Delayed Hemolytic Transfusion Reaction Case Study

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Last Updated: Oct. 28, 2016[All links fixed]

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Learning Outcomes

Upon completion of this exercise, participants should be able to:

  1. Discuss the concept of dosage as it relates to cells used for antibody screening.
  2. Describe the follow-up investigation required when a patient has a positive antibody screen.
  3. Explain the risk involved in releasing donor units that are crossmatch-compatible before the patient's antibody has been identified.
  4. Discuss reasons  why a patient with a clinically significant antibody may have a negative antibody screen while experiencing a hemolytic transfusion reaction.
  5. Describe what happens to antibody levels (antibody kinetics) following primary and secondary immune responses to red blood cell antigens.
  6. Discuss best practices aimed at preventing delayed hemolytic transfusion reactions.

Case Report

A 60-year-old female (SJ) was admitted to hospital complaining of bloody diarrhea and dizziness. Two days later she experienced severe GI bleeding and underwent emergency surgery. A crossmatch for 6 units of RBC was ordered.

History

  • Transfusion: none
  • Pregnancy: four (uneventful)
  • Medications: Patient reported occasional aspirin use and had been on hormone replacement therapy since menopause.

Laboratory results (Day 0*)

  • Hemoglobin:70 g/L (reference range:120 - 160 g/L)
  • Total bilirubin: 8.6 µmol/L (reference range: 1.7 - 17.1 µmol/L)
  • Lactate dehydrogenase: 224 U/L (reference range: 113-226 U/L)

* As used for this case study, Day 0 is the day of the first transfusion. Day 3, etc., refers to days post-transfusion.

Transfusion Service Results

Initial pretransfusion testing results (Day 0)

The technologist notified the attending physician that the patient had an unexpected antibody (or antibodies) present but that units crossmatched by indirect antiglobulin method were compatible and available if needed. Because the transfusion service performs only Type and Screen/Crossmatch the samples were sent to a reference laboratory to have the antibody identified.

  • The decision was made to transfuse the donor RBC before the positive antibody screen had been resolved and the patient received all six units over the next 24 hours without complication.
  • The cause of SJ's bleeding was found to be diverticulitis and a colectomy was performed. Her hemoglobin rose as expected and at Day 5 her hemoglobin was 127g/L.

Reference laboratory results (Reported on Day 3)

On Day 8 SJ's condition deteriorated. Peripheral blood smears were consistent with acute hemolysis (anisocytosis, poikilocytosis, nucleated RBCs). Her reticulocyte count was 8.8 percent.

Additional laboratory results (Day 8)

  • Hemoglobin: 72 g/L (reference range:120 - 160 g/L)
  • Total bilirubin: 59.9 µmol/L  (reference range: 1.7 - 17.1 µmol/L)
  • Lactate dehydrogenase: 1055 U/L (reference range: 113-226 U/L)

Transfusion reaction investigation results(Day 8)

Follow-Up and Case Outcome

  • The patient stabilized and was later transfused with 2 units of crossmatch-compatible Jk(a-) RBC.
  • By Day 14 her antibody screen was again positive, reacting 2+ with Jk(a+b-) screen cells and 1+ with Jk(a+b+) screen cells.
  • Her DAT remained  positive upon discharge three weeks after admission.

Discussion

See the case discussion, including interactive questions with feedback.

Final Quiz

This quiz is offered as a self assessment.

  1. Why is dosage an important concept in pretransfusion antibody screening tests?
  2. Which follow-up tests are routinely done when investigating possible delayed hemolytic transfusion reactions?
  3. Why should donor units that are crossmatch-compatible NOT be released, unless life-threatening, before the antibody is identified?
  4. Why can a patient with a clinically significant antibody sometimes have a negative antibody screen while experiencing a delayed hemolytic transfusion reaction in which antibody levels are rising?
  5. Provide six best practices for preventing delayed hemolytic transfusion reactions.

Further Reading

Cash KL, Brown T, Sausais L, Uehlinger J, Reed LJ.Severe delayed hemolytic transfusion reaction secondary to anti-At(a). Transfusion 1999 Aug;39(8)834-7. [Medline]

Davenport RD. Hemolytic transfusion reactions. In: Popovsky M, editor. Transfusion reactions, 2nd ed. Arlington, VA: AABB Press;2001. p.1-44.

