Lesson 11
Hypersensitivity
Type II Hypersensitivity
Examples include:
Haemolytic Disease of the Foetus and New-born (HDFN)
Haemolytic Transfusion Reactions (HTRs)
Overview of Videos
Goals of the videos include:
Discuss the immune response to blood group antigens in HDFN and HTRs.
Explore the link between pregnancy and the pathogenesis of HDFN.
Present methods for prevention, monitoring, and treatment of HDFN.
Learning outcomes:
Explain the immune response to blood group antigens in HDFN and HTRs.
Articulate how pregnancy increases risk.
Describe prevention mechanisms, testing, and monitoring for disease progression in mothers.
Contents
Focus Areas:
Type II hypersensitivity and alloantibodies (atypical antibodies) in HDFN
Normal immunity during pregnancy
Symptoms for atypical antibodies and HDFN in maternal and fetal cases
Diagnosis of HDFN including detection and monitoring
Laboratory tests for HDFN
Prevention or cure strategies
Type II Hypersensitivity: Alloantibodies and HDFN
Sensitization and Type II Hypersensitivity
Objectives:
Learn about the sensitization process leading to Type II hypersensitivity reactions.
Understand how sensitization to blood group antigens leads to haemolytic anaemia.
Gain knowledge on extravascular haemolysis nature and process.
Definitions
Natural antibodies:
Example: IgM anti-A or anti-B
Produced without prior immune challenge directly from foreign blood.
Atypical alloantibodies:
Require exposure to foreign red blood cells, produce antibodies against antigens not present on patient's own cells.
Usually clinically significant and composed of IgG.
Routes of Exposure
Blood transfusion:
Mandatory and discretionary grouping, requiring ABO and RhD types and matching on available blood types.
Foetal-maternal haemorrhage:
Maternal and fetal blood mixing occurs during labor, birth, and third trimester.
Mechanism of Type II Hypersensitivity
Type II hypersensitivity involves an inappropriate IgG response to an immunological challenge, contrasting Type I hypersensitivity (IgE).
Sensitization Process:
Initial large immunological challenge stimulates a robust response.
A second immune response results from repeated smaller stimulations, leading to enhanced IgG levels.
Each subsequent immune challenge raises antibody concentration in the serum.
Timeline of Immune Response
Primary Response:
Involves initial exposure to an antigen, leading to the development of IgM and IgG within a timeline of about 10 to 20 days.
Secondary Response:
Characterized by quicker and larger IgG responses upon re-exposure to the same antigen, demonstrating memory effect.
Differences in Sensitization and Subsequent Immunization
Initial sensitization involves significant volumetric exposure (<4ml), while subsequent immunizations can occur with microliter exposures.
Most common sensitizing events involve ABO blood groups, with clinically relevant events linked to the Rh D antigen and other variants such as Rh c and K.
Extravascular Hemolysis
Mechanism:
IgG antibodies opsonize red blood cells, prompting their removal in the reticuloendothelial system (liver and spleen).
Macrophages digest opsonized red cells, leading to metabolic byproducts and jaundice.
Normal Immunity During Pregnancy
Objectives
Understand the role of the placenta in maternal and fetal immunity.
Learn about immunoglobulin classes involved in passive immunity.
Acknowledge how maternal immunity changes throughout pregnancy.
Function of Immunity in Pregnancy
Aim:
Protect both mother and foetus, while efficiently clearing any perceived foreign agents.
The placenta acts as a physical barrier to protect the fetal environment.
Passive Immunity Mechanism
Maternal IgG, predominantly IgG1 and IgG3, is transported across the placenta via FcRn, providing passive immunity up to labor onset.
The neonatal immune system develops gradually until 3-6 months postpartum, relying on colostrum for initial passive immunity.
Maternal Immune Timetable
1st Trimester:
Increased inflammatory response due to implantation.
2nd Trimester:
Regulated anti-inflammatory immune response; higher miscarriage risks due to reduced T-reg cells.
3rd Trimester:
Transition to a pro-inflammatory immune response.
Patient Symptoms of Atypical Antibodies / Symptoms of HDFN
Learning Objectives
Recognize presentation patterns associated with HDFN and HTRs.
Understand the pathophysiological mechanism of HDFN and detect disease progression effectively.
Presentation of HDFN and HTR Symptoms
Delayed transfusion reaction:
Symptoms appear 3-4 weeks post transfusion; typical anemia symptoms include tiredness, shortness of breath, and pallor.
Testing reveals presence of atypical antibodies that must be identified for cross-matching.
Presentation Patterns in HDFN
First pregnancies with antigen-negative mothers pose risk when the mother experiences her first foetal exposure.
Subsequent pregnancies may present with slower development, miscarriage, and risks of Kernicterus and hydrops fetalis affecting the newborn.
Diagnosis of HDFN, Detection, and Monitoring
Learning Objectives
Role of laboratory medicine in diagnosing and monitoring HDFN.
Understand the patient's journey through pregnancy with regards to blood type relevance.
Diagnosis and Monitoring Process
Compatibility Schematic: - Blood group and antibody screening methodologies; include steps like electronically matching red cells, identifying antibodies, and performing tests for unexpected results.
Importance of Blood Groups
Significant populations show different Rh D positivity rates, affecting clinical considerations. - Common Issues: AB0 incompatibility more prevalent, but less clinically significant than Rh incompatibilities. - The severity of HDFN aligns with the accessibility and frequency of antigens.
Follow-Up Samples and Interventions
Monitor antibody activity through fortnightly samples. Adjust treatment based on titres and quantify additional antibody responses. - Intrauterine transfusions (IUT): can be performed for conditions identified with high antibody titres, essential for correcting foetal anemia prior to term.
Laboratory Tests for HDFN
Learning Objectives
Understand laboratory testing techniques for identifying patient and foetal blood types.
Understand how foetal-maternal hemorrhage can lead to sensitization and its implications.
Key Laboratory Testing Techniques
Initial blood group testing at booking (ABO and Rh D types) to assess potential immunisations.
Non-invasive methods: - Chorionic Villus Sampling, Amniocentesis for foetal blood sampling; advantages and risks identified through analysis.
Detecting Foetal-Maternal Hemorrhage
The use of techniques such as flow cytometry for direct measurement of foetal RhD positive cells in maternal blood for accurate identification of foetal blood volume.
Prevention or Cure
Learning Objectives
Understand how HDFN can be prevented, distinguishing between prevention and treatment measures.
Historical Context of Prevention
Highlight key historical developments in Rh prophylaxis, starting resolutions emphasizing immunization prevention following maternal exposures to foreign foetal red blood cells.
Current Guidelines for Administration of Rh Prophylaxis
Antepartum: 500 i.u. of anti-D Ig at weeks 28 and 34, and as additional doses as needed based on foetal-maternal hemorrhage estimates. - Postpartum: Standards stipulate administering anti-D Ig to Rh D negative mothers after delivery if the neonate is Rh positive or unknown.
Success Stories in HDFN Prevention
The impact of routine antenatal anti-D prophylaxis (RAADP) on reducing the incidence of perinatal deaths; significant decreases noted from historical rates to achieved levels today.
Myths Vs. Reality: Discussion on persisting immunization rates despite preventive measures, indicating gaps in adherence to guidelines and process improvements needed.
Conclusion
Key Takeaways
Review the theoretical frameworks surrounding RAADP and HDFN's impacts historically and clinically; embrace learnings to enhance clinical practices going forward.