Cold sensitive antibodies (CSA) are antibodies sensitive to cold temperature. Some cold sensitive antibodies are pathological and can lead to

blood disorder Hematologic diseases are disorders which primarily affect the blood & blood-forming organs. Hematologic diseases include rare genetic disorders, anemia, HIV, sickle cell disease & complications from chemotherapy or transfusions. Myeloid * Hemog ...

. These pathological cold sensitive antibodies include cold agglutinins, Donath–Landsteiner antibodies, and cryoglobulins which are the culprits of

cold agglutinin disease Cold agglutinin disease (CAD) is a rare autoimmune disease characterized by the presence of high concentrations of circulating cold sensitive antibodies, usually IgM and autoantibodies that are also active at temperatures below , directed again ...

paroxysmal cold hemoglobinuria Paroxysmal cold hemoglobinuria (PCH) is an autoimmune hemolytic anemia featured by Complement system, complement-mediated intravascular hemolysis after cold exposure. It can present as an acute non-recurrent postinfectious event in children, or chr ...

in the process of

Donath–Landsteiner hemolytic anemia Donath–Landsteiner hemolytic anemia (DLHA) is a result of cold-reacting antibody immunoglobulin (Ig) induced hemolytic response inside vessels leading to anemia and, thus, a cold antibody autoimmune hemolytic anemias (CAAHA). In most patients ...

, and

vasculitis Vasculitis is a group of disorders that destroy blood vessels by inflammation. Both arteries and veins are affected. Lymphangitis (inflammation of lymphatic vessels) is sometimes considered a type of vasculitis. Vasculitis is primarily caused ...

, respectively.

Cold agglutinin antibodies

Cold agglutinins are antibodies, typically

immunoglobulin M Immunoglobulin M (IgM) is one of several isotypes of antibody (also known as immunoglobulin) that are produced by vertebrates. IgM is the largest antibody, and it is the first antibody to appear in the response to initial exposure to an antige ...

( IgM), that are acquainted with and then binding the antigens on red blood cells, typically antigens "I" or "i" on the RBC surface, in the environment in which the temperatures are lower than normal core body temperature and, thus, ends up leading to agglutinations of the red blood cells and hemolysis reaction occurring outside the vessels (extra-vessels), resulting in anemia without

hemoglobinuria Hemoglobinuria is a condition in which the oxygen transport protein hemoglobin is found in abnormally high concentrations in the urine. The condition is caused by excessive intravascular hemolysis, in which large numbers of red blood cells (RBCs) ...

in ordinary cases. Cold agglutinins can cause two pathological conditions, that are, primary cold agglutinin disease (CAD) and secondary cold agglutinin syndrome (CAS), both of which are sole two subtypes of

. Primary cold agglutinin disease is idiopathic, meaning the phenomenons of agglutinations of the red blood cells and hemolysis reaction occurring outside the vessels are absent from any underlying cause. Nevertheless, what is known is, those with idiopathic cold agglutinin disease are susceptible to having or developing mild

clonal bone marrow disorder Mastocytosis, a type of mast cell disease, is a rare disorder affecting both children and adults caused by the accumulation of functionally defective mast cells (also called ''mastocytes'') and CD34+ mast cell precursors. People affected by mas ...

. Secondary cold agglutinin syndrome refers to cold agglutinin disease that is identified to be caused by

viral infection A viral disease (or viral infection) occurs when an organism's body is invaded by pathogenic viruses, and infectious virus particles (virions) attach to and enter susceptible cells. Structural Characteristics Basic structural characteristics, s ...

autoimmune disorder An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...

, lymphoid malignancy, or any other underlying disease.

Thermal amplitude

Cold agglutinins (CA) are autoantibodies that agglutinate RBCs with a temperature optimum of 3-4 °C but may also act in a warmer environment, depending on the

thermal amplitude Atmospheric temperature is a measure of temperature at different levels of the Earth's atmosphere. It is governed by many factors, including incoming solar radiation, humidity and altitude. When discussing surface air temperature, the annual atmo ...

of the CA. If the thermal amplitude exceeds 28–30 °C, the CA will be pathogenic. Low- affinity CA also occurs in many healthy individuals; these nonpathogenic CA are

polyclonal Polyclonal B cell response is a natural mode of immune response exhibited by the adaptive immune system of mammals. It ensures that a single antigen is recognized and attacked through its overlapping parts, called epitopes, by multiple clones ...

