Extracorporeal device and matrix for removing fibrinolytic proteins from biological fluids, methods and uses thereof
Inventors
HIJAZI, Abd Alrauf • DVASHI, Zeev
Assignees
Publication Number
US-11975132-B2
Publication Date
2024-05-07
Expiration Date
2039-02-28
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Abstract
The presently disclosed subject-matter provides specific compositions, conjugates, device, kits and systems for depleting fibrinolytic agents from biological fluids. The presently disclosed subject-matter further relates to the resulting biological fluid products that are devoid in fibrinolytic activity, therapeutic methods and uses thereof. The conjugates comprise a particle, at least one linker and at least one amino acid, derivative thereof or analog thereof being at least one of 4-(aminomethyl)-cyclo-hexane-carboxylic acid (tranexamic acid), epsilon-amino caproic acid, lysine, cyclohexanecarboxylic acid and 4-methyl-cyclohexanecarboxylic acid. A plurality of different conjugates (e.g. differing in particle size or type of linker) can be used.
Core Innovation
The invention provides specific compositions, conjugates, devices, kits and systems for efficiently depleting fibrinolytic agents, specifically plasminogen and tissue plasminogen activator (tPA), from biological fluids such as blood, plasma, and blood-derived products. The compositions comprise conjugates formed by a particle, at least one chemical linker, and at least one amino acid, derivative or analog thereof, particularly including 4-(aminomethyl)-cyclo-hexane-carboxylic acid (tranexamic acid) and related compounds. The plurality of conjugates includes at least two different conjugates differing in one or more components, such as particle size or linker type. Devices embedding these conjugates allow selective affinity-depletion of fibrinolytic proteins to generate biological fluid products lacking fibrinolytic activity.
The problem addressed arises from the challenge of managing hemostasis, wherein an imbalance between coagulation and fibrinolytic activity can lead to excessive bleeding or pathological clotting. Fresh-frozen plasma (FFP), the standard treatment for bleeding disorders, contains fibrinolytic proteins which can induce unwanted clot lysis, limiting its efficacy especially in conditions of hyperfibrinolysis seen in trauma, surgery, childbirth, and other bleeding disorders. Existing methods to remove fibrinolytic proteins either remove crucial coagulation factors or fail to adequately eliminate fibrinolytic activity systemically. Thus, there is a need for a device and compositions that specifically and effectively remove fibrinolytic proteins from plasma and blood products to improve therapeutic outcomes for bleeding conditions.
Claims Coverage
The patent includes several independent claims centered on compositions of conjugates for fibrinolytic protein depletion, devices embedding these conjugates for processing biological fluids, and methods for depleting fibrinolytic proteins from body fluids. These claims cover the inventive composition, apparatus and methods for treatment.
Composition of conjugates for fibrinolytic protein depletion
A plurality of conjugates or composition comprising conjugates each having a particle, at least one linker and an amino acid, derivative or analog, specifically 4-(aminomethyl)-cyclo-hexane-carboxylic acid (tranexamic acid), with at least two different conjugates differing in particle or linker.
Device for depleting fibrinolytic proteins from body fluids
A device having a housing with fluid inlet and outlet ports, containing a control volume with a plurality of groups of particles including at least two size-different groups of conjugated particles comprising the aforementioned conjugates for affinity depletion of fibrinolytic proteins.
Battery of devices for enhanced fibrinolytic protein depletion
A battery comprising interconnected plurality of the devices in fluid communication, arranged serially or in parallel to enhance depletion efficiency or handle larger fluid volumes.
Kit comprising the device and reservoirs
A kit including the device with saline, acceptor plasma and wash waste reservoirs, configured for selective and non-concurrent fluid communication for processing biological fluids.
System for fibrinolytic protein depletion including the device and fluid handling components
A system integrating at least one device with saline and donor reservoirs at the inlet, and acceptor plasma and wash waste reservoirs at the outlet, allowing controlled treatment of biological fluids.
Method for depleting fibrinolytic proteins from body fluids
A method involving subjecting body fluids to an affinity depletion procedure by contacting body fluids with an effective amount of the described conjugates or compositions or devices embedding them, to recover fibrinolytic protein-depleted fluids.
Method for extracorporeal depletion of fibrinolytic proteins in subjects
A method comprising transferring body fluids of a subject into an extracorporeal apparatus including the device to deplete fibrinolytic proteins and reintroducing the depleted fluids to the subject.
The claims comprehensively cover the composition of conjugates with particles and linkers conjugated to tranexamic acid or analogs for depletion of fibrinolytic proteins, devices and systems incorporating these conjugates for fluid treatment, as well as methods for their application in depleting fibrinolytic activity from biological fluids including extracorporeal procedures.
Stated Advantages
Efficient and specific depletion of fibrinolytic proteins like plasminogen and tPA from biological fluids resulting in products devoid of fibrinolytic activity.
Improved hemostasis and prevention of massive bleeding by shifting the balance from hyperfibrinolysis to coagulation.
Generation of enhanced blood and plasma products with antifibrinolytic qualities for better clinical outcomes in bleeding disorders, trauma, surgery and other conditions.
Capability to use devices and methods in extracorporeal procedures such as plasmapheresis and cardiopulmonary bypass for real-time fibrinolytic protein depletion.
Use of mixed particle sizes in conjugates improves fluid flow and efficiency while reducing material costs.
Safety demonstrated in animal models and compatibility with anticoagulant treatments without inducing thrombotic complications.
Documented Applications
Treatment, prevention, prophylaxis, amelioration, inhibition of bleeding and hemostatic disorders in subjects in need, including hereditary and acquired bleeding disorders.
Improvement of blood and blood-derived products such as fresh frozen plasma (FFP), platelet rich plasma (PRP), cryoprecipitate by depletion of fibrinolytic proteins.
Extracorporeal treatment of body fluids in subjects via plasmapheresis or cardiopulmonary bypass machines for fibrinolytic protein depletion.
Management of bleeding in trauma surgery, childbirth, disseminated intravascular coagulation (DIC), gastrointestinal bleeding, burns, hemorrhagic stroke, liver transplantation, open heart surgery, and minor and major surgeries.
Use in patients undergoing fibrinolytic or thrombolytic therapy and those requiring anticoagulation treatment to reduce bleeding risk.
Treatment of conditions associated with excessive fibrinolysis such as hyperfibrinolysis and associated bleeding symptoms.
Use in veterinary and non-human mammals for analogous bleeding disorders and hemorrhagic conditions.
Potential use in orthopedics such as intra-articular injections in knee osteoarthritis to improve outcomes by reducing fibrinolytic degradation.
Clinical use demonstrated in a multicenter randomized controlled trial for acute upper gastrointestinal bleeding patients.
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