Acquired Haemolytic Anaemias & AIHA

Haemolytic Anaemias- III: Acquired Disorders (AIHA)

• This presentation focuses on acquired haemolytic anaemias, specifically Autoimmune Haemolytic Anaemia (AIHA).
• AIHA is mainly due to extra-corpuscular disorders, except for Paroxysmal Nocturnal Haemoglobinuria (PNH).
• PNH is an acquired intra-corpuscular disorder.

Acquired Haemolytic Anaemias

• Immune: includes Alloimmune, Autoimmune, and Drug-related causes.
• Non-immune: includes red cell fragmentation syndromes, march haemoglobinuria, infections (malaria, clostridia), chemicals and physical agents (burns, substances), secondary causes (liver/renal disease), and Paroxysmal Nocturnal Haemoglobinuria (PNH)

Immune Haemolytic Anaemias

• Characterized by shortened red blood cell survival (haemolysis) due to immune reactions.
• Can be antibody-mediated or complement-mediated.

Antibody Mediated Immune Haemolytic Anaemias

• Antibody-mediated haemolysis is an important cause of acquired haemolytic anaemia.
• Auto-antibodies: produced by the patient's immune system and directed against their own red cell antigens.
• Allo-antibodies: directed against foreign red cell antigens, introduced via blood transfusion or Haemolytic Disease of Newborn (HDNB).
• IgG and IgM are commonly involved in immune haemolytic anaemias.
• IgA is rarely involved.
• Red cells are typically coated with IgG alone or with complement.

Complement Mediated Immune Haemolytic Anaemia

• Complement system enhances the ability of antibodies and phagocytic cells to clear microbes and damaged cells.
• Composed of plasma proteins that act in a cascade to destroy microbes, mediate inflammation, and promote phagocytosis.
• Proteins labelled C1-C9 are synthesized by the liver and circulate as inactive precursors.
• C3c and C3d are common complement components involved in haemolysis.
• Proteins account for about 10% of the globulin fractions of blood stream.
• Classical, Alternate, Lectin pathways activate the complement system.
• Classical pathway is initiated with antigen-antibody complexes.
• C5-9 complex forms the Membrane Attack Complex (MAC), which results in cell lysis.

Classification of Immune Haemolytic Anaemia

• Autoimmune: Warm antibody and Cold antibody types.
• Alloimmune: Haemolytic transfusion reactions, Haemolytic disease of the newborn, and Allografts.
• Drug-associated.

Auto Immune Haemolytic Anaemia (AIHA)

• Acquired haemolytic disorder with auto-antibodies produced against red cell surface antigens.
• Characterized by shortened red cell survival, presence of autoantibodies against autologous red cells, and a positive direct anti-globulin test (Coombs test).
• Autoantibodies attack red blood cells (RBCs), leading to haemolysis.
• The structural and functional characteristics of the antibody dictate the site and severity of red cell destruction.
• Accounts for ~10% of all haemolytic anemias.

Classification of Autoimmune Haemolytic Anaemia (AIHA)

• Based on temperature at which autoantibodies bind: Warm (most common, 70%) and Cold.
• Warm AIHA: IgG-mediated, extravascular hemolysis associated with autoimmune diseases (e.g., SLE).
• Cold AIHA: IgM-mediated, intravascular hemolysis secondary to infections (e.g., Mycoplasma pneumoniae, EBV).
• Based on presence of underlying disease: categorized as primary or secondary.
• Warm-reactive autoantibodies
• It can be primary or idiopathic
• Secondary causes include disorders like Systemic Lupus Erythematosus, Rheumatoid arthritis, Lymphoproliferative, Non-lymphoid neoplasms, Infections, if associated with immune thrombocytopenic purpura, it is called Evan's syndrome.
• Drug induced

Warm AIHA

• Warm-acting antibodies are most active in vitro at 37°C.
• Constitutes about 48-70% of AIHA cases.
• Antibodies are mainly IgG and polyclonal.
• Antibodies may or may not fix complement.
• RBC destruction occurs via extravascular haemolysis in the spleen.
• Rare types include anti-U, Duffy, K, JK, LU.

Mechanism of antibody mediated haemolysis

• IgG antibodies: Extravascular destruction, Fc receptor-mediated, may fix complements.
• IgM antibodies: Intravascular destruction, complement fixing.

Pathogenesis

• Warm AIHA involves extravascular, cell-mediated, and complement-mediated red cell destruction.
• Macrophages possessing Fc receptors for IgG1 & IgG3 destroy IgG-coated RBCs mainly in the spleen.
• In partial phagocytosis, portions of the RBCs are removed leaving spherocytes that enter circulation.
• In warm AIHA, red cells coated with IgG and complement are phagocytosed via cell surface receptors for the IgG Fc fragment.
• The loss of membrane transforms cells into microspherocytes.
• Coated red cells are eventually destroyed in the spleen or liver.
• Complement-mediated red cell destruction causes intravascular haemolysis. Complement-induced intravascular haemolysis in warm AIHA is most likely to occur when more than one class or subclass of Ig is present on the red cell surface.
• Warm AIHA:
• IgG autoantibodies bind to RBC membranes at body temperature
• IgG antibodies opsonize RBCs
• Fc receptors on macrophages in the spleen recognize IgG-coated RBCs → phagocytosis → extravascular hemolysis
• Complement activation can occur but is usually incomplete
• Cold AIHA:
• IgM autoantibodies bind to RBCs at cold temperatures (4°C-30°C)
• IgM activate complement → C3b opsonization → RBC destruction in the liver (Kupffer cells) or complement-mediated lysis (intravascular hemolysis) occurs typically in peripheral circulation

Drug-induced immune haemolytic anaemia

• Drug adsorption mechanism:
• (Hapten): The drug gets adsorbed onto the red cell membrane, forming a drug-red cell membrane complex to which antibodies are formed against.
• Splenic Macrocphages recognize the complex
• The red cells eventually get destroyed in the RES extravascular hemolysis, e.g. penicillin, ampicillin.
• True autoimmune mechanism: Drug forms circulating immune complexes with plasma antibodies (IgG or IgM) these complexes bind and activate complement leading to intravascular hemolysis, e.g., quinidine, rifampicin, methyldopa.
• Membrane modification mechanism: Drugs modify red cell membrane components.
• This causes immunoglobulins and complement to attach via non-immune mechanisms, e.g. Cephalosporins.
• Haemolysis usually occurs on the second or subsequent exposure is required.

Thermal Range for Antibodies

• Defines the temperature at which an antibody is most active,
• Warm-acting antibodies: most active in vitro at 37°C.
• These antibodies are polyclonal and IgG predominates.
• Cold-acting antibodies: predominantly IgM and are most active in the cold (4°C).

Factors influencing Presentation

• Degree of anaemia present.
• Rate of RC destruction.
• Bone marrow capacity to compensate, dependent on BM function.
• Presence of AutoAbs against reticulocytes & erythrocyte. and Folate deficiency due to increase demand.

Clinical features

• Affects all age groups across all sexes, presentations with anaemia symptoms, fatigue, dyspnea, tachycardia.
• Anaemic heart failure in severe anaemia.
• Jaundice.
• Mild splenomegaly about 2-3cm is usual.
• Patients may present with fulminant haemolysis marked jaundice, pallor and haemoglobinuria.
• Splenomegaly present especially in warm AIHA.
• Acrocyanosis and Raynaud’s phenomenon (cold AIHA).
• Warm AIHAs are the commonest with up to 70-90% of AIHA cases.

Laboratory Features

• Extravascular haemolysis with peripheral blood film indications, Reticulocytosis, Moderately elevated Bilirubin, Increase LDH, Positive DAT and low haptoglobin.

Diagnostic Approach

• Coombs Test is important to diagnose immune haemolytic anaemia.
• The Direct Direct Antiglobulin Test (DAT), also known as the Coombs test detects antibody or complement on the surface of red cells .
• is a could be direct or indirect test.
• Direct Coomb’s test detects antibody or complement present on red cell membrane.
• is presnet on the cells.
• Indirect Coomb’s test detects antibody or complement in the serum.

Treatment

• Remove underlying cause.
• Corticosteroids-Prednisolone is the usual first line drug.
• Splenectomy in those who fail to respond to steroids.
• Monoclonal antibody: anti CD 20.
• Folic acid supplement.
• Red cells transfusion (in severe cases).
• High dose immunoglobulin.

Cold AIHA

• Cold AIHA can be primary, Idiopathic or Secondary too.
• In includes lymphoproliferative diseases, infections, Paroxysmal cold haemoglobinuria (rare).

Cold AIHA

• The antibodies are usually IgM, binding to red cells mainly in cool peripheral circulation.

• IgM autoantibody binds red cells optimally at 4°c.

• IgM antibody fixes complements well, causing predominantly intravascular haemolysis.

• The IgM antibody could be monoclonal in cold haemaglutinin syndrome or polyclonal in infections.

• Antibody is mostly directed against I antigen on the red cell surface,in infectious mononucleosis directed against anti-i.

• Red cell destruction is mediated by autoantibody binding to red cell in colder parts of the body and by complement fixation.

• Laboratory findings are similar to warm AIHA except that spherocytosis is less marked, there are Marked red cells agglutination and DAT reveals complement (C3d) only on the red cell surface.

• Patients present with Chronic haemolytic anaemia aggravated by cold, features of intravascular haemolysis, mild jaundice,, splenomegaly and acrocyanosis.

• It consists of keeping the patients warm and transfusing with ABO and RH compatible blood through a blood warmer.

• Treat underlying cause e.g Chlorambucil and alkylating agents or anti-CD20 (rituximab) can be used.

• Splenectomy isn't indicated and Corticosteroids are of no value. In underlying lymphoma patients it should be excluded.

• The rare acute syndrome of Paroxysmal cold haemogobinuria is a exposure to cold is required.

• There antibody is the Donath-lansteiner antibody, an IgG antibody with specificity for P blood group antigens and it self limiting disease.

Conclusion

• AIHA is an autoimmune disorder causing hemolysis of RBCs.
• Warm AIHA (IgG-mediated) and Cold AIHA (IgM-mediated).
• Diagnosis relies on hemolysis markers and Coombs test.
• Management depends on subtype and severity.