- Joyce Niblack (team leader)
- Barb Abernathy
- Dan Levy
- Sharon Glazer
Statements contained herein are of a general nature and should not be construed as personal advice in lieu of recommendations by your physician or other relevant professional consultant
Polycythemia vera is one of the myeloproliferative disorders (MPD). In this variant, there is uncontrolled production of mature red cells leading to high hematocrit (Hct), hemoglobin (Hg) and red cell mass with increased blood volume and viscosity which can lead to complications involving clotting or bleeding episodes if not controlled. The MPDs also include essential thrombocythemia (ET), agnogenic myeloid metaplasia (AMM), secondary myelofibrosis (MF) and chronic myelogenous leukemia (CML). Each of these variants have predominant features which permit classifications which are named for the cell type showing the most marked involvement. There is a great deal of overlap in the features of these various syndromes and transition from one to another is common. This is discussed in greater detail below.
PV is fairly rare and is considered an orphan disease. Between its rarity and the fact that many PV patients live a long time, it hasn't been studied the way "major" diseases have and there is no consensus among the experts about who, what, why, and how to treat. You will find that many decent local hem-oncs may have little experience with PV and that the major drugs used to treat PV patients are not approved for that particular use. We hope that the information in this FAQ, in the MPD-NET online discussion group, the MPD web page and the MPD VOICE newsletter will help newly diagnosed PV patients sort this all out.
"Myelo" is the Greek word for marrow "Proliferative" means growing or reproducing "Disease" is the improper function of a body organ.
MPD is literally "Marrow Proliferative Disease" or improper function of the bone marrow organ.
Bone marrow is the body's blood-forming (hematopoeitic) organ. It contains blood-forming cells called "hematopoeitic precursor or stem cells" that have two important functions. (1) self-renewal to maintain a pool of stem cells for future proliferation or growth. (2) ability to mature into adult blood cells that will leave the marrow and enter the circulation.. These precursor cells produce several types of blood cells; red blood cells (RBC), some varieties of white blood cells (WBC) and platelets. Because of this versatility, they are called "pluripotential hematopoeitic precursor cells ("PHPC"). Each PHPC is a stem cell that can reproduce itself (clone) as well as produce a number of daughter cells (blasts). Normal bone marrow is composed of a family of hematopoeitic clones all reproducing themselves and forming daughter cells that will, in turn, develop into red blood cells, white blood cells and platelets. The dedicated daughter cells divide over and over again and it is their growth that fills the marrow with the diverse types of immature and developing blood cells that are seen in a normal bone marrow specimen. The normal marrow also balances production of different cell types so they appear in the blood in their proper proportions.
In MPD, one abnormal PHPC clone has a growth advantage that allows it to overgrow at the expense of the normal PHPC clones. While this PHPC clone is "abnormal", it is still able to self-renew and to produce several types of blood cells. The cells produced by the abnormal clone may be difficult to distinguish from those produced by normal cells. But what we do have in the myeloproliferative disorders is abnormal over or under production of a particular cell type. Thus MPD involves the improper balance between production of different blood cell types just as much as it involves abnormality of any given blood cell type.
As mentioned above, in this variant, the PHPC clone (stem cell responsible for blood production) produces too many red blood cells which literally causes the patient to have "too much blood". The resulting increased blood volume and thickness leads to the complications associated with this disease. The risks of complications can be reduced by appropriate treatment.
Polycythemia Vera is primarily a disease of middle-aged or elderly patients but we are seeing young patients as well In a retrospective study of 1231 PV patients followed for 20 years, the largest cluster of PV patients were found in the 41 to 80 age groups with the highest numbers in the 51-75 age groups. (The ages ranged from under 10 to over 90). See Polycythemia Vera: The Natural History of 1213 Patients Followed for 20 years, Gruppo Italiano Studio Polycythemia, Annals of Internal Medicine, Volume 123, Number 9, 1 November 1995.
PV is insidious in onset and may be present for 1 to 2 years medical attention is sought. During the asymptomatic phase, polycythemia vera may be discovered at the time of a routine examination which reveals an elevated hematocrit. Polycythemia vera (PV is the only myeloproliferative disease in which involvement of the erythrocytes (red cells) results in an increased red cell mass. This feature of "too much blood" results in unique symptoms and complications. Basically, patients are at higher risk of clotting or bleeding problems related to the resulting hypervolemia (increased blood volume) and viscosity (thickness). Thrombosis and hemorrhaging are big problems at the outset, especially before diagnosis but once this is properly controlled, risks are reduced.
