We’re all about helping Canadians who want to learn about or who are impacted by the different blood disorders know together as Myeloproliferative Neoplasms, or MPNs.
Myeloproliferative Neoplasms (MPNs) is the name given to a group of conditions sometimes referred to as blood cancers.
MPNs originate in the bone marrow – the soft tissue in the middle of the bones where blood cells are made. In a healthy person, bone marrow makes blood stem cells that, in time, develop into mature blood cells – red blood cells, white blood cells or platelets.
Each of these “mature” blood cells is vital to maintaining our health. Red blood cells carry oxygen and other materials to the
tissues of your body; white blood cells fight infection and disease; platelets help to prevent bleeding by causing blood clots to form. MPNs are stem cell disorders and develop when abnormal stem cells produce excess quantities of one or more of these blood cell types. As these blood cells are unable to function properly, they can trigger serious health problems if not treated and controlled.
MPNs are virtually unknown in children, and very rare in young adults. All three conditions primarily affect people over the age of 50.
Myelofibrosis (MF) MF is a disorder of the bone marrow. It occurs when abnormal stem cells in the bone marrow produce too many mature cells causing chronic inflammation and development of scar tissue (fibrosis). This scarring means the marrow is not able to make enough blood cells. The liver and spleen then compensate by producing their own blood cells, causing them to swell in size, which may lead to liver failure. MF can also cause anaemia and bleeding problems, as well as leaving patients at higher risk of infections.
Polycythemia vera (PV) In PV, too many red blood cells are produced (white blood cells and platelet counts are also increased). An increase in red blood cells makes blood thicker than normal, meaning clots form more easily. Around 30 per cent of people with PV experience blood clots. These can, in turn, cause blockages in arteries and veins, leading to complications such as heart attacks or strokes. Because thicker blood doesn’t flow as quickly through your body as normal blood, the body’s organs suffer from lack of oxygen. This in turn causes other serious problems such as angina and heart failure.
Essential thrombocythemia (ET) ET (also previously known as primary thrombocythemia) occurs when the bone marrow makes more platelets than the body needs. Platelets are needed to help the blood clot, but because there are too many of them, in people with ET they don’t work properly. This results in serious complications like thrombosis – where excess platelets cause a blood clot that blocks a vein or artery and stops blood flowing – and excess bleeding.
Chronic myeloid leukemia (CML) is also an MPN. CML is a chronic, progressive hematologic disorder in which there is abnormal production of blood cells by stem cells in the bone marrow. Most people with CML have a genetic mutation in which part of the genetic material from one chromosome is transferred to another chromosome. The resulting chromosome is called the Philadelphia chromosome. This chromosomal abnormality results in a great overproduction of white blood cells by the bone marrow.
Less common types of MPNs include:
It is not clear what causes MPNs. There is no single factor known to trigger PV or ET – they are most likely caused by a number of different factors. MF is slightly different because it can develop on its own (idiopathic) or, in some cases, develop in people who have ET or PV (known as secondary MF).
Role of stem cells: MPNs are often called “monoclonal blood stem cell disorders,” which means they result from a change (or mutation) in the DNA of a single blood cell. This change results in abnormal blood cell development and the overproduction of blood cells. In MPNs, the change in a single blood stem cell’s DNA (also known as the primary mutation), becomes more widespread when the affected stem cell divides and produces clones of identical stem cells, all with the same defect.
Gene mutations: A number of gene mutations have been identified in people with MPNs, including mutations in the JAK2, MPL and CALR genes. About 50% to 60% of patients with MF will have the JAK2 gene mutation, 24% will have the CALR gene mutation and 5% to 10% will have the MPL gene mutation. Around 95% of people with PV have a JAK2 mutation. Around 60% of people with ET have the JAK2 gene mutation, 30% have the CALR mutation and 5% have the MPL mutation.
Lack of oxygen: Another type of polycythaemia, called secondary polycythaemia, isn’t related to the altered JAK2 gene, but is caused by long-term exposure to low oxygen levels. If your body doesn’t have access to enough oxygen, it produces more of a hormone called erythropoietin (EPO), which in turn can lead to the production of more red blood cells than normal. This results in thicker blood, and PV. Therefore, people who have severe heart or lung disease are at risk of developing secondary polycythaemia, as are people who smoke, spend long hours at high altitude or who are exposed to high levels of carbon monoxide.
