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Current Projects
Red Blood Cells : Platelets : Pluripotential Mononuclear Cells : Fresh Frozen Plasma
Hemostasis : Resuscitation

Red Blood Cells

a.  FDA approval for the extension of frozen storage of red blood cells:  One of the things we hope to accomplish is to persuade the FDA to allow for longer frozen storage of red blood cells.  The FDA has approved the frozen storage of red blood cells for up to 10 years.  However, our laboratory has provided data to the Navy Blood Program Office and Armed Services Blood Program Office which shows that red blood cells can be frozen for up to 37 years with no significant damage.   FDA is currently reviewing our submission for extension of the frozen red blood cell storage and a decision is expected soon.

Military significance: The Department of Defense currently has more than 60,000 units of frozen red blood cells stockpiled.  Several thousand of these frozen red blood cell units are nearing the 10-year outdate.  FDA-approval of an extension in the acceptable period for frozen storage of red blood cells will save the Department of Defense the cost of replacing these high-quality frozen red blood cells.

Civilian significance:  Like DOD, some civilian facilities have also stockpiled frozen red blood cells for use in emergency shortages and approval of this extension will also save them the costs of replacing these red cells.

b.  FDA approval of a closed, automated system to glycerolize (freeze) and deglycerolize (wash) red blood cells:  Also as part of our frozen red blood cell program, we have evaluated a new automated machine, the Haemonetics Model 215, which the FDA considers a 'closed' system.  The term 'closed' means that there is no potential for bacterial contamination to occur during the red blood cell freezing and washing procedures.  The current systems are considered 'open', and have the potential for bacterial contamination occurring during either the freezing or washing procedure, and the FDA has determined that these previously frozen red blood cells can be stored for only 24 hours following thawing and washing.  The need for the limited 24-hour post-wash storage period with the current systems is understandable.  If the red blood cells did become contaminated during the freezing or washing procedures, the longer they are stored in the refrigerator following washing, the better the chance the bacteria could repopulate and cause a transfusion reaction.    However, this limited post-wash storage period requires that frozen red blood cells be thawed and washed only when the need to use them within the 24 hour period is certain.  The new 'closed' system eliminates the potential for bacterial contamination.  Data provided to FDA by our laboratory as part of a multi-center study have shown that red blood cells processed using the Haemonetics 215 closed system can be stored for up to 15 days following washing with acceptable results.  Based on these data, the FDA has approved the Haemonetics 215 system with post-wash storage of previously frozen red blood cells for 14 days following washing.  It is expected that this extension will result in an increased use of frozen red blood cells in both the civilian and military communities.

Military significance:  The Department of Defense currently stockpiles frozen red blood cells for use in emergency situations.  This new, automated system will not only allow for increased post-wash storage but will also increase productivity.  Because the new system is automated, 1 technician can operate 8 to 10 machines at 1 time.

Civilian significance:  Approval of a closed, automated system with an extended post-wash storage period will simplify the use of frozen red blood cells allowing civilian centers to use frozen red blood cells for inventory control.  This is especially important in light of the recent American Red Cross blood shortages.

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Platelets

The NBRL is attempting to obtain FDA approval for frozen platelets.  Platelets, the cells in the blood which are used to stop bleeding, can be stored at room temperature for no more than 5 days.  Platelets cannot be stored in the refrigerator at 4 C because they undergo shape changes that reduce their survival following transfusion.  The disadvantage of the warmer room temperature storage is that it increases the risks of bacterial contamination.  Our laboratory began evaluating methods to freeze platelets in 1972.  From that time to the present, we have developed a relatively simple procedure to freeze platelets with a chemical called dimethyl sulfoxide (DMSO) which allows for frozen storage of the platelets at -80 C for up to 2 years.  The data we have obtained using this platelet freezing method have been submitted to FDA and we are currently awaiting their response.    We are currently developing a method where we remove most of the DMSO before the platelets are frozen, thereby eliminating the washing step after freezing.  This would significantly simplify the procedure for use by the civilian and military communities.

Military significance:  The limited 5-day liquid storage period does not allow enough time for the platelets to be collected at fixed facilities and transported to the field.  The Department of Defense currently has stockpiled more than 60,000 units of frozen red blood cells.  Once our platelet program is FDA approved, frozen platelets can be stockpiled along with frozen red blood cells.  The military would then be ensured of a supply of platelets adequate for their needs.

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Civilian significance:  Platelet availability in the civilian community is also affected by their limited storage period.  Single-donor platelets are expensive to collect and a method is needed to preserve them when quantities are high.

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Pluripotential Mononuclear Cells

Pluripotential mononuclear cells isolated from peripheral blood can be frozen with 10% DMSO and stored at -80 C for 1?years. The procedure to freeze pluripotential mononuclear cells has been modified by the removal of supernatant DMSO prior to freezing. This modification eliminates the need for post-thaw washing prior to transfusion.

Military and civilian significance: These HLA and ABO compatible previously frozen mononuclear cells can be used to treat individuals exposed to radiation injury.

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Fresh Frozen Plasma

We are continuing to evaluate prolonged frozen storage of the plasma component of blood.  Plasma is the component of the blood that contains clotting proteins and it is used to treat individuals who are actively bleeding.   Until our data was provided to FDA, plasma could only be stored at -20 C for up to 1 year.  Data collected at our laboratory demonstrated that the plasma could be stored at the colder temperature of -80 C for as long as 7 years.  Studies are now being done to determine if the plasma can be stored at -80 C for up to 12 years.

Military and civilian significance:  Extension of the acceptable frozen storage of plasma will save both the military and civilian communities the cost of replacing stockpiled frozen plasma.

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Hemostasis

For the past 5 years, our laboratory has expanded its focus from the preservation of blood to the evaluation of ways to reduce blood loss and stop bleeding in wounded individuals. Studies are being done in animals, normal volunteers and patients.

Role of Red Blood Cells in the Reduction of Blood Loss: The hemostatic function of red blood cells to prevent non-surgical blood loss is a current area of active investigation. Studies are being done to document that red blood cells are very important in hemostasis and transfusion of red blood cells to increase the hematocrit to 35 V% should be done in patients with non-surgical blood loss prior to the transfusion of platelets and fresh frozen plasma.

Current in vitro studies indicate that red blood cells may be responsible to activate platelets to improve their function. Flow cytometric studies of red blood cell and platelet surface markers are being performed to determine the mechanism of the red blood cells action on the platelet.

Role of Poly-N-Acetyl Glucosamine (p-GlcNAc) in the Reduction of Blood Loss in Patients Subjected to Cardiac Procedures and in Rodents Subjected to Hemorrhagic Shock: A new polymer, poly-N-acetyl glucosamine (p-GlcNAc) has been identified and found to be effective in achieving hemostasis in surgical procedures and trauma. The p-GlcNAc material is a unique polymer structure isolated and purified from large scale cultures of a marine microalga. The p-GlcNAc polymer structure has been determined via infra-red (FTIR), NRM and CD spectral data and is characterized as an ordered and regular (pseudo-crystalline) structure. This unique structure has been linked to the hemostasis performance of the product. Other polymers containing N-acetyl glucosamine such as chitin, chitosan, and hyaluronic acid do not have the same structure and do not exhibit the hemostatic activity, as demonstrated by in vitro and in vivo assays.
A bandage composed of the substance poly-N-acetyl glucosamine (p-GlcNAc or NAG) has been shown to reduce bleeding and blood loss in animals. The NAG bandage is being evaluated as a safe, simple and effective method for minimally trained military personnel to reduce bleeding time and blood loss in injured casualties.

The NAG bandage may also be used to control blood loss following injuries or surgical procedures in the civilian community. It is simple enough so that the first medical personnel at the scene could control the bleeding until the patient could be transported to the hospital. In addition to saving lives lost due to uncontrollable bleeding, the NAG bandage may also reduce blood transfusion requirements, which may be an important issue in these times of severe blood shortages.

A symposium on the results obtained with poly-N-acetyl glucosamine was held at Brigham and Women's Hospital on February 25, 2003. The symposium was organized by C. Robert Valeri, M.D. of the Naval Blood Research Laboratory and hosted by Herbert Hechtman, M.D. of Brigham and Women's Hospital and Harvard Medical School. The abstracts presented at this meeting may be reviewed here.

Taken together the animal and clinical data indicate that poly-N-acetyl glucosamine, an FDA approved agent manufactured by Marine Polymer Technologies Inc is an effective hemostatic agent whether applied directly to gastric varices; topically against bleeding surfaces of spleen or liver; against major wounds of the abdominal aorta; or on cardiac cathetherization sites in the groin.

