A curious case of a DHTR reaction from the Dombrock blood group system

Oct. 24, 2019

The Dombrock blood group system contains the antigens Doa and Dob, Gya, Hy, Joa, DOYA, DOMR and DOLG.1,2 More specifically, Joa is suspected as the culprit of a 2017 case of a delayed hemolytic transfusion reaction (DHTR).3 In 1992, the Dombrock group was expanded to include the antigens Gya, Hy and Jo,a which coincided with the discovery of the Gy(a-) as the null phenotype.4 Limited reports and literature regarding anti-Joa exists; however, this antibody has been linked to DHTRs.5

The case study

A 32-year-old African American female patient was preparing to undergo a complex orthopedic procedure and total hip arthroplasty due to avascular necrosis of the femoral head. 3 The patient had a history of sickle cell disease (SCD) and acquired anti-Fya from a transfusion two years earlier. The patient had no history of transfusion reactions and was not undergoing a chronic transfusion regimen.

On the day of surgery, the patient had a blood type and an antibody panel performed. The patient typed as O and Rh positive. The antibody panel showed weak to 1+ panreactivity with Fy(a-) cells. Both the autocontrol and direct antiglobulin test (DAT) performed resulted as negative.  The antibody identification yielded inconclusive results, and a sample was sent to a reference laboratory for further identification and red blood cell (RBC) genotyping.

During the surgery, the patient’s hemoglobin decreased from 10.2 g/dL to 8.6 g/dL, and an estimated blood loss of 450 mL was assumed. One unit of weakly crossmatched incompatible RBCs were transfused without issue. As a precaution, the unit issued was typed Fy(a-), C-, E-, K- and sickle cell (SC) hemoglobin S-negative. The unit was ordered emergently, and was issued accompanied with the risk form “transfuse with caution.” After surgery and post-operative care, the patient was released with no issues from transfusion or surgery and was in stable condition.

Several days later, the reference laboratory reported two new antibodies, anti-Joa and anti-Jkb, in conjunction with anti-Fya. The laboratory confirmed the transfused unit to be Jk(b-). At the reference laboratory, Anti-Joa was reactive by indirect antiglobulin test (IAT), polyethylene glycol and ficin-IAT. Genotyping determined the patient’s RBCs to be Fy(a-b-), Do(a+b+), Jo(a-) and Hy+. The patient was homozygous for the Duffy null promoter FY*02N.01 and for RHCE*01.01, which is associated with altered expression of e and the presence of the variant e allele.6

After approximately two weeks, the patient returned in a sickle vaso-occlusive pain crisis due to noncompliance with prophylactic medications. Of note, nearly all individuals with SCD experience a vaso-occlusive crisis in their lifetime.7,8 The patient’s hemoglobin resulted at 6.7 g/dL and one unit of Fy(a-), Jk(b-), C-, E-, K- HbS- RBCs was emergently transfused, but weakly crossmatched as incompatible. Lactic acid dehydrogenase (LDH) and potassium results were increased, and creatinine resulted in the normal range.

A few hours after transfusion, the patient’s temperature increased 1.3 degrees. The following day, the patient’s hemoglobin was unchanged from 6.7 g/dL. The LDH and potassium results significantly increased from the initial labs performed the day prior, and creatinine remained normal.

A delayed hemolytic transfusion reaction

A DHTR from anti-Joa was suspected, and the patient was informed. Consequently, the crossmatch incompatibility was likely due to the anti-Joa. This high-prevalence antigen is found in 100 percent of most populations.1,2 Unfortunately, the patient left the hospital against medical advice. A DHTR was suspected due to the episode occurring two weeks after the unit of RBCs administered during surgery, and the unit not being identified as negative for Joa antigen. Each transfusion the patient received was weakly crossmatch incompatible. The second unit transfused during the patient’s return to hospital yielded no change to her hemoglobin, yet continual increases in potassium and lactate dehydrogenase (LDH).

Treatment for most DHTRs requires monitoring the patient’s hematocrit and supportive care.9 Generally, patients do not exhibit symptoms, but have unexplained anemia.10 SCD patients require a combination of supportive care, optimization of erythropoiesis, consideration of immunosuppression and minimizing further transfusion is recommended.9

At initial recognition of a transfusion reaction, the providing staff immediately stops the transfusion, as every added milliliter of blood equates to a more significant impact.10,11 Providing staff will change the intravenous administration set and run 0.9 percent sodium chloride at a keep-open rate, allowing immediate administration of medication.10,12

