Reported by: Dr. V. S. Karra, Ph.D.
“Emergency treatments for stopping the flow of blood from cuts and other external injuries save thousands of lives each year,” Lavik pointed out. “But we have nothing that emergency responders or military medics can use to stop internal bleeding permanently or at least long enough to get a patient to a hospital. There’s a tremendous need in the military, where almost 80 percent of battlefield traumas are blast injuries. In civilian life, there are many accidents, violence-related injuries and other incidents that result in internal bleeding.”
Lavik’s team, which is at Case Western Reserve University, was inspired by studies showing there are few options to treat soldiers in Afghanistan and Iraq who suffer internal injuries from the roadside bombs known as improvised explosive devices and other blasts. They wanted to develop a treatment military medics could use in the field to stabilize wounded soldiers en route to definitive care in a hospital.
“The military has been phenomenal at developing technology to halt bleeding, but the technology has been effective only on external or compressible injuries,” Lavik said. “An emergency treatment for internal bleeding could provide a broader ability to stop life-threatening hemorrhage.”
Currently, no effective treatments exist that are portable and can stop internal bleeding at the scene, Lavik explained. At the hospital, however, patients typically undergo surgery and receive donated platelets or something called factor VIIa, which helps with clotting, but both can cause immune problems. Factor VIIa also can potentially cause blood clots elsewhere in the body, not just at the site of bleeding, increasing stroke risk. Other alternatives have been developed in the laboratory, but they’ve had similar side effects and are not currently used in hospitals.
Lavik and colleagues are developing synthetic platelets. These are artificial versions of the disc-shaped particles in blood that collect on the jagged edges of cut blood vessels and launch the chain of biochemical events that result in formation of a clot that stops the flow of blood. The synthetic platelets are special nanoparticles, so small that 10 would fit across the width of a single human hair. Their role is to stick to natural platelets and leverage quicker and more efficient clotting at the site of an internal wound.
The nanoparticles are spheres that are made of the same polyester material used in dissolvable sutures, and they disappear from the body after doing their work. The particles have an outer coating of polyethylene glycol (PEG), the same thick, sticky substance used as a thickening agent in skin creams, toothpastes and other consumer products. Researchers then attach a peptide, or small piece of protein, that sticks to platelets. The end product is a white powder that has a shelf-life without refrigeration of at least two weeks — almost twice as long as the donated natural platelets now administered to control bleeding. Unlike donated platelets or factor VIIa, the synthetic platelets do not require refrigeration.
In tests on laboratory rats, stand-ins for humans in such experiments, the artificial platelets worked better than factor VIIa in stopping internal bleeding and increased survival, explained Lavik. Emergency medical technicians or battlefield medics could carry the powder out into the field to treat patients immediately, which could mean the difference between life and death, Lavik noted.
Lavik explained that the development process is ongoing, and it will take several years for the treatment to reach first-responders. So far, the nanoparticles appear safe, and all of the materials used to make them are already approved for medical use.
Erin Lavik, Sc.D., who described the advance toward developing synthetic platelets, said it is among the efforts underway world-wide to treat bleeding from “blunt-force” injuries ― in car accidents like the crash that killed Princess Diana, for instance, and the battlefield blast waves from bombs and other weapons that are the leading cause of battlefield deaths. Sports injuries, falls and other problems likewise can cause internal bleeding.
Progress toward a new emergency treatment for internal bleeding ― counterpart to the tourniquets, pressure bandages and Quick Clot products that keep people from bleeding to death from external wounds ― was reported at the 244th National Meeting & Exposition of the American Chemical Society, the world’s largest scientific society.
source:
[…] Nano-particles as Synthetic Platelets to Stop Internal Bleeding Resulting from Trauma. Share this:TwitterFacebookLinkedInPILike this:LikeBe the first to like this. Tags: […]
Dr. Karra, thank you for this important post on Emergence Medicine and new technologies to accelerate plug formation and the coagulation cascade in site at trauma site.
I wonder if that technology can be further develop with expansion of indication for patients on anti coagulation therapy, blood thinners post PCI or CABG?
Following recent post (and the references there in) is one such plausibility to clear the blood clots and to avoid even the said PCI or CABG and any other invasive techniques.
http://tginnovations.wordpress.com/2012/08/16/nano-postman-delivers-a-targeted-drug-directly-to-a-site
noteworthy points from the current post are….
