Human blood-derived products having decreased fibrinolytic activity and uses thereof in hemostatic disorders
Inventors
HIJAZI, Abd Alrauf • Higazi, Muhamed
Assignees
Publication Number
US-11491186-B2
Publication Date
2022-11-08
Expiration Date
2037-08-31
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Abstract
The present invention provides therapeutic products with decreased fibrinolytic activity of t-PA-deficient and/or plasminogen-deficient blood products, as well as compositions, kits and methods using the same in treating bleeding associated with hereditary or acquired bleeding disorders. The invention further provides extracorporeal apparatus for blood or blood products Plasmapheresis aimed to prevent or treat bleeding disorders.
Core Innovation
The invention provides blood and blood-derived products that have reduced fibrinolytic activity by being tissue plasminogen activator (tPA)-deficient and/or plasminogen-deficient, including absence of plasmin activity. These products retain at least one coagulation factor and exhibit decreased clot lysis, as demonstrated by decreased R value in thromboelastography (TEG) analysis. The invention also includes compositions, biological glues or sealants comprising these products, kits combining the products with coagulation promoting agents, and methods of using them in treating bleeding or hemostatic disorders.
The problem addressed arises from the delicate balance between coagulation and fibrinolytic systems in normal hemostasis. Fresh-frozen plasma (FFP) and other blood products used to treat bleeding disorders contain both coagulation factors and fibrinolytic proteins like tPA and plasminogen. The presence of fibrinolytic proteins can undesirably induce clot lysis and impair effective hemostasis. Existing methods either remove fibrinogen, rendering the product unsuitable for clot formation, or remove plasminogen but retain tPA, resulting in residual fibrinolytic activity and limiting their use to topical applications.
To solve this, the inventors developed methods and products wherein blood or blood-derived products are treated to deplete both tPA and plasminogen, thereby reducing fibrinolytic activity. The products including tPA-deficient and plasminogen-deficient whole blood, plasma, FFP, platelet rich plasma (PRP), and cryoprecipitate contain coagulation factors with reduced capacity for clot dissolution. These products exhibit enhanced pro-coagulant and antifibrinolytic properties both in vitro and in vivo, improving efficacy in treating bleeding and providing superiority over commercial products that fail to remove tPA.
Claims Coverage
The patent discloses 12 main inventive features centered on blood or blood-derived products with reduced fibrinolytic activity, methods for their preparation and use, compositions including glues, methods of treatment, kits, and extracorporeal procedures involving specific depletion of tPA and plasminogen.
Reduced fibrinolytic blood product comprising coagulation factors
A blood or blood-derived product that is tissue plasminogen activator-deficient and plasminogen-deficient or devoid of plasmin activity, which exhibits reduced fibrinolytic activity demonstrated by a decreased R-value in thromboelastography (TEG) compared to untreated product.
Specific blood components as source of the reduced fibrinolytic product
The product can be whole blood, plasma, fresh frozen plasma (FFP), platelet rich plasma (PRP), or cryoprecipitate of autologous or allogeneic origin.
Composition incorporating the reduced fibrinolytic blood product with pharmaceutical carriers
Compositions comprising the blood or blood-derived product along with pharmaceutically acceptable carriers, excipients, additives, diluents, and adjuvants, optionally supplemented with fibrinogen or other coagulation factors.
Biological glue or sealant comprising reduced fibrinolytic blood product and coagulation agents
A biological glue or sealant that includes the blood product deficient in tPA and plasminogen along with at least one coagulation promoting agent such as fibrinogen, thrombin or any fibrinogen cleaving enzyme, and calcium, each provided in separate compartments.
Biological glue or sealant further comprising fibrinolytic inhibitors
The glue or sealant also includes at least one inhibitor of plasmin, plasminogen, or plasminogen activator to enhance antifibrinolytic activity.
Therapeutic methods for treating bleeding using the reduced fibrinolytic products or compositions
Administering to subjects having hemostatic or bleeding disorders a therapeutically effective amount of the blood product or compositions or biological glues containing the tPA- and plasminogen-deficient product.
