Expanded utility of red-cell derived microparticles (RMP) for treatment of bleeding

Abstract

Red blood cell membrane derived microparticles (RMP) are safe, economical, effective hemostatic agents in the treatment of a wide range of bleeding conditions and can, therefore, be considered as universal hemostatic agents. Effective RMP are produced from red blood cells using a high-pressure extrusion membrane shear process. The RMP can be lyophilized after production and retain activity even when stored at room temperature. RMP can be administered to original donors (autologous treatment), thus avoiding transfusion complications, or can be administered to blood type compatible recipients. RMP produced from type O, Rh negative red cells can be given to any person regardless of blood type. RMP can be administered to reduce excessive bleeding resulting from trauma, surgeries, invasive procedures and various bleeding disorders such as platelet disorders, either congenital or acquired, and coagulation disorders, either congenital or acquired. Administration of RMP prepared according to the invention demonstrates effectiveness in safely reducing bleeding.

Description

CROSS-REFERENCE TO PRIOR APPLICATIONS[0001]The present application is a divisional of U.S. patent application Ser. No. 13 / 357,106, filed Jan. 24, 2012 which claims benefit and priority from U.S. Provisional Application No. 61 / 457,203, filed on Jan. 28, 2011 and is also a continuation-in-part of and claims benefit and priority from U.S. patent application Ser. No. 11 / 792,399, filed Jun. 6, 2007, now U.S. Pat. No. 8,105,632, issue date of Jan. 31 2012, which application was the U.S. National Phase of PCT / US2005 / 044064, filed Dec. 7, 2005, which was based on U.S. Provisional Patent Application No. 60 / 633,417, filed Dec. 7, 2004; all of the aforementioned applications are incorporated herein by reference.U.S. GOVERNMENT SUPPORT[0002]N / ABACKGROUND OF THE INVENTION[0003]Area of the Art[0004]The present invention is in the area of hematology and more specifically in the area of novel treatment for bleeding.[0005]Description of the Background[0006]The invention relates to improved compositi...

AI Technical Summary

Benefits of technology

[0017]The present invention (RMP) shows significant advantages over existing treatment options. In contrast to blood bank products, (a) RMP have indefinite shelf-life with room temperature storage and does not need to be stored in blood banks; (b) RMP produced from type O Rh negative red cells (universal RMP) can be administered immediately without cross-matching; and (c) RMP can often substitute for blood-bank products. In addition, use of autologous RMP (made from patient's own blood), can be used to eliminate major risks of transfusion complications.

[0021](3) Autologous option. RMP can be made from the patient's own blood and infused back to the original donors when they bleed or are at high risk of bleeding. The use of autologous RMP will eliminate complications of allogeneic blood transfusion. This option is well suited to patients who anticipate bleeding problems such as prior to surgery or diagnostic or therapeutic invasive procedures or chemotherapy which often induces bone marrow failure and severe thrombocytopenia. Systemic diseases may also result in thrombocytopenia. Those who take anticoagulants or antiplatelet drugs or agents frequently suffer bleeding complications. They can prepare their own autologous RMP to be used safely in case of bleeding. In addition, religious groups which refused normal transfusion could benefit by this option.

[0024]RMP produced by the methods described herein can be used fresh or stored. Fresh RMP can be made in local blood banks or laboratories and distributed to operating rooms, clinics, hospitals and other medical settings. RMP can be stocked almost anywhere including in pharmacies, ambulances, operating rooms, clinics and hospitals. Initial work on RMP produced the product by various types of red cell membrane disruption such as sonication and treatment with ionophores. However, these methods were cumbersome, difficult to scale up and might produce RMP that were suboptimal. We have now developed a method of producing RMP using high-pressure membrane shear technology. This method produces RMP free of any additives and is readily scalable and easy to implement.

[0027]The use of RMP will reduce the strain on limited supplies at blood banks. In addition, since RMP produced from expired blood have been found to be as effective as RMP from very fresh blood, their production will not place added burden on supplies. It is anticipated that RMP will replace the need for transfusion in many situations. Since RMP have unlimited shelf-life, and can be produced economically, their use is expected to be at least cost-competitive with currently used blood products, resulting in an overall substantial saving in health care costs.

Problems solved by technology

The bleeding patient poses a major medical challenge in all medical specialties such as surgery, trauma, obstetrics / gynecology, cardiology, neurology, hematology, etc.

At present, transfusion of banked blood products is the mainstay of treatment for excessive bleeding, but transfusion is very expensive [1] and carries risks of serious short- and long-term complications.

Therefore, blood transfusion as presently employed often fails to save the lives of many bleeding victims.

Furthermore, since blood products must often be given before the cause of bleeding is identified, transfusion may fail to arrest bleeding and merely replaces lost blood while the bleeding continues.

Without these specific therapies to correct underlying etiology, bleeding will not stop and patients will be exposed to endless transfusions.

No such agent is yet available in spite of a century-long search.

As already explained, blood can be a life-saving resource, but blood is becoming increasingly scarce and expensive due to rising demand, limited supply, and more stringent regulations.

This situation can only get worse with increasing age of the population.

All these new anticoagulants and antiplatelet medications have serious side effects of promoting bleeding and, thus, increase bleeding complication and, hence, the demand for more transfusions.

However, there is no effective antidote for new anticoagulants such as low molecular weight heparin, e.g., Lovenox (enoxaparin) (which can be partially reversed by protamine) and Fragmin (dalteparin), Arixtra (fondaparinux), Pradaxa (dabigatran) and Xarelto (rivaroxaban) and for most antiplatelet drugs (e.g., aspirin, Plavix and their analogs).

Therefore, bleeding resulting from new anticoagulants and antiplatelet drugs imposes new challenges in patient management.

Although transfusion of banked blood is a mainstay of therapy for bleeding, other measures have been advocated, such as antifibrinolytic agents, DDAVP [2], but these treatments are not widely used because their efficacy is unproven.

Recombinant Factor Vila (i.e., NovoSeven) gained much attention and showed great promise [3], but its use is limited by prohibitive cost (e.g., in excess of $1 million for a single patient with high levels of FVIII inhibitors) and by reports of serious thrombotic complications.

Lyophilized platelets (LyoPLT) are under current study but may be impractical compared to RMP due to (i) the high costs of scarce platelets, (ii) risk of thrombogenesis, and (iii) immuno-reactivity.

The total volume of circulating platelets in blood is only 20 ml, about 1 / 250 that of red cells, so starting material is costly and scarce.

Platelets are highly immunogenic due to HLA, ABO, Rh, and platelet-specific antigens, which are impractical to cross match, hence adverse reactions are frequent.

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