Guidelines for the Diagnosis and Management of AIHA PDF

Guidelines for the diagnosis and management of AIHA Supervised by : Dr. Zainab E. Al-Hatim Presented by : Aya Mohammad/3rd stage Iraqi board of hematology Introduction : The acquired hemolytic anemias are divided into two main categories, depending on the mechanism by which the...

Guidelines for the diagnosis and management of AIHA Supervised by : Dr. Zainab E. Al-Hatim Presented by : Aya Mohammad/3rd stage Iraqi board of hematology Introduction : The acquired hemolytic anemias are divided into two main categories, depending on the mechanism by which the premature destruction of red blood cells is produced : 1) Immune, in which antibodies are the main agents of RBC destruction 2) Non-immune, resulting from diverse causes and mechanisms of hemolysis. The immune hemolytic anemias are distinguished from the non immune by detecting antibody on the surface of red cells by the direct antiglobulin test (DAT), or Coombs test which detects antibody, with or without complement, on the red blood cell surface.  Direct antiglobulin test (DAT) : o Once hemolysis is confirmed, further investigation is needed to establish whether that hemolysis is immune, principally by the direct anti-globulin test (DAT). o If patient RBCs harbor either IgG or complement, the polyclonal reagent will cause agglutination. o Further testing after a positive polyclonal agglutination with monoclonal reagents determines if IgG and C3 are each present individually. o Once an antibody is identified, it can be eluted from the patient RBC and its specificity determined by analysis against RBC panels of known blood antigens. It should be remembered that a positive DAT can occur as a result of other processes such as : 1. Passive deposition of antibodies or immune complexes in: Liver disease, Chronic infection, Malignancy, Systemic lupus erythematosus (SLE), Renal disorders 2. Following drug therapies, such as IV Ig or anti-thymocyte globulin. If no alternative cause is identified, a diagnosis of AIHA can be made. Immune Hemolytic Anemia : It refers to an antibody-mediated hemolysis. Antibodies may be : 1) Autoantibodies produced by a patient’s own immune system and directed against epitopes of his own red cell antigens. Auto-Abs are divided into ‘warm’ and ‘cold’ types depending on the characteristic temperature at which the red cell autoantibody is mostly reactive.  Warm (IgG) autoantibodies bind to red cells more strongly at 37 ◦C and have decreased affinity at lower temperatures Cold (IgM) autoantibodies bind to red cells more strongly at 4 ◦C, with little affinity at physiologic temperatures. 2) Alloantibodies produced by the patient and directed against antigens not present on that person’s own red cells, but introduced as foreign red cell antigens by blood transfusion or secondarily acquired by the patient’s red cells, as in drug- induced hemolysis. Alloantibodies directed against the patient’s red cell antigens might also be introduced from outside the patient, most notably from the mother in hemolytic disease of the newborn. Features of warm-acting antibodies : Those are mostly active in vitro at 37 ◦C, They are polyclonal and IgG antibodies predominate, The antibody detected in the patient’s serum is pan-reacting with all cells in a routine group O panel. Those antibodies may be detected in the serum at 37 ◦C by the indirect antiglobulin test (IAT) in about 50–60% of patients; rising to more than 90% of cases when the red cell membrane of the reagent cells is modified with papain or another proteolytic enzyme.  The specificity of warm type Abs is most commonly in the Rh blood group complex, I. 10–15% showing specificity for either anti-e, anti-D or anti-c. II. A greater proportion show specificity by reacting with all cells except –/–Rhnull cells. III. Other rare specificities include anti-Ena, anti-Wrb or anti-U. Features of cold-acting antibodies : Those are predominantly IgM, They are most actively bound to antigen in the cold (4 ◦C). They act both as agglutinins and lysins in vitro; the two functions may have different thermal ranges. They produce no clinical disturbance above 32 ◦C ▪ The IgM can potently activate complement, which causes C3 deposition on the red cells. ▪ C3 deposition can mediate RBC engulfment by splenic or hepatic macrophages, and cause RBC lysis. ▪ In vitro, the IgM antibodies elute off the red cell membrane, leaving bound complement to be detected by anti-C3d in the DAT.  