SAMPLE CANCER TREATMENT TRANSCRIPT
Polycythemia Vera, or "PCV" for short, is a disorder of the bone marrow in which too many Red Blood Cells (RBC's) are produced. There are other types of Polycythemia will be discussed. PCV is not actually "cancer", since the Red Blood Cells that are overproduced to not go on to divide themselves. Rather, it is a "myeloproliferative disorder", which simply means that too many NORMAL Red Blood Cells are being made. A problem with any myeloproliferative disorder is that the bone marrow loses "equilibrium" and does not make necessary cells in the proper ratios. This impacts all the cells normally produced by the bone marrow. Thus, to understand PCV, we need to discuss what the normal bone marrow is and how it functions. Then we will look at the specifics of PCV. What is the Bone Marrow? The bony skeleton of our body has two major functions. The first is to support our frame against the constant pull of gravity, so that we may grow tall instead of flat! This is primarly done by the hard white "cortex" of each bone, that is the outside portion. Inside of most bones is a network of small "spicules" (little spines) which are softer than the cortex; the bone is mostly hollow. These "spicules" of bone are very rich in blood, have special cells gathered upon them which produce new blood, and are called the "bone marrow". It is easy to visualize this when looking at a large bone from the butcher shop, sawed in half. One will see the hard thick white cortex, over which a thin translucent membrane ("periosteum") is tightly bound. Within the shaft of the the bone the softer marrow will be soaked with blood, and may be scraped out with a knife. The nerves of the bone are in the periosteum, and this is the area the bone "hurts" when broken or invaded by cancer. There are periodic holes ("fossas") seen in the cortex of the bone where blood vessels penetrate through to nourish the bone and marrow, and carry away newly formed blood from the marrow. While forming in the womb and through early childhood, the cortex of the bones are made up of & "cartilage", that is a strongly woven but soft connective tissue. Two basic types of bone form, the first being "long bones" are seen in the extremities, and the second being "flat bones" as found in the skull, hips and vertebrae. Both types of bones have the inner hollow where the marrow develops. In long bones the cortex encircles the marrow, while in flat bones the cortex is like two "plates" which sandwich the marrow. While the cortex is initially made of soft cartilage, it is gradually replaced by hard, immature bone. This is accomplished by a bone forming cell called the "osteoblast", which lays down hard mineral calcium into the cartilage to convert it to bone. This happens both within the cortex, and in the spicules of the marrow. The bone as first formed in early childhood is not as strong as adult bone, and so must be re-architechtured. This is done by a reformating process, whereby immature bone is re-absorbed through puberty, by cells called "osteoclasts". These osteoclasts return the calcium in the immature bone to the bloodstream. Simultaneously, new "mature" bone is layed down in stronger patterns by the osteoblasts; this will be the permanent bone. Mature long bones have "Haversian Canals", these are cylindrical structures that run down the length of the bone to re-enforce it-- much like cement rods. These canals also allow blood vessels to travel within their hollow centers, to nourish the bone. Even though mature bone is fully calcified, it still is full of living cells and is subject to infection from germs ("osteomyelitis") or dying ("osteonecrosis"). The symptoms of these problems are usually severe, demanding prompt expert attention. Long bones are described by their shaft ("diaphysis"), area near their growing ends ("metaphysis") and the actual ends ("epiphysis"). Marrow tends to be most plentiful in "proximal extremities" -- long bones nearer to the center of the body (e.g. thigh and upper arm), with relatively less in the "distal extremities" (e.g. fingers and toes). The marrow actually recedes closer to the center of the body as we age. Flat bones are described by their aspect closes to the skin ("outer table"), "middle marrow", and the portion deepest in the body ("inner table"). They can have very irregular shapes, as seen in the vertebrae and pubic bones, and they are generally rich in marrow. One can puncture the hard cortex with a special boring needle and suck out the soft marrow inside the bone-- this is called a "bone marrow aspiration". It is usually performed on bones with a thin cortex, lots of marrow, and near the skin surface. The site most commonly chosen to aspirate bone marrow for testing or transplant are the paired "iliac wings"-- the flaring hip bones at the belt line level, above each buttock. An aspiration may be done from one side or both, depending upon the circumstance. For understanding bone marrow transplant, we must understand how the normal marrow works. The marrow is a wonderful cell-synthesizing laboratory, which repopulates the blood with crucial cells that are essential to life. Normally the marrow is producing new cells by the billions every day, never stopping until the person dies. This constrasts strongly with most other body systems, which make the majority of their cells during womb life and childhood, slowly drastically in the mature adult. Furthermore, the marrow can be activated in response to stress, such as bleeding, infection, or shock, to go into high gear and crank out blood cells quickly. If the marrow fails, we expect rapid, progressive problems with infections, poor blood clotting, and anemia (in that order). We now examine the individual cells in the marrow that will go on to serve these purposes. The bony spicules in the marrow serve to support it, giving it a lose network structure which serves as an expansion base and surface area for new cells to form. The spicules were themselves formed by the osteoblasts, as mentioned. Aside from the bony spicules, and fat and connective tissue which may infiltrate the marrow, all cells developing in the marrow arise from a single type of "precursor" cell. This precursor is called the "Pleuripotential Stem Cell" or "Stem Cell" for short. Now these Stem Cells can, and do, develop into every known type of blood cell-- a process known as cell "differentiation". Firstly, the Stem Cells divide to produce other Stem Cells. Then, they divide into 2 major lines-- the "Lymphoid" and "Myeloid" lines. The "Lymphoid" cells go on to mature into crucial White Blood Cells called "Lymphocytes". These will be further described later, since they are critical to proper immune system activity in preventing infections. The "Myeloid" cells differentiate into 4 other major White Blood Cell groups-- the "Neutrophils", "Basophils", "Monocytes" and "Eosinophils". Erythrocytes also come from the Myeloid Line. Erythrocytes is another name for Red Blood Cells. Polycythemia Vera will be seen to be a disorder of Myeloid Cell Line maturation. Each of these cell types are standardly found when examining a "smear" of whole blood or the bone marrow. This smear is called a "differential", it gives the type and number of White Blood Cells and Red Blood Cells seen. Regarding White Blood Cells: 1) Lymphocytes 60% in children, 30% in adults-- especially increase with viruses. 2) Neutrophils 30% in children, 60% in adults-- especially increase with bacteria. 3) Monocytes-- about 5-10% in children or adults, increase with viral infections. 4) Eosinophils -- 2-5% in children & adults, increased by allergies or parasites. 5) Basophils-- 1% in children & adults, do not commonly increase with infection. Not only do the relative percentages of certain White Blood Cells increase with infections or inflammation, but the total number (per milliliter of whole blood) usually do also. For instance, a normal White Blood Cell count is 4,000 to 10,000 per milliliter, with infections this may increase by several thousand-- or even tens of thousands. An exception is if the White Blood Cells are being "consumed" by the invading germ-- leading to an initial decrease in the number of circulating cells. Another reason that White Blood Cells may be drastically increased is when a cancer of White Blood Cells occurs-- called a "leukemia". However, even though the absolute number of [cancerous] White Cells may be increased (sometimes over 100,000 per milliliter) they are ineffective at fighting infection and actually retard immune system functioning. White Blood Cells live live between 8 hours and 20 years (depending upon the subtype). The majority of important Neutrophils (also called "Granulocytes") are short lived, just 12 to 36 hours, and so they must be continuously replenished by the bone marrow. If the marrow "Fails" and produces no cells at all ("pancytopenia") then infection will be the first sign. If accompanied by a fever (as is common), the condition of insuffient Granulocytes is called "Febrile Neutropenia" and is usually fatal if not quickly addressed with multiple antibiotics ("triple therapy"). As will be seen, febrile Neutropenia is a known, and commonly dealth with, complication of aggressive therapy for PCV. Fortunately we have better tools to deal with it now than ever before. To form the Red Blood Cells and Platelets, the Myeloid line further splits into 2 other crucial types of blood component forming cells-- the "Erythroblasts" and the "Megakaryocytes". The Erythroblasts go on to differentiate into the "Erythocytes"-- they are the "Red Blood Cells". These circulate within the bloodstream, carrying fresh oxygen (from the lungs) to the body cells. They also collect and transport the waste product "carbon dioxide" (produced by metabolizing sugar) from the body cells back to the lungs to be breathed out. The actual substance within the Red Blood Cells which transports oxygen is called "Hemoglobin", and contains Iron and makes the whole blood red in color. Normally, Red Blood Cell production is stimulated by a protein called "Erythropoetin" produced by the kidneys. As will be seen, this protein has been artificially synthesized and is very helpful in stimulating new Red Blood Cell production IF there are Stem Cells present. When there are insufficient Red Blood Cells circulating, the "oxygen tension" of the blood will decrease, and the body is in danger of suffocating. There are typically 11 to 16 grams of Hemoglobin per 100 milliliters ("deciliter") of blood, with men having a higher amount than women. If the Hemoglobin is too low, this is called "anemia". Various anemias have ddifferent causes ("etiologies"). Examples include too little Iron intake ("Iron Deficiency Anemia") where the Red Blood Cells look small ("microcytic"), pale and washed out, and Folate or Vitamin B-12 Deficiency where they are too large ("megaloblastic"). Also, of course, an anemia can arise as a result of failure of the bone marrow to produce blood cells ("aplastic anemia"). This can result from a cancer invading the bone marrow, getting too much toxic chemotherapy or irradiation which kills the marrow, or even as a birth defect ("Blackfan's anemia"). Whatever the cause, too few oxygen carrying Red Blood Cells results in patients being pale, weak, dizzy and fatigued. Patients will usually be get a "transfusion" of Packed Red Blood Cells when their Hemoglobin falls below 8.0 grams or when they start getting "symptomatic"-- with shortness of breath, palpitations, or severe weakness and dizzyness. Once "Packed Unit" oif Red Cells ("RBC's) usually raises the hemoglobin by about 1.0 gram, so several "units" are commonly necessary. Normally Red Blood Cells live ~120 days, so if the Bone Marrow FAILS completely infection will be seen prior to Red Cell anemia. The final important Myeloid cell line are the "Megakaryocytes", giant cells which produce "Platelets" essential to blood clotting. Platelets are not actual cells (as White cells and Red cells are) but "fragments" of membranous material. Platelets contain special enzymes which become activated on contact with air. In conjunction with an elaborate "cascade" of enzymatic reactions from "clotting factors" produced by the liver, as well as "substrate" proteins from injured blood vessels, platelets form clots. Normally, the platelet count is between 150,000 and 400,000 per milliliter of whole blood. Low platelets are seen with many leukemias, with intense chemotherapy, and with a failing bone marrow. A low platelet count is called "thrombocytopenia" and is a serious medical concern. The patient with low platelets will show easy bruising ("echymosis"), and a prolonged "bleeding time" if injured. Platelet counts below 50,000 are considered worrisome, and below 20,000 demand a "transfusion" of platelets. This is owing to the high risk of spontaneous internal bleeding ("hemorrhage") with such low platelet counts. Interestingly, the common drug aspirin irreversibly damages the enzymatic clotting ability of platelets, and raises bleeding time. This is why aspirin is discouraged ("contraindicated") in late pregnancy and prior to major surgery. Normally platelets "live" (they are not really alive) for 10 days after being released by the Megakaryocytes into the bone marrow, and carried into the bloodstream. A transfused "unit" of platelets typically raises the Platelet Count by 10,000, so may units are often necessary. To complicate matters, the body's immune system can become sensitized to, and destroy, transfused platelets as "foreign bodies". The more transfusions a person has had, the greater the risk for this immune response. If the person can produce their own platelets, the body's immune system will generally not destroy them. This is far preferable to transfusions which at best last a couple weeks. Again, the increasing order of longetivity for blood cells is White Cells, Platelets, then Red Blood Cells. Thus, if a person has total failure of the bone marrow, the first sign (within days) will be infection due to low White Count, the second (within weeks) is easy bruising due to low Platelets, and the third (within months) is Anemia due to low Red Cells count. In practice, infection and internal bleeding are lethal before anemia becomes a noticeable ("clinical") problem. Nonetheless, transfusions are RBC's are frequently necessary to combat the anemia of partial bone marrow failure. In Polycythemia Vera an inordinately large number of Red Blood Cells are produced, but often at the expense of fewer normal White Blood Cells and Platelets. You can see that the Bone Marrow comprises a very dynamic system for new blood cell production, without which the body will fail rapidly. What is the Difference between Bone Marrow and Circulating Blood? The Bone Marrow is the "factory" where new cells are manufactured, but most move on out into the circulation. The marrow tends to be densely "packed" with cells, while in the whole blood they are diluted by the blood serum. Commonly, less "mature" forms of cells are found in the marrow than in circulating blood. For instance, fledgling Red Blood Cells formed in the marrow (from erythroblasts) still have a nucleus, and are called "reticulocytes". Once they migrate out into the circulation, they lose their nucleus to become the familial disk-shaped Red Blood Cells. When we find a high number of reticulocytes in the circulating blood, this suggests that new Red Cells are being formed very rapidy in response to bleeding. On the other hand, finding too few in the bone marrow presages failure of production and eventual anemia. To properly diagnose persistent ("refractory") anemias, we need to get a sample of bone marrow to see what is going on there. These anemias can be the harbingers of leukemias, since Red Cell production usually goes down as abnormal White Blood Cell production goes up. The White Blood Cells formed in the marrow similarly tend to be less mature, and when they go into the circulating blood they may cling ("adhere") onto blood vessel walls or go into lymph nodes. There they mature as they are exposed to foreign proteins ("antigens"). They also subdivide into their particular classes of lymphocytes, such as "B" and "T" cells, after they are released from the marrow. Stress to the body (i.e. from trauma or infection) releases stress hormones (i.e. cortisol) which "demarginate" White Blood Cells out of their sanctuary areas, and quickly raise their level in the circulation. This explains how the circulating WBC count can go up so rapidly, before the bone marrow has time to "respond" to the stress. Platelets are usually released into the circulation as soon as they are formed; they are not alive and do not require maturation time. However, they will go up quickly with shock or stress, as a result of the "Megakaryocytes" in the bone marrow releasing young platelets. The blood vessels to the marrow are "two way streets"; they take new cells out and send established cells (from the circulation) back in. This is how the bone marrow gets nourishment and oxygen. However, this process can transmit infection or cancer cells into the bone marrow. The bone marrow is a delicate "organ" which can easily become damaged. When damage occurs, then problems such as White Blood Cell cancers (e.g. leukemia, lymphoma), Red Cell Cancers ("erythroleukemia") and Myeloproliferative Disorders like Polycythemia Vera can result. What are the Different Types of Polycythemia? The term "polycythemia" itself means that there are too many cells, but it is not specific as to the reason for this. The first type is called "Absolute Polycythemia", and is seen in all newborns. In fetal life, much less oxygen is delivered through the umbilical cord than will be obtained at birth when the lungs start functioning. Since Red Blood Cells carry the oxygen, many more of them are needed in fetal life-- and thus newborns have "high" hematocrits (over 50% of their blood volume is RBC's). The excess RBC's are rapidly destroyed in the first few weeks after birth; the inability of the immature liver to handle the breakdown products of these RBC's accounts for the newborn jaundice commonly seen. Thus, techically, all newborns suffer from relative "polycythemia". A "Relative Polycythemia" occurs when there is a dramatic loss of blood fluid volume without losing RBC's-- as occurs with severe dehydration. In Relative Polycythemia, there is not an inordinate number of RBC's being produced-- instead the concentration of them is too high owing to loss of diluting blood fluid. A "Compensatory Polycythemia" means that more RBC's are required due to low oxygen delivery to the body tissues. For example, if people live at very high elevations, where the air is rarified, they will need relatively more RBC's to latch onto the availble oxygen. Their blood counts will slowly normalize if they return to live at low altitudes. Also, if patients suffer from lung diseases like emphysema that intefere with diffusion of oxygen between the lungs and RBC's, then more RBC's will be needed to absorb what oxygen does get through. "Stress Polycythemia" is a condition affecting mostly white, middle aged, mildly obese men who are physically active and anxiety prone-- but in contrast to Polycythemia Vera, only RBC's are elevated-- not other blood cells. Lastly, "Polycythemia Vera" is a myeloproferative disorder of unknown origin where ALL BLOOD CELL COMPONENTS ARE INCREASED. Thus we expect to see an increase in concentration of White Blood Cells and Platelets in Polycythemia Vera, as well as RBC's. The thick Red Cell mass makes the blood more viscous and sluggish-- problems seen in all cases severe polycythemia. The increase in RBC's is the most significant factor in Polycythemia Vera-- since they contribute the most viscosity to the circulating blood. The increase in Platelets and White cells will be further discussed. What Causes Polycythemia Vera? The cause of Polycythemia Vera is unknown-- however, various "risk factors" for contracting the disease have been identified. These are recognized by studying groups of patients for common elements in their histories. Factors increasing risk are: 1) Male Gender-- PCV is slightly more common in men. The reasons for this may be due to a higher baseline hemoglobin in males, generally 14.0 -16.0 as opposed to females who normally run 12.0 - 14.0. Men make more red cells. 