Composition comprising red cell-derived microparticles and method of treating excessive bleeding
Inventors
Ahn, Yeon S. • Jy, Wenche • Horstman, Lawrence L. • Pamukcu, Rifat
Assignees
Rxmp Therapeutics LLC • Rxmp Therapeutics Inc
Publication Number
US-11241457-B2
Publication Date
2022-02-08
Expiration Date
2037-11-29
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Abstract
The disclosure provides a composition comprising red cell-derived microparticles (RMPs) demonstrating acetylcholine esterase (AchE) activity of less than 350 pmol/min/106 particles/uL. The disclosure further provides a method of treating excessive bleeding comprising administering the composition to a subject.
Core Innovation
The invention provides a composition comprising red cell-derived microparticles (RMPs) demonstrating acetylcholine esterase (AchE) activity of less than 350 pmol/min/106 particles per microliter, with optional features including 20%-50% phosphatidylserine display and a mean diameter of about 0.40-0.6 μm. The composition optionally shortens time to initial clot formation by at least two minutes as measured by thromboelastography (TEG) in whole blood and plasma. A method of treating excessive bleeding by administering this composition to a subject is also provided.
The problem solved is the need for safe, effective, and economical agents to treat excessive bleeding, which is a common life-threatening complication. Current therapies such as blood transfusions and platelet transfusions suffer from drawbacks including scarcity, high cost, immunogenicity, and risks of adverse effects like anaphylaxis, hemolytic reactions, and transfusion-related lung injury. Platelet-derived therapies also carry risks of thrombogenesis and immunoreactivity. The invention addresses these limitations by providing RMP compositions with reduced toxicity, good hemostatic efficacy, and ease of production and storage.
The composition is based on a novel subpopulation of RMPs characterized by significantly reduced AchE activity correlating with reduced toxicity, reduced lipid raft content, and an optimal level of phosphatidylserine that balances procoagulant activity and minimizes thrombogenic potential. These RMPs can be produced from fresh or stored red blood cells using high-pressure extrusion and fragmentation techniques. Notably, RMPs from frozen RBCs are as effective as those from fresh RBCs, enabling scalable and economical production. The composition can be administered in various routes for effective and immediate treatment of bleeding caused by multiple disorders or medications including blood thinners.
Claims Coverage
The patent includes two independent claims covering a composition of RMPs with specific biochemical and physical characteristics and a method of treating excessive bleeding using this composition.
Composition with red cell-derived microparticles demonstrating low acetylcholine esterase activity
A composition comprising red cell-derived microparticles demonstrating acetylcholine esterase (AchE) activity of less than 350 pmol/min/106 particles per microliter.
Composition having RMPs with specific phosphatidylserine display and size characteristics
RMPs display 20%-50% phosphatidylserine; the composition shortens clot formation time by at least two minutes as measured by thromboelastography; mean RMP diameter is about 0.40-0.6 μm; internal density of RMPs is less than 3.5% of whole red blood cells.
Method for treating excessive bleeding by administering the RMP composition
A method for treating excessive bleeding comprising administering to a subject the composition described, targeting bleeding caused by conditions such as thrombocytopenia, platelet dysfunction, or anticoagulant treatment including Coumadin, low molecular weight heparin, and inhibitors of coagulation factors.
The claims cover compositions of RMPs with reduced AchE activity and defined physical and functional profiles that confer hemostatic efficacy with reduced toxicity, as well as methods of treating excessive bleeding by administering these compositions.
Stated Advantages
RMPs offer ease and economy of production due to the abundance of red blood cells as source material.
RMPs have minimal immunogenicity, unlike platelet-based therapies which carry risks of immune reactions.
The composition has an indefinite shelf-life with room temperature storage, eliminating the need for blood bank storage and making it advantageous in emergency situations.
RMPs from universal donors (type O Rh negative) can be administered without cross-matching, enabling immediate use.
The unique subpopulation of RMPs shows reduced toxicity and adverse side effects compared to previous RMP compositions.
The composition effectively shortens clotting time and restores normal clot formation even in presence of blood thinners, providing universal hemostatic activity.
Documented Applications
Treatment of excessive bleeding caused by platelet disorders, coagulation disorders, chronic liver disease, trauma, surgery, intracerebral hemorrhage, renal disease, thrombocytopenia, platelet dysfunction, hematomas, internal hemorrhage, hemarthroses, hypothermia, menstruation, pregnancy, and Dengue hemorrhagic fever.
Treatment of bleeding caused by drug therapies including anticoagulants such as Coumadin, heparin, inhibitors of prothrombinase complex, FXa inhibitors, thrombin inhibitors, aspirin, and clopidogrel.
Administration in subjects undergoing therapy with blood thinners, to correct hemostatic defects induced by such medications.
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