View large Download PPT. Cold agglutinin disease revisited: a multinational, observational study of patients. New insights in the pathogenesis and therapy of cold agglutinin-mediated autoimmune hemolytic anemia. Search ADS. Occurrence, thromboembolic risk, and mortality in Danish patients with cold agglutinin disease. Diagnosis and treatment of autoimmune hemolytic anemia in adults: recommendations from the First International Consensus Meeting [published online ahead of print 5 December ].
Bendamustine plus rituximab for chronic cold agglutinin disease: results of a Nordic prospective multicenter trial. Inhibition of complement C1s with sutimlimab in patients with cold agglutinin disease CAD : results from the phase 3 Cardinal Study. Inhibition of complement C1s in patients with cold agglutinin disease: lessons learned from a named patient program.
Sanofi launches global patient registry to advance understanding about cold agglutinin disease. Add comment Close comment form modal. Submit a comment. Comment title. You have entered an invalid code. Submit Cancel. Thank you for submitting a comment on this article. Your comment will be reviewed and published at the journal's discretion. Please check for further notifications by email. Volume , Issue 4. Previous Article Next Article. In most cases of warm antibody hemolytic anemia, the antibody is an IgG identified only as a panagglutinin, meaning the antigen specificity of the antibody can not be determined.
Antibody titers can usually be determined but do not always correlate with disease activity. The direct antiglobulin direct Coombs test may be positive in the absence of autoimmune hemolytic anemia, and thus should be ordered only in the proper clinical setting.
A false-positive direct antiglobulin test may result from the presence of clinically insignificant antibodies. A positive indirect antiglobulin test and a negative direct test generally indicate an alloantibody caused by pregnancy, prior transfusions, or lectin cross-reactivity rather than immune hemolysis. A positive result suggests the presence of autoantibodies to RBCs if the patient has not received a transfusion in the last 3 mo, alloantibodies to transfused RBCs usually seen in acute or delayed hemolytic reaction , or drug-dependent or drug-induced antibodies against RBCs.
This test is also used to determine the specificity of an alloantibody. Once autoimmune hemolytic anemia has been identified by the antiglobulin test, testing should differentiate between warm antibody hemolytic anemia and cold agglutinin disease as well as the mechanism responsible for warm antibody hemolytic anemia.
This determination can often be made by observing the pattern of the direct antiglobulin reaction. Three patterns are possible:. The reaction is positive with anti-IgG and negative with anti-C3. The reaction is positive with anti-IgG and anti-C3. This pattern is common in patients with systemic lupus erythematosus SLE Systemic Lupus Erythematosus SLE Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women.
The reaction is positive with anti-C3 but negative with anti-IgG. This pattern occurs in cold agglutinin disease where the antibody is most commonly an IgM. It can also occur in warm antibody hemolytic anemia when the IgG antibody is of low affinity, in some drug-associated cases, and in PCH. Other studies can suggest the cause of AIHA but are not definitive.
In cold agglutinin disease, RBCs clump on the peripheral smear, and automated cell counts often reveal an increased mean corpuscular volume and spuriously low hemoglobin due to such clumping; hand warming of the tube and recounting result in values significantly closer to normal. Because the PCH antibody fixes complement at low temperatures, the direct antiglobulin direct Coombs test is positive for C3 and negative for IgG. For drug-induced warm antibody hemolytic anemia, drug withdrawal and sometimes IV immune globulin.
For idiopathic warm antibody hemolytic anemia, corticosteroids and, in refractory cases, rituximab , IV immune globulin , or splenectomy. For PCH, avoidance of cold, immunosuppressants, and treatment of syphilis if present. Blood transfusion is the most important treatment for symptomatic patients who rapidly develop severe, life-threatening anemia. In this situation, transfusion should never be withheld due to lack of "compatible" units. In general, patients who have not had a previous blood transfusion or been pregnant are at low risk for hemolysis of ABO-compatible blood.
Even if transfused cells are hemolyzed, blood transfusion can be life-saving until more definitive therapy can be done. In drug-induced warm antibody hemolytic anemias, drug withdrawal decreases the rate of hemolysis. With hapten-mediated AIHA, hemolysis ceases when the drug is cleared from the plasma. When stable RBC values are achieved, corticosteroids are tapered slowly with laboratory monitoring of hemolysis eg, by hemoglobin and reticulocyte counts.
The goal is to wean the patient completely from corticosteroids or to maintain remission with the lowest possible corticosteroid dose. About two thirds of patients respond to corticosteroid treatment. In patients who relapse after corticosteroid cessation or who are refractory to corticosteroids, rituximab is usually used as a second-line drug.
About one third to one half of patients have a sustained response after splenectomy. In cases of fulminant hemolysis, immunosuppression with high-dose pulse corticosteroids or cyclophosphamide can be used. For less severe but uncontrolled hemolysis, immune globulin infusions have provided temporary control.
