Immune Hemolytic Anemia
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***All Acquired Immune Hemolytic Anemia have Reticulocytosis (compensates for the anemia)***
Accelerated destruction or hemolysis of RBCs by an antibody.
Isoimmune Hemolytic Anemia
Isoantibodies - Isoimmune Hemolytic Anemia
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Alloantibodies
Develop when a person is exposed to antigens that are found in the SAME SPECIES but are not found
on the person.
Autoantibodies - Autoimmune Hemolytic Anemia
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Antibodies that react with the host’s own cells or antigens.
Drug-Induced Autoantibodies - Drug-Induced Hemolytic Anemia
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Antibodies that resemble autoantibodies induced in some persons by certain drugs.
ALL ANEMIAS CAUSED BY ANY OF THESE ANTIBODIES ARE ACQUIRED!
3 Types of Acquired Immune Hemolytic Anemia:
Complement System
Consists of serum proteins that interact to mediate certain effects of the inflammatory response.
Classic Pathway and Alternative Pathway
○ Classic - Activated by IgG or IgM > C5bC6C7C8C9 (Membrane Attack Complex) > Involved in
Some Autoimmune Hemolytic Anemias
○ Alternative - Activated by Microorganism > Membrane Attack Complex > Non Immune
Mechanism of Defense
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Extravascular Hemolysis in Acquired Immune Hemolytic Anemia
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Caused by C3b binding to RBC surface w/c results to Extravascular Destruction of RBC in the Liver via
Kupffer Cells (Liver Macrophage)
Intravascular Hemolysis in Acquired Immune Hemolytic Anemia
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Presence of Isoantibodies
HTR and HDFN
Hemolytic Transfusion Reaction
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Isoimmune Hemolytic Anemia
Autoimmune Hemolytic Anemia
Drug-Induced Hemolytic Anemia
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***Bone Marrow Examination - Usually Not Required to Diagnose Acquired Immune Hemolytic Anemia***
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ACQUIRED IMMUNE HEMOLYTIC ANEMIA AND ANEMIA OF BLOOD LOSS
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Results from transfusion of RBCs bearing antigens that are foreign to the recipient’s immune system.
Primary Transfusion - No or Delayed Reaction; Antibodies are still being produced.
Secondary Transfusion - Immediate Reaction; Antibodies are already present in plasma.
Caused by Incompatible ABO, Rh and Kell Blood Groups
ABO IgM Antibodies - Intravascular Hemolysis
Rh IgG Antibodies - Extravascular Hemolysis in Spleen and Liver
Initial Symptoms of HTR
○ Clammy Skin
○ Back, Leg and Chest Pain
○ Facial Flushing
○ Anxiety and Nausea
Physical Findings of HTR: (HIF)
○ Hypotension
○ Increased Pulse and Respiratory Rates
○ Fever
Renal Failure and DIC may develop
Hemoglobinemia occurs in ABO Intravascular Hemolysis
Decreased Factor VIII, Fibrinogen and Platelets
Increased Partial Thromboplastin Time
D-d Dimer Test - Indicates Intravascular Coagulation
○ Specific for fibrin split products and indicate coagulation and fibrinolysis in vivo.
Direct Antiglobulin Test - Positive: Demonstrates Sensitization or Coating of Transfused Cells w/ IgG
Antibodies.
Treatment - Prevention
○ Treatment of Immediate HTR - Treat Hypotension and Renal Failure by Diuretics
Hemolytic Disease of the Fetus and Newborn (Erythroblastosis Fetalis)
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Caused by C5bC6C7C8C9 (Membrane Attack Complex or Terminal Complex) which penetrates RBC
surface by forming Transmembrane Pore resulting in Intravascular Hemolysis.
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***Erythroblastic Hyperplasia - Typical Bone Marrow Response in All Acquired Immune Hemolytic Anemia.***
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Destruction of Infant’s RBCs when Maternal Antibody specific to an antigen on Infant’s RBCs crosses
the placenta.
Rh Negative Mother bearing an Rh Positive Baby may receive small amounts of fetal blood which
causes antibody production to RBCs of Rh Positive Baby.
Caused by ABO, Rh and Kell Blood Groups
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1st Born - Normal
2nd Born - HDFN
○ Hepatosplenomegaly, Anemia, Jaundice (leads to Kernicterus)
○ Infant Skin - Paler than Icteric
Cord Blood - Normal or Decreased Hb, Increased # of Nucleated RBCs (hence Erythroblastosis
Fetalis), Macrocytosis and Polychromatophilia
DAT - Positive; IAT - Positive (if antibody is already present in mother)
Treatment - Exchange Transfusions, Phototherapy, RhoGAM (Anti-Rh Antibodies)
Autoimmune Hemolytic Anemia
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Production of Autoantibodies
Occurs when T-Cell Regulation of B-Cells is Impaired
Warm-Antibody AIHA, Cold-Antibody AIHA and Cold Paroxysmal Hemoglobinuria
Warm-Antibody AIHA
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Patient’s own immune system produces Anti-RBC Antibodies that react most effectively in vitro at
37C.
75% of all AIHA are of Warm-Antibody Type
Usually of IgG Type but some maybe IgM or IgA
○ Unable to bind to complement
Warm-Antibodies - Incomplete Antibodies > Do not cause Direct Agglutination of RBCs
Causes Extravascular Destruction of RBCs in the Spleen
Primary - Idiopathic
Secondary - Chronic Lymphocytic Leukemia, Lymphoma, Systemic Lupus Erythematosus (SLE), Viral
Infections and Immunodeficiency
Seen slightly more often in women
Acquired at any age but frequency is higher after 40 years of age
Weakness, Fever, Pain, Hemoglobinuria, Jaundice, Hepatosplenomegaly and LYMPHADENOPATHY
Macrocytic RBCs w/ Marked Anisocytosis, Marked Reticulocytosis and Spherocytes occurs
Thrombocytopenia occurs
DAT = Positive (requires addition of Polyvinylpyrrolidone or Polybrene to increase test sensitivity)
IAT = Positive (during active hemolysis)
Warm Autoantibodies - Specificity for Rh Antigens
Treatment for Secondary Warm-Antibody AIHA - Treat the Underlying Disease
Treatment - Corticosteroids, Intravenous Immune Globulins and Splenectomy
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Cold-Antibody AIHA (Cold Agglutinin Syndrome)
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Development of a Pathologic Form of Anti-I Antibody that could lead to hemolysis.
Reacts most effectively at 0-10C in vivo and in vitro
Identified by Landsteiner
Associated w/ Raynaud’s Phenomenon (Acrocyanosis)
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Peripheral Circulation Abnormality
Obstruction of Capillary Circulation by RBC Agglutination causing Numbness, Pain and
Blue/Red Skin Discoloration
○ Tip of Nose, Ear Lobes or Fingers
○ Severe Cases - Gangrene
Usually of IgM Type against the I Antigen and are able to activate and bind w/ complement
Causes Extravascular Hemolysis of RBCs in Liver due to Kupffer Cells
Intravascular Hemolysis may also occur to a lesser extent
Primary - Idiopathic; Most common in Elderly
Secondary - Mycoplasma pneumoniae, Epstein-Barr Virus or Lymphoproliferative Diseases; Seen in
All Ages
Acrocyanosis, Hemoglobinuria and Renal Failure may occur
MCV - Extremely Elevated (due to RBC Clumping)
MCH and MCHC - Unrealistic
Must warm blood samples w/ Cold-Antibody AIHA @ 37C for 15 mins. before testing
Decreased Haptoglobin and Complement Levels
Cold Agglutinin Screening Test - Diagnosis of Cold-Antibody AIHA
○ Ability of Patient Serum to Agglutinate Normal RBCs Suspended in Saline after Mixture is First
Incubated at Room Temp then in Cold Water @ 20C
○ If Agglutinated RBCs @ 20C, Serum Cold Agglutinin must be Titrated @ 4C and the Thermal
Amplitude must be determined.
○ Cold Agglutinin Titer @ 4C of Patients experiencing Hemolysis = Over 1000
○ Thermal Amplitude of Pathologic Anti-I Antibodies = 0-32C
○ Property of Cold Agglutinins is Reversed @ 37C
DAT Positive
Treatment for Idiopathic Cold Agglutinins - Steroid Therapy, Immunosuppressive Therapy, Use of
Alkylating Agents or Plasmapheresis
Treatment for Secondary Cold Agglutinins - Keep Patient Warm and Treat Underlying Disease
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Similar to Cold-Antibody AIHA but is caused by binding of Donath-Landsteiner Antibodies to RBCs
after cold exposure.
Results to Intravascular Hemolysis and Gross Hemoglobinuria
Represents less than 1% of Acquired AIHAs
Usually of IgG Antibody that acts as a Powerful Hemolysin
Primary PCH - Idiopathic
Secondary PCH = Advanced Syphilis, Mumps, Measles, Chickenpox, Infectious Mononucleosis and
Flu
Binds to RBCs at temperatures below 15 C in presence of Complement
Shows specificity to the Pp Blood Group System
Hemolysis occurs upon warming
Physical Findings - Jaundice and Hepatosplenomegaly
Spherocytes, Fragmented RBCs and Polychromasia are seen
Leukopenia (due to Phagocytosis of RBCs) followed by Leukocytosis occurs
Immature Leukocytes are seen
Donath-Landsteiner Test Positive
○ Incubate Serum w/ Normal Group O, P-Positive Cells @ 4C then Warm Mixture to 37C
○ If D-L Antibody is present, complement binding and hemolysis occurs when mixture is
warmed to 37 C
DAT Positive (performed at Cold Temp)
Treatment for Secondary PCH - Treat Underlying Disease
General Treatment - Avoid Cold
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Paroxysmal Cold Hemoglobinuria
Antibody
IgG (Incomplete Type)
Complement Binding
May or May Not
Type of Hemolysis
Extravascular (Spleen)
Blood Group Specificity
Rh Antigens
Optimal Reaction Temperature
37C
Thermal Amplitude
20-37C
Occurs more in Women
Any Age (More Frequency @ 40 Years of Age and Above)
Lymphadenopathy
Unique Clinical Feature
Unique Laboratory Findings
Diagnosis
Treatment
Drug-Induced Hemolytic Anemia
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Macrocytic RBCs w/ Marked Anisocytosis, Marked
Reticulocytosis and Thrombocytopenia
DAT Positive after Addition of Polyvinylpyrrolidone or
Polybrene
Steroids, Splenectomy, Immunosuppressants
Resembles autoantibodies
Hapten (Drug Adsorption) Mechanism, Immune Complex (Innocent Bystander) Mechanism and
Alpha-Methyldopa (Unknown Mechanism)
Hapten (Drug Adsorption) Mechanism
Paroxysmal Cold Hemoglobinuria
Donath-Landsteiner Antibody (Hemolysin)
Anti-P
Yes
Complement-Mediated Intravascular Hemolysis
0-10C
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Cold-Antibody AIHA
IgM (Agglutinin)
Anti-I
Yes
Major = Extravascular (Liver)
Minor = Complement-Mediated Intravascular
Hemolysis
Ii Antigens
0-32C
Primary = Elderly
Secondary = All Ages
Raynaud’s Phenomenon or Acrocyanosis
MCV = Extremely Elevated
MCH and MCHC = Unrealistic
Decreased Haptoglobin and Complement Levels
Cold Agglutinin Screening Test:
Cold Agglutinin Titer @ 4C = Over 1000
Avoid Cold
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Age and Gender Preference
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Warm-Antibody AIHA
Haptens - Low Molecular Weight Proteins of Less than 5000 Daltons
Haptens bind w/ Serum Proteins and are Adsorbed Nonspecifically to RBC Surfaces
Induces Antibody Production specific for the drug
Antipenicillin, Anticephalothin and Anticephalosporins
Anti Drug Antibody attaches to the drug adsorbed to RBC Surface and subjects RBCs to Extravascular
Destruction in Spleen
Usually of IgG Type and is Non-Complement Binding
Sensitization (Ab-Ag Binding) is more common following Intramuscular Penicillin Therapy
Typical Symptoms of Anemia and Hemolysis
DAT Positive - Most Significant Finding - Patient RBCs React Strongly w/ Antihuman Globulin
(Anti-IgG)
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Pp Antigens
0-4C (Binding of Antibody to RBC)
37C (Hemolysis occurs)
< 15C
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Gross and Significant Hemoglobinuria
Leukopenia Occurs (due to Phagocytosis of RBCs) followed by
Leukocytosis
Presence of Immature Leukocytes
Donath-Landsteiner Test:
RBCs Incubated @ 4C Exhibiting Hemolysis when Warmed to 37C
Avoid Cold
Thrombocytopenia and Neutropenia occurs
Treatment - Removal of Offending Drug
Complex (Innocent Bystander) Mechanism
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Nonimmune-Mediated Attachment of Immunogenic Complexes to RBC Surface w/c leads to
Complement-Mediated Intravascular Hemolysis
RBC = Innocent Bystander (immunogenic complex does not actually bind to any RBC Antigen)
1st Described in a Patient w/ Schistosomiasis treated w/ the drug Stibophen
Other Drugs: Quinine, Quinidine, Sulfonamides, Phenacetin (commonly ends with –in sound)
Antibody may be of IgM or IgG Type and Binds to Complement
Common Symptoms of Hemolysis occurs
Renal Failure = Common Finding in Immune Complex Mechanism
Thrombocytopenia and Leukopenia occurs
Elevated Partial Thromboplastin Time and Decreased Factor VIII and Fibrinogen Levels Occur =
Indicate Intravascular Coagulation
DAT Positive using Polyvalent (Anti-IgG + Anti-Complement) Reagent
Treatment = Removal of Offending Drug and Steroids
Other Name
Hapten Mechanism
Drug Adsorption
Immune Complex Mechanism
Innocent Bystander
Stibophen
Quinine and Quinidine
Sulfonamides
Phenacetin
Drugs Associated
Penicillin
Cephalosporins (Cephalothin)
Antibody Type
IgG
IgM or IgG
Complement Binding
Type of Hemolysis
None
Extravascular (Spleen)
Unique Information
DAT Positive is its Most Significant Finding
Thrombocytopenia and Neutropenia
Yes
Intravascular (Complement-Mediated)
Renal Failure is a Common Finding
Thrombocytopenia and Leukopenia
Elevated PTT
Decreased Factor VIII and Fibrinogen
Removal of Offending Drug
Steroids
Treatment
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Drug induces formation of antibody with specificity to RBC Antigens rather than to drug itself
Alpha-Methyldopa (Aldomet) = Drug for Hypertension
Unclear Mechanism
Usually of IgG Type similar in Activity to that of Warm-Antibody AIHA
Has specificity for Rh Antigens
Suggested to have been rooted from the capacity of Methyldopa to Inhibit Normal T-Cell Suppressor
Function leading to Abnormal, Uncontrolled B-Cell Autoantibody Production
Other Drugs = Levodopa and Mefenamic Acid
Insidious Onset
Treatment = Removal of Methyldopa and Corticosteroid Therapy
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Alpha-Methyldopa (Unknown or Autoimmune) Mechanism
Removal of Offending Drug
Alpha-Methyldopa Mechanism
Autoimmune/Unknown
Alpha-Methyldopa
Levodopa
Mefenamic Acid
IgG (similar to Warm-Antibody AIHA)
Specific to Rh Antigens
Unclear
Unknown
Unknown Mechanism
Insidious Onset
Removal of Methyldopa
Corticosteroid Therapy
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Anemia of Blood Loss:
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Minor Blood Loss - 500mL or Less; Generally Not Serious and Doesn’t Require Laboratory Analysis
Problem w/ Blood Loss - Hemorrhage and Shock
Acute or Chronic
Normal Blood Volume for Women: 4.0 – 4.5 L
Normal Blood Volume for Men: 5.0 – 5.5 L
Normal Blood Volume is Regulated by: ADH, Aldosterone, Erythropoietin and Osmotic Phenomenon
(Plasma Refill)
Acute Blood Loss
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Catecholamines, Cortisone and Growth Hormone - Causes Hyperglycemia - Provides Glucose for
Energy during Osmotic Transfer of Fluids from Inside RBCs to Extracellular Space
Changes in Blood Flow due to Volume Variations:
○ Affect Cerebral Blood Flow - Headaches and Confusions
○ Affect Renal Blood Flow - Decreased Glomerular Filtration Rate (GFR) and Reduced Urine
Formation
Affects Hematopoietic Systems via Blood Volume Depletion
○ Hematopoietic Systems work at an accelerated pace to replace lost RBCs needed
immediately for O2 Delivery to Tissues
Affects Cardiovascular Systems due to Its Sensitivity to Volume Shifts
○ Cardiac Arrest and Death may occur
Increased 2,3-DPG occurs and causes a Shift to the Right in the O2 Dissociation Curve
Blood Flow Redistribution occurs which prioritizes the heart and brain over other organs
Epinephrine = Vasoconstriction
○ Increased Heart Rate and Stroke Volume
○ Causes an Auto-Transfusion Effect of about 500mL in Adults (since vasoconstriction
temporarily reduces circulatory volume that needs filling)
○ Plasma Refill Phenomenon - 40-60mL of Extravascular Fluid flows to Circulation every
minute during first 6-10 hours after blood loss-= Complete Refill after 30-40 hours later
Hallmarks of Shock
○ Circulatory Insufficiency
○ Inadequate Tissue Perfusion
3 Types of Shock in Conjunction w/ Blood Loss
○ Hypovolemic (Hemorrhagic) Shock - Follows Severe Blood Loss of More than 20% of Total
Blood Volume
■ Caused by Traumatic Hemorrhage, GIT Hemorrhage, Operative Hemorrhage,
Ruptured Aortic Aneurysm, Obstetric Complications and Massive Hemoptysis
○ Cardiogenic Shock = Caused by Inadequate or Abnormal Cardiac Function
■ Congenital Heart Disease
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■ Acute Myocardial Infarction
Shock due to Vasodilation and Hypotension
■ Sepsis
■ Anaphylaxis
Degree of Signs and Symptoms of Volume Depletion depends on Patient’s Age
○ Elderly - Symptoms of Cardiac Failure and Anemia after Blood Loss
Severe Anemia of Rapid Onset - RETINAL HEMORRHAGES
Other S/S:
○ Hypotension
○ Weak and Rapid Pulse
○ Shallow and Rapid Respiration
○ Altered Mental State
○ Cold and Pale Skin
○ Decreased Urine Output
○ Acidosis (Decreased Blood pH)
First Few Hours of Blood Loss - No Change in Hematocrit or Hemoglobin; Due to Initial
Compensatory Vasoconstriction
After 3-4 hours - Hematocrit and Hemoglobin Decreases
WBC Count Increases (due to outpouring of neutrophils from marginating pool) and Platelet Count
Increases
Bands and Metamyelocytes present on Blood Film
Nucleated RBCs may also be seen
12-24 hours after - Anemia is Evident
Macrocytic RBCs with Polychromasia
Bone Marrow - Erythrocytic Hyperplasia
Serum Ferritin - Best Measure of Patient’s Iron Storage Status; Decreased if Large Amounts of Iron
are Lost during Bleeding
Increased Levels of Plasma Erythropoietin
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Treatment - Preserve Fluid Balance
○ Initial Treatment = Crystalloids and Electrolyte Solutions = Cause Relative Decrease in
Hematocrit and Appears as More Severe Anemia
○ Oral Iron Therapy = Compensates for Iron Loss
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40-50
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Blood Loss (%)
S/S
None at Rest
Lightheadedness
Hypotension
Exertional Tachycardia
Angina Pectoris (Chest Pain, Pressure or Squeezing)
Decreased Cardiac Output
Hypotension
Rapid Pulse
Cold, Clammy Skin
Severe Shock
Death
Anemia of Chronic Blood Loss
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Takes time to develop and produce symptoms
Menstrual Blood Loss = 35 – 80mL per month w/ 40 mg Iron Loss per month
Other Causes:
○ GIT Bleeding
○ Occult Carcinoma of the Colon
○ Hookworm Infestation (Necator americanus and Ancylostoma duodenale) - May Cause
Blood Loss of up to 200mL per Day
Nonspecific Symptoms and Symptoms of Anemia do not appear until many months after blood loss
begins
Decreased Tissue Oxygenation - Inability to Concentrate
Tarry (Tar-Colored) Stools = Indicates GIT Bleeding - 60mL of Blood Needed to Cause Tarry Stools =
One of 1st Symptoms of GIT Problem
OFTEN LEADS TO IRON DEFICIENCY ANEMIA
Microcytic, Hypochromic Anemia w/ Moderate to Severe Iron Loss
Decreased Serum Ferritin and Increased TIBC
MCV, MCH and MCHC - Normal in Early Stages > Microcytic, Hypochromic
Confirmatory for GIT Bleeding - Positive for Stool Occult Blood Test
Treatment: Oral Iron Therapy or Transfusions (if Hb is < 7 g/dL)
○ Check Reticulocyte Count and RPI after 7-10 days to ensure patient is responding to iron
therapy
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