Platelet Rich Plasma Dosing For Shoulder And Knee Conditions

Hi, my name is Doctor Don Buford. I'm an orthopedic surgeon in Dallas, Texas. I'm honored once again to be invited to speak at this equine Regenerative Medicine and Ortho Biologic Summit. I'm going to talk about platelet dosing for knees and shoulders, and I'm gonna focus on Osteoarthritis in the Knee and Rotator Cuff tendinopathy.

If you'd like to have a handout for this talk, you'll see the QR code listed on several slides during the course of the talk, so just have your phone ready and you can uh snap a quick uh picture of the QR code and that'll take you to the handout.

These are my disclosures.

So, let's jump right in. Let's talk about PRP dosing for Shoulder, and specifically, let's talk about Rotator Cuff tendonopathy. There are, of course, many different ways to quantify, uh, platelet-rich plasma. We can talk about leukocyte-rich, leukocyte-poor. We can talk about platelet dosing, usually in billions per cc. We can talk about the PRP Injection volume.

We can even talk about the Injection schedule. Is it a single Injection? Is it one Injection a week for 3 weeks?

In 321.

I am going to try and focus on some of the recently published clinical Research to give us some understanding of where we're currently at with PRP dosing for Rotator Cuff tendinopathy.

In 2016 in the Journal of arthroscopy, there was a level two prospective randomized study published with an NF 40, and what they discovered in comparing one group treated with PRP to the control group treated with steroid, was that the PRP group was better than the steroid group at 3 months, but the results at 6 months were the same.

They also found no significant MRI differences between the two treatment groups.

And so that was one of the early articles that really uh was a a dissatisfying conclusion. But then when you dig underneath the hood a little bit, you can see that they did not quantify the PRP. We don't know if this was high dose or low dose. We don't know the, the company uh commercial kit that was used, and we don't know any Other quantification data about the PRP. So, interesting study, but not very helpful clinically, in my opinion.

In 2018, we have a level one prospective randomized study.

A relatively large N of 138.

They divided patients into 4 groups. A group got normal saline injections, one group got sodium hyaluronate, another group got PRP by itself, and then the 4th and final group got sodium hyaluronate plus PRP.

And as I mentioned, it was a reasonably powered study. There were between 44 and 48 patients in each of the four groups.

These authors did make an attempt to quantify the PRP at least better than in the prior prior study.

They described drawing 20 cc's of blood. They described a two-spin system, and they detailed that they injected 4 cc's of PRP that was somewhere between 3 and 4X. Uh, they also noted that it was leukocyte 4. And so, a couple comments about the quantification, um, reported, this was a relatively low blood draw of only 20 cc's, and they made 4 cc's of PRP. So we can assume.

That in terms of a, a per Injection platelet dose, that this was a relatively low dose version of uh PRP. Nonetheless, they did find that patients in the uh sodium hyaluronic plus PRP group did do better clinically for one year.

So we would characterize the PRP used in this study in general as a low dose PRP because the blood draw was 20 ccs. They went down to a volume of 4 cc's, and although they describe it as leukocyte poor, we do note that the number of platelet counts um from the very beginning was probably no more than 4 to 5 billion, and I'm sure they lost some in the centrifuging and PRP um manufacture process.

In 2019,

Some authors attempted to do a meta-analysis of the currently available PRP literature.

They were only able to find 5 studies that met their inclusion criteria, and as you would expect based on the studies you just reviewed, these authors were not able at that point to come up with any significant conclusions or recommendations for or against the use of PRP for Rotator Cuff tendinopathy. There was just too little data on PRP quantification.

There is too little data on biases and study Protocols, and the end result was that it was basically too early to do a meta-analysis.

I think we're getting closer though. In 2020, Ian Lowe and his group in Canada did a level one study with an N of 99. They looked at PRP versus steroid for Rotator Cuff tears, partial tears, or tendonopathy. And what they found was that three-month follow-up, PRP patients had significantly better Pain scores.

That had to be tempered with the data that 23% of the PRP treated patients had failures by 1 year, meaning another Injection or, or progression to Surgery.

And so, although we have some positive early numbers at 3 months in terms of Pain, at 1 year, the effects of PRP seem to, to wane at best and to not be as clinically significant.

When we look at what Doctor Lowe and his colleagues used to make PRP, it was the Regen Lab system. It was a 10 cc blood draw, so now we're talking about very low dose PRP. They injected 5.5 cc's of that low dose PRP at an average platelet concentration of 1.6X as detailed in their paper. We don't have an actual platelet, platelet number yet.