2) White Race-- The disease is uncommon in Blacks and Asians. It is most common in American and European caucasians. 3) Age-- The disease is most common to develop in late middle age, the average patient is 55 years old. The disease is exceeding rare in children. 4) Jewish Extraction-- PCV is found with increased frequency in Jews and other peoples of mediterranean famiily origin. 5) Chromosome Damage-- All myelodysplastic syndromes, and cancers for that matter, are thought due to critical genetic damage within a particular cell. Many things can cause genetic damage presaging disease, including intake of chemicals, radiation exposure, or inborn (inherited) gene problems. We have yet to identify every initiating sequence of gene damage that leads to PCV. At the present time, abnormal chromosome patterns are seen in 15% of untreated patients with PCV and 30% of treated patients. The abnormal structures most commonly involve a duplication of the long arm of Chromosome #1, deletion of the long arm of Chromosome #20, and bone marrow cells with duplication of chromosomes # 8 and 9. If PCV proceeds to leukemia (see below) then 85% of these patients can be shown to have had abnormal Chromosome patterns. Within the "leukemic phase" of PCV that some patients develop, loss of material from Chromosome #7 is seen in 20% and from the long arm of Chromosome #5 is seen in 40%. These changes may be due to prior treatment. With the ongoing Human Genome Project, we expect to define more clearly the genes involved. 6) Family Dispostion-- In spite of the factors above, paradoxically PCV is rarely found in more than one member of a single family at a time. Thus other family members have little reason to be concerned about "inheriting" the disease. How Common Is Polycythemia Vera? It is difficult to say exactly how common PCV is, since many patients "smolder" with it for years without coming to medical attention. Since many of these patients are elderly, they end up succumbing to some other ("comorbid") medical condition like a heart attack or stroke. A reasonable estimate of the number of any people in the U.S.A affected at any given time ("point prevelance") is 40,000 patients. Worldwide the disease follows the proportion of aging caucasians. The disease appears to be more common now with the general aging of the population. What are the Signs and Symptoms of Polycythemia Vera? A "sign" is something that can be measured, such as fever or spleen size. A "symptom" is something felt by the patient, such as fatigue or headache. Common manifestations of Polycythemia Vera include: 1) Plethora-- this means increased redness (" ruddiness") of the body, especially noticeable in the face, neck and hands and feet. Normally we see plethora in newborns who have temporarily high hematocrits. The redness is from increase in RBC's flowing through these areas. The plethora will get more severe with rising hematocrit-- indicating worsening disease. Conversely, the plethora will diminish with effective therapy. 2) Headache is of pounding nature and thought due to both a decrease in the amount of blood permeating the brain ("cerebral perfusion") and an increase in the viscosity of the blood. Similarly, headache is seen when patients have high blood pressure, since the blood vessels supplying the brain constrict and patients end up with less blood perfusing the brain. 3) Dizziness and Vertigo-- Dizziness is a feeling a unsteadiness as though one might faint, and vertigo is a sensation of the room spinning around. These are both caused by decreased blood flow throught the brain. A "rushing" sensation in the ears and a sensation of "fullness" in the head are also common. Outright fainting spells ("syncope") may occur with vey viscous blood. 4) Visual Changes-- These also result from decreased blood flow to the visual nerves (cranial nerve II) and the part of the brain that interprets vision (occipital lobe). Changes include visualizing starts or "fortification" structures that are not there, double vision, or blurred vision. 5) Blood Clotting-- Over 35% of patients have an episode of abnormal bleeding ("hemorrhage") or premature blood clotting ("thrombosis") during the diseae. If spontaneous bleeding occurs, it is commonest from the nose or a peptic ulcer. There can also be easy bruising in the muscles and joints. Too rapid clotting of blood can result in heart attack, stroke, or clots in the lungs (pulmonary embo- lism). Whenever the blood is too thick and viscous, the changes of spontaneous clotting are increased. There is also accelation of "hardening of the arteries"-- that is calcified plaques forming within the interior ("lumen") of arteries, in those with PCV. This simultaneously contributes to higher risk of heart attack or stroke. 6) Itching ("Pruritis") is common in PCV patiets and is particularly severe after bathing. It may be so bad as to be disabling. Easy formation of welts ("uticaria") may also be observed. 7) Gout and Kidney Stones are the result of too much uric acid building up in the tissues and kidneys. The excess of uric acid is due to the body's attempt to breakdown the excessive number of blood cells being produced. With chronic high uric acid, the kidneys eventually may start to fail (uric acid nephropathy). Fortunately there are medications available (e.g. allopurinal) to help the body excrete out excess uric acid. 8) Spleen Enlargent is due to trapping Red Blood Cells and Platelets by this organ. The spleen is located in the left upper abdomen and normally is above the bottom rib on the left side. With enlargement ("splenomegaly") it can grow to huge sizes, giving a feeling of bloating in the abdomen, increasing beltsize, and interfering with eating and digestion. The capsule surrounding the spleen contains its nerves, and so pain may be felt in the left upper abdomen with an enlargement of the spleen. Occasionally the enlargement may be so dramatic that it is advisable to remove the spleen surgically ("splenectomy), or possibly shrink it using low dose radiatin therapy. 9) Leukemia-- PCV predisposes to leukemia, but it occurs in just 2% of those patients getting no treatment except bloodletting ("phlebotomy"-- see below). Up to 15% of patients getting treated with specific drugs may get leukemia. How is Polycythemia Vera Diagnosed? Many patients with PCV are incidently diagnosed when they come in to get a blood test for some other purpose, such as prior to an elective surgery. It is common to see patients without the full "clinical spectrum" of the disease-- that is mild manifestations. If a patients "presents" appearing plethoric (ruddy), has an enlarged spleen, shows increases in all blood cell elements on their Complete Blood Count ("CBC") and has no obvious heart or lung disease, then the diagnosis is straightforward. However, in many patients increased hemoglobin or hematocrit is discovered at routine laboratory evaluation, and then it is important that the diagnosis of PCV be properly confirmed. The first step is to rule-out that the increase in hemoglobin concentration is due to dehydration ("relative polycythemia") or is due to heart or lung disease that is preventing proper oxygen concentrations from getting to the body tissues. There are tests to measure the actual blood cell mass, to determine whether the hormone erythropoetin is increased, and to look for kidney tumors ("hypernephroma") that might be increasing Red Blood Cell mass. The tests to diagnose PCV, from most common to most complex, are as follows: a) Red Blood Cell Count-- the Red Blood Cells, or "RBC's" carry oxygen to body cells and take carbon dioxide away from them them. RBC's are made in the bone marrow by the "erythroid" precursor cells; they are stimulated by lack of oxygen and by the kidney hormone erythropeitin. Chronic bleeding, malnutrition, invasion of the bone marrow by cancer, chemotherapy, and radiation can all lower the RBC count, and then the patient is "anemic" and appears pale and fatigued. Very low counts can cause heart attacks for lack of oxygen to the heart muscle. Red Cells commonly live 120 days in circula- tion, and if they are low they can be transfused as "Packed RBC's". A normal RBC count is between 4 and 6 million per milliliter of whole blood. In PCV patients, the character of the RBC's may be pale and washed out looking due to a decrease in available iron (see below). b) Hematocrit also refers to the Red Blood Cells, this indicator shows what the percent volume of the whole blood is that they occupy. That is, if we take a tube of whole blood, and call the top level 100%, we can "spin it down" in a centrifuge and the RBC's will compact on the bottom, leaving the clear fluid serum floating on top. The percent of volume that these packed cells occupy is called the hematocrit. In Polycythemia Vera and dehydration, there are too many RBC's in the blood for the available serum, and the hematocrit is high. In anemic conditions, there are too few RBC's and the hematocrit is low. A normal hematocrit is between 40% and 50%; it is higher in men than women. In PCV the hematocrit is commonly in the 60% range. c) Hemoglobin is the iron containing protein which actually carries oxygen in the RBC's and gives the blood its red color. It is low if the patient has too few RBC's or is deficient in iron or vitamin B12 or folate necessary to make RBC's. We use the hemoglobin value to decide when to transfuse patients. In general, each "Unit" of Packed RBC's raises the hemoglobin value by 2 points. Normal hemoglobin is ~12 grams per deciliter in women and 14 grams per deciliter in men. Below 8 grams, patients start showing severe symptoms of anemia. In patients with PCV, the hemoglobin is commonly about 18 grams per deciliter but can be quickly reduced by bleeding the patient (discussed ahead). d) Red Blood Cell Indices include Mean Cell Volume or MCV which says how big the average RBC is. RBC's will be too small and look washed out if the patient is iron deficient, this commonly occurs with chronic bleeds. This is called a "microcytic anemia". Conversely, they will be too big if the patient is deficient in vitamin B12 or Folate. This is called a "megaloblastic anemia", Normal MCV is between 85 and 95. Mean Corpuscle Hemoglobin Concentration or MCHC is gotten by dividing the hemoglobin by the number of RBC's to figure how much hemoglobin is in each one, so it tells how well the RBC's are packag- ing hemoglobin. Mean Corpuscle Hemoglobin of MCH tells the same thing but uses the hematocrit instead of the hemoglobin to divide into. All of these tests tell how normal in size and color the RBC's are. In PCV, we often see an iron deficiency anemia with a smaller RBC size than normal ("microcytosis"). There may be a variety of shades of red to the RBC's ("polychromasia"). e) White Blood Cell Count or WBC's is a very important indicator of how well the bone marrow is making new White Cells. These will be lowered by Chemo- therapy that suppresses the bone marrow, by cancer invading bone marrow, by Radiation Therapy, certain leukemias, rapid infections that are gobbling up the existing WBC's, and chronic steroid use. Conversely, WBC's will be very high in specific Chronic Leukemias where lots of abnormal ones are being manufactured (they don't work to combat infection) and with infections when the bone marrow is capable of generating WBC's to fight germs. There are sub- types of WBC's which will be discussed below under "Differential". A normal total WBC count is between 3 and 10 thousand per milliliter. In PCV, we often see an elevated WBC count of 15,000 - 25,000 per milliliter, it sometimes gets as high as 60,000 without indicating infection. Recall that in PCV, all the blood cell elements are increased. f) Platelet Count is a measure of fragments put out by giant "megakaryocyte" cells in the bone marrow; these fragments are not individually "alive" but help form blood clots. Low platelets is called "thrombocytopenia" and is caused by chemotherapy that suppresses the bone marrow, antibodies formed by WBC's against our own platelets in "auto-immune diseases" like Idiopathic Thrombo- cytopenic Purpura (ITP), and certain leukemias that interfere with production of platelets. The platelets will also be lowered by "consumptive coagulopathies" that are forming lots of clots in the bloodstream and using up all of the available platelets, like DIC. When the are too low (below 100 Thousand) then little purple bumps called "purpura" form on the skin. If the platelets are extremely low (less than 20 Thousand) then the risk is very high for spontaneous internal bleeding. When platelets are too high it is called "thrombocytosis" as this is seen with some infections or leukemias of platelet forming megakaryocytes. Then the risk for spontaneous blood clots increases. Normal platelet counts are 200 to 500 thousand ("200 to 500 K") per milliliter of whole blood. In PCV the platelet count is usually about 500,000 and perhaps as high as 1 million per millilier. g) Reticulocytes are immature RBC's that still have their nucleus, they normally lose this as they move from the bone marrow to circulating blood. They may be ordered separately from the CBC or as part of it. They show that new RBCs are capable of being formed in the bone marrow, and normally go up with acute bleeding. The patient is "reticking" if the reticulocyte count is over 2.0%. In PCV we expect a relatively high number of reticulocytes owing to the large number of new RBC's being produced. h) Sedimentation Rate means basically that a sample tube of whole blood is shaken up and the time it takes for the blood cells to settle toward the bottom is measured. The sedimentation rate is checked over 60 minutes and the normal rate is 10 - 30 millimeters per first hour as measured in a calibrated tube. It the "sed rate" is higher, it is a non-specific but important finding. It can mean any sort of inflammation, from temporal arteritis to bone infections to rheumatoid arthritis. It is thus a "non specific indicator" of something going on, but it doesn't say what! If it is high, it gives reason to order further tests to determine the cause. In general "sed rates" are normally higher in women than men. In PCV, the sedimentation rate is often very low (0 - 3 mm/hr) owing to the viscosity of the blood. i) Differential means a visual smear of the blood cells stained with Wright's dye that highlights the cells for microscopic examination. They are stained a deep purple and counted manually by the Laboratory Technologist. Many subtle details can be told by an experienced microscopist. The most basic thing to see is the types of cells present and their shape ("morphology"). The White Blood Cells, Red Blood Cells and Platelets can all be visualized as to the number and appearance: 1) White Blood Cells or "WBC's" are counted within a small field to 100, and the number of each type is tallied. The basic types of circulating WBC's are: A) Lymphocytes are relatively small, round, blue staining cells that help fight all sorts of infections. They are plentiful and especially increase with viral infections (or other non-malignant "leukemoid reaction" causes) and with lymphoctytic leukemias,notably ALL and CLL. They normally number about 4000 (but range considerably) per milliliter and comprise 30 - 60% of WBC's depending upon age; children have proportionately more. The lymphocytes have lifespans of days to decades depending upon subtype, and carry the immune instructions from vaccinations and previous infections. In PCV we expect an increase in all subtypes of WBC's, including lymphocytes. B) Neutrophils are large cells with small "granules" in them; they appear speckled under the microscope and are called "granulocytes". They are the primary defense against bacterial infections, without granulocytes we are at risk for overwhelming infection of the normally sterile blood, called " bacteremia". This quickly leads to poisoning of the blood by the bacterial waste products, "septicemia", which is rapidly fatal if unsuccessfully treated. Neutrophils actually identify and eat ("phagocytize") bacteria, and are thus so important that they are the WBC's we transfuse for low White Count (called "leucopenic") patients. When they are increased markedly, it generally means either overwhelming infection the body has not had a chance to respond too, a large infection that is being responded to, or myelogenous leukemia like AML or CML. Normally the total Neutrophil count is over 2000 per milliliter of blood, and they represent 30 - 60% of WBC's depending on age. We get worried when the neutrophil count is under 1000, and especially below 500, called "neutropenia". If a fever develops, patients need immediate triple type intravenous antibiotics for "febrile neutropenia", and will be hospitalized. The nuclei (center portion) of neutrophils seems to expand and show more points sticking out ("hypersegmented") during acute infections. Neutrophils often live for only 12 - 24 hours in the bloodstream! In advanced PCV, the marrow may "burn out" (become "fibrotic") and then less WBC's than normal are produced-- this can predispose to infections. C) Monocytes look like large lymphocytes and have no granules. They are important in the detection of germs, as part of the "monocyte-macrophage" system. The macrophages consume invading bacteria after identification, much like neutrophils above. Monocytes are increased with mononucleiosis, ("kissing disease"), some other viral infections and rare monocytic leukemia. The normally represent less than 10% of the circulating blood cells. D) Eosinophils are also larger than lymphocytes and have red-staining granules floating in their fluid portion ("cytoplasm"). They are important against parasites, protozoa and unusual foreign substances (like wood). When the number of eosinophils increases it is termed "eosinophilia". Eosinophils will commonly increase with worm infections, allergies, and rare leukemias arising from them. They normally represent less than 8% of the circulating blood cells. E) Basophils are large cells with blue staining granules, so are "granuloctyes". They have general immune functions at helping recognize and destroy germs. Lots of Basophils is called "basophilia" and is seen in rare infections or even rarer leukemias arising from basophils. Normally they comprise just 1 - 2 % of the circulating blood. In PCV an increase in the absolute basophil count to about 100 per milliliter is seen in 70% of patients. F) Blasts are newly minted WBC's that are obviously immature and are being pushed out very quickly by the bone marrow. Having blasts shows either a severe infection that the body is responding to, or a leukemic crises ("blast crises") where billions of useless blasts are being churned out of the marrow. We can often distinguish acute from chronic leukemia based upon the blasts. Various "smoldering leukemias" will show a low amount (i.e. <3%) of blasts, and then lots of blasts (ie. >30%) when they "transform" into acute leukemia. Between 2% and 15% of PCV patients will have an eventual transition to an acute leukemia, and a high blast count in the circulating blood may show this. 2) Red Blood Cells or "RBC's" are examined as to their character, shape and size during the differential. Anemia will be obvious my the relative lack of RBCs and the basic subtype can be determined. Lack of iron makes for poor hemoglo- bin synthesis, and so the RBC's are small and washed-out appearing, that is a "microcytic anemia". This is the most common type in chronic bleeding patients. Poor intake of vitamins B12 and Folate lead to a giant red blood cells, that is a "megaloblastic anemia". In PCV vitamin B-12 levels vary and are increased in about 30% of patients. Chronic disease often leads to anemia with relatively normal sized RBC's, this is called "normocytic anemia" or "anemia of chronic disease". If the red blood cells have nuclei, they are called "reticulocytes" and a high count shows that they are being (too) rapidly produced "reticulocytosis". Sickling of the RBC's makes the diagnosis for sickle cell disease, and lots of other changes in "morphology" are witnessed. If the RBC's have an abnormal array of shapes, it is called "poikilocytosis", and if they vary in size it is called "anisocytosis". Various rare genetic causes of anemia, like "thallasemia" can lead to all sorts of bizarre RBC shapes, like teardrops ("dacrocytosis") or lots of broken up "helmet" and "burr" cells. Being forced out a bone marrow crowded with cells can produce bizarre shapes, this can indicate a "myeloproliferative disorder" where bone marrow gets stuffed with abnormal cells. Conversely, if the marrow gets "burned out" ("fibrotic") and no longer produces many viable blood cells, the RBC's will have abnormal morphology. Spleen problems and infections can cause the RBC's to stack like coins, this is the "Rouleaux sign". RBC's with rings around them in the bone marrow ("ringed sideroblasts") show lead or other heavy metal poisoning. Large increase in RBC's is "erythocytosis"; as with Polycythemia Vera. A common treatment for this is bleeding the patient! It can also show an "erytho-leukemia", since the RBC's and WBC's (excluding the lymphocytes) arise from a common "precursor" cell in the bone marrow-- so leukemias can arise as an apparent cross between them!). In general bizarre patterns of RBC's are called "dyscrasias" and may indicate serious diseases. 