Clinical Manifestation

AUTOIMMUNE HEMOLYTIC ANEMIA(AIHA)Compiled by:G.A.R. Sampath Kalhari GiharaChanaka LakshanAqeela Manuideen1

ContentIntroductionEpidemiologyClinical ManifestationSymptomsDiagnosisImmunological basisTreatments2

IntroductionAutoimmune 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 RBCs thus shortening their life span.

If this destruction is at a high enough rate, & exceeds the bone marrows capacity to regenerate RBCs, 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

EpidemiologyAIHA 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 immunodeficiencyMajor is idiopathicSecondary malignant lymphoproliferative diseases, drugs, and viral infections4

Classification of Autoimmune Hemolytic AnemiaWarm Autoimmune Hemolytic Anemia

Cold Autoimmune Hemolytic Anemia Cold Agglutinin SyndromeParoxysmal Cold Hemoglobinuria

Mixed-type Autoimmune Hemolytic Anemia

Drug-induced Immune Hemolytic Anemia

5

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 hemolysisUsually associated with the development of IgG (also IgA & IgM)Abs bind to the surface of the RBC membraneAb is activated at warm temperature of 37 degrees celciusMaybe either Primary or Secondary in etiologyPrimary - Idiopathic in natureSecondary Due to an underlying disease (eg: lymphoproliferative disorders, autoimmune disorders etc.)

6

2) COLD AUTOIMMUNE HEMOLYTIC ANEMIA

In the cold antibody type, the autoantibodies become mostactive 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 elderlyOccurs due to the development of of an IgM antibodyAntibody is active at cold temperature (4 degrees celcius) and not usually physiologically significant

Either primary or secondary in etiologyPrimary - Idiopathic in natureSecondary due to an underlying disease

7

Mechanism of destruction

Intravascular hemolysisIgM antibodies activate the compliment system resulting in cytolysis

Extravascular hemolysisC3b & iC3b rather than the fc portion of IgM are recognizedHemolysis occurs in the liver via kuppfer cells

8

Cold agglutination syndrome (CAS)

Cold agglutinin disease (cold antibody disease) is caused by autoantibodies that react at temperatures7.5 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

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 childrenAntibody involved is IgGRBCs 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

3) MIXED-TYPE AUTOIMMUNE HEMOLYTIC ANEMIA

Features similar to both WAIHA & CASBoth IgG & C3d are detectedIgG warm antibodyC3d activated by IgM cold autoantibodyIdiopathicSecondary (lymphoproliferative disorders, autoimmune disorders)

4)DRUG INDUCED IMMUNE HEMOLYTIC ANEMIA

Antibodies directed against or one of its metabolitesAll may involve IgG & C3Mechanisms:Autoimmune typeDrug adsorption typeNeo antigen type11

12

Immunological View

Warm Autoimmune Hemolytic Anemia

IgG binds to RBC surface antigensThis drives monocytes & macrophages to grab & pick off portions of RBC membraneRBCs become spherocytesDestructed in spleen

EXTRAVASCULAR HEMOLYSIS13

Cold Agglutination Disease

In cold temperature, IgM binds to polysaccharide region of glycoproteins on RBC surfaceThis 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 surfaceThis opsonisation enhances RBC phagocytosis in liver, spleen & lungs

EXTRAVASCULAR HEMOLYSIS 14

Paroxysmal Cold Hemoglobinuria

During certain infections, microbes trigger formation of Abs that react with the P antigen of RBC surfaceAfter the infection, these polyclonal anti-P autoantibody binds to P-Ag of RBC in cold temperatureWhen 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

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 37C)Cold Autoantibodies - Act best at temperatures of 04C

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

Clinical ManifestationThe common symptoms are; Paleness of the skin FatigueFeverConfusionLightheadednessDizzinessWeakness or inability to do physical activityLess common;Dark urineYellowing of the skin and the whites of the eyes (jaundice)Heart murmurIncreased Heart rateEnlarged spleenEnlarged liver17

18

Diagnosis

Tests

FBC (hemoglobin, hematocrit)Absolute reticulocyte countCoombs Test ( direct, Indirect)Hemosiderin in the urineProtein electrophoresis

19

Full Blood countWarm Antibody AIHAHematocrit level less than 10%Platelets are normal

Cold AIHAExhibit mild to moderate anemiaHematocrit level- low as 15-20%

Drug induced AIHASimilar to those warm antibody AIHA

20

Coombs TestDirect Coombs 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. Coombs reagent is added to washed RBCs from the patient.If IgG or C3 is bound to RBC membranes, agglutination occurs it is a positive result.

21

Indirect Coombs Test (Indirect Antiglobulin Test)The indirect antiglobulin (indirect Coombs) test is a complementary test that consists of mixing the patients plasma with normal RBCs to determine whether autoantibodies are free in the plasma.

Normal RBCs are added to patients plasmaThen Coombs reagent is addedAgglutination occurs if autoantibodies are present in patients plasma positive test

INDIRECT TEST is used to determine if theres a potential bad reaction to a blood transfusionDIRECT TEST is used to check for AUTOIMMUNE HEMOLYTIC ANEMIA

22

23

TREATMENTS

TreatmentsFor Warm autoimmune hemolytic anemia

Corticosteroids & immunoglobulins are 2 common treatments.Initial medical treatment consists of prednisoneOther 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

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.

25For Paroxymal Cold Hemoglobinuria

Role of Rituximab

26

27

SUMMARY

28