Haemostasis (control of bleeding)
Haemostasis is initiated 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. Platelets are cell fragemnts about 3 um in diameter that pinch off from large cells in the bone marrow and contain actin and myosin. 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: Commercial 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, trauma and 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 and 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 crystals 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 release 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 linkable 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.
Types of Wounds:
McGowan Institute (the Pitt-McGowan Wound Research Consortium includes 20 wound clinics acress the state of Pennsylvania and one site in Maryland.
Chronic wounds: are wounds that do not heal in the expected timeframe (usually defined as between 4 weeks and 3 months), resulting in a lack of sustainable anatomical or functional tissue. Chronic wounds and their treatment reportedly cost healthcare systems USD 28 billion and USD 31.7 billion for primary and secondary diagnoses, respectively. However, as elderly populations are at higher risk of developing chronic wounds, and the proportion of people aged 65 and over is predicted to increase from 1 in 11 in 2019 to 1 in 6 in 2050, this cost will likely increase dramatically without the development of novel interventions. See Liu
Of the bacteria associated with chronic wound infections, the opportunistic pathogens Staphylococcus aureus and Pseudomonas aeruginosa are the most common. Both Gram-positive S. aureus and Gram-negative P. aeruginosa are also associated with biofilm production and the recent surge in the emergence of antimicrobial and multidrug-resistant strains. Biofilms consist of a range of bacterial and microbial communities connected by a robust layer of extracellular polymeric substances (EPS): primarily polysaccharides, proteins, nucleic acids, and lipids.
Antibiotics can be employed as a standalone treatment or alongside debridement, a treatment that involves thoroughly cleaning the wound and the chemical or mechanical removal of all unviable, infected, or thickened tissues from the wound area. However, up to 50% of antibiotic treatments may be unnecessary, resulting in the potential development of antimicrobial resistance. Naturally derived compounds, such as retinol, present in animal products and as chemical precursors in fruits and vegetables, have also been identified as potential candidate compounds for inclusion in chronic wound treatments. This is due to retinol’s antibacterial effect against various Gram-positive and Gram-negative bacteria, including both S. aureus and P. aeruginosa. In addition, curcumin, a lipophilic bioactive compound obtained from the rhizome of Curcuma longa Linnean plant has also displayed both antiseptic and potential antibiofilm abilities being tested against multiple species of bacteria and fungi. See Liu
Ulcer is a type of wound, but it’s specifically a chronic wound that develops due to underlying issues like poor blood flow or internal conditions. Wounds can be caused by external forces like cuts or abrasions, while ulcers are often caused by internal factors or diseases.
–Diabetic Foot Ulcers:
NexaBiome (pioneering the use of pahges to treat DFIs)
Each year 20 million people are affected by diabetic foot ulcers. Such ulcers are difficult to manage and often lead to minor (blow the ankle) or major (above the ankle) amputations. In fact, 80% of lower extremity amputations in people affected by diabetes are preceded by foot culers. For patients with a diabetic foot ulcer, the 5 year mortality rate is about 30% (>70% for those with a major amputation).
Diabetic foot ulcers are wounds that form on the feet of people with diaetes. They can subsequently be infected by opportunistic bacteria that cause diabetic foot infections. These infected ulcers are a common and highly morbid consequence of longstanding and/or poorly managed diabetes.
One promising treatment ot help address the growing threat of AMR is the use of bacteriophages (or pahges). Although there are not yet any phage products licensed as human medicine for pahge therapy, apges already are used as food treatment agents and in agriculture to treat plant diseases. They have only been used to treat infections in humans udner “compassionate use” where all other treatments have failed.
Proteins Involved in Wound Healing:
SerpinB3: long recognized as a disease marker has also been found to play a role in healing wounds. Many serpins are linked with disease when their balance goes awry, showing up in inflammation, fibrosis and cancer. SerpinB3 has been used extensively in cancer tests as an indicator of aggressive disease. But SerpinB3 in lab tests has also been shown to make skin cells move and cover wounds faster, working as effectively as a well-known healing booster Epidermal Growth Factor.
SerpinB3 works by activating Keratinocytes, the skin cells that normally move in to repair damage. When switched on, these cells become less sticky adn more mobile, allowing them to slide into the wound and rebuild tissue.