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The increase in haemoglobin, packed cell volume and red cell count is defined as Polycythaemia.A Hb 170g/L in men or 150gL in women or a PCV haematocrit in men or >0.45 in women is indicative of polycythaemia.The concentration of red cells in the blood is reflected by Haemoglobin and packed cell volume - thus, they can be comparatively high in dehydration.Nevertheless, a total increase in the red cell mass is clearly a symptom of polycythaemia, or erythrocytosis.
True polycythaemia could be primary or secondary.The Secondary causes result in polycythaemia either by causing hypoxia (and for this reason stimulation to increase red cell production) or by increasing levels of erythropoietin (the hormone stimulating red cell producing) - eg: tumours.
Primary polycythaemia is known as Polycythaemia rubra vera, or simply polycythaemia vera which is a type of abnormal bone marrow growth.
Primary polycythaemia (Polycythaemia rubra vera/ Erythremia)
People who suffer from physiologic polycythemia, have a pathological state known as polycythemia vera.Under this condition the red blood cell count may be 7 to 8 million/mm3 and the hematocrit may be 60 to 70 percent than the normal 40 to 45 percent.
The genetic aberration in the hemocytoblastic cells that produce the blood cells cause Polycythemia vera.The blast cells stops producing red cells as there are too many cells already present.This triggers an excess production of red blood cells in a similar way that a breast tumor causes excess production of a specific kind of breast cell.In addition, it most often causes excess production of white blood cells and platelets.In polycythemia vera, it is not only the hematocrit that increases, but also the total blood volume.On certain occasions it increases to approximately twice the normal.Thus, the entire vascular system becomes extremely distended. In addition, many blood capillaries get blocked by the viscous blood; the viscosity of the blood in polycythemia vera sometimes increases from the natural level of 3 times the viscosity of water to 10 times that of water.
Many high-oxygen affinity haemoglobin mutants (HOAHM) have been described which causes increased oxygen affinity but decreases oxygen delivery to the tissues, resulting in compensatory polycythaemia.A congenital autosomal recessive disorder (Chuvasch 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 an 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.
Hypoxia is O2 deficiency at the tissue level. It is a more acceptable term than anoxia, with a no O2 condition in the tissues. There are four types,
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.
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.
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. The liver and maybe the brain are damaged by hypoperfusion 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.
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.
Other causes for Hypoxia
Major causes include heart attack, asthma, pulmonary embolism, severe head injuries,chronic alveolar hypoventilation, carbon monoxide poisoning, suffocation and choking.Circumstances under which the body is deprived of oxygen can result in hypoxia. If the body does not receive the necessary amount of oxygen, this will lead to a low oxygen partial pressure in arterial blood. This leads to hypoxic hypoxia. The main causes of hypoxic hypoxia-altitude mountaineering, insufficient ventilation or heart-failure mechanism. It can also occur due to shunts in the pulmonary circulation of the heart. Collapsed alveoli in the lungs may also shunts.
Anoxia results in the absence of oxygen. In hypemic hypoxia, there is an obstruction in oxygen distribution through the blood . This is caused by carbon monoxide poisoning. If the required amount of oxygen reaching the cells is not effectively used by some disturbance in the cells, it causes histotoxic hypoxia. Stagnant hypoxia occurs when something obstructs flow of blood carries a sufficient amount of oxygen.
The symptoms and signs of hypoxia
Generalized hypoxia symptoms depends on the severity and frequency accelerated. In the case of altitude sickness, hypoxia progressive development, symptoms include headache, fatigue, shortness of breath, the feeling of excitement and nausea. In severe hypoxia, hypoxia occur 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 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 the oxygen from another molecule, such as carbon monoxide shift in the skin cherry ', instead can appear cyanosis.
This can be a fatal condition. If someone is suffering from this condition, it is vital to open up the airway by assisted breathing. The individual should instantly be taken to a hospital, where he should be put on a ventilator to assist in breathing. The blood pressure and heart rate should be monitored constantly. The blood pressure and the pulse should be regularized with the help of fluids or medicines. Seizures, if any, should be suppressed. Sometimes cold blankets are used as they slow down the activity of the brain cells and decrease the need of oxygen.
In case this situation arises while climbing or living at high altitudes, one should disengage themselves from those activities and take plenty of fluids. After resting, one should climb down to a position where the body starts receiving more oxygen. In case of hypoventilation, the patient should be made to sit or rest in a moderately high position. This will allow the oxygen to reach the lungs and overcome low oxygen levels. These patients are given supplemental oxygen therapy and are asked to wear a face mask connected to an oxygen cylinder. Blood transfusions are given to patients with hypoxemic hypoxia which helps in increasing the oxygen-carrying capacity of the blood.
The patient should be given proper medications and the critical signs such as cardiac rate, respiratory rate, blood pressure and temperature should be monitored regularly. During the path to recovery, the patient may experience amnesia, personality regression, hallucinations, memory loss, muscle spasms and twitches. In a situation where the brain has not been deprived of oxygen for a long period recovery is a possibility. Therefore, giving enough air and medical aid to the person suffering from it is necessary.
Quick medical attention and treatment should be sought. The patient should be given essential life support and his/her breathing rate has to be maintained. Intravenous medications should be given which helps in prevention of seizures and speeds up blood pressure. Thus, to save a life or prevent serious complications, medical intervention is very important.
The tissues become hypoxic because of the lack of oxygen in the breathed air for example at high altitudes, or because of failure of oxygen delivery to the tissues and in such conditions cardiac failure, the blood-forming organs automatically produce huge quantities of extra red blood cells. This condition is known as secondary polycythemia, and the red cell count generally rises to 6 to 7 million/mm3,about 30 per cent above normal. A common type of secondary polycythemia, called physiologic polycythemia, is a common among the natives who live at altitudes of 14,000 to 17,000 feet, where the atmospheric oxygen is very low. The blood count is generally 6 to 7 million/mm3 at such altitudes and this allows these people to perform at reasonably high levels of constant work even in a complex environment.
Statistics on Polycythaemia
Secondary polycythaemia has become a common disease, as there are a large number of conditions 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.
Normal ranges of hematocrit, red cell counts, and hemoglobin
Hematocrit is the ratio of the volume of red cells to the volume of whole blood. The general level for hematocrit varies between sexes and is approximately 45% to 52% for men and 37% to 48% for women.
The number of red blood cells in a volume of blood is signified by the red cell count. The normal range for men is approximately 4.7 to 6.1 million cells/ul (microliter). The normal range for women ranges from 4.2 to 5.4 million cells/ul, according to National Institutes (NIH) of Healthdata. Hemoglobin is a protein in the red blood cells that carries oxygen and gives blood its red color. The average range for hemoglobin may differ between the sexes and is approximately 13 to 18 grams per deciliter for men and 12 to 16 grams per deciliter for women.
Polycythemia Secondary Causes
Contrary to primary polycythemia in which overproduction of red blood cell results from increased sensitivity or responsiveness to erythropoetin(EPO) (often with lower than normal levels of EPO), in secondary polycythemia, more red cells are produced because of high levels of circulating EPO.
Chronic hypoxia (poor blood oxygen levels over the long-term), poor oxygen delivery due to abnormal red blood cell structure, and tumors releasing inappropriately high amounts of EPO.55555 are the causes of the higher than normal EPO levels.
Efforts to understand the molecular basis of oxygen-regulated erythropoiesis have led to the identification of EPO, which is essential for normal erythropoiesis and to the purification of hypoxia-inducible factor (HIF), the transcription factor that controls EPO synthesis and mediates cellular adaptation to hypoxia. A classic physiologic response to hypoxia in humans is the up-regulation of the EPO gene, which is the central regulator of red blood cell mass. Hypoxia inducible factor triggers the EPO gene. HIF is a transcription factor which consists an alpha subunit (HIF-alpha) and a beta subunit (HIF-beta). Under normoxic conditions, prolyl hydroxylase domain protein (PHD, also known as HIF prolyl hydroxylase and egg laying-defective nine protein) site specifically hydroxylates HIF-alpha in a conserved LXXLAP motif (where underlining indicates the hydroxylacceptorproline). This provides a recognition motif for the von Hippel Lindauprotein, a component of an E3 ubiquitin ligase complex that targets hydroxylated HIF-alpha for degradation. Under hypoxic conditions, this inherently oxygen-dependent modification is arrested, thereby stabilizing HIF-alpha and allowing it to activate the EPO gene. We previously identified and characterized an erythrocytosis-associated HIF2A mutation, G537W. More recently, two additional erythrocytosis-associated HIF2A mutations, G537R and M535V were reported. Here, we describe the functional characterization of these two mutants as well as a third novel erythrocytosis-associated mutation, P534L. These mutations affect residues C-terminal to the LXXLAP motif. Erythropoetin is another kidney hormone released as a result of hypoxic condition. As the main regulatory factor of erythropoiesis. Erythropoietin, or its alternatives erythropoetin or erthropoyetin or EPO, is a glycoprotein hormone that
controls erythropoiesis, or red blood cell production. It is a cytokine (protein signaling molecule) for erythrocyte (red blood cell) precursors in the bone marrow.
Also known as hematopoietin or hemopoietin, it is produced by interstitial fibroblasts in the kidney in close association with peritubular capillary and tubular epithelial cells. It is also produced in perisinusoidal cells in the liver. While liver production predominates in the fetal and perinatal period, renal production is predominant during adulthood. Erythropoietin is the hormone that regulates red blood cell production. It also has other biological functions. For example, erythropoietin plays a vital role in the brain's response to neuronal injury. EPO is also involved in the wound healing process.
When exogenous EPO is used as a performance-enhancing drug, it is classified as an erythropoiesis-stimulating agent (ESA). Exogenous EPO can often be detected in blood, due to a small difference from the endogenous protein, for example in features of posttranslational modification.
Erythropoetin increases the production of red blood cells with the main exception of some forms of anemia. Polycythaemia is useful after blood loss but harmful (increased blood viscosity) in pulmonary and heart disease.
Some of the common conditions that can result in elevated erythropoietin due to chronic hypoxia or poor oxygen supply include:
chronic obstructive pulmonary disease (COPD, emphysema, chronic bronchitis),
congestive heart failure,
obstructive sleep apnea,
poor blood flow to the kidneys, and
living in high altitudes.
2,3-BPG deficiency is a condition in which the hemoglobin molecule in the red blood cells has an abnormal structure. In this condition, hemoglobin has a higher affinity to hold on to oxygen and is less likely to release it to the tissues. This results in more red blood cells being produced in response to what the tissues in the body perceive as an inadequate oxygen level. The outcome is more circulation of red blood cells.
Some tumors have a tendency to secrete inappropriately high amounts of EPO, leading to polycythemia. The common EPO-releasing tumors are:
(liver cancer hepatocellular carcinoma)
(kidney cancer (renal cell carcinoma) cancer
adrenal adenoma or adenocarcinoma, and
Furthermore there are benign conditions that may increase EPO secretion, such as kidney cysts and kidney obstruction.
Chronic carbon monoxide exposure can also lead to polycythemia. Hemoglobin obviously has a higher affinity for carbon monoxide than for oxygen. Therefore, when carbon monoxide molecules and hemoglobin mingles, polycythemia (increased red cell and hemoglobin production) could take place with the purpose of compensating for the poor oxygen delivery by the available hemoglobin molecules. Long-term cigarette smoking causes similar effects on people.
Polycythemia in newborns (neonatal polycythemia) is often caused by transfer of maternal blood from the placenta or blood transfusions. Prolonged poor oxygen delivery to the fetus (intrauterine hypoxia) due to insufficiency of the placenta can also lead to neonatal polycythemia
Symptoms of polycythemia can vary widely. While some people show symptoms of the disease the others do not visibly show any symptoms.
In secondary polycythemia, most of the symptoms are related to the underlying condition responsible for polycythemia.
Symptoms of polycythemia vera can be vague and quite common. Some of the important symptoms include:
blood clot formation (potentially leading to heart attacks, strokes, blood clots in the lungs pulmonary embolism:
bone and joint pain (hip pain or rib pain);
itching after taking a shower or bath (post-bath pruritus);
Effect of Polycythemia on Function of the Circulatory System
Because of the greatly increased viscidness of the blood in polycythemia, blood flow through the peripheral blood vessels is often very sluggish. According to the factors that regulate the return of blood to the heart, as discussed in Chapter 20, increasing blood viscosity reduces the rate of venous return to the heart. Conversely, the blood volume is greatly increased in polycythemia, which tends to increase venous return. In fact, the cardiac output in polycythemia is almost close normal, because these two factors more or less neutralize each other. The arterial pressure normally ranges at a normal level in most people with polycythemia, although in about one third of them, the arterial pressure is elevated. This means that the blood pressure-regulating mechanisms can usually counterbalance the tendency for increased blood viscosity to increase peripheral resistance and, in this manner, increase arterial pressure. Beyond certain limits, however, these guidelines fail, and hypertension develops. The color of the skin depends to a great degree on the quantity of blood in the skin sub papillary venous plexus. In polycythemia vera, the quantity of blood in this plexus is greatly increased. Further, because the blood passes sluggishly through the skin capillaries before entering the venous plexus, a larger than normal quantity of hemoglobin is deoxygenated. The blue color of all this deoxygenated hemoglobin masks the red color of the oxygenated hemoglobin. Therefore, a person with polycythemia vera ordinarily has a ruddy complexion with a bluish (cyanotic) tint to the skin.
Exams and Tests
In many situations, polycythemia may be recognized incidentally in routine blood work ordered by a physician for an unrelated medical reason. This may then call for further investigation to find the source of polycythemia.
A comprehensive medical history, physical examination, family history, and social and occupational history are very important factors in evaluating a patient suffering from polycythemia. In the physical exam, in depth attention may be paid to the heart and lung exam. A spleen (splenomegaly) is one of the prominent features of polycythemia vera; hence, a careful abdominal exam to evaluate for an inflamed spleen is essential.
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.
In polycythemia vera, usually other blood cells are also affected, represented by an unusually high number of white blood cells (leukocytosis) and platelets (thrombocytosis). Bone marrow examinations (bone marrow aspiration or biopsy) are sometimes necessary to examine blood cell production in the bone marrow. Guidelines also recommend checking for the JAK2 gene mutation as a diagnostic criterion for polycythemia vera.
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.
Distinguishing Polycythemia Vera from Pathologic Secondary Erythrocytosis
The traditional consensus diagnostic criteria for polycythemia vera were (a) an increased quantity 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 (>400,000/mm3, WBC count (>12,000/mm3,leukocyte alkaline phosphatase level, 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. Such testing can be expensive and should be limited to patients with a reasonable pretest probability of having the disease (e.g., manifesting at least one or two of the characteristic features in addition to an elevated hematocrit, such as generalized pruritus after bathing, splenomegaly, persistent leukocytosis, persistent thrombocytosis, or atypical thrombosis).
Traditionally, either direct measurement of red cell mass or an estimation based on red cell volume was considered necessary for diagnosis; however, this measurement is expensive and often not readily available, and it does not distinguish between polycythemia vera and pathologic secondary erythrocytosis, the most important differentiation that needs to be made. The determination of serum erythropoietin is very useful in helping to make the distinction. A high erythropoietin level virtually rules out polycythemia vera and suggests secondary erythrocytosis because erythropoietin production should be suppressed in polycythemia vera. A low erythropoietin level strongly supports the diagnosis of polycythemia vera while ruling out pathologic secondary erythrocytosis (which is driven by excess erythropoietin production).
If the erythropoietin level is normal (which can occur in mild disease, after phlebotomy, and with secondary disease), then a bone marrow biopsy is indicated. If the histology is characteristic of polycythemia vera (hypercellularity, increased number of megakaryocytes, giant megakaryocytes, mild reticulin fibrosis, decreased marrow iron stores), then the diagnosis can be considered confirmed. In the few instances in which diagnosis remains elusive, platelets can be tested for the expression of thrombopoietin receptor protein, which is deficient in polycythemia vera. Testing granulocytes for the polycythemia vera-1 gene, which appears to be unique to the condition, is another option available in some centers. Others perform in vitro testing of erythroid stem cells, which manifest colony growth in the absence of exogenous erythropoietin.
Treatment of secondary polycythemia depends on its cause. Supplemental oxygen can be provided for individuals with chronic hypoxia. Other therapies can be directed towards treating the cause of polycythemia (for example, appropriate treatment of heart failure or chronic lung disease).
Treatments for primary polycythemia play an important role in improving the outcome of the disease and will be discussed in the following sections.
Phlebotomy (blood letting) remains the basic of therapy for polycythemia vera. The goal of phlebotomy is to keep the hematocrit around 45% in men and 42% in women. Initially, it may be necessary to do phlebotomy every 2 to 3 days and remove 250 to 500 milliliters of blood each session. Once the goal is reached, maintaining phlebotomy can be performed less frequently.
A commonly recommended medication for the treatment of polycythemia is called hydroxyurea (Hydrea). This is especially prescribed for people who are at the risk of clot formation. At an age more than 70, having both an elevated platelet count (thrombocytosis) greater than 1.5 million and cardiovascular disease makes the use of hydroxyurea more favorable. Hydroxyurea is also recommended for patients who are unable to tolerate phlebotomy.
Aspirin has also been used in treating polycythemia to lower the risk of clotting (thrombotic) events. Its use is generally avoided in those people with any bleeding history. Aspirin is usually used in conjunction with phlebotomy.
Many causes of secondary polycythemia are not preventable. However, some potential preventive measures are:
avoid prolonged carbon monoxide exposure; and
appropriate management of diseases such as chronic lung disease, heart disease or obstructive sleep apnea.
Primary polycythemia due to mutation of genes is generally not preventable.
Outlook (prognosis) for polycythemia
The outlook of polycythemia depends on the underlying cause. Overall the general outlook is favorable for people suffering from this disease especially those with secondary causes. The outlook for primary polycythemia is fair; while it is typically incurable and long standing, for many people, it is controllable and treatable. For example, untreated, polycythemia vera (PV) was initially thought to have a poor diagnosis with a life expectancy of one to two years from the time of diagnosis. However, polycythemia vera prognosis is now greatly improved to 10-15 years survival after diagnosis with treatment by phlebotomy alone. The addition of medications, such as, hydroxyurea or aspirin may improve the chances of survival even to a greater degree.