3) Platelets-- the number and appearance of the Platelets, discussed previously, is also visually confirmed on the Differential. In some leukemia patients with swollen spleens ("spleenomegaly"), the platelets are "trapped" in there, they show low in the circulating blood, even while the marrow is producing them. In these patients removing or irradiation the spleen often raises platelet counts. Platelets live an average of 10 days in the circulation. When platelets are being transfused, each "unit" raises the platelet count by about 10K. However, if the patient has been "sensitized" by prior platelet transfusions, their immune system may destroy them very quickly, and daily transfusions may be needed. In PCV the platelets may function poorly, even though there are many of them, leading to easy bleeding ("bleeding diathesis") and hemorrhage. Alternately, the may clot within the blood vessels ("intravascularly') causing heart attack or stroke. This is one reason it is important not to let the blood be too viscous. Chemistry Tests are commonly performed from blood serum, we add a specific chemical ("reagent") to the serum that reacts with the substance of interest-- and goes on to form a certain shade of color in the serum. We analyze how deep this shade is with a spectrophotometer, and compare it to known shades for known amounts. Then we can elucidate just how much substance ("concentration") there was in the original serum. Like hematology tests, chemistry tests are much cheaper to "batch" onto a large "auto-analyzer"; it often costs as much for one test "stat" as for 20 tests on a "routine panel". The number of chemistry tests given on various panels is different between laboratories, as is the name of the panels. It is usually something like "SMA-6" or "Chem Panel 20" where the number shows how many tests are being done. The simplest panel usually contains the "electrolytes"-- sodium, potassium, chloride and bicarbonate-- as well as glucose and perhaps Creatinine or BUN. These will be described below. More elaborate panels often give protein and cholesterol subtype breakdowns, enzymes released from damaged heart, kidneys or liver and even thyroid function results. "Toxicology" tests tell drug levels in the blood or urine. In general, chemistry tests take less than 1 day and can be run "stat" within an hour: Sodium is the salt of the blood, water tends to follow this substance. "Electrolyte" means something that assists electricity in traveling across a fluid, and sodium is our most plentiful electrolyte. Normal sodium is between 135 - 148 milliequivalents per liter (meq/L) of blood. When sodium is too high it is called "hypernatremia", this can be due to dehydration or excessive salt intake with poor kidney function. Low sodium, called "hyponatremia" is more commonly seen in cancer patients. It can be due to the SIADH syndrome (Syndrome of Inappropriate secretion of anti-diure- tic Hormone) which causes a lot of water retention in the blood with dilution of the sodium there. SIADH is seen with expanding brain tumors and some Small Cell Lung Cancers. Abnormal sodium can be corrected with intravenous fluids, if it goes severely out of normal range it will lead to stupor, coma and death. When the blood is too viscous, sodium will be increased; when it is to dilute the it will be decreased. The patient with PCV and "hemoconcentration" (too concentrated a blood cell mass in the circulating blood) may be intravenous fluids for dilution. Potassium is the salt of the body cells; it is high within blood cells but low in the serum-- exactly opposite sodium's concentrations. Like sodium, it is an electrolyte. Potassium must stay delicately balanced in the blood. Normal potassium is 3.5 - 5.2 meq/L. High potassium is called "hyperkalemia" and occurs with kidney failure, lack of insulin production, bursting of blood cells, increasing acidity of the blood, and by taking too much supplemental potassium. Normally excess potassium in the bloodstream is forced into the blood cells by insulin, along with glucose. With kidney failure the blood becomes more acidic, and potassium leaks of the body cells. One of the important features of dialysis is to correct hyperkalemia and too much acidity of the blood ("acidemia"). Too low potassium is "hypokalemia" and is common in patients taking heart medicines, taking diuretics which leech out potassium flowing through the kidneys, and in malnourished patients. If potassium is either too high or low it interferes with the contractions of the muscles, and most worrisome is abnormal heartbeats or even heart attacks from abnormal potassium. Low potassium can be corrected by supplemental pills, we are careful not to give them too fast (e.g. more than 80 MEQ/ day) to avoid overshooting. High potassium can be lowered by fluids, "ka-excelate", lasix diuretic and insulin (in the hospital!). In PCV, there are many more blood cells than normal, and these cells are high in potassium within them. If they burst too quickly (such as when chemotherapy is given), then it may dangerously increase blood potassium, so this is monitored. Chloride, from chlorine, is the negative "counter-ion" that electrically balances the positive charges of sodium and potassium; it is also an electrolyte. Normal chloride is 98 - 108 meq/L, which adds up to less than the sodium and potassium. The rest of the electrolyte balance is made up of "Bicarbonate" (below) and a few other ions like phosphate and sulfate. The difference between the sodium plus potassium and the chloride plus bicarbonate is called the "anion gap" and increases if there is too much acidity to the blood, such as from taking excess vitamin C or aspirin. Too high Chloride is called "hyperchloremia" and too low is "hypochloremia", these are most commonly found along with sodium and potassium abnormalities. When chloride is too low it may be from excess bicarbonate and dehydration, called "contraction alkalosis". Implanting the draining ureters into the bowel after (after bladder cancer has forced removal of the bladder) disturbs blood chloride from excess absorption. Abnormal chloride is commonly corrected along with potassium and sodium. Bicarbonate is the other negative counter-ion to the positive potassium and sodium, as mentioned above. It is crucial for keeping the acid-base balance of blood. Normal bicarbonate is 22 to 30 meq/L and is crucial for balancing the acidic carbonic acid formed when carbon dioxide is dissolved in the blood water. Recall that we breath oxygen and combust carbon molecules from the food we take in to generate carbon dioxide, which is then breathed out. If excess acid accumulates in the body, it is called "acidosis". Excess base is called "alkalosis". The cause of these can be either "metabolic" or "respiratory". Metabolic means from the kidneys (or another source); they produce bicarbonate to balance the acidic tendencies of the blood. Respiratory means from breathing out too much or too little carbon dioxide. If we cannot breath well, say from severe asthma or Chronic Obstructive Pulmonary Disease, then carbon dioxide builds up in the blood, turning it more acidic. The kidneys try to compensate by manufacturing more bicarbonate to balance the acid. Conversely, if we are rapidly breathing ("hyperventilating") then over time the blood becomes to alkaline; the kidneys will then produce less bicarbonate and dump existing bicarbonate into the urine to compensate. It is common for patients with kidney failure on dialysis to require extra bicarbonate ampules to balance the excess acid in their blood. Also, when patients stop breathing are we are attempting resuscitation, bicarbonate may be administered to counteract the progressive increase in blood acidity as soon as breathing has stopped. Too much acid or alkali in the blood eventually results in other electrolyte imbalance (particularly potassium), stupor, coma and death. Creatinine is a substance put out by the muscles of the body and filtered by the kidneys, it normally ranges between 0.2 and 1.3 milligrams per deciliter. When increased, it can indicate kidney damage. In fact, for every doubling of creatinine value, there is a halving of kidney function. In long term PCV, the kidneys can be damaged by hemoglobin released from fractured RBC's, uric acid (see below) dehydration and other factors. Creatinine is particularly important to compare with the BUN (below) to determine whether the patient is dehyrated or not. BUN is Blood Urea Nitrogen, it is made from conjugation of ammonias released by proteins digested in the liver. The importance of BUN is that it will go up if there are a lot of blood cells being broken down, and if the patient is dehydrated. A Normal BUN is between 5 and 20 milligrams per deciliter of blood. In diagnosing PCV, we want to rule out that the increased hemoglobin and hematocrit is simply due to chronic dehydration. We