where the activated Factor XII forms the IXa-VIIIa-Ca2+-PL complex, which subsequently activates Factor X.
    The extrinsic pathway refers to the release of TF and the formation of TF-VIIa-Ca2+ complex, which activates Factor X. The common pathway is that part of the process where activated factor Xa and Va bind and activate thrombin, resulting in the conversion of fibrinogen to fibrin.
    Figure.1. Coagulation pathway mechanism diagram.webp
    Figure.1. Coagulation pathway mechanism diagram
  • Figure.2. Common anticoagulant targets.webp
    Figure.2. Common anticoagulant targets
    As our understanding has deepened, modifications and supplements have been made to the traditional coagulation cascade. It is now recognized that the coagulation process is not predominantly driven by the intrinsic pathway, but rather primarily activated through the tissue factor pathway. The maintenance of coagulation involves the participation of Factor VIII and IX. Additionally, the coagulation process is regulated by TFPI and other anticoagulant proteins. The VIIa-TF complex can also activate Factor IX, and the activation of Factor XII and XI is not necessary. Furthermore, Zn2+ and Mg2+ are also involved in the coagulation process. Therefore, the new model of coagulation activation suggests that in the initial phase, a small amount of thrombin is formed through TF release. Subsequently, thrombin further activates platelets, Factor VIII and V, resulting in amplification and acceleration of the coagulation process.
    The regulation of the coagulation mechanism is accomplished through various enzymes and complexes, and the main role is through thrombin. After the formation of thrombin, its functions can be involved in at least five aspects: initiation, amplification, termination, clearance of the blood clot and repair. Throughout the process of coagulation, a delicate balance with the anticoagulant system is necessary to maintain normal blood flow.
Medicilon case study
  • Case One: Detect the Activation Effects of FXIa and FVIIa on BeneFⅨ®
    BeneFIX is a recombinant human blood coagulation factor IX indicated for adults and children with hemophilia B (congenital factor IX deficiency or Christmas disease) for:
     On-demand treatment and control of bleeding episodes.   Perioperative management of bleeding.   Routine prophylaxis to reduce the frequency of bleeding episodes.
    BeneFIX is not indicated for induction of immune tolerance in patients with hemophilia B.
    BeneFIX activation by FXla.webp
    BeneFIX activation by FXla-2.webp
    FX activation by FIXa-FVIlla.webp
  • Case Two: Detect FX Activation by Novoseven and the Affinity of Novoseven and ATIII
    NovoSeven is a medicine used to treat bleeding episodes and to prevent bleeding after surgical procedures. It is used in patients with the following conditions:
     congenital haemophilia (a bleeding disorder present from birth) who have developed or are expected to develop ‘inhibitors’ (antibodies) against factor VIII or IX; acquired haemophilia (a bleeding disease caused by the development of inhibitors to factor VIII); congenital factor VII deficiency; Glanzmann’s thrombasthenia (a rare bleeding disorder), whose patients cannot be treated with a transfusion of platelets (components that help the blood to clot).
    FX activation by FVIla.webp
    Affinity of Novoseven and ATIII.webp
  • Case Three: Testing the Selective Inhibition on Factor XIa by BAY2433334
    Factor XI is a protein in the blood, which is converted into activated form factor XIa in the coagulation reaction. Factor XI  is a differentiated target used to develop more secure anticoagulant drugs. Because it plays a key role in the transformation of pathological and normal thrombosis, it can decouple coagulation and thrombosis. Patients with congenital factor XI deficiency (Hemophilia C) have a lower risk of venous thromboembolism and ischemic stroke, but rarely experience spontaneous bleeding.
    Asundexian (BAY2433334), developed by Bayer, is an oral Factor XIa inhibitor that can directly, effectively, and reversibly binds to the active site of Factor XIa, thereby inhibiting its activity. It can be used for secondary prevention in non -cardiac ischemic stroke patients, as well as the treatment of atrial fibrillation (arrhythmia) and recent myocardial infarction (heart attack). The inhibitory effect of Asundexian on Factor XIa is considered to reduce thrombotic incidents without increasing the risk of bleeding.
    Our company has tested the inhibitory effects of BAY2433334 on FXIa, FVIIa, FXa, FXIIa, Thrombin, Trypsin, Plasmin, TPA, Urokinase, Plasma Kallikrein, Chymotrypsin, Activated Protein C and TAFIa. The results, as shown in the figure below, indicate that BAY2433334 can selectively inhibit Factor XIa .
    美迪西案例-BAY2433334选择性抑制XIa因子的检测-1.png
    美迪西案例-BAY2433334选择性抑制XIa因子的检测-2.png
    美迪西案例-BAY2433334选择性抑制XIa因子的检测-3.png
    美迪西案例-BAY2433334选择性抑制XIa因子的检测-4.png
    美迪西案例-BAY2433334选择性抑制XIa因子的检测-5.png
    美迪西案例-BAY2433334选择性抑制XIa因子的检测-6.png
    美迪西案例-BAY2433334选择性抑制XIa因子的检测-7.png
    美迪西案例-BAY2433334选择性抑制XIa因子的检测-8.png
    美迪西案例-BAY2433334选择性抑制XIa因子的检测-8.png
    美迪西案例-BAY2433334选择性抑制XIa因子的检测-8.png
    美迪西案例-BAY2433334选择性抑制XIa因子的检测-8.png
    美迪西案例-BAY2433334选择性抑制XIa因子的检测-8.png
    美迪西案例-BAY2433334选择性抑制XIa因子的检测-8.png
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