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Diagnosis and Discussion: Case 1146

Final Diagnosis

Hyperhemolysis Syndrome (HS) in the setting of Sickle Cell Disease

Discussion

Sickle cell disease (SCD) is an autosomal recessive hemoglobinopathy in which a point mutation replacing valine for glutamic acid in β-chain hemoglobin subunits leads to abnormal hemoglobin S (HgbS) formation1. HgbS causes sickling of RBCs when in low oxygen conditions, which in turn can lead to vaso-occlusive symptoms including osteonecrosis, skin ulcers, organ failure, acute chest syndrome (ACS), and cerebrovascular accidents (CVA)1. The atypical RBCs also have a shorter lifespan, which contributes to a hemolytic anemia1. Worsening of symptoms can be triggered by several factors such as dehydration, high altitudes, or infections, as evidenced by our patient having flu-like symptoms a week prior to presentation.

Acute non-life-threatening vaso-occlusive episodes are treated with supportive therapy, including hydration, antibiotics, heat application, anti-inflammatory medications, and analgesics such as opioids1. Hydroxyurea increases fetal hemoglobin (Hgb F) concentrations, thereby decreasing HgbS concentration and polymerization1. RBC transfusions to increase tissue oxygenation and decrease HgbS concentrations should be considered in patients with CVA, splenic sequestration, or symptomatic anemia1.

The transfusion of RBCs in patients with SCD is not without risk. Due to differences in RBC antigens between the primarily Caucasian donor pool and recipients mostly of African descent in the United States, the chronic inflammatory state present in SCD, and potential frequent RBC transfusion, individuals with SCD are at an increased risk of alloimmunization2. Providing antigen-matched RBC units based on the patient’s RBC phenotype helps minimize this sensitization risk3. When our patient was admitted to our institution, our blood bank contacted hospitals the patient had previously been transfused at, obtained records of the patient’s RBC phenotype, and ordered RBC units based on this information to be prepared in the event he would require transfusion. Immunohematology testing performed at the outside hospitals prior to the patient’s admission did not detect any antibodies. While the American Society of Hematology guidelines do not explicitly recommend full phenotypic matching prophylactically for SCD patients without antibodies receiving transfusion3, the outside hospital had transfused units based on a full phenotypic match, and so we continued this practice out of abundance of caution. Given the high prevalence in people of African ancestry of the GATA box promoter mutation that leads to Fyb antigen expression being lost on RBCs but maintained in other tissues, thereby protecting from Fyb alloimmunization 4, RBC units positive for Fyb were approved for potential transfusion. RBC genotyping was performed for our patient and confirmed the presence of the GATA box mutation.

Additionally, patients with SCD can develop delayed hemolytic transfusion reactions, of which hyperhemolysis syndrome (HS) is the most severe variant and occurs in approximately 3% of transfusions given to SCD patients5. HS is not unique to SCD and has been described in patients with other disease processes such as thalassemia, myelofibrosis, anemia of chronic disease, and lymphoma1. In HS, posttransfusion Hgb levels are below pretransfusion levels due to hemolysis and reduced erythropoiesis. Laboratory testing shows increased bilirubin, increased lactate dehydrogenase (LDH), and decreased haptoglobin levels as indicators of hemolysis, and decreased reticulocyte count may be noted. Because of the bystander hemolysis that occurs, in which the activation of macrophages through complement leads to destruction of both patient and donor RBCs6, it is important to avoid further RBC transfusion unless necessary. For our patient, a “Do Not Transfuse” protocol was added to his profile in the blood bank’s Laboratory Information System (LIS) to prevent the release of blood products without the approval of a transfusion medicine physician. While an immune component contributes to their development, many cases do not have any evidence of alloantibodies6, as was the case with our patient. Free heme released from lysed RBCs create oxidative stress, which can exacerbate vaso-occlusive symptoms6.

If further transfusion is warranted in a patient with HS despite the risk, such as with worsening clinical condition in our patient, administration of IVIG, steroids, or rituximab before administering the RBC unit is indicated1,3,6. While IVIG can ameliorate macrophage-mediated RBC destruction6, it is important to consider its side effects of renal toxicity and thromboembolic events, especially considering that these patients are at higher risk of thrombosis and organ failure1. To address reduced RBC production, rituximab promotes reticulocyte count recovery, and erythropoietin promotes erythropoiesis1. Eculizumab is a C5 convertase inhibitor that interferes with the complement cascade and can help stop bystander hemolysis1. Therapeutic plasma exchange may be of potential utility but has limited evidence to support its implementation7.

Hyperhemolysis syndrome is a rare but severe complication of sickle cell disease. Our patient presented with a significant drop in hemoglobin after receiving a transfusion of RBCs to address the symptoms of an acute sickle cell crisis. With appropriate supportive and immunomodulatory therapy, he was successfully transfused with a unit of RBCs at our institution without any adverse event or further hemolysis. Throughout his admission, his hemolysis improved, as reflected in the decrease in his bilirubin and LDH levels and increase in his hemoglobin and hematocrit levels (Figure 1 & Figure 2).

References

  1. Banks M, Shikle J. Hyperhemolysis syndrome in patients with sickle cell disease. Archives of Pathology & Laboratory Medicine. 2018 Nov 1;142(11):1425-7.
  2. Yazdanbakhsh K, Ware RE, Noizat-Pirenne F. Red blood cell alloimmunization in sickle cell disease: pathophysiology, risk factors, and transfusion management. Blood, The Journal of the American Society of Hematology. 2012 Jul 19;120(3):528-37.
  3. Chou ST, Alsawas M, Fasano RM, Field JJ, Hendrickson JE, Howard J, Kameka M, Kwiatkowski JL, Pirenne F, Shi PA, Stowell SR. American Society of Hematology 2020 guidelines for sickle cell disease: transfusion support. Blood advances. 2020 Jan 27;4(2):327-55.
  4. Howes RE, Patil AP, Piel FB, Nyangiri OA, Kabaria CW, Gething PW, Zimmerman PA, Barnadas C, Beall CM, Gebremedhin A, Ménard D. The global distribution of the Duffy blood group. Nature communications. 2011 Apr 5;2(1):266.
  5. Kalter JA, Gupta R, Greenberg MR, Miller AJ, Allen J. Hyperhemolysis syndrome in a patient with sickle cell disease: a case report. Clinical Practice and Cases in Emergency Medicine. 2021 Jan 26;5(1):101.
  6. Pirenne F, Pondarré C. Alloimmunization and hyperhemolysis in sickle cell disease. Hematology. 2023 Dec 8;2023(1):653-9.
  7. Adkins BD, Kaylani SZ, Nero A, Ibrahim IF, Shen YM, Sarode R. How do we manage hyperhemolysis syndrome. Transfusion. 2024 Oct;64(10):1822-9.