Administration of product containing fibrinolytic inhibitors
Products administered may also contain at least one inhibitor of plasmin, plasminogen, and plasminogen activator to enhance the therapeutic effects.
Parenteral administration for hereditary or acquired bleeding disorders
The tPA-deficient and plasminogen-deficient blood-derived product is administered parenterally for treating hereditary or acquired hemostatic disorders including coagulation factor deficiencies and undefined bleeding tendencies.
Treatment of acquired hemostatic disorders with extracorporeal apparatus
Use of the products or methods involving extracorporeal apparatus such as apheresis or cardiopulmonary bypass to prepare or administer the reduced fibrinolytic blood products for bleeding management in acquired bleeding conditions.
Topical use of the biological glue or sealant comprising reduced fibrinolytic blood product
Topical administration of the biological glue or sealant containing the tPA- and plasminogen-deficient blood product for treatment or prevention of bleeding induced by surgery, trauma, or fibrinolytic/thrombolytic therapy.
Kit comprising reduced fibrinolytic blood product and coagulation agents
Kits that include at least one blood or blood-derived product deficient in tPA and plasminogen and one or more coagulation promoting agents such as fibrinogen, thrombin, and calcium, optionally provided in separate compartments.
Methods and apparatus for preparing reduced fibrinolytic blood products
Methods for preparation by affinity depletion using agents that specifically bind tPA and plasminogen, including use of tranexamic acid or lysine analogs, and extracorporeal procedures and apparatus (e.g., apheresis, CPB machines) incorporating such techniques to prepare and return depleted blood to subjects.
The claims comprehensively cover the concept of blood or blood-derived products depleted of both tPA and plasminogen to reduce fibrinolytic activity, their preparation methods using specific affinity depletion, compositions including biological glues and therapeutic methods for treating bleeding related to hereditary or acquired disorders. Kits and extracorporeal apparatus for preparation and administration are also protected, providing an extensive framework for the invention's clinical applications.
Stated Advantages
Reduced fibrinolytic activity enhances clot stability and prevents premature clot dissolution during treatment of bleeding disorders.
Improved hemostatic efficacy compared to conventional plasma products that retain fibrinolytic proteins.
Products are suitable for both systemic (parenteral) and topical administration including biological glue applications.
Pro-coagulant and antifibrinolytic properties of the products minimize administered dose and reduce bleeding risk.
Extracorporeal preparation methods allow autologous or allogeneic use with depletion of fibrinolytic components.
The inventive products show increased shelf-life due to absence of fibrinolytic proteins.
Superior efficacy over existing commercial products that do not remove tPA, as demonstrated by in vitro and in vivo models of bleeding.
Documented Applications
Treatment, prevention, prophylaxis, or amelioration of bleeding and hemostatic disorders including hereditary coagulation factor deficiencies (I, II, V, VII, X, XI) and undefined bleeding tendency.
Management of acquired bleeding disorders such as surgery-induced bleeding, trauma-induced bleeding, acute gastrointestinal bleeding, burns, hemorrhagic stroke, bleeding in emphysema and COPD, bleeding associated with childbirth, disseminated intravascular coagulation (DIC), and fibrinolytic or thrombolytic therapy-induced bleeding.
Use during major surgeries including open heart surgery with cardiopulmonary bypass and liver transplantation surgery.
Topical application as biological glue or sealant for surgical wound hemostasis, tissue adhesion, and prevention of bleeding or fluid leaks.
Extracorporeal blood treatment procedures including apheresis and cardiopulmonary bypass to produce blood products with reduced fibrinolytic activity for autologous or allogeneic transfusion.
Treatment or prevention of bleeding in inherited and acquired conditions at sites rich in fibrinolytic activity.
Treatment of specific bleeding conditions such as postpartum hemorrhage and Goodpasture syndrome.
Potential use in improving outcomes in intra-articular injection treatments such as platelet-rich plasma (PRP) therapy for knee osteoarthritis by reducing deleterious fibrinolytic activity.
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