Acute PCH tends to be transient and self-limited, particularly in children. Chronic PCH associated with syphilis resolves after the syphilis is treated with appropriate antibiotics. Chronic idiopathic PCH is usually mild.

People with PCH, a polyclonal IgG anti-P autoantibody binds to red blood cell surface antigens in the cold. This can occur in a susceptible individual as blood passes through cold extremities in cold weather. When the blood returns to the warmer central circulation, the red blood cells are lysed with complement, causing intravascular hemolysis. Hemoglobinuria and anemia can then occur. The anemia may be mild or severe.

A common complaint among patients with cold agglutinin disease is painful fingers and toes with purplish discoloration associated with cold exposure. In chronic cold agglutinin disease, the patient is more symptomatic during the colder months.

Cold agglutinin mediated acrocyanosis differs from Raynaud phenomenon. In Raynaud phenomena, caused by vasospasm, a triphasic color change occurs, from white to blue to red, based on vasculature response. No evidence of such a response exists in cold agglutinin disease.

Other symptoms

- Respiratory symptoms: May be present in patients with "M pneumoniae" infection.

- Hemoglobinuria (the passage of dark urine that contains hemoglobin), A rare symptom that results from hemolysis, this may be reported following prolonged exposure to cold, hemoglobinuria is more commonly seen in paroxysmal cold hemoglobinuria.

- Chronic fatigue, Due to anemia.

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)

Cold agglutinins develop in more than 60% of patients with infectious mononucleosis, but hemolytic anemia is rare.

Classic chronic cold agglutinin disease is idiopathic, associated with symptoms and signs in relation to cold exposure.

Causes of the monoclonal secondary disease include the following:

- B-cell neoplasms - Waldenström macroglobulinemia, lymphoma, chronic lymphoid leukemia, myeloma

- Non hematologic neoplasms

Causes of polyclonal secondary cold agglutinin disease include the following:

- Mycoplasma infections.

- Viral infections: Infectious mononucleosis due to Epstein-Barr virus (EBV) or CMV, Mumps, varicella, rubella, adenovirus, HIV, influenza, hepatitis C.

- Bacterial infections: Legionnaire disease, syphilis, listeriosis and "Escherichia coli."

- Parasitic infections: Malaria and trypanosomiasis.

- Trisomy and translocation: Cytogenetic studies in patients with cold agglutinin disease have revealed the presence of trisomy 3 and trisomy 12. Translocation (8;22) has also been reported in association with cold agglutinin disease.

- Transplantation: Cold agglutinin–mediated hemolytic anemia has been described in patients after living-donor liver transplantation treated with tacrolimus and after bone marrow transplantation with cyclosporine treatments. It is postulated that such calcineurin inhibitors, which selectively affect T-cell function and spare B-lymphocytes, may interfere with the deletion of autoreactive T-cell clones, resulting in autoimmune disease.

- Systemic sclerosis: Cold agglutinin disease has been described in patients with sclerodermic features, with the degree of anemia being associated with increasing disease activity of the patient’s systemic sclerosis. This may suggest a close association between systemic rheumatic disease and autoimmune hematologic abnormalities.

- Hyperreactive malarial splenomegaly: Hyperreactive malarial splenomegaly (HMS) is an immunopathologic complication of recurrent malarial infection. Patients with HMS develop splenomegaly, acquired clinical immunity to malaria, high serum concentrations of anti-"Plasmodium" antibodies, and high titers of IgM, with a complement-fixing IgM that acts as a cold agglutinin.

- DPT vaccination: Diphtheria-pertussis-tetanus (DPT) vaccination has been implicated in the development of autoimmune hemolytic anemia caused by IgM autoantibody with a high thermal range. A total of 6 cases have been reported; 2 followed the initial vaccination and 4 followed the second or third vaccinations.

- Other: Equestrian perniosis is a rare cause of persistent elevated titers of cold agglutinins. Also rarely, the first manifestations of cold agglutinin disease can develop when a patient is subjected to hypothermia for cardiopulmonary bypass surgery.

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.

Warm antibody autoimmune hemolytic anemia (WAIHA) is the most common form of autoimmune hemolytic anemia. About half of the cases are of unknown cause, with the other half attributable to a predisposing condition or medications being taken. Contrary to cold autoimmune hemolytic anemia (e.g., cold agglutinin disease and paroxysmal cold hemoglobinuria) which happens in cold temperature (28–31 °C), WAIHA happens at body temperature.

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.

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.

Acquired hemolytic anemia can be divided into immune and non-immune mediated forms of hemolytic anemia.

Drug induced hemolysis has large clinical relevance. It occurs when drugs actively provoke red blood cell destruction. It can be divided in the following manner:

- Drug-induced autoimmune hemolytic anemia

- Drug-induced nonautoimmune hemolytic anemia

A total of four mechanisms are usually described, but there is some evidence that these mechanisms may overlap.

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).

Rh deficiency syndrome is a type of hemolytic anemia that involves erythrocytes whom membranes are deficient in Rh antigens. It is considered a rare condition.

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).

Hemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis fetalis, is an alloimmune condition that develops in a fetus, when the IgG molecules (one of the five main types of antibodies) produced by the mother pass through the placenta. Among these antibodies are some which attack antigens on the red blood cells in the fetal circulation, breaking down and destroying the cells (hemolysis). The fetus can develop reticulocytosis and anemia. This fetal disease ranges from mild to very severe, and fetal death from heart failure (hydrops fetalis) can occur. When the disease is moderate or severe, many erythroblasts (immature red blood cells) are present in the fetal blood, and so these forms of the disease can be called "erythroblastosis fetalis" (or "erythroblastosis foetalis").

HDFN represents a breach of immune privilege for the fetus or some other form of impairment of the immune tolerance of pregnancy. Various types of HDFN are classified by which alloantigen provokes the response. In order of incidence, the types include ABO, anti-RhD, anti-RhE, anti-Rhc, anti-Rhe, anti-RhC, multiantigen combinations, and anti-Kell.

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

Signs of hemolytic disease of the newborn include a positive direct Coombs test (also called direct agglutination test), elevated cord bilirubin, and hemolytic anemia. It is possible for a newborn with this disease to have neutropenia and neonatal alloimmune thrombocytopenia as well.Hemolysis leads to elevated bilirubin levels. After delivery bilirubin is no longer cleared (via the placenta) from the neonate's blood and the symptoms of jaundice (yellowish skin and yellow discoloration of the whites of the eyes) increase within 24 hours after birth. Like other severe neonatal jaundice, there is the possibility of acute or chronic kernicterus, however the risk of kernicterus is higher because of the rapid destruction of blood cells. It is important to note that isoimmunization is a risk factor for neurotoxicity and lowers the level at which kernicterus can occur. Untreated profound anemia can cause high-output heart failure, with pallor, enlarged liver and/or spleen, generalized swelling, and respiratory distress.

HDN can be the cause of hydrops fetalis, an often-severe form of prenatal heart failure that causes fetal edema.

Thrombocytopenia usually has no symptoms and is picked up on a routine full blood count (or complete blood count). Some individuals with thrombocytopenia may experience external bleeding such as nosebleeds, and/or bleeding gums. Some women may have heavier or longer periods or breakthrough bleeding. Bruising, particularly purpura in the forearms and petechiae in the feet, legs, and mucous membranes, may be caused by spontaneous bleeding under the skin.

Eliciting a full medical history is vital to ensure the low platelet count is not secondary to another disorder. It is also important to ensure that the other blood cell types, such as red blood cells and white blood cells, are not also suppressed.

Painless, round and pinpoint (1 to 3 mm in diameter) petechiae usually appear and fade, and sometimes group to form ecchymoses. Larger than petechiae, ecchymoses are purple, blue or yellow-green areas of skin that vary in size and shape. They can occur anywhere on the body.

A person with this disease may also complain of malaise, fatigue and general weakness (with or without accompanying blood loss). Acquired thrombocytopenia may be associated with a history of drug use. Inspection typically reveals evidence of bleeding (petechiae or ecchymoses), along with slow, continuous bleeding from any injuries or wounds. Adults may have large, blood-filled bullae in the mouth. If the person's platelet count is between 30,000 and 50,000/mm, bruising with minor trauma may be expected; if it is between 15,000 and 30,000/mm, spontaneous bruising will be seen (mostly on the arms and legs).