1. particles are made of the same polyester material used in dissolvable sutures (lets say for e.g. PGA).
2. particles have an outer coating of polyethylene glycol (PEG) – sticky substance
3. then attach a peptide, or small piece of PROTEIN THAT STICK TO PLATELETS.
what is probably needed is the reverse engineering at step 3 in order to explore the plausibility of avoiding the invasive ways of clearing a clot.
In addition to the content of your last two comment, I wonder if it would have an effect on the ubiquitous use of Warfrin and Levonox type of drug thinners and other classes of thrombi blasters??
I think one may think of trying out drugs like Levonox rather (taking its safety in pregnant women as well – FDA approved), especially in ACS, by combining the techniques developed in earlier post where the drug can be delivered directly to the point of action needed.
The method looks like it can offer something new, and possibly safe, certainly when considering the cost of platelet transfusion, the very short shelf life, and the highest risk of infection among donor products.
I have reservations about the end result in half the cases. If there is massive transfusion, the platelets will be exhausted in about 2 (10 unit) full exchanges. If there is massive trauma with suspected internal bleeding, it should be a lifesaver.
There is more of a problem with unsuspected internal bleeding. There is an unusual case told to me about the 90 year old man who was anemic and had a pretty extensive workup, for shortness of breath, with cardiologists surrounding the patient and unable to get it at first glance, but the daughter, a gastroenterologist spotted the missed diagnosis of anemia from blood loss.
The problem of both surgical and oncology patients is of great interest. The red flag goes up when the platelet count drops below 100,000/ml, but the conservative approach is to transfuse below 50,000/ml if there is blood loss. The oncology patient is transfused at under 10,000/ml.
Having 35 years in transfusion medicine and personally having reviewed more transfusions than I would like to remember, this is a difficult area. Reviewing transfusions is costly, and it always comes down to “clinical judgement”. Years ago a hospital was inspected, (ha ha) and found to not be doing enough transfusions! The medical staff told the inspectors that they were very careful about transfusion, as my colleague had taught them well on the dangers.
The idea of making the platelets the patient has who is at high risk more sticky may have merit. We have to keep in mind that this would not be a consideration for many patients who are at high risk of thrombus generation from already sticky platelets – related to obesity and type 2 DM.
Dr. Larry,
Can you please address all the comments I made above.
I had a patient, 78 yo female, with hemoglobin of 8, been sent from a SNF to ER. Been sent back to have a blood transfusion at the SNF, attending at ER said her case of anemia, does not belong to Trauma center ER. SNF do not transfuse blood only LTACH do. She was sent back to the ER and received the transfusion.
This is a big problem – patients sent to ER by SNFs. What happened is as surprising as the tale I told. When a 78 year old patient comes to the ER with a Hb of 8, what is the most likely cause. If the ER was triaging patients, than they still had to accomodate this and other patients.
I would guess that the first though might be lower GI bleeding. The patient has to be worked up for the cause of the anemia. A patient doesn’t HAVE to be transfused at 8, just like the number 10 was not a valid transfusion trigger. However, there is a lot of unease about not transfusing an elderly patient with moderately severe anemia at 8. The textbooks indicate that the danger is below 7. The decision really depends on the cardiac and circulatory status of the patient.
I know the ED docs are often criticized. I’ve seen errors, even in the case where the nursing head of ED Research Coordinations son was sent home, even though he felt queazy. He was healthy, but he had appendicitis. She brought him back and it was fixed.
We talk about quality and preventing human error, but these guys are really loaded up with patients.
Dr. Larry,
Thank you for a review of the coagulation cascade.
What are the relations between the nano particles and curbing internal bleed and thrombus buster and blood thinners
I don’t see a connection at this point, but I’ll need some time to review it. The first step in clotting is platelet aggregation. The nanoparticles are intended to enhance the aggregation locally. If there is to be a connection, then we have to know if it would interact with the Factor X, as TF and Factor X have the role in producing FXa, and there is inhibition FXTI. I mentioned the anti-FXa, which is superior for all bleeding because the extracted heparins (brain) behave differently than LMWHs, so that the anti-Xa is essential for LMWH to stop the bleeding.The question is a reasonable basis for further exploration. In the case of anti-FXa, the target is not for local clotting. Tempering the bleeding when there is massive bleeding is still a challenge. When an obstetrical patient bleeds from placenta previa, this is not a daily occurrence and the delivery room goes nuts.
