The incidence of autoimmune hemolytic anemia (AIHA) is about 1/80 000, the frequency increases beyond 40-50 years. Cases of paroxysmal hemoglobinuria frigore are distinguished by their rarity and their onset in childhood after a viral infection; evolution is usually transient. More than half of autoimmune hemolytic anemia remains idiopathic, one must put aside immuno-allergic haemolysis, mostly drug, which does not belong strictly speaking to autoimmune haemolysis but that should be mentioned because of the frequent positivity of a Coombs test (see: To deepen 2). In autoimmune hemolytic anemia, there is loss of tolerance vis-à-vis some of the red cell antigens; if its mechanism is unknown, associated disorders, hematological malignancies, autoimmune diseases, immunodeficiency reveal genetic anomalies or acquired humoral immunity. Among lymphoproliferative disease, chronic lymphocytic leukemia is the underlying condition most common (7-25%), while the incidence of other diseases, non-Hodgkin lymphoma or Hodgkin’s much more rare (less than 2%) . Special attention should be made to angio-immunoblastic lymphadenopathy (type of T-cell lymphomas with hypergammaglobulinemia and autoantibody) indeed, in nearly half the cases there is an autoimmune hemolysis. Among the autoimmune diseases, hemolysis is common in systemic lupus rare in rheumatoid arthritis and ulcerative colitis. The association with immunologic thrombocytopenia (Evans syndrome) is fairly common; the prognosis of this disease with double autoimmune red blood cell and platelet is worse than each of cytopenias in isolation. Many of these autoimmune disorders may succeed or be observed immediately. Autoimmune hemolytic anemia, sometimes associated with other cytopenias involving platelet or granulocyte line can be observed in some genetic or acquired immunodeficiencies (immune deficiency in adults said common variable). Various solid tumors have been associated with autoimmune hemolysis; the strongest link concerns ovarian tumors that must be systematically sought (ovarian cyst) since the treatment of the tumor can lead to healing autoimmune hemolysis. Autoimmune haemolysis coinciding with an infectious disease, usually viral take on the appearance of a transient acute anemia, especially in children. A high titer of cold agglutinins and (or) moving towards a pneumonia mycoplasma disease;anti-red blood cell autoantibodies are common in infectious mononucleosis. Most often, the virus is not identified. A few cases of autoimmune hemolysis revealing itself during pregnancy and disappears after childbirth have been reported.
A- Clinical signs:
The beginning of an autoimmune hemolysis varies. It can be acute, anemia settling in a few days with fever, gastrointestinal symptoms and signs of anoxia even hypovolemic shock with haemoglobinuria. This mode of revelation is common in acute transient hemolysis of the child. Usually the onset is gradual with symptoms related to anemia (asthenia, dyspnea, palpitations, angina), sometimes unexplained fever. Rarely jaundice or dark urine lead to the discovery of anemia. Clinical examination revealed pallor, often moderate jaundice, splenomegaly. Clinical signs of an associated disease can also be revealing. Specific clinical signs are observed in the cold hemagglutinin disease. There is indeed upon exposure to cold extremities vascular events: Raynaud’s syndrome, acrocyanosis caused by the agglutination of red blood cells in the subcutaneous tissue of the nose, toes, ears, sudden discoloration skin accompanied by numbness and sometimes pain. These events are responsible for trophic disorders up to the necrosis. The intensity of anemia varies from March to October g / dL, normocytic, normochromic macrocytic sometimes reflecting the reticulocytosis sometimes érythroblasto- myelemia. A spherocytosis is suggestive of autoimmune hemolysis. Reticulocytosis is frankly high between 100 and 800,000 / mm3. It can be delayed or even absent in some clinical forms where there is a simultaneous destruction of red blood cells and erythroblasts, marrow while being the seat of ineffective erythropoiesis. PRCA may be immune mediated or related to infection with parvovirus B19. Myelogram may have diagnostic value when there is an underlying lymphoid hematological. Note the frequency on the blood count of leukocytosis with normal blood counts and thrombocytosis showing a spinal cord repair certainly interesting erythroid but other myeloid lineages. Other biological signs bear witness to the destruction of red blood cells, increased unconjugated bilirubin which however is inconstant; its degree is a function of the intensity of anemia and severity of hemolysis. Urine contains urobilin, hemoglobin in acute hemolysis. The fall of haptoglobin is proportional to the degree of hemolysis, almost constant, indicating, whatever the mechanism and the seat of the red blood cell destruction of intravascular destruction also reflected by the increase in lactic dehydrogenase rates. When the clinical and laboratory tests can not formally say autoimmune hemolysis, the study of the life of the red blood cells of the patient, such as that of normal red blood cells of allogeneic same phenotype reveals a peripheral destruction of red blood cells Immunological principle; this examination can also learn about the siege of destruction, splenic, hepatic, or mixed.
B- immuno-hematological diagnosis:
It is based on the direct Coombs’ test, because of its simplicity and sensitivity, is the examination but also on the critical study of the eluate of the red blood cells and the characterization of the serum antibodies. These examinations should affirm the presence of autoantibodies directed against an antigen of red blood cells and identify their specificity.
The direct antiglobulin test detects the red cell surface anti-red blood cell autoantibodies or complement components. The reagents used are so-called polyspecific antiglobulin containing antibodies against different classes of human immunoglobulins and against various complement components (two multipurpose antiglobulins that might be used as the quality of these reagents is variable); an antiglobulin directed against the human IgG immunoglobulins characteristic of autoimmune hemolytic anemia in hot and antiglobulin antibody recognizing the complement fractions including C3d, C3b, C4d. Other reagents are used only in rare situations (reacting with IgM globulin or IgA, rarely involved in autoimmune haemolysis). The conventional technique is based on the agglutination of red blood cells of the patient after washing. The agglutination reaction takes place on plate, tube or may be sensitized by macromolecules (technique autoanalyzer). The lower limit of detection of IgG molecules bound to the surface of red blood cells is about one hundred per red cell. Direct Coombs test, however, has some limitations; there are hemolytic anemias autointraimmunes Coombs negative the density of autoantibody to the surface of the red cell is low or that the reagent (antiglobulin) has insufficient quality. Secondly, the positivity of a Coombs test can be observed outside an autoimmune hemolysis after blood transfusion (transfused erythrocytes are sensitized by alloantibodies produced by the recipient), as a result of injections of therapeutic human products (IVIG) or animal (antilymphocyte serum). It is unusual to observe a positive Coombs test in the absence of autoimmune hemolysis although the presence of IgG or certain complement components have been described in normal subjects.
2- eluate Study:
Elution is designed to detach from the surface of the erythrocytes the antibodies fixed to allow to study their specificity. It is performed by physical or chemical methods (heat, ether). It can be positive while the direct Coombs test is negative.
3- serum Study:
It allows an indirect Coombs reaction to confirm the presence of autoantibodies to specify the nature of the antibody in question (IgG or IgM), analyzing the optimum temperature and thermal amplitude the antibody to study the specificity of the autoantibodies for the presence of hemolysin, appreciate in time the title of autoantibodies and monitor the response to treatment. The absence of serum auto-antibodies did not rule out the autoimmune nature of hemolysis. Cold agglutinins are searched by a tube agglutination reaction at 4 ° C.
A- hot Autoantibodies:
They are essentially IgG nature, their ability to fix complement differs depending on the IgG subclass and the amount of autoantibodies present on the red cell surface. The direct Coombs test is usually IgG type, rarely IgG and complement. There are more exceptionally warm autoantibodies IgM type complement fixing which is then detected by the direct Coombs test, IgM antibodies are detected in serum rarely in the eluate. Hemolytic activity (hot hemolysin) may also be highlighted. IgG antibodies are directed against epitopes expressed by the Rh antigen complex (only red blood cells not expressing the complex are Rh negative in the Coombs test). Some IgG antibodies recognize clearly identified antigens of the Rh locus (E, C, E, C). Other antigen specificities are rare.
B- cold Autoantibodies:
It is of low thermal optimum autoantibodies (+ 4 ° C), such IgM and complement-fixing. Their temperature range is variable and can reach 37 ° C. This amplitude plays a role in the clinical expression of these autoantibodies. It may be polyclonal IgM autoantibodies (acute illness with cold agglutinins) or monoclonal IgM (chronic cold agglutinin disease). The Coombs test is positive, complement one type. Autoantibodies are rarely present in the eluate are detected by against, to a high titer in the serum. The specificity of these IgM autoantibody is usually directed against blood group Ii (only anti-I antibodies cause hemolysis as adult RBCs are usually lacking the antigen i). Specificity for blood group Pr is not exceptional. Autoantibodies (or hemolysin) “biphasic” are rare; it is IgG nature of complement fixing antibodies. The two-phase term is used in reference to the 2-stroke technique requiring their demonstrated in vitro binding of antibodies at low temperature, incubation at 37 ° C with elution of the antibodies and complement activation. The direct Coombs test is usually supplement type, rarely type supplement IgG. The specificity of this biphasic hemolysin is directed against an antigen of the group P; hemolysin is responsible for acute anemia, usually postinfectious of the child. This classification of autoimmune hemolytic anemia is useful for diagnosis, prognosis and treatment of patients. The combination hot and cold antibody is not exceptional. The Coombs test is positive while IgG and complement. There are high antibody cold thermal amplitude. Usually hemolysis is severe. Hot and cold antibody antibodies may succeed in time in the same patient.
A- Hemolysis in “hot” antibodies:
Corticosteroids (Cortancyl) is an effective treatment but rarely allow healing. Corticosteroids may decrease the synthesis of autoantibodies, modify the affinity of the antibody for the target antigen on the red cell finally change the clearance of cells sensitized by the macrophage system. Corticosteroid therapy is used, unless formally against-indication, at a dose of 1 to 2 mg / kg; the reduction of hemolysis is observed between 1 and 6 weeks with ascent of hemoglobin and lower indirect hemolysis. The use of high doses of cortisone bolus intravenously in severe hemolysis may be considered. The reduction in dosage should be conservative, started when the hemoglobin level reaches 11-12 g / dL and occurs in 6 to 12 months. In case of relapse, a higher dose may be taken, it will prove effective and usually a more gradual reduction should be attempted. In over 80% of cases, corticosteroids can not be abandoned and maintenance therapy continued at a variable dose between 0.1 and 0.2 mg / kg. The limits of corticosteroids frequently leads to consider splenectomy effective in about 50% of cases. However, early or late relapses can be observed. Corticosteroids may be needed when remission is incomplete. Failures or cons-indications of corticosteroids and (or) splenectomy can lead to immunosuppressive therapy that, in these situations will inevitably be prolonged and can be used azathioprine (Imurel) or cyclophosphamide (Cytoxan) . This effective immunosuppressive treatment in a third of patients may also allow a “savings” steroid. Other possible treatments are danazol, a synthetic androgen low androgenic activity or use of intravenous immunoglobulin in high doses. The short- and long-term results of these treatments are still very uncertain. The treatment of associated diseases including malignant lymphoid proliferations or autoimmune diseases, have little influence on the therapeutic approach; However, it is legitimate, especially in recent affections, to try to treat the underlying disease effectively.Symptomatic treatment of anemia may require transfusions of packed red cells. This treatment is considered in cases of extreme anemia or resistance after a few days or initial ineffectiveness of corticosteroids. The characteristics of autoantibodies does not avoid hemolysis of transfused red blood cells and must therefore adapt transfusions functional impact of anemia (anoxia, angina). Rarely ablation of a tumor or a colectomy in ulcerative colitis allow healing of hemolysis.
B- Hemolysis in “cold” antibodies:
Corticosteroid therapy is usually ineffective except perhaps when the title of cold agglutinins is low and wide temperature range between 4 and 37 ° C. Splenectomy is usually ineffective since the destruction of erythrocytes takes place in the liver. In chronic cold agglutinin disease, when there is an associated lymphoid blood disease, chemotherapy reduces the clone B synthesizing autoantibodies therefore reduced under cold agglutinins and attenuation or absence of hemolysis . When there is no associated lymphoid hematological, this treatment is rarely effective. When hemolysis is moderate, symptomatic treatment, common sense precautions to avoid exposure to cold-related accidents must be advised. In case of hemolytic thrust, blood transfusions warmed to 37 ° C are justified.
Highlights to understand:
• autoantibodies responsible for autoimmune hemolytic anemia were first characterized pathogenic autoantibodies in human pathology. They are responsible for shortening the lifespan of red blood cells (see: To deepen 1).
• intensity of anemia is variable, there is a regenerative acquired anemia accompanying biological signs of destruction of red blood cells (increased bilirubin, the lactic dehydrogenase [LDH], decreased haptoglobin).
• The immuno-hematology diagnostic centers on the Coombs test for defining the nature and specificity of autoantibodies. We distinguish autoimmune hemolytic anemia in hot and cold antibody antibody according to temperature to which these antibodies have a maximum affinity for the red blood cell. These two entities represent different clinical and developmental charts. Immuno-hematology also for the presence of antibodies in serum or hemolysin.
• About half of autoimmune hemolytic anemia is idiopathic, the other half associated lymphoid blood disease, an autoimmune disease or an immune deficiency.
• The hemolytic anemias immunoallergic, involving a drug, ask different questions.
• The treatment according to the characteristics of hemolysis based on corticosteroids and immunosuppressants splenectomy.
Strong Points to remember:
• The diagnosis of autoimmune hemolytic anemia is easy to talk in front of a regenerative anemia gained; the Coombs test is essential diagnostic argument, however there are autoimmune haemolysis with Coombs negative diagnosed on shortening the life of autologous red cells and those of a healthy subject. There are also situations where the Coombs test is positive without overt hemolysis (normal lifespan).
• The treatment of autoimmune hemolytic anemia in so-called warm antibodies (Coombs test IgG or complement IgG) based on corticosteroids, splenectomy and (or) immunosuppressive therapy.
• In chronic forms, corticosteroid therapy, regardless associated treatments must often be continued for many years.
• An associated condition justifies own treatment and its evolution is often dissociated from autoimmune haemolysis (chronic lymphocytic leukemia for example).
• In autoimmune hemolytic anemia Cold antibody, Coombs test is positive complement type and there is a high titer of autoantibodies of IgM class.
• Chronic forms correspond to the monoclonal proliferation of B cell clone synthesizing anti-red blood cell autoantibodies that are monoclonal, usually directed against determinants of Ii blood.
• The destruction of red blood cells are liver, treatment is often only symptomatic; when there is a blood disorder associated lymphoplasmacytic, chemotherapy should be proposed as the efficacy of lymphoid hematological causes a decrease in the rate of red blood cell anti-autoantibodies.
1 / red cell destruction mechanism:
Hemolysis results of various mechanisms. Complement activation can result in the formation of the membrane attack complex (C7, C8, C9) causing the intravascular erythrocyte lysis. In fact, because of the inhibitory systems complementary way, activation usually stops at the C3 fraction resulting in the degradation of this molecule and the binding to the membrane of red blood cell fragment C3 (C3b in particular). The presence of these fractions will allow their interaction with complement receptors, including CR3 receptor present on monocytes, macrophages and neutrophils that play a major role in phagocytosis and destruction of red blood cells. In hemolysis in hot IgG, awareness of red blood cells also leads to increased phagocytosis. The destruction of red blood cells sensitized with IgG autoantibody is mainly in the spleen (hence the efficiency of splenectomy in this variety of autoimmune haemolysis) whereas erythrocytes sensitized by the addition (in the chronic disease cold agglutinin) is mainly in the liver (ineffective splenectomy).
2 / Anemia Drug-induced immune hemolytic:
Drug hemolysis belong to the differential diagnosis of an autoimmune hemolysis. Different mechanisms have been proposed to explain the production of antibody antimédicaments and (or) of autoantibodies resulting in hemolysis.The a-methyldopa results in approximately 15% of the patients the occurrence of hot autoantibodies identical to those of idiopathic forms. Hemolysis is observed that in 10% of patients with a positive Coombs test. This drug appears to favor the production of anti-Rh autoantibody positivity Coombs test disappears a few weeks or months after discontinuation of medication. A drug (or one of its metabolites) may be absorbed on the surface of red blood cells resulting in the production of antibodies against the red blood-drug complex. The Coombs test is positive then only in the presence of the drug. Finally, it is accepted that drug-antibody complexes can be established in serum and absorb secondarily on the red cell membrane resulting in complement activation and hemolysis. The immuno-haematological diagnosis is often very difficult because the chemical responsible for the immune response may be one of the drug in vivo metabolites and a search for negative anti-drug antibodies can rule out the diagnosis of anemia.