ARE ALL PRPs THE SAME? WHAT ABOUT PRXP?
In the Regenerative Medicine field, there has for some time been controversy concerning certain aspects of Platelet Rich Plasma or PRP as it is called. There seems to be a misconception in some circles that some components of a PRP are bad. There is a belief amongst many Regenerative Medicine doctors that a leukocyte poor (LP) PRP is more effective than a PRP product that contains leukocytes. Leukocytes are the white blood cells found in blood. Moreover, there is a perception that the only important component of a PRP are the platelets which contain the growth factors. When one delves deeper into the science of PRP we understand that this is far from the truth. As a matter of fact, there is little scientific literature to support the idea that LP-PRP is preferred over the Leukocyte Rich (LR) PRP. However, there is a copious amount of literature to support the concept that all components of the blood are necessary to achieve an optimal result.
Recently I read an article by Dr. William R. Parrish. The title of his article was: “Platelet rich plasma in osteoarthritis: more than a growth factor therapy”. This title certainly rang true to my beliefs. I have been stating for years that having a PRP product with a minimal amount of white blood cells (Leukocytes) was probably not a good thing. Furthermore, Dr. Parrish stated that there is a notion (not his own) that other blood products such as red blood cells also contribute to an increased inflammatory response in a PRP product. The one concept that was ignored was that these studies that lead to the concept that WBCs and RBCs were detrimental were studies performed in the lab (in vitro).
Studies in the lab many times produce far different results than those in real life (in vivo). When we are studying a lab situation this is far different than real life. The environment is far different and thus the results can be far different. A review of the literature shows little in the way of support for the use of low concentrations of WBCs. The pendulum of research now supports the idea that greater concentrations of leukocyte and RBCs yielded a greater therapeutic effect on the patient. This is something I have known for the last ten years or so. I will concede that there may a bit more discomfort from a LR-PRP but at most this may last a day or so. We also have some propriety methods to help reduce this inflammation.
What is potentially so special about these other blood components. One thing we know is that platelets require some form of activation. Typically, when platelets come into contact with tissue (collagen) they become activated. RBCs help in platelet activation. RBCs will help generate additional amounts of thrombin. Thrombin is a very potent stimulator of platelet activation. When some stem cell processes are given intravenously the platelets are mixed with thrombin so that they will release their growth factors. We would not want to use platelets intravenously since they could form a blood clot in a vein leading to serious consequences. The growth factors would not be a problem.
Other factors that lead to the importance of RBCs is their content. RBCs are considered a sink of Nitric Oxide. (NO) is a gas which has numerous effects on cells. NO is a multifaceted compound that can act as a growth, immune and neuro-stimulator as well as causing angiogenesis (formation of blood vessels). They also contain Glutathione. Glutathione is a very potent antioxidant that can alter cell functions in a very positive way. It can help disable some free radicals at the site of injury. Free radicals rob the cells of energy and alter cell function in a negative way.
As Dr. Parrish pointed out eventually, the RBCs will be attacked by WBCs. When this occurs, the WBCs will release a variety of anti-inflammatory growth factors which will quell the inflammatory response and allow healing to occur. Many regenerative medicine docs continue to have the idea that RBCs cause an inflammatory response. Perhaps under certain conditions this might be true. However, this is usually not the case. A good clinical example of RBCs not causing an inflammatory response in what is called a “blood patch”. A blood patch is used when a patient had a spinal tap (typically by accident) and then develops a severe headache. The headache results from leaking spinal fluid. A blood patch occurs when whole blood is taken from a vein and injected into the area of the spinal leak. The blood plugs the leak and the headache goes away. Moreover, the blood which is in direct contact with the spinal cord covering (dura) does not cause any type of inflammation. A similar example occurs when a patient suffers a bleed inside the knee. This bleed might be traumatic in nature such as an ACL tear. The blood in the joint does not cause an inflammatory response.
The leukocytes (WBCs) have a very important aspect in the overall scheme of regenerative therapies. As was pointed out in Dr. Parrish’s article there is an extremely important relationship between platelets and neutrophils. It seems that these two cells will work in a type of symbiosis helping to limit the magnitude and duration of the inflammatory response. These two cells work together to form an entity called a lipoxin. The lipoxin is produced by the platelet. Lipoxins are very potent anti-inflammatory molecules. The limit the neutrophil activation. They have far reaching effects but the bottom line is that they foster an anti-inflammatory environment.
What else might be thrown away when producing a PRP? One discard might be a macrophage. Macrophages come in two forms. They are an M-1 and M-2 macrophage. These are very important in our immune system. The following slides are from one of my lectures
In the above we can see the macrophages at work in their normal environment. Interestingly enough the mesenchymal stem cell can have a direct effect on these cells depending upon the environment. However, if we remove these cells from the PRP product than we cannot cause these reactions to occur. The second slide explains these actions.
Another type of white blood cell which is very important is called a neutrophil. Neutrophils have been for years thought to be culprits to instigate inflammation. Under certain circumstances this is true. In the course of a PRP injection neutrophils can have an opposite effect. They can actually quell an inflammation and help release anti-inflammatory compounds. Once the platelets become activated they will “prime” the neutrophils. A primed neutrophil will help to release anti-inflammatory growth factors and limit the inflammatory response. This is very important for otherwise more neutrophils would be called to the area and cause more inflammation.
We must also realize that there are some stem cells in a PRP product. These cells are called Hematopoietic Stem cells (HSCs). We now think that the HSCs are probably the cells that may help direct tissue repair. When we are trying to make a PRP product which is devoid in leucocytes we are also “throwing away” these valuable cells. A tantalizing thought is to give some medications that are able to help mobilize more of these stem cells into the circulation. There are some cancer therapies which stimulate the bone marrow to release more stem cells to the circulation but they have significant problems such as cost and potential side effects. We have come across a supplement which has a similar effect with a very reasonable cost and essentially no side effects. Some food for thought about the numbers of stem cells in a typical PRP product. HSCs (represent 0.06% of circulating TNCs) translates into 3-7K HSCs per ml of blood processed. Is this number significant? No one can say for sure but I would rather have stem cells present than not.
A question one may ask is why not just use whole blood? The problem with that is we will not get enough of the platelets. We have to concentrate the platelets. This is the whole idea behind Platelet Rich Plasma. The bottom line is to try to make full use of the tools nature has given us in blood. This probably gives us the best chance of success when using PRP for a Regenerative Medicine treatment. Thanks Dr. P