Heddle NM, Soutar RL, O'Hoski PL, Singer J, McBride JA, Ali MA, Kelton JG. A prospective study to determine the frequency and clinical significance of alloimmunization post-transfusion. Br J Haematol 1995 Dec;91(4):1000-5. [ Medline ]

Hillman NM. Fatal delayed hemolytic transfusion reaction due to anti-c + E. Transfusion 1979 Sep-Oct;19(5)548-51. [ Medline ]

Pineda AA, Vamvakas EC, Gorden LD, Winters JL, Moore SB. Trends in the incidence of delayed hemolytic and delayed serologic transfusion reactions. Transfusion 1999 Oct;39(10):1097-103.  [ Medline ]

Sazama K. Reports of 355 transfusion associated deaths:1976 through 1985. Transfusion 1990;30:583-90. [ Medline ]

Schonewille H, Haak HL, van Zijl AM. RBC antibody persistence. Transfusion 2000 Sep;40(9):1127-31. [ Medline ]

Final Diagnosis -- Hemolytic transfusion reactions caused by the Kidd blood group


FINAL DIAGNOSIS

HEMOLYTIC TRANSFUSION REACTIONS CAUSED BY THE KIDD BLOOD GROUP.

DISCUSSION

Transfusion Reactions

These two cases represent hemolytic transfusion reactions caused by the Kidd blood group. Case one is a delayed hemolytic transfusion reaction (DHTR) and case two is an acute hemolytic transfusion reaction (AHTR). What should I do if a patient developed transfusion reaction?

  1. STOP THE TRANSFUSION!
  2. Keep the IV open with 0.9% NaCL.
  3. Check the product tags & patient identification.
  4. Notify the Blood Bank.

    If the transfusion is terminated:

  5. Collect & send blood & urine samples to the Blood Bank.
  6. Send the unit, tags & the blood administration set to the Blood Bank [1].

A transfusion reaction workup is initiated by the clinician. Laboratory findings in AHTRs include hemoglobinemia, hemoglobinuria, elevated lactate dehydrogenase (LDH), hyperbilirubinemia, and low haptoglobin [3]. During hemolysis, hemoglobin decreases as red cells are been destroyed. Haptoglobin is a mucoprotein that binds to free hemoglobin in the plasma, and thus decreases in hemolysis. If the amount of free hemoglobin is too much for the kidney to tolerate the patient can develop hemoglobinuria. The blood urea nitrogen and creatinine can be elevated if renal dysfunction occurs. The direct antiglobulin test (DAT) may be positive [3].

A transfusion reaction workup in the blood bank includes clerical check, visual inspection for hemolysis (serum), and DAT. The DAT detects the presence of antibody attached to red cells in the patient's circulation. DAT can be positive if there are alloantibodies attached to the transfused red cells, or there are antoantibody bound to patient's own RBCs (if the patient has not been transfused) [2]. DAT starts with the patient's red cells, which are washed to remove unbound antibodies, then polyspecific anti-globulin reagent is added to observe agglutination. If the polyspecific DAT is positive, then anti- IgG, or anti-C3d specific reagent is used. If the DAT is positive with anti-IgG, an elution procedure is performed. An elution procedure is when an antibody is removed from the red cells with acidic glycine solution and the solution is called an eluate. A red cell panel is performed to identify the antibody in the eluate [2]. Newly developed antibodies may be initially only detected in the eluate and not the serum, because the eluate concentrates the antibody [1]. Cases of positive DAT tests with anti-IgG and negative eluates may be due to the eluate was not tested against panel cells with the antigen (in the case of low incidence antigens) or nonspecific IgG binding [1].

Hemolytic Transfusion Reactions

DHTR is an anamnestic antibody production (preformed antibodies are absent or too low for methods to detect). The patient has been exposed to the antigen previously and lymphocytes are ready to produce antibodies when exposed. This usually occurs 5 to 14 days after transfusion with more commonly extravascular hemolysis but some cases have intravascular hemolysis [2 and 3]. Signs include jaundice, fever, pain or shortness of breath. Laboratory findings in DHTRs may include anemia, elevated LDH, hyperbilirubinemia, low haptoglobin, the present a new red cell antibody or antibodies, and a positive DAT [3]. Kidd alloantibodies account for 1/3 of DHTRs. The remainder of DHTRs are caused by anti- D, c, E, K or Fya [2]. Subsequent units given to the patient must be antigen negative for the antibody that caused the reaction. Most delayed hemolytic reactions are not clinically significant and not reported [1].

Acute hemolytic transfusion reaction is the activation of complement, release of cytokines inducing a systemic inflammatory response within 24 hours of transfusion [3]. There are two explanations for the Kidd blood group's activation of complement. Kidd antigens are thought to be clustered close together allowing for complement activation by IgG and since a subset of Kidd are IgM, Kidd IgM antibodies activate complement [4 and 5]. Signs include fever, tachycardia, hypotension, pain, or shortness of breath [3]. In AHTRs, there may be renal damage due to vasoconstriction. Free hemoglobin released into the bloodstream following intravascular hemolysis binds to nitric oxide causing vasoconstriction and nephrotoxicity. C8-9 mediated destruction is in involved in AHTRs [6]. Most AHTRs are from intravascular hemolysis and the most common cause is from ABO incompatibility [3].