Long-term management with immunosuppressants including cyclosporine has been effective in patients in whom corticosteroids and splenectomy have been ineffective. The presence of panagglutinating antibodies in warm antibody hemolytic anemia makes cross-matching of donor blood difficult. In addition, transfusions could superimpose an alloantibody on the autoantibody, accelerating hemolysis.
Thus, transfusions should be avoided when anemia is not life-threatening but should not be withheld in patients with severe autoimmune hemolytic anemia, particularly when the reticulocyte count is low. In many cases, avoidance of cold environments and other triggers of hemolysis may be all that is needed to prevent symptomatic anemia.
In cases associated with a lymphoproliferative disease, treatment is directed at the underlying disorder. Rituximab is commonly used, and chemotherapy regimens used to treat lymphoproliferative disorders can be effective. In severe cases, plasmapheresis Plasmapheresis Apheresis refers to the process of separating the cellular and soluble components of blood using a machine.
In cases where an underlying cause is established, specific therapy directed at that cause or removal of an inciting agent may be effective. Glucocorticoids oral prednisone or IV methylprednisolone should affect hemolysis within days. Steroids reduce the production of autoantibody and splenic sequestration of red blood cells. The anti-CD20 monoclonal antibody rituximab is another alternative strategy that serves to deplete the B-cells presumed to be producing the autoantibody.
However, many patients require repeated treatments. Untreated hepatitis B is a relative contraindication to rituximab. Splenectomy can be effective in refractory cases or those cases where corticosteroids are not effective. Immunosuppressive agents such as cyclophosphamide, azathioprine, mycophenolate mofetil or 6-mercaptopurine can reduce hemolysis over time, presumably by reducing the amount of autoantibody production.
Danazol, a synthetic anabolic steroid, may have activity, particularly when combined with glucocorticoids. Since the anemia tends to be episodic in relation to ambient temperature, the severity of cold agglutinin disease is related to the thermal amplitude of the cold agglutinin. Primary therapy is avoiding temperatures lower than the threshold of the autoantibody.
Unlike in warm agglutinin disease, glucocorticoids tend to offer little benefit since they do not affect complement-mediated lysis of red blood cells, which is the primary mechanism of hemolysis in cold agglutinin disease. Splenectomy is of no benefit as red blood cells coated in C3 undergo phagocytosis in the liver or are destroyed by complement-mediated lysis.
The most important piece of management is attempting to identify and treat an underlying cause, such as malignancy. Case series have shown modest activity of rituximab with or without fludarabine in refractory cases. Plasmapheresis can be effective in removing IgM from serum; however, it does not provide long-term control as antibody production continues. Cytotoxic chemotherapy to reduce antibody production is of little benefit unless the antibody is related to underlying hematologic malignancy.
In patients with severe hemolysis, multiple transfusions may be necessary to maintain adequate oxygen delivery. In cases of cold agglutinin disease, transfused blood should be administered through a blood warmer. Initial response to transfusion may be poor as hemolysis of both transfused and autologous cells continues during transfusion. Response to steroid therapy should occur within hours of initiation.
Acutely, the expectation is reduction in hemolysis, not resolution. Ultimately, most patients will have cessation of hemolysis.
Relapses are not uncommon. Disease monitoring occurs by following hemoglobin level, reticulocyte count, and LDH. The patient should be followed by a hematologist until resolution of hemolysis. Continued evaluation may reveal an underlying disease process, manifested initially by AIHA. Antibodies responsible for this syndrome are typically IgG antibodies against protein antigens on the red cell surface.
In primary AIHA, they are typically specific for a single protein, suggesting an underlying abberrant immune response to a self antigen or a foreign antigen very similar to a self protein.
Defective immune regulation may lead to the antibody production in secondary AIHA, as in patients with lymphoma.
RBC destruction is mediated by these autoantibodies, which occurs by phagocytosis or complement-mediated lysis.
Phagocytosis occurs primarily in the cords of Billroth in the spleen. There, macrophages with Fc receptors and complement receptors bind IgG and complement present on the surface of affected RBCs.
This process can occur, to a lesser extent, by Kupffer cells in the liver as well. Macrophages can completely or partially ingest RBCs. Partially ingested RBCs lose more cell membrane than cell volume. This leads to spherocyte formation, as a sphere has the lowest surface area to volume ratio.
Spherocytes are less flexible than normal red blood cells and can be destroyed subsequently in the spleen. Intravascular complement-mediated lysis occurs infrequently in warm AIHA as most IgGs do not efficiently fix complement.
Antibodies responsible for this syndrome are typically IgM antibodies against polysaccharides on the red cell surface. IgG antibodies are rarely implicated in this process an exception would be IgG Donath-Landsteiner autoantibodies present in Paroxysmal Cold Hemoglobinuria.
Each IgM can bind two red blood cells, requiring a smaller number of antibodies than IgG for in vitro agglutination to be apparent.
Phagocytic cells do not have IgM receptors, so much of hemolysis due to cold autoantibodies is due to complement-mediated lysis. When red blood cells and the responsible IgM are present at sufficiently cold temperatures usually in the distal extremities, nose, and ears , the autoantibody binds to red blood cells and fixes C3 and C4.
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