YutuCold agglutinin disease is a subtype of autoimmune hemolytic anemia (AIHA), usually caused by high concentrations of circulating immunoglobulin IgM autoantibodies (cold agglutinins), which bind to the “I” antigen on erythrocytes.
A rare disease with an estimated incidence of approximately one per million.
It is caused by a population of lymphocytes that makes an antibody that reacts against red blood cells, leading to either agglutination or hemolysis.
It is characterized by complement on the red cells surface.
In the cold agglutinin disease the direct anti-globulin test (DAT) is positive for C3d by definition and it is usually negative for immunoglobulins but is weekly positive for IgG in up to 20% of cases.
Activation of the classical pathway results in erythrocyte coating with the split product C3b.
C3b opsonized cells are prone to phagocytosis by the mononuclear phagocytic system, mainly in the liver, resulting in extravascular hemolysis.
C3b can also form C5 convertase, which initiates the terminal complement cascade, which leads to formation of the membrane attack and intravascular hemolysis, at least in some patients.
Most patients with stable cold agglutinin disease, C3 opsonization and phagocytosis comprise the predominant mechanism of hemolysis.
Yet, hemoglobinuria is reported in 15% of cases of cold agglutinin disease, hemosiderinuria occurs relatively frequently, and a beneficial effect of blocking the terminal complement pathway and is seen at least in severely hemolytic patients and during acute exacerbations: terminal pathway activation with intravascular hemolysis does occur in some patients and situations.
About half of patients observation is in appropriate management, as the hemolysis is compensated.
Exacerbation of hemolysis occurring during febrile infections and other conditions with acute phase reaction has been found to occur and at least 70% of these patients.
Constant compliment consumption during steady state disease results in low serum levels of C3 and C4.
A polyclonal form and monoclonal form exist, the former is self limited, and the latter results and sustain chronic hemolysis.
An IgM protein, which can be monoclonal or polyclonal fixes complement to the red cell surface.
Cold agglutinins are characterized additionally by their thermal amplitude, the highest temperature of which the cold agglutination would react with its antigen.
The thermal amplitude is assumed to be more important than the titer with respect to pathogenicity.
IgM is it potent activated of the classical complement pathway resulting in the fixation of the C1qrs complex and subsequent binding and activation of C4 and C2:these combine to form C3 converters which cleaves the next complement proteins, C3 and C3a causing hemolysis.
C3 is deposited on the surface of the red blood cells.
C3 convertase removes C3a, and the red cells are then covered with C3d.
The mono nuclear phagocyte system recognizes C3d, and binds and removes the fragment of the red cell resulting in spherocytes in the peripheral blood.
C3 coated red cells can be recognized for direct antiglobulin testing for complement.
Hemolysis is usually moderate because the C3b coated red cells are eventually cleaved leaving C3d on the surface.
C3d does not interact with mononuclear phagocyte system and so the cells become resistant to hemolysis resulting in a well compensated chronic hemolytic state that may not be transfusion dependent.
The direct Coombs test is very sensitive and specific: A positive test result is graded 1+, 2+, or 3+.
If a direct and indirect globulin test is negative for the complement complement in a patient with anemia, the likelihood of finding a cold agglutinin is only 1%.
Cold agglutinins preferentially bind to erythrocytes at lower-than-core body temperature and can cause erythrocyte agglutination due to their multivalent structure.
A clonal B-cell lymphoproliferative disorder of the bone marrow.
Flow cytometry findings of monoclonal, most often IgMkappa positive, B cell population.
IgM monoclonal protein is identified in 90% of cases.
Bone marrow biopsy shows a lymphoid infiltration consisting of nodular B-cell aggregate and involvement varying from 5%-80%.
Cold agglutinin disease is a difficult-to-treat autoimmune hemolytic anemia in which immunoglobulin M antibodies bind to erythrocytes and fix complement, resulting in predominantly extravascular hemolysis.
CAD Lacks the MYD88 L265 mutatation which distinguishes it from lymphoblastic lymphoplasmacytic lymphoma.
Almost all patients displays circulating monoclonal antibodies encoded by the immunoglobulin heavy changing IGHV 4-34.
The autoantibodies cause hemolysis going to erythrocytes at an optimum temperature of 3-4°C.
Cold agglutinins may show activity at 28-30°C in occasionally approaching 37°C.
C1-activated hemolysis drives risk in CAD.
The biological activity of cold agglutinin is evaluated by its titer, expressed as an inverse value of the highest serum dilution at which agglutination of erythrocytes can be detected.
The titer will be at least 64 and the integer represents the activity of the antibody and the inverse of the dilution, and it is usually much higher.
C1 activates the classical complement pathway triggering a cascade that results in both intravascular and extravascular hemolysis.
This C1-activated hemolysis leaves patients chronically compromised by an unstable hemolytic state.
Cold agglutinins associated with cold agglutinin disease are monoclonal and most often immunoglobulin IgM with gamma chain restriction.
Are hemolysis and cold agglutinin disease is complement dependent.
Hemolysis in cold agglutinin disease is complement dependent.
After IgM cold agglutinin binds to an antigen on the red blood cell surface, complement is activated by the classical pathway: complement activation is essential for hemolysis.
Cooling of blood in acral parts of circulation allows for binding of cold agglutinins and impaired passage through the capillaries.
About half of patients with cold agglutinin disease have cold induced circulatory symptoms such as acrocyanosis or Raynaud- like phenomenon.
Median age of onset 67 years.
A slight female predominance is noted.
It is more severe than previously believed.
It has been linked to increased risk for severe thromboembolic events.
It can result in anemia, fatigue, jaundice, and shortness of breath.
In some cases the urine can darken as the kidneys clear the heme released by red blood cells.
Is blood circulates to the peripheral areas of the body clumping of red cells may result in cooler fingers, toes, tip of the nose and ears, with the development of acrocyanosis.
If the process of acrocyanosis continues for a prolonged period of time, the blood supply to the peripheral tissues is affected and the tissues can ulcerate and die.
To confirm the diagnosis, the blood sample must be kept warm, at 37ᵒC to 38ᵒC from the time it is drawn until it is tested to avoid potential false-negatives.
Refrigeration of the blood specimen must be avoided.
Accounts for 1/5-1/4 of cases of autoimmune hemolytic anemias.
May be transient or of chronic nature.
Transient disease commonly associated with postinfectious illness.
Chronic cases frequently in association with lymphoid malignancies.
Chronic disease seen primarily in individuals over the age of 50 years.
Predominately affects elderly or middle-age people, but it may occur in people as young as 30 years.
Involves binding of antibody in the periphery of the circulation in the cold and release of the antibody on warming.
Monoclonal IgM fixes complement to the red cell membrane, resulting in extravascular hemolysis.
The antibody usually involved is an IgM and rarely an IgG that binds to the red blood cells in a cold environment.
The presence of an antibody on the red blood cell surface leads to the deposition of complement at that site and can lead to hemolysis.
Cold agglutinin titers are determined by the presence of red blood cell agglutination when the patient’s cells are exposed to serial dilutions of the patient’s serum.
The direct antiglobulin test is positive for complement but does not detect IgG or IgM on red blood cell surface.
Low levels of polyclonal cold agglutinins may be present in normal people without clinical significance.
A cold agglutinin titer of 1:64 or less is normal.
Transient elevations of polyclonal cold agglutinins may be observed following infections and in collagen diseases.
The carbohydrate I red blood cell surface antigen is frequently associated with Mycoplasma pneumoniae infection.
In mononucleosis caused by Epstein-Barr virus the target antigen is frequently i.
Patients may complain of acrocyanosis of fingers, toes, nose, ears or Raynaud’s syndrome when exposed to call, with rapid improvement with warming.
Diagnosis: hemolysis is assessed by markers such as lactate dehydrogenase, bilirubin, indirect bilirubin and haptoglobin, and reticulocyte count.
Monospecific direct anti-globulin testing and cold agglutinin titration are essential for a reliable diagnosis.
Peripheral blood smear examinations may show erythrocyte agglutinates, anisocytosis, and polychromasia.
The main corpuscular volume is often spuriously high and red cell count tends to be falsely low, so the calculated hematocrit values are unreliable.
A bone marrow examinationAll patients with suspected CAD should have a bone marrow examination with biopsy and flow cytometry for a B cell clone, IgG quantification, protein electrophoresis and immune fixation.
Anemia in CAD is often mild to moderate, but can be severe.
Anemia in CAD is often mild to moderate, but can be severe.
The median hemoglobin level among CAD patients in cold climates is estimated to be 8.9 g/dL.
Studies of large groups have indicated 40 to 50% of patients with CAD have received transfusions.
Treatment has been mainly supportive in nature.
Recent literature suggest treatment for patients with clinical symptoms of anemia, hemoglobin levels below 10 g/dL, a transfusion requirement, or disabling cold induce circulatory symptoms.
Any bacterial infection should be treated promptly.
Transfusions can be administered if the patient and extremity chosen for infusion are kept warm and an in-line blood warmer is used.
Because corticosteroid therapy responses are probably less than 20% and frequently need unacceptable high maintenance doses among the few responses they should not be used to treat CAD.
No evidence for treatment with these with azothioprine, cyclosporine or other unspecific immuno suppressive therapies is available.
Folic acid administration is recommended but many patients have normal levels in the absence of supplementation.
EPO it relatively high dose has been shown to increase hemoglobin levels.
Effective therapy has been aim to target the pathogenic behaving cell clone.
Rituximab may result in transient improvement in 40 to 50% of patients, although it takes up to several months for that to occur.
A combination of rituximab and bendamustine has reported to suppress the population of lymphocytes with a response rate of more than 60%:median duration of response approximately one year.
There are more responses and complete remissions with rituximab and bendamustine, suggesting that it is the first line treatment in severely affected patients.
Preventing cold exposure and warming transfusions are helpful.
Patients with mild anemia or compensated hemolysis should be monitored without treatment.
Non-pharmacological management includes thermal protection to limit hemolysis and relieve ischemic symptoms.
Therapy includes reduction in the production of the immunoglobulin M monoclonal protein responsible for mediating hemolysis and recently complement inhibitor therapies are attempting to eliminate complement mediated hemolysis.
Steroids and splenectomy are not useful but cytotoxic chemotherapy may be helpful in treatment.
Glucocorticoids should not be used to treat cold agglutinin disease because responses rates are low and patients often require unacceptably high doses to maintain remission.
Inhibition of complement C1s improves severe hemolytic anemia in cold agglutinin disease.
Sutimlimab rapidly stops C1s complement–mediated hemolysis in patients with cold agglutinin disease, significantly increasing hemoglobin levels and precluding the need for transfusions.
Secondary cold agglutinin disease is a rare group of autoimmune hemolytic disorders secondary to other diseases such as mycoplasma pneumoniae, Epstein-Barr virus infection, cytomegalovirus infection, Covid-19, or malignancies such as aggressive B cell lymphoma.
Among treatments directed at the pathogenic B cell clone rituximab is the most commonly used first line therapy with response rates of 45 to 60%, but only with rare complete responses.
Bendamustine plus Rituximab is efficacious: overall and complete response rates of 71% and 40%, respectively.
Bendamustine plus Rituximab estimated median response duration is more than 88 months.
Bortezomib monotherapy is associated with a 32% response rate.
Early studies suggest Ibrutinib , a Bruton’s tyrosine kinase inhibitor is very effective.