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
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
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
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.
- There are several different ways our blood may clot and then thrombose (sounds grandiose, doesn't it?!).
- Aspirin reduces one kind of risk (arterial clots).
- Warfarin/Coumadin reduces another kind of risk (venous clots).
- Hydrea reduces yet another kind of risk (platelet-leukocyte aggregates).
- 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.
- It is possible to suffer from a thrombosis AND internal bleeding at the same time.
- PVers and ETers have different blood thrombosis challenges.
- Women's hematocrit should be at or below 42%.
- Men's hematocrit should be at or below 45%.
- Endothelial cells can influence the blood that flows through the blood vessels. This is a leading edge in study.