Why Your Doctor Is Either Depressed or Retiring

Why Your Doctor Is Burned Out or Retiring

There is a growing litany of acronyms and alphabet soup organizations and algorithms that are designed to confuse, obfuscate and subordinate physician discretionary thinking. Funneling physician thinking into more pre-defined and standardized patterns. With the notion that these patterns are always superior, more efficient and accurate.  More than traditional physician discretionary thought, observation and formulation of diagnosis and treatment plans.

This dizzying array is one of the many reasons why virtually every physician over the age of 65 is retiring. You are losing an entire generation of extremely well educated and experienced physicians. The ones who cared.  Who were trained to observe.  Who were taught to exhaust all testing means. To use deductive and inductive logic.

We have entered the era of economic zero sum medicine.  Simple agents of health insurance reimbursement schemes. A world in which medicine becomes thoroughly and inexhaustibly politicized. That is what is being played out in Washington today.

Do you care?

  • ACO = Accountable Care Organization
  • MA = Medicare Advantage, original Medicare + choice
  • ACA (aka PPACA, patient protection and affordable care act) – disastrously branded as ObamaCare
  • MSSP = Medicare Shared Savings Programs (built into the ACA).
  • MUHIT = Meaningful Use of health information technology
  • GPRO = Group Practice Reporting Option (CMS provider value modifier, 2010 present
  • MACRA = Medicare Access and CHIP Reauthorization (an acronym within an acronym)
    • MIPS = Merit Incentive Payment Systems (has 4 components)
      • ACI = Advancing care information (replaces MUA’s IT).
      • CPI = Clinical practice improvement activities
      • TCoC = Total cost of care (usually expressed as annual cost per beneficiary)
      • Quality = replaces the PQRS (physician quality reporting system)
    • APM = Alternative payment models
  • SGR = Sustained growth rate physician formula (1997 – 2016)
  • RAF = Risk adjustment factor (adjustment used for and a payments)
  • HCC = Hierarchical condition category (codes that derive the RAF)
  • TIN = Taxpayer identification number
  • CMS = Center for Medicare Services — formerly HCFA (Healthcare Financing Administration)
  • CPC+ = Comprehensive primary care plus (a CMS driven Advance Primary Care Medical Home Model)
  • CPT = Current procedural terminology (procedure or billing codes)
  • ICD-10 = Diagnosis coding module currently used in the United States (supersedes the ICD-9)
  • VM or PVBM = Value Modifier or physicians value-based modifier
  • CAHPS = Consumer assessment of healthcare providers and systems (HCAHPS, CGCAHPS, HHCAHPS, OASCAPS, etc.)
  • HiTECH = Health Information Technology for Economic and Clinical Health Act (HITECH Act)

Makes your head spin.  Doesn’t it?  My mission is and has been the development of a new HealthCare paradigm.  Health and Well Being for the next twenty years.  Enhancing your healthspan. Enhancing cognitive function (smarter brains). You are going to need it in these times.




Compounding pharmacies – a vanishing breed

Compounding Pharmacies – Service like it used to be

Why are my  prescription medication prices increasing and not reimbursed?

Compounding pharmacies and the individualization of specific formulations is an integral part of antiaging, age management, functional medicine and similar holistic practices. There was a time in the distant past when most formulations were compounded. That is the source of the mortar and pestle that was so ubiquitous in all pharmacies. I think that symbol has vanished.

Mortar and pestle – universal sign of pharmacy

The advantage of compounding is preparation of very specific formulations, combinations and dosages. There are many nonstandard dosages that are not commercially available. Compounding pharmacies is a very dedicated group of highly professional caliber. Really good people. The old-fashioned pharmacist is rapidly vanishing. Maybe the same with solo private practices.

Stifling regulation and pressure from Big Pharma has contributed to the steady decline of compounding pharmacists throughout the Bay area and probably across the state of California. This is not a healthy trend. Furthermore, you have seen most of the major insurance carriers are progressively denying all your compounded medications. Under the ruse of FDA non-approval. That is not the reason. They want you to buy prescription medications from large pharmacies.  At a very high premium.

The one constant is an accelerating increase in the cost of all medications. I have never been an advocate of insurance coverage of medications. I know this a losing proposition. But it contributes to the subsidization of ever-increasing price increases. Medication prices are out of sight. And now that the major carriers are denying more and more coverage.  So you are left with high prices without the subsidies. You are then forced into generic formulations. Generic drugs do not have the same degree of quality assurance and consistency as proprietary medications. I do not recommend generic preparations.

Stifling and onerous regulations – USP 800

Image result for usp 800Here is a very personal summary of the onerous regulations in the state of California that will contribute to a manifest decline in the number of compounding pharmacists.  And further price increases because of the costs of preparation.   This is a direct quote from my good friend, Dana Gordon of CAPRx. One of the best pharmacists in the business. A Pharm.D. A doctor of pharmacy with an advanced degree.

 

 

Well, “D-Day” or “USP 800-Enforcement Day” has arrived. Effective Jan 1, many substances that were commonly compounded under normal environmental/exposure conditions must now be handled/manipulated under specific environmental areas (dedicated, externally vented, negative pressure room with a minimum 13 air changes per minute . Also externally vented source capture units/hoods within the room).

Let me be clear, the drugs/substances have ALWAYS been considered “hazardous” if an individual was exposed to them at certain levels and under certain exposure routes (i.e. respiration, mucous membranes).  Although the list is quite extensive (see NIOSH link attached), some of the ones you are familiar with are: Progesterone, Estrogen, Testosterone, Thyroid, Anastrazol, Retinoic Acid, Fluconazole to name a few.

Understand, the language in USP 800 was pretty much already in existence for many years. What occurred is the renumbering of the chapter to an “enforceable” chapter. Prior to this, the chapter was only “voluntary”. Now, in addition to our 3 (three) accreditations for compounding that hold us accountable to this chapter, we now are potentially subject to FDA oversight should we be in violation of USP 800. Very few pharmacies are as decorated as we are.  Our choice, our standards, our commitment to our patients, our providers and ourselves.

Although I have previously communicated with you the significance of this new law, its broad and extensive effects it will have on the compounding industry, and the enormous economic/cost impact it will have on those that have decided and/or are able to comply with the newly implemented regulations, both its repercussions and effects will now become quite evident.

