Autoimmune hemolytic anemia pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Assosciate Editor(s)-In-Chief: Prashanth Saddala M.B.B.S; Shyam Patel [2], Irfan Dotani [3]
Overview
The pathophysiology of autoimmune hemolytic anemia is different for warm-antibody type and cold-antibody type anemia. The pathophysiology of warm-antibody type autoimmune hemolytic anemia involves the coating of red blood cells with IgG, followed by extravascular hemolysis by splenic macrophages. The pathophysiology of cold-antibody type autoimmune hemolytic anemia involves the coating of red blood cells with IgM, followed by intravascular hemolysis. The complement system has a significant role in autoimmune hemolytic anemia and involves the binding of classical complement proteins on the red blood cell surface, followed by cell lysis by the membrane attack complex. In summary, a variety of cell-mediated immunologic mechanisms underlie the pathophysiology of autoimmune hemolytic anemia.
Pathophysiology
Warm autoimmune hemolytic anemia
The pathophysiology of warm autoimmune hemolytic anemia involves immunoglobulin G (IgG) antibodies binding to red blood cells at a temperature of 37 degrees Celsius. [1] The designation of warm is based on the fact the optimal binding temperature is 37 degrees Celsius, or normal body temperature. The IgG antibodies are typically polyclonal, meaning that they recognize a variety of antigens.[2] Macrophages bind to the antibody-coated red blood cells via the Fc receptors and result in extravascular destruction. The Fc receptors include Fc-gammaRI (CD64), Fc-gammaRII (CD32), and Fc-gammaRIII (CD16). In 15-20% of cases, the autoantibody involved is IgA.[2] It has been shown that induction of autoimmune hemolytic anemia is controlled by an immunosuppressive population of T lymphocytes known as regulatory T cells.[1]
Cold autoimmune hemolytic anemia
The pathophysiology of cold autoimmune hemolytic anemia, or cold agglutinin disease, involves immunoglobulin M (IgM) antibodies binding to Ii carbohydrate antigens of red blood cells at a temperature of 3-5 degrees Celcius. Agglutination typically occurs in the distal aspects of the extremities, such as the fingers and toes, because these areas have the lowest temperature.[3] Clinical manifestations of this pathophysiology includes Raynaud's phenomenon and acrocyanosis.[3] The IgM molecules will trigger activation of the complement system, which results in red blood cell lysis.[3] When IgM-bound red blood cells circulate towards warmer areas of the body, such as the trunk, IgM will dissociate from the red blood cells and complement C3b will remain bound.
Role of the complement system
The complement system is partially involved in the pathophysiology of warm autoimmune hemolytic anemia. There is a stronger role for the complement system in certain types of autoimmune hemolytic anemia, such as paroxysmal cold hemoglobinuria, cold agglutinin disease, and cold agglutinin syndrome.[3] The complement system plays a role in both extravascular hemolysis and intravascular hemolysis in autoimmune hemolytic anemia.
- Complement activation by immunoglobulin subclasses: The immunoglobulin type that is most potent in activating complement is immunoglobulin M (IgM). However, IgM is not typically detected in the Coombs' test, so IgM-mediated hemolysis will likely manifest as a Coombs'-negative hemolytic anemia. Immunoglobulin G (IgG) can activate complement, and the different IgG subclasses have differentially ability to activate complement. IgG3, for example, is a more potent activator of complement than IgG1. IgG4 and immunoglobulin A (IgA) are unable to activate complement.[3]
- Extravascular hemolysis: The pathophysiology of extravascular hemolysis in autoimmune hemolytic anemia involves destruction of red blood cells outside the blood vessels and inside the liver and spleen. This is largely due to complement protein C3b-mediated phagocytosis of red blood cells. This process begins with the C3 convertase, which leads to production of complement protein C3b. This protein normally functions to opsonize bacteria and prevent infection, as part of the innate immune system. However, in pathological conditions such as autoimmunity, C3b binds to the surface of red blood cells. Opsonization by C3b triggers the macrophages of the reticuloendothelial system to phagocytose these opsonized cells via complement receptors on the surface of macrophages. This phagocytosis occurs extravascularly, typically in the liver or spleen. In some cases, ectoenzymes that are located on the surface of macrophages can perforate red blood cell membranes and create spherocytes.[3] When the amount of red blood cell membrane removed exceeds the intracellular volume removed, the biconcave disc shape becomes a spherocytic shape. This is the pathophysiologic basis for spherocytes in autoimmune hemolytic anemia.[3] Upon passage through the splenic vasculature, spherocytes can destroyed.
- Intravascular hemolysis: The pathophysiology of intravascular hemolysis in autoimmune hemolytic anemia involves destruction of red blood cells inside the blood vessels. This is largely due to activation of the terminal complement system.[2] This complement cascade begins with complement protein C5, which is activated to C5a and C5b by the C5 convertase. C5a is a potent anaphylactic molecule, C5b is a membrane-bound protein that binds to downstream complement molcules, such as C6 though C9. The union of C5b and C6 though C9 forms the membrane attack complex. This complex can exert direct cytotoxic activity via the creation of pores in red blood cell membranes, resulting in cell lysis intravascularly.[2]
Excess complement activation
- In some cases, the complement system can become activated very strongly, resulting in excess immune activation and red blood cell destruction, which can be lethal. This is due in part to a feedforward loop or positive feedback system, in which activation of the initial components of the complement cascade triggers activation of additional complement components.[2]
References
- ↑ 1.0 1.1 Mqadmi A, Zheng X, Yazdanbakhsh K (2005). "CD4+CD25+ regulatory T cells control induction of autoimmune hemolytic anemia". Blood. 105 (9): 3746–8. doi:10.1182/blood-2004-12-4692. PMC 1895013. PMID 15637139.
- ↑ 2.0 2.1 2.2 2.3 2.4 Berentsen S (2015). "Role of Complement in Autoimmune Hemolytic Anemia". Transfus Med Hemother. 42 (5): 303–10. doi:10.1159/000438964. PMC 4678321. PMID 26696798.
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Berentsen S, Sundic T (2015). "Red blood cell destruction in autoimmune hemolytic anemia: role of complement and potential new targets for therapy". Biomed Res Int. 2015: 363278. doi:10.1155/2015/363278. PMC 4326213. PMID 25705656.