In general, signs of anemia (pallor, fatigue, shortness of breath, and potential for heart failure) are present. In small children, failure to thrive may occur in any form of anemia. Certain aspects of the medical history can suggest a cause for hemolysis, such as drugs, consumption of fava beans due to Favism, the presence of prosthetic heart valve, or other medical illness.

Chronic hemolysis leads to an increased excretion of bilirubin into the biliary tract, which in turn may lead to gallstones. The continuous release of free hemoglobin has been linked with the development of pulmonary hypertension (increased pressure over the pulmonary artery); this, in turn, leads to episodes of syncope (fainting), chest pain, and progressive breathlessness. Pulmonary hypertension eventually causes right ventricular heart failure, the symptoms of which are peripheral edema (fluid accumulation in the skin of the legs) and ascites (fluid accumulation in the abdominal cavity).

Anemia goes undetected in many people and symptoms can be minor. The symptoms can be related to an underlying cause or the anemia itself.

Most commonly, people with anemia report feelings of weakness or tired, and sometimes poor concentration. They may also report shortness of breath on exertion. In very severe anemia, the body may compensate for the lack of oxygen-carrying capability of the blood by increasing cardiac output. The patient may have symptoms related to this, such as palpitations, angina (if pre-existing heart disease is present), intermittent claudication of the legs, and symptoms of heart failure.

On examination, the signs exhibited may include pallor (pale skin, lining mucosa, conjunctiva and nail beds), but this is not a reliable sign. There may be signs of specific causes of anemia, e.g., koilonychia (in iron deficiency), jaundice (when anemia results from abnormal break down of red blood cells — in hemolytic anemia), bone deformities (found in thalassemia major) or leg ulcers (seen in sickle-cell disease).

In severe anemia, there may be signs of a hyperdynamic circulation: tachycardia (a fast heart rate), bounding pulse, flow murmurs, and cardiac ventricular hypertrophy (enlargement). There may be signs of heart failure.

Pica, the consumption of non-food items such as ice, but also paper, wax, or grass, and even hair or dirt, may be a symptom of iron deficiency, although it occurs often in those who have normal levels of hemoglobin.

Chronic anemia may result in behavioral disturbances in children as a direct result of impaired neurological development in infants, and reduced academic performance in children of school age. Restless legs syndrome is more common in those with iron-deficiency anemia.

Hemolytic anemia or haemolytic anaemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular, but usually in the spleen). It has numerous possible consequences, ranging from relatively harmless to life-threatening. The general classification of hemolytic anemia is either inherited or acquired. Treatment depends on the cause and nature of the breakdown.

Symptoms of hemolytic anemia are similar to other forms of anemia (fatigue and shortness of breath), but in addition, the breakdown of red cells leads to jaundice and increases the risk of particular long-term complications, such as gallstones and pulmonary hypertension.

Anemia may lead to malaise, pallor and associated symptoms such as palpitations.

Low platelet counts (thrombocytopenia) if present is associated with an increased risk of hemorrhage, bruising and petechiae. Low white blood cell counts (leukocytopenia) if present leads to an increased risk of infections which can be severe.

AIHA is classified as either warm autoimmune hemolytic anemia or cold autoimmune hemolytic anemia, which includes cold agglutinin disease and paroxysmal cold hemoglobinuria. These classifications are based on the characteristics of the autoantibodies involved in the pathogenesis of the disease. Each has a different underlying cause, management, and prognosis, making classification important when treating a patient with AIHA.

Anisocytosis is a medical term meaning that a patient's red blood cells are of unequal size. This is commonly found in anemia and other blood conditions. False diagnostic flagging may be triggered by an elevated WBC count, agglutinated RBCs, RBC fragments, giant platelets or platelet clumps. In addition, it is a characteristic feature of bovine blood.

The red cell distribution width (RDW) is a measurement of anisocytosis and is calculated as a coefficient of variation of the distribution of RBC volumes divided by the mean corpuscular volume (MCV)

A dimorphic appearance on a peripheral blood smear occurs when there are two simultaneous populations of red blood cells, typically of different size and hemoglobin content (this last feature affecting the color of the red blood cell on a stained peripheral blood smear). For example, a person recently transfused for iron deficiency would have small, pale, iron deficient red blood cells (RBCs) and the donor RBCs of normal size and color. Similarly, a person transfused for severe folate or vitamin B12 deficiency would have two cell populations, but, in this case, the patient's RBCs would be larger and paler than the donor's RBCs. A person with sideroblastic anemia (a defect in heme synthesis, commonly caused by alcoholism, but also drugs/toxins, nutritional deficiencies, a few acquired and rare congenital diseases) can have a dimorphic smear from the sideroblastic anemia alone. Evidence for multiple causes appears with an elevated RBC distribution width (RDW), indicating a wider-than-normal range of red cell sizes, also seen in common nutritional anemia.

Mechanical hemolytic anemia is a form of hemolytic anemia due to mechanically induced damage to red blood cells. Red blood cells, while flexible, may in some circumstances succumb to physical shear and compression. This may result in hemoglobinuria. The damage is induced through repetitive mechanical motions such as prolonged marching ("march hemoglobinuria") and marathon running. Mechanical damage can also be induced through the chronic condition microangiopathic hemolytic anemia or due to prosthetic heart valves.

Mild macrocytosis is a common finding associated with rapid blood restoration or production, since in general, "fresh" or newly produced red cells (reticulocytes) are larger than the mean (average) size, due to slow shrinkage of normal cells over a normal red cell circulating lifetime. Thus, chronic obstructive pulmonary disease (COPD), in which red cells are rapidly produced in response to low oxygen levels in the blood, often produces mild macrocytosis. Also, rapid blood replacement from the marrow after a traumatic blood loss, or rapid red blood cell turnover from rapid hemolysis (G6PD deficiency), also often produces mild macrocytosis in the associated anemia.

Autoimmune hemolytic anemia (or autoimmune haemolytic anaemia; AIHA) occurs when antibodies directed against the person's own red blood cells (RBCs) cause them to burst (lyse), leading to an insufficient number of oxygen-carrying red blood cells in the circulation. The lifetime of the RBCs is reduced from the normal 100–120 days to just a few days in serious cases. The intracellular components of the RBCs are released into the circulating blood and into tissues, leading to some of the characteristic symptoms of this condition. The antibodies are usually directed against high-incidence antigens, therefore they also commonly act on allogenic RBCs (RBCs originating from outside the person themselves, e.g. in the case of a blood transfusion). AIHA is a relatively rare condition, affecting one to three people per 100,000 per year.

The terminology used in this disease is somewhat ambiguous. Although MeSH uses the term "autoimmune hemolytic anemia", some sources prefer the term "immunohemolytic anemia" so drug reactions can be included in this category. The National Cancer Institute considers "immunohemolytic anemia", "autoimmune hemolytic anemia", and "immune complex hemolytic anemia" to all be synonyms.

Normocytic anemia is a type of anemia and is a common issue that occurs for men and women typically over 85 years old. Its prevalence increases with age, reaching 44 percent in men older than 85 years.

Congenital hemolytic anemia (or hereditary hemolytic anemia) refers to hemolytic anemia which is primarily due to congenital disorders.

Drug-induced nonautoimmune hemolytic anemia is a form of hemolytic anemia.

Non-immune drug induced hemolysis can occur via oxidative mechanisms. This is particularly likely to occur when there is an enzyme deficiency in the antioxidant defense system of the red blood cells. An example is where antimalarial oxidant drugs like primaquine damage red blood cells in Glucose-6-phosphate dehydrogenase deficiency in which the red blood cells are more susceptible to oxidative stress due to reduced NADPH production consequent to the enzyme

deficiency.

Some drugs cause RBC (red blood cell) lysis even in normal individuals. These include dapsone and sulfasalazine.

Non-immune drug-induced hemolysis can also arise from drug-induced damage to cell volume control mechanisms; for example drugs can directly or indirectly impair regulatory volume decrease mechanisms, which become activated during hypotonic RBC swelling to return the cell to a normal volume. The consequence of the drugs actions are irreversible cell swelling and lysis (e.g. ouabain at very high doses).

Anisocytosis is identified by RDW and is classified according to the size of RBC measured by MCV. According to this, it can be divided into

- Anisocytosis with microcytosis – Iron deficiency, sickle cell anemia

- Anisocytosis with macrocytosis – Folate or vitamin B deficiency, autoimmune hemolytic anemia, cytotoxic chemotherapy, chronic liver disease, myelodysplastic syndrome

Increased RDW is seen in iron deficiency anemia and decreased or normal in thalassemia major (Cooley's anemia), thalassemia intermedia

- Anisocytosis with normal RBC size – Early iron, vit B12 or folate deficiency, dimorphic anemia, Sickle cell disease, chronic liver disease, Myelodysplastic syndrome

A normocytic anemia is defined as an anemia with a mean corpuscular volume (MCV) of 80–100 which is the normal range. However, the hematocrit and hemoglobin is decreased.

Basically classified by causative mechanism, types of congenital hemolytic anemia include:

- Genetic conditions of RBC Membrane

- Hereditary spherocytosis

- Hereditary elliptocytosis

- Genetic conditions of RBC metabolism (enzyme defects). This group is sometimes called "congenital nonspherocytic (hemolytic) anemia", which is a term for a congenital hemolytic anemia without spherocytosis, and usually excluding hemoglobin abnormalities as well, but rather encompassing defects of glycolysis in the erythrocyte.

- Glucose-6-phosphate dehydrogenase deficiency (G6PD or favism)

- Pyruvate kinase deficiency

- Aldolase A deficiency

- Hemoglobinopathies/genetic conditions of hemoglobin

- Sickle cell anemia

- Congenital dyserythropoietic anemia

- Thalassemia

The term macrocytic is from Greek words meaning "large cell". A macrocytic class of anemia is an "anemia" (defined as blood with an insufficient concentration of hemoglobin) in which the red blood cells (erythrocytes) are larger than their normal volume. The normal erythrocyte volume in humans is about 80 to 100 femtoliters (fL= 10 L). In metric terms the size is given in equivalent cubic micrometers (1 μm = 1 fL). The condition of having erythrocytes which (on average) are too large, is called macrocytosis. In contrast, in microcytic anemia, the erythrocytes are smaller than normal.

In a macrocytic anemia, the larger red cells are always associated with insufficient "numbers" of cells and often also insufficient hemoglobin content per cell. Both of these factors work to the opposite effect of larger cell size, to finally result in a "total blood hemoglobin concentration" that is less than normal (i.e., anemia).

Macrocytic anemia is not a disease in the sense of having a single pathology but, rather, is a condition. As such, it is the class name for a set of pathologies that all produce somewhat the same red blood cell abnormality. Many specific pathologies are known which result in macrocytic-type anemias. Some of these produce slightly different sets of appearances in blood cells that are detectable from red and white cell morphology, and others are only detectable with chemical testing.

Congenital hypoplastic anemia (or constitutional aplastic anemia) is a type of aplastic anemia which is primarily due to a congenital disorder.

Associated genes include "TERC", "TERT", "IFNG", "NBS1", "PRF1", and "SBDS".

Examples include:

- Fanconi anemia

- Diamond-Blackfan anemia

Spherocytosis is an auto-hemolytic anemia (a disease of the blood) characterized by the production of spherocytes (red blood cells (RBCs)) or erythrocytes that are sphere-shaped rather than bi-concave disk shaped. Spherocytes are found in all hemolytic anemias to some degree. Hereditary spherocytosis and autoimmune hemolytic anemia are characterized by having "only" spherocytes.

Spherocytosis most often refers to hereditary spherocytosis. This is caused by a molecular defect in one or more of the proteins of the red blood cell cytoskeleton, including spectrin, ankyrin, Band 3, or Protein 4.2. Because the cell skeleton has a defect, the blood cell contracts to a sphere, which is its most surface tension efficient and least flexible configuration. Though the spherocytes have a smaller surface area through which oxygen and carbon dioxide can be exchanged, they in themselves perform adequately to maintain healthy oxygen supplies. However, they have a high osmotic fragility—when placed into water, they are more likely to burst than normal red blood cells. These cells are more prone to physical degradation.

Spherocytes are most commonly found in immunologically-mediated hemolytic anemias and in hereditary spherocytosis, but the former would have a positive direct Coombs test and the latter would not. The misshapen but otherwise healthy red blood cells are mistaken by the spleen for old or damaged red blood cells and it thus constantly breaks them down, causing a cycle whereby the body destroys its own blood supply (auto-hemolysis). A complete blood count (CBC) may show increased reticulocytes, a sign of increased red blood cell production, and decreased hemoglobin and hematocrit.

The term "non-hereditary spherocytosis" is occasionally used, albeit rarely.

Repetitive impacts to the body may cause mechanical trauma and bursting (hemolysis) of red blood cells. This has been documented to have occurred in the feet during running and hands from Conga or Candombe drumming. Defects in red blood cell membrane proteins have been identified in some of these patients. Free haemoglobin is released from lysed red blood cells and filtered into the urine.

Normochromic is a form of anemia in which the concentration of hemoglobin in the red blood cells is within the standard range. However, there are insufficient numbers of red blood cells. This includes: aplastic, posthemorrhagic, and hemolytic anemias and anemia of chronic disease.

MCH or MCHC in these cells are normal.

The condition needs to be differentiated from pure red cell aplasia. In aplastic anemia, the patient has pancytopenia (i.e., leukopenia and thrombocytopenia) resulting in decrease of all formed elements. In contrast, pure red cell aplasia is characterized by reduction in red cells only. The diagnosis can only be confirmed on bone marrow examination. Before this procedure is undertaken, a patient will generally have had other blood tests to find diagnostic clues, including a complete blood count, renal function and electrolytes, liver enzymes, thyroid function tests, vitamin B and folic acid levels.

The following tests aid in determining differential diagnosis for aplastic anemia:

1. Bone marrow aspirate and biospy: to rule out other causes of pancytopenia (i.e. neoplastic infiltration or significant myelofibrosis).

2. History of iatrogenic exposure to cytotoxic chemotherapy: can cause transient bone marrow suppression

3. X-rays, computed tomography (CT) scans, or ultrasound imaging tests: enlarged lymph nodes (sign of lymphoma), kidneys and bones in arms and hands (abnormal in Fanconi anemia)

4. Chest X-ray: infections

5. Liver tests: liver diseases

6. Viral studies: viral infections

7. Vitamin B and folate levels: vitamin deficiency

8. Blood tests for paroxysmal nocturnal hemoglobinuria

9. Test for antibodies: immune competency

AIHA may be:

- Idiopathic, that is, without any known cause

- Secondary to another disease, such as an antecedent upper respiratory tract infection, systemic lupus erythematosus or a malignancy, such as chronic lymphocytic leukemia (CLL)

Diamond–Blackfan anemia is characterized by normocytic or macrocytic anemia (low red blood cell counts) with decreased erythroid progenitor cells in the bone marrow. This usually develops during the neonatal period. About 47% of affected individuals also have a variety of congenital abnormalities, including craniofacial malformations, thumb or upper limb abnormalities, cardiac defects, urogenital malformations, and cleft palate. Low birth weight and generalized growth delay are sometimes observed. DBA patients have a modest risk of developing leukemia and other malignancies.

Drug-induced autoimmune hemolytic anemia is a form of hemolytic anemia.

In some cases, a drug can cause the immune system to mistakenly think the body's own red blood cells are dangerous, foreign substances. Antibodies then develop against the red blood cells. The antibodies attach to red blood cells and cause them to break down too early. Drugs that can cause this type of hemolytic anemia include:

- Cephalosporins (a class of antibiotics) – most common cause

- Dapsone

- Levodopa

- Levofloxacin

- Methyldopa

- Nitrofurantoin

- Nonsteroidal anti-inflammatory drugs (NSAIDs)

- Phenazopyridine (pyridium)

- Quinidine

Penicillin in high doses can induce immune mediated hemolysis via the hapten mechanism in which antibodies are targeted against the combination of penicillin in association with red blood cells. Complement is activated by the attached antibody leading to the removal of red blood cells by the spleen.

The drug itself can be targeted by the immune system, e.g. by IgE in a Type I hypersensitivity reaction to penicillin, rarely leading to anaphylaxis.