Haemostasis (control of bleeding)

Haemostasis is initaited by the formation of a complex between tissue factor (TF) being exposed to the circulating blood following an injury to the vessel wall, and FVIIa which is present in the circulation in an amount corresponding to about 1 of the total FVII protein mass. This complex is anchored to the TF-bearing cell and activates FX into FXa and FIX into FIXa on the cell surface. FXa activates prothrombin to thrombin which activates FVIII, FV, FXI and FXIII. In addition, the limited amount of thrombin formed in this initial step of haemostasis also activates the platelets. Following the action of thrombin on the platelets, the platlets change shape and expose charged phospholipids on their surface which form the template for the further FX activation and the full thrombin generation. Further FX activation on the activated platelet surface occurs via a FIXa-FVIIIa complex formed on the surface of the activated platelet, and FXa then converts prothrombin into thrombin while still on the surface. Thrombin then converts fibrinogen into fibrin which is insoluble and which stabilizes the initial platelet plug. This process is compartimentalized (i.e., localised to the site of TF expression or exposure, thereby minimizing the risk of a systemic activaiton of the coagulation system. The insoluble fibrin forming the plug is also stabilised by FXIII-catalysed cross linking of the fibrin fibers. 

Diseases of Haemostasis

Haemophilia: is a group of hereditary disorders which impairs the control of bleeding.

–treatment: 

(i) FVIIa: Commerical preparations of recombinant human FVIIa are sold as NovoSeven® for treatment of bleeding episodes in haemophilia A and B patients.

(ii) Plasminogen Activator Inhibitor (PAI-1): is also referred to as endothelial type plasminogen activator inhibitor (c-PAI) and inhibits urokinase type plasminogen activator (u-PA) and tissue type plasminogen activator (t-PA). Rojkjaer (US 2006/0030531) discloses use of PAI-1 for treating bleeding episodes due to surgery, traumaand other forms of tissue damage. The bleedings can occur in organs such as the liver, lung, gastrointestinal tract. Jian-Dong (US 12/670,778) also disclose a method for treatment of a hemorrhagic lung condition by administering PAI-1.

Wound Healing: (Process)

Would healing is a complex biological process involving extracellular matrix, blood cells, parenchymal cells and mediators such as cytokines. After the wound reaches hemostasis, the point where bleeding stops, the healing process begins. It occurs in 3 stages: (1) inflammation, (2) tissue formation (proliferation), and (3) tissue regeneration. 

(1) Within 4-6 hours after injury, inflammation begins. During inflammation, neutrophils, monocytes and macrophages infiltrate the wound. These phagocytic cells release growth factors for the proliferative phase, enzymatic mediators (proteases) that degrade proteins, and phagocytose bacteria, dead and dying cells thus debriding the wound.

(2-3) In the proliferation phase, collagen is deposited, forming scar tissue. Fibroblasts produce proteoglycans, which bind the collagen fibers together. Over time, the collagen is degraded by proteases adn remodeled into a stronger scar structure.

Wound Healing Products 

Surgical wound closure is currently acheived by sutures and staples that facilitate healing by pulling tissues together.

QuikClot: mineral zeolite cyrstals cause adsorption of the water molecules in the blood, thus concentrating the clotting factors and accelerating blood clotting. The water adsorption mechanism of mineral zeolite cannot occur without the rlease of a large amount of heat. As such, application results in high termperatures and severe burns at the injury site, making later medical care more complicated.

HemCon bandage: contains a chitosan mixture which has a positive charge and attracts red blood cells which have a negative charge. The red blood cells are drawn into the dressing, forming a seal over the wound and stabilizing the wound surface. However, the chitosan network can be saturated with blood and fail quickly when faced with brisk flow. The HemCon bandage patch is available only as a stiff patch that cannot fit easily into irregular wounds.

Gelatin:Preiss-Bloom (WO2008076407)  discloses a cross linikable protein and a non-toxic material which induces crooss linking of the cross linkable protein. Preferably, the cross linkable protein includes gelative and the non-toxic material is transglutaminase. When actied upon by a translutaminase, gelatin, which is a denatured form of the protein collagen, undergoes rapid crosslinking to form a virant gel. The gelation process that takes place is extremely similar to the nature late stage clotting cascade that frigin underoges when it comes into contact with Factor XII and calcium.

Italdermol® Triticum vulare: is a creme used for wound healing whcih includes Tricum vulare (see natural products below) and the antimicrobiotic 2-Fenoxietanol. Pehnooxyethanol is a germicidal aromatic alcohol often used with quaternary ammonium compounds. 

Natural Products for Wound Healing

Tumeric: reportedly augments the healing process of both chronic and acute wounds (see US Patent No. 5,401,504).

Triticum vulare: is the commonly known weat plant and is well-known for accelerating tissue repair. A specific aqueous extract of Triticum vulgare (TVE-DAMOR) manufactured by Farmaceutici DAMOR (Naples, Italy) is currently an active component in the manufacture of certain pharmaceutical products already marketed in Italy and abroad under the brand name Fitostimoline®, in the formulation of cream and medicated gauze and is commonly used for the treatment of decubitus ulcers, burns, scarring delays, dystrophic diseases, and in conditions in which it is necessary to stimulate re-epithelialization or tissue regeneration processes.