Symptoms caused by the elevated hematocrit are present initially in 30 to 50% of patients and may cause the patient to seek medical attention for symptoms such as plethora (too much blood), headache, dizziness, visual disturbances, inability to concentrate and parethesis (numbness). Related findings at diagnosis can include hypertension, a high cardiac output state and evidence of vascular status. Significant arterial or venous thrombosis occurs in one third to one half of uncontrolled cases, and these events may precede the diagnosis (heart attack, stroke, pulmonary embolism, portal vein clots (veins leading to liver), etc.
While we have heard of cases where a diagnosis is made simply based on blood counts, most hematologists follow the guidelines of the Polycythemia Vera Study Group and run certain diagnostic tests. If the Study Group findings are present, then a diagnosis can be made with certainty. Therefore, certain physical and laboratory findings are believed critical by many doctors to reach a diagnosis of polycythemia vera. Differential diagnosis from relative polycythemia due to abnormalities in plasma volume from, for example, dehydration, rather than red cell production, requires the demonstration of absolute erythrocytosis (elevated red cell count) by direct measurement of red cell mass and plasma volume. Once an elevated red cell mass is documented, polycythemia vera must be distinguished from conditions producing isolated erythrocytosis. However some doctors feel that determining erythropoeitin levels is an appropriate indicator if the value is below 4. Researchers at Mayo Clinic are working on a more sensitive test for this purpose.
The criteria that must be met for a diagnosis of polycythemia vera and the incidence of these abnormalities at diagnosis are a demonstration of increased red cell mass combined with an enlarged spleen (splenomegaly) which is presenting 75% of cases or any two other features of pluripotential precursor cell involvement, such as increased platelet counts (35-50%), neutrophilia (50-80%), increased leukocyte alkaline phosphate activity (80%), or increased vitamin B12 binding protein (67%).
There are certain features in the bone marrow as well. The bone marrow uniformly shows panmyelosis (increase of all the bone marrow elements) with erythroid hyperplasia (excessive proliferation of red cells) and increased megakarocyte (platelet precursor) proliferation. Increased reticulin is present in 20% of patients but fibrosis is usually absent. Cultured bone marrow produces erythroid colonies, and there is a marked increase in the number of erythroid colonies formed with the addition of erythropoeitin (increased erythropoeitin sensitivity).
As mentioned above, the increased blood volume and increased circulating red cell mass play a key role in the symptoms and complications experienced in cases of uncontrolled polycythemia vera. Thrombosis and hemorrhage are the major complications. Thrombosis may be arterial (coronary, cerebral, peripheral vascular) or venous (involving peripheral, hepatic or portal veins). Small vessel insufficiency produces cyanosis (slightly bluish, grayish or dark purple discoloration), erythromyelagia (pain in fingers and toes), or even gangrene of the digits. Mild hemorrhagic phenomena such as nosebleeds (epistaxis), bleeding gums and easy bruisability are common. More severe bleeding problems such as melena (black tarry stool), hemostatsis (stagnation of blood-lack of circulation), menorrhagia (excessive menstrual bleeding) or hemoptysis (coughing up blood which can originate from the mouth, larynx, trachea, bronchi or lungs) occurs in 10% of patients. However, there is good news. With modern treatment, many PV patients are enjoying a normal life expectancy.
Restoration of a normal blood volume and hematocrit markedly reduces the incidence of complications in polycythemia Vera. Management based on this insight into the causes of the complications and symptoms of polycythemia vera has resulted in a significant improvement in survival. Treatment of erythemia is targeted at reduction of the hematocrit to normal levels at which optimum cerebral blood flow is achieved. Views on what this level should be varies among different hem-oncs and one should always discuss this with your own doctor. Treatment options also vary depending upon the particular circumstances of each patient.
There are a number of other metabolic abnormalities which occur in MPD patients, including patients with PV. Briefly, MPD patients, including PV patients may exhibit high uric acid levels (hyperuricemia, 50%) which can lead to joint pain and gout, low cholesterol levels (hypocholesterolemia), high histamine levels (hyperhistaminea) and histaminuria occur in two thirds of MPD patients which can produce puritus (itching), heart burn, acid eructation, peptic ulcer, small bowel hyper motility, flushing and angioneurotic edema. Hypermetabolism is commonly manifested as weakness and fatigue that occur in MPD patients not experiencing anemia.
Phlebotomy has been one of the most common initial therapies for many polycythemic patients. There has been a lot of experience with it. The purpose of phlebotomy is to reduce the red blood cell mass (RBC mass)-that is, the total number of circulating red blood cells, and to do it fairly quickly, at least in the beginning when the hematocrit (Hct) is high.