So without that, we can't really calculate the dose, right? Because dose is volume times platelet concentration. Here we know the volume at 5.5 ccs, but we don't know the platelet count in the PRP. We don't know if it was 500, 400, 800.

So in summarizing the results of this level one study, very low dose PRP was shown to have potentially beneficial effect in terms of Pain management for up to 3 months, but by 1 year, those benefits of PRP in this low dose construct were just not, not seen. It just wasn't as good.

So now that we've looked at low dose PRP for Rotator Cuff tendinopathy, are there any studies that look at high dose PRP? And the answer is yes, they're recent. Here's a 2021 study.

This is a very, very well done level 2 prospective study. The NS 50. They use 3T MRI scans to look at the Rotator Cuff and ensure there's no full thickness tearing.

All of these patients had 2 standard treatment modalities before the PRP injections. They all had at least 1 steroid shot at least 6 months prior, and all of them had gone through at least 3 months of Physical therapy before the PRP Injection.

These authors did a very good job quantifying their injecting.

This was a leukocyte rich PRP. It was made in a two-spin system. This was a 30 cc blood draw, so better than the Canadian study, but still not quite up to the 60 cc blood draw that many of us do clinically now.

From that 30 cc blood draw, these authors concentrated back down into an in volume of 5 cc's. And here's the, here's the trick. They actually got platelet counts on their PRP.

And so once they did that, they were able to calculate their platelet dose, which came out to be 5 billion platelets per single PRP Injection.

With that information in hand, we can now properly interpret the results of this study.

94% of their patients treated showed improvements in the Pain scores in their American Shoulder and elbow scores, and in their constant scores. All of these scores and all of these things improved by 6 months.

84% of their patients returned to sports at the same level within 3 months of the Injection, and only 7% of these patients required a second Injection. So finally, we have an indication that high dose PRP actually gives us quite good results compared to low dose PRP. Let's look at the dose response curve and see what it looks like.

And so from the Canadian study, that's where we got the data that at a dose of 2 billion, it wasn't really giving us any sustained clinical benefit. But now we have the study that shows at a 5 billion dose, we're getting a good result with under 3 months Return to play and long-term uh clinical improvement that lasts out to a year.

So taking this information and trying to incorporate it into a clinical practice, what that means for me is I would like my PRP dose to be above 5 billion in that leukocyte rich PRP. And so now we have something we can translate into daily clinical practice.

OK, let's change gears and let's talk about the Knee. We're going to look at the same basic PRP quantifying measures.

And I want to spend a little time evaluating this article because it was um well discussed in Social Media. Uh, it's relatively controversial because of the strength of the study and the quality of the protocol versus the conclusions that they drew. And so this was published in JAMA in 2021. This came out of Australia with some Australian lead authors, and the title was Effective intraarticular PRP uh versus placebo.

On Pain and medial tibial cartilage volume in patients with Knee Osteoarthritis. Got a fancy name called the Restore Randomized Clinical Trial, and just reading the title, most of us probably got excited if we were, were geeking out on Orthobiologics that day, because here we have a level one study. It's well powered with 140 patients.

We look at leukocyte 4 PRP versus normal saline.

The Injection protocol is 1 Injection a week for 3 weeks with the uh the injectate and patients were followed for a year, which seems reasonable for these types of orthobiologic interventions.

The first red flag is we look at how they made the PRP because they do a really good job of describing it and quantifying it. And so now we're looking at this and, and we see that it's a Regen Labs single spin system. We already have some concentrating data on the Regen Labs protocol, and it's not great in terms of how much this system can concentrate platelets.

We see that it's a 20 cc blood draw, and they make 5 cc's of PRP. And so now we're looking at a blood draw where even the beginning platelets um in that blood draw are relatively low, and would be considered low dose PRP even if you kept all the platelets from the initial blood draw.

And then the final nail in the coffin is these authors did a fantastic job of actually quantifying what the platelet count was in the PRP. And they say that they raised the platelet count from 271 on average to 325. Does anybody have a problem or see the problem with that?

Well, let me tell you why you should.

The normal human platelet count is 150 to 450 platelets per microliter of blood.

And so in this restore randomized Clinical Trial.

They raised the platelet count from 271 to 325. Well, that's still within normal human range. That is not really a platelet concentrating type of intervention in, in my opinion, we'll just leave it at that.

They did not get the platelet count above normal human values.

The platelet dose.

When you concentrate the volume of 5 cc's injected times the concentration in the PRP of 325, that gives you a platelet dose per Injection of 1.625 billion. Now, we don't know if NOA is different than Rotator Cuff tendinopathy, but we already know from the Rotator Cuff work that under 2 billion platelets, these soft tissues don't seem to respond. And I get that it's a different clinical situation, but now the red flags are, are popping up everywhere.

