FAQ: About Polycythemia Vera
- What is polycythemia vera?
- Who can get polycythemia vera?
- What are the symptoms and risks of polycythemia vera?
- How is polycythemia vera diagnosed?
- What causes complications of polycythemia vera?
- How do I reduce the risk of complications of polycythemia vera?
- What else might I experience with polycythemia vera?
- How is polycythemia vera treated?
- What can I expect following initial treatment?
- Are phlebotomies dangerous?
- Is there anything I can do to reduce post-phlebotomy symptoms?
- Is phlebotomy the only treatment used?
- What about iron deficiency following phlebotomy?
- What Is the effect of iron deficiency on your body?
- What treatments other than phlebotomy have been used?
- Is Hydrea safer than the other agents?
- How long do I have to take Hydrea?
- Will I still need phlebotomies if I am taking Hydrea?
- Are there any other treatment options?
- How is Interferon administered?
- What side effects can I expect from Interferon?
- What is post polycythemic myeloid metaplasia?
- What about bone marrow transplants?
- Can I pass polycythemia vera on to my children?
1. What is polycythemia vera?
In this variant, the PHPC clone (stem cell responsible for the production of various blood cell types) 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.
2. Who can get polycythemia vera?
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). SourcePolycythemia 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.
3. What are the symptoms and risks of polycythemia vera?
Polycythemia vera is insidious in onset and may be present for 1 to 2 years before 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 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 haemorrhaging 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, clots in the veins leading to liver, etc).
4. How is polycythemia vera diagnosed?
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 criteria are met, then a diagnosis can be made with certainty.
The criteria that must be met for a diagnosis of polycythemia vera 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).
5. What causes complications of polycythemia vera?
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 (mortification) 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.
6. How do I reduce the risk of complications of polycythemia vera?
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 and one should always discuss this with your own doctor. Some experts feel that the hematocrit should be maintained below 42 in women and below 45 in men. According to a recent article, some also feel that platelet counts should be maintained below 400,000. Treatment options also vary depending upon the particular circumstances of each patient.
7. What else might I experience with polycythemia vera?
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 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.
8. How is polycythemia vera treated?
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.
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 (½ 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.
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.
9. What can I expect following initial treatment?
At the beginning of your polycythemia vera you will have an elevated hematocrit (Hct). As the initial salvo of phlebotomies are performed, the red blood cell (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.
10. Are phlebotomies dangerous?
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.
11. Is there anything I can do to reduce post-phlebotomy symptoms?
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.
12. Is phlebotomy the only treatment used?
No. In many instances, phlebotomy is used to rapidly bring down the red cell mass and then myelosuppressive 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.
13. What about iron deficiency following phlebotomy?
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 red blood cell 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 polycythemia vera 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.
14. What Is the effect of iron deficiency on your body?
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 polycythemia vera 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 polycythemia vera patient who has a normal hematocrit.
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.
15. What treatments other than phlebotomy have been used?
A number of older chemotherapeutic agents have been tried in the past. 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) occurrence of newly diagnosed 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 non haematologic 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 (abnormal blood clotting) and hemorrhage (bleeding) in the first two years of treatment. This is one of the reasons why attention is focused on the agents discussed above.
16. Is Hydrea safer than the other agents?
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 suggests that the risk of secondary leukemias is lower with prolonged Hydrea therapy in comparison to older agents.
17. How long do I have to take Hydrea?
Unless your doctor changes you to another treatment agent, for life. Polycythemia vera is a chronic condition. The rapid rebound following drug withdrawal requires continuous administration.
18. Will I still need phlebotomies if I am taking Hydrea?
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.
19. Are there any other treatment options?
Yes, interferon has been used in the treatment of polycythemia vera (PV) and other myeloproliferative disorders (MPD) 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 essential thrombocythemia (ET). In Diagnosis and Treatment of Polycythemia Vera, Leukemia and Lymphoma 2000, Vol 36(3-4)pp 239-253, interferon is referred to as first line treatment for PV. 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 interferon before her platelet counts started to rise. Even then, much of the improvement in her bone marrow was still seen. After a second course, studies of Dr. Joseph Prchal showed that she was polyclonal, that is there was a return of normal hematopoeitic stem cells and only a small percentage of the PV clone.
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.
20. How is Interferon administered?
Usually the patient self-administers subcutaneous shots. The dose and frequency varies depending upon the bias of your doctor. Some doctors 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.
21. What side effects can I expect from Interferon?
Initial flu like symptoms are experienced by nearly everyone. 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.
22. What is post polycythemic myeloid metaplasia?
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, spent phase polycythemia vera and essential thrombocythemia as well as chronic myelogenous leukemia.
23. What about bone marrow transplants?
There is not much literature on this for polycythemia vera (PV) patients. Transplantion is used in PV patients who have progressed to the post polycythemic myeloid metaplasia stage, have progressed to acute leukemia, or who cannot be controlled by other therapies. Stem cell harvest and storage is being recommended for PV patients in the proliferative stage who may progress to myeloid metaplasia with myelofibrosis.
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.
24. Can I pass polycythemia vera on to my children?
There are a number of literature reports on occurrences of polycythemia vera 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.