Management of hemolysis includes recognition and stop the transfusion. For further units, administer antigen negative units. Supportive measures for hypotension are pressors and fluid resuscitation. Furosemide and fluids can be given to protect renal function. The patient's renal function should be monitored [6]. In severe cases, exchange transfusion with antigen negative units can be considered [3].

Kidd Blood Group System

Jka was discovered in 1951 when an undiscovered antibody caused hemolytic disease of the newborn in the sixth child of Mrs. Kidd. JK was the initials of the baby. Jkb was found two years later in a woman with a transfusion reaction [7]. The Kidd blood group has two co-dominant antigens, Jka and Jkb, on SLC14A1, an urea transporter protein. The red cell urea transporter, HUT11 (human urea transporter 11) contains the Kidd antigens. The transporter uptakes urea in the renal medulla and disperses it away from the kidney without affecting the cell size. The Jka-b- is not associated with a clinical significant disorder from lacking the urea transporter [1].

Anti - Jka and Jkb are mostly IgG1 and IgG3 with minor component of IgG2, IgG4, or IgM [1]. Antibodies can cause both intravascular and extravascular hemolysis [8]. Antibodies rapidly decease in the absence of the antigen and may be undetectable on antibody screening [1]. Both Anti- Jka and Anti-Jkb can cause AHTRs and DHTRs. To enhance Kidd antibody identification, use a fresh sample, use proteolytic enzymes to destroy other antigens on the red blood cell and make the Kidd antigen more available for binding and use LISS to promote IgG binding [9].

Kidd antibodies can cause hemolytic disease of the fetus/ newborn but is usually not severe [7]. Anti- Jka is more frequent and more severe [8]. Kidd antibodies are characteristically found with other antibodies [7]. Auto antibodies against Kidd antigens have been seen in autoimmune hemolytic anemia including drug induced hemolysis. Other sources of auto antibodies to Kidd antigens have been documented from food preservatives, cosmetics and Proteus mirabilis [9].

Table 5: Kidd Phenotype Frequencies

(Harmening, Modern Blood Banking and Transfusion Practices, 4th edition, 1999 [9] ) Jka is more prevalent than Jkb in African Americans. Most of our blood product donations in Pittsburgh are from Caucasians. Since 72% of Caucasians have Jkb antigens and 57% of African Americans are Jkb-, there is the potential to make anti-Jkb antibodies with exposure to blood products in this area.

Kidd Protein

The Kidd gene is located on chromosome 18 and contains 11 exons however only exons 4- 11 code for the protein [1]. The Kidd glycoprotein protein has ten transmembrane domains and the N and C termini are located intracellularly. The Kidd polymorphism is located on the fourth loop and caused by a single amino acid substitution. Kidd protein is expressed on red cell surfaces, neutrophils and endothelial cells in the kidney [7 and 8]. The phenotype is the product of alleles in which Jka is Asp280 and Jkb is Asn280 [1].

Kidd Blood Group in the Literature

Kidd antibodies may function as histocompatibility antigens in renal transplants and may be linked to acute transplant rejections [10].

REFERENCES

  1. Roback, J. D., & American Association of Blood Banks. Technical Manual. 16th ed. Bethesda, Md.: Aabb; 2008.
  2. Petrides, M., Stack, G., Cooling, L., & Maes, L. Y.. Practical Guide to Transfusion Medicine. 2nd ed. Amer Assn of Blood Banks; 2007.
  3. Mintz, Paul D,ed. Transfusion Therapy: Clinical Principles and Practices. 3rd edition. Bethesda, MD: AABB Press; 2011.
  4. McCullough, J. J.. Transfusion Medicine. New York: McGraw-Hill; 1998.
  5. Yates, J., Howell, P., Overfield, J., Voak, D., Downie, D. M., & Austin, E. B. IgG anti-Jka/Jkb antibodies are unlikely to fix complement. Transfusion Medicine. 1998; 2: 133-140.
  6. Klein, H. G., Mollison, P. L., Anstee, D. J., & Mollison, P. L. Mollison's Blood Transfusion in Clinical Medicine. 11th ed. Malden, Mass.; Oxford: Blackwell Pub.; 2005.
  7. Westhoff, C. M., & Reid, M. E. Review: The kell, duffy, and kidd blood group systems. Immunohematology / American Red Cross. 2004; 20(1):37-49.
  8. Rossi, E. C., & Simon, T. L. Rossi's Principles of Transfusion Medicine. 4th ed. Hoboken, NJ: Wiley-Blackwell; 2009.
  9. Harmening, D. Modern Blood Banking and Transfusion Practices. 4th ed. Philadelphia: F.A. Davis; 1999.
  10. Holt, S., Donaldson, H., Hazlehurst, G., et al. Acute transplant rejection induced by blood transfusion reaction to the kidd blood group system. Nephrology Dialysis Transplantation. 2004; 19(9):2403-2406.

Contributed by Lisa Radkay, MD and Lirong Qu, MD, PhD






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