this diagnosis, because it is not a single disease. MPN comprises several specific diseases, including essential thrombocytosis (ET), polycythemia vera (PV), and myelofibrosis (MF). In the simplest of terms, MPNs are a closely-related group of rare blood cancers.
Though MPNs were originally described in the late 1800s (See Sidebar: The History of MPN), it wasn’t until 2005 that several scientists discovered that patients with MPNs share a common gene mutation—the JAK2 mutation—within bone marrow stem cells. Gene mutations or alterations can cause many diseases, including MPN and other forms of cancer.
Our bodies function through a type of internal communications system. JAKs are specific proteins (Janus-associated kinases), which act as signaling mechanisms with cells. In other words, they “tell” blood cells in the bone marrow to divide and grow. When JAKs are working normally, they help the body make the proper amount of blood cells. However, if a mutation is present, the signal malfunctions and stays on permanently.
If you think of JAK genes as a factory, then a mutation flips the “on” switch and leaves the factory in constant production mode, causing too many cells to be manufactured. Just as a factory would eventually have difficulty handling this type of malfunction, the overproduction of cells begins to cause problems within the body, including blood clotting/bleeding, organ enlargement, bone marrow scarring and other symptoms.
Since the JAK2 mutation was discovered, additional gene mutations have been found in MPN patients, including MPL (myeloproliferative leukemia protein) and CALR (calreticulin protein), among others. Although no one knows exactly what causes MPN, most people with the disease have one of these gene mutations. The presence of these mutations helps to diagnose the disease, and with newer techniques, can help us to better understand how the disease may progress, as well as provide a prognosis.
As mentioned, MPNs are a group of linked disorders, and this grouping is referred to as disease spectrum. However, because they are so closely related, they tend to share certain features and there is variability between the individual types of MPN. This means there is the possibility of transformation from one diagnosis to another within the MPN spectrum. For example, someone may be originally diagnosed with essential thrombocytosis (ET), and over time this disease could change into polycythemia vera (PV), with a new set of symptoms. (See diagram.) Let’s look at each diagnosis more closely.
With MPNs, one disease may change into another disease within the spectrum over time.
ET PV MF Acute Myeloid Leukemia (AML)
The History of MPN
This group of blood disorders was originally described in the late 1800’s, a time when medicine and the knowledge of organ systems were in their infancy. In fact, medical practice at that time was very primitive. In 1879, myelofibrosis (MF) was described by a German surgeon named Gustav Heuck as “peculiar blood and bone marrow findings.” More than a decade later, in 1892, Louis Henri Vasquez, a French physician, was the first to describe polycythemia vera (PV). Soon, other renowned physicians began complementing their work and expanding their observations of the disease.
In 1934, essential thrombocythemia (ET) was formally described as hemorrhagic thrombocythemia. They noted similarities and differences between the earlier diagnoses of MPN. Eventually it was William Dameshek, a prolific American-trained physician, who described the group of diseases as myeloproliferative disorders (MPDs), which included PV, ET and MF. He referred to them as “closely related disorders” sharing similar bone marrow findings and patient symptoms.”1 (The name was later changed to myeloproliferative neoplasms or MPN.)
Who was William Dameshek?
William Dameshek (1900-1969) was considered by some as the father of MPNs, although his work was expansive, and he made many other contributions to hematology (the study of blood disorders). He was born in Russia, but moved to the United States at a young age with his parents. He attended Harvard Medical School in Boston, and later was a founder of a medical journal, BLOOD, and served as its first editor-in-chief. BLOOD remains a prestigious medical journal in hematology.
Dameshek was also integral to the formation of the American Society of Hematology (ASH) and served as president of the organization. There is now an annual William Dameshek Prize awarded to individuals who have made outstanding contributions to the field of hematology.
Essential Thrombocytosis (ET)
What is ET?
ET occurs when your body produces too many platelets in the blood. Platelets are “sticky” parts of the blood that help stop bleeding. When a blood vessel in your body is injured and starts to bleed, platelets react by clumping together and forming a blood clot. Obviously, we need platelets to help us stop bleeding, but having too many in the blood can cause abnormal clotting or bleeding. Other symptoms may include headaches, lightheadedness, dizzy spells, changes in vision, burning feeling in hands and feet and more.
There is also the chance of forming a blood clot in a major vessel, such as one that supplies the heart, lungs or brain. If you develop sudden chest pain, shortness of breath, weakness in your face, arm or leg, difficulty speaking or understanding speech, seek urgent medical attention. These may be signs of a serious medical condition.
In rare cases, ET may cause unusual bleeding, such as frequent nosebleeds, easy bruising, bleeding gums or bloody stool. Again, if you experience any abnormal bleeding, it’s important to seek immediate medical attention.
How is ET diagnosed?
ET is an uncommon disorder. It is more likely to be found in people over the age of 50 and slightly more common in women, although young people can still develop ET. If you have a mild form of ET, you may never develop symptoms or require treatment.
In many cases, the first indication that you have ET is the discovery of a blood clot (thrombus). Blood clots can form in any part of the body, but with ET, they occur most often in the brain, hands and feet. The symptoms a person experiences depends on where the clot is located (i.e., if the clot is in the brain, you may develop headaches and/or dizziness, while a clot in the hands or feet may lead to numbness, tingling, redness, throbbing and/or burning pain in the hands and feet).
ET can be diagnosed with a routine blood test, which will reveal an abnormal platelet count. More extensive tests, such as molecular tests or a bone marrow biopsy, may also be ordered depending on your physician. A bone marrow biopsy is done to evaluate changes in the bone marrow that confirm the diagnosis and to rule out other diseases, such as fibrosis (scarring) in the bone marrow.
World Health Organization (WHO) Criteria for Essential Thrombocytosis:
Diagnosis requires meeting all four major criteria or three major criteria and the minor criterion.
| Major Criteria | Minor Criterion |
| Platelet count > 450 x 10°/L | Presence of a clonal marker or absence of evidence for reactive thrombocytosis |
| Bone marrow biopsy consistent with ET | |
| Not meeting criteria for another MPN | |
| Presence of JAK2 mutation |
How is ET treated?
Treatment for ET is based on the severity of the symptoms, which can range from mild to severe. Physicians will also base treatment on your “risk group.” Your risk is determined by your age, your history of blood clots and the presence of the JAK2 mutation. Patients are divided into low, intermediate and high risk. Depending on which group you are in, your healthcare team may recommend no therapy, a daily dose of aspirin (which helps to thin the blood), or drug therapies such as hydroxyurea, interferon, or anagrelide, to help alleviate symptoms and lower your risk of a blood clot.
What