GREAT discussion above. A post like this one stimulate discussion among EAW and any reader of the comments is been edified by the clinical experience that is brought to bear on the research topic.
Thank you, Dr. Larry for the detailed comment especially regarding the transfusions and the complications associated with it in various situations.
In case of poly-trauma, it may not be able to completely address due to the very obvious reasons. However, another noteworthy point from the original post is that:
“…Factor VIIa also can potentially CAUSE BLOOD CLOTS ELSEWHERE in the body, NOT JUST AT THE SITE OF BLEEDING, increasing stroke risk. Other alternatives have been developed in the laboratory, but they’ve had similar side effects and are not currently used in hospitals.
But the synthetic platelets developed by Lavik and colleagues EXPECTED TO STICK TO NATURAL PLATELETS and LEVERAGE quicker and more EFFICIENT (???how to measure in real time) CLOTTING AT THE SITE (??? how to pin point and assure in real time) OF AN INTERNAL WOUND”.
This statement (in capital letters) gives a ray of hope in some, if not all, poly-trauma cases as well.
The real-time situation could be different, but lets hope it will deliver what is anticipated from this new exciting technology.
Warfarin has been the choice for outpatient control of thromboembolic risk because there was no oral alternative, and it is cheap. It was discovered in the midwest by an organic chemist who saw that cattle that grazed on fungal contaminated crop bled. He extracted and purified the Warfarin (coumadin)and it was shown that it inhibited the hepatic production of Prothrombin. The result is that clot formation is reduced by decreased prothrombin, that has to be converted to thrombin in the first step of coagulation. It was effectively used for “rat poison”.
The need for is made somewhat more urgent now that so many patients are put on lifelong coumadin if they have atrial fibrillation or related disorders, and eating cabbage and related foods potentiates the effect so that the patient has to be educated and they have to be followed (by the prothrombuin time). There are also patients who may be put on the drug and it is ineffective because of a genotype that is unknown when they start on the drug. This has raised much interest and driven research in the Clinical Chemistry community, and is a subject of an ongoing study be Alan Wu, PhD and clinical Associates at the University of California, San Francisco Medical Center.
Patients who have had orthopedic implants may also be on coumadin when they leave the hospital, and if they come for a procedure they have to be tapered off and put on a heparin drug IV. Not everyone on heparin develops a reaction, but it has real dangers.
Lovenox is a low molecular weight heparin that has become widely used to minimize the risk of a reaction. The drug is LMW, but not free of risk. It has to be admistered by subcutanous injections, and requires patient education. There has been research for years to develop a heparin that is risk free. The medication is followed closely by the activated partial thromboplastin time (APTT) and there are clinical standards for the range of a normalized PTT index to correct for the variations in preparation. In addition, the thrombin clotting time is monitored, but it is not adequate monitoring for many patients.
Therefore, the laboratories have turned to monitoring with an anti-Factor Xa.
The problem occurs because LMHs, unlike unfractionated heparins, are unable to bind with both thrombin and ATIII so that the rate of inactivation of ATIII is not followed, but they do retain the ability to catalyze the inhibition of Factor Xa by ATIII. The antiFXa assay is the most useful test for following the action of a wide variety of heparins.
Factor VIIa is a serine protease in the coagulation cascade. FVII binds to tissue factor and is converted to FVIIa. It is blocked by TF pathway inhibitor.
FVII deficiency is an uncommon condition presenting like a hemophilia. It is treated with recombinant FVIIa (NovoSeven, NovoNordisk). But it has been used in uncontrolled hemorrhage, but a large meta-analysis showed a risk of thrombi in older patients. A large problem today is that in trauma surgery for almost a decade, a standard was developed to use very large volumes of saline, intentionally overhydrating the patient, with significant success. This would present a problem for dosing.
Thank you for a review of the coagulation cascade. Is there a connection between nano particles and thrombi busters or blood thinners?
[…] http://pharmaceuticalintelligence.com/2012/08/22/nano-particles-as-synthetic-platelets-to-stop-inter… […]
[…] http://pharmaceuticalintelligence.com/2012/08/22/nano-particles-as-synthetic-platelets-to-stop-inter… […]
[…] http://pharmaceuticalintelligence.com/2012/08/22/nano-particles-as-synthetic-platelets-to-stop-inter… […]
[…] http://pharmaceuticalintelligence.com/2012/08/22/nano-particles-as-synthetic-platelets-to-stop-inter… […]
PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette