True polycythaemia could be primary or secondary. The secondary causes result in polycythaemia either by causing hypoxia or for this reason stimulation to increase red cell production or by increasing stages of erythropoietin (the hormone stimulating red cell production) - eg: tumors (5).
Primary polycythaemia is known as Polycythaemia rubra vera, or simply polycythaemia vera which is a type of abnormal bone marrow growth (1,2,3).
Primary polycythaemia (Polycythaemia rubra vera)
People who suffer from physiologic polycythemia, have a pathological state known as polycythemia vera (1,5). Under this condition, the red blood cell count may be 7 to 8 million/mm3 and the hematocrit may be 60 to 70 percent more than the normal 40 to 45 percent.
The genetic aberration in the cells causes the hemocytoblastic corpuscles polycythemia vera. The blast cells stop producing red blood cells because there are too many cells already present. This solves an excessive production of red blood cells in a similar way that a breast tumor causes an excess of production of a particular type of breast cell. In addition, most often it causes excessive production of white blood cells and platelets(3,4,5). In polycythemia vera, it is not only that the hematocrit increases, but also the entire blood volume(1,2,5).In certain occasions it rises to about twice the normal. Thus, the entire vascular system is distended very much. Additionally, many capillaries are to be blocked by the viscous blood. The viscosity of the blood in polycythemia is sometimes increased by the ordinary content of 3 times the viscosity of water to 10 times that of water (15).
Secondary polycythaemia
Many high-oxygen affinity hemoglobin(MHOAH) mutants have been described which causes increased oxygen affinity but decreases oxygen delivery to the tissues, resulting in compensatory polycythaemia. A congenital autosomal recessive disorder (Chuvash polycythaemia) is as a result of a defect in the oxygen-sensing erythropoietin synthesis pathway caused by a mutation of the Von Hippel Lindau (VHL) gene, resulting in a raised synthesis of erythropoietin. Serum erythropoietin (EPO) levels are normal or increased in secondary polycythaemia. Rarely the discovery of a high EPO level may be the clue to the existence of an EPO secreting tumour (5).
Hypoxia
Hypoxia is O2 deficiency at the tissue level. It is a more acceptable term than anoxia, with a no O2 condition in the tissues(1,2,8). There are four types,
Hypoxic hypoxia
Hypoxic hypoxia is a condition of decreased arterial PO2 left in the tissue. Hypoxic hypoxia is a problem in ordinary individuals at high altitudes and is a complication of pneumonia and a range of other diseases of the respiratory system(1,2,15).
Anemic hypoxia
Hypoxia due to anemia is not harmful at rest unless the hemoglobin deficiency is marked, because red blood cell 2,3 Bis Phospo Gliserate (2,3 BPG) increases. Nevertheless, anemic hypoxia could possibly have substantial difficulty during exercise as a result of limited ability to increase O2 delivery to the active tissues(1,2,15).
Stagnant hypoxia
Hypo perfusion hypoxia, or stagnant hypoxia , is due to slow circulation and causes problems in organs such as the kidney and heart during the shock(1,6). The liver and maybe the brain are damaged by hypo perfusion hypoxia in congestive heart failure. The flow of blood to lung is on the whole very large, and it takes prolonged hypotension to produce significant damage. However, acute respiratory distress syndrome can develop when there is a lingering circulatory collapse(1,2,15).
Histotoxic hypoxia
Hypoxia due to inhibition of tissue oxidative processes is most commonly the result of cyanide poisoning. Cyanide inhibits cytochrome oxidase and probably other enzymes. Cyanide poisoning is usually treated by using Methylene blue or nitrites(1,2,15).
Other causes of hypoxia
Major causes include heart pulmonary embolism, severe head injuries, chronic alveolar hypoventilation, carbon monoxide (CO) poisoning, attack, asthma, suffocation and choking. Circumstances under which the body is deprived of O2 can result in hypoxia (2,15). If the body does not receive the required amount of oxygen, this will guides to a low oxygen partial pressure in arterial blood. This guides to hypoxic hypoxia. The main causes of hypoxic hypoxia-altitude mountaineering, insufficient ventilation or heart-failure mechanism(2,15). It can also occur because of shunts in the pulmonary transmission of the heart. Shrunken alveoli in the lungs may also guides to shunts. When there is no oxygen , calls anoxia. Hypemic in hypoxia is a condition where there is an obstacle on the ability of the blood to deliver O2. This is caused by CO poisoning. If the required amount of O2 reaching the cells is not effectively used by some disturbance in the cells, it causes histotoxic hypoxia. Stagnant hypoxia establishes when something obstructs the flow of blood carrying a sufficient amount of oxygen(2,15).
The symptoms and signs of hypoxia
Generalized hypoxia symptoms depend on the severity and frequency accelerated. In the case of altitude sickness with symptoms include headache, fatigue, shortness of breath, the feeling of excitement and nausea(2,5,6,7). In severe hypoxia, it occurs by very rapid onset, changes in the degree of loss of consciousness, seizures, coma, priapism, and death. Severe hypoxia induced blue discoloration of the skin is called cyanosis. Since hemoglobin oxygen (oxyhemoglobin) binds without oxygen (deoxyhemoglobin), it is not a rich red, dark red, there is a rising trend through the skin, to reflect the blue light to the eyes. In the case where oxygen from another molecule, such as carbon monoxide shifts in the skin cherry ', instead can appear cyanosis(2,5,6,7).
Treatment
It can be a deadly disease. If someone suffer from this circumstance, it is very important to establish the air route by respiration. Individuals should be immediately taken to hospital, where he is to be put on a ventilator support for breathing(2,3,5). Blood pressure and heart rate should be checked. They should be kept in the control system with the aid of fluids or medication. Seizures, if any, should be defeated. Sometimes cold covers are used, as they slow down the activity of brain cells and reduce the need for oxygen.
If it happens when climbing or living at high altitudes, should stop every activity and drink plenty of fluids. After a rest, people should descend to a point where the body begins to reach more oxygen(2,5,6,7). In the case of hypoventilation, the patient has to sit or lie on a moderately high position. This will useful the oxygen reach into the lungs and to overcome low oxygen levels. These patients need supplemental oxygen therapy and will be asked to wear a face mask with an oxygen cylinder. Patients with hypoxic hypoxia are given blood transfusions. This useful in increasing the oxygen carrying bulk of the blood(2,5,6,7).
The patient should be given correct medication, while vital signs such as heart rate, respiratory rate, blood pressure and temperature are monitored. While the road to recovering, the patient may suffer from amnesia, personality regression, hallucinations, memory loss, muscle cramps and spasms. Recovery is possible if the brain has not been withdrawn from oxygen for a extensive period. Therefore it is essential, that sufficient air and medical help for the person suffering be given(2,5,6,7).
Prompt medical notice and treatment should be wanted. The patient is given vital support and his / her respiratory rate must be maintained(5). Intravenous drugs should help in the prevention of seizures and accelerates the blood pressure. To save the life or prevent serious complications medical intervention is very vital.
Secondary polycythemia.
When the tissues become hypoxic due to lack of oxygen in the air, such as at high altitudes, or because of the loss of oxygen supply to the tissues, as in the heart failure, the blood forming organs automatically need huge amounts of additional red blood cells. This situation is called secondary polycythemia, and the red blood cells typically rises to 6 to 7 million/mm3, about 30% above the usual(1,5,6,).A common type of secondary polycythemia called physiological polycythemia occurs in natives who live on altitudes from 14,000 to 17,000 feet, where atmospheric oxygen level very low(16).
Statistics on Polycythaemia
Secondary polycythaemia has become a common disease, as there are a large number of circumstances that can cause it. Primary polycythaemia (PV) occurs in 2 per 100,000 people. It is widely seen in men in the older age group, and more common in women in their pregnant period. PV is likely to occur in patients over 60 years of age(15).
Normal ranges of hemotocrit, red cell counts, and hemoglobin
The hematocrit is the ratio of the volume of red blood cells to volume of whole blood, . The normal range for hematocrit changes between the sexes, about 45-52% in men and 37% to 48% in women(13,15).
Erythrocyte count is the number of red blood cells in a volume of blood. Approximately within the normal range for men 4700000-6100000 cells / UL (microliter). The normal range for women is the range of 4200000 to 5400000 cells / UL according to the health data(13,15).
Hemoglobin is a protein in red blood cells that carries oxygen and gives blood its red color. The average values ​​for hemoglobin may differ according to the sexes and is nearly 13 to 18 grams per deciliter for males and 12 to 16 grams per deciliter for females(13,15).
Polycythemia in hypoxia and other causes for polycythaemia
Against primary polycythemia in which the production of red blood cells results from increased sensitivity and responsiveness to erythropoietin (EPO)(12,14).In secondary polycythemia there are more red blood cells due to high levels of circulating EPO production. The main reasons for higher than normal EPO are chronic hypoxia (poor blood oxygen levels over the long term), poor oxygen supply due to abnormal red blood cell structure and tumors releasing unreasonable amounts of EPO(12,14).
Efforts to understand the molecular basis of oxygen regulated erythropoiesis have identification of EPO, which is needed for usual erythropoiesis and conveys to the purification of hypoxia-inducible factor (HIF), the transcription factor that EPO produces and cellular adaptation regulated led to hypoxia(12).
A standard physiological response to hypoxia in humans is the up regulation of the EPO gene, which is the main regulator of red blood cell volume. HIF is a transcription factor of an alpha subunit (HIF-alpha) and one beta-subunit (HIF-beta). (Known PHD, HIF prolyl hydroxylase as well as and about nine defective egg protein)(12). Under normoxic conditions prolyl hydroxylase domain protein site specifically HIF-alpha hydroxylated in a conserved motif LXXLAP (where underscores of hydroxyl acceptor shows proline). These supply a recognition motif for the von Hippel-Lindau protein, a component of an E3 ubiquitin ligase complex, hydroxylated HIF alpha targeted for degradation. Under hypoxic circumstances, this is inherently oxygen dependent change arrested and stabilizes HIF-alpha and makes it possible to activate the EPO gene(12,14).
Erythropoietin is another kidney hormone found in each hypoxic published condition as the most important regulatory factor of erythropoiesis. Erythropoietin or EPO is a glycoprotein or erythropoietin erythropoiesis which controls the production of red blood cells. It is a cytokine (protein signal molecule) for red blood cells in the bone marrow precursors(14).
Control erythropoietin, or red blood cell production is in the bone marrow precursor cells (red blood cells).
Even haemopoietin, or hemopoietin is produced in renal interstitial fibroblasts. It is also produced in the liver in the perisinusoidal cells. It is dominant in the adult kidney production, mainly in the production of fetal and perinatal liver. Erythropoietin is a hormone regulating the production of red blood cells. It also has other biological functions. For example, erythropoietin neurons in the brain injury plays a vital role. EPO is also involved in wound healing(14).
Exogenous EPO as a performance enhancing drug is classified as erythropoiesis stimulating agent (ESA). Exogenous EPO can often be detected in the blood, due to the characteristics from the endogenous protein in the post-translational modification.
Erythropoietin increases the production of red blood cells in anemia with some exceptions. Polycythemia vera is a very useful blood loss, but harmful to (increased blood viscosity), lung and heart diseases.
An increase in erythropoietin EPO can occur due to chronic hypoxia or depleted oxygen supply(1,5,12,14). Also the same condition may result in the following situation,
• Chronic obstructive pulmonary disease (COPD, emphysema, chronic bronchitis)
• pulmonary hypertension,
• hypoventilation syndrome,
•Congestive heart failure,
•Obstructive sleep apnea
• adverse kidney and blood circulation,
•Living at high altitudes.
2,3-BPG is the molecular structure of hemoglobin in the red blood cells. Efficiency state of 2,3 BPG cause for abnonrmal structure of red blood cell. Hemoglobin has a higher affinity for oxygen and as a result this situation leades to increased red cell cells(1,2).
In tumors there is more secretion of erythropoietin(5,6,7) .
Common erythropoietin release tumor:
• Liver cancer, (hepatocellular carcinoma)
•Kidney cancer (renal cell carcinoma)
• adrenocortical adenoma or adenocarcinoma
• Uterine
In addition, a benign condition of erythropoietin secretion, such as kidney and renal cysts may increase disability.
Long term exposure to carbon monoxide can cause polycythemia. Hemoglobin has a higher affinity for carbon monoxide than for oxygen. Therefore, when the carbon monoxide molecules and hemoglobin are mixed the hemoglobin content increases as a compensation mechanism.
Neonatal polycythemia can be caused due to transfusion of mother's blood through the placenta. Long term lack of oxygen supply to the placenta can also be the case of fetal hypoxia neonatal polycythemia(11).
Polycythemia symptoms
Symptoms of polycythemia can vary widely. While some people show symptoms of the disease, the other does not show visible symptoms(1,5,15).
In secondary polycythemia, most of the symptoms are responsible for polycythemia.
Symptoms of polycythemia can spread far and vague(1,5,15). Some of the main symptoms are:
• easy bruising;
• easy bleeding;
• blood clots (possibly leading to heart attack, stroke, blood clots in the lungs pulmonary embolism)
• bone and joint pain (pain in the hip or rib pain);
• headache;
• itching;
• itching after taking a shower or bath (post bath pruritus);
• tiredness;
• dizziness and
• abdominal pain.
Effect of polycythemia on function of the circulatory system
Due to the sharp rise in viscosity of blood in polycythemia, the blood flow through the peripheral blood vessels are often very slow(1). The factors that regulate the flow of blood back to the heart, increase the viscosity of the blood and the rate of venous return to the heart is reduced. Conversely, the volume of blood is greatly increased, for the purpose of venous return. In fact, the cardiac output in polycythemia is almost normal, since these two factors neutralize each other more or less(1,2). Arterial blood pressure is usually at normal levels in most people with polycythemia, although about a third of them, experience increased arterial pressure. This means that the blood pressure values ​​can control mechanisms normally counterbalance the tendency to increase the viscosity of the blood, in order to increase the total peripheral resistance and thus increase arterial pressure. Beyond certain limits, do not result in hypertension. The color of the skin depends largely on the amount of blood in the skin sub papillary plexus(1,2). In polycythemia vera, the amount of blood is greatly increased in this network. Furthermore, because the blood passes through the skin cappilaries before entering the venous plexus,a larger than normal quantity of hemoglobin is deoxygenated. The blue color of all these deoxygenated hemoglobin masks the red colour of oxygenated hemoglobin. Therefore, a person with polycythemia usually has a ruddy complexion and a bluish (cyanotic) skin(1,2).
Examinations and Tests
In many situations, polycythemia might be identified incidentally in regular blood work ordered by a physician for an unrelated medical reason. Then this may then call for further examine to find the source of polycythemia(5).
A comprehensive medical history, physical examination, family history, and social and occupational history are very important factors in evaluating a patient who is suffering from polycythemia. In the physical examination, deep attention should be paid to the heart and lungs. Splenomegaly is one of the prominent features of polycythemia vera; hence, a careful abdominal exam is essential to evaluate for an inflamed spleen(5).
Routine blood work including a complete blood count (CBC), clotting profile, and metabolic panel are basic modules of laboratory tests in assessing the cause of polycythemia. Other typical tests to find out the likely causes of polycythemia include chest X rays, electrocardiogram (ECG), echocardiogram, hemoglobin analysis, and carbon monoxide measurement(5).
In polycythemia vera, customary other blood cells are also affected, represented by an unusually high amount of white blood cells (leukocytosis) and platelets (thrombocytosis). Bone marrow examinations (bone marrow aspiration or biopsy) are sometimes necessary to look at blood cell production in the bone marrow(5).
Checking EPO levels are not necessary but these can sometimes provide helpful information. At the initial level polycythemia, the EPO level is typically low, whereas in EPO-secreting tumors, the level may be much higher than usual. The results need to go through a careful interpretation as the EPO level may be appropriately high in response to chronic hypoxia, if that is the underlying cause of polycythemia(5).
The distinction polycythemia vera from secondary polycythaemia
The traditional consensus diagnostic criteria for polycythemia were (a) an increased amount of red cell volume, a normal arterial oxygen saturation, and splenomegaly, or (b) in the absence of splenomegaly, an elevation in at least two of the following: platelet count more than 400,000 / mm3, WBC more than 12,000 / mm3, leukocyte alkaline phosphatase, serum B12 level or unbound B12 binding capacity. However, the lack of specificity of these criteria has led to the development of additional diagnostic tests to confirm the diagnosis(1,5). Such tests can be expensive and should be used with a reasonable pre-test probability (limited as at least one or two of the characteristics manifested in addition to an increased hematocrit, such as generalized pruritus after bathing, splenomegaly, persistent leukocytosis, thrombocytosis or persistent atypical thrombosis) with the disease.
Traditionally, either direct measurement of the red cell mass or an estimate on red cell volume basis is necessary for the diagnosis, but this measurement is expensive and often not readily available, and it cannot distinguish between polycythemia and pathological secondary erythrocytosis(1,5). The distinction is the most important, that must to be made. The measurement of serum erythropoietin is very useful to make the difference. A high erythropoietin level virtually excludes polycythemia and suggests secondary erythrocytosis as anti-production should be suppressed in polycythemia. A low erythropoietin level supports the diagnosis of polycythemia, while pathological exclude secondary erythrocytosis (driven by the excess erythropoietin production).
If erythropoietin is normal (which occur in mild disease after phlebotomy and with secondary disease), then suggested a bone marrow biopsy(1,5). If the histology is characteristic polycythemia (hyper-cellularity decreased increased number of megakaryocytes, giant megakaryocytes, mild reticulum fibrosis, bone marrow iron stores), then the diagnosis can be confirmed. In the few cases where diagnosis remains difficult, can platelets for expression of thrombopoietin receptor protein, which is deficient in tested polycythemia. Test granulocytes for polycythemia vera-1 gene, which appears to be unique to the state is a further option in some centers. Others perform in vitro testing of erythroid stem cells obvious colony growth in the absence of exogenous erythropoietin(1,5).
Polycythemia Treatment
Treatment of secondary polycythemia depends on its cause. Supplemental oxygen can be supplyed to people with chronic hypoxia. Other therapies to treat the cause of polycythemia should be addressed (for eg:, appropriate treatment for heart failure or chronic lung disease)(1,5,6,7).
Treatments for primary polycythemia play an important role in improving the cause of the disease.
Medical Treatment
Phlebotomy (bloodletting) remains the basic treatment for polycythemia. The goal is bloodletting, by keep the the hematocrit at approximately 45% in men and 42% in women. Initially, it may be necessary to remove 250-500 ml of blood in each session in every 2 to 3 days. Once the goal is reached, the maintenance phlebotomy may be performed less frequently(1,5,6,and 7).
A commonly recommended drug for the treatment of polycythemia is called hydroxyurea (Hydrea). This is especially true for people who are prescribed at the risk of clot formation. At an age over 70, both with an increased platelet count (thrombocytosis) are greater than 1.5 million and cardiovascular diseases through the using of hydroxyurea cheaper. Hydroxyurea is also recommended for patients who do not tolerate phlebotomy(1,5,6,and 7).
Aspirin has also been used in the treatment of polycythemia vera to reduce the risk of clotting (thrombotic)(1,5,6,7). Its use is generally avoided in people who blood clotting does not take place. Aspirin is normally used in conjunction with phlebotomy.
prevention
Many causes of secondary polycythemia are not preventable(10). However, some possible preventive measures
• stop smoking
• Avoid prolonged exposure to carbon monoxide,
• appropriate treatment of diseases such as heart disease chronic lung disease, or obstructive sleep apnea.
Primary polycythemia as result of a mutation of genes is generally unavoidable(10).
Outlook (prognosis) for polycythemia
The prognosis of polycythemia depends on the underlying cause. Overall, the common outlook is favorable for the people suffering from this disease mainly with secondary causes(1,5). The outlook for primary polycythemia is fair, while it is usually not curable for many years. For many people it is manageable and treatable. For example, untreated, polycythemia vera (PV) was initially thought to have a bad diagnosis with a life expectancy of 1-2 years from the time of diagnosis(1,5). However, polycythemia vera is now much improved with a forecast of 10-15 year survival after diagnosis with the treatment for bloodletting alone. The addition of drugs, such as, hydroxyurea and aspirin can improve survival even to a greater degree(1,5).
