Abstract

Following liver transplantation, patients require immunosuppressive medications to prevent graft rejection. However, these drugs can have significant side effects including severe anemia. Tacrolimus is now commonly used in pediatrics patients after liver transplantation. Case reports indicate that tacrolimus rarely can cause microangiopathic hemolytic anemia and also hemolytic anemia due to cold reactive IgM antibodies (cold agglutinin disease). We have seen 4 patients with symptomatic cold agglutinins thought to have been triggered by tacrolimus. Four patients, 6 to 26 months post-ABO-compatible liver transplant, presented with severe anemia (hemoglobin < 6g/dL), indirect hyperbilirubinemia, reticulocytosis and low serum haptoglobin (Table 1). Peripheral blood smear exhibited marked autoagglutination but no evidence of microangiopathic changes. The direct antiglobulin test (DAT) initially was strongly positive in all 4 patients (Table 2). After warm saline washes, the DAT remained positive for complements in 3 out of 4 patients. Cold agglutinin titers were low (1:4 – 1:16) but thermal amplitude studies were positive at 37°C in the two tested patients. Viral serologies significant for cold agglutinin syndrome were negative. None of the patients had clinical evidence of post-transplant lymphoproliferative disorder. All 4 patients had brisk hemolysis requiring multiple uncrossmatched packed red blood cells (PRBC) transfusions. Favorable resolution of the hemolytic anemia occurred following steroids, plasmapheresis and withdrawal of tacrolimus. Subsequently, patients were placed on cyclosporin and none exhibited liver rejection or recurrence of their hemolytic anemia. The above observation indicates that acute cold-agglutinin induced hemolysis occurs in patients following liver transplantation and these events appear to have temporally associated with tacrolimus administration.

Patient Profiles

PatientAgeDiagnosisMonths after transplantPresenting hemoglobin (g/dL)Reticulocyte (%/Abs k/μLTotal/Direct BilirubinTreatments (in addition to withdrawal of tacrolimus)
ND=not done. MP=methylprednisolone 
8 mos Neonatal iron storage disease 2.8 41%/469 4.2/0.6 MP 4mg/kg/d plus
 30mg/kg/d x 3 days.
 Plasmapheresis x 6. 
13 mos Biliary atresia Idiopathic 5.3 8%/250 3.2/0.4 MP 4mg/kg/d.
 Plasmapheresis x 15. 
2 yrs 5 mos fulminant hepatic failure 14 4.6 19.5%/237 2.6/0.3 MP 10mg/kg/d.
 Plasmapheresis x 10. 
4 yrs Biliary atresia 26 5.3 5%/ND 8.8/0.5 MP 2mg/kg/d→ 4mg/kg/d.
 Plasmapheresis x 10. 
PatientAgeDiagnosisMonths after transplantPresenting hemoglobin (g/dL)Reticulocyte (%/Abs k/μLTotal/Direct BilirubinTreatments (in addition to withdrawal of tacrolimus)
ND=not done. MP=methylprednisolone 
8 mos Neonatal iron storage disease 2.8 41%/469 4.2/0.6 MP 4mg/kg/d plus
 30mg/kg/d x 3 days.
 Plasmapheresis x 6. 
13 mos Biliary atresia Idiopathic 5.3 8%/250 3.2/0.4 MP 4mg/kg/d.
 Plasmapheresis x 15. 
2 yrs 5 mos fulminant hepatic failure 14 4.6 19.5%/237 2.6/0.3 MP 10mg/kg/d.
 Plasmapheresis x 10. 
4 yrs Biliary atresia 26 5.3 5%/ND 8.8/0.5 MP 2mg/kg/d→ 4mg/kg/d.
 Plasmapheresis x 10. 

Immunohematology Profiles

Admission DATPatient 1Patient 2Patient 3Patient 4
Admission DATPre/post saline washPre/post saline washPre/post saline washPre/post saline wash
DAT-Direct antiglobulin test, M-microscopically, NT-not tested, +-positive, 0-negative, 
Polyspecific 3+/0 1+/M+ 4+/4+ 3+/1+ 
Anti-IgG 2+/0 M+/0 4+/1+ 3+/1+ 
Anti-C3 2+/0 2+/1+ 4+/4+ 3+/1+ 
Saline Control 2+/0 1+/0 1+/0 1+/0 
Eluate NT Panreactive 1+ Panreactive 1+ 
Cold agglutinin titer at 4°C in saline NT 16 
Thermal amplitude screen at 30°C NT NT Reactive Reactive 
Donath-Landsteiner Test NT NT Negative Negative 
Admission peripheral blood smear 4+ polychromatophilia. 4+ microcytosis 4+ autoagglutination. 3+ polychromatophilia. 3+ spherocytes. 3+ microcytes 3+ autoagglutination. 3+ polychromatophilia. 3+ spherocytes. 2+ macrocytes 4+ autoagglutination. 4+ spherocytes. 2+ polychromatophilia. 2+ macrocytes 
Admission DATPatient 1Patient 2Patient 3Patient 4
Admission DATPre/post saline washPre/post saline washPre/post saline washPre/post saline wash
DAT-Direct antiglobulin test, M-microscopically, NT-not tested, +-positive, 0-negative, 
Polyspecific 3+/0 1+/M+ 4+/4+ 3+/1+ 
Anti-IgG 2+/0 M+/0 4+/1+ 3+/1+ 
Anti-C3 2+/0 2+/1+ 4+/4+ 3+/1+ 
Saline Control 2+/0 1+/0 1+/0 1+/0 
Eluate NT Panreactive 1+ Panreactive 1+ 
Cold agglutinin titer at 4°C in saline NT 16 
Thermal amplitude screen at 30°C NT NT Reactive Reactive 
Donath-Landsteiner Test NT NT Negative Negative 
Admission peripheral blood smear 4+ polychromatophilia. 4+ microcytosis 4+ autoagglutination. 3+ polychromatophilia. 3+ spherocytes. 3+ microcytes 3+ autoagglutination. 3+ polychromatophilia. 3+ spherocytes. 2+ macrocytes 4+ autoagglutination. 4+ spherocytes. 2+ polychromatophilia. 2+ macrocytes 

Disclosure: No relevant conflicts of interest to declare.

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