The DFPP/SHED Exosome Protocol for Vaccine Injury

A pharmacist reviews the McCairn-Edogawa hospital protocol, and potential risks for scale up in Canadian/US hospitals

1) Introduction

As I understand it, the protocol being used in the Edowaga hospital in Japan includes;

• Combines DFPP with SHED exosomes

So I thought I would assess the protocol like I would if it was being introduced into my hospital. This approach does not assess whether the protocol is effective or not, this is a systems approach. What are the pharmacological, pharmacokinetic issues. What is the pharmacological control system? What are the failure modes? Monitoring etc. Most people think procedures are independent of pharmacology. Au contraire. Timing of antibiotics for surgery, adjusting for obese patients, heparin monitoring for dialysis, drug removal, fluid and electrolyte monitoring.

Pharmacists are the invisible stabilizer in hospital treatment protocols you never see. Like plumbers, they keep everything flowing, and if properly imbeded can flag impending catastrophe. I have not finished my final assessment because I dont have all the data but preliminary assessment is:

This protocol requires comprehensive pharmaceutical review before scale up

2) My core concern

Modern extracorporeal and biologic therapies are being scaled faster than the pharmacologic governance systems required to safely control them.

• DFPP = double filtration plasmapheresis

• Exosomes = non-standardized unregulated biologic product

• Level of care +real-time pharmacologic environment

In Asia, it is well known that the state of pharmacy is behind US/UK/CAN/AUS by 15-20 years, though much has improved. So what, is what I often hear. Does it matter?

Another notable difference found in Japanese hospitals

was that pharmacists are placed on each hospital floor. These floor pharmacists are responsible for verifying the medications, identifying interaction potentials, administering medications to patients, and answering questions for the medical staff on that floor. The administration of medications by the pharmacist was considered by the observers to be a unique responsibility due to this task typically being done by someone on the nursing staff in the U.S.

OK good they are available on the ward, but they are administering meds? Seriously? Then they dont have time to do the other stuff, uniquely suited to their training.

Japan regulatory environment is quite different too.

So that means unless the doc says it is ok, you have little leg to stand on, even if you think the procedure/drug/dose is risky. No laws or regulations to back you up. And much more leeway for the doc to do what he/she thinks is necessary. Better for experimental protocols (so it is no surprise this treatment method comes from Japan), but its riskier too.

3) Systems dependency

I don’t know what happens in Japanese hospitals. But in North America, high-acuity hospital environments (ICU, transplant, tertiary care) have achieved strong pharmacist integration into real-time decision-making. However, as therapies have moved outward into procedural or outpatient delivery, pharmacist involvement often becomes less embedded, even when things are really complex. This has been seen in some cases, resulted in many errors. Like outpatient chemotherapy.

What is often missed in these transitions is not clinical competence, but system control architecture. High-acuity settings work, like ICU, because multiple, partially invisible control loops are embedded into routine care:

• defined monitoring intervals,

• pharmacist-driven dose adjustment,

• oversight of anticoagulation, antimicrobial and other drugs

• compatibility checks, and

• rapid feedback between lab results and therapeutic changes.

These controls are rarely documented as a single system because they are distributed across disciplines (nursing, medicine, pharmacy) and therefore easy to overlook when a therapy is relocated or scaled. So when interventions such as DFPP and exosomes move into environments that do not reproduce these tightly coupled feedback loops, they are effectively converted from closed-loop pharmacologic systems into open-loop procedures.

The result is not an immediate catastrophic failure, but then you see a gradual loss of control: delayed recognition of instability, increased variability in response, and a higher likelihood of preventable error. This pattern is not new, I saw in in hospital all the time. Pull the ICU pharmacist and in a week there were serious critical errors.

The Double Filtration Plasmapheresis

4. The Double Filtration Plasmapheresis, it is NOT

The protocol is marketed as Double Filtration Plasmapheresis (DFFP), which is a legitimate, albeit intense, medical procedure.

I tried to find out exactly what was being used.

The first filter is which has a large pore size of 0.3 microns. That is the Plasmaflo OP

But I was told the SECOND filter is the Immsorba TR on X.

So this isn’t just filtration. It’s immunoadsorption. Filtration separates components based on size. Adsorption uses chemical resins (PVA gel) to strip the blood of immunoglobulins and immune complexes. So describing it as filtration is NOT ACCURATE. I like accurate. I like to be accurate A LOT. This bothered me, lol.

OK, I have questions.

Note the "Microparticle filter" at the bottom of the adsorber loop? I think it is there to prevent resin particles or aggregates from the adsorber from returning to the patient. The fact that they have a filter there is a tacit admission that the adsorber itself can shed debris. What does that mean for the patient?

This column is specific for neurological disease. As I understand it, this resin is designed to grab "pathological" IgG, they cannot distinguish between the IgG that is causing a disease and the IgG that is protecting you from the common cold, pneumonia, or a potential wound infection. So are you getting rid of adaptive immunity? Are they now vulnerable more or less than before to colds/viruses? Do the patients become transiently hypogammaglobunemic? How specific is it for anti-actylcholine receptor antibodies?

Grok tells me this cartridge removes:

• high molecular weight targets (IgG, immunocomplexes, fibrinogen(!!!!), some complement factors (C3 and C4) and rheumatoid factor)

• does NOT remove albumin and other smaller plasma proteins.

• and for DRUGS

  • highly protein bound drugs like phenytoin, warfarin, abixiban but also

  • monoclonal antibodies

  • IVIG

This process depletes fibrinogen by 30-70% which could be a bleeding risk especially with jugular access, and if the patient is on nattokinase, abixipan etc? How long does it take for the fibrinogen levels to go back up again?

So is anyone reviewing the drugs the patients are on prior to this procedure? Like say monoclonal antibodies? Is a Best Possible Medication History performed? This is standard of care in Canada and the US. Is it being done in Japan?

Are there guidelines or a reference for drugs that must be reviewed and dosed if you are on this DFPP? I found something but it is behind a paywall.

Here is a review article from India¹ which mapped how much IgG was removed, and fibrinogen

.

That is a lot of removal of immunoglobulins and fibrinogen. What about complications? They noted hypotension (17-33%), bleeding (20%) and loss of access (7%) and although it is called DFPP, is it the same cartridges as that used in Japan? Because those complication rates aren’t what I call GOOD. Did the Indian hospital have the same system architecture as Japan does? These invisible factors? It is likely safer in Japan. Still.

5) Anticoagulation

Guys, you can’t get away from anticoagulation. This is a 2-3 hour procedure, I doubt heparin is used so it is likely citrate. BUT Japan has an anticoagulant they use in these machines ONLY AVAILABLE IN JAPAN. So is this nafamostat is an interesting drug. ARE THEY USING IT?

Why I Believe Nafamostat Mesilate (NM) is a Clinical Red Flag

Unlike heparin or citrate, which have well-understood systemic effects and reversal agents, Nafamostat is a potent, short-acting, broad-spectrum protease inhibitor unknown in the west.

• The “Regional” Anticoagulation Trap: NM is favored in Japan because it has an extremely short half-life of approximately 8 minutes in plasma). This makes it excellent for “regional anticoagulation,” meaning it keeps the blood from clotting inside the machine but supposedly degrades before it causes systemic bleeding issues in the patient.

• The Danger of “High-Flow” Abuse: Because nafamostat is so effective at preventing clotting in the machine, it allows providers to run extremely high blood flow rates through small, traumatic catheters like the 18 gauge jugular line I have been seeing. It essentially acts as a “chemical bypass” for the limitations of the equipment.

• The “Protease” Blind Spot: Because Nafamostat inhibits all serine proteases, it doesn’t just block coagulation. It blocks a wide array of other biological processes, including complement activation and other inflammatory pathways.

Here is a review article for those interested.² This is one of those things I was talking about, where we really dont know what is being used, and it it would make a difference. Oh and there is NO ANTIDOTE to nafomostat (as opposed to heparin or citrate)

How about Citrate?

In apheresis, citrate is a regional anticoagulant. Is this what they are using? That is, working inside the plasmapheresis system. It works by chelating (binding) ionized calcium in the blood. Since calcium is a necessary cofactor for the coagulation cascade, removing it prevents clotting in the circuit. However, once that “de-calcified” blood and excess citrate return to the patient, it must be metabolized by the liver into bicarbonate. Are they using citrate? Or BOTH citrate and nafomostat?

What you need for monitoring for citrate:

1. IONIZED calcium levels pre, during, post (not total)

2. a calcium replacement protocol

3. monitoring parameters and automatic orders to start calcium if certain criteria is met.

My community hospital screwed this up so many times when we started doing a thyroid surgery (NOT DFPP). I told them, lets get a calcium replacement protocol plus monitoring parameters. Doc said why? But he came from another hospital in which these were EMBEDDED for so long he didn’t have to write orders anymore. This is the issue I am talking about.

6) Jugular Vein Access

This is just not scalable, imho. You need either an interventional radiologist or an anaesthetist to insert these under ultrasound guidance. And they are not always available. And it is risky. And the rationale is sketchy at best imho. The claim that you must access the jugular vein to “target cerebral outflow” to “clear the brain” is a gross oversimplification of human physiology. Blood from the vein via the internal jugular vein mixes immediately with the ENTIRE system venous return in the superior vena cava and right atrium. The real reason, imho, is for flow dynamics with the DFPP since peripheral veins will collapse under the negative pressure of the plasmapheresis pump.

If you are going to do a series of plasmapheresis interventions, then a Port-A-Cath would be safest.

And if you are using nafamostat it might mask the signs of catheter-induced hemolysis. If the jugular catheter is shearing red blood cells, the drug might prevent the resulting debris from instantly forming a clot in the machine, but the patient is still being subjected to massive mechanical trauma and you might not even know.

I really cant see the reason for this approach. I think they are prioritizing flow convenience over the patient risk of neck cannulation. As a hospital pharmacy director, I would flag this for sure.

What I need to lockdown as a pharmacy director (with nursing and medicine) for DFPP ALONE.

1. Anticoagulation protocol (citrate-based only because nafamostat is unapproved, and does that make a difference in outcomes?)