The blood in your normal circulation contains red blood cells and plasma. Normally the red blood cell mass is 40 to 45 percent of the blood and the other 60 percent is plasma. The hematocrit (Hct) is the percentage of red blood cells in the blood relative to plasma. Normal amounts of red blood cells in the circulation are 1800cc (60 oz, about 4 pints) in women and 2200 cc (72 ozs, about 4.5 pints) in men. The rest of the blood volume is made up of plasma (liquid) and is about 2400 cc (80 oz or about 5 pints).
Phlebotomy is a rapid way of reducing the increased red blood cells down to normal levels. When red cells are removed by phlebotomy about 400-450cc (one pint) of blood) is removed, of which approximately 60 percent are red blood cells (about 300 cc). The body only makes about 17 cc (˝ oz) of red blood cells a day, so in a normal individual it would take about one month to make up for one phlebotomy under normal conditions. The rate at which polycythemia vera patients regenerate can vary.
Since red blood cells are made so slowly, rapid changes in the blood volume (RBC plus plasma) are accomplished by changes in the plasma which are controlled by the kidney, as plasma is mostly water. The blood volume is adjusted by the body to maintain an adequate blood pressure. When the blood volume falls quickly, as in bleeding, the body gets a signal to increase the amount of fluid that is circulating. That is why an early sign of blood loss is thirst.
After phlebotomy, as the blood increases its plasma content, the hematocrit falls, so the red blood cells are now diluted. The benefit of reducing the hematocrit(Hct) is to get the blood to a normal consistency (viscosity), as the heart and blood vessels are designed to pump and hold a fluid close to the viscosity of water, not oil. You can imagine what would happen if you filled your water tank and plumbing system with motor oil instead of water.
Once the blood volume is replete and the viscosity of the blood is normal, the red blood cells can fulfill their function of oxygen delivery to the tissues much better. The red blood cells have a fantastic capacity to increase their oxygen delivering ability by many adaptive mechanism so that, with the proper compensations in fluid replacement, your body should not be deprived of adequate circulation or oxygen.
At the beginning of your PV you will have an elevated Hct. As the initial salvo of phlebotomies are performed, the RBC mass and plasma volume are reduced to normal levels. After that, depending on the rate of your RBC production and how fast you build up your red blood cell mass, it should take periodic phlebotomies to maintain your Hct at a normal level unless you are receiving other therapy which controls your counts and reduces or eliminates the need for further phlebotomies. The frequency of phlebotomy after the initial series varies widely from patient to patient and within one individual, depending on the disease activity.
Most patients tolerate phlebotomies rather well. Special care must be taken in patients with cardiovascular instability. Also phlebotomy may temporarily cause an increase in platelet counts.
Yes. The immediate post-phlebotomy period symptoms of weakness, headache, etc. are due to the acute change in blood volume. Drink plenty of fluids just before and for two days after the phlebotomy. Also, do not engage in strenuous physical activity during that time. Low dose aspirin (81 mg/day) especially pre- and post-phlebotomy is suggested to keep the platelets from being too sticky. This helps in maintaining good circulation even if there is a post-phlebotomy increase in the platelet count. This should be taken only if there are no contraindications so check with your doctor before taking aspirin.
No. In many instances, phlebotomy is used to rapidly bring down the red cell mass and then drugs are added to the treatment plan. Some patients will not tolerate phlebotomies or may have such active red cell production that the required frequency of phlebotomy is unacceptable. In addition, some patients have other elevated cell lines such as high platelets or high white cell counts. Some experts use phlebotomy initially but think it speeds the process toward the spent phase. For a variety of reasons, Phlebotomy is combined with myelosuppressive therapy to control very active erythrocytosis, thrombocytosis or myeloid metaplasia. Hydrea and Interferon are the drugs most frequently employed today and if elevated platelets are a problem, anagrelide may be used.
Of necessity, if it is not replaced it will decrease. In fact, the long term objective of phlebotomy is to inhibit red blood cell production by creating a state of iron deficiency. Red blood cell production requires iron stores in the bone marrow. The iron is incorporated into hemoglobin (Hg). When iron is absent, the red blood cell parent cells (precursors) will turn out RBC that contain less Hg. That is why they are smaller in size and the mean corpuscular volume (MCV) is low.
It is not appropriate to replenish the iron stores if the PV is still active because this will stimulate production of more red blood cells and raise the hematocrit and blood viscosity and you will be back where you started-needing more frequent phlebotomies.
