The Traffic Jam Within: A Primer on Blood Clots and Thrombosis

The 6th Annual International MPN Patient Symposium began with Dr. Babette Weksler giving us a fascinating overview on the invisible threat to people living with Polycythemia Vera (PV) and Essential Thrombocythemia (ET):  thrombosis.

Dr. Weksler is with the Weill Cornell Medical College and Center.  She has studied and treated patients with thrombosis for over 35 years.  Dr. Weksler focuses on diseases of platelets, bleeding and thrombotic disorders, sickle cell anemia, and immunologically mediated blood disorders.  She is a teacher, researcher, and clinician.

This article includes some blood basics along with the specialized information provided by Dr. Weksler.

We all have arteries, which flow blood from the heart to the rest of the body and veins, which return blood from various organs and parts of the body back to the heart.

There are “major” (large) and “minor” (smaller) veins and arteries throughout the body system.  There are also capillaries (very small passageways) for blood to move through the system.

Remember, the blood clotting function is necessary for us to heal wounds and prevent excessive bleeding.  Thrombosis is when the blood clotting function works against the body’s interest (also called “dis-regulated clotting”).   A thrombosis can fill a vein or artery and prevent blood from flowing to its intended destination.  This causes blood to back up, organs to suffer, and often end life as we know it.  This happened to me;  the cascade of problems from three blocked veins is now legendary in my family.

Sometimes a clot gets pushed from where it formed to an organ; this is called an “embolism.”  An “embolism” is an obstruction of a blood vessel (typically a blood clot) that travels through the bloodstream and lodges, resulting in loss of blood flow.  The embolus could be a blood clot, fat mass, air bubble, or other mass.  The most common is a blood clot in the leg gets pushed up into a lung and causes trauma or
death.

So... clots are good;  thromboses are bad.

An “aneurism” is when the wall of a blood vessel (vein or artery) bulges out and weakens.

Anatomy of a Blood Clot:
The clotting function produces fibrin strands, creating a mesh;  then platelets contribute to clot initiation and firmness of the mesh.  Red blood cells get trapped in the mesh and give the clot bulk.

Dr. Weksler explained that the clots in MPN patients are different from blood-healthy patients.  People with MPNs experience thrombosis due to their blood composition and abnormal functioning of the blood, endothelium, and platelets.

Hemostasis is limited clotting that preserves the integrity of blood vessels and maintains normal blood circulation.  It is important to maintain the vascular integrity (healthy blood vessels) and normal blood flow despite continual minor injuries.

High hemoglobin (Hb) in Polycythemia Vera leads to high blood viscosity (thickness), which slows blood flow and leads to thrombosis.  Think about a milkshake going through a straw compared to water).  If the milkshake contains small bits of fruit, it can get clogged in the straw.

The abnormal vessel wall favors thrombosis and blocks clot dissolution.  If the vascular integrity is compromised (blood vessels are weak or damaged) the risk for clots and thrombosis is increased.

Blood clots and thrombosis are frequent in Polycythemia Vera (PV) and Essential Thrombocythemia (ET).
They occur in both veins and arteries, and in large and small vessels.  Clots and thrombosis are major contributors to morbidity (death) for MPN patients.

Interesting note:   Both clots and excessive bleeding may occur in the same person at the same time or different times.

The Why:  Pathophysiology of Thrombosis in MPNs
It is generally understood that when blood stops moving, it clots.  For example, in Polycythemia Vera, a high red blood cell count (seen in high hematocrit) can block small vessels and slow blood flow.  Did you know there are other causes?  I didn’t.

Dr. Weksler offered the clearest explanation I’ve heard of the many ways MPNers experience clots.
There are four different causes of Blood Clots:

1. Endothelial Activation
The endothelial cells line the veins and arteries.  They issue commands to the blood elements and certain organs.  With MPNers, the endothelial cells may shift from non-reactive/anti-thrombotic to pro-thrombotic surface properties.

2. Platelet Activation
Sometimes platelets are activated for enhanced adhesion, aggregation, secretion.  The platelets then gather together and form a clot mesh that catches RBCs that try to flow through the vessel.

3. Blood Coagulation
The blood can initiate the clot when its viscosity (thickness) is increased and thereby slows the flow.  The thick blood can also cause increased thrombin generation and fibrin formation, causing clot formation.
Blood coagulation can also cause decreased fibrinolysis (the body's natural way to break down clots).

4. Red Blood Cells
The RBCs also sometimes push platelets to sides of blood vessels where platelets can interact with vascular endothelial cells.  The RBCs trigger the response by the platelets and endothelial cells.   This can cause microscopic clotting of the platelets.

