Internal Medicine/Anemia and Polycythemia

Hamatopoiesis
Hematopoiesis is the process through which the various components of blood are manufactured in the body. It is a carefully orchestrated sequence that originates with hematopoietic stem cells, capable of producing a wide array of blood cells, including red blood cells, different white blood cells, platelets, and immune system cells. The exact genetic mechanisms governing the stem cell's commitment to a specific blood cell lineage remain incompletely understood.

In mice, it has been observed that erythroid cells, the precursors of red blood cells, stem from a common erythroid/megakaryocyte progenitor, which depends on the expression of specific transcription factors like GATA-1 and FOG-1. As the differentiation process unfolds, hematopoietic progenitor and precursor cells become increasingly subject to the control of growth factors and hormones. In the context of red blood cell production (erythropoiesis), the hormone erythropoietin (EPO) plays a principal role. EPO is necessary for the survival of committed erythroid progenitor cells; without it, these cells undergo programmed cell death (apoptosis). The entire regulated process of red blood cell production is termed erythropoiesis.

Within the bone marrow, the earliest identifiable erythroid precursor is the pronormoblast. It can undergo multiple cell divisions, ultimately yielding 16 to 32 mature red blood cells. Enhanced production of EPO or EPO administration as a medical treatment can boost the number of early progenitor cells, which in turn leads to an increased output of red blood cells. The regulation of EPO production is intrinsically linked to tissue oxygen levels.

In mammals, oxygen is transported to tissues by binding to hemoglobin within red blood cells. Mature red blood cells lack a nucleus, are disk-shaped, about 8 μm in diameter, and are highly flexible to navigate through tiny blood vessels. The cells generate ATP internally to maintain their membrane integrity. Normal red blood cell production replaces approximately 0.8-1% of the body's circulating red blood cells every day, as the average red blood cell lives for about 100-120 days. The system responsible for red blood cell production is called the erythron, which consists of a rapidly proliferating pool of bone marrow erythroid precursor cells and a large population of circulating mature red blood cells. The size of the erythron reflects the equilibrium between the production and destruction of red blood cells. Understanding the physiological mechanisms behind red blood cell production and destruction is crucial for comprehending the causes of anemia.

The hormone EPO is the central regulator of red blood cell production and is produced and released primarily by specialized cells lining the capillaries in the kidneys, known as peritubular capillary lining cells. A smaller amount of EPO is produced by hepatocytes in the liver. The primary trigger for EPO production is the availability of oxygen to meet the metabolic needs of body tissues. A key element in EPO gene regulation is hypoxia-inducible factor (HIF)-1α. When oxygen is plentiful, HIF-1α is hydroxylated, leading to its degradation via the proteasome pathway. But when oxygen is limited, this critical hydroxylation step does not occur, allowing HIF-1α to activate the EPO gene and others.

Factors that can impair kidney oxygen delivery include a decreased red blood cell mass (anemia), difficulties with oxygen loading onto hemoglobin or the presence of high-affinity mutant hemoglobin (hypoxemia), or in rare cases, impaired blood flow to the kidney (e.g., renal artery stenosis). EPO governs day-to-day red blood cell production, and its levels in the bloodstream can be measured with sensitive immunoassays, with normal levels ranging from 10-25 U/L. As hemoglobin levels drop below 10-12 g/dL, plasma EPO levels rise in proportion to the severity of the anemia. In circulation, EPO has a half-clearance time of 6-9 hours. EPO acts by binding to specific receptors on bone marrow erythroid precursors, stimulating their proliferation and maturation. Under EPO stimulation, red blood cell production can increase significantly over a period of 1-2 weeks, provided there are adequate nutrients, especially iron, available. Hence, the proper functioning of the erythron relies on the normal production of EPO by the kidneys, a functional erythroid marrow, and an adequate supply of materials for hemoglobin synthesis. A deficiency in any of these key components can lead to anemia. Typically, anemia is identified in the laboratory when a patient's hemoglobin or hematocrit levels fall below expected values for their age and sex.

To initially categorize anemia, essential elements of erythropoiesis—EPO production, iron availability, bone marrow's ability to produce red blood cells, and effective maturation of red cell precursors—are used as reference points.

Clinical Manification of Anemia
Clinical manifestations of anemia are typically identified through abnormal results in routine laboratory tests, as patients with advanced anemia and its related symptoms are less frequently encountered. Acute anemia is typically caused by blood loss or hemolysis. When blood loss is minimal, the body compensates for reduced oxygen levels by modifying the oxygen-hemoglobin dissociation curve, primarily driven by a drop in pH or an increase in CO2 (known as the Bohr effect). In cases of acute blood loss, the most prominent issue is hypovolemia, overshadowing hematocrit and hemoglobin levels, which do not accurately reflect the amount of blood lost. Clinical indications of vascular instability emerge when there is an acute loss of 10-15% of the total blood volume. In such cases, the primary concern is not anemia but rather hypotension and reduced organ perfusion. When more than 30% of the blood volume is lost suddenly, the usual mechanisms of vascular contraction and regional blood flow changes fail to compensate. Patients tend to prefer a supine position and may exhibit postural hypotension and increased heart rate. If blood loss exceeds 40% (equivalent to more than 2 liters in an average-sized adult), signs of hypovolemic shock manifest, including confusion, difficulty breathing, profuse sweating, low blood pressure, and rapid heart rate. Such patients have significant deficits in vital organ perfusion and require immediate volume replacement.

In the case of acute hemolysis, the symptoms and signs vary based on the mechanism leading to the destruction of red blood cells. Intravascular hemolysis, with the release of free hemoglobin, can be associated with sudden back pain, the presence of free hemoglobin in the plasma and urine, and renal failure. For chronic or slowly progressive anemia, the symptoms experienced depend on the patient's age and whether critical organs are receiving an adequate blood supply. Symptoms associated with moderate anemia typically include fatigue, reduced stamina, shortness of breath, and an increased heart rate, especially during physical exertion. However, due to the body's built-in compensatory mechanisms that govern the oxygen-hemoglobin dissociation curve, the gradual onset of anemia, especially in young patients, may not display signs or symptoms until the anemia becomes severe (hemoglobin levels drop below 70-80 g/L or 7-8 g/dL). When anemia develops over days or weeks, the total blood volume remains normal to slightly increased, and adjustments in cardiac output and regional blood flow help compensate for the overall loss in oxygen-carrying capacity. Some of the compensatory responses to anemia are due to changes in the position of the oxygen-hemoglobin dissociation curve. In chronic anemia, intracellular levels of 2,3-bisphosphoglycerate increase, causing the dissociation curve to shift to the right, facilitating the unloading of oxygen. However, this compensatory mechanism can only maintain normal tissue oxygen delivery in the face of a 20-30 g/L (2-3 g/dL) hemoglobin deficit.

Furthermore, protection of oxygen delivery to vital organs is achieved by diverting blood away from organs that have relatively abundant blood supply, particularly the kidneys, gut, and skin.

Several medical conditions are commonly linked to anemia. Chronic inflammatory states (e.g., infection, rheumatoid arthritis, cancer) often result in mild to moderate anemia, while lymphoproliferative disorders such as chronic lymphocytic leukemia and specific B-cell neoplasms may lead to autoimmune hemolysis.

Diagnosis of Anemia
Evaluating a patient with anemia requires a thorough examination of their medical history and a physical assessment. This assessment should also include an exploration of the patient's nutritional history, drug or alcohol use, and family history of anemia. Additionally, it's important to consider certain geographic and ethnic backgrounds, as they can be associated with a higher risk of inherited hemoglobin or intermediary metabolism disorders. For instance, individuals of Middle Eastern or African descent, including those of African descent, have a higher prevalence of conditions like glucose-6-phosphate dehydrogenase (G6PD) deficiency and specific hemoglobinopathies. Other valuable information to gather includes potential exposure to toxic substances or drugs, as well as symptoms related to disorders commonly linked to anemia. These symptoms and signs may encompass bleeding, fatigue, general weakness, fever, unexplained weight loss, night sweats, and other systemic symptoms. Physical examination findings that may offer clues to the underlying cause of anemia include signs of infection, the presence of blood in the stool, lymph node enlargement (lymphadenopathy), an enlarged spleen (splenomegaly), or small, reddish-purple spots on the skin (petechiae). Splenomegaly and lymphadenopathy may suggest underlying lymphoproliferative diseases, whereas petechiae may indicate platelet dysfunction. Past laboratory test results can also provide insights into the timeline of the anemia's onset.

In an anemic patient, a physical examination might reveal a strong heartbeat, robust peripheral pulses, and a systolic "flow" murmur. If hemoglobin falls below 8-10 g/dL (80-100 g/L), the skin and mucous membranes could appear pale. It's essential to focus the examination on areas where blood vessels are close to the surface, such as the mucous membranes, nail beds, and the palmar creases. An indication of anemia might be when the palmar creases are lighter in color than the surrounding skin when the hand is hyperextended.

Laboratory Assessment
A standard complete blood count (CBC) is a crucial part of the evaluation and includes measurements of hemoglobin, hematocrit, and red cell indices: mean cell volume (MCV), mean cell hemoglobin (MCH), and mean cell hemoglobin concentration (MCHC). MCH is the least useful of these indices and typically mirrors MCV. Numerous physiological factors can influence the CBC, including age, gender, pregnancy, smoking, and altitude. High-normal hemoglobin levels can be observed in individuals living at high altitudes or heavy smokers due to the replacement of oxygen by carbon monoxide (CO) in hemoglobin binding. Additional valuable information is derived from the reticulocyte count and iron-related measurements, such as serum iron, total iron-binding capacity (TIBC), serum transferrin, and serum ferritin. Significant deviations in red cell indices are typically indicative of maturation disorders or iron deficiency. A careful analysis of the peripheral blood smear is essential, and clinical laboratories often provide descriptions of both red and white blood cells, a white blood cell differential count, and the platelet count. In cases of severe anemia and irregularities in red cell morphology or a low reticulocyte count, a bone marrow aspirate or biopsy may be necessary for diagnosis. Additional tests that may be helpful in diagnosing specific anemias are discussed in chapters focusing on specific disease states.

The components of the CBC also aid in classifying anemia. Microcytosis is indicated by an MCV below the normal range (<80), while values above the normal range (>100) indicate macrocytosis. Hypochromia, reflecting defects in hemoglobin synthesis, is mirrored by MCHC. Automated cell counters provide data on the red cell volume distribution width (RDW), but the MCV, representing the peak of the distribution curve, may not always detect small populations of macrocytes or microcytes. Experienced laboratory technicians can often identify minor populations of unusually large or small cells or hypochromic cells on the peripheral blood film before the red cell indices change.

Peripheral Blood Smear
The peripheral blood smear is a valuable tool for detecting defects in red cell production. Alongside the red cell indices, it reveals variations in cell size (anisocytosis) and shape (poikilocytosis). The degree of anisocytosis is usually linked to changes in RDW or the range of cell sizes. Poikilocytosis suggests issues in the maturation of red cell precursors in the bone marrow or the fragmentation of circulating red cells. The blood smear might also show polychromasia, which represents red cells that are slightly larger than normal and appear bluish-gray when stained with Wright-Giemsa stain. These cells are reticulocytes that have been prematurely released from the bone marrow and their color indicates residual ribosomal RNA. They enter the bloodstream in response to erythropoietin (EPO) stimulation or due to structural damage in the bone marrow (such as fibrosis or infiltration by malignant cells) that leads to their unregulated release. The presence of nucleated red cells, Howell-Jolly bodies, target cells, sickle cells, and other variations can offer hints regarding specific disorders.

Reticulocyte Count
An accurate reticulocyte count plays a crucial role in the initial classification of anemia. Reticulocytes are red cells that have been recently released from the bone marrow. They can be identified through staining with a supravital dye that precipitates ribosomal RNA. These precipitates appear as blue or black punctate spots and can be counted manually or with modern techniques involving fluorescent dyes that bind to RNA. This residual RNA is metabolized within the first 24-36 hours of a reticulocyte's lifespan in circulation. Under normal circumstances, the reticulocyte count ranges from 1% to 2% and represents the daily replacement of approximately 0.8-1.0% of the circulating red cell population. A corrected reticulocyte percentage or the absolute number of reticulocytes provides a reliable measure of effective red cell production.

To estimate the marrow's response based on the reticulocyte count, two corrections are necessary. The first correction adjusts the reticulocyte count based on the reduced number of circulating red cells. In cases of anemia, the percentage of reticulocytes may appear elevated while the absolute number remains constant. This correction factor takes into account the patient's hemoglobin or hematocrit relative to the expected hemoglobin/hematocrit for their age and sex. This provides an estimate of the reticulocyte count corrected for anemia. To convert the corrected reticulocyte count into an index of marrow production, an additional correction is needed, which depends on whether some of the reticulocytes in circulation have been released prematurely from the bone marrow. For this second correction, the peripheral blood smear is examined to check for the presence of polychromatophilic macrocytes. These cells, representing prematurely released reticulocytes, are referred to as "shift" cells, and the relationship between the degree of shift and the necessary shift correction factor is detailed in a figure. The correction is necessary because these prematurely released cells remain in circulation as reticulocytes for more than a day, leading to a falsely high estimate of daily red cell production. If polychromasia is increased, the reticulocyte count, which is already corrected for anemia, should undergo an additional correction by a factor of 2, accounting for the prolonged reticulocyte maturation time. A correction factor of 2 is often used for simplicity. If the blood smear does not show polychromatophilic cells, the second correction is unnecessary. The reticulocyte count, now doubly corrected, becomes the reticulocyte production index, offering an estimate of marrow production relative to the normal range. In many hospital laboratories, the reticulocyte count is reported as both a percentage and an absolute number, in which case no correction for dilution is required.

Premature release of reticulocytes usually occurs due to heightened EPO stimulation. However, when the integrity of the bone marrow release process is compromised by tumor infiltration, fibrosis, or other disorders, the presence of nucleated red cells or polychromatophilic macrocytes should still trigger the second reticulocyte correction. The shift correction should be consistently applied to patients with anemia and very high reticulocyte counts to provide an accurate index of effective red cell production. In cases of severe chronic hemolytic anemia, red cell production can increase by as much as six- to sevenfold. This alone confirms that the patient has a proper EPO response, a normally functioning bone marrow, and sufficient iron for new red cell formation. If the reticulocyte production index falls below 2 in the context of established anemia, a defect in erythroid marrow proliferation or maturation must be present.

Tests for Iron Supply and Storage
Laboratory measurements that reflect the availability of iron for hemoglobin synthesis include serum iron, total iron-binding capacity (TIBC), percent transferrin saturation, and serum ferritin. Percent transferrin saturation is calculated by dividing serum iron levels by TIBC and then multiplying by 100. Normal serum iron levels range from 9 to 27 μmol/L (50-150 μg/dL), while TIBC ranges from 54 to 64 μmol/L (300-360 μg/dL), and the normal transferrin saturation is 25-50%. There is a diurnal variation in serum iron levels, leading to changes in percent transferrin saturation. Serum ferritin is used to assess overall body iron stores. In adult males, the average serum ferritin levels are around 100 μg/L, representing iron stores of about 1 gram. Premenopausal adult females have lower serum ferritin levels, averaging around 30 μg/L, reflecting lower iron stores of around 300 mg. A serum ferritin level of 10-15 μg/L indicates depletion of body iron stores. It's important to note that ferritin is also an acute-phase reactant and, in the presence of acute or chronic inflammation, its levels may rise significantly. Typically, a serum ferritin level exceeding 200 μg/L suggests the presence of some iron in tissue stores.

Bone Marrow Examination
In certain cases, a bone marrow aspirate, smear, or needle biopsy can be helpful in evaluating patients with anemia. Patients with hypoproliferative anemia, normal renal function, and normal iron status may require a bone marrow examination. This assessment can help diagnose primary marrow disorders like myelofibrosis, defects in red cell maturation, or infiltrative diseases. An evaluation of the balance between different cell lineages (myeloid vs. erythroid) in a bone marrow smear is obtained through a differential count of nucleated cells, referred to as the myeloid/erythroid (M/E) ratio. In patients with hypoproliferative anemia and a reticulocyte production index below 2, an M/E ratio of 2 or 3:1 is expected. In contrast, patients with hemolytic diseases and a production index exceeding 3 are likely to have an M/E ratio of at least 1:1. Maturation disorders are identified through the discrepancy between the M/E ratio and the reticulocyte production index. Either the bone marrow smear or biopsy can be stained to assess the presence of iron stores or iron in developing red cells. Iron stores are typically found in the form of ferritin or hemosiderin. Small ferritin granules can normally be seen under oil immersion in 20-40% of developing erythroblasts on carefully prepared bone marrow smears. These cells are called sideroblasts.

Classification of Anemia
Anemia is a complex and multifaceted medical condition, with a wide array of underlying causes and manifestations. It's essentially a deficiency in the number of red blood cells or a decrease in the quality or quantity of hemoglobin in the blood. These red blood cells are essential for transporting oxygen from the lungs to the body's tissues and organs. When anemia occurs, it can lead to a range of symptoms and health issues, depending on its severity and root causes.

To fully understand and classify anemia, medical professionals employ a functional classification that divides it into three major categories:


 * 1) Marrow Production Defects (Hypoproliferation): This category is marked by a low reticulocyte production index, indicating that the bone marrow isn't generating red blood cells at an adequate rate in response to the anemia. Moreover, there's little to no significant change in the morphology of the red blood cells. Consequently, this type of anemia results in a normocytic and normochromic anemia, where the size and hemoglobin content of red blood cells appear to be within the normal range.
 * 2) * The majority of hypoproliferative anemias can be traced back to underlying causes like iron deficiency, chronic inflammation, marrow damage due to factors such as drug toxicity, or inadequate stimulation by erythropoietin (EPO) because of issues like renal dysfunction.
 * 3) * In these cases, red blood cells often exhibit characteristics typical of a normocytic, normochromic anemia, with the red blood cells appearing to be of normal size and hemoglobin content. However, there can be instances where microcytic, hypochromic cells emerge, particularly in cases of mild iron deficiency or prolonged chronic inflammatory conditions.
 * 4) * The diagnostic process for these anemias usually involves a battery of tests, including assessments of serum iron, iron-binding capacity, renal function, thyroid function, and a possible bone marrow examination to determine the presence of damage or infiltrative diseases. Additionally, serum ferritin is measured to gauge iron stores within the body.
 * 5) Red Cell Maturation Defects (Ineffective Erythropoiesis): This class of anemias presents with a reticulocyte production index that is somewhat elevated when compared to normal values. This elevated index is accompanied by the appearance of macrocytic or microcytic red cell indices on a peripheral blood smear. Macrocytic anemia is characterized by the presence of larger-than-normal red blood cells, while microcytic anemia features smaller cells with less hemoglobin.
 * 6) * Nuclear maturation defects can be linked to various causes, such as deficiencies in vitamin B12 or folic acid, damage due to specific drugs, or myelodysplastic syndromes. Medications that interfere with cellular DNA synthesis, including methotrexate or alkylating agents, can induce a nuclear maturation defect. Alcohol, when consumed excessively, may lead to macrocytosis and anemia, often related to folic acid deficiency.
 * 7) * Anemia arising from a deficiency in vitamin B12 or folic acid typically falls under the category of macrocytic anemia, characterized by larger-than-normal red blood cells. To pinpoint the specific cause of these anemias, the measurement of folic acid and vitamin B12 levels is critical since these reflect different pathogenetic mechanisms.
 * 8) * In contrast, cytoplasmic maturation defects often result from severe iron deficiency or abnormalities in globin or heme synthesis. Here, iron deficiency occupies an interesting position in the classification of anemia. Mild to moderate iron deficiency leads to a blunted erythroid marrow response and is thus classified as hypoproliferative. However, if iron deficiency becomes severe and prolonged, the erythroid marrow's proliferation becomes hyperplastic, and the anemia is categorized as ineffective erythropoiesis with a cytoplasmic maturation defect.
 * 9) * In both cases, the reticulocyte production index is inappropriately low, and a peripheral blood smear typically reveals either macrocytosis or microcytosis and hypochromia. Specialized iron studies help in distinguishing iron deficiency from other cytoplasmic maturation defects, such as the thalassemias.
 * 10) Decreased Red Cell Survival (Blood Loss/Hemolysis): Anemia resulting from reduced red cell survival, which can occur due to blood loss or hemolysis (the premature destruction of red blood cells), exhibits an increased reticulocyte production index, often exceeding 2.5 times normal values. This elevation of the index signals the bone marrow's response to compensate for the rapid loss of red blood cells.
 * 11) * Blood loss anemia can manifest as either acute or chronic, with acute cases usually marked by a reticulocyte production index that's not significantly elevated. This is because it takes some time for the body to respond to the sudden decrease in red blood cell count by increasing erythropoiesis.
 * 12) * Subacute blood loss, on the other hand, may result in modest reticulocytosis as the body starts to compensate for the loss of red blood cells.
 * 13) * The evaluation of blood loss anemia is typically less challenging than other forms of anemia. However, complications may arise when a patient presents with an increased red cell production index as a result of an episode of acute blood loss that went unrecognized.
 * 14) * Hemolytic disease, on the other hand, is among the least common forms of anemia. Hemolysis leads to a high reticulocyte production index, reflecting the bone marrow's ability to compensate for the loss of red blood cells. The extent of this response depends on the severity of the anemia and the nature of the underlying disease.
 * 15) * Hemoglobinopathies, like sickle cell disease and the thalassemias, often present a mixed picture. The reticulocyte index may be high, but it is inappropriately low for the degree of marrow erythroid hyperplasia.
 * 16) * Hemolytic anemias can present in various ways. Some occur suddenly as acute, self-limited episodes of intravascular or extravascular hemolysis, often observed in patients with autoimmune hemolysis or inherited defects in specific metabolic pathways. On the other hand, individuals with chronic hemolytic diseases, such as hereditary spherocytosis, may not present with anemia but rather with complications stemming from prolonged increased red cell destruction, like symptomatic bilirubin gallstones or splenomegaly.
 * 17) * Chronic hemolysis can also make patients susceptible to aplastic crises when an infectious process interrupts red cell production.
 * 18) * The differential diagnosis of an acute or chronic hemolytic event requires the careful integration of family history, clinical presentation, and a thorough examination of the peripheral blood smear. Precise diagnosis may necessitate specialized laboratory tests, such as hemoglobin electrophoresis or screenings for red cell enzymes. Acquired defects in red cell survival are often immunologically mediated and require tests like direct or indirect antiglobulin tests or cold agglutinin titers to detect the presence of hemolytic antibodies or complement-mediated red cell destruction.

Anemia is a broad and intricate medical condition with various underlying mechanisms and clinical presentations. A thorough understanding of the specific type of anemia is crucial for appropriate diagnosis and treatment, as each category requires a distinct approach to address the underlying issues and alleviate the patient's symptoms.

Treatment of Anemia
A fundamental guiding principle is to commence the treatment of mild to moderate anemia only when there's a precise diagnosis. On rare occasions, in urgent situations, when anemia is exceptionally severe, red cell transfusions might be necessary even before a specific diagnosis can be established. Whether the anemia develops suddenly or gradually, the choice of the most suitable treatment hinges upon the identified cause or causes of the anemia. Frequently, the origins of the anemia can be multifaceted. For instance, a patient grappling with severe rheumatoid arthritis, who has been prescribed anti-inflammatory medications, might exhibit a hypoproliferative anemia linked to persistent inflammation and, concurrently, chronic blood loss due to sporadic gastrointestinal bleeding. In all scenarios, a thorough assessment of the patient's iron levels is of paramount importance both before and during the course of treating any type of anemia.

Over the last three decades, there has been a remarkable expansion in therapeutic options for addressing anemias. The utilization of blood component therapy has not only become more prevalent but also notably safe. The introduction of recombinant erythropoietin (EPO) as a complement to managing anemia has been transformative, significantly improving the quality of life for patients with chronic renal failure undergoing dialysis and decreasing the necessity for transfusions in individuals with anemia resulting from cancer treatments like chemotherapy. Moreover, there is a promising future on the horizon, where patients dealing with inherited disorders related to the synthesis of globin or those with specific mutations in globin genes, such as sickle cell disease, might eventually reap the benefits of targeted genetic therapies.

Polycythemia
Polycythemia is characterized by an elevation in hemoglobin levels beyond the normal range. This elevation may be real or only apparent, often due to a reduction in plasma volume, a condition known as spurious or relative polycythemia. While some people use the terms "erythrocytosis" and "polycythemia" interchangeably, a subtle distinction can be made: erythrocytosis implies that an increase in red cell mass has been documented, whereas polycythemia simply refers to any rise in red cell count. Typically, individuals with polycythemia are identified when their hemoglobin or hematocrit levels are incidentally found to be elevated. Concern usually arises when hemoglobin levels reach or exceed 17 g/dL (170 g/L) in men and 15 g/DL (150 g/L) in women. Hematocrit levels surpassing 50% in men or 45% in women might also raise concern, while hematocrit levels above 60% in men and 55% in women are almost always indicative of an increased red cell mass. Since the machines used to measure red cell parameters primarily assess hemoglobin concentrations and calculate hematocrits, hemoglobin levels may be a more reliable indicator.

To aid in the differential diagnosis, certain aspects of the patient's medical history can be quite informative. These include factors such as smoking, residing at high altitudes, a history of diuretic use, congenital heart disease, sleep apnea, or chronic lung conditions.

Patients with polycythemia may either have no symptoms or experience various issues related to the elevated red cell mass or the underlying condition causing this increase. The primary symptoms resulting from an increased red cell mass are often linked to hyperviscosity and an increased risk of thrombosis, both venous and arterial, due to the logarithmic rise in blood viscosity when hematocrit levels exceed 55%. These manifestations encompass neurological symptoms like vertigo, tinnitus, headaches, and visual disturbances. Hypertension is frequently observed. Patients with polycythemia vera may experience aquagenic pruritus, as well as symptoms associated with hepatosplenomegaly, easy bruising, nosebleeds, or gastrointestinal bleeding. Peptic ulcers are common in this group. Some patients may also present with issues like digital ischemia, Budd–Chiari syndrome, or thrombosis in hepatic or splenic/mesenteric veins. Those with low oxygen levels might develop cyanosis with minimal exertion or report symptoms such as headaches, reduced mental alertness, and fatigue.

During a physical examination, individuals with polycythemia often exhibit a ruddy or reddish complexion. The presence of splenomegaly suggests a diagnosis of polycythemia vera. The occurrence of cyanosis or evidence of a right-to-left shunt may point to congenital heart diseases that present in adulthood, particularly conditions like tetralogy of Fallot or Eisenmenger's syndrome. Elevated blood viscosity can lead to increased pulmonary artery pressure, while hypoxemia can raise pulmonary vascular resistance, together potentially leading to cor pulmonale.

Polycythemia can have spurious causes, often related to reduced plasma volume (a condition known as Gaisbock's syndrome), or it can be of primary or secondary origin. Secondary causes are typically associated with the hormone erythropoietin (EPO), either due to a physiologically appropriate response to tissue hypoxia (as seen in lung diseases, high-altitude living, carbon monoxide poisoning, or high-affinity hemoglobinopathies) or an abnormal overproduction of EPO (resulting from conditions like renal cysts, renal artery stenosis, or tumors with ectopic EPO production). In rare instances, a familial form of polycythemia may occur, characterized by normal EPO levels but hyperresponsive EPO receptors due to specific genetic mutations.