If you do the math on the total dose given over three weeks, it comes out to just under 5 billion, 4.875 billion platelets were delivered in three separate injections.

Let's evaluate some Other comments that were made by both Virgin Labs and the authors.

In their supplemental data.

You can find the quantification numbers. It's, it's relatively hidden, but, but it's there, and so I commend the authors for doing that work for us, so we can actually know exactly what they did.

When you do the math on the platelet concentrating, 325/270 is only 1.2x. So, this system did not concentrate very well at all, and it doesn't. And this result has been mirrored by multiple researchers actually in various countries around the world. I realized that the protocol is, is, uh, marketed as concentrating 1.6 to 5X, but nobody's really been able to reproduce that in their own lab in an independent study.

The Other issue is platelet recovery.

We are expecting a platelet recovery of approximately 80% as detailed by these authors.

However, what we see, if you do the math.

Is that we started, remember this is a 20 cc blood draw with a 271 platelet count. So we started with about 5.4 billion platelets.

How many platelets did we end with?

We ended with 5 cc's of PRP at a 325 platelet uh uh count. That gives us 1.6 billion platelets in our 5 cc's of PRP. And so that is only a 30% platelet recovery. And, and the last time I checked, 30 doesn't equal 80. So, not only is it a low concentrating system, it's a very low platelet recovery system.

So what did these authors find? They followed these patients getting PRP versus normal saline for a year, and lo and behold, they found no difference in Pain scores at a year. They found no difference in medial tibial cartilage volume at a year. They found no difference. And then they took that, and this is where it became a headline.

PRP does not work for Knee Arthritis was their conclusion, and that got picked up by the media.

The problem with that

This is crazy low dose PRP. This is PRP made on a system with a low blood draw, a low concentrating protocol, and a low platelet recovery. It's got 3 strikes against it. It would have been fantastic if it worked, because that would have shown that even low dose PRP is effective, but this really showed that is, if you're under a certain

Uh, platelet dose, it's not going to work very well, no matter how many times you inject the person with that low dose. It's not just total platelets injected over time. I really think that these, um, uh, situations are responding to a specific platelet dose at a specific Injection time point. So, in Other words, a single Injection, um, of 2 billion is not going to work, no matter how many times you give it. The analogy that we often use.

If I give you 1/8 of a Tylenol for your headache, it doesn't matter how many times I give it to you. I can give it to you 5 times, it's still not going to equal 1 Tylenol, and your headache will not get better no matter how many times I do that. It won't get better until I give you 2 Tylenol.

And that's what we're gonna look at next.

Their original conclusion that PRP does not work for Knee Arthritis to decrease Pain or increase cartilage volume, I, I think was, was extremely oversimplified and, and highly inaccurate. I think a better, more legitimate, uh, conclusion supported by their study is that very low dose leukocyte 4 PRP.

Does not decrease Knee Arthritis Pain or improve cartilage volume at one year versus placebo. We have to be that specific in the literature because all PRP is not the same. We cannot draw global PRP conclusions from a very specific type of PRP.

My further conclusion would be that this study gives us great level one evidence that low dose PRP and we'll further define that as a dose under 2 billion.

That that low dose PRP does not work for Knee Osteoarthritis, at least not in any way that that makes any kind of cost benefit sense in my world. So, I don't think there's any need to repeat this study, and I commend the authors for publishing it because it takes this uh potential option off the table for me. I don't think there's any role for low dose PRP for NOA, especially when it actually is more expensive than the high dose PRP.

So finally, let's look at the dose response curve for this low dose PRP for NOAC. It looks like this. All we've done at this point is define the left half of the graph. We have a platelet dose of 2 billion, and we know that it is essentially of no value.

What about high dose PRP? Has anybody looked at that yet? And, and fortunately, the answer is yes. There was a fantastic paper published last year coming out of India, and the lead author is Doctor Himanshu Bansal.

And he did a very well designed level one study where he uh quantified the PRP so that we know the dose, which was 10 billion in 8 cc's of PRP and his control group was a high molecular weight Hyaluronic acid, um, commercially known as monobisc, and those patients in that part of the study got 4 cc's of that, also in a single Injection.

75 patients were randomized to each group, and finally, we have a study that looks at what's happening clinically right now. This is a 60 cc blood draw, so I think this is best Practices. This was part of his study protocol.

And what he found was significant. The PRP Group had improved Womack, Bass, and walking distance scores.

It was interesting that in his study, like in many studies, including mine, the MRI scan showed no cartilage changes in either group. And so we're just not seeing significant um uh cartilage regrowth with this procedure, and it may just come down to the fact that it's chondroprotective, but it's not chondro regenerative as a single uh liquid Injection without a scaffold.