Laboratory testing in response to DHTR

Laboratory testing in response to a DHTR may include repeat testing on pre-transfusion samples, visual evaluation for hemolysis on the post-reaction sample, DAT, eluate, LDH, haptoglobin, total bilirubin, hematocrit and urinalysis.10,12 Results are utilized as markers to identify hemolysis.10,12 Interestingly, the patient’s creatinine level did not change, which would typically yield elevated results in DHTR.10,12

The patient’s SCD presents a unique circumstance; albeit, not uncommon.8 Transfusions aid SCD management by providing RBCs with normal hemoglobin.8 While transfusions can be used to provide a method of therapy, they also bring additional complications and risks to include iron overload, alloimmunization and hyperviscosity.8 Several weeks after the transfusion reaction, the patient returned to the hospital in stable condition for outpatient services.3

The driving mechanism behind a DHTR is generally an amnestic immune response to a foreign RBC antigen that is seen with a decrease in hemoglobin. Alternately, upon transfusion hemoglobin may fail to rise.11,12 Antigens can occur from previous transfusions, pregnancies or exposures. Importantly, hemolysis is generally extravascular.11,12

During extravascular hemolysis, antibodies opsonize the RBC instigating macrophages to sequester RBCs, causing phagocytosis.12 Furthermore, the active macrophages increase proinflammatory cytokines that induce a systemic response. The systemic results generate patients experiencing fever, chills, abdominal flank pain and back pain.11,12 Fortunately, DHTRs cause significantly less clinical issues for patients when compared to other transfusion reactions.12

Although DHTRs are common, their prevalence is somewhat of an enigma due to the difficulty in detection.7,9,10 DHTRs can occur from days to months, and on rare occasions, years after transfusion.8,9 The time between transfusion and symptoms is so diverse that reactions are difficult for providers to distinguish.10 Patients do not exhibit symptoms but have unexplained anemia.8,10,12 When detected, transfusion reactions are typically signified by a change in the patient’s vitals.13 This was observed during the second transfusion the patient received.

DHTR statistics

The International Society of Blood Transfusion (ISBT) gathered data from 12 countries from 2006 through 2012 for 39.7 million transfused units and identified that 75 percent of adverse reactions are not severe. Moreover, DHTRs comprise a mere 16.6 percent of severe adverse reactions.14

The treatment for most DHTRs generally only requires supportive care for cardiac, respiratory or renal function distress, as well as monitoring of a patient’s vitals.9,10,12 In severe cases, patients may require subsequent transfusions or red blood cell exchange to remove incompatible red cells.12

The incidence of DHTRs is .04 percent of transfusions; however, this increases to 11 percent in patients with SCD.15 A 2014 evidence-based report noted that many SCD patients receive and continue to receive multiple RBC transfusions, placing them at increased risk for several complications.8 In a 2016 study of 99 SC patients with DHTRs, it was found that 62 percent formed new antibodies in their post-transfusion work-ups.16 Further, DHTRs were frequently misdiagnosed and 18 percent had been diagnosed at a subsequent medical visit with a median diagnosis of 10 days. These misdiagnoses would have been easily identifiable based on hemoglobinuria, noted in approximately 95 percent of the patients.

By treating SCD patients with RBC transfusions prior to medium-risk surgery, and ensuring their hemoglobin level reaches a minimum of 10 g/dL, post-operative complications can be reduced.8 Treatment regimens including long-term continual transfusions have variable impact to patients.8 Long-term transfusions require chelation therapy to remove excess iron, due to the lack of a physiological means to mitigate iron overload.8

Dombrock antibodies are IgG-restricted, weakly reactive and do not activate complement.1 The DO gene is located on chromosome 12p12.3 and contains three exons. It encodes a protein compromised of 314 amino acids group system located on the chromosome.1-2,5

Due to the high prevalence of the Joa antigen, difficulty of finding suitable units for this patient was next to impossible, especially in an emergent setting. According to the American Rare Donor Program, approximately 6.5 percent of requests for rare donor units were not fulfilled from 2012 to 2014.17 This is an 8 percent decrease from 2004 to 2006.18 Although there is improved distribution to products, there still exists concern for attaining compatible units in emergent situations.

In conclusion

Blood transfusions are one of the most frequent procedures in hospitals, and yield high risks to patients and facilities.19 Moreover, transfusion reactions can cause severe distress to the patient and an inevitable cost to the health care facility.20-22 Based on this case study and research, emergency room clinicians should be acutely aware that SCD patients presenting for vaso-occlusive symptoms may actually have a DHTR.16

Subsequently, evidence suggests that a proportional relationship between transfused units and adverse events exists: the higher the number of transfusions a patient receives, the greater the risk of cardiac or respiratory complications, postoperative infection or death.23 Ultimately, the patient did survive; however, providing the patient with future safe transfusions may prove difficult with her risk for DHTR and multiple antibodies.