At a normal hematocrit, there should be none. In the immediate post-phlebotomy period the symptoms of weakness, headache, etc. are due to the acute change in blood volume.
The state of iron deficiency in patients without PV leads to iron deficiency anemia and when the hematocrit gets low enough they will feel weak and tired and have headaches and other symptoms. That is due to a low hematocrit with compromise of oxygen delivery. This is not the case in an iron deficient PV patient who has a normal Hct.
Iron is needed for many metabolic tasks in the body, but these take priority over hemoglobin synthesis, so that the iron left in your body is usually sufficient for these needs. If your body does not need the excess red blood cells that you are making, then you are better off without them and there should be a net gain in your health status and a net decrease in your risk of thrombosis or bleeding.
According to one specialist, Dr. Harriet S. Gilbert, you should be cheered by the recent report that iron contributes to cardiovascular and coronary heart disease and that iron deficiency may protect against heart attacks. Your phlebotomies may be doing more than just correcting your blood viscosity and might actually be contributing to your increased survival. Dr. Gilbert has mentioned that she has often wondered why patients with PV and al the risks that the disease poses have a normal life expectancy. It certainly suggests that there are factors at play that prolong life.
A number of older chemotherapeutic agents have been tried in the past to "unrev" the marrow and lower counts. Past experience has demonstrated, for example, that administration of 32P (radioactive phosphorus) in doses required to achieve and maintain a normal blood count or the use of certain alkylating agents resulted in unacceptable high (20 to 30 percent in some literature reports) incidence of acute leukemia, with a peak onset of 8 years after diagnosis. In a comparison by the Polycythemia Vera Study Group between management with limited doses of 32P (5mC per year), unlimited chlorambucil, and phlebotomy alone, the incidence of acute leukemia and nonhematologic malignancies was increased in both groups receiving myelosuppressive therapy by a factor of 4:1 Acute leukemia developed earlier and with a greater frequency in the chlorambucil-treated cases and was a dose-related phenomenon. In contrast, patients treated with phlebotomy alone had an incidence of acute leukemia of less than 1%. However, this group had a higher incidence of thrombosis and hemorrhage in the first two years of treatment. This is one of the reasons attention is focused on the agents discussed above.
Some doctors feel very comfortable with its use, some do not like to use it in younger patients who will require treatment for many years but feel comfortable using it in older patients who are unlikely to remain on it long enough to develop any secondary problems. The literature reports of secondary leukemias associated with prolonged Hydrea therapy indicate the risk is lower than older agents. There was a recent abstract in which the authors claimed to have found no statistically significant different but their figures for phlebotomy patients were higher than in other reports. This is something you need to discuss with your doctor.
Unless your doctor changes you to another treatment agent, for life. PV is a chronic condition. The rapid rebound following drug withdrawal requires continuous administration.
Because hydroxyurea has less of a suppressive effect on erythropoiesis (red cell production ) than on platelet and neutrophil production, supplementary phlebotomies may be required for the maintenance of an optimal hematocrit.
Yes, interferon has been used in the treatment of polycythemia vera and other myeloproliferative disorders since the mid-1980's. Some literature reports suggest that interferon is proving superior to phlebotomy and may become the treatment of choice for PV and related MPD disorders as it may offer the best option for improving the marrow status and delaying or preventing development of the "spent phase" in PV and Et. But not all doctors are in agreement on this. One of the main advantage of interferon is that patients can be cycled. This agent actually improves the marrow in some patients and the improvement is lasting so they can go months to years before needing further treatment. One patient in the MPD-NET discussion group was able to go without treatment for 3 years after stopping inteferon before her platelet counts started to rise. Even then, much of the improvement in her bone marrow was still seen.
However, there is no consensus among the experts as to how long, how much and whether to stop interferon and start it again when counts rise or the spleen enlarges or whether patients should remain on a lower maintenance dose forever.
Anagrelide, an agent which lowers platelet counts, is also used in PV patients. In some cases, anagrelide is combined with hydrea.
While oral dosage forms are being tested in PV, ET, and MF patients by Dr. Murray Silverstein at Mayo Clinic Rochester, and low dose "oral" interferon has been used to treat conditions such as hepatitis, at the moment, interferon for myeloproliferative disorders involves an injectable drug. Usually the patient self-administers subcutaneous shots. The dose and frequency varies depending upon the bias of your doctor. Some hem-oncs prescribe daily injections for a period of time until there is improvement, then cut back to a lower maintenance dose for a period of time. Some use a three times a week routine. There is no agreement on dose, frequency of injection, how long patients should stay on the drug, whether they should remain on for life at a lower maintenance dose or cycle. This is frustrating for patients who need to review the literature and discuss their options with their hem-onc. Results are what are important.