Other known risk factors for MPNs
A number of factors may increase the chances of developing an MPN.
Most people diagnosed with MPNs have never heard of the condition before. It is virtually unknown in children, and very rare in young adults (particularly MF and PV). All three conditions primarily affect people over the age of 50.
Myelofibrosis (MF): In the US in 2010, MF prevalence ranged from 3.6 to 5.7 per 100,000.It can be diagnosed at any age, but is most common in people aged between 60 and 70 and affects men and women in relatively equal numbers. Around one third of people who are diagnosed with MF will have previously been diagnosed with ET or PV. This is known as post-polycythemia vera MF (post-PV MF) or post-essential thrombocythemia MF (post-ET MF).
Polycythemia vera (PV): In 2010 PV prevalence estimates in the US ranged from 45 to 57 cases per 100,000. It is very rare in children and young adults, mostly affects people over the age of 50, and is more common in men than women.
Essential thrombocythaemia (ET): ET prevalence in the US in 2010 ranged from 39-57 cases per 100,000 population.It is most common among those over the age of 60, although 20% of people with ET are under the age of 40. The average age at diagnosis is between 65 and 70 years. It’s more common among women, with two women diagnosed for every one man.
Diagnosing an MPN can be challenging. In the early stages, there are often no symptoms, and even when symptoms appear, such as fatigue, they can often be mistaken for signs of other diseases. It is not unusual for an MPN to be detected during tests for unrelated problems. Doctors use a combination of lab tests, examining the blood and bone marrow, and physical tests, to diagnose MPNs. Typical tests may include
Physical examination. Your body is checked for anything that seems unusual. A doctor will also compile a history of your health, any relevant lifestyle information and any past illnesses and treatments.
Complete/full blood count. A sample of blood is taken and checked for:
Peripheral blood smear. A sample of blood is checked for:
Bone marrow aspiration and biopsy. Bone marrow, blood and a small piece of bone will be removed by inserting a hollow needle into the hipbone or breastbone. This is then checked for abnormal cells.
Cytogenetic analysis. Cells from a sample of blood or bone marrow are viewed under a microscope to look for certain changes in the chromosomes, which can diagnose or rule out certain diseases or disorders.
Gene mutation test. Bone marrow or blood samples are checked in a lab for mutations in genes. A JAK2 gene mutation is often found in patients with polycythemia vera, essential thrombocythemia, or primary myelofibrosis. MPL or CALR gene mutations are found in patients with essential thrombocythemia or primary myelofibrosis.
Learn about individual MPNs:
Thicker blood and/or higher numbers of platelets can cause blood clots in the arteries that interfere with the blood and oxygen supply to the brain. This can result in a stroke.
In PV, a lack of oxygen-rich blood reaching the heart may result in heart failure or angina (chest pain).
In MF and PV, the body uses organs other than the bone marrow to make blood cells. This can cause the liver to become enlarged (hepatomegaly).
MF and PV affect the bone marrow, and its ability to make red blood cells. This means the spleen may take over the job, causing it to enlarge (called splenomegaly). An enlarged spleen may put pressure on the stomach, causing a feeling of fullness, indigestion and loss of appetite, which in turn can lead to weight loss.
In PV, the extra blood cells make the blood thicker and move more slowly, which can lead to clots as well as excess bleeding and bruising. In ET, excess platelets are produced, which may also lead to blood clots. These blood clots may affect the blood and oxygen supply to the heart (which may lead to heart attacks), the brain (which may trigger a stroke), lungs, kidneys and liver. In MF, the changes in blood cells tends to result in a lack of the oxygen-rich red blood cells, which may cause anaemia, leaving people affected feeling tired, weak and short of breath.
A higher than normal level of red blood cells may cause a red complexion, as well as reddening of the palms, soles of feet, ear lobes, mucous membranes and eyes. Excessive sweating, especially at night (known as night sweats) and itching (also known as pruritis) can also be caused by MPNs, usually as a result of chronic inflammation.
Hands and feet
PV and ET can both cause an intense burning pain, and increased skin temperature in the feet (and sometimes the hands). This is known as erythromelalgia.