In a nutshell and in summary

1)      California version of USP Chapter 800 becomes effective Jan 1, 2017 (All California pharmacies must be compliant on this date)

2)      Official version of  USP Chapter 800 becomes effective July 1, 2018 (California Pharmacies still must be compliant Jan 1, 2017)

3)      Hazardous Drug-Definition: See attached definition. Really, nothing has changed and nothing new has been discovered about the handling of all of these drugs. The purpose of USP 800 is to protect the individuals handling and manipulating such substances. How this will be translated to patients will require some delicacy and discretion. Regardless, literature will be provided with each drug categorized on the NIOSH list. This is a requirement. Also, such substances will be dispensed separately in a plastic back titled “Hazardous”. Also a requirement.

4)      CAPRx has been painfully, expensively (over $200K and still counting) invested in preparing for this eminent enforcement date for over a year. Also taxing was the BUD (Beyond-Use-Date) limitations that USP (795 and 797) has determined and now the California State Board of Pharmacy will enforce. All of this at the detriment of causing delays in the production and provision of compounded drugs.




Minivelle Vivelle Shortages Explained

Minivelle and Vivelle continue to be in short supply in most pharmacies across the country.  Initially, I was not able to determine any reason. Nothing revealed by simple Google searches.  No FDA drug recalls.  Not evident from FDA drug shortage surveillance lists.

Now, one of my astute and persistent patients was able to track down the reason.   The FDA has been very critical of testing and quality assurance methods for this product.  Adherence to CGMP.  Current Good Manufacturing Practices.  The reasons seem sound but are not technically safety related.

Here is the full FDA warning letter which is long and tedious.  It is illuminating for you.

The summary is quite ominous — dated Aug 05 2016:

Violations cited in this letter are not intended to be an all-inclusive list. You are responsible for investigating, for determining the causes, for preventing their recurrence, and for preventing other violations.

If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at [email protected], so that FDA can work with you on the most effective way to bring your operations into compliance with the law.  Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356C(b) and allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.

After you receive this letter, you have 15 working days to respond to this office in writing. Specify what you have done since our inspection to correct your violations and to prevent their recurrence.

Based upon the nature of the violations we identified at your firm, we strongly recommend engaging a consultant qualified as set forth in 21 CFR 211.34, to assist your firm in meeting CGMP requirements. Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for fully resolving all deficiencies and ensuring ongoing CGMP compliance.

If you cannot complete corrective actions within 15 working days, state your completion date and reasons for delay.

Bureaucratic Over-reach

Quite frankly, this is how we force good companies out of business. Oppressive bureaucratic dictates.

The same with recent lipid testing with the plaque LpPla2 test for oxidized LDL. Forced out of business.  Because of impossible compliance requirements.  This is not necessarily in your best interest.  Bureaucratic over reach is legendary.  And sometimes, as in this case, there is an inference of personality conflicts.

The generic houses such as Mylan that are producing the knock off product may not be as effective.  They are never subject to the same level of scrutiny as the original manufacturer. And you are being forced, by state law, to accept generic knockoffs unless you specifically protest. “No generics.”  Since this is a cost issue, most of you will not contest the automatic substitution of generics for the brand name.

There is no doubt that the cost of the brand names is out of sight which only complicates this issue further. You accept inferior products in the name of saving costs.  What is your health and happiness worth to you?   The never ending question.  What is your well being worth? Estrogen is your friend and life saver.

Call This Number

You can call this number,  1-800-320-3789, for a list of pharmacies in your area that might still have Minivelle or Vivelle in stock. The list is growing shorter by the week. Tell me if you find new information that I can share with my audience.




Minivelle Vivelle Short Supply

Minivelle 17 beta estradiol system

Minivelle and Vivelle are severely backordered. We have not been able to determine the source of this short supply. It emanates from the manufacturer. This is not a local pharmacy problem it is not a distribution problem. For obscure reasons it is not being manufactured. We have not seen any recalls.

The 0.1 mg dose is in most demand and in short supply. Many of you have been dispensed a generic form of estradiol patches. Mylan is the leading generic house. Generic patches are not the same as the proprietary drug — Minivelle or Vivelle dot.

Estrogen patches are not about the drug which is bioidentical. It is 17-beta-estradiol. That is bioidentical.  Biologically identical to your own internally produced hormones.  The FDA prohibits the manufacturer labeling this as bioidentical.    That is a legal-political issue.  Not a medical issue.

Minivelle and Vivelle dotc

Dosing

The Minivelle and Vivelle dots are a patented delivery system.  It is unique.   It assures a constant stream of low dose estradiol (E2 estrogen) day and night. Climara is old technology.  You cannot dose once weekly.   The manufacturer, per FDA approval, recommends twice weekly dosing. That will translate to a 3 day leg and a 4 day leg. It does not last more than 3 days.   If you dose twice weekly then one day of the week you get nothing.  I do not recommend twice weekly dosing.

Over the years I have strongly advised dosing Minivelle or Vivelle every 3 days. That assures a more constant delivery of sufficient estrogen day and night. The generic patches may not even last for 3 days.

Alternative Minivelle Vivelle Resolution:

You have a few alternatives until this supply problem is resolved.

  1. Apply 2 separate 0.05 mg patches changing every 3 days. Some women have noticed that 2 x 0.5 mg is more effective than 1 x 0.1 mg. Effect: increased cost.
  2. Reduce the dose to 0.075 mg from 0.1 mg.  The 0.075 mg is not currently in short supply. Effect: decreased effectiveness.
  3. If you are committed to the generic estradiol dot, consider changing every 2 days. Not every 3 days. Make sure this is the Mylan brand.  Effect: increased cost for more effectiveness.

Remember, estrogen is your friend.   Estrogen has 400 separate effects.   This story is to be continued.




Vitamin K, Calcification and GLA Proteins

Vitamin K2 is a potent anti-calcification nutrient via GLA protein carboxylation.  Let’s look at this process of calcification and the potency of these various forms of vitamin K2.   Then talk about the MK-4 vs Mk-7.    Which is best for you?   And why?

Vitamin K2 forms

There are currently three forms of vitamin K available. Vitamin K1 (phylloquinone) has been extensively studied. It is not the most potent form. Vitamin K2 is currently available in two forms. MK-4 also known as menaquinone-4 or menatetranone. MK-7 (menaquinone-7) is currently advocated as the most potent form of vitamin K2. You can see in fig 1 that the MK-4 and MK-7 have long “tails” with multiple (poly unsaturated) double bonds.  This increases lipid solubility.  These are fat soluble as opposed to water vitamins.