look at he BUN to Creatinine ratio-- if it is more than 20, it indicates possible dehydration and "relative polycythemia". Uric Acid is released from cells as they are broken down and normally excreted by the kidneys. If the uric acid builds up in tissues, it can crystalize causing gout. Long term excess uric acid being processed by the kidneys can damage them, causing "urate nephropathy" and kidney stones. PCV patiets are thus prone to gout and kidney stones. Fortunately, medications to help the kidneys excete uric acid ("allopurinal") and to reduce the inflammation of gout ("cholchicine") are readily available. Other Tests: Arterial Blood Gas ("ABG")-- This test is important to determine how well oxygen is being absorbed by the lungs into the bloodstream, and how effectively carbon dioxide is being expelled. We can use this test to help rule-out or confirm PCV, since poor absorption of oxygen from the lungs or poor blood pumping by a weak heart will also raise the RBCs. Disturbances of blood gases, such as low oxygen or retained carbon dioxide result in fatigue and acid-base disturbances of blood.The "ABG" test is typically done by inserting a syringe into the radial artery of the wrist, as opposed to the venous blood used for other blood tests Ideally, it should immediately be obvious that arterial blood has been drawn, since it is of brighter red color than deoxygenated venous blood. It is extremely important to apply proper pressure to the artery afterwards to stop bleeding; fail- ure to do so can interrupt the blood supply the extremity it was drawn from. This is why we discourage arterial blood draws (though often it is easier to find a pulsating artery than a relatively flat vein) for tests except the Arterial Blood Gas. Lung and Heart Function Tests-- As noted above, poor heart or lung function will cause a reflex increase in RBC's, to carry forth whatever oxygen is available. If the diagnosis is in doubt, we can perform "Pulmonary Function Tests" that will describe how well oxygen is diffusion through the lung membrane. Long term use of tobacco or industrial exposures to soot can reduce the "diffusion capacity" of the lungs, raising RBC production. So too can poor heart function reduce ability of blood to get where it needs to be-- the tissues-- causing them to "cry out" for more oxygen and hormonally raising RBC production. If necessary, a thallium stress test or MUGA can test the heart's efficiency ("cardiac function"). Kidney Imaging-- Rarely, a kidney tumor can increase RBC production, this is since the kidney produces the erythropoietin hormone that stimulates the marrow to crank out new RBC's. A CT scan or the kidneys, and/or Intravenous Pyelogram that images them, will effectively rule-out whether a kidney tumor is the problem. Erythropoietin Levels-- In heart, lung or kidney problems, the increase in RBC will be attributable to elevated erythropoietin hormone. However, in PCV, this hormone is typically DECREASED. This is due to the marrow sending a back a Chromium -51 labeled Autologous RBC's-- If the cause of the increased red blood cell mass remains elusive, we can determine the actual concentration of RBC's separate from dilutional or dehydration concerns. To do this, we extract out a known quantity of RBC's (simple blood draw), label them with a radioactive isotope as a marker, and then inject them back into the bloodstream. We then take a new blood sample, allowing time for the labeled RBC's to be distributed. By assessing the concentration of labeled RBC's in our new sample, we can calculate the total RBC mass in the body. Hematocrits of over 60 are rarely just due to decreased plasma volume (plasma is the liquid portion of the blood). For hematocrits of 50 - 60, where the diagnosis remains in doubt, this test can help. Bone Marrow Biopsy -- This test is listed under "hematology" since we are looking at the blood forming elements of the bone. The only way to diagnose many leukemias, and whether other cancers (like Hodgkin's Disease or Small Cell Lung Cancer) have spread to the bone marrow is by biopsy. A small core of bone and marrow is taken with a boring needle from the hip wing(s) above the buttocks, under local anesthetic. The test can be uncomfortable but is not dangerous. The bone marrow removed is suspended in preservative solution and smeared onto microscope slides for a Differential. The bone marrow looks different than the circulating blood since the cells are less mature. All blood cells originate from primordial "Pleuripotential Stem Cells" in the marrow, the process of "differentiation" turns them into various WBC's, RBC's and Platelets. From an examination of the bone marrow, we can determine what the circulating blood will look like at later times, as the cells mature and are released. We can also identify spread of other cancers into the marrow. Doing "bilateral" bone marrow biopsies (both hips) is about 15% more accurate than just doing one. In PCV, we expect to see a very cellular ("hypercellular") bone marrow, cramped with new blood cells, early in the disease. Later, the overworked marrow tends to scar up (undergo "fibrosis") and then fewer than normal cells are seen ("hypocellular"). Sampled cells can be sent to look for characteristic chromosomal abnormalities. What is the Natural Course of Polycythemia Vera? Since the disease has a predilection to patients older than 50 years old, it is most common for patients to die with, rather than from, the disease-- especially if it is properly treated. It is usual for patients to have other medical problems ("co-morbid conditions") like heart and lung disease to which they succumb first. Most patients die of "vascular complications" (e.g. heart attack, stroke) of the disease, or of unrelated causes. Over time, about 20% of patients "progress" to marked spleen enlargement, anemia, and scarring ("fibrosis") of the bone marrow. This is called the "spent phase" of the disease. Some researchers believe that ALL patients will eventually enter the "spent phase"-- if they live long enough. As mentioned, many patients only have partial manifestations of the disease, which can stretch out over many years. However, once the diagnosis is made, it is crucial to consider treatment (discussed below). If no treatment is give, the average survival is only 2 years. With treatment survival is commonly extended to over 10 years. An important drawback of aggressive treatment is a rise in the later rates of acute leukemia. Without chemotherapy or radiation therapy, the risk of leukemia with PCV is just 1-2%. However, if these are given then the leukemia risk jumps to 15 - 20%. These later leukemias are very refractory to treatment and tend to be quickly lethal. As will be seen, newer aggressive treatments are less likely to markedly increase leukemia risk, while still extending overall survival times. What was the Historical Treatment for Polycythemia Vera? The historical, effective treatment for PCV was "phlebotomy"-- that is letting out excessive blood through an arm vein. The procedure is identical to donating blood for the Red Cross, and is extremely safe when done properly. Interestingly, phlebotomy was a treatment for many illnesses used by midieval physicians-- they wanted to let out the pent up "poisonous humors" in the body. It was generally useless, and often harmful, especially in anemic or dehydrated patients. Leeches were a way of causing slow bloodletting, or a cut was made in a vein. The treatment did often give apparent benefit for patients with congestive heart failure, who have backup of blood into the limbs and lungs, and a similar "plethoric" appearance in the face as PCV patients. It might also temporarily benefit patients with very high blood pressure, reducing headache, heart attack and stroke risk. The usefullness of bloodletting is now confined to PCV, where the average life span has been increased from 2 to 12 years with phlebotomy alone. Phlebotomy is not a "cure" but rather a therapy for the disease. Letting out the excess RBC's lowers the hematocrit and hemoglobin levels, causing improvement in plethora, headache, ear ringing ("tinitus"), fatigue, visual disturbances, dizziness, and other myriad manifestations of the disease. It can also reduce the viscosity of the blood, and lessen the changes of spontaneous blood clots ("thrombosis") leading to heart attack or stroke. The lost blood volume is replaced by drinking fluids, and this helps further dilute the blood. There may be some reduction in spleen size with proper phlebotomy, but part of the reason that the spleen gets enlarged is that it may become an area of RBC production outside the bone marrow-- that is so called "extramedullary hematopoeisis". There are actually areas in the spleen and liver which start forming new RBC's-- especially as the bone marrow becomes more fibrotic and "burnt-out". Thus the spleen remains enlarged in 75% of patients with the disease. Phlebotomy has great benefits of improving signs and symptoms of the disease, extending lifespan, and not raising leukemia risk as is seen with other therapies. The later leukemia risk with phlebotomy alone is 1 - 2%-- the same as in a patient receiving no treatment. The frequency of phlebotomy will vary with the particular patient-- it is typically monthly to every six months. It takes only an hour or so in the physician's office. The times to do phlebotomy can be determined by the CBC results and level of symptoms. Phlebotomy is a simple, safe, time-tested and effective treatment for PCV. It proportionately removes all the excess cells being produced in PCV-- RBC's, WBC's and platelets. Other newer treatments discussed below must be compared to phlebotomy when considering their effectiveness, side-effects and overall safety. Sometimes phlebotomy is crucial. Phlebotomy remains the "gold standard" with which to compare the usefullness of newer treatments. The therapeutic options for PCV have increased over the past three decades, but their net effect on improving survival remains debatable. Part of the reason for this is that when we consider life expectancy with PCV, we are also considering all other possible diseases that mostly elderly patients will succumb to. When we say that the survival with phlebotomy alone is 10 - 12 years, it means we are also including death from heart attacks, kidney failure, car accidents etc. into that survival statistic. While thrombotic events (e.g. heart attacks and strokes) may be increased secondary to PCV, they may also have occured in the absence of this disease. That is, standard survival statistics include mortality from all causes, whether related to the disease in question or not. Also, certain treatments may INCREASE the chance for early death by virtue of their side effects. Thus we must very carefully consider the risks and benefits and newer treatments before recommending them to a specific patient. The basic treatment strategies for PCV involve reducing the excess RBC burden-- since that is the main cause of clinical problems. The strategies involve three ways of doing this-- Phlebotomy, Chemotherapy and Radioactive nuclides. They may be used alone or in combination. Phlebotomy was discussed in the previous section, and continues to be a widely used and effective treatment for the disease. Chemotherapy involves using chemicals to suppress the bone marrow, so less of all blood cell types are produced. Interestingly, this "bone marrow suppression" by chemotherapy is generally an undesirable side effect when using chemicals to treat cancer-- since it causes the classic side-effects of anemia, fatigue, easy bruising and increased infection risk. However, in treating PCV with chemotherapy, we are actually utilizing the side-effects of chemotherapy for a therapeutic purpose! Nonetheless, chemotherapy must be strictly monitored to ensure that we do not "over-suppress" the marrow causing severe side-effects ("toxicity"). Radiation therapy is also a potent suppressor of the bone marrow-- especially when the whole body is irradiation ("Total Body Irradiation"). Instead of using classical "External Beam" irradiation, which gives high doses to the skin and organs, we use special radioactive chemicals, particularly Phosphorus-32. This "radionuclide" is injected into the bloodstream, and preferentially circulates into the marrow to suppress its production of new blood cells. Both chemotherapy and radiation therapy are described in further detail below. Chemotherapy was first used in the 1940's; the first chemotherapy "agents" used were called "alkylating agents" and derived from mustard gas. In World War I, the use of this poisonous gas was seen to destroy victims bone marrow. Those affected would first develop fevers from lack of White Blood Cells, then bruising from depletion of platelelts, and finally (if they lived long enough) anemia from lack of RBC production by the injured bone marrow. It was soon realized that the preferential action on bone marrow of mustard gas derivatives could be exploited to help destroy cancers of White Blood Cell origin (e.g. Hodgkin's disease, leukemias, lymphomas). The alkylating agents were popularized with the observation that they could sometimes cure White Blood Cell cancers, albeit they did have serious adverse side effects-- owing to their global suppression of the bone marrow. They were NOT specific for cancer cells, but seemed to kill them at a quicker rate than normal cells. This difference accounted for their clinical usefullness-- but they were dosed very cautiously ("titrated") to be safe. Various Alkylating agents were tried for treating PCV. They Include: Melphalan, Busulfan, Cyclophosphamide ("Cytoxan"), Cis and CarboPlatin, BCNU, CCNU, Dacarbazine, Procarbazine, Mechlorethamine, and Ifosphamide. They all "alkylate" DNA, which means add a methyl or ethyl group, resulting in a "chain termination" when the DNA tries to divide-- that is a useless fragment of DNA instead of the whole necessary piece. Since they are not specific for any particular cells, they have this effect on any quickly dividing cells in the body. Alkylators produce "bone marrow suppression" with lowered Red Blood Cells ("anemia"), which is the goal in PCV. However, they also lower White Blood Cells ("leucopenia") leading to easy infections and platelets ("thrombocytopenia") causing easy bruising or internal bleeding. The combination of all of these is called "pancytopenia". BCNU and CCNU are used primarly for brain tumors since they penetrate through the protective blood-brain barrier. Cyclophosphamide and the similar Ifosphamide can cause sloughing of the bladder's inner lining (called "hemorrhagic cystitis") which can be partly prevented by using the drug MESAa "uroprotectant"). They also cause more scalp baldness ("alopecia") than the other alkylators. Cisplatin (more than Carboplatin) causes nerve damage, first felt as numbness in the toes and progressing upward ("peripheral neuropathy"), as well as decreased hearing. It also causes kidney damage ("nephrotoxicity"), the dose should be reduced if kidney or liver damage are present to avoid excess buildup of the durg in the bloodstream. Busulphan can cause a syndrome resembling lung scarring and malfunction of the adrenal glands. As a "Late" effect (if occurs it averages 10 years after treatment) some patients get "non-lymphocytic leukemias" which tend to be very aggressive, they are somewhat more likely if patients get radiation also. The rate of later leukemias in PCV patients getting alkylating agents is as high as 20% in some studies. The tendency of a drug to cause later leukemias means it's "leukemogenic". Some alklyators can be taken by mouth (e.g. Busulfan, CCNU, Cytoxan). These are the ones most commonly used in PCV treatment. For the ones that can't, leakage of the IV into the skin can cause local tissue damage. Another type of chemotherapy agent used for PCV are the "antimetabolites", these were developed after the alkylating agents. They are used more commonly owing to less propensity to be "leukemogenic"-- that is less chance of causing later leukemia. These drugs have been supplanting the alkylating agents over the past 15 years. Various Anti-metabolites have been tried for treating PCV. They include: Hydroxyurea (hydrea-- very common), 6-Mercaptopurine, Methotrexate, Thiotepa Cytarabine ("ARA-C"), Cladribine, and 5-Fluorouracil (with/without leucovorin). They interfere with DNA and protein synthesis by "pretending" to be something they are not, such as 1 of the 5 needed bases (RNA has Aerosol); this "Trojan horse" results in a useless product being synthesized, or a premature end to a product ("chain termination"). The are called "anti-metabolites" since they compete with normal metabolites. Again, it does this to any quickly dividing cells. Anti-metabolites interfere with quickly dividing cells, so well see pancytopenia, nausea and vomiting, mouth soreness, and peripheral nerve damage (from damage to "myelin", the insulating coating of the long nerve processes that keeps them from short-circuiting). The affect on white blood cells (as with the other bone-marrow suppressing anti-neoplastic agents) can cause a marked decrease in the germ fighting "neutrophil" white cells, that is "neutropenia". If a fever develops with this, it is called "febrile neutropenia" and this is a medical emergency; the patient requires antibiotics immediately or may die. This is since the body's ability to fight infection is so low when neutropenic (less than 1000 neutrophils per milliliter of blood). Usually, three complementary intravenous antibiotics are given for febrile neutropenia, and the patient not released from the hospital until the fever is gone ("afebrile"). As with the alklylating agents, some anti-metabolites can be taken by mouth (e.g. methotrexate, hydroxyurea, 6-MP ). Hydroxyurea ("Hydrea") used in oral doses of 1 to 3 grams per day is currently the drug of choice for most patients in whom chemotherapy is utilized. It does not apear to increase later leukemia risk. It helps control the symptoms of elevated metabolism, but has more effect on elevated WBC and platelet counts than on RBC's. As such, occasional phlebotomy is commonly required in addition to this chemotherapy. As above, it must be carefully titrated and monitored so that immune function is not too severely depressed by the depletion of WBC's. This will require periodic Complete Blood Counts ("CBC") to check the blood cell status. Using Hydroxyurea may increase survival compared to phlebotomy alone, as noted inthe European Cooperative Group Studies. The indications for using chemotherapy are discussed more fully in the Comparison of Therapies section ahead. Radiation Therapy has been used since 1940, with injected forms of radioactive isotopes being the preferred method of administration. It was found the radionuclide Phosphorus-32 preferentially gravitated to bone marrow (the bones have a propensity to absorb phosphorus and calcium). The administration of Phosphorus-32 is easy; it is simply injected into an arm vein in the Nuclear Medicine Department of a hospital. It provides long, touble-free remissions from PCV in most cases, and successfully reduces signs and symptoms of the disease. The dose is commonly 85.2 MBq ("MegaBequerals") of Phosphorus-32 per "square meter" of patient body surface area. Most people have between 1.2 - 2.0 square meters of skin surface area. The patient is then closely followed with Complete Blood Counts for 3 months, and retreated (if needed) with a dose 25% greater than the initial dose. This can be further repeated after 3 more months, but is rarely necessary. The typical remission with Phosphorus-32 lasts between 1 and 2 years, during which the patient is commonly symptom-free. The Phosphorus-32 therapy may be repeated if relapse occurs. One serious concern is the increased risk for developing leukemia when Phosphorus-32 is used; this risk is as high as 15% in some studies. While this means that 85% of patients avoid this problem, those who get leukemia will almost inevitably die from it. Higher total dose of Phosphorus-32, repeat treatments, and simultaneous chemotherapy increase risk. As with chemotherapy discussed above, suppression of bone marrow function with Phosphorus-32 can have undesired side effects. If the degree of suppression is too great, then the patient can develop intractable anemia, consistently low WBC counts causing immune system malfunction, and low platelet counts with resultant easy bruising and internal bleeding risk. Thus the dose of Phosphorus-32 must be carefully titrated with an eye on blood counts to avoid "over-shooting" and annihilating the necessary bone marrow. There may be a "delayed recovery" of months to years after radioisotope administration, or sufficient recovery may never occur. If the bone marrow is irreversably damaged, it leads to "pancytopenia" meaning that all crucial blood cells will be low. Bone marrow "aplasia" means that the marrow is destroyed. If this occurs, then the patient will need regular transfusions or a bone marrow transplant procedure to live. However, it is extremely unlikely from therapeutic doses of chemotherapy or Phosphorus-32. The more common cause of bone marrow aplasia over time in PCV is a "burnt out", fibrotic marrow that has been replaced by scar tissue. In this situation of advanced PCV, paradoxically RBC and platelet transfusions may be needed to sustain life-- since the marrow has finally failed. Phosphorus-32 puts out a gamma ray with a maximum energy of 1.7 Megavolts, this is somewhat more penetrating than Cobalt-60 (which is 1.25 Megavolts). The radiation emitted falls off very quickly from where the Phosphorus-32 is located, and so it is negligible at a foot or so away from the patient. The time is takes for half of the isotope to "decay" (lose radioactivity) is called "half-life"; for phosphorus-32 it is 14.3 days. Thus, 99% of the isotope is gone after 10 half lives (143 days). The isotope is rapidly absorbed into bone; some is also exceted into the urine. You can see that it is relatively long lasting in the bone. It is advisable, for extra caution, for patients who get Nuclear Isotopes to avoid holding small children for several weeks. The very young are more susceptible to later cancers from low dose radiation exposure than adults. In general though, Phosphorus-32 is a safe and effective therapy for getting most patients with PCV into remission. It is only the tendency for increasing leukemias that prevents its more frequent use. Comparison of Therapies: Studies comparing treatments for PCV have been perfomed by the Polycythemia Vera Study Group and the results published through the past two decades. In a landmark study, this group randomly assigned patients to one of three therapies: 1) Phlebotomy Alone-- This was discussed above and represents safe and effective therapy for PCV. As is seen from the other "arms" of the Polycythmia Vera Study Group below, it is often necessary to use Phlebotomy in conjunction with Chemotherapy and Radiation Therapy-- since those treatmens may not sufficiently reduce Red Blood Cell mass quickly enough. If a PCV patient goes for emergency surgery (coronary angioplasty is common example) then it is CRUCIAL that they be properly phlebotomized (bled) to control Red Blood Cell mass prior to surgery. If Red Blood Cell mass is NOT properly controlled prior to surgery, then the death rate from surgery is 4 - 5 times higher than in patients properly controlled (phlebotomized) prior to surgery. Fluid "plasma expanders" can be put in to avoid too rapid a dimunition of blood volume that occurs with rapid bleeding, thus avoiding low blood pressure problems ("hemodynamic instability"). The most likely side-effects of rapid Phlebotomy are dizziness and nausea, much the same as when blood is donated for transfusions. Side effects can be lessened by slower Phlebotomy, giving fluids, and possibly anti-nauseant (e.g. Compazine) or tranquilizer (e.g. Valium) pills prior to the procedure. It is important the patients have had a good breakfast before going in for Phlebotomy, but eating a lot right before the procedure isn't recommended to reduce possible nausea. Again, it is an easy and safe therapy to get which requires only about an hour in the clinic. As mentioned above, neither chemotherapy nor radiation therapy are guaranteed to produce sufficient decrease in Red Blood Cell Mass-- and so at least occasional Phlebotomy is likely to be necessary anyway. Phlebotomy remains the mainstay of both historic and current therapy for PCV. In the orginal Polycythemia Study Group trials, patients getting Phlebotomy alone were more likely to have heart attacks or strokes during the first four years of therapy, but after the seventh year the survival was BETTER with Phlebotomy alone, mostly due to leukemias from other therapy. 2) Chemotherapy and Phlebotomy-- Chemotherapy which depresses bone marrow function was tried in the International Polycythemia Group Studies, it was chosen to reflect what was being used in Oncologist's offices. It was necessary, as discussed above, to supplement Chemotherapy with Phlebotomy to ensure that the Red Blood Cell mass was properly reduced. Chemotherapy is fickle, it has differering effects in different patients. Some patients tolerate Chemotherapy very well, have little or no side effects, and an excellent overall result. However, other patients are inexplicably stricken with all sorts of side effects, tolerate the treatment poorly, and/or don't get satisfactory results. Treatment must therefore be individualized; the Chemotherapy agent chosen is very carefully adjusted ("titrated") to give optimal effects. In the original Polycythemia Group Studies, the agents used were either Melphalan, Busulfan, or Chlorambucil-- they were all Alkylating agents. Chlorambucil was dropped since over 10% of patients being treated with it later developed leukemia-- it is no longer recommended. Busulfan remains somewhat popular, although it can cause a syndrome resembling lung scarring ("pulmonary fibrosis") with difficulty breathing. The syndrome commonly improves, but does not totally resolve, when Busulfan is discontinued. The dose for Busulfan is usually 4 to 6 milligrams per day by mouth; however the effect is more on lowering platelets and White Blood Cells than RBC's. Thus Phlebotomy is also added as needed. Again, there is a later leukemia risk from Busulfan or any Alkylating Agent. The best current Chemotherapy agent is Hydroxyurea, this "Hydrea" is also given by mouth and is not known to cause leukemia. It is given in doses of 1 - 3 milligrams per day by mouth titrated by blood counts. In the original Polycythemia Study Group Trials, patients who got Chemotherapy had overall POORER survival than those who didn't. Part of this was due to some patients having more aggressive PCV disease and so requiring more treatment. However, European studies have shown IMPROVED survival and normal leukemia risk in those patients getting new Chemotherapy, compared to Phlebotomy alone. 3) Phosphorus-32 and Phlebotomy-- As mentioned, marrow suppression with Phosphorus-32 isotope is easy, provides long and problem-free remissions in most cases, and reduces the signs and symptoms of PCV. It may be repeated as necessary, stimulating a new remission. The duration of successive remissions does tend to be shorter than the initial remission. In Polycythemia Study Group Trials, 85.2 MegaBequerals (MBq) of the isotope per square meter of patient's body surface area were injected into a vein in the Nuclear Medicine Department. The effect of the Phosphorus-32 was not immediate, but took weeks to a couple of months to plateau. During this time, and periodically thereafter, patients still required Phlebotomy for reductive of excessive Red Blood Cell mass. The worst complication of Phosphorus-32 is a higher risk for later leukemias, refractory to cure. An analysis of a large number of patients getting Phosphorus-32 showed leukemia risk of about 15%, while NOT ENHANCING SURVIVAL OVER OTHER FORMS OF THERAPY. Again, the risk of leukemia is related to the total dose of Phosphorus-32 given over time, so it is increased with repeated treatments. Also, The longer patients live after treatment, the more chance they have to develop leukemia. Thus, Phosphorus-32 should only be considered for elderly patients who do not have a very long (>5 years) life expectancy owing to other medical conditions. In these patients Phosphorus-32 can be relatively safe, effective ther- apy that reduces symptoms and the need for frequent Phlebotomy. Some Other Things To Consider: Since most early deaths from the disease are due to clotting events (like heart attack or stoke) it may be advisable to take a mild dose of aspirin (such as an 80 mg. children's aspirin) daily to help "thin the blood". Large studies have shown that this reduces clotting ("thrombotic") events in the general population, and it should be especially helpful for PCV patients. It is important to avoid becoming dehydrated, as this further increases the viscosity of the blood and the risk for clots. Drinking about 6 glasses of water per day (presuming normal kidney and heart function) helps keep the blood "thinner" and preserve normal kidney function by flushing out contaminants. It is also important to change diet to reduce cholesterol if it is elevated, and get enough vitamins and minerals. It is further crucial to get a reasonable amount of exercise to assist circulation and relieve stress. These habits will reduce complications from PCV, reduce odds for other medical problems, and enhance the general quality of life. What is the Survival Outlook with Polycythemia Vera? At present, using a rational approach to therapy tailored to the individual patient, the survival with PCV is commonly 10 - 20 years. Most patients succumb to other co-morbid diseases that come with aging, such as heart disease or cancers. Without any treatment, the survival after diagnosis averages just 2 years, and so it is crucial to get appropriate therapy and be carefully monitored by a specialized physician. If proper care is attended to the disease, there is little reason for the average patient with PCV to have a reduced life expectancy owing to PCV itself. Thus, there is more hope today than ever for PCV patients to have a normal lifespan. 
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