Autoimmune Hemolytic Anemia (AIHA)

Autoimmune hemolytic anemia (or autoimmune haemolytic anaemia; AIHA) occurs when antibodies directed against the person's own red blood cells (RBCs) cause them to burst (lyse), leading to insufficient plasma concentration.

1. AUTOIMMUNE HEMOLYTIC ANEMIA (AIHA) Compiled by: G.A.R. Sampath Kalhari Gihara Chanaka Lakshan Aqeela Manuideen 1

2. Content Introduction Epidemiology Clinical Manifestation Symptoms Diagnosis Immunological basis Treatments 2

3. Introduction Autoimmune Hemolytic Anemia (AIHA) is characterized by an abnormal production of antibodies that bind to Antigens on the erythrocyte surface. These antibodies then leads to the destruction of RBC’s thus shortening their life span . If this destruction is at a high enough rate, & exceeds the bone marrow’s capacity to regenerate RBC’s, the patient develops anemia and the associated signs and symptoms. AIHA can be primary, where no evidence for a secondary causative disorder exits; or secondary in which hemolytic anemia is directly attributable to another systemic disease. 3

4. Epidemiology AIHA is a fairly uncommon disorder, with estimates of the incidence at 1-3 cases per 100,000 people per year. Primarily found in adults (more severe) Also in children with primary immunodeficiency Major is idiopathic Secondary – malignant lymphoproliferative diseases, drugs, and viral infections 4

5. Classification of Autoimmune Hemolytic Anemia Warm Autoimmune Hemolytic Anemia Cold Autoimmune Hemolytic Anemia Cold Agglutinin Syndrome Paroxysmal Cold Hemoglobinuria Mixed-type Autoimmune Hemolytic Anemia Drug-induced Immune Hemolytic Anemia 5

6. WARM AUTOIMMUNE HEMOLYTIC ANEMIA In the warm antibody type, the autoantibodies attach to and destroy red blood cells at temperatures equal to or in excess of normal body temperature.  It is the most common form of autoimmune hemolytic anemia (AIHA); more common among women.  Primarily due to extravascular hemolysis Usually associated with the development of IgG (also IgA & IgM ) Ab’s bind to the surface of the RBC membrane Ab is activated at warm temperature of 37 degrees celcius Maybe either Primary or Secondary in etiology Primary - Idiopathic in nature Secondary – Due to an underlying disease ( eg : l ymphoproliferative disorders, autoimmune disorders etc.) 6

7. 2) COLD AUTOIMMUNE HEMOLYTIC ANEMIA In the cold antibody type, the autoantibodies become most active and attack red blood cells only at temperatures well below normal body temperature . Caused by Cold agglutination syndome (CAS) or Paroxysmal cold hemoglobinuria (PCH) Mainly affects middle-aged or elderly Occurs due to the development of of an IgM antibody Antibody is active at cold temperature (4 degrees celcius ) and not usually physiologically significant Either primary or secondary in etiology Primary - Idiopathic in nature Secondary – due to an underlying disease 7

8. Mechanism of destruction  Intravascular hemolysis IgM antibodies activate the compliment system resulting in cytolysis Extravascular hemolysis C3b & iC3b rather than the fc portion of IgM are recognized Hemolysis occurs in the liver via kuppfer cells 8

9. Cold agglutination syndrome (CAS) Cold agglutinin disease (cold antibody disease) is caused by autoantibodies that react at temperatures <37° C. Causes includeInfections (especially mycoplasmal pneumonias or infectious mononucleosis) Lymphoproliferative disorders (antibodies are usually directed against the I antigen) Idiopathic (usually associated with a clonal B-cell population) Infections tend to cause acute disease, whereas idiopathic disease (the common form in older adults) tends to be chronic . The hemolysis occurs largely in the extravascular mononuclear phagocyte system of the liver and spleen . The anemia is usually mild ( Hb  > 7.5 g/ dL ). Autoantibodies in cold agglutinin disease are usually IgM . The higher the temperature ( ie , the closer to normal body temperature) at which these antibodies react with the RBC, the greater the hemolysis 9

10. Paroxysmal cold hemoglobinuria (PCH) Paroxysmal cold hemoglobinuria is a rare type of cold antibody hemolytic anemia. Destruction of red blood cells results from exposure to cold. (28 – 31 degrees celcius ) Occurs more in children Antibody involved is IgG RBC’s may be destroyed even when cold exposure is limited to a small area of the body, such as when the person drinks cold water or washes hands in cold water. Intravenous hemolysis occurs ( It occurs most often after a bacterial infection (syphilis, mycoplasma pneumoniae ) or a viral illness (measles, mumps, influenza etc.). Can be caused due to vaccines as well. 10

11. 3) MIXED-TYPE AUTOIMMUNE HEMOLYTIC ANEMIA Features similar to both WAIHA & CAS Both IgG & C3d are detected IgG – warm antibody C3d – activated by IgM cold autoantibody Idiopathic Secondary ( lymphoproliferative disorders, autoimmune disorders) 4) DRUG INDUCED IMMUNE HEMOLYTIC ANEMIA Antibodies directed against or one of its metabolites All may involve IgG & C3 Mechanisms: Autoimmune type Drug adsorption type Neo antigen type 11

12. 12 Immunological View

13. Warm Autoimmune Hemolytic Anemia IgG binds to RBC surface antigens This drives monocytes & macrophages to grab & pick off portions of RBC membrane RBCs become spherocytes Destructed in spleen EXTRAVASCULAR HEMOLYSIS 13

14. Cold Agglutination Disease In cold temperature, IgM binds to polysaccharide region of glycoproteins on RBC surface This triggers complement system to lyse RBC INRAVASCULAR HEMOLYSIS If complement system fails to form membrane attack complex (when trigger is insufficient), complement proteins deposit on RBC surface This opsonisation enhances RBC phagocytosis in liver, spleen & lungs EXTRAVASCULAR HEMOLYSIS 14

15. Paroxysmal Cold Hemoglobinuria During certain infections, microbes trigger formation of Abs that react with the P antigen of RBC surface After the infection, these polyclonal anti-P autoantibody binds to P-Ag of RBC in cold temperature When temperature increased, complement system lyses these RBCs INTRAVASCULAR HEMOLYSIS This leads to hemoglobinuria & anemia whereas the anemia would either be mild or severe 15

16. 16 AIHA cannot be attributed to any single autoantibody. To determine autoantibody/ ies in a patient, direct Antiglobulin test (DAT) is performed. Classification of the Abs is based on their activity at different temperatures and their etiology; Warm Autoantibodies. - High activity at physiological temperature (approximately 37 °C) Cold Autoantibodies - Act best at temperatures of 0–4 °C Patients with cold-type AIHA, therefore, have higher disease activity when body temperature falls into a hypothermic state. Antibody becomes active when it reaches the limbs & opsonizes RBCs. When these RBCs return to central regions, they are damaged by complement. Patients may present with one or both types of Autoantibodies; if both are present, it is called "mixed-type" AIHA. ANTIBODY

17. Clinical Manifestation The common symptoms are; Paleness of the skin Fatigue Fever Confusion Lightheadedness Dizziness Weakness or inability to do physical activity Less common; Dark urine Yellowing of the skin and the whites of the eyes (jaundice) Heart murmur Increased Heart rate Enlarged spleen Enlarged liver 17

18. 18 Diagnosis

19. Tests FBC (hemoglobin, hematocrit ) Absolute reticulocyte count Coomb’s Test ( direct, Indirect) Hemosiderin in the urine Protein electrophoresis 19

20. Full Blood count Warm Antibody AIHA Hematocrit level – less than 10% Platelets are normal Cold AIHA Exhibit mild to moderate anemia Hematocrit level- low as 15-20% Drug induced AIHA Similar to those warm antibody AIHA 20

21. Coomb’s Test Direct Coomb’s Test ( Direct Antiglobulin Test) This test is used to determine whether the RBC-binding autoantibody ( IgG ) or compliment (C3) is bound to Ag on RBC membranes. Coomb’s reagent is added to washed RBC’s from the patient.   If IgG or C3 is bound to RBC membranes, agglutination occurs it is a positive result. 21

22. Indirect Coombs Test (Indirect Antiglobulin Test) The indirect antiglobulin (indirect Coomb’s ) test is a complementary test that consists of mixing the patient’s plasma with normal RBCs to determine whether autoantibodies are free in the plasma . Normal RBCs are added to patient’s plasma Then Coomb’s reagent is added Agglutination occurs if autoantibodies are present in patient’s plasma – positive test INDIRECT TEST is used to determine if there’s a potential bad reaction to a blood transfusion DIRECT TEST is used to check for AUTOIMMUNE HEMOLYTIC ANEMIA 22

23. 23 TREATMENTS

24. Treatments For Warm autoimmune hemolytic anemia Corticosteroids & immunoglobulins are 2 common treatments. Initial medical treatment consists of prednisone Other options include rituximab , donazol , cyclosphosphamide , azathioprine & ciclosporine . High dose immunoglobulin IV is possible; it controls hemolysis , but the benefit is short lasting (1-4 weeks); also expensive. If ineffective, splenectomy is considered. 24

25. For cold agglutination disease Removal of underlying cause is important. [i.e. if caused by a pathology, treat it]. Rituximab treatment [medication for autoimmune diseases & types of cancer]. Avoiding cold weather & cold drinks is important. Treat the infections that lead to paroxysmal cold hemoglobinuria . i.e. if caused by syphilis, treat with narrow spectrum penicillin. 25 For Paroxymal Cold Hemoglobinuria

26. Role of Rituximab 26

27. 27 SUMMARY

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