Immune Hemolytic Anemias

Introduction

Definition = pathologic states in which red cell destruction is mediated by allo- or autoantibodies, with or without complement involvement in the process

Immune hemolytic disorders:

autoimmune hemolytic anemia – idiopathic "warm" antibody or secondary "cold" antibody
hemolytic disease of newborn
drug related immune hemolytic anemias
transfusion reactions – immediate or delayed

Autoimmune Hemolytic Anemia – "warm" and "cold" antibody types

Definition = uncommon disorders in which accelerated red cell destruction results from an autoantibody which reacts with a specific blood group antigen present on the subjects own red cells; recognized by positive antiglobulin test.

Classification

idiopathic = 30%; secondary 70%
"warm" reacting = 85% (usually IgG); "cold" reacting = 15% (usually IgM)

Secondary causes – collagen vascular disease (lupus erythematosus); lymphoid malignances (chronic lymphocytic leukemia lymphoma); infections (mycloplasmic pneumonia, infectious mononucleosis); immune deficiency disorders; drugs (many and variable); others (ulcerative colitis, sarcoidosis, dermoid tumors, preleukemia)

Blood group specificity of antibody

cold agglutinin disease – IgM – anti I
infectious mononucleosis – Igm (or IgG) – anti I
paroxysmal cold hemoglobinuria – IgG – anti P
warm antibody autoimmune disease – IgG - usually anti Rh of some kind
hemolytic disease of newborn – IgG – many antigens

(1) "Warm" antibody type – behave like Rh-antibodies

clinical characteristics

anemia, spherocytosis, reticulocytosis, jaundice, splenomegaly; antiglobulin test positive
usually chronic persistent course
severity correlates with level of free antibody in the serum
often responsive to corticosteroids or splenectomy

pathophysiology

virtually always IgG antibody – may active complement; specificity for portion of Rh antigen is common
destruction of cells coated with Rh like antibodies is by macrophages in RE system

receptors for Fc portion of IgG and for C3b

spleen (sequesters spherocytes) is most efficient for IgG coated cells

liver (Kupffer cells) more efficient for C3b coated cells

process produces a hemolytic reaction (quite acutely) usually with intravascular or extravascular hemolysis

clinical approach

maintain red cell production – folate administration

interfere with interaction between macrophage and IgG-C3b – Corticosteroids (IV gamma globulin, Danazol, splenectomy)

interfere by ß antibody production – splenectomy (cytotoxic drugs such as cyclophosphamide)

(2) "Cold" antibody type – usually IgM

classification

idiopathic – IgM (monoclonal); Chronic (persistent); Neoplastic (preneoplastic); Antibody specificity (anti I); Cell agglutination (4 to 32° C); hemolysis may occur in vivo

secondary – IgM (polyclonal); Infection (mycoplasma pneumoniae, infectious mononucleosis); lymphoid malignancies; often self-limited; titers commonly very high; antibody specificity (anti I); cell agglutination (4 to 32° C)

paroxysmal cold hemoglobinuria – IgG (anti P); Infection (syphilis, rubella, other); complement activation (intravascular hemolysis); Donath Landsteiner Reaction in vitro; biphasic hemolysin

pathophysiology – red cell destruction

acute episode of intravascular hemolysis – exposure to cold leads to intravascular Ag-Ab reaction with initiation of complement activation. On warming, transient hemoglobinemia and –uria occurs as the complement cascade is completed to C9.

chronic hemolytic process of extravascular hemolysis – antibody usually anti-I; continuous Ag-Ab reaction

clinical approach

avoid cold exposure; treat underlying disease
attempt to reduce antibody production – Cytotoxic drugs
attempt to interfere with macrophage (C3b interaction) – Steroids less effective, splenectomy helpful

Hemolytic Disease of the Newborn

Definition = hemolytic disorder characterized by extravascular destruction of red cells of the fetus or neonate caused by specific IgG antibody transported across placenta from the maternal circulation to the fetal circulation.

pathogenesis

fetus inherits from father a red cell antigen which the mother lacks (maternal-fetal blood group incompatibility)

mother previously alloimmunized (transfusion or pregnancy) to the red cell antigen (any antigen including A or B)

maternal antibody (always IgG) transported across placenta and reacts with antigen of fetal red cells

extravascular hemolysis in the liver and spleen results – bilirubin, unconjugated; anemia with reactive extramedullary erythropoiesis (reticulocytosis, erythroblastosis, hepatosplenomegaly); severe anemia Þ hypoxia Þ liver cell damage (hypoalbuminemia, edema, hydrops fetalis, pulm edema); intrauterine death; live birth with anemia and edema

cell antibody = any IgG; anti-A most common; anti-Rh (D, C, E – others); anti-KELL (1^st application of Coombs serum)

management at birth -– prevent bilirubin encephalopathy; treat anemia; treat fluid accumulation

prevention of Rh alloimmunization

administration of Rh immune globulin if no Rh antibody is detectable in the woman’s serum
all Rh negative women who have no demonstrable anti-Rh (D) antibody: during 3^rd trimester; after delivery of Rh positive infant; after abortion, miscarriage, amniocentesis; received Rh positive platelets or Rh positive blood

Drug Related Immune Hemolytic Anemias

Definition = disorders in which, by one of three mechanisms, a drug results in an Ab which causes immune red cell destruction

(1) Hapten type (ex: Penicillin and some of its synthetic derivatives) – large doses required (10 million units); drug binds to red cell firmly Þ IgG or IgM directed against the drug Þ Antibody (F_ab portion) binds to drug on red cell which is then destroyed extravascularly in reticulo-endothelial system by macrophages.

clinical manifestation – rarely significant hemolysis; moderate anemia; drug can be continued

(2) Antigen Antibody Complex – Innocent bystander type – drug (i.e., Stibophen, Quinine, Quinidine, others) binds to red cell surface forming a new-foreign-antigen ("neoantigen") which leads to antibody production (IgG or IgM). On re-exposure to drug (small amt required), antibody coats the red cell (an innocent bystander) and activates complement

clinical manifestation – demonstrable in vitro; reaction not inhibited by addition of drug in vitro

(3) Allergic - Autoimmune type – (ex: methyldopa) – drug alters immune system (ß # of suppressor T cells (CD8)) and facilitates production of anti-Rh like antibody (IgG) which binds to red cells by F_ab portion and triggers cell destruction by macrophages of the reticuloendothelial system (which cannot be stimulated in vitro)

clinical manifestation – gradual onset (3-6 mo) related to drug dose; reaction continues for days/wks after withdrawal of drug; moderate hemolytic anemia; not life threatening (drug may be continued); severity correlates with dose of Aldomet; drug not involved in antibody reaction; methyldopa, levodopa, mefenamic acid, procainamide all work in similar manner

Hemolytic Transfusion Reactions

Definition = accelerated destruction of transfused red cells by specific alloantibodies resulting in intravascular or extravascular hemolysis. The reaction may occur immediately as the blood is transfused or be delayed 3 to10 days.

(1) Immediate Reactions – often with intravascular hemolysis

clinical manifestations – maybe fatal; sudden onset, chill, fever, flushing, diaphoresis; N/V, diarrhea; flank pain

lab findings – Intravascular destruction (hemoglobinemia, -uria, haptoglobin depleted; methemalbuminemia, hemosiderinuria; complement levels ß ); Extravascular destruction (chill, fever, Ý bilirubin, malaise, + Coombs test)

pathophysiology – usually human error; IgM antibody - anti-A or anti-B (complement activation, cascade complete to C9 Þ osmotic hemolysis, activation of coagulation cascade, conversion of plasminogen to plasmin Þ DIC); IgG antibody - Rh, Kell, Duffy (extravascular hemolysis, destruction by phagocytosis or membrane damage)

(2) Delayed Transfusion Reactions

pathophysiology (either IgM or IgG) - prior alloimmunization by transfusion or pregnancy; undetectable antibody present; transfusion re-exhibits antigen, anamnestic immune response occurs resulting in rapid rise in antibody titer and destruction of transfused cells (either intravascular or extra-vascular)

clinical lab signs – extravascular hemolysis (mailaise, fever; splenomegaly; Ý unconjugated bilirubin; spherocytosis; + Coomb’s test); intravascular hemolysis (chill, fever, ß hematocrit)