Vitamin K1 and vitamin K2 MK-4 MK7
fig 1

So what is the connection between Vitamin K2 and tissue calcification? Why do we petrify as we grow older? Why do we grow stiffer? This is a combination of calcification and glycation.  Glycation is secondary to excess carbohydrates, rising hemoglobin A1c (>5.6%), and impaired fasting blood sugars (>100 mg).

Calcification is an impaired healing process. Arterial injuries initiate a process of calcium deposition as a repair mechanism. Calcification is the end result of chronic inflammatory processes.   This is a key concept.

How can we prevent or reverse this ossification process?

For many years I have struggled to understand the process of “reverse calcification.”  As we grow older there is a tendency to lose bone calcium matrix causing osteopenia or osteoporosis. And contrariwise, an increase in arterial and cardiac (heart) valvular calcification. When we were younger, calcium deposition was a bone building process.  As we age it becomes a cardiovascular risk. 

Coumadin as an Experimental Model

As it turns out, we have an excellent model from widespread use of Coumadin (Wafarin) anticoagulation. From empirical observation over 20 years and through extensive medical literature research, it is now proven that Coumadin accelerates osteoporosis and arterial calcification – coronary artery disease.   How is that possible? Because Coumadin’s main action is antagonizing vitamin K2 action.  That is the goal.   Depleted Vitamin K thins the blood.  It inhibits thrombosis and emboli (blood clots). Fig 2 shows the essential vitamin K-dependent steps that are blocked.  [refer back my earlier discussion of coagulation and the prevention of heart attacks and strokes]

coagulation pathways blocked by Warfarin VKA
fig 2

Now the good news is high doses of vitamin K2 does not cause the opposite. It does not cause abnormal clotting or thickening. The Japanese have carried out experiments using high doses of vitamin K2 for up to two years without any untoward effects. Even the World Health Organization has not determined an upper limit of vitamin K intake.  It is only the insufficiency  or blockage of vitamin K2 that thins the blood.

Carboxylation of GLA Proteins

Now the rest of the vitamin K2 calcium connection is the effect on GLA proteins. These are proteins that are absolutely essential for calcium regulation. And this is where so much of the vitamin K research has been focused.  The activation of these GLA proteins are all Vitamin K dependent.  See figure 3 the Vitamin K cycle. Once again, notice where warfarin blocks the final production of the active form of vitamin K (KH2) that is essential for carboxylation.

Vitamin K Cycle is essential for carboxylation
fig 3

So what are these GLA proteins? This is a contraction or acronym for gamma-carboxyglumatic acid proteins.  Each one of these is essential for calcium regulation. The most important of these include:

  • Osteocalcin (BGP — bone GLA proteins)
  • MGP (matrix GLA proteins)
  • GRP (GLA rich proteins)
  • and more

Experimentally, these proteins have been classified as either under-carboxylated (ucMGP or ucOC) or sufficiently carboxylated (cMGP or cOC). Under-carboxylated forms of these GLA proteins promotes vascular and valvular calcification.  There is a rare syndrome – the Keutel Syndrome — characterized by abnormal calcifications and defective MGP.   Now refer to figure 4.

Carboxylation of GLA proteins is essential for arterial health and bone density
fig 4

The picture is now complete. You want healthy inflow of calcium for strong bones.  We want to reverse or prevent calcium outflow and accumulation in arteries and heart valves.   Vitamin K2 as MK-4 or MK-7 are potent activators of matrix GLA proteins (MGP) and Osteocalcin.

We have long struggled with this paradox. Progressive arterial calcification leading to coronary artery disease or peripheral vascular disease. Very little attention has been focused on valvular calcification which is even more serious. Eventually leading to open heart surgery with aortic or mitral valve replacements.

My friends in the alternative community at ACAM (American Academy for Advancement in Medicine) have long advocated the use of chelation therapy. Chelation therapy uses EDTA and other micronutrients infused intravenously to reverse calcification.  Various alternatives to intravenous EDTA include oral and even rectal  suppositories with some degree of success.

To further strengthen this connection let’s consider one final pathologic model. Chronic renal disease.  Refer to figure 4.

osteocalcin-and-bone-health
fig 5

Repeating, Osteocalcin  is essential for bone building and health.  It is a strong biomarker for vitamin K levels and activity.   Osteocalcin must be carboxylated to exhibit full activity.  Under carboxylated Osteocalcin is not fully active.   It is totally Vitamin K2 dependent.  So measuring ucOsteocalcin (under carboxylated) is a stronger biomarker for Vitamin K2 activity.    Until recently this test was not available.  This is slowly changing.  Genova Diagnostics is one source.

MK-4 vs MK-7 Research

A large body of research on the phylloquinone or vitamin K1 form has been conducted. It has been concluded that this is an insufficient approach to the carboxylation of the GLA proteins. So that more recent experimentation with MK-4 has demonstrated sufficient potency to activate the carboxylated GLA proteins.

Then the MK-7 form was investigated. MK-7 is naturally found in the natto bean which is the source of Nattokinase. So much of the controversy currently is focused on MK-4 versus MK-7. Both of these are lipids soluble as previously mentioned..

Extensive literature research will reveal various shortcomings. Most experiments fail to use good basic pharmacological principles of the dose response curves. That is, what is response at various doses.

I frequently use the example of Lipitor. If we conduct an experiment with 1 mg of Lipitor for 1 to 5 years as an example, we will conclude that Lipitor is ineffective at lowering LDL. On the other hand, if we use a dose of 100 mg Lipitor for even one year we will find a very high rate of significant side effects intolerances and eventual discontinuation of the drug. So based on the initial dose we will find an appropriate response.

I have often questioned how researchers even pick the initial dose of any agent they are studying. What is this decision-making process?

So there have never been direct comparisons between high doses of MK-4 and MK-7. The Japanese of studied vitamin K2 (MK-4) in doses up to 30 to 40 mg (30,00 – 45,000 µg). These are “attack” doses. MK-7 has been tested in doses initially from 45 µg and much more recently as high as 400 µg. But there are no studies that compare head-to-head high doses of MK-4 with high dose of MK-7.

So Which Form of Vitamin K2 is Best for Me?