The hardening of the bone marrow and inflammation of the connective tissue around the bones may lead to severe bone and/or joint pain.
In MF, extra blood cells can lead to a build-up of uric acid, resulting in painful swelling in a joint (gouty arthritis), usually the big toe.
MF is caused by abnormal blood stem cells in the bone marrow. These abnormal stem cells produce more mature cells that grow quickly and take over the bone marrow, causing both fibrosis (scar tissue formation) and chronic inflammation. As a result, the bone marrow becomes less able to create normal blood cells and blood cell production may move to the spleen and liver.
As your bone marrow isn’t able to make normal blood cells your spleen and liver usually try to compensate, however they, can’t compensate sufficiently. The lack of normal blood cells causes low blood count which leads to anaemia, which can make you feel very tired and short of breath. Low white blood cell count or diminished production of antibodies can place you at a higher risk of infections. Also, your liver and spleen can end up swelling. Symptoms of MF can include:
As time goes on, we are learning more about MF and its causes. What causes MF is not fully understood. About 50% to 60% of MF patients have a change (mutation) in a protein that regulates blood cell production (this protein is known as JAK2 and the mutation as JAK2 V617F).
This mutation causes JAK2 to signal blood cells to grow and divide even when the body is not asking for more blood cells which dysregulates the JAK/STAT pathway involved in the blood cell production process in the bone marrow. 5% to 10% of MF patients have a mutation in a gene named MPL, which also affects the JAK/STAT pathway. In 2013 another gene mutation called CALR was discovered. It affects about 24% of MF patients. Research is ongoing to determine how the CALR mutation affects the treatment and prognosis for MF patients.
People are not born with these mutations but acquire them during their lives. These mutations may also be triggered by past exposure to ionizing radiation (a type of radiation that has very high energy, like medical X-rays) or to petrochemicals such as benzene and toluene. It is also important to note that MF is rarely inherited and is not passed on from parent to child, although some families do seem to develop the disease more readily than others.
Primary MF (which means it occurs on its own) usually develops slowly in people aged between 60 and 70. One third of people diagnosed with MF have been previously diagnosed with polycythemia vera (PV) or essential thrombocythemia (ET). This is known as secondary MF and more specifically as post-PV MF or post-ET MF.
A sample of blood is checked under a microscope for red blood cells that are shaped like tear drops. The number and types of white blood cells, the number of platelets and the presence of immature blood cells can also help your doctor diagnose MF. Your doctor will use cytogenetic testing to check for other signs, including mutation in the JAK2, CALR or MPL genes.
MF is generally regarded as incurable and the course of MF can vary considerably between people. In some people the disease remains stable for long periods, allowing them to live a normal life with minimal interruptions. For others, MF progresses more quickly and people require treatment to help relieve symptoms. Up to 20% of cases may transform into acute myeloid leukaemia (AML), a cancer. If you’d like to know more about your individual prognosis, you should talk to your doctor.
Doctors and scientists have been developing methods to predict disease prognosis for myelofibrosis patients. One of the methods is referred to as DIPSS (Dynamic International Prognostic Scoring System). The following factors are considered in this scoring system (one point for each except Hemoglobin which is two points)
Your doctor will tailor the management of your MPN to your particular case. When you’re first diagnosed, they may suggest the “watch and wait” approach, if you don’t have symptoms or complications such as anemia or an enlarged spleen. This means your MPN and related symptoms will be monitored regularly through check-ups and blood tests.
PV is a disorder of the bone marrow that causes an overproduction of red blood cells, although white blood cell and platelet counts are also increased. The extra red blood cells make your blood thicker than it should be.
A lot of people don’t have symptoms to begin with and PV is often picked up during routine blood tests. When symptoms do occur, they usually develop gradually over time. Thicker blood increases your risk of blood clots forming and blocking veins or arteries, potentially causing a stroke or heart attack. Blood clots are a common complication of PV, affecting about 30% of people with the condition. As thicker blood flows around your body more slowly than it should, it may not get enough oxygen to your organs, which can cause other serious problems such as angina and heart failure (where your heart can’t pump enough blood around your body, leading to symptoms such as fatigue). And because your spleen tries to compensate by producing red blood cells, up to 75% of people with PV develop an enlarged spleen and some people also get an enlarged liver. As a result of what’s happening in your body, you might notice symptoms including:
One study asked 405 patients with PV about their most significant symptoms, the results showed that 85% had fatigue as a symptom, followed by itching reported by 65%. Other symptoms were night sweats (49%), bone pain (43%), fever (13%) weight loss (10%) and spleen pain (4%).
