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Polycythemia Vera

Chronic myoproliferative diseases are disorders of the blood that originated from a multipotent hematopoietic progenitor cell and presents with a clonal dominance of the malignant progenitor cells . It also exhibits a profuse production of one or more of the formed elements of the blood, extramedullary hematopoiesis and disorders that fall under this category show a possibility of incurring acute leukemia in the latter course of the disease. Disorders under this category include idiopathic myelofibrosis, chronic myelogenous leukemia, essential thrombocytosis, and polycythemia vera.

These disorders all affect the integrity of the blood and albeit they share some of the aforementioned characteristics, they essentially vary in their clinical course. Idiopathic myelofibrosis is characterized by the presence of an abnormal deposition of collagen material in the bone marrow and by the presence of an extramedullary hematopoiesis, this is a common description for idiopathic myelofibrosis. The disease fits under the category of being a myoproliferative disorder because of extramedullary hematopoiesis.

Idiopathic myelofibrosis is named as such due to the fact that its origin and cause is still unknown. Chronic myelogenous leukemia, on the other hand, is characterized by the presence of certain hematopoietic precursors that are arrested in an early developmental stage . Moreover, it is known as a disease with a profuse production of white blood cells. The disorder has a cytogenic abnormality that consists of a shared translocation between the chromosomes 22 and 9 which resulted in a shorter chromosome 22. This is called the Philadelphia chromosome, named after the city of its discovery.

The consequence of the translocation of chromosome 22 and 9 is that an abl, an oncogene, is transferred from chromosome 9 to 22, in the bcr area. The fusion of the bcr/abl gene results in a strapping tyrosine kinase activity. This results to the development of the chronic myelogenous leukemia phenotype, albeit the exact process is still undiscovered. This translocation is the hallmark morphologic symptom of chronic myelogenous leukemia. The presence of this translocation in addition to the clinical manifestations of chronic myelogenous leukemia is considered to be diagnostic of the disease.

Essential thrombocytosis is another myoproliferative disease which presents peripheral thrombocytosis and megakaryocytic hyperplasia. Thrombocytosis is abundance in the platelets of the individual. The presence of an increased production of one of the formed elements of the blood places this disease under the myoproliferative category. Polycythemia vera, the last disease aforementioned in the category of the myoproliferative diseases, most commonly affects males aged fifty and onwards, according to Bullock and Henze.

The main characteristics of polycythemia vera is that there is an increase in the production of all the formed elements found in the blood, such as the red blood cells, granulocytes and the platelets. Like all of the other myoproliferative diseases, polycythemia vera has been very difficult to diagnose. In fact, only chronic myelogenous leukemia has the specific marker for diagnosis, and this is the 9-22 chromosomal translocation, giving rise to the Bcr-Abl, a tyrosine kinase.

Diagnosis of the chronic myeloproliferative diseases is still being studied until now. Polycythemia Vera A chronic myeloproliferative disease, polycythemia vera is distinguished by the presence of an enlarged spleen or splenomegaly, panmyelosis or a proliferation of bone marrow cells of all types, and a predisposition to venous or arterial thrombosis, acute leukemia and myelofibrosis . Polycythemia refers to an increased volume of the red blood cells due to dysregulated erythropoiesis that result to an expansion of red blood cell mass .

This term is usually used when the hematocrit level is elevated, usually more than 55% in males and more than 50% in females . Albeit there can be other reasons as to why hematocrit levels can become elevated, like dehydration, shock, burns, which does not usually reach the level of increase polycythemia vera patients encounter. Polycythemia vera has two morphologic phases. The first phase is called the proliferative phase, and the second phase is the spent phase or the post-polycythemic phase.

An increase in red cells, white cells, and platelets occur during the morphologic phase. It is manifested by neutrophilia with left-shifted granulocytes, a platelet count of greater than 600 x 109/L . Moreover, iron deficiency with microcytic red blood cells can also be observed. The second phase is the spent phase. The spent phase exhibits a marked marrow fibrosis and is thought to be akin to the one occurring in chronic idiopathic myelofibrosis with leukoerythroblastic peripheral blood changes, splenomegaly and marrow fibrosis .

There are approximately 15% of those with polycythemia that progress to this phase. The cells undergo further mutations and no longer overproduce red cells in this phase. It results in anemia, which is due to the red cell count dropping below normal. Myelofibrosis will also result due to the further enlargement of the spleen and the bone marrow becoming more fibrous. Platelet counts will also decrease, and immature white cells will be released from the bone marrow into the blood. Polycythemia vera is classified as either primary polycythemia or secondary polycythemia.

Primary polycythemia is distinguished from secondary polycythemia from its disease mechanism. Primary polycythemia is a myeproliferative disorder in which the myeloid stem cells seem to have escaped normal control mechanisms . The factors that usually serve as precursors to this disease are intrinsic to the red cells . The bone marrow is hypercellular, and the erythrocytes, leukocytes, and the platelet count in the peripheral blood is elevated . However, the most abundant in this cell proliferation is that of the red blood cells and can last up to ten years or more .

The spleen of the individual suffering from polycythemia resumes its embryonic function of hematopoiesis, and thus it enlarges, producing the manifestation of splenomegaly . After which, the spleen may become fibrotic, hindering its ability to produce any more cells. Secondary polycythemia is caused by extrinsic red cell precursors . There is an excessive production of erythropoietin and this may be a response to a reduction in oxygen inside the body . It can be a hypoxic stimulus, such as in smoking cigarettes, cyanotic heart disease or in high altitude.

Secondary polycythemia may be congenital or acquired, driven circulating factors, which are autonomous of the role of hematopoietic stem cells. It can also be a complication of chronic obstructive pulmonary diseases. Secondary polycythemia is also known as spurious, stress polycythemia, or Gaisbock’s syndrome. Being obese, a smoker, having hypertension, taking diuretics, can predispose a middle-aged white man to Gaisbock’s syndrome. Spurious polycthemia, on the other hand, can be caused by incurring burns, diarrhea, having a higher than normal hemoconcentration, and stress.

Distinguishing secondary causes of polycythemia vera is important to rule out this diagnosis. A number of signs and symptoms have been included in the category of secondary causes of polycythemia that can help rule it out namely, the presence of a chronic obstructive pulmonary disease, the presence of a cardiac disease, a decrease in 2,3-diphosphoglycerate, residing in an area of high altitude, hemoglobinopathy and an increase in the individual’s carboxyhemoglobin and methemoglobin.

In addition, the occurrence of an adrenal cortical hypersection, the presence of a tumor that produces erythropoietin or certain anabolic steroids, stress, hydronephrosis, and several disease that result in a reduction in the plasma volume such as diarrhea, vomiting, and a renal disorder are also useful in ruling out secondary polycythemia. Pathophysiology Albeit the exact pathophysiology of polycythemia vera is not known, there are several explanations to the nature of the disease process. According to Bullock and Henze , the abnormal bone marrow proliferation initially involves white cell and red cell elements at first.

This occurrence will then prompt thrombocytosis as well as the disease progresses. Other evidence suggests that polycythemia vera is a neoplastic disorder that stimulates abnormal erythropoietin – hypersensitive stem cells and at the same time it suppresses the normal stem cells . Thus, an over production of stem cells occur. The proliferation of hematopoietic cells will result in increased blood counts, an increased blood viscosity, and blood volume as well . The liver and the spleen will become congested with packed red blood cells and this will result in stasis and thrombosis leading to infarction.

Clinical manifestations The individual affected with this disease experiences lightheadedness, visual disturbance, headaches, tinnitus, fatigue, and vertigo due to the increased blood volume . An increase in blood viscosity will cause symptoms of angina, claudication, dyspnea, and thrombophlebitis . Patients are expected to exhibit a ruddy complexion and a presence of a generalized pruritus because of the histamine release by the basophils . Other symptoms include clubbing of the fingers and toes, erythema, drowsiness, bloodshot eyes, scleral injection, and facial malar, among many others.

Diagnostic tools used As aforementioned, being a part of the four diseases categorized under the myoproliferative disorders sharing very similar characteristics, diagnosing is rather difficult. Studies have shown that there are nine diagnostic tools most commonly utilized in order to affirm the diagnosis of polycythemia vera, albeit the specificity of some of these are questioned. These are the red cell volume or RCV, the serum erythropoietin level, the leukocyte alkaline phosphatase or LAP score, serum vitamin B12 level, bone marrow aspiration or biopsy.

Diagnosing polycythemia vera used to depend on three factors only, the presence of erythrocytosis, cyanosis, and splenomegaly, according to Osler . However, this criterion was later changed to include an increase in red cell mass, a normal arterial oxygen saturation, and splenomegaly. If there is no splenomegaly, any two of the following will suffice, a leukocytosis value of greater than 12,000/uL, thrombocytosis level greater than 400,000/uL, a leukocyte alkaline phosphatase or LAP score of greater than 100, serum B12 levels of greater than 900 pg/mL, and/or, vitamin B12 binding capacity greater than 2200 pg/mL .

The major criteria is that the patient should exhibit an increased red cell mass, and the second major criterion is that the etiology of secondary polycythemia has to be ruled out, and the third is there should be evidence of proliferation, as in splenomegaly . The physician needs to have all the major criteria present in the patient, or at least the first two major criteria and two more minor . Red Cell Volume (RCV) In measuring the red cell volume, the procedure consists of labeling the erythrocytes with 51Cr to be able to measure red cell mass using radio-iodine-labeled human serum albumin to measure plasma volume .

However, before using this method, plasma volume is measured with 125I as the radionuclide. Instead of using the newer technology in measuring both the red cell mass and plasma volume, which is 51Cr for measuring red cell mass and the radio-iodine-labeled human serum albumin for measuring plasma volume, only 125I-albumin is suggested for use . There is no significant difference between the two radionuclides in determining the measure of red cell volume. In fact, the older 125I-albumin does not only prove to be cheaper for the patients, but also consumes less time for the laboratory technicians to utilize.

Due to the high demand of accuracy and cost-effectiveness needed in this particular diagnostic exam, most especially for diagnosing polycythemia vera, it is suggested that to achieve this goal, the 125I-albumin should be used instead of the 51Cr, for measuring both red cell mass and plasma volume. Patients who undergo this exam are positive for polycythemia vera if the results showed a greater than 60% hematocrit level for males and a hematocrit level greater than 50% in females. However, an elevated red cell mass volume will not suffice alone because this symptom can also account for other chronic myeloproliferative disorders.

Serum erythropoietin level The normal values used for this particular product is provided by the manufacturer of the Quantikine IVD Erythropoietin ELISA as 3. 3 to 16. 6 IU/L . Serum erythropoietin levels should be the first diagnostic tool to be utilized when ruling out absolute erythrocytosis . This diagnostic tool is simple, inexpensive, and reliable in measuring the serum eryhthropoietin level. Taking this diagnostic exam can help differentiate if the patient is suffering from polycythemia vera or secondary polycythemia.

If the erythropoietin levels increase in a patient with decreased arterial oxygen saturation, then he or she is negative for polycythemia vera. In addition, this test can determine which type of polycythemia is present after phlebotomy. If erythropoietin levels after phlebotomy increase, this means that it is secondary polycythemia. If it remains unchanged then it is polycythemia vera. However, the assay for serum erythropoietin levels is not recommended to be a part of the diagnostic routine for polycythemia vera.

This is because measurement of erythropoietin cannot be relied on to distinguish between the autonomous and erythropoietin driven erythrocytosis . This is due to the fact that red cell mass expands and both enhanced tissue oxygenation and the related raise in blood viscosity reduces the erythropoietin production, all happening while the plasma residence of erythropoietin is decreased through an increase in catabolism by the expanded erythroid progenitor cell pool. The result of such a process is a decrease in erythropoietin levels .

The normal erythropoietin levels range from four to twenty-six mU/mL, and this can actually become a hindrance in detecting whether there are abnormalities in its value. Considering the fact that even if the erythropoietin levels increase or decrease four times its value, the result is that it is still in the range of the normal values. An increase in erythropoietin levels can be due to tissue hypoxia and will result in erythrocytosis. Leukocyte Alkaline Phosphatase or LAP score A leukocyte alkaline phosphatase (LAP) score is a usual diagnostic test ordered for patients who have an elevation of white blood cells.

This test will be able to differentiate reactive progression of polycythemia vera from chronic myelogenous leukemia. In accurately measuring the leukocyte alkaline phosphate, naphthyl AS-B1 phosphate is hydrolyzed to phosphate . An aryl maphthylthalamide by alkaline phosphatase in the cytoplasm of WBCs is also hydrolyzed. Then, the aryl naphthylthalamide would be coupled to diazonium salt, which in turn forms an insoluble blue dye within the leukocyte’s cytoplasm . Scoring of the neutrophils and the bands are from zero to four, and the sum of one hundred of the cells is the one that makes up the leukocyte alkaline phosphatase score .

The normal LAP score for adults range from thirteen to 130. Patients suffering from polycythemia vera will have either a normal or an elevated leukocyte alkaline phosphatase score . A decrease in LAP score confirms chronic myelogenous leukemia. Bone Marrow aspiration or biopsy A smear sample from a bone marrow biopsy or aspiration is needed in order to diagnose for this exam. More than one air-dried smear is prepared just after seconds from the actual collection. Fresh, air-dried smears are the best samples to examine.

However, larger volumes can also be preserved in EDTA and should be prepared within one to two hours, but is not as good as the air-dried samples . The fluid off the bone marrow sample is allowed to drain off. After which the marrow sample is gently placed onto the slide. A second slide is placed over the bone marrow sample. The slide should cling through by capillary action and there should be no pressure . Morphologic changes that can be seen in the smear which can indicate polycythemia vera include a greater than normal myelocyte and myeloblast numbers.

An increase in eosinophils and basophils can also be observed. In addition, there is an absence of the iron pigment in approximately ninety percent of the individuals with polycythemia vera. A morphologic hallmark for a secondary form of erythrocytosis is the presence of an increase in the iron stores of bone marrow. This result can help rule out erythrocytosis and aid in the diagnosis of polycythemia vera. If there is a demonstration of reticuloendothelial iron stores in the bone marrow smear, essential thrombocytosis can be assumed present in the patient .

If there is a demonstration of marrow fibrosis in the results, then a myelofibrosis can be assumed. The presence of both diseases can help in diagnosing polycythemia vera. However, bone marrow aspiration is not recommended to be a part of the routine diagnostic exams for polycythemia vera. This is because bone marrow aspiration results can become abnormal in cases such as an increase in megakaryocytes and cellular hyperplasia with a loss of the fat spaces . Bone marrow aspiration alone cannot be the only diagnostic tool used to diagnose polycythemia vera, and it also cannot rule out the use of other tests.

In addition, this test is very expensive and painful. Bone marrow cytogenetics The study of chromosomal abnormalities is called cytogenetics . Chromosomes can be collected from dividing cells and the collecting process of chromosomes from a single cell is termed metaphase spread. Spontaneous cell division that occurs throughout life is specifically found in certain body parts such as the bone marrow tissues. The red blood cells, the white blood cells, and the platelets are being produced by the bone marrow.

If a bone marrow is to be cultured, and it can be, a sample is placed in a culture tube containing a nutrient rich medium. The presence of the Philadelphia chromosome or the bcr-abl in chromosomal studies has been linked to chronic myelogenous leukemia. Chronic myelogenous leukemia is present in majority of polycythemia vera patients. Moreover, the valine position at 617 of the Janus kinase 2 gene in a patient with polycythemia vera has been proven to be replaced by phenylalanine, and this is one of the forerunners of the newest recommended diagnostic testing for polycythemia.

Approximately 95% of the patients suffering from polycythemia vera have a JAK2 gene that has been replaced by phenylalanine. Janus kinase 2 or JAK2 is a cytoplasmic tyrosine kinase, which transmits signals triggered by hematopoietic growth factors like erythropoietin in neoplastic cells and normal cells. The substitution of phenylalanine for valine at codon 617 results from a point mutation in exon 14. This substitution makes the JAK2 gene constitutively active. The induction of these gene types in mice resulted to a polycythemia vera-like disease.

The mutation of these JAK2 genes have been an essential element in the development of polycythemia vera and can therefore become a diagnostic tool in diagnosing this disease. Erythroid progenitor cell assay Erythroid progenitor cell assay is also not recommended as a routine diagnostic tool in diagnosing polycythemia vera because it is not specific to this disease alone. This test can result in a positive test even in non-clonal cases of erythrocytosis, in healthy individuals, and in essential thrombocytosis. In addition, other patients affected with polycythemia vera showed up negative for this test.

Impaired expression of Mpl Mpl is a thrombopoietin receptor and there is an impaired expression of this receptor in platelets and in megakaryocytes for patients with polycythemia vera . The impaired expression was shown to be due to a defect in post-translational processing . By utilizing quantitative densitometry of Mpl in immunoblots of whole platelet lysates, the difference between these can be determined. There is also a 95% specificity of the test, in addition to a ninety-six percent sensitivity. An alternative to platelet Mpl immunoblotting is immunohistochemistry of the bone marrow megakaryocyte Mpl.

The impaired Mpl expressions appears to tract with the abnormal clone because the Mpl post-translational processing defect is present in polycythemia vera CD34+ cells. Real-time reverse transcriptase polymerase chain reaction or RT – PCR Another potential clonal assay for polycythemia vera is measuring the expression of PRV- 1 or polycythemia rubra vera – 1, an allele of the CD177 gene. PRV-1 gene is a member of the receptor family of uPAR uniquely over expressed in the granulocytes of individuals affected with polycythemia vera .

The mechanism underlying the upregulation of PRV-1 is still not known and several clinical results have been misleading. Henceforth, its relevance as diagnostic tests for polycythemia vera should be further studied. Polycythemia vera is not a life threatening disease and it’s symptoms can be managed. However, it is of utmost important that the disease is diagnosed accurately, because the treatment for it is specific for the disease and any miscalculations can pose as a threat to the health of the individual.

Henceforth, diagnosing polycythemia vera requires a series of routine diagnostic tests and not just one. In lieu of several studies that are being asserted by researchers claiming that there are unnecessary tests being done for polycythemia vera, they however suggest that the measurement of both the red cell mass and the plasma volume should be the most important diagnostic tool and cannot be removed from the routine diagnostic exam for polycythemia vera. The red cell mass and the plasma volume have to be taken simultaneously because individual tests provide no information about the other and is inaccurate.

Moreover, erythrocytosis is the one and only diagnostic feature that differentiates polycythemia vera from the other chronic myeloproliferative diseases. Diagnosing polycythemia vera can only be concluded through the measurement of the red cell mass. Granted the potential diagnostic clonal assays are proven to be very useful in the succeeding studies to come, there will still be a need to determine red cell mass, not only for diagnostic purposes, but for treatment as well. It is still recommended that more research is to be conducted for this disease, as there is still no definitive diagnostic test for polycythemia vera yet.

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