Blood coagulation is a major and complex process, which occurs in a response to blood vessel injury.  It consists in a formation of clots to stop bleeding and begin repair of the damaged vessel: its wall is covered by platelets and fibrin containing clot.  The process almost begins instantly after the injury. 
Blood coagulation process involves two types of components: cellular components called platelets and protein components called coagulation factors.  Platelets immediately form a plug at the site of injury; this is called primary haemostasis.  Secondary haemostasis occurs simultaneously: proteins in the blood plasma, called coagulation factors or clotting factors, respond in a complex cascade to form fibrin strands which strengthen the platelet plug. 
The coagulation cascade of secondary haemostasis is divided into two pathways called the intrinsic pathway, or contact activation pathway, and the extrinsic pathway, also called tissue factor pathway.  Many coagulation factors are involved, but also cofactors and regulators, to correctly maintain the process. 
For instance, Protein C is an essential factor of a major mechanism for regulating clotting, named “anticoagulant pathway”.  The active form of protein C (activated protein C) is a serine protease which, when associated with another cofactor (protein S), degrades two factors of the clotting cascade essential to the massive generation of thrombin: factors Va and VIIIa.  The destruction of these factors negatively regulates the amount of thrombin formed, resulting in an anticoagulant effect.  This protein is particularly known to have pleiotropic biological activity: not only antithrombotic activity (Taylor et al, 1987; Gruber et al, 1990; Chesebro et al, 1992; Hanson et al, 1993; Arnljots et al, 1994; Sakamoto et al, 1994, Jang et al, 1995, Kurz et al, 1997; Gresele et al, 1998; Mizutani et al, 2000; Bernard et al 2001), but also anti-inflammatory activity (Emson, 2000), anti-apoptotic activity (Joyce et al, 2001) and pro-fibrinolytic activity (Comp et al, 1981; Rezaie, 2001). 
Factor IX (hereinafter referred to as FIX) is one essential serine proteases of the blood coagulation.  Deficiency of this protein causes a bleeding disorder called hemophilia B. During blood coagulation, activated FIX (FIXa) associates with its activated cofactor, factor VIIIa (hereinafter referred to as FVIIIa), converts its specific substrate factor X (FX hereinafter referred to as FX) into its activated derivative, activated factor X (hereinafter referred to as FXa). 
Factor X is another essential factor of the clotting cascade.  The activated form of FX (FXa) is the only serine protease which, associated with its cofactor (clotting factor Va), is capable of activating prothrombin to thrombin.  Furthermore, factor X long considered a passive bystander, is now presented as a direct player on a wide variety of cell types via activation of its two main receptors, protease-activated receptor-1 (PAR-1) and PAR-2.  Recent findings suggest that PAR-2 plays a crucial role in fibro-proliferative diseases such as fibrosis, tissue remodeling and cancer and point towards factor X as the important mediator coordinating the interface between coagulation and disease progression (Borensztajn et al.,  2008). 
The protein C, factor IX, and factor X are respectively glycoproteins of 62 kDa, 55 kDa, and 59 kDa synthesized in the liver.  Before their secretion into the plasma, their polypeptide chains undergo several post-translational maturations in order to become functional proenzymes. 
The two zymogens protein C and factor X are composed of an amino-terminal light chain and a carboxy-terminal heavy chain, resulting from a cleavage of peptide chain, where light and heavy chains are connected by a disulfure bridge.  The zymogen factor IX is a single chain glycoprotein. 
Like most serine protease precursors, protein C, factor IX, and factor X are zymogens lacking catalytic activity.  Their activation is the result of proteolytic cleavage in their heavy chains.  In protein C, this cleavage takes place at the N-terminal end of the heavy chain, releasing a 12 amino acid “activation” peptide.  In factor X, this cleavage takes place between the Arg193 and Ile194 residues of the zymogen, also releasing an “activation” peptide, of 52 amino acids.  In factor IX, two cleavages take place also releasing an activation peptide of a molecular weight approximately equal to 11 kDa from the internal region of the precursor molecule. 
Blood coagulation has to be well controlled to avoid any risk of bleeding or of clotting.  Thus, deregulation of blood coagulation process leads to serious disorders such as haemorrhage (increased risk of bleeding) and thrombosis (increased risk of clotting).  Pathologies due to an increased risk of clotting include serious disorders such as venous or arterial thromboses, in particular thromboses affecting the large calibre vessels, myocardial infarction, thrombotic disease, pulmonary embolism, coronary reocclusions after an angioplasty or a thrombolysis, and also clotting abnormalities in patients suffering from genetic abnormalities affecting the protein C gene or that of thrombomodulin.  Anticoagulants are given to people to stop thrombosis (blood clotting inappropriately presents in the blood vessels).  This is useful in primary and secondary prevention of deep vein thrombosis, pulmonary embolism, myocardial infarctions and strokes in those who are predisposed.  Bleeding is the most serious complication of the use of oral anticoagulation in the prevention and treatment of thromoboembolic complications.  Individuals anticoagulated with warfarin or heparin are typically treated with specific antidotes such as vitamin K or protamine, respectively, if they bleed or require surgery.  Unfortunately the therapeutic activities of warfarin, heparin, vitamin K, and protamine are associated with untoward side effects that complicate their use.  In contrast, specific and effective antidotes are not available for the reversal of the anticoagulant effects of the low molecular weight heparins (LMWH) or the new oral anticoagulants targeting factor Xa (fXa) (see for reviews Harenberg, 2008, Bauer, 2008, Khoo et al.,  2009).  When these new anticoagulant therapies are used, major bleeding might be observed.  Thus, prompt appropriate action, both mechanical and systemic, to control the bleeding is necessary.  This includes the cessation of anticoagulation therapy and, if possible, reversal of anticoagulation effects, using available, specific reversal agents.  There is currently a need for specific antidotes directed against these anticoagulants. 
On the other hand, pathologies of the haemorrhagic type particularly include haemophilias A or B (deficiencies respectively in factor VIII and IX).  These serious diseases are often complicated by the presence of “inhibitors” which are neutralizing allo-antibodies directed against the factor VIII or IX conventionally used for treatment. 
There is currently a need for improving treatment for these pathologies. 
The first strategy of treatment is to bypass the deficient steps of clotting cascade and regulation.  Another strategy for improving current treatment is to improve the half-life of used compounds, mainly proteins that are easily neutralized in plasma.  Another approach for improving treatment is to re-establish the auto-amplification system or retro-control. 
Treatments administered for hypercoagulation disorders like protein C deficiencies are protein C, activated protein C, protein C derivatives . . . .  Current treatments for haemophilias are administration of factor VIII or IX for haemophilia A and B, respectively. 
These treatments are expensive, in particular because of a need for repetitive injections due to the short half-lives of compounds, and show limits, like the development of inhibitors or neutralizing allo-antibodies directed against the factor VIII or IX conventionally used for treatment of haemophilias A and B. Furthermore, it has been observed that administration of recombinant proteins, especially factor IX to treat haemophilia B, is hampered due to a lower recovery compared to the administration of plasma derived product. 
Potential solutions have been proposed as new treatment strategies.  Particularly, the WO03035861 patent application described thrombin-cleavable chimeric derivatives of protein C and factor X.
However, the short half-life of these compounds limits their use for blood coagulation disorders.  The invention proposes a new approach to solve this technical problem.