1. Interesting Case Conference: ABO Incompatible Heart Transplant
Jonathan Douds
August 14, 2013

2. Case Presentation 2 month old male (currently)
HPI: Born at 36.1 w EGA, 2930 g via emergent C section. At birth, baby was noted to be cyanotic with oxygen saturation at 70% on room air. Baby was intubated with improvement
Family history: Father with DCM as a neonate
Radiology: CXR showed cardiomegaly; Echo demonstrated depressed LV and RV wall motion, mitral and tricuspid insufficiency

3. Case Presentation Echo worsened Patient evaluated for heart transplant
An ABO incompatible heart was available on 8/1/13 (B donor, O recipient)
Patient’s ABO titers were 1:1
Patient remains critically ill with respiratory failure and feeding intolerance

4. Brief Background
UNOS (United Network for Organ Sharing) listed 51,837 patients for transplantation in 2010 and had only 28,664 organs available
Limitations in pediatric transplant have included:
ABO type
HLA type
Size

5. Review of ABO Blood Groups
4 blood groups, A, B, O, and AB described by Karl Landsteiner in 1900
Located on chromosome 9q
Gene encodes glycosyl transferases
Specific sugars added to a precursor H antigen determine blood type
A has a N-acetyl galactosamine
B has a galactose
O type only has H antigen
Lack of H antigen is known as Bombay
Antibodies to these blood groups develop naturally in response to environmental antigens that share structural similarity to A and B antigens
Type A people develop anti-B antibodies and express the A antigen

6. Clinical Background
ABH antigens are expressed on the mesothelial cells on the epicardium and on vascular endothelium
Immunosuppression administered according to standard protocol, regardless of ABOi
Measure isohemagglutinins regularly in the immediate post-transplant period but they correlate poorly with clinical, echocardiographic or pathologic signs of AMR

7. ABO Type and Transplant
Following mismatch transplants in adults, hyperacute antibody-mediated rejection occurs owing to the pre-formed antibodies in the serum of the recipient that bind to the antigens on the cell of the donor
Leads to activation of complement and coagulation cascades leading to ischemic necrosis of the graft

8. ABO Type and Transplant
In 2004, it was found that instead of this expected response, a severe form of acute antibody mediated rejection occurred during the first 2 weeks post transplant – “delayed hyperacute rejection”
Two proposed mechanisms
Decreased antigenicity of the vascular endothelium owing to ischemic injury to the graft
Decreased antibody in the recipient either owing to antibody removal prior to transplant or due to immunosuppressive therapy
This rarely occurred beyond one month due to “accommodation”
Therefore, the first two weeks are the critical period

9. ABO Type and Pediatric Transplant
Humoral responses to ABOi in adults do not seem to occur in children
There are little or no antibodies to ABO antigens in young infants as these are predominantly formed following exposure
Anti-A and anti-B antibodies are absent at birth and appear from 4 to 8 months of age after colonization of the GI tract with E. coli
Development of antibodies to carbohydrate epitopes on these bacteria

10. Acceptance of ABOi Organs
Subramanian V, et al. (2012)

11. ABO Type and Pediatric Transplant
The first 10 patients to undergo intentional ABOi cardiac transplantation were reported in 2001
Had no or very low titers of isohemagglutinins
No hyperacute rejection occurred
2 patients died both with causes unrelated to ABO incompatibility

12. Effect of ABOi Transplants
UNOS policy change in 2006 allowed for listing of infants with ABOi transplants with a maximum age limit of <2 years and a maximum isohemagglutinin titer of LE 1.4
ABOi hearts offered once ABOc possibilities are exhausted
One study indicated that infants eligible for ABOi hearts have a median waiting time of 2 weeks or less than those only listed for ABOc hearts
Canadian data has shown a decrease in wait listing mortality for infants under 6 months of age from 58% to 7% with ABOi transplants making up to 40% of transplants

13. Henderson, et al. (2012)
Previous studies have shown that children who received ABOi heart transplants have similar survival when compared to ABOc
Prior to study, published studies have had small number of patients and small follow-up data
Goal was to analyze patients in Pediatric Heart Transplant Study database
Analyzed ABOi and ABOc done at PHTS transplant centers
Compared clinical characteristics and short term freedom of death, rejection, and infection in the ABOi patients with the ABOc patients

14. Henderson, et al. (2012)
Analyzed 502 heart transplants done at PHTS centers that performed at least 1 ABOi transplant (85)
ABOi transplant patients had equivalent one year survival and freedom from rejection compared with those that received an ABOc transplant
In spite of the favorable outcome, many centers appear to reserve ABOi transplantation for sicker patients
Recommended reevaluation of the current United Network for Organ Sharing policy that gives priority to ABOc over ABOi transplnation in the US

15. Costanzo, et al. (2010) Guidelines
“Upper limit of age or titer for ABOi pediatric heart transplant remains unclear”
“ABOi heart transplant can be safely performed in the pediatric population in the presence of positive isohemagglutinin titers against the donor organ”
“Serial measurements of isohemagglutinin titers should be done in the post-operative period”
Whole blood products should never be administered
Group O RBCs and group AB blood elements are safe
If RBC transfusions are given to any ABO-incompatible recipient, base the match on the recipient’s ABO blood type
If platelets or plasma is needed, base the match on the donor’s ABO blood type
All recommendations are level of evidence C (based on expert consensus and not on clinical trials)

16. Costanzo, et al. (2010) Guidelines

17. Kobayashi and Saito (2006) 2 surveys performed in Japan 2003 survey
In 2003, serum samples from six healthy donors were sent to 29 hospitals
Measured isohemagglutinin assays in serial-doubling time dilutions of serum
Inter-institutional difference between maximum and minimum value was as high as 32 fold in IgM and 256 fold in IgG
They noted that protocol for the assay varied between institutions, so a standardized protocol was created
2004 survey
Intra-institutional variation was reduced to below eight-fold
Conclusions
Periodical control survey is necessary and standardization of the assay of anti-A and anti-B antibody titer is important

18. 2013 VUMC CAP Survey Titers were performed for anti-A and anti-D
Anti-A result was a titer of 64, with CAP acceptable results of 64, 128, and 256
Given a result of “good”
Anti-D result was a titer of 32
Result was listed as acceptable when compared to similar methodologies

19. References
Henderson HT, Canter CE, Mahle WT, Dipchand AI, LaPorte K, Schechtman KB, Zheng J, Asante-Korang A, Singh RK, Kanter KR. ABO-incompatible heart transplantation: Analysis of the Pediatric Heart Transplant Study databse. The Journal of Heart and Lung Transplantation, Vol 32, No 2, February 2012.
Subramanian, V, Ramachandran S, Klein C, Wellen JR, Shenoy S, Chapman WC, Mohanakumar T. ABO-incompatible organ transplantation. Intl Journal of Immunogenetics, 2012, 39,
Irving C, Gennery A, Kirk R. Pushing the boundaries: The current status of ABO-incompatible cardiac transplantation. The Journal of Heart and Lung Transplantation, Vol 31, No 8, August 2012
Costanzo MR et al., The International Society of Heart and Lung Transplantation Guidelines for the Care of Heart Transplant Recipients. The Journal of Heart and Lung Transplanation, Vol 29, No 8, August 2010
Kobayashi T and Saito K. A series of surveys on assay for anti-A/B antibody by Japanese ABO-incompatible Transplantation Committee. Xenotransplantation 2006: 13: