Introduction
Blood production is the process during which bone marrow stem cells give rise to the red cells, white cells, and platelets that circulate in the blood stream. Bone marrow stem cells are unique, since only they have the ability to reproduce themselves, unlike their daughter cells which mature and, after populating the blood stream, have a limited life span. Normally, blood cell production is controlled to meet bodily needs. Diseases affecting bone marrow stem cells, therefore, can result in a decrease in blood production affecting all blood cells (aplastic anemia), impaired maturation of blood cells (acute leukemia), or chronic overproduction of one or more of the different types of blood cells alone or in combination, a condition called chronic myeloproliferation to distinguish it from the normal transiently increased production of blood cells in response to acute bodily needs.
There are three chronic myeloproliferative disorders (MPD), polycythemia vera (PV), in which red cell, white cell, and platelet production are increased, essential thrombocytosis (ET), in which platelet production alone is increased and primary myelofibrosis (PMF), in which white cell or platelet production can be increased but there is usually a decrease in red cell production. PV is the most common of the three and PMF is the least common. The designation MPD has been recently changed to MPN (myeloproliferative neoplasm) because each of these disorders arises in a marrow stem cell, defining them as clonal disorders, but the name change does not correspond to the severity of a particular MPD or its potential duration.
PV affects adults of all ages but is most common in women, particularly below age 40, and in both sexes after age 60. PV occurs in families but most often it is an acquired disorder in individuals whose genetic makeup for unknown reasons makes them susceptible to it.
Cause
The cause of PV is unknown but most patients acquire a mutation in the gene Janus Kinase 2 (JAK2), the protein product of which is essential for the production of red cells, white cells, and platelets. JAK2 gene mutations allow the JAK2 protein to function continuously rather than on demand, with overproduction of all three types of blood cells (polycythemia). Importantly, although JAK2 mutations account for the major clinical manifestations of PV, they primarily affect the behavior of the maturing cells and not the involved bone marrow stem cell, but it is the activity of this stem cell that dictates disease behavior. The affected marrow stem cell multiplies at the expense of normal marrow stem cells and eventually, all the marrow stem cells may be descendants of the original diseased stem cell. Indeed, those patients with the most benign forms of PV still have normal stem cells present in their bone marrow, while those with the most aggressive disease will not. Importantly, however, expansion of the diseased stem cell is a slow process, usually taking a decade to occur.
Symptoms and signs
In PV, too many red cells will produce headache, often migrainous, visual disturbances, tinnitus, dizziness, concentration difficulties, transient weakness or paresthesias of the face, arms or legs, and burning pains in the extremities. Itching, particularly after a bath or shower, can be a presenting manifestation. Easy bruising and nose bleeds due to a high platelet count, gout due to a high white cell count and abdominal fullness, inability to eat a full meal and abdominal pain due to splenomegaly may occur. Acid reflux may be due to Helicobacter pylori.
Systolic hypertension due to the expanded red cell count and splenic enlargement are common physical findings along with a ruddy complexion. In some patients, a blood clot in the extremities, lung, abdomen, or brain may be the initial disease manifestation.
Tests
In PV, there is an increase in red cell, white cell, and platelet numbers, often accompanied by an increase in spleen size. However, patients can present with an increase in red cell number alone or with various combinations of erythrocytosis (increased red cells), leukocytosis (increased white cells), and thrombocytosis (increased platelets). In some patients, a large spleen can mask the increase in red blood cells and in others, particularly women, thrombocytosis alone can be the initial manifestation with erythrocytosis occurring later. Since over 95% of PV patients have a JAK2 mutation, this test establishes the presence of an MPD and puts the focus on PV since it is the commonest MPD. But since ∼50% of ET and PMF patients have the same JAK2 mutation, the elevated red cell count is the feature distinguishing PV from them. Since PV, ET, and PMF share the same mutation, a bone marrow examination is not recommended as a diagnostic test.
Table 1. The complications of polvcvthemia vera and their management
Treatment options
Excess red cell accumulation is the immediate problem in PV and phlebotomy (removal of blood similar to blood donation) to reduce the hematocrit to normal (male <45%; female <42%) will alleviate symptoms and periodic phlebotomies (initially monthly) to keep it normal while inducing a state of iron deficiency to maintain it there, are all that is needed. Itching can be alleviated with antihistamines, doxepin, PUVA light therapy or interferon. Paresthesias, numbness or burning pain in extremities, and migraine symptoms can often be alleviated with aspirin alone. There is no proof that a high platelet count causes blood clots in PV but it can be associated with bleeding and intractable migraine, in which case anagrelide or interferon can be used. Leukocytosis is an expected event in PV but in the absence of symptoms needs no therapy. Hyperuricemia or gout can be treated with allopurinol. Symptomatic or progressive splenomegaly is best treated with interferon, its pegylated derivative or low dose thalidomide. Chemotherapy because of its long-term marrow effects is best avoided unless other treatments are ineffective. JAK2 inhibitors alleviate symptoms in PV but are not yet approved for clinical use.
Outlook
For most patients, PV is a chronic indolent illness that be controlled by simple measures with a life span measured in decades. In some, the disease can become aggressive, usually after a period of 5 years, as recognized by progressive splenomegaly. In these patients, more intensive therapy is warranted, with interferon and its pegylated derivative as the initial choice.
Websites
MPN Research Foundation: http://www.mpnresearchfoundation.org/
Polycythaemia vera (PV): Cancer Research UK: CancerHelp UK: http://www.cancerresearchuk.org