Hemostasis was achieved, even in the presence of full heparinization and in acquired and congenital hemostatic defects. The mechanism of action is due to local vasoconstriction and by the activation of the clotting cascade through platelets and red cell activation.

The preclinical and clinical data presented at this symposium support a role for poly-N-Acetyl glucosamine in medical and surgical conditions, particularly in trauma.

Effect of Zeolite (QuikClotTM) To Reduce Blood Loss: Studies are currently being done to assess the safety and efficacy of zeolite as a hemostatic agent

In vitro studies done to date have shown that addition
of zeolite to platelet rich plasma allowed the platelet-rich plasma to quickly form a clot. Additional studies have shown that addition of zeolite to platelet-rich plasma results in activation of the platelets along with release of platelet-derived growth factors. Platelets treated with zeolite produced about four times the platelet-derived growth factors than untreated platelet-rich plasma. Additional studies are being performed to determine how the zeolite interacts with red blood cells, platelets and plasma proteins to form the clot.

Studies were performed in rodents subjected to blood loss which demonstrated that the QuikClotTM method reduced
blood loss and mortality. The zeolite "QuikClotTM" was shown to be effective in reducing blood loss and improving survival. Studies are being performed to determine if treatment with zeolite produces adverse effects.

You may review a PowerPoint presentation of the study that was done to evaluate the safety and therapeutic effectiveness of zeolite (QuikClot™) to restore hemostasis in the rodent and to assess the mechanism of action of zeolite on blood in vitro. (This slide show was presented at the annual ATACCC (Advanced Technical Applications for Combat Casualty Care) meeting held in St. Pete, FL in August 2003.)

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Resuscitation

Novel resuscitation solutions: The NBRL is currently involved in studies to assess new solutions to resuscitate individuals. Dr. Richard Veech of the National Institutes of Health developed a novel resuscitation solution to replace the commonly used lactated Ringer's intravenous solutions. Studies done by Dr. Veech, as well as other investigators, have shown that the lactate in Ringer's lactate solution may produce deleterious effects. This new solution, referred to as Ringer's ketone solution, uses ketones in place of the lactate.

The NBRL has worked with commercial companies to prepare large volumes of the Ringer's ketone solutions for evaluation by our laboratory and other investigators. The solution is being evaluated by our laboratory for chemical composition and stability as well as efficacy in a rodent shock model. Other Office of Naval Research-funded investigators are also evaluating the solutions we prepared in their animal models: Drs. Peter Rhee and Hasan Alam of the Uniformed Services University of Health Sciences (USUHS), Dr. George Kramer of the University of Texas and Dr. Susan Stern of the University of Michigan.

This PowerPoint presentation evaluates the storage stability of large volume parenteral ringer's ketone solutions prepared by filter sterilization. (This slide show was presented at the annual ATACCC (Advanced Technical Applications for Combat Casualty Care) meeting held in St. Pete, FL in August 2003.)

Hemoglobin-based oxygen carriers: Routinely crystalloid and colloid solutions are used to resuscitate hypovolemic, hypotensive individuals. These solutions have limited effectiveness in maintaining blood pressure. Colloid solutions had been considered to be superior to crystalloid solutions because they remain in the circulation longer. Recent studies, however, have suggested that the use of albumin may increase morbidity and mortality.

Hemoglobin based oxygen carrier solutions were developed as colloid solutions with the added benefit of having the ability to carry and deliver oxygen. Studies have shown that unmodified HBOC is not an optimum resuscitation solution because it has an unacceptably high oxygen affinity and it induces vascular constriction of vascular beds. HBOC solutions were modified using various techniques to reduce these adverse effects.

Studies are being done by our laboratory to assess the effect of hemoglobin-based oxygen carriers (HBOC) in rats subjected to a 50% exchange transfusion. The hemoglobin based oxygen carriers are compared to fresh blood and oncotic substances like hetastarch or pentastarch. This study will examine the effects of an exchange of 50% of the blood volume in rats with whole blood, a clinically available colloid (albumin, hetastarch or pentastarch) and two modified SFH solutions.

View the PowerPoint presentation that examines the effects of a 50% exchange transfusion in rats with hemoglobin based oxygen carrier solutions. (This slide show was presented at the annual ATACCC (Advanced Technical Applications for Combat Casualty Care) meeting held in St. Pete, FL in August 2003.)

 

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