The cause of PV is unknown. However, it is known that the disease is driven by dysregulation of the JAK/STAT pathway that is involved in the blood cell production process in the bone marrow. Nearly all people with PV have a change (mutation) in a protein known as JAK2 (short for Janus kinase) that regulates blood cell production.
People are not born with these mutations but acquire them during their lives. It is also important to note that PV is not inherited and is not passed on from parent to child, although some families do seem to develop the disease more readily than others.
PV can occur at any age, but people over 50 are more likely to be affected. Men are slightly more likely to be diagnosed.
If you have PV, your blood sample will show you have too many red blood cells. You’ll also have other blood tests to measure substances including uric acid and oxygen, and you might have a test to check your blood is clotting normally. Chest X-rays, abdominal ultrasounds and CT scans may be used to rule out other diseases and to measure the size of your spleen and liver, which can become enlarged in PV. Finally, your doctor will use cytogenetic testing (testing of chromosomes in blood cells) to check for the JAK2V617F mutation, found in 90-95% of people with PV.
In about 15% of cases, PV can evolve into myelofibrosis (MF, known as post-polycythemia vera myelofibrosis or post-PV MF) and in a smaller number, it can progress to acute myeloid leukemia, which are both more serious conditions. But most people with PV live without complications for a long time, and it’s likely having it won’t have any effect on your life expectancy as long as your symptoms are monitored and managed.
Polycythemia vera is a chronic myeloproliferative disorder affecting people in the sixth decade of life. The disease is considered long-lasting; median survival exceeds 18 years. As thrombosis is the main complication during follow-up, scoring systems have focused on the risk of thrombosis. Age over 60 years and prior thrombosis are considered the standard risk factors for thrombosis and represent the state of the art for risk stratification in decision making regarding treatment. However, new disease-based risk factors-leukocytosis and the JAK2V617F mutation burden-seem to be emerging as indicators of prognosis in polycythemia vera. Leukocytosis, as a marker of disease proliferation, seems to have an impact on thrombosis, post-polycythemia vera myelofibrosis, leukemia, and survival. The role of the JAK2V617F mutation as a prognostic factor requires further validation, but it may have a dominant role in disease progression and in the activation of platelets and leukocytes.
Your doctor might adopt a ‘watch and wait’ policy, simply monitoring you without further action, particularly in the early stages after your diagnosis. Further information about managing symptoms is available, Click here.
ET occurs when your bone marrow makes too many platelets – substances that help your blood clot – and the blood platelet count is persistently elevated.
As your bone marrow makes too many platelets, you’re at higher risk of having a blood clot (or thrombosis) that blocks a vein or an artery, potentially causing a stroke or heart attack; too many white blood cells have been linked with increased risk of thrombosis too. You might also have a higher risk of excess bleeding.As a result of these changes in your blood, some of the other common symptoms of ET include:
One study asked 304 patients with ET about their most significant symptoms, with the results showing that 72% had fatigue as a symptom, followed by night sweats and bone pain, both reported by 41%. Other symptoms were itching (40%), fever (9%), spleen pain (9%) and weight loss (7%).
The cause of ET is unknown.
However, it has recently been discovered that mutations can alter the activity of signalling pathways. About 50% of people with ET have a change (mutation) in a protein known as JAK2 (short for Janus kinase) that regulates blood cell production. Mutations in the MPL gene are seen in about 5% of people with ET and about 30% have a mutation in the CALR gene.
People are not born with these mutations but acquire them during their lives. There is a rare form of ET that is inherited, likely caused by a genetic mutation, resulting in people in some families developing the disease more readily than others.
If you don’t have symptoms, your doctor might be happy to just monitor you for a period of time. You’ll have regular check-ups and blood count tests to check the progression of your condition. You might be monitored in this way for a long time.
More information about the management of ET can be found Click here
Mostly people between the age of 50 and 70, although it sometimes affects younger people. It occurs more frequently in women than men.