1. Lomas-Francis C, Reid ME. The Dombrock blood group system: a review. Immunohematology 2010;26:71–8.

2. Reid ME, Lomas-Francis C, Olsson ML. The blood group antigen factsbook. 3rd ed. San Diego, CA: Academic Press, 2012.

3. Jajosky RP, Lumm WC, Wise SC, Bollag RJ, Shikle JF. A suspected delayed hemolytic transfusion reaction mediated by anti-Joa. Immunohematology. 2017 Jun;33(2):73-5.

4. Daniels GL, Anstee DJ, Cartron JP, Dahr W, Henry S, Issitt PD, et, al. Terminology for red cell surface antigens. Vox sanguinis. 1996 Nov 1;71(4):246-8.

5. Reid ME. Complexities of the Dombrock blood group system revealed. Transfusion 2005;45:92S–9S.

6. Westhoff CM, Silberstein LE, Wylie DE, et al. 16Cys encoded by the RHce gene is associated with altered expression of thee antigen and is frequent in the R0 haplotype. Br J Haematol 2001;113:666–71.

7. Rees DC, Robinson S, Howard J. How I manage red cell transfusions in patients with sickle cell disease. Br J Haematol. 2018 Jan 29. doi: 10.1111/bjh.15115.

8. Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, et, al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. Jama. 2014 Sep 10;312(10):1033-48.

9. Gardner K, Hoppe C, Mijovic A, Thein SL. How we treat delayed haemolytic transfusion reactions in patients with sickle cell disease. Br J Haematol. 2015 Sep 1;170(6):745-56.

10. DeLisle J. Is This a Blood Transfusion Reaction? Don't Hesitate; Check It Out. Journal of Infusion Nursing. 2018 Jan 1;41(1):43-51.

11. Harewood J, Master SR. Transfusion, Hemolytic Reaction. [Updated 2017 Oct 6]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2017 Jun-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK448158/

12. Delaney M, Wendel S, Bercovitz RS, Cid J, Cohn C, Dunbar NM, et, al. Transfusion reactions: prevention, diagnosis, and treatment. The Lancet. 2016 Dec 3;388(10061):2825-36.

13. Elliott M, Coventry A. Critical care: the eight vital signs of patient monitoring. Br J Nurs 2012; 21: 621–25.

 14. Politis C, Wiersum JC, Richardson C, Robillard P, Jorgensen J, Renaudier P, et, al. The international haemovigilance network database for the surveillance of adverse reactions and events in donors and recipients of blood components: technical issues and results. Vox sanguinis. 2016 Nov 1;111(4):409-17.

 15. Talano JA, Hillery CA, Gottschall JL, Baylerian DM, Scott JP. Delayed hemolytic transfusion reaction/hyperhemolysis syndrome in children with sickle cell disease. Pediatrics 2003; 111: e661–65.

 16. Habibi A, Mekontso‐Dessap A, Guillaud C, Michel M, Razazi K, et, al. Delayed hemolytic transfusion reaction in adult sickle‐cell disease: presentations, outcomes, and treatments of 99 referral center episodes. Amer J of Hema. 2016 Oct 1;91(10):989-94.

17.  Meny GM, Flickinger C, Marcucci C. The American rare donor program. J of Crit Care. 2013 Feb 1;28(1):110-e9.

18. Flickinger C, Petrone T, Church A. American rare donor program. Immunohematology. 2004;20(4):239-43.

19.  Pfuntner A, Wier LM, Stocks C. Most Frequent Procedures Performed in U.S. Hospitals, 2011. Rockville: Agency for Healthcare Research and Quality, 2013.

 20.  Bolton-Maggs PHB, ed, on behalf of the Serious Hazards of Transfusion (SHOT) Steering Group. The 2013 Annual SHOT Report. Manchester: SHOT, 2014.

 21.  Riley W, Smalley B, Pulkrabek S, Clay ME, McCullough J. Using lean techniques to defi ne the platelet (PLT) transfusion process and cost-eff ectiveness to evaluate PLT dose transfusion strategies. Transfusion 2012; 52: 1957–67.

 22. Ezidiegwu CN, Lauenstein KJ, Rosales LG, Kelly KC, Henry JB. Febrile nonhemolytic transfusion reactions. Management by premedication and cost implications in adult patients. Arch Pathol Lab Med 2004; 128: 991–95.

 23. Salpeter S, Buckley JS, Chatterjee S. Impact of more restrictive blood transfusion strategies on clinical outcomes: a meta-analysis and systematic review. Am J Med. 2014;127(2):124-131.