2. Filter supply chain redundancy

3. Fibrinogen / calcium monitoring algorithms

4. Strict inclusion criteria

5. Defined treatment endpoints (is there a rebound phenomenon?)

6. Stopping rules (ie if Calcium level drops, jugular vein access lost, etc etc)

7) The SHED Exosomes

What are these exosomes?

• SHED = stem cells from human exfoliated deciduous teeth

• They’re a subtype of mesenchymal stromal cells (MSCs)

So the product being infused is NOT cells but extracellular vehicles. The same size as an LNP of about 30-150nm that contain: microRNA, proteins and lipids.

• 

Here is what they look like. Some similar features as LNPs but no charged lipids, and they aren’t nanostructured or solid.

Think of EVs as:

• More complex than monoclonal antibodies

• More fragile than vaccines

• Less characterized than traditional biologics

• Requiring unprecedented quality oversight

Are they even worse than LNPs in that regard? And here is what they contain (on the right). It is not a defined mixture, lol.

8) The Regulatory Reality

This is the first major constraint since these are unregulated biological drugs.

Canada (Health Canada)

• Exosome products = biologic drugs and require clinical trial authorization and GMP manufacturing. They are not approved for systemic infusions.

US (FDA)

• Same classification: biologic / 351 product and there are no approved “exosome therapies”

Japan

• More flexible under regenerative medicine framework so they can be used even though they are experimental but it still requires physician-led protocols and oversight

What you have in Japan are GUIDELINES³ for their use but not regulation.

THE JAPANESE GUIDELINES

Let me just include a few quotes from these guidelines

"EVs are complex, heterogeneous, and non-uniform. Thus, identifying and managing all critical quality attributes (CQAs) related to risk factors that may interfere with the safety or efficacy of the product would be difficult even when all possible quality attributes are listed."

and

"Ensuring high purification of EVs and the inactivation or elimination of all viruses during the preparation (manufacturing) process is difficult."

including mycoplasma? Yikes!

9) My Biggest Worry: Resin Particle + Exosome Interaction

FAILURE SCENARIO

1. the immunoadsorption cartridge releases the resin particles

2. the exosomes are given just after the DFPP

3. both the exosomes and the microparticles are nano-sized

4. the microparticle filter designed for the resin particles may also remove the EVs.

Could the the therapeutic exosomes be removed before they even reach the patient? Do we have the pharmacokinetics or biodistribution data on these exosomes?

From the Guidance (Section 2.1.1):

“Any medical intervention using EVs prepared (manufactured) under the direction of a physician or dentist and administered to patients at the medical institution wherein the physician or dentist practices does not fall under the scope of the ‘The Act on the Safety of Regenerative Medicine’ (ASRM) in Japan. Hence, the Certified Special Committee for Regenerative Medicine or Certified Committee for Regenerative Medicine does not review these therapies.”

Translation:

NO REGULATORY OVERSIGHT
NO INDEPENDENT REVIEW
NO QUALITY VERIFICATION
PHYSICIAN SELF-REGULATION ONLY

OK I need to stop here for now and do more work on this. This is getting complicated. Here is what I am looking at as a Director of hospital pharmacy.

Can I combine a subtractive therapy (DFPP) with an additive biologic (exosomes) in a pharmacologically and pharmacokinetically reproducible way?

But right now I have:

DFPP = defined engineering system

Exosomes = heterogeneous unregulated biological signalling mixture

They don’t in the middle in a controlled, reproducible way I would like to see for patient care. It’s an open loop system and those are prone to drift and then significant errors that “come out of the blue”.

10) Failure Mode Analysis

Here is a preliminary failure mode analysis performed by Claude.

This is all based on the PDMA regulatory guidelines, except the resin and filtration loss.

It may be that the hospital has data to support that the exosomes are not being filtered out by the plasmapheresis. I am not sure of the timing of the exosome administration and the DFPP procedure. I think they give infusions of the exosomes for several days until the DFPP maybe to overcome this possibility? If so, that is $$$$ and also more “drug” with more adverse events.

And I havent even got into the dosing, preparation, and handling. Once unfrozen, the exosomes have to be given within 2 hours. That is a logistical nightmare in most US/CAN hospitals. Especially if they are reconstituted in a controlled environment of a pharmacy clean room following USP<797>. So this makes me ask if they are reconstituted at the bedside in Japan? Maybe by the pharmacists who give the meds? Cause that wouldn’t fly in North America.

So far, I would say the DFPP is scalable, pending supply and strict protocols and training. I understand it is resource heavy requiring 1:2 nursing, plus the jugular approach and the anticoagulant monitoring. But doable with planning. I am much more concerned about scaling up the exosome portion. This will be a formidable task, given what I see so far, and will examine this in more detail in another substack at a later date.

In the meantime, please keep praying the rosary, especially for my daughter and her baby (and for my mom).

1. https://pmc.ncbi.nlm.nih.gov/articles/PMC5590415/

2. https://pmc.ncbi.nlm.nih.gov/articles/PMC12896118/

3. https://www.sciencedirect.com/science/article/pii/S2352320425000343?via%3Dihub