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Type II Hypersensitivity Reaction: Hemolytic Disease of the Fetus and Newborn

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Type II Hypersensitivity Reaction: Hemolytic Disease of the Fetus and Newborn

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By: Yesenia Cano, Aaliyah Edgar, Peyton Hammerich, and Antonia Vita

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Overview: Type 2 Tissue-Specific Hypersensitivity (Second Mechanism): Hemolytic Disease of the Fetus & Newborn

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Overview: Type 2 Tissue-Specific Hypersensitivity (Second Mechanism): Hemolytic Disease of the Fetus & Newborn

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A Type II Hypersensitivity Reaction refers to "an antibody-mediated immune reaction in which antibodies (IgG or IgM) are directed against cellular or extracellular matrix antigens, resulting in cellular destruction, functional loss or damage to tissues" occurring through multiple mechanisms (Bajwa, et. al., 2023).

As defined by the National Library of Medicine, Hemolytic Disease of the Newborn is a "red blood cell mismatch between mothers and their fetuses that can cause significant morbidity and mortality" with fatalities from the disorder becoming rare with the application of immunoprophylaxis (Hall, et. al., 2022).

Risk Factors

Mother & baby blood type incompatibility:

Rh negative mother & Rh positive father - problems arising if the baby's Rh factor is positive

Cellular Pathophysiology

Comprised of three mechanisms:

1. Complement Mediated Lysis

2. Antibody-dependent Cellular Cytotoxicity

3. Antireceptor Antibodies

Premature destruction of erythrocytes in newborn due to blood-type incompatibility of child and mother.

Tissue/organ level pathophysiology

Cause --> Effect relationship:

Hemolysis of erythrocytes --> thyroid, heart, liver, & pancreas

Erythropoiesis --> liver & spleen

Excessive circulating bilirubin --> brain

Clinical manifestations

Pigmentation changes of skin, eyes, amniotic fluid & umbilical cord

Enlarged spleen or liver

Hypoxemia

Hydrop Fetalis

Severe hyperbilirubinemia

Possible kernicterus

Therapuetic Management

Administration of immunoprophylaxis

Phototherapy

Exchange transfusions

Intravenous immunoglobulin

Bajwa, S. F., & Mohammed, R. H. (2023, July 4). Type II hypersensitivity reaction. StatPearls - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK563264/

Hall, V., & Avulakunta, I. D. (2022, November 22). Hemolytic disease of the newborn. StatPearls - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK557423/

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Hemolytic Disease of the Newborn (HDN), Animation

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Hemolytic Disease of the Newborn happens most often when an Rh negative mother has a baby with an Rh positive father.

Problems may arise if the baby's Rh factor is positive (similar to the father's), most often occurring during delivery when RBCs from the unborn baby cross into the mother's blood when the placenta detaches. Hemolytic Disease of the Newborn then occurs when the immune system of the mother sees a baby's red blood cells as foreign, forming antibodies against the baby's RBCs, attacking these cells in the baby's blood and causing them to break down too early (MedlinePlus, 2023).

Hemolytic disease of the newborn: MedlinePlus Medical Encyclopedia. (2021, November 9). https://medlineplus.gov/ency/article/001298.htm

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Mechanisms of Type II, Tissue Specific Reactions (Rogers, 2023)

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Type II Hypersensitivity reactions Tissue specific response against haptens

Haptens are targeted by three mechanisms:

Complement Mediated Lysis

Antibody-dependent Cellular Cytotoxicity

Antireceptor Antibodies

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ADCC Mechanism 2: Type II Hypersensitivity reactions 

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Antibody-Dependent Cell-Mediated Cytotoxicity- Mechanism 2 of Type II Hypersensitivity Reactions

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Antibody-Dependent Cell-Mediated Cytotoxicity- Mechanism 2 of Type II Hypersensitivity Reactions

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This mechanism occurs when antibodies bound to tissue-specific antigens activate macrophages, neutrophils, and natural killer cells that will attack the target cells

Antibodies then cause a deposit of C3b on the target cell surface

Macrophage and Neutrophilic receptors then recognize and bind the antibody and C3b (an opsonin) which increases phagocytosis of the target cell

Toxic products (lysozymes and toxic oxygen free radicals) produced by neutrophils also cause tissue damage

i.e. Autoimmune conditions in which autoantibodies are made against antigens on platelets or RBC's causing them to be removed by phagocytes in the spleen (Rogers, 2023, p. 259).

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Rh Blood Group image detailing the Rh factor courtesy of Sagar (2022)

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Hemolytic disease of the fetus and newborn (HDFN)

Erythrocytes of a fetus or new-born are destroyed prematurely due to blood-type incompatibility of the child and mother

When the mother is Rh-negative and the child is Rh-positive, antibodies from the mother cross the placenta and attack fetal erythrocytes

This causes the mother to produce D-antigens is large quantities from the IgG antibody with each successful pregnancy of an Rh+ fetus (Rodgers, 2023, p. 268)

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Hemolytic disease of the fetus and newborn (HDFN) Pathophysiology graphic  de Caen, Genny & Schweitzer, Christina (2017)

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Alila Medical Media (2019). Hemolytic Disease of the Newborn (HDN), Animation [Video]. YouTube.

Aryal, S. (2022). Rh Blood Group image detailing the Rh Factor [Photograph]. Retrieved from @ 2024 Microbe Notes.

Bajwa, S. F., & Mohammed, R. H. (2023, July 4). Type II hypersensitivity reaction. StatPearls - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK563264/

de Caen, Genny & Schweitzer, Christina (2017). Hemolytic disease of the fetus and newborn: Pathogenesis and clinical findings. The Calgary Guide to Understanding Disease. Retrieved from thecalgaryguide.com.

Drozdowska-Szymczak A, Proczka J, Chrzanowska-Liszewska D, Truszkowski K, Mazanowska N, Krajewski P. Liver Dysfunction with Severe Cholestasis and Coagulation Disorders in the Course of Hemolytic Disease of the Newborn Requiring Chelation Therapy—A Case Report and Review of the Literature. Journal of Clinical Medicine. 2023; 12(24):7645. https://doi.org/10.3390/jcm12247645

Rogers, J. (2023). McCance & Huether's Pathophysiology (9th ed., pp.  259, 268). Elsevier Health Sciences (US).

Ford, S. (2022, February 15). Hemolytic Disease of the Fetus and Newborn (HDFN). Med Lab Study Hall. https://medlabstudyhall.com/hdfn/

Hemolytic Disease | Boston Children’s Hospital. (n.d.). https://www.childrenshospital.org/conditions/hemolytic-disease

Hemolytic disease of the newborn: MedlinePlus Medical Encyclopedia. (2021, November 9). https://medlineplus.gov/ency/article/001298.htm

Hall, V., & Avulakunta, I. D. (2022, November 22). Hemolytic disease of the newborn. StatPearls - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK557423/

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Drozdowska-Szymczak A, Proczka J, Chrzanowska-Liszewska D, Truszkowski K, Mazanowska N, Krajewski P. Liver Dysfunction with Severe Cholestasis and Coagulation Disorders in the Course of Hemolytic Disease of the Newborn Requiring Chelation Therapy—A Case Report and Review of the Literature. Journal of Clinical Medicine. 2023; 12(24):7645. https://doi.org/10.3390/jcm12247645

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Hemolysis of the fetal erythrocytes results in the accumulation of bilirubin in the bloodstream and iron in the thyroid, heart, liver, and pancreas.

Erythropoiesis accelerates in the liver and spleen to compensate for destruction of the erythrocytes, resulting in enlargement of these organs.

Excessive circulating bilirubin may be deposited in the brain. In severe cases of HDFN, fetuses may experience fatal system-wide gross edema called hydrops fetalis.

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HDFN and General Type II Hypersensitivity

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HDFN and General Type II Hypersensitivity

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While hemolytic disease of the fetus and newborn largely adheres to the general definition of type II hypersensitivity, one unique characteristic is the birth order onset pattern.

In the first pregnancy in which the mother and fetus have an antibody mismatch, no disease will occur. The first pregnancy primes the body for the hypersensitivity reaction in the second pregnancy, but does not occur immediately during the first exposure, as in ABO transfusion reactions, or other type II hypersensitivities

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Ford, S. (2022, February 15). Hemolytic Disease of the Fetus and Newborn (HDFN). Med Lab Study Hall. https://medlabstudyhall.com/hdfn/

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The newborn will present with yellowing of the skin, eyes, amniotic fluid, and umbilical cord and or an enlarged liver or spleen.

In utero mild anemia can occur and cause hypoxemia. Severe anemia can cause enlargement of the liver and spleen since the body is trying to compensate for the breakdown of the red blood cells, the body will make more RBCs in the liver and spleen which causes the organs to enlarge. These RBCs are often immature and will not function well which will then manifest in anemia. Hydrop Fetalis can also occur where the heart will begin to fail and large amounts of fluid will build up in the tissues and organs.

After birth, there will be severe hyperbilirubinemia and possible kernicterus. Kernicterus is the buildup of bilirubin that can spill over into the brain and can lead to permanent brain damage.

Hemolytic Disease | Boston Children’s Hospital. (n.d.). https://www.childrenshospital.org/conditions/hemolytic-disease

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Ford, S. (2022, February 15). Hemolytic Disease of the Fetus and Newborn (HDFN). Med Lab Study Hall. https://medlabstudyhall.com/hdfn/

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treatment planning:

The protocol calls for the administration of immunoprophylaxis at 28-34 gestational weeks in Rh-negative mothers with Rh-positive infants. This includes giving Rh-immunoglobin known as RhoGAM, which helps the mother antibodies from reacting with the infant Rh-positive antibodies. Affected pregnancies can be managed by monitoring titers and possible early delivery, this is seen in infants with severe anemia as they cannot tolerate full-term labor. Transcutaneous bilirubin or serum bilirubin screening occurs within 24 hours of life. Hour-specific Bhutani nomogram can be used to stratify the amount of bilirubin in the infant's blood. This provides a threshold on whether to start phototherapy or transfusions based on the infant's risk level (pictured in the slide).

Therapeutic managements include phototherapy, exchange transfusions, and intravenous immunoglobulin. Phototherapy induces photo isomerization causing the transformation of bilirubin into water-soluble isomers that are then easily excreted by the kidneys and stool and bypass the need to be processed in the liver. Exchange transfusions are needed for severely anemic infants and when phototherapy is insufficient or if signs of bilirubin encephalopathy are present. This will replace RBCs with antigen-negative RBCs and can aid in the prevention of further hemolysis of RBCs. However, albumin levels should be monitored as bilirubin binds to albumin, and with the combination of exchange transfusions, it will begin to decrease albumin levels and can therefore increase bilirubin levels which will elevate the risk for kernicterus. Intravenous immunoglobulin (IVIG) blocks Fc receptors on macrophages which will then decrease the breakdown of antibody coated-RBCs.

Hall, V., & Avulakunta, I. D. (2022, November 22). Hemolytic disease of the newborn. StatPearls - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK557423/

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Ford, S. (2022, February 15). Hemolytic Disease of the Fetus and Newborn (HDFN). Med Lab Study Hall. https://medlabstudyhall.com/hdfn/