, have low thermal amplitude, and are present in low

titer Titer (American English) or titre (British English) is a way of expressing concentration. Titer testing employs serial dilution to obtain approximate quantitative information from an analytical procedure that inherently only evaluates as posit ...

s, not higher than 256 and usually lower than 64. More than 90% of pathogenic CA are of the IgM class and these IgM macromolecules can be pentameric or hexameric.

Donath–Landsteiner antibodies

Donath–Landsteiner antibodies share similarities with cold agglutinin disease in recognition and connection of the antigens on the red blood cells' surface in the presence of relatively lower temperatures compared to core body temperature. Yet, the place where the hemolysis taking place differentiates between antibodies and cold agglutinin. D-L antibodies rather fix

complement system The complement system, also known as complement cascade, is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and ...

which result in hemolysis in vessels (intra-vessels).

Blood vessel Blood vessels are the structures of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide away from ...

s are pathways carrying living-required elements to reach everywhere inside the body through circulation. This explains why the clinical manifestations of hemolysis caused by D-L antibodies are in line with representations of

hemoglobinemia Hemoglobinemia (or haemoglobinaemia) is a medical condition in which there is an excess of hemoglobin in the blood plasma. This is an effect of intravascular hemolysis, in which hemoglobin separates from red blood cells, a form of anemia. Hemog ...

and

. D-L antibodies, typically IgG, are characterized by targeting against red blood cells' on-surface antigens called "P". The

pathophysiology Pathophysiology ( physiopathology) – a convergence of pathology with physiology – is the study of the disordered physiological processes that cause, result from, or are otherwise associated with a disease or injury. Pathology is t ...

has been entitled as

Cryoglobulins antibodies

Cryoglobulins are abnormal antibodies that only dissolve/disappear at temperature higher than and form solid or gel-like immune complexes in presence of the environment under , which can block blood vessels and cause a variety of health problems including inflammation and organ damage. Many people affected by cryoglobulins will not experience any unusual signs or symptoms. When present, symptoms vary but may include

breathing problem Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing dis ...

fatigue Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...

;

glomerulonephritis Glomerulonephritis (GN) is a term used to refer to several kidney diseases (usually affecting both kidneys). Many of the diseases are characterised by inflammation either of the glomeruli or of the small blood vessels in the kidneys, hence the ...

;

joint pain Arthralgia (from Greek ''arthro-'', joint + ''-algos'', pain) literally means ''joint pain''. Specifically, arthralgia is a symptom of injury, infection, illness (in particular arthritis), or an allergic reaction to medication. According to MeSH, ...

muscle pain Myalgia (also called muscle pain and muscle ache in layman's terms) is the medical term for muscle pain. Myalgia is a symptom of many diseases. The most common cause of acute myalgia is the overuse of a muscle or group of muscles; another li ...

;

purpura Purpura () is a condition of red or purple discolored spots on the skin that do not blanch on applying pressure. The spots are caused by bleeding underneath the skin secondary to platelet disorders, vascular disorders, coagulation disorders, ...

;

Raynaud's phenomenon Raynaud syndrome, also known as Raynaud's phenomenon, eponymously named after the physician Auguste Gabriel Maurice Raynaud, who first described it in his doctoral thesis in 1862, is a medical condition in which the spasm of small arteries cau ...

;

skin death Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal coverings, such as the arthropod exoskeleton, have different ...

; and/or

skin ulcer An ulcer is a sore on the skin or a mucous membrane, accompanied by the disintegration of tissue. Ulcers can result in complete loss of the epidermis and often portions of the dermis and even subcutaneous fat. Ulcers are most common on the skin ...

s. In some cases, the exact underlying cause is unknown; however, cryoglobulinemia can be associated with a variety of conditions including certain types of infection; chronic inflammatory diseases (such as autoimmune disease); and/or cancers of the blood or immune system. Treatment varies based on the severity of the condition, the symptoms present in each person and the underlying cause. At least 90% of cases having cryoglobulins in body,

hepatitis C Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection people often have mild or no symptoms. Occasionally a fever, dark urine, ...

is to blame,