In blood and bone marrow tests for ET, doctors look for a persistently raised platelet count. Normal platelet counts vary between 150,000 and 400,000 per microliter of blood but in ET, the count can be many times higher.Your doctor will rule out other causes of a raised platelet count, and then send you for further tests, including a bone marrow examination and a gene mutation test. Once your diagnosis is confirmed, your doctor might recommend further blood tests to check your health and work out how well organs such as your liver and kidneys are functioning.
ET is regarded as incurable, however, in people who receive treatment, the disease can remain stable for long periods of time. Rarely, ET can change into myelofibrosis (MF, post-essential thrombocythemia myelofibrosis, or post-ET MF). There is a relatively low risk (<1%) of ET transforming into myeloid leukemia.
The life expectancy of patients with essential thrombocytosis (primary thrombocythemia) is nearly that of the healthy population. Median survival is approximately 20 years. For patients younger than age 60 years, median survival is 33 years.
Before starting the treatment, it is recommended to determine the risks of having complications according to the age, medical history and the presence of specific mutations to decide which the best treatment should be. The available treatments are not curative and do not prevent further evolution of the disease to acute myeloid leukemia or myelofibrosis (which only happens in very rare cases). The treatment of essential thrombocythemia is based in reducing the platelet countto avoid complications.
The most common medication include hydroxyurea, interferon-alpha, Phosphorus 32, anagrelide. Aspirin in low doses can be used to control microvascular symptoms such as redness and pain in the fingers and toes, insufficient blood flow (ischemia), infections in the limbs (gangrene), strokes, syncopes, instability or visual disturbances.
It often takes a while to be diagnosed with an MPN, partly because there may be no symptoms in the early stages. In some cases, even if you did have symptoms, such as fatigue, these might have been mistaken for signs of other diseases.
Your doctor will need to carry out a number of tests before you are officially diagnosed with an MPN. More tests may be required to work out the type of MPN you have before it can be managed. This is to make sure that the management plan you’re given is the very best for you. You’ll also need to have regular blood tests to check on the progression of your condition.
1. A physical examination
Doctors begin by doing a physical examination, checking for symptoms such as an enlarged spleen which can occur in MPNs, and will also ask about your symptoms and your lifestyle.
2. Full blood count
Your doctor will take a sample of blood, to check for the number of red blood cells and platelets, and the number and type of white blood cells, as well as the amount of hemoglobin in red blood cells and the portion of the blood sample that is made up of red blood cells. This is known collectively as a full blood count or complete blood count (CBC).
3. Bone marrow aspiration and biopsy
This is done by inserting a hollow needle into the back of your hip bone (or, sometimes, the front of this bone or your breast bone) to remove a sample of marrow, the spongy material inside your bone. You may also have a bone marrow biopsy, which is performed in exactly the same way, but removes a small amount of bone, fluid and cells from inside the bone marrow.
The sample will be looked at in a lab. MPN bone marrow cells look different from normal cells, there may be too many or too few, and the bone marrow may have too much or too little iron. There might be signs of infection in the bone marrow, or it may have been replaced by fibrous or scar tissue.
Most people have had blood tests before, but the chances are a bone marrow test will be new to you. First, you’ll be given a local anesthetic to numb the area where the sample will be taken. Then the nurse will insert the hollow needle that will draw out the sample. You may hear a crunching sound when the needle goes into your bone, which can be a bit alarming, but is completely normal. You might also feel some pressure and perhaps pain. During an aspiration, you may notice a quick, shooting pain that goes down your leg as the sample is taken.
The procedure itself usually takes about 20 minutes. You might notice a bruise on the site and the area may feel stiff or sore for a few days.
4. Cytogenetic and molecular testing
The cells in your blood or bone marrow sample are examined under a microscope to look for the presence of the Philadelphia chromosome, a chromosomal abnormality which can lead to a diagnosis of chronic myeloid leukemia (CML) rather than ET, PV or MF. Other molecular tests will also look for the JAK2V617F (JAK2),CALR or calreticulin, and MPL mutations found in MPNs.
Any kind of medical test can make you feel anxious and with MPNs the process can be particularly stressful as you may end up having lots of tests before your doctor can give you a diagnosis. This can trigger anxiety, so here are some tips to help you manage: