Transfusion Medicine and Hemolytic Diseases of the Newborn

Question 1

hemolytic disease of the newborn

Answer 1

Hemolysis in a newborn or fetus caused by blood-group incompatibility between mother and child.

Question 2

Immune hydrops

Answer 2

accumulation of edema fluid in the fetus during intrauterine growth. It is not specific to HDN, but can occur in many different fetal conditions including cardiovascular conditions, chromosomal disorders like Down syndrome, non-immune fetal anemia, twin-twin transfusion, infections, tumors, and metabolic disorders

Question 3

Hydrops fetalis

Answer 3

(When the accumulation of fluid is severe and generalized, it is called hydrops fetalis.)

Question 4

Erythroblastosis fetalis

Answer 4

Erythroblastosis means that early red cell precursors are showing up in the peripheral blood. This can happen in any severe anemia, not just HDN.)

Question 5

Mechanism

Answer 5

. Fetus inherits blood group antigens (usually Rh D antigen or ABO antigens) from the father that are foreign to the mother.

2. Fetal blood gets into mom’s circulation (either during last trimester of pregnancy, when cytotrophoblast is no longer present, or during childbirth).
3. Mom makes antibodies to these blood group antigens.
4. Antibodies cross the placenta, attack baby’s red cells, causing hemolytic anemia and its consequences.

Question 6

• Extramedullary hematopoiesis

Answer 6

If the anemia is mild, extramedullary hematopoiesis in the liver and spleen may produce enough red cells to maintain normal numbers.

Question 7

• Heart and liver failure

Answer 7

If the anemia is severe, the heart and liver may suffer hypoxic injury, resulting in circulatory and hepatic failure. Liver failure causes decreased protein levels (proteins are synthesized in the liver) and a reduction in oncotic pressure in the circulation. Heart failure causes an increase in venous pressure (blood is backing up behind the failing heart). If severe enough, the combination of reduced oncotic pressure and increased venous pressure leads to generalized edema and ascites, a condition called hydrops fetalis, which can be fatal. Lesser degrees of edema can also occur.

Question 8

• Jaundice

Answer 8

If hemolysis is severe, jaundice can occur due to accumulation of unconjugated bilirubin.

Question 9

• Kernicterus

Answer 9

Unconjugated bilirubin is water insoluble; it binds to lipids in the brain (the blood-brain barrier in the fetus is poorly developed), causing serious damage to the CNS, termed kernicterus. The affected brain is enlarged, edematous, and yellow.

Question 10

Rh-mediated HDN Mechanism

Answer 10

• Most often involves the D antigen (sometimes involves E or c; rarely involves e or C).
• Baby inherits D Ag from father
• Mom is D negative (same as saying “Rh negative”)
• Fetal blood gets into mom’s circulation (through trauma, ruptures in the placenta during pregnancy, medical procedures carried out during pregnancy that breech the uterine wall, or childbirth).
• Mom makes anti-D antibodies (Amount of antibody made depends on dose of antigen received from baby! Mom only makes anti-Rh antibodies when she has received more than 0.5 - 1 mL of Rh + cells; some people say not until 4 mL has been transferred.)
• Just like any other developing antibody, IgM appears first, and IgG appears later. This is important because IgG can cross the placenta, but IgM can’t. So HDN is uncommon in a first pregnancy. But if the mom gets pregnant again, and the fetus inherits D again, mom will now make IgG antibodies, and HDN can happen then.

Question 11

Diagnosis and prevention of Rh-mediated HDN

Answer 11

• Direct antiglobulin test will be positive in baby (baby’s cells are coated with mom’s antibodies)
• Indirect antiglobulin test will be positive in mother (though if the mother has received Rhogam at 28 weeks – see the next bullet – the IAT will be artificially positive!)
Administration of anti-D antibody (Rhogam) at 28 weeks and again within 72 hours of delivery to Rh negative moms mops up any circulating D+ fetal red cells (by coating them with antibody) before mom is able to make any anti-D antibodies! Incidence of Rh-mediated HDN has gone way down since Rhogam was developed
• Must quantify the amount of fetomaternal hemorrhage (using Kleihauer-Betke test or immunophenotyping assay) to determine the appropriate dose of Rhogam.

Question 12

Kleihauer-Betke test

Answer 12

1. Prepare blood smear from mom’s blood.
2. Expose blood smear to acid bath (this removes adult hemoglobin, which is acid-sensitive) but not fetal hemoglobin
3. Stain smear (fetal cells appear pink; maternal cells look like “ghosts”.
4. Count lots of cells and report percentage of cells that are fetal.

Question 13

Flow cytometry test

Answer 13

1. Use mom’s blood
2. Apply anti-HbF antibody
3. Run flow, look for cells staining intensely with anti-HbF (These are baby’s cells! A few of mom’s cells will have weak HbF staining – this is normal.)

Question 14

ABO-mediated HDN

Answer 14

• ABO incompatibility occurs in 20-25% of pregnancies, but laboratory evidence of hemolytic disease occurs only in 1 of 10 such infants, and the hemolytic disease is severe enough to require treatment in only 1 in 200 cases.
• Reasons ABO incompatibility is rarely serious:
• Most anti-A and anti-B antibodies are IgM (hence they don’t cross the placenta)
• Neonatal RBCs express A and B poorly
• Many cells other than red cells express A and B Ag, and thus sop up some of the transferred Ab.
• ABO hemolytic disease occurs almost exclusively in infants of A or B type born of group O mothers
• Normal anti-A and anti-B are IgM and don’t cross placenta
• For reasons not understood, however, some group O women have IgG anti-A and anti-B even without prior sensitization! Therefore, firstborn may be affected
• Fortunately, even with transplacentally acquired Ab, lysis of infant red cells is minimal.
• ABO incompatibility is diagnosed with same tests as Rh incompatibility (DAT, IAT, Kleihauer-Betke test)
• There’s no effective protection against ABO reactions!

Question 15

ABO-mediated HDN Treatment

Answer 15

• Minimally affected newborns can be treated with phototherapy: light oxidizes unconjugated bilirubin (toxic) to water-soluble, readily-excreted dipyrroles (harmless).
• Severely affected fetuses can be treated by total exchange transfusion of the infant (through umbilical vein).
• Mother can be treated with plasmapheresis (removes antibody)
• High-dose intravenous immunoglobulin can be used too – but the best dosage and timing are not well defined.

Question 16

How do you make A, B, and H antigens?

Answer 16

How do you make A, B, and H antigens?
• Start with a protein precursor
• Add fucose to make H antigen
• Add N-acetylgalactosamine to H antigen to make A antigen.
• Add galactose to H antigen to make B antigen.

Question 17

Whole blood

Answer 17

Contents: Red cells, plasma, white cells (nonfunctional), and platelets (nonfunctional)
Used for: Patients who are actively bleeding and who have lost more than 25% of their blood volume (“massive bleed”).

Question 18

Red blood cells

Answer 18

Contents: Red cells (with a little plasma, a few white cells, and a few platelets)
Used for: Patients who are anemic but have a normal blood volume.

Question 19

Leukoreduced red blood cells

Answer 19

Contents: Red cells (with very little plasma, and virtually no white cells or platelets)
Used for: Patients who have had repeated febrile transfusion reactions (which may be due to anti-
leukocyte antibodies in the recipient)
Patients who will be getting lots of transfusions (to cut down on alloimmunization to
HLA antigens)

Question 20

Frozen red blood cells

Answer 20

Contents: Red cells (with a few white cells, and no plasma or platelets)
Used for: Patients with rare blood types (can keep red cells frozen for 10 years)

Question 21

Granulocytes

Answer 21

Contents: Neutrophils (with some lymphocytes, platelets, and red cells)
Used for: Patients with severe neutropenia and infection unresponsive to antibiotics.

Question 22

Platelets

Answer 22

Contents: Platelets (with plasma and a few red cells and white cells)
Used for: Bleeding due to thrombocytopenia or platelet abnormalities

Question 23

Fresh Frozen Plasma

Answer 23

Contents: Plasma (including all coagulation factors and complement)
Used for: Bleeding due to multiple factor deficiencies (e.g., DIC, liver failure)

Question 24

Cryoprecipitate

Answer 24

Contents: Fibrinogen, factors VIII and XIII, and von Willebrand factor
Used for: Hemophilia A, von Willebrand’s disease, congenital factor XIII deficiency, decreased
fibrinogen

Question 25

Albumin

Answer 25

Contents: Albumin and a little bit of other plasma proteins
Used for: Volume expansion in patients with low blood volume who also have decreased levels of plasma proteins (e.g., patients in shock, and patients with nephritic syndrome). Albumin exerts oncotic pressure which helps keep fluid inside vessels. The use of albumin is somewhat controversial.

Question 26

IvIG

Answer 26

Contents: IgG, mostly (some preparations are specific for a certain infectious agent, like chickenpox)
Used for: Disease prophylaxis, replacement therapy in primary immunodeficiency states, patients with autoimmune disorders, patients with graft-versus-host disease after bone marrow transplant.

Question 27

Acute Hemolytic Transfusion Reactions

Answer 27

• Cause: Patient has pre-formed antibodies against the donor red cells (usually directed at ABO antigens). These are usually IgM, which means they can bind complement and lyse red cells.
• Most common reason: clerical error! (Wrong blood to wrong patient.)
• Symptoms: fever, chills, chest pain, hypotension, low back pain, shortness of breath, and nausea.
• Lab tests showing hemolysis (from any cause!) include: decreased haptoglobin, increased bilirubin, hemoglobinemia and hemoglobinuria.
• A type and cross-match (using the recipient’s plasma and the donor red cells) should detect the offending antibody in the patient’s serum (as well as the corresponding antigen on the surface of the donor cells).

Question 28

What to do if you suspect an acute transfusion reaction:

Answer 28

1. STOP THE TRANSFUSION!
2. Verify that the right unit of blood was given to the right patient
3. Keep the IV in
4. Maintain blood pressure and adequate ventilation
5. Notify the attending physician and blood bank
6. Obtain blood and urine for transfusion reaction workup
7. Send the blood bag to the blood bank

Question 29

Delayed Hemolytic Transfusion reactions

Answer 29

• Hemolysis occurs at some point well after transfusion (1 day to 1 week)
• Usually occurs in patients who have been previously sensitized to red cell antigens (multiparous women, patients with prior transfusions)
• Due to antibodies to non-ABO antigens (most common: Rh)
• Hemolysis usually occurs extravascularly.
• Most commonly detected by noticing a falling hemoglobin after transfusion. Symptoms, if present, are usually not severe (weakness, malaise, fever).
• A DAT will detect donor cells coated with patient antibody. An antibody screening test will detect the offending antibody in the patient’s serum.

Question 30

Febrile Non-Hemolytic Transfusion reactions

Answer 30

• Caused by antibodies in the patient that react against donor white blood cells or platelets, releasing fever-causing cytokines.
• Symptoms include fever (obviously, given the name), headache, malaise, nausea, vomiting, and chest/back pain.
• If this has happened more than once to your patient, you can decrease the chances of another reaction by using leukocyte-depleted blood next time, or by giving acetaminophen.

Question 31

Allergic Reactions

Answer 31

• The most frequent kind of reaction (1% of all transfusions).
• Probably caused by reactions to donor plasma proteins.
• The only symptom is hives!
• Treatment: give the patient an antihistamine, and restart the transfusion in 15-30 minutes.
• Rarely, patients may have a severe allergic reaction, presenting with shortness of breath, laryngeal edema, or even anaphylaxis. These patients are given epinephrine and monitored closely.

Question 32

Infections

Answer 32

• Transfusion-related bacterial infection is uncommon but serious.
• Patients present suddenly (during transfusion, or up to a few hours later) with fever, hypotension, and shock.
• Treatment includes aggressive resuscitation and antibiotic therapy.
• The patient – and the suspected unit of blood – must be tested (gram stain and culture).
• Despite testing of donor blood for HIV, HTLV, Hepatitis B and C, and syphilis, these diseases are still transmitted through transfusion (though rarely).
• Other transmissible infectious agents include EBV, CMV, Babesia, Plasmodia (malaria), Trypanosoma cruzi (Chagas’ disease), Borrelia burgdorferi (Lyme disease).

Question 33

Circulatory Overload

Answer 33

• Happens when too large a volume of blood is given too quickly.
• Signs and symptoms include headache, shortness of breath, congestive heart failure, and hypertension.
• Symptoms usually subside if transfusion is stopped and patient is given diuretics.

Question 34

Iron Overload

Answer 34

• Accumulation of too much iron (hemosiderosis) can damage the heart and liver.
• Patients with chronic anemias are at particular risk, because of the need for repeated transfusions.
• There is no physiologic mechanism for eliminating excess iron. Intravenous iron-chelating agents (like deferoxamine) must be used to prevent iron overload.

Question 35

Graft-vs-Host Disease

Answer 35

• A rare complication caused by donor lymphocytes in the transfused blood product.
• Usually occurs in immunocompromised patients, but can occur in immunocompetent patients (especially in donations from blood relatives, in which the donor HLA type may be so similar to the host that the host doesn’t recognize the donor lymphocytes as foreign).
• The donor T cells proliferate in the recipient, recognizing host HLA antigens and attacking host tissues.
• Symptoms start about 10 days after transfusion: fever, skin rashes, diarrhea, hepatitis, and bone marrow failure. Most cases are fatal.
• Irradiating the blood products prevents GVHD, because it prevents donor lymphocytes from proliferating.