Dr. Weksler also discussed several differences between Arterial and Venous thrombosis:

Arterial (arteries – taking clean blood from the heart to the body) thrombosis:
Arteries are the fast flow system.
Endothelial injury key
Platelets initiate when activated
“White clots”
Primary preventive treatment:  Antiplatelet therapy (e.g., aspirin)

When the platelet count is over 1 million or 1.5 million, it promotes bleeding:
Acquired von Willebrand (vWD)
These platelets absorb von Willebrand factor, an important clotting factor, resulting in mucosal bleeds.

Venous (veins – taking “used” blood from the body to the heart) thrombosis:
Veins are a slow flow system
Venous stasis key
Fibrin formation mainly;  platelets less involved
“Red clots”
Primary preventive treatment:  Anticoagulant therapy mainstay  (e.g., warfarin)

What are the chances I’ll experience thrombosis?
If you meet any of the following criteria, you are at higher risk for a thrombosis than the general population:
• Advanced age (>65 years of age)
• Control of MPN anti thrombosis with medication
• Prior Thrombosis
• JAK2 mutation burden *
• Acquired risk factors:  hypertension, high cholesterol, smoking, diabetes, CV disease
• Inherited thrombophilia

Persons with Polycythemia Vera have a 33% risk of a major thrombotic event.
Persons with Essential Thrombocythemia have a 17% risk of a major thrombotic event.

*  The JAK2 mutation burden affects thrombosis in MPN patients due to:
1. More immature and activated platelets
2. Higher numbers of activated WBC
3. More RBC precursors capable of epo-independent growth

Interesting Note: In Essential Thrombocythemia (ET), the presence of JAK2 mutation increases the risk of arterial thrombosis.

Platelet-Leukocyte aggregates and micro-particles promote thrombosis.  The different kinds of cells can act together to promote thrombosis.

To reduce the risk of a thrombotic event, MPN patients should lower the hematocrit (HCT) to normal (men <45%, women 42%).  This decreases blood viscosity.
Note:  If one only lowers platelet count, thrombosis may still be a risk.  

Role of Various Drugs with Thrombosis (clots):
• Hydrea inhibits Tissue Factor expression, decreases platelet-leukocyte aggregates, and decreases the immature platelets
• Aspirin relieves erythromelalgia (excessive dilation of blood vessels of feet or hands)
• Interferon preferentially decreases JAK2+clones
To date, JAK2 inhibitors have not decreased thrombosis

For those of us taking warfarin (Coumadin), Dr. Weksler said that the newer anti-coagulants are “not there yet”.  Some patients have tried Pradaxa and gone back to warfarin.  Pradaxa must be taken twice a day consistently and this is problematic for many patients.  She believes that we’ll have a better alternative in a few years.

Here are my take-aways:

1. There are several different ways our blood may clot and then thrombose (sounds grandiose, doesn't it?!).
2. Aspirin reduces one kind of risk (arterial clots). 
3. Warfarin/Coumadin reduces another kind of risk (venous clots).
4. Hydrea reduces yet another kind of risk (platelet-leukocyte aggregates).
5. All the preventive treatments must be closely monitored by your physician.  If the blood levels get out of whack (CBC and for those on warfarin, the INR), thrombosis can occur.  
6. It is possible to suffer from a thrombosis AND internal bleeding at the same time.
7. PVers and ETers have different blood thrombosis challenges.
8. Women's hematocrit should be at or below 42%.
9. Men's hematocrit should be at or below 45%.
10. Endothelial cells can influence the blood that flows through the blood vessels.  This is a leading edge in study.

I am grateful for those with healthy blood who donate regularly.  Our MPN blood, when taken out by phlebotomy/venesection, can not be shared with others;  thanks to Dr. Weksler, I understand why.

Myeloproliferative Neoplasms Conference - Day 2 Highlights

All the powerpoint presentations from the conference will be available through the MPD Net listserv sometime in the next week or so (let's give Ian, Antje, and Bob time to get home and back to their computers).

The morning began with Dr. Richard Silver, Director of Leukemia & MPD Center at Weill Cornell Medical College.  He talked about Primary Myelofibrosis and a study with low-risk PMF patients on interferon.  The study showed clinical benefits in 60% of patients and disease stability in 24% of patients.

Dr. Silver is a long-time proponent of the benefits of interferon alpha as treatment for PV and MF.

More info to come in full notes.