The Hyaluronic acid group had improvements in terms of Pain and walking, but those improvements maxed at 1 month. And by 3 months, the patients in the Hyaluronic acid group were no better than they were before the Injection.

That matches a lot of Hyaluronic acid published data, by the way.

What about the PRP Group?

Well, the PRP group at one year, we're still doing great. They were still reporting improvements in their functional and Pain measures that were better than they were at baseline prior to the initial PRP Injection one year prior.

In addition, these authors did a great job quantifying several cytokines, and they showed that the PRP dose actually decreased some inflammatory and catabolic cyt cytokines.

In the Knee, uh, synovial fluid. And so that gives us a little bit of an idea that this may be disease modifying in some aspects.

And so now we can go back to our dose response curve. Now we have a second data point, right? We know from the initial study out of Australia that 2 billion or less is, is rubbish.

We know now from this Indian study from Doctor Bansal that a dose of 10 billion in 8 ccs is fantastic. We can tell people that on average they can get a year of benefit.

So the clinical question is, how do I get there? How do I get to a 10 billion dose, especially if I don't have a hematology machine in my office. And there's a couple tips I can give you for that. Always draw 60 cc's of blood. If you assume low, that your patient's platelet count is 200, for example, at least if you draw 60 cc's, you're starting with 12 billion platelets.

Inject 8 cc's like Doctor Bonsall did in his study. If you inject 8 ccs after having drawn 60 cc's of blood.

Then your platelet count only needs to rise to 1250 for you to get that 10 billion platelet dose.

And finally, we should all check our PRP. We obviously cannot believe Marketing. We obviously cannot believe words that are just coming out of some guy's mouth, not even mine. We obviously need to check this for ourselves. And fortunately, we can quantify this, and it's not that difficult. It's a machine that gives us an answer in about 60 seconds.

So, if you don't have the bandwidth to get one of these for your own clinic, at least find a hematology lab someplace close to you, where you can at least send in some PRP from whatever you're currently using. Uh, obviously, you can send in PRP if you're thinking about changing kits, and you wanna fact check, um, your results, then I think you, you have to do this. You have to quantify it.

Ideally, we would quantify every dose so we can create these beautiful dose response curves and answer even more clinical questions.

So let's finally make some conclusions. I hate to call them conclusions, they're more final thoughts because the data may change next week for all we know.

This won't change though.

All of us that are interested in using Platelet-rich plasma, and really any orthobiologic, need to become relatively expert at evaluating the orthobiologic clinical literature, because mistakes are made.

And the editors and reviewers may be uh unintentionally allowing something to be published that leads to a wildly different clinical conclusion that is not supported by the data in the paper. We saw that happen with the JAMA article. And so you have to be able to evaluate platelet dose, evaluate the protocol, evaluate the conclusion versus the actual hypothesis and the methods done to reach that conclusion.

Final thought number 2

When we're looking at Rotator Cuff tendonopathy, I think with the current data that we have in the literature, we should strive to reach a PRP dose of 5 billion in a single Injection.

Based on the best data in my humble opinion, that's an effective short-term therapy option where we can tell patients that they should get up to about a year of symptomatic relief with a platelet Injection at that dose. Where you inject is another discussion, but obviously a little bit intratendinous, perhaps a little bit subacromial, and perhaps a little bit intra-articular.

Let's talk about Knee Osteoarthritis. I think the data is pretty compelling that we need to get to 10 billion platelets or pretty darn close to 10 billion platelets in a single Injection. And if we can do that, most of our patients should get somewhere around a year of clinical improvement. And so that is a number that we can now track.

And we haven't really defined the right side of that dose response curve yet, have we? We don't know how many platelets we can give and still continue to get a better result.

So the final thing to talk about is cost. Cost matters. These are cash pay procedures. They're not cheap in the United States. And as a result, as clinicians, I think we're, we should be required to know our cost.

To draw 60 cc's of blood and to create PRP with a dose of 10 billion platelets for NOA.

All kits are not the same. You can see there's tremendous differences in blood draws, there's tremendous differences in concentrating ability, there's tremendous differences in platelet recovery ability. Some PRP systems are way, way, way, way, way, way, way, way, way more efficient, 8 times more efficient.

And so go to that example for your patients. I can give you 1/8 of a Tylenol or I can give you 1 whole Tylenol. Which one do you think is going to work better for your headache? And now, fortunately, we have some clinical data to back up that analogy.

So, thank you for your attention. I hope that some of this has been clinically useful, and you can take home some of these pearls and put them into use right away. Thank you.