Hereditary spherocytosis (also known as Minkowski–Chauffard syndrome) abnormality of erythrocytes. The disorder is caused by mutations in genes relating to membrane proteins that allow for the erythrocytes to change shape. The abnormal erythrocytes are sphere-shaped (spherocytosis) rather than the normal biconcave disk shaped. Dysfunctional membrane proteins interfere with the cell's ability to be flexible to travel from the arteries to the smaller capillaries. This difference in shape also makes the red blood cells more prone to rupture. Cells with these dysfunctional proteins are taken for degradation at the spleen. This shortage of erythrocytes results in hemolytic anemia.

It was first described in 1871 and is the most common cause of inherited hemolysis in Europe and North America within the Caucasian population, with an incidence of 1 in 5000 births. The clinical severity of HS varies from symptom-free

carrier to severe haemolysis because the disorder exhibits incomplete penetrance in its expression.

Symptoms include anemia, jaundice, splenomegaly, and fatigue. On a blood smear, Howell-Jolly bodies may be seen within red blood cells. Primary treatment for patients with symptomatic HS has been total splenectomy, which eliminates the hemolytic process, allowing normal hemoglobin, reticulocyte and bilirubin levels.

As in non-hereditary spherocytosis, the spleen destroys the spherocytes. This process of red blood cells rupturing directly results in varying degrees of anemia (causing a pale appearance and fatigue), high levels of bilirubin in the blood (causing jaundice), and splenomegaly.

Acute cases can threaten to cause hypoxia through anemia and acute kernicterus through high blood levels of bilirubin, particularly in newborns. Most cases can be detected soon after birth. An adult with this disease should have their children tested, although the presence of the disease in children is usually noticed soon after birth. Occasionally, the disease will go unnoticed until the child is about 4 or 5 years of age. A person may also be a carrier of the disease and show no signs or symptoms of the disease. Other symptoms may include abdominal pain that could lead to the removal of the spleen and/or gallbladder.

Chronic symptoms include anemia, increased blood viscosity, and splenomegaly, and some symptoms are still unknown at this stage. Furthermore, the detritus of the broken-down blood cells – unconjugated or indirect bilirubin – accumulates in the gallbladder, and can cause pigmented gallstones to develop. In chronic patients, an infection or other illness can cause an increase in the destruction of red blood cells, resulting in the appearance of acute symptoms, a "hemolytic crisis". Spherocytosis patients who are heterozygous for a hemochromatosis gene may suffer from iron overload despite the hemochromatosis genes being recessive.

Cold agglutinin disease can be either primary (arising spontaneously) or secondary (a result of another pathology).

- The primary form is caused by excessive cell proliferation of B lymphocytes.

- Secondary cold agglutinin disease is a result of an underlying condition.

- In adults, this is typically due to a lymphoproliferative disease such as lymphoma and chronic lymphoid leukemia, or infection. Waldenström's macroglobulinemia may also be positive for cold agglutinins.

- In children, cold agglutinin disease is often secondary to an infection, such as "Mycoplasma" pneumonia, mononucleosis, and HIV.

Cold agglutinin disease is an autoimmune disease characterized by the presence of high concentrations of circulating antibodies, usually IgM, directed against red blood cells. It is a form of autoimmune hemolytic anemia, specifically one in which antibodies only bind red blood cells at low body temperatures, typically 28–31 °C.

Cold agglutinin disease was first described in 1957.

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

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.

Hereditary pyropoikilocytosis (HPP) is an autosomal recessive form of hemolytic anemia characterized by an abnormal sensitivity of red blood cells to heat and erythrocyte morphology similar to that seen in thermal burns. Patients with HPP tend to experience severe haemolysis and anaemia in infancy that gradually improves, evolving toward typical elliptocytosis later in life. However, the hemolysis can lead to rapid sequestration and destruction of red cells. Splenectomy is curative when this occurs.

HPP has been associated with a defect of the erythrocyte membrane protein spectrin and with spectrin deficiency.It was characterized in 1975.It is considered a severe form of hereditary elliptocytosis.