All we know is that researchers have concluded that even the “high” doses of MK-7 do not fully carboxylate the GLA proteins. So what is the appropriate dose of MK-7? Some researchers speculate it may be as high as 1000 µg.

I contend that both are lipid soluble. There are various factors including lipid solubility, volume of distribution (Vd), half-lives and ultimately carboxylation of GLA proteins. That is the goal. It is not serum levels. It is not half-lives. It is what is the optimal dose that fully carboxylates these GLA proteins? Especially MGP – matrix GLA protein and osteocalcin. There is a realization that this is the realistic approach.

So you will read that MK-7 is more potent than MK-4. This is primarily based on persistent blood levels of the MK-7 version. There is a difference between lipid solubility, tissue activity and blood levels. Even I measure serum levels of all hormones knowing that there are other part compartments such as saliva, urine.

Now I am beginning to see a combination of MK-4 and MK-7 to “hedge your bets.”  We do not know the ideal dose. We do know that there is no upper dose of vitamin K that is toxic. This is why am now recommending at least 30 mg (30,000 µg) of vitamin K2 in the MK-4 version in at-risk patients.  While 15 mg is my standard daily dose of Vitamin K2 MK-4.  The MK-7 dosing is still in evolution. There is a sense that 400 µg is far more potent than the 45-90 µg that you have currently been taking in various combinations.

Conclusion

arteries-and-vitamin-k
fig 6

The reverse calcification paradox is solved.   The experimental evidence is so compelling.  Vitamin K2 is essential for healthy arteries and heart valves.    This extends to healthy veins as well.   The only controversy or decision is the form?

MK-4, MK-7 or a combination of both?  Some of this will be practically solved by prices.  What is more “affordable” to you?   In the end it is all so much more efficient and less expensive than even a single day in a hospital or an extended ER visit.

I continue to recommend 15-30 mg of the MK-4 but remain open to a combination.  I always had difficulty rationally understanding how 45 mcg of MK-7 was more potent than 15,000 – 30,000 mcg of MK-4.   That would be at least 666 times.   Nearly 3 orders of magnitude?  I have seen no evidence in the literature to prove this assertion.

The real issue is monitoring.   We have been testing Vitamin K with SpectraCell analysis for the last 20 years.   Testing functional sufficiency levels.   ucMGP and ucOS, as they are more available, will be the real test of Vitamin K efficacy.   Will we see evidence of calcification reversal and increased bone density with higher doses?   Imaging studies can confirm effectiveness of our therapies. Carotid ultrasound, CIMT (carotid intimal media thickness), ultrafast CT HeartScans and DEXA scans.

Take your vitamin D3 and Vitamin K2 together.   My unfailing recommendation to you for the last 15-20 years.

PostScript

I want to personally thank Lara Pizzorno for help with background literature research.  Her writings on Vitamin K are highly recommended.

References and Bibliography

[1] Rogier Caluwe, Lotte Pyfferoen, Koen Boeck, An S. De Vriese: Effects of vitamin K supplementation vitamin K antagonists on progression of vascular calcification: ongoing randomized controlled trials.  Clinical Kidney Journal, 2016, volume 9, no 2, 273-279

[2] Elke Theuwisse, Egbert Smit, and Cees Vermeer:  The role of vitamin K in soft tissue calcification. Adv. Nut 3: 166-173, 2012

[3] Masataka Shiraki andNaoko Tsugawa, Toshio Okano: Recent advances in vitamin K -dependent GLA containing proteins and vitamin K nutrition.   Korean Society of Osteoporosis 2015

[4] Takafumi Okura, Mie Kurata, Daijiro Enomoto, Masanori Jotoku, Tomoaki Nagao, Veena Raiska Desilva, Jun Irita, Len Ichi Miyoshi, Jitsuo Higaki: Under carboxylation of osteocalcin is a biomarker of carotid calcification in patients with essential hypertension. Kidney Blood Pressure Res 2010, 33:66-71.

[5] Rick H van Gorp and Leon J. Schurgers: New insights into the pros and cons of the clinical use of vitamin K antagonists (VKA’s) versus direct oral anticoagulants (DOACs). Nutrients 2015, 7, 9538-9557; DOI: 10.3390/nu7115479.   citation link

[6] Toshiro Sato, Leon J. Schurgers and Kazuhiro Uenishi: Comparison of menaquinone-4 and menaquinone-7 bioavailability in healthy women. Sato et al nutrition Journal 2012, 11. citation link

[7] Ellen G.H.M.van den Heuvel, Natasha M. van Schoor, Paul Lips, Elke J.P. Magdeleyns, Dorly J.H. Deeg, Cees Vermeer, Martin den Heijer: Circulating un carboxylated matrix GLA protein, a marker of vitamin K status, is a risk factor of cardiovascular disease. Maturitas 77 (2014) 137-140 1  citation link

Philip Lee Miller, MD

California Age Management Institute

Monday, October 10, 2016




Your Personal Supplement Prescription for Optimal Health

Supplementation Regimen Can Optimize Your Health

Personal supplement daily regimen for your health and vitality

Patients often ask how do you maintain your health and youthfulness? What do you personally take? I need to walk the walk and practice what I preach.  I need to set an example for you.

You can do this.  You may need our help and motivation.  There are many variations of this rigorous approach.  You do not need to follow this implicitly.   But the closer you can approximate this, the better your results.

For 20 years I have advocated the same routine. The basic approach is consistent. Variations on a theme. The Paleo diet. Low Carb. Modified Atkins diet. Basically high protein low carbohydrate.  You can read the classic Protein Power by Michael and Mary Eades.

My good friend and highly successful entrepreneur, David Asprey, is the next chapter in in this tradition.  His BulletProof diet consists of high-fat, high protein and low carbohydrate. He especially emphasizes high-quality high-fat.  I caution against bacon, sausage, bratwurst and other forms of high free radical containing proteins sources.  But we all agree that carbohydrates is the problem, not fat.

Then read my own best seller, Life Extension Revolution.

