Cold sensitive antibodies (CSA) are

antibodies An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that caus ...

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 and blood-forming organs. Hematologic diseases include rare genetic disorders, anemia, HIV, sickle cell disease and complications from chemotherapy or transfusions. Myeloid * ...

. These pathological cold sensitive antibodies include cold agglutinins, Donath–Landsteiner antibodies, and cryoglobulins which are the culprits of cold agglutinin disease, paroxysmal cold hemoglobinuria in the process of Donath–Landsteiner hemolytic anemia, and

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

, respectively.

Cold agglutinin antibodies

Cold agglutinins are

, typically

immunoglobulin M Immunoglobulin M (IgM) is the largest of several isotypes of antibodies (also known as immunoglobulin) that are produced by vertebrates. IgM is the first antibody to appear in the response to initial exposure to an antigen; causing it to also ...

( 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 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 cold agglutinin disease. 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. 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. Examples include the common cold, gastroenteritis, COVID-19, t ...

autoimmune disorder An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated tha ...

, 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 of the CA. If the thermal amplitude exceeds 28–30 °C, the CA will be pathogenic. Low-

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CA also occurs in many healthy individuals; these nonpathogenic CA are polyclonal, have low thermal amplitude, and are present in low titers, 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 humoral, innate immune system and enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inf ...

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

Blood vessel Blood vessels are the tubular structures of a circulatory system that transport blood throughout many Animal, animals’ bodies. Blood vessels transport blood cells, nutrients, and oxygen to most of the Tissue (biology), tissues of a Body (bi ...

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

pathophysiology Pathophysiology (or physiopathology) is a branch of study, at the intersection of pathology and physiology, concerning disordered physiological processes that cause, result from, or are otherwise associated with a disease or injury. Pathology is ...

of Donath–Landsteiner hemolytic anemia has been entitled as paroxysmal cold hemoglobinuria.

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

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;

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;

joint pain Arthralgia () literally means 'joint pain'. Specifically, arthralgia is a symptom of injury, infection, illness (in particular arthritis), or an allergic reaction to medication Medication (also called medicament, medicine, pharmaceutic ...

muscle pain Myalgia or muscle pain is a painful sensation evolving from muscle tissue. It is a symptom of many diseases. The most common cause of acute myalgia is the overuse of a muscle or group of muscles; another likely cause is viral infection, espec ...

;

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, is a medical condition in which the spasm of small arteries causes episodes of reduced blood flow to end arterioles. Typically the fingers, and, less commonly, the toes, are involved. Rare ...

; skin death; and/or

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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 period, people often have mild or no symptoms. Early symptoms can include ...

is to blame, reflecting the importance of preclusion of hepatitis C. The presence of cryoglobulins in body satisfies the criterion of the diagnosis of

cryoglobulinemia Cryoglobulinemia is a rare medical condition characterized by the presence of cryoglobulins in the blood. Cryoglobulins are abnormal proteins composed of immunoglobulins and sometimes complement components. Cryoglobulins specifically form g ...

, a disease that inflame the blood vessels and organs like kidney, nerves, joints, lungs and skin. Normally, no cryoglobulins should be found in the body. Cryoglobulins more than often do not interact with red blood cells, unless it combines the features of cold agglutinin with cryoglobulins, although the chance is deemed rare. Therefore, cryoglobulins don't produce hemolysis effect, however its serious complications such as systemic inflammatory or neoplastic disorders can in turn lead to anemia.

Comparisons between cold agglutinin, Donath–Landsteiner antibodies and cryoglobulin

Although there is some overlap of symptoms, cryoglobulinemia and cold agglutinin disease differ in the process by which blood vessels become blocked. In cryoglobulinemia, antibodies accumulate and block blood vessels. In cold agglutinin disease, antibodies (different from those in cryoglobulinemia) attack and kill red blood cells, which then accumulate and block blood vessels. Common features among the three conditions above include: *All can trigger

. *All may be caused by infections, autoimmune disorders as well as lymphoma or other lymphoproliferative disorders.

Complement

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

plays a definitive but limited role in warm-antibody AIHA (w-AIHA), whereas primary cold agglutinin disease (CAD), secondary cold agglutinin syndrome (CAS), and paroxysmal cold hemoglobinuria (PCH) are entirely complement-dependent disorders.

Hemolysis site

Hemolysis induced by cold agglutinin disease taking place ''outside'' the vessels while which of Donath–Landsteiner antibodies is taking place ''inside'' the vessels.

References

{{Spleen Antibodies Autoimmune diseases Hematology