Dr. Ruben Mesa shared these thoughts after hearing feedback on the uncertainty and unanswered questions about our diseases:

• We know much more about the cause of the MPN illness than we have ever known.
• We have many more therapies than ever before.
• As you look at the range of cancers, some 300-500 of them, there is probably only 1 that goes away with a single drug.  It is unrealistic to expect that 1 drug will cure any of the MPNs.
• MPN Patients can expect to have many therapies over time.
• All the therapies are in evolution.
• Science is a journey.  It is a muddy road, but we are making progress.  It is a hopeful road.

Stem Cell Transplant Panel

This was really cool!

Four gentlemen who have had Stem Cell Transplants (Rick Posner, Larry Gersh, Ron Anderson, and Julius Dix) and Dr. Joachim Deeg from Fred Hutchinson Cancer Research Center, Seattle answered questions about the experience.   They range from 2 to 11 years post-transplant.

Here are some highlights:

Greatest Challenges:

• Physical:  the chemo can give you sores from your mouth all the way down to the other end -- very painful.
• Huge mental adjustment.
• Maintaining sense of self through overwhelming illness.

Advice:

• Work with your insurance company before hand and get everything figured out and approved.  It is stressful enough without those worries. 
• Try to keep some sort of normal routine.
• Stay ahead with meds for nausea.
• Develop communication mechanism and use a web-based tool like Caringbridge so you don't have to take all the calls.

Graft vs. Host Disease (GVHD):

• Would expect more GVHD with female donor to male recipient, particularly if female had been pregnant; yet relapse rate would be lower (per the Doc).
• Sibling donor makes it milder.
• Patients who acquire GVHD require prednisone for about 2 years; some may need it longer.
• Patients often report they need to take more notes, get tired, have shorter attention span.
• Common issues are dry eyes, dry skin.
• UV light helps with some skin GVHD issues, but prednisone is still the mainline medicine at this time.

Any Big Surprises?

• The day-to-day living after getting out of the hospital;  the amount of time and energy it takes for cleaning the house, prepping food, cleaning the lines, hydration, going out...
• Naive about GVHD.
• Takes a year to feel better.

Research Trends in Stem Cell Transplants:

• Donor Matches -- looking at partial matches to improve the regimens.
• Refine cellular therapy as a vehicle to implant modified T-cells to combat viruses.

= = = 

there's more, but i'm tired... stay tuned!

Making It Through With an MPN

Dr. John Camoriano, Mayo Clinic

Dr. Camoriano had us laughing throughout the conference as the master of ceremonies.  On Sunday morning, he shared eight (8) key principals of being a successful patient and caregiver.  He called them TENACITY principals.

T = Training and Teaching:   learn as much as you can about your disease & share with your doctors

E = Exercise  (single most beneficial thing most can do to improve health) 

N = Nutrition:  eat whole foods, lean meats, olive oil, reserveratrol-laden foods, less milk products...

A = Activism,   Anti-aging:   get involved with the MPN community as you can

C = Calming & Connecting:  keep the limbic system strong, keep laughing, keep connected with others.

I =  Individualization:  personalized medicine is the way of the future

T = Team Building:  be the glue to connect your primary doctor with your haematologist;  connect with MPNers

Y = Yes You Can   “Act As If…”

Know Thyself & Thine Disease.

Become as much of an expert on your illness(es) as you can be.

Bring your physician along with you as your learn:

·       With peer-reviewed literature when possible.

·       With updates at office visits from experts

·       With respect & deference

Exercise Recommendations:

·       Aerobics:  Increase heart rate for 1 hr/day, 6 days a week.

·       Stretching.  Yoga and slow stretches.  15 minutes/day, 2 days per week

·       Resistance.  Weights and bands and calisthenics 2 days per week.

·       Make it fun.

·       Make it a joint exercise.

"You gain strength, courage, and confidence by every experience by which you really stop to look fear in the face.  You are able to say to yourself, ‘I lived through this horror.  I can take the next thing that comes along.”  ~ Eleanor Roosevelt.

Living an Intimate Life with Blood Disease

Teri Britt Pipe, PhD, RN

We got to talk about sex on Sunday!
Dr. Mesa introduced the session by reminding the group that intimacy is more than sex; and intimacy begins in infancy.  In the international survey of MPN patients, Sexuality Problems was ranked #4.

Dr. Pipe

Assumptions:

·       There’s more right with you than wrong with you.

·       You are a unique individual.

·       You are dynamic;  you change.

·       You are on the journey together and alone. 

·       Sexuality and Intimacy “belong” in the clinical encounter, even if it is uncomfortable for the provider.

Where does sexuality reside?

·       Mind/brain – the most important sex organ.

·       Senses – experience what you see, hear, taste, feel.

·       Body – the skin is the largest organ and touch is important.

·       Communication

·       Being – a sense of being in this world.