Life Extension Revolution by Philip Lee Miller, MD
Life Extension Revolution

Upon arising

As soon as I arise (40 minutes before breakfast) I take the following:

  • 1 tablespoon Pro Omega fish oil — anti-inflammatory and prevents red blood cell aggregation
  • vitamin E 800 units –prevent red blood cell aggregation and major antioxidant
  • vitamin D 10,000 units –strong bones, prevents cancer, enhances immune function
  • CoQ10 200-400 mg –mitochondrial function and heart health
  • Ultra-K vitamin K2 – 15 mg –strong bones and to prevent arterial calcification
  • phosphatidylserine 100 mg – cognitive enhancement
  • Nattokinase 100 mg –prevent heart attacks and strokes

Breakfast – fortified with dietary supplements

Now I start my breakfast with whey-based a protein shake. This protein shake is heavily fortified with the following:

  • 1 teaspoon of carnitine tartrate– 3000 mg – for mitochondrial function and energy
  • 1 tablespoon of phosphatidyl choline –energy and memory
  • one scoop of FiberPlus –fiber for colon health
  • 6-8 ounces Odwalla organic orange juice
  • 1 tablespoon Maca root – four sexual enhancement
  • 6 mg of l-deprenyl (Selegiline) – for cognitive enhancement

and a bowl of Bob’s Red Mill gluten-free oatmeal. Using 1/3 cup of oatmeal and sufficient amount of Vanilla hemp milk.

That starts the day.

These micro-nutrients fortify breakfast:

  • nutrient 950 multivitamins
  • selenium 200 µg – immune function
  • Optizinc Inc. 30 mg – immune function
  • vitamin B2 10 mg — energy substrate
  • ginkgo biloba 60 mg – memory and cardiovascular protection
  • 4Sight from Orthomolecular –enhance vision.
  • Diaxinol all from Orthomolecular – prevent diabetes
  • AminoIron two tablets – improve iron and red blood cell function
  • DHEA 50 mg – enhanced sense of well-being and stress coping
  • alpha lipoic acid 300 mg –mitochondrial function and high dose antioxidants
  • FolaPro 1600 µg (two tablets)
  • vitamin B12 (methylcobalamin) 10,000 µg sublingually
  • SpectraZyme digestive enzymes – digestive fortification
  • Metagest – digestive function and protein hydrolysis

That may seem like a lot. I make up a series of seven packets at the beginning of the week. You can find these packets at the following address.  One of many sources.

I only need to pop a plastic packet of the above each morning. Takes no time at all. Even on vacation I set out 14 individual packets.

Lunch

For lunch I have another protein shake. Fortified with 1 teaspoon of carnitine tartrate (3 grams), two scoops of whey based protein. That’s it for the rest of the day until dinner.

Dinner

I have a rather light dinner with vegetables and protein usually chicken sometimes red meat and sashimi twice weekly.

At night my micronutrient routine usually consists of the following which is a lighter routine than the morning:

  • Micronutrient 950 — mutlivitamin
  • Alpha lipoic acid 300 mg — mitochondrial function
  • Diaxinol – to prevent diabetes
  • Foresight – for healthy eyes and heart
  • Spectrazyme digestive enzymes – to enhance digestion
  • Metagest – to enhance protein digestion and prevent gas
  • 1 tablespoon Calcium Magnesium Citrate — for good calcium magnesium balance

I might “cheat” bit with organic ice cream. I recommend Talenti, Strauss or similar organic brands.  It must be organic. Make certain that it does not contain high fructose corn syrup. Unfortunately, even Ben & Jerry’s has been “polluted.”  [ they were bought long ago ]

Bedtime

Just prior to bedtime I take one more batch:

  • Nattokinase 100 mg – as an anticoagulant prevent heart attacks and strokes.
  • 1 tablespoon calcium magnesium – to enhance sleep and prevent restless legs

It’s a routine that have kept up for the last 20 years. The goal is to promote health and well-being, stress reduction, cognitive enhancement. Prevent heart attacks and strokes. Prevent hospitalizations.

You want to keep healthy, fit and active. It is always been the goal that I am trying to foster with each of you. Keep you out of hospitals.  Maintain independence health and fitness well until late 80s and even 90s.

You can do this.   Call us for help.

 

Dr. Philip Lee Miller

 

Philip Lee Miller, MD

California Age Management Institute  

Wednesday, August 17, 2016




Anticoagulant Natural Alternative

Novel anticoagulant regimen to prevent strokes and heart attacks

Natural Anticoagulant Regimen

A natural anticoagulant routine. How could this benefit you? How can you implement this? Why is this a time-proven alternative to conventional approaches?

Hopefully, you have read part1, part2, and part 3 of this 4 part series. Primers on coagulation and thrombosis. I have carefully explained the process of coagulation resulting in heart attacks and strokes. We have talked about platelet aggregation. Which then leads to fibrin aggregation. Which leads to the final clot. All clots cause obstruction. Obstruction causes heart attacks and strokes. How can we prevent this?

I have alluded to the most powerful natural anticoagulants. These include the following:

  • Nattokinase — 100 mg twice daily
  • Ginkgo biloba — 120mg daily
  • High-dose fish oils — 1 tablespoon (10 grams) daily
  • Vitamin E — 800-1200 units daily
  • Adequate hydration — many glasses of pure water daily

Nattokinase

Nattokinase is a fibrinolytic anticoagulant. NSK-SD brandLet’s start with Nattokinase. Nattokinase is a derivative of the natto bean.  This is a Japanese food source. Nattokinase is a serine protease produced by Bacillus subtilisduring during fermentation. Nattokinase is very bitter to the taste!  Unpalatable. Therefore, the standardized extract is preferable and convenient.

Nattokinase is a fibrinolytic agent. You can refer back to all previous fibrin pathways. The goal is to prevent fibrinogen converting to fibrin.

Nattokinase has been studied extensively by the Japanese.  Nattokinase biochemical activity is labeled in FU. That is fibrinolytic units. These activity units have a mg equivalent. A typical dose is 100 mg (2000 FU) twice daily. It is essential that you take this twice daily. Once daily is insufficient.  This has been time proven through empirical observation.

I have treated thousands of cases with Nattokinase preventing recurrent thrombophlebitis, strokes and heart attacks.  It is essential that you source NSK-SD.

There are alternatives to Nattokinase.  Lumbrokinase is derived from the earthworm.  It is commonly sold as Bolouke in Canada.  By the manufacturer’s claims, it is even more potent.  Higher biological activity. Serrapetase has similar but not identical properties.  I use Serrapetase to treat arterial plaques.

Here is a great reference paper on the fibrinolytic and anticoagulant properties of Nattokinase.

 Ginkgo Biloba

ginkgo biloba is one of the most ancient plants on earth. anti-platelet anticoagulantGinkgo biloba has many actions. This is a time-honored and venerated Chinese herb. Ginkgo biloba has multiple constituents. These are flavonol and flavone glycosides, lactone derivatives (ginkgolides), bilobalide, and much more. We use a standardized 26% ginkgo extract. The Germans have studied this in detail.  Reference the German E Commission. Here is a more readable guide.

The dose I recommend is 120 mg daily.  Or 60 mg split twice daily. German studies have advocated as high as 240 mg. Through empirical observation, I find this dose to be way too aggressive. Ginkgo is so potent that 240 mg will probably cause adverse bleeding.

Ginkgo Biloba exerts its action primarily as an anti-platelet anticoagulant drug. It inhibits platelet aggregating factor. Ginkgo has many other uses. It is an antioxidant. Ginkgo may have vasodilatory effects. It is used for cognitive enhancement. I find it much more effective as a cardiac protective drug.

Be careful with your dosing ginkgo biloba. I advocate the use of 4Sight. This is a potent combination used to prevent eyesight deterioration. It includes 60 mg of ginkgo biloba. It is one example of adjusting the total dose of ginkgo biloba. And that is, again, 120 mg.

Because of its action, ginkgo biloba should not be combined with aspirin or NSAIDs. It will have synergistic effect.

High-dose fish oils

Fish Oil ProOmega rich in EPA and DHAHigh-dose fish oils have a “rheological” effect. That is the prevent aggregation of red blood cells. It is the aggregation of platelets and/or red blood cells is the initiating process. High-dose fish oils act like Teflon to prevent this aggregating effect. The dose that I recommend is aggressive. 1 tablespoon daily. You will rarely achieve these doses with oral capsules. I highly recommend fish oils in liquid form.

Fish oils contain EPA (eicosapentanoic acid) and DHA (docsoahexanoic acid).    I recommend 4000-5000 mg of EPA and 3000-4000 mg of DHA. That would total approximately 10 grams of fish oil. 1 tablespoon of high potency fish oil will yield this high dose of 5000 mg EPA and 4000 mg of DHA. I stress again, you will not achieve these doses with fish oil capsules.

Fish oils, in addition to their anticoagulant effect, may have multiple benefits:

  • enhance brain function – cognitive enhancement
  • prevent cardiovascular events
  • antidepressant
  • improve skin turgor
  • lower blood pressure
  • treat gastric reflux

Vitamin E

vitamin E tocopherolsVitamin E also has rheological properties.  It prevents red blood cell aggregation.  Vitamin E exists as a family of tocopherols.

I highly recommend mixed tocopherols. This is a isomeric mix of natural tocopherols including the alpha, beta, gamma and delta forms of vitamin E. There is a difference between “natural” vitamin E and “synthetic” natural vitamin E. Synthetic vitamin E is a tocopheryl not tocopherol.

I routinely recommend a 400-800 units of mixed tocopherols (vitamin E) daily. In many instances I will recommend 800-1200 units of vitamin E.  Studies have shown that Gamma tocopherol is much more potent than alpha tocopherol. Most studies only investigate the alpha form of Vitamin E.

Water – Hydration

bottled water in glass is free of plasticizers And last but not least, hydration. Keep well hydrated. Hydration will also prevent red blood cell and platelet aggregation. It will improve skin turgor.  I highly recommend water in glass bottles, not plastic bottles. You should avoid all plasticizers.  PVCs, phthalates and BPA. The softer the plastic bottle the higher the plasticizer content.  Never tap drink water.  Most likely, all your municipal water sources are contaminated or polluted.  Chlorine, chloramine, flouride, and heavy metals. Flint Michigan is just the tip of the iceberg.

Potency and efficacy

So this routine when fully implemented will prevent platelet and red blood cell aggregation. It prevents the conversion of fibrinogen to fibrin. This treats all pathways of coagulation. It is a much more comprehensive approach to anticoagulant therapy than conventional drugs. Less expensive. With fewer complications. Is it effective?

Virtually every surgeon now has been taught to ask, “what other vitamins and herbs are you taking?” Every surgeon knows that each and all of these agents clearly have anticoagulant effects. Surgeons see the effects of drugs. Internists only infer the effects of drugs. Surgeons know that prior to surgery anticoagulants can significantly increase complications. However, just following surgery the opposite effect is noted. The body may react with a vigorous coagulation response.

So empirically and rationally you can see this routine has the ability to effectively prevent heart attacks, strokes and recurrent thrombophlebitis.

Medical Supervision is Essential

Physician Supervision is within your reachA major caveat! I never advocate abruptly stopping conventional anticoagulant routines. You need medical supervision to start and monitor your progress. This anticoagulant routine requires special knowledge of potency, dosing and the value of these natural sources. I have been treating thousands of cases over the past 20 years. This is time-tested. It is effective. But this regimen is not “validated” through conventional guidelines or task force committees. It is not the “standard of care.” For this reason, your internist, cardiologist or family practitioner will have little understanding of the rationale or efficacy of this routine.

This is not a DIY — do it yourself advocacy.

So where do we go from here? Let me give you some suggestions.  Call us or write for further information.

[email protected]

call 408-358-8855




AntiPlatelet AntiCoagulant Drugs

Coagulation and Anticoagulatant Therapy

Read part I and part II of this series for background.  So you will have a basic understanding of coagulation pathways. Yes, it is complex.

Remember, coagulation or clotting starts with platelet aggregation.  That initiates the complex coagulation cascade. This causes the mature thrombus or blood clot. Aggregated platelets with a thick fibrin mesh causes the thrombus.  The thrombus causes heart attacks, strokes or thrombophlebitis.  Here is the final complete picture:

injury activates platelets causing thrombus formation
fig 1- click for full size

So let’s discuss anticoagulant therapy medications.

Antiplatelet Agents – Aspirin and Plavix are first line of defense

Figure 2 shows how we prevent platelet aggregation and activation at various stages.  Look at figure 1.  Aspirin has been the mainstay of antiplatelet therapy. There has been a succession of drugs over the last three decades. Newer antiplatelet drugs supersede older ones.  Are these true advances or simply marketing campaigns?

antiplatelet drugs classified by site of action. Aspirin and Plavix are the most common platelet inhibitors
fig 2 – click for full size

Aspirin has been well studied in the literature.  A full 325 mg dose will prevent platelet aggregation.  Over time, aspirin has significant adverse reactions. These are direct and indirect reactions. It can cause tinnitus (ringing or buzzing noises in the ear).   It can cause major gastrointestinal bleeding.   This is a significant problem.

