Hyperhemolysis syndrome with
associated reticulocytosis after red
cell exchange in a patient with sickle
cell disease
Yijun Zhu, David Chapel, Geoffrey Wool
Department of Pathology, University of Chicago
Case:
• An African-American man in his 40s with HbSS SCD was admitted to
UCM for pain crisis
• Progressed to acute chest syndrome with right middle lobe infiltrate,
generalized chest pain, and dyspnea requiring nasal cannula (but no
fever).
• Hgb dropped to <7.0
– Baseline hemoglobin was 8-9 g/dL.
• Never previously been transfused at UCM.
– Remote history of transfusion at another institution
– Denied any history of RBC antibodies or transfusion reactions
• Five prior negative antibody screens at UCM over 16 months.
2
Presentation Title Here | 3
• He underwent RBC exchange transfusion (RCE) with seven
units of C/E/K-matched, HbS-negative, electronically
compatible RBCs on day three of admission.
– Settings: End Hct 24%, FCR 30%
• Pre-exchange and post-exchange hemoglobin were 6.2 and 8.7
g/dl, respectively. The percentage HbS declined from 88.2% to
28.5% after RCE.
4
RCE
5
• Patient’s chest pain significantly improved, patient-controlled
analgesia (PCA) use declined, and he was able to maintain SpO2
>92% on room air.
• The patient was discharged with Hb 9.6 g/dL on day seven of
admission (four days after RCE).
6
• Readmitted five days after discharge with worsened persistent
VOC pain, as well as dark urine. He reported fevers at home,
but was not febrile at UCM
• Admission Hgb was 8.1 g/dL
– Antibody screen and DAT (with IgG and C3) all negative
– HgbS 61.1%.
– Unconjugated bilirubin 11.7 mg/dL (7.8 before prior
discharge)
7
• His hemoglobin dropped to 4.9 and he received two units of
RBCs one day after readmission.
• His hemoglobin increased from 4.9 to 7.8 g/dl, but fell to 5.8
g/dl one day later.
• The patient received another RBC unit with no post-transfusion
increase in hemoglobin.
• Repeat antibody screen on day 2 of readmission was negative.
• No transfusion reactions were suspected clinically.
8
RCE
2U
xfusion
1U
xfusion
IVIG
Solumedrol
9
• Due to the concern for hyperhemolysis syndrome, RBC
transfusions were halted and IVIG and methylprednisolone were
administered.
• Hemoglobin decreased to a nadir of 4.1 g/dl eight days after
readmission before gradually increasing to 7.7 g/dl at discharge
(13 days after readmission).
• Reticulocyte increased to 30.5% two days before discharge.
• LDH decreased to 541 and unconjugated bili to 2.9
11
The differential diagnosis included
1. Sickle-related hemolysis
 unlikely due to significantly increased HgbS%
2. Delayed hemolytic transfusion reaction (DHTR)
 unlikely due to repeatedly negative antibody screens and
negative DAT
3. Hyperhemolysis syndrome
 favored due to drop in Hgb below pre-RCE values, increased
HgbS% as both endogenous and allogeneic RBC are
hemolyzed, repeatedly negative antibody screens and negative
DAT
12
Another consideration…
Bone marrow necrosis/fat embolization syndrome
• Presents with dropping Hgb and platelets, leukoerythroblastosis,
respiratory failure, altered mental status/encephalopathy
• Can present with TMA and therefore requests for TPE
• Best treatment is RCE
–
–
–
–
Adamski J et al. Am J Hematol. 2012. 87:621
Tsitsikas DA et al. Blood Rev. 2014. 23.
May J et al. Am J Med. 2016. 129:e321.
Gangaraju R et al. South Med J. 2016. 109:549.
Presentation Title Here | 13
Hyperhemolysis syndrome (HHS)
• Relatively rare, severe hemolytic complication of red cell
transfusion.
• HHS generally presents in the days following transfusion with a
negative Ab screen (or no new Ab) and post-transfusion
hemoglobin lower than pre-transfusion levels.
– HbS percentage may increase sharply in HHS, as donor
RBCs (as well as endogenous RBC) are destroyed.
14
Reticulocytopenia
• Interestingly, our patient’s reticulocyte count remained elevated
– Though some of his lowest Hgb were associated with lowest
reticulocyte counts
• HHS is classically associated with reticulocytopenia
– Presumably immune-mediated suppression of erythropoiesis
• Our patient’s finding may reflect a subset of HHS cases that lack
suppression of erythropoiesis, or simply missing the reticulocyte
nadir in the inter-admission period.
15
Possible mechanisms for hyperhemolysis
Macrophage activation:
• Hemolysis of both transfused and self RBCs without necessity of detectable
Ab or bound C3
Bystander hemolysis:
• Antibodies against other non-RBC antigens such as HLA, plasma proteins
– Our patient did not have detectable anti-HLA Ab
• Formation of immune complexes interacting with RBC.
RBC apoptosis
16
Management
• Abstention from further RBC transfusion (as possible)
• Folate, vit B12
• Intravenous immune globulin (IVIG)
• Corticosteroids
• EPO
• Rituximab
• Eculizumab
17