Possible Impact of Chronic Illness on Sexuality

Performance                                                           

Relational

Sexual Response model by Masters & Johnson

We’ve learned that it’s not as linear as M&J described.

Sometimes the arousal curve gets disrupted by a negative thought…

It’s much more useful and comforting if the orgasm is not the goal.

Mind/Brain

Signals:

Gender Differences
Personal differences – change over time

Mind-Body Approach

Preparation for Conversation with Your Partner

·       Reflect on your own preferences and needs:  what is it like when I feel loved and cared for?

·       Reflect on what your partner may be experiencing.

·       Breathe, cultivate an attitude of appreciation.

·       Listen with appreciation and compassion.

Conversation(s)

·       I feel close to you when ___

·       I like it when ___

·       I want to show you how much I care for you.  Please share with me some ways you  might like me to show you.

·       I would like to try ___  Would that be okay with you?

Limitless Expressions

·       Cuddling

·       Holding hands

·       Eye contact

·       Humor

·       Art, poetry, music, food

·       Phone calls, cards, tokens

Location, Location, Location

·       Keep the bedroom as a place for intimacy and sleep

·       Talking about difficult/awkward things elsewhere

·       Having shared signals for intimacy 

·       Comfort, serenity, peace, belonging

Mindfulness

Paying attention, intentionally

Enjoyment with awareness

Bringing attention to the senses

Asking for Additional Resources

Health care team

“Cuddle Sutra” book by Rob Grader

“Relationships” cd by Bellaruth Naparsek

“Baggage Claim”  -- this illness time is a good time to

To love a person is to learn the song in their heart and sing it to them when they have forgotten.

Supplements and MPNs

Larry Bergstrom, MD

Dr. Bergstrom provides integrative medical consultations for patients.  Integrative medicine is a holistic medical program that addresses the physical aspect of health but also treats the emotional, mental and spiritual aspects within the framework of exercise, nutrition, and stress reduction.

While there is no consensus or recommendations for incorporating supplements into the treatment of myelodysplastic or myeloproliferative disorders, supplements are helpful when people do not eat a balanced diet.

Utilizing food as a source of health and energy.

Emphasis is on food first.

Supplements are used to fill in where food is not there.

He promotes:

Mediterranean/Anti-Inflammatory Diet

Mediterranean Diet Pyramid

Apoptosis =  cancer cells die

Anti-cancer foods:

tomato, garlic, carrots, tea, ginger, soy, basil, rosemary, turmeric/cumin, broccoli, watercress,

Cruciferous vegetables:  broccoli, brussel sprouts, cabbage, …

Any mushrooms must be cooked to get any benefit from them.

Alzheimer protector:  cumin/turmeric

These are the Recommended Supplements Summary  

·       Resveratrol:  500-1000 mg/d  (inhibitor of CYP2D6 and CYP2D9)

·       Indole-3-Carbinol 300-400 mg/d   (replaces broccoli)

·       Turmeric (black pepper (300-100 mg/d

·       EGCG 500-750 mg/d                                   ~3 cups of green tea per day

·       DIM 300 mg/d

·       Vit D  1000 IU/d

·       PEITC    watercress

·       Fish Oil (sum of DHA+EPA) 1000 mg/d   <-  pay attention to the DHA and EPA Omega 3’s

Cancer cells makes lots of reactive oxygen species (ROS) – stimulates cell production.  Watercress suppresses ROS.

A Medical Doctor asks:  What’s making you sick?

A Naturopath asks:  What’s keeping you from being well?

Closing Session:  Mindfulness Meditation

Teri Pope

Mindfulness Meditation

An awareness of moment-by-moment experiences that arises from intentional

Mindfulness Based Stress Reduction (MBSR) by Jon Kabat-Zinn at U-Mass Medical Center

Attitudinal Foundations:

·       Non-judging

·       Patience

·       Beginner’s mind

·       Trust

·       Non-striving

·       Acceptance

·       Letting go

This is an effective tool in leadership. 

Resonant Leadership (Boyatzis & McKee, 2005)

Healthy Mindfulness Practices

·       Breath awareness

·       Positive emotion/relive a positive emotion

·       Mindful eating:  look at your food, notice the texture, taste it, chew it, enjoy it before you swallow; what would it be like if I did every meal like this?  Think about all the hands that brought this to you.

·       Kindness tracking:  those that have come to you and that you’ve extended to others.

·       Gratitude practice:  even with your to do list

·       Gentle movement: 

Please Note:   These are ROUGH notes.  A more complete report will be written when the powerpoints are made available and my mom's notes are combined.  I'll make them available in a PDF document.