Therefore, baby aspirin (81 mg) is a reputedly safer dose.  This lower dose is effective.   We now know this is subject to individual variations.  Fast or slow metabolizers.  There are ways of testing for aspirin efficacy.  Aspirin Resistance (11-Dehydrothromboxane B2) is one available test. Realistically, we rarely perform this test.  So that empirically, an 81 mg (baby aspirin) dose is less toxic. Interestingly, we rarely treat babies and toddlers with baby aspirin any longer.

Aspirin is a COX inhibitor. COX is an acronym for cyclo-oxygenase.   There are COX-1 and COX-2 enzymes.

Fish oils are potent COX inhibitors.  I will talk about Fish Oils in the final chapter – part 4.

Plavix (Clopidogrel) is now the second most commonly prescribed drug in the US. A 75 mg dose is common. Plavix is an ADP antagonist.  A totally different site of action from aspirin. Plavix combined with aspirin has never been a rational choice.  It is over treating, potentially causing more complications. Various studies have proven this.  Lancet argument against using Plavix and aspirin together:

Adding aspirin to clopidogrel in high-risk patients with recent ischaemic stroke or transient ischaemic attack is associated with a non-significant difference in reducing major vascular events. However, the risk of life-threatening or major bleeding is increased by the addition of aspirin.

Dr Mercola also writes:

Sadly, Plavix also has serious side effects you may not be aware of. Six years ago, I warned my readers that when combined with aspirin, the drug nearly doubled the death rate from heart disease among patients who had not had a previous heart attack but were at risk, compared to those taking aspirin alone.

Anti Fibrin and Standard Anticoagulant Drugs – Coumadin

During acute episodes in hospital, physicians use heparin.   This is intravenous dosing.   Once discharged, physicians prescribe Coumadin (Warfarin) for long-term therapy.   Yes, Warfarin is rat poison.

Typically, Coumadin anticoagulant therapy is continued for a variable period of time depending on the condition.  Coumadin blocks vitamin K -dependent conversion steps. So you are advised not to ingest any extra vitamin K. Or foods that are high in vitamin K such as leafy green vegetables.

Prothrombin time (PT) was used in the past to monitor the efficacy and dosing of Coumadin which is quite variable. Today we use the INR (international normalized ratio).  Weekly monitoring is necessary initially.  Then less frequently as the INR activity stabilizes.  But I stress, there is considerable variability in dosing from 2 mg up to 12 mg.

A typical Coumadin dose is 5-6 mg daily.

Coumadin has serious adverse consequences because it blocks vitamin K.  Matrix GLA is a vitamin K-dependent protein that regulates calcium flow. It prevents prevents “reverse calcium flow.” That is, calcium flowing out of the bones into the arteries (and heart valves). Coumadin can accelerate osteoporosis and arterial calcification.   That is why high doses of vitamin K in healthy adults is so vital.  So the risk-benefit ratio seems questionable.   Here is one journal citation

Fourteen years ago in this journal, Price and colleagues reported that 2 weeks of warfarin treatment in young rats “caused massive focal calcification of the artery media” (1). It had been known for years that Warfarin could induce mineral deposition in the arteries of rodents (2), and the phenomenon was so robust that Warfarin was often used as an experimental model for vascular calcification, but the mechanism was unknown.

Newer Anticoagulant – Xa (10a) blockers

So time marches on. Newer drugs, with which are not vitamin K antagonists, are now the “latest advance.”  These are Xa (10a) antagonists.  They eliminate the variability of Coumadin dosing and the necessity for frequent testing.  And we suspect marketing decisions are in play.

What are these newer drugs?

  • Dabigatran Etexilate – Pradaxa 150 mg twice daily
  • Rivaroxaban – Xarelto 20 mg daily
  • Apixaban – Eliquis 5 mg twice daily 
  • Edoxaban – Savaysa 60 mg daily 

These newer drugs avoid frequent monitoring.   What are the downsides?   There are no currently available “antidotes” to unintentional overdose.   Vitamin K is a simple antidote to Coumadin. And, long term, there are consequences yet to be fully determined.    In one study from BMC Musculo-skeletal Disorders, there was a direct toxic effect on osteoblasts.  These are the cells that build new bone:

In conclusion, rivaroxaban and enoxaparin treatment led to a reduction in alkaline phosphatase activity and a reduction in BMP-2, osteocalcin and Runx2 mRNA expression, indicating that treatment with both drugs leads to a general negative effect on osteoblast activity.

The Medical Letter lists these as the major toxic effects.  Common to all anticoagulants:

The most common adverse effect of edoxaban in clinical trials was bleeding. Edoxaban has no established antidote to reverse its anticoagulant effect, which persists for about 24 hours after the last dose, and it is not dialyzable. Epidural or spinal hematomas resulting in permanent paralysis could occur in patients taking the drug who require neuraxial anesthesia or spinal puncture.

We will eventually discover other long term consequences.  This class is certainly far more convenient.  And way more expensive.

So let us turn our attention in the final Part 4 to a comprehensive and time-tested natural anticoagulant routine.




Coagulation Heart Attack and Stroke – Part 2

It is necessary to understand the interaction of fibrin coagulation pathways and platelet aggregation. Once we understand these interactions we can then discuss current treatment modalities. My goal is to show you a more creative and natural approach to anti-coagulation.

Initial Platelet Aggregation

activated platelet aggregation
fig 1

In part one I emphasized the importance of platelet aggregation as the initial step.  There is an initial injury to an arterial or venous wall.  As a response, activated platelets cause a clumping reaction to repair the injury.  Somewhat like Hans Brinker’s “finger in the dike.”

This injury could be a laceration. It could be a rupture of a atheromatous plaque. It could simply be a tear in an arterial wall.   Or simply from low-flow stasis.  Atrial fibrillation is an example.

 

platelet activating factor PAF
fig 2

You can see from fig 2 above that the platelets initiate an array of reactions.  I will elaborate even more detail in the next post.  This is ever-increasing overview.

Aspirin is the most common drug to prevent platelet aggregation.  We will look at an array of  drugs that have been used over the years. But there is a more creative approach.

Once the initial platelet plug has formed the long-term fibrin coagulation pathway is initiated. 

 Fibrinogen pathways

fibrin to fibrinogen cascade from intrinsic and extrinsic pathways
fig 3

The classic fibrin clotting pathway is divided into the intrinsic and extrinsic systems. The intrinsic system starts with Factor XII.  There is a cascading series of reactions to the final common pathway. This is prothrombin activating thrombin. Thrombin then catalyzes the reaction of fibrinogen to fibrin. Finally, fibrin is polymerized to an insoluble mesh.  The extrinsic arm interacts with the intrinsic arm.

As discussed previously, the production of fibrin can be blocked at various stages.  The conversion of fibrinogen to fibrin can be reversed through a process called fibrinolysis.  An important concept.

So now we have a complete picture. The following diagram summarizes the evolution of this thrombus from platelet aggregation to fibrin clot.

Decision-making – Blocking Which Pathway?

Now we have rapidly covered the two aspects of thrombosis (clot) production.    This is where the subject becomes indeterminate.  Some “guidelines” emphasize the prevention of platelet aggregation. While other guidelines emphasize the long-term use of anti-fibrin drugs.  What is the best strategy? Depends on the guidelines.  These evolving guidelines are determined by age, associated risk factors, and preceding condition.

These guidelines were originally developed to make decision-making simple. And uniform. And coherent. The community standard of care. But guidelines eventually become bloated and incoherent. Much like IRS tax code. I anticipate this decision-making process will soon be totally computerized.  Remove the human discretionary input. I do not agree.   Look here to see just how complex this decision tree for anticoagulant therapies can be.

The entire purpose of this series of posts is to present a novel combination of anti-fibrin anti-platelet modalities.

Now you have an overview of the basic flow.   In part 3 we will examine current and past drug interventions.




Coagulation Stroke Heart Attack Part 1

Heart Attack and Stroke Coagulation Basics

Let’s talk about heart attack and stroke causes and the complexity of the underlying coagulation (clotting) pathways.    What a heady subject.    You need a PhD in medical hematology, just to fully understand the complexities of coagulation.   So let’s work through this step by step.  This will be a multi part series.  I will help you achieve a clearer understanding. None of us wants to suffer a heart attack or stroke!

What causes these these catastrophic vascular events? What are the risks?  What medications are commonly used?    Why are they not necessarily the best or even the healthiest choice?   Can we assess risk benefit ratios?   And what are the natural herbal-based alternatives?  Ones that can be just as effective with fewer side effects and less costly.   This is what you will not hear from your personal internist, cardiologist or even family physician.

Blood Clot is a Thrombus or Embolus

A thrombus totally blocks (occludes) blood flow from activated coagulation factors
fig 1

A blood clot usually starts with an injury to a vascular wall.  This could be one of your arteries or veins.  An intricate series of reparative or reactive events is set in motion.   Your body tries to rapidly repair injury to the vascular wall.   Atrial fibrillation is an alternative source of thrombus formation.  In this instance, stasis and not injury, initiates the reaction.

Fig 1  above shows you a representation of the well formed blood clot. It has the potential for blocking blood flow (vascular occlusion) which deprives tissues distal to the block of vital cell oxygenation. The medical term is myocardial infarction or cerebral infarction. Cells die from lack of oxygen.

The initial early phase begins with activation and aggregation of platelets.

Blood clot (thrmbus) forming in arterial plaque. Credit: Annie Cavanagh. Wellcome Images images@wellcome.ac.uk http://images.wellcome.ac.uk Digital artwork illustrating a blood clot forming in a blood vessel. Atherosclerosis is a condition in which an artery wall thickens as the result of a build-up of fatty materials such as cholesterol. Suffering with atherosclerotic disease, plaque deposits form along the lining of the artery and grow to cause a narrowing of the vessel which may cause a heart attack or stroke. The plaque can rupture causing a blood clot which forms at the site of the ruptured plaque the clot can completely or partially occlude the blood flow at that point. In arteries, the primary clotting mechanism depends on platelets Digital artwork/Computer graphic Published: - Copyrighted work available under Creative Commons by-nc-nd 2.0 UK, see http://images.wellcome.ac.uk/indexplus/page/Prices.html
fig 2

 

Fig 2 shows you the beginning of the activated platelet aggregation sequence.

 

 

 

 

 

 

 

the thrombus clot composed of an aggregate of activated platelets in a rich fibrin polymer mesh
fig 3

 

The final result of thrombus formation is illustrated in fig 3.   An artistic rendering of the platelet-rich polymerized fibrin lattice.

 

 

 

 

 

 

Now, I want you to look at this animated video of this rapidly evolving sequence of events.   It will more visually summarize this first part.  This two-minute video is well worth watching.  Then we will move on to the individual steps of each coagulation pathway. Once we understand the sequence of events can begin to understand the rationale for various treatment modalities.

fig 4

Thrombin Fibrinogen Fibrin Pathways – Balancing Act

a series of coagulation factors with balancing fibronolysis factors
fig5

Here is the classic series of reactions in the fibrin producing pathway.   What a complex picture!   Let’s see if we make some sense of this rich set of reactions.   How does this affect stroke and heart attack (myocardial infarction) risk?

First look at the pink box.  That is the fibrin cascade.  The common pathway is the activation of thrombin. This cascades to fibrinogen. Fibrinogen is converted to fibrin. Mono-filament fibrin is elaborated.  It will become a fibrin polymer.  This is not yet a mature thrombus (clot). We will talk about the platelet contribution in Part 2.  We routinely measure fibrinogen in all our patients — every time.

What is important in this diagram is the internal and homeostatic balance. Bleeding vs clotting (thrombosis) .  There are various counter mechanisms to thin the blood. Your body has its own internal set of reactions.  Now look at the green box.  The most common is plasmin. Another is a less recognized but highly important PAI-1  (plasminogen activator inhibitor).   The PAI-1 is susceptible to 3 critical genetic variations. If it is mutated, you will see decreased fibrinolysis (clot breakdown).  This can accelerate thrombus or clotting formation.  This diagnosis is frequently missed by most hematologists.  It can be source of severe pulmonary embolus or deep vein thrombophlebitis.

We will explain fibrin and platelet pathways in greater detail in Part 2.