Initial flu like symptoms are experienced by nearly everyone. Tylenol controls these and they subside as the body adjusts to this medication. Some people experience fatigue and find they have to slow down while on interferon. Some tolerate the drug better than others and are able to carry out a fairly normal routine. Others discontinue treatment. We have a number of people on interferon in our MPD-NET discussion group who will be happy to discuss this issue with you. Your doctor should give you written information about side effects and the package literature also lists reported side effects.
Post polycythemic myeloid metaplasia (PPMM) is also referred to as the "spent phase". After years of hyperactivity, the marrow may become increasingly fibrotic (scarred), hematopoiesis (blood production) becomes ineffective and peripheral blood counts decrease. The marrow becomes hypocellular as opposed to the hypercellular state in the proliferative phase. During this phase, hematopoiesis may resemble that seen in aplastic anemia, sideroblastic anemia, refractory anemia, or paroxysmal nocturnal hemoglobinuria.
Some patients seem to have growth factors that predispose them to the development of fibrosis. Interferon has retarded or reversed this is some patients but is not effective in all. Bone marrow transplantation is being used at some centers to treat myelofibrosis.
There is not much literature on this for PV patients but Dr. Jeanne Anderson, formerly of Fred Hutchinson Cancer Center in Seattle, Washington, recently advised our mpd-net group that they now have protocols for bone marrow transplants in patients with PV. Dr. Anderson recently left the Hutch but there are others who can help you find information. There is a link to the Hutch website on our web page.
Bone marrow transplants have been used in patients with post polycythemic myeloid metaplasia and we have a parent of a 3 year old PV patient in MPD-NET who has reported his son will have a bone marrow transplant with the father as the donor. Many PV patients tend to live out normal life spans so unless there is conversion to a more aggressive form of these diseases, bone marrow transplants are not presently considered as first line treatment. The CML FAQ has a lot of information about bone marrow transplants since this procedure is more commonly used in that MPD variant. To get the CML FAQ, address your message to
Listserv@listserv.acor.org andhave a 1 line message that reads get mpd-net.cml faq.
Some PV patients are bothered by itching (pruritis). One of Dr. Gilbert's earliest research studies in PV dealt with this issue. She has written " I found that it was the result of histamine release by the basophiles. Basophils are the type of segmented white blood cells produced by the bone marrow precursor involved in PV. An increased number of basophils are produced and they do maintain their function, as do most of the cells produced in the PV marrow. Basophils produce and release histamine in response to many stimuli. In PV the most common stimulus is exposure to water-Hct or cold, depending upon the patient. Thus, post-bathing or post-showering pruritis is common. Exposure to air, as after removing clothing, is another common stimulus. Histamine and related substance released by the basophil may also contribute to the higher incidence of upper gastrointestinal (GI) problems, such as ulcer and gastritis seen in PV. (Histamine stimulates the release of hydrochloric acid in the stomach.) Histamine may also produce diarrhea and increased bowel motility.
For pruritis, you can start with mild antihistamines such as Benadryl® diphenhydramine hydrochloride antihistamine (or your doctor may prefer some of the newer agents) taken one-half hour before exposure to whatever brings on the itching. If its bathing, it is best done at night, since Benadryl can make you drowsy. You can work up to one of the histamine type I blockers such as Seldane® (terfenadine), Claritin® (loratadine) or hismanol which can be taken during the day, as they are not soporific. If itching is still a problem, the stronger antihisitmine, Periactin® (cyproheptadine) can be tried at night and in low dose because it is also soporific. One patient in the MPD-NET group has mentioned his allergist gave him "zyrtec" which has been tested in Europe and he says works great for him. For increased acidity, histamine type II (H-2 blockers such as Zantac® (ranitidine hydrochloride) and antacids may help. Consult your doctor about using any of the above measures to combat pruritis and GI symptoms.
If none of the supportive measures work, pruritis is an indication for myelosuppressive therapy, since fewer basophils will be produces and less histamine will be released.
There are a number of literature reports on occurences of PV or other myeloproliferative disorders in the same family. If you have young children, you probably should mention your condition to their pediatrician. If you have grown children, you may want to suggest that they have their blood counts checked periodically and make sure that their doctor knows of the family history. There is an article by Dr. Harriet S. Gilbert on our web page about familial occurences at MPD-NET
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