The IgM antibodies have specificity mainly for the I antigen although anti-i specificity may be found in: I. Epstein–Barr virus (EBV)- associated infection II. Some cases of LPD. III. In cold agglutinin syndrome, anti-i specificity is usually seen. Cold antibody specificity is rarely for anti-Pr, anti-P, anti-M or anti-N and even cold reacting anti-A or anti-B. ❑ The cold antibodies could be : Monoclonal (IgM κ) , as those In idiopathic cold haemagglutinin disease (CHAD) and most cases associated with LPD. Polyclonal, as those associated with viral infections.  The antibodies in a subtype of cold AIHA, paroxysmal cold hemoglobinuria (PCH), are IgG and bind to antigen below 20 ◦ C. When the temperature is raised to 37◦C in the presence of complement, lysis occurs. This biphasic reaction is the basis of the Donath– Landsteiner reaction. In PCH, the specificity of the autoantibody is anti-P. Autoimmune hemolytic anemia (AIHA) It is a family of immune-mediated disorders precipitated by autoantibodies against RBC antigens. It is characterized by a positive coombs test. Hemolysis is mainly extravascular; the red cells are more commonly coated with IgG only and IgG-coated red blood cells are destroyed in the spleen. In cases where the red blood cells are coated with a combination of IgG and complement or with complement alone, the main site of destruction is the liver, but intravascular hemolysis may also occur.  In the majority of cases of AIHA, the pathogenesis involves a disturbance of the immune system in which T-lymphocyte control of autoreactive B lymphocyte clones is reduced.  Most cases of AIHA in adults are mediated by IgG that recognizes RBC at physiologic temperature (37°C), termed warm AIHA. IgM autoantibodies are clinically relevant at lower temperatures, termed cold AIHA. Some patients can have both IgG and IgM, termed mixed AIHA, this type tends to produce a more severe hemolysis with an intravascular component. It is most commonly associated with SLE or lymphoproliferative disease (LPD). Around 10% fail to demonstrate a positive Coombs test, which is termed atypical or Coombs-negative AIHA (due to a low-affinity antibody or an IgA-only antibody  The classifications are further characterized as primary or secondary. In primary (idiopathic) AIHA no clear provoking or associated condition is present. Secondary AIHA occurs when the AIHA is associated with an underlying disorder; however, this disorder may not be evident on presentation. Evaluation for secondary causes is helpful as this may change medical management.  Mechanisms for immune red cell destruction : There are two main mechanisms in vivo: 1. Cell mediated immune destruction which is predominantly extravascular 2. Complement-mediated intravascular hemolysis  Cell-mediated immune destruction The destruction of antibody-coated red cells is carried out by macrophages and monocytes which have cell-surface receptors for the Fc portion of IgG and for antigenic determinants present on activated C3. Macrophages of the reticuloendothelial system within the spleen, liver and bone marrow are the main site of destruction in vivo  Role of the spleen As blood passes through the central arteries, the branches of these arteries have a plasma-skimming effect that raises the hematocrit of the blood as it passes towards the splenic cords. There, red cells come into close contact with splenic macrophages. The low plasma content and the relative lack of free plasma IgG molecules allow red-cell bound IgG to interact preferentially with macrophage Fc receptors, leading to phagocytosis of coated red cells  When phagocytosis is partial, only portions of the cell membrane are removed, so the remaining circulating red cell becomes spherocytic. Those rigid spherocytes may be trapped in the splenic sinusoids and destroyed. The spleen is the major site of red cell destruction when IgG alone is the main Fc- binding protein on the red cell surface.  Role of the liver Kupffer cells are macrophages that are present in the liver sinusoids and which express Fc receptors on their surface. Blood flow through the sinusoids is rapid compared with the spleen and there is no plasma-skimming effect so IgG-coated red cells are not preferentially destroyed in this situation. Instead, there is competition for the Fc receptors from circulating IgG and red cell destruction is more dependent on cells being coated with C3.  C3 receptor mechanism: Two types of C3 receptor have been identified on macrophages: CR1 and CR3 Immune adherence of C3b coated red cells to macrophages occurs mainly through CR1, whereas CR3 binding triggers phagocytosis. The largest concentration of C3b-binding macrophages is found in liver sinusoids and the liver becomes the major site for trapping and phagocytosing C3b-coated red cells.  Complement activation and Complement-mediated intravascular hemolysis: Complement activation on the red cell membrane may be caused by autoantibodies against red cell antigens. IgM molecules, IgG1, IgG2 and IgG3 can activate complement, whereas IgG4 and IgA do not. In AIHA, complement activation usually stops at the C3 stage where C3b is bound to the membrane and further proteolysed to form the inactive component C3d, which is detected by the appropriate DAT.  Complement activation beyond the C3 stage may lead to the formation of the membrane attack complex resulting in intravascular haemolysis. Complement-mediated intravascular haemolysis is a minor mechanism for red cell destruction in most patients with AIHA. Other factors influencing red cell destruction and production Bone marrow function and capability to provide a compensatory increase in erythropoiesis following significant red cell destruction may be impaired by autoantibodies that bind to and destroy reticulocytes and erythroblasts as well as mature red cells. Reticuloendothelial function plays an important role because the severity of cellular immune red cell destruction depends largely on macrophage function Reticuloendothelial function may be reduced in SLE by the clearance of immune complexes, a process known as reticuloendothelial blockade  In methyldopa-induced AIHA, the drug has been shown to reduce reticuloendothelial clearance of IgG-coated red cells, a possible explanation for the fact that many patients with a strongly positive DAT due to methyldopa have little or no haemolysis. Warm type autoimmune hemolytic anaemia (AIHA) : It affects all age groups and accounts for up to 70% of AIHA cases. Hemolysis is caused by high-affinity IgG antibodies produced by reactive polyclonal B cells. An underlying or associated disorder can be identified in 50–70% of cases There is a preponderance of female patients in both idiopathic and secondary AIHA The most frequent patterns detected by the DAT on the red cell surface are as follows: IgG alone, IgG and complement, and complement alone. Clinically : Presentation is variable : Typically, the onset is insidious, with gradual awareness of symptoms of anaemia or observation of pallor or mild icterus by friends or relatives. Occasionally, the onset is acute, with rapidly developing anaemia and, in older patients, the risk of heart failure. Rarely, severe fulminating haemolysis may occur, resulting in life-threatening anaemia Where intravascular haemolysis occurs, patients pass very dark urine caused by haemoglobinuria and haemosiderinuria Mild splenomegaly is common, rarely more than 2–3 cm below the costal margin; marked splenomegaly suggests the possibility of an underlying LPD. Investigations : Anemia with marked reticulocytosis is present. The peripheral blood film is characterized by: ✓ Polychromasia, ✓ Spherocytes, ✓ Circulating nucleated red cells, ✓ In some cases, red cell agglutination. Rarely, there may be reticulocytopenia associated with a positive DAT. Reticulocytopenia is worrisome because the uncompensated anemia can rapidly become life-threatening, This may be caused by immune attack on late-stage erythroid precursors  o The blood smear often demonstrates micro spherocytes , nucleated RBCs also may be present.  The DAT is positive, commonly with IgG alone or with IgG and complement (the latter pattern commonly seen in SLE). There is an increase in lactate dehydrogenase (LDH) due to red cell lysis, but other liver function tests are normal unless there is associated liver or biliary tract disease. A moderate increase in unconjugated serum bilirubin and excess urinary urobilinogen occurs as a result of extravascular haemolysis. More marked icterus (bilirubin >90 μmol/L) suggests coexisting liver disease or biliary tract obstruction Management of warm type AIHA : 1) Supportive therapy Blood transfusion must be given : I. if the clinical situation demands it, II. if the haemoglobin continues to fall III. if heart failure develops. The least incompatible grouped blood should be used and transfused slowly Intravenous immunoglobulin (IVIg) has been used in AIHA, particularly when IgG is the main component on the red cell surface.AIHA responds less frequently to IVIg than does ITP 2) First-line treatment Corticosteroids are effective in warm AIHA Response rates may be improved when steroids are used in combination with Rituximab. 3) Second-line treatment Splenectomy is considered if there is no response after 3 months’ trial of corticosteroids. Patients with predominantly IgG on the red cell surface respond best, and those with complement respond poorly Monoclonal antibody therapy has been introduced with variable success in warm AIHA. Rituximab has been shown to be effective in idiopathic and secondary warm AIHA as well as in cold agglutinin disease  Longer-term concerns are related to the fact that rituximab causes a rapid depletion of CD20-expressing B cell precursors and mature B cells which remain at undetectable or at very low levels for up to 1 year post-therapy. Significant B-cell depletion causes hypogammaglobulinaemia and prolonged immunosuppression, exposing patients to increased risk of severe infections such as hepatitis B, cytomegalovirus reactivation. 3) Third-line treatment Treatment with cytotoxic immunosuppressive drugs is reserved for: ✓ steroid-refractory patients, ✓ relapse following steroid withdrawal ✓ non-response to splenectomy.  Prognosis Prognosis depends on age, associated diseases and severity of hemolysis. Most children with AIHA recover completely, and mortality is about 5%. Treatment-related side-effects, particularly prolonged high-dose steroid therapy, can result in considerable morbidity Idiopathic warm AIHA : It accounts for approximately 30% of patients with a DAT positive hemolytic anemia. It may occur at any age; peak incidence occurs in infancy and early childhood with a second rise during the third decade and the majority of cases occurring after the fifth decade Clinical presentation may vary from gradual onset of symptomatic anemia to an acute, fulminating and life-threatening hemolytic process A careful drug history should be taken in all cases to exclude hemolysis induced by drugs or by chemical exposure.  In infancy, the onset is often acute, transient and typically precipitated by infection. There is a male preponderance in the childhood setting in contrast to females in adult cases. In girls, AIHA may precede clinical or immunological evidence of SLE which should not be excluded on account of initial negative serology.  Warm AIHA associated with other autoimmune diseases : It is well described in patients with : I. SLE, especially in young women, II. Other autoimmune diseases, ex. rheumatoid arthritis, Sjogren syndrome and ulcerative colitis. Autoantibodies are usually IgG, and both IgG and C3d are found on the red cell surface. DAT may be positive because of immune complexes adsorbed onto the red cell surface. The spleen is important for clearing such coated cells and splenectomy should be avoided if possible. Otherwise, treatment is as for idiopathic AIHA Evans syndrome It is defined as the combination of AIHA and immune thrombocytopenia (ITP) in the absence of any underlying disorder. The onset of thrombocytopenia may coincide with hemolysis or may arise separately. The platelet and red cell antibodies are distinct and do not cross-react The condition runs a chronic course characterized by relapses and remissions. The diagnosis is important because there is a higher incidence in these cases of: Immunodeficiency or autoimmune lymphoproliferative disease (ALPS) in children SLE or T-cell lymphoma in adults ❑ Management is as for warm AIHA or ITP but patients with Evans syndrome tend to be more resistant to initial therapy with steroids. ❑ Second-line therapeutic options include immunosuppressive drugs such as vincristine. ❑ Response to splenectomy is inferior in comparison with cases of uncomplicated ITP. ❑ ❑ The monoclonal anti-CD20 antibody, rituximab, has produced significant remission rates of both cytopenias in children and adults with steroid-refractory cases. ❑ Stem cell transplantation is the only hope of cure in severe, refractory patients. Cold type autoimmune hemolytic anaemia (AIHA) : o Here, the IgM autoantibody attaches to red cells mainly in the peripheral circulation where the blood temperature is cooled. o In cold AIHA, the IgM is reactive against I or i antigen. Idiopathic cold haemagglutinin disease (CHAD) It is relatively uncommon disorder occurring mainly in the elderly and typically runs a chronic course. It is traditionally defined by the absence of an underlying disorder. CHAD is mostly benign, but the clinical features can be very disabling. Hemolysis results in anemia and the patient may be mildly icteric. Cold agglutinin disease is indolent, but may transform to an aggressive lymphoma  Purplish skin discoloration, maximal over the extremities (acrocyanosis), may be present in cold weather. Acrocyanosis is due to stasis in the peripheral circulation secondary to red cell agglutination. On warming the skin, the colour returns to normal or there is transient erythema, thus distinguishing acrocyanosis from Raynaud’s syndrome.  recent studies using sensitive tests including flow-cytometry and immunohistochemical assessments have demonstrated a monoclonal CD20-positive κ-positive B-lymphocyte population in the bone marrow of 90% of patients with CHAD. Also, lymphoplasmacytic lymphomas are frequently associated with CHAD; therefore some authorities consider CHAD a premalignant B-cell disorder.  In the laboratory : 1. Laboratory evaluation of patient with CAD will require quickly transporting blood samples to the lab with hot packs, to prevent agglutination after phlebotomy which can affect testing results. 2. Spontaneous agglutination of red cells is frequently observed, both macroscopically and on the peripheral blood film if made at room temperature. 3. Abnormalities in cell counts, MCV, MCHC can occur from agglutination of cells before cell counting or from hemolysis. 4. DAT is positive with only C3d on the red cell surface; IgM cold agglutinins are not detected because they elute from the cell surface in vitro. Spherocytosis is less marked than in warm type Management of cold haemagglutinin syndromes 1) Supportive therapy All patients should avoid exposure to cold; Folic acid supplements should be given to patients with chronic haemolysis. Blood transfusions should be given with due regard to the difficulty in cross- matching in the presence of cold haemagglutinins. Blood should be given through an in-line blood warmer. Plasmapheresis may be needed initially to treat hyper viscosity. 1) Definitive treatment ❑ Rituximab is the best first-line therapy with response rate of about 50%, it is effective in idiopathic CHAD and in cold agglutinin syndromes associated with LPD ❑ Unlike warm-type AIHA, corticosteroids are rarely of use in CHAD ❑ Alkylating agents such as chlorambucil can be effective in reducing antibody production in the context of an underlying B-cell neoplasm such as CLL. Long-term treatment carries the risk of bone marrow suppression and the development of secondary haematological malignancies Splenectomy is ineffective as the red cells are coated with C3b and destruction occurs mainly in the liver.  Paroxysmal cold hemoglobinuria (PCH) This rare syndrome occurs in children following acute viral infections or childhood immunization. A history of cold exposure is not always present and presentation is acute with significant intravascular hemolysis resulting in pallor, hemoglobinuria, abdominal pain and sometimes collapse  The cold antibody is a biphasic polyclonal IgG antibody (Donath–Landsteiner antibody) that reacts with the P antigen on red cells below 20 ◦C in the peripheral circulation, with subsequent lysis by complement activation on rewarming to 37 ◦C in the central vessels. Treatment involves strict avoidance of cold and keeping the patient warm, preferably at an ambient temperature of 37 ◦C until hemolysis subsides, which is usually self- limitings.  Rarely, brisk hemolysis causing symptomatic anemia occurs and blood transfusion is required. The P antigen is a high incidence antigen, and obtaining compatible blood for transfusion is difficult Blood should be transfused using a blood warmer or if not available, the patient is kept warm and transfused slowly.  References : Postgraduate Hematology 7th edition-2016/ chapter 9 ASH SAP 8th edition-2022/ chapter 8 Hoffbrands Essential hematology 9th edition-2024/ chapter 6