Article

Fatal hyperhemolytic delayed transfusion reaction in sickle cell disease: A case report and literature review

Case Report

Fatal hyperhemolytic delayed transfusion reaction in Sickle cell disease: A case report and literature review?

Abstract

Patients with Sickle cell disease may require repeated red blood cells transfusion, putting them at risk for minor blood group alloimmunization and the development of hyperhemolytic delayed transfusion reac- tions (HDTR). We recently cared for an adolescent with SCD who was admitted to the hospital with a severe HDTR. The patient had been discharged from the hospital five days previously, and had been transfused while hospitalized. The patient continued to hemolyse, despite the use of antigen compatible blood and end-up by disseminated intravascular coagulopathy (DIC), Acute kidney injury and he went on to develop cardiac arrest and could not be resuscitated. In addition to demonstrating the potential severity of HDTR we are focusing on potential side effects of Transfusion therapy in SCD. Physicians caring for patients with SCD should be aware of the unique complications and Transfusion requirements in this population. HDTR is a potentially life- threatening complication. It is of crucial that when a patient presents with symptoms of a painful episode with worsening anemia and has a history of recent transfusion, the clinician be alert to the possibility of a HDTR.

Some patients with SCD experience significant decrease in their hemoglobin level and significant increase in reticulocyte count during the progression of uncomplicated acute painful episodes [1]. Blood transfusion is naturally a mainstay of treatment; however, transfusion therapy for SCD may incur special and distinctive adverse effects. Years of unsystematic clinical observations, followed by more carefully designed and in some cases randomized studies, have contributed substantially to our knowledge of transfu- sion reaction in SCD. However, much remains unknown and areas of controversy persist. In addition the syndrome of massive HDTR in SCD persists as a Life-threatening complication for which appropriate clinical management is

? Conflict of interest: None

not yet defined [2]. Herein we report of a case of fatal massive HDTR in patient with SCD.

A 20-year-old African American male with SCD was readmitted for pain crisis. His medical history included pulmonary hypertension, and congestive heart failure. Five days prior to readmission, he was discharged from the hospital with a Hb of 9.9 g/dL after a sickle cell crisis was treated with hydration, pain medications, oxygen, and received 3 units of cross-match-compatible RBCs that was antigen negative for his antibodies. On readmission, he had Hb of 8.1 g/dL and he was treated again for painful crisis with hydration, pain medicine and oxygen. On the 2nd day of readmission Hb dropped to 5.7 g/dL and the pain was not controlled with Large doses of morphine and dilaudid and he was anxious, irritable and drowsy. On the 3rd day his Hb was further dropped down to 3.5 g/dL, developed dark-colored urine, he was tachycardic, tachypnic and lethargic and in severe pain despite of maximal doses of dilaudid. He developed decompensated heart failure and oliguric AKI. Uncorrected reticulocyte count was 15.6%. His reticulocyte production index, a reticulocyte count corrected for the degree of anemia and reticulocyte maturation time, was elevated at 2.4. Other pertinent laboratory tests included total bilirubin 18 mg/dL (direct 9.5 and indirect 8.5), lactate dehydrogenase 1175 U/L. Table 1 showed the laboratory values at different time points of HDTR episode.

The transfusion reaction investigation revealed no clerical error or incompatibility, a positive direct antiglobulin (DAT) test, and an antibody panel identical to that from pretransfu- sion testing. He had received several transfusions and consequently had developed antibodies to six clinically significant red blood cell antigens. Alloantibodies were directed against Rh (C and E), Duffy (Fya), Kidd (Jkb), and MNSs (M and S) antigens. The DAT was performed with anti-IgG, anti-IgA, anti-IgM, and anti-C3b/3d. The DAT was positive for IgG, but the specificity of the antibody in the eluate could not be characterized. The last 3 RBCs were recent, allogenic and transfused slowly over a total period of 6 hours.

The patient was treated with methylprednisolone at 125 mg every 6 hours. Trials of finding match-compatible blood were finally successful (from another big hospital) and he was transfused with 3 units of phenotypically matched and crossmatch-compatible RBCs. He was deteriorated rapidly and had a DIC with INR 9.3, PTT 55 seconds,

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Measure

First admission’s initial values

1st admission’s values after receiving 3 units RBCs

Readmission initial values

Readmission’s morning 3rd day values

Readmission’s 3rd day values after receiving 3 units RBCs

Hb (g/dL)

7.0

9.9

8.1

3.5

9.1

Hct (%)

20.2

29.2

24.4

10.5

27.6

Reticulocytes (%)

20.9

9.5

15.6

24

26

NRBC+ count

1

1.11

1.2

10

13

per 100 WBCs

RDW (%)

18.7

20.9

18

18.6

19.9

WBC count (x103/uL)

15.3

10.0

23

25.1

25.6

PLTs (x103/uL)

293

514

174

70

49

Total bilirubin (mg/dL)

3.4

2.7

5.4

14

18

direct bilirubin (mg/dL)

1.6

0.78

1.8

7.5

9.5

LDH (IU/L)

260

417

517

890

1175

AST (IU/L)

25

37

39

378

423

ALT (IU/L)

15

21

31

114

121

Serum creatinine (mg/dL)

0.8

0.8

0.8

1.3

2.4

BUN (mg/dL)

7

8

8

23

28

INR

1.15

1.18

1.45

7.15

9.28

bleeding time 12 minutes, platelet count 49 x 10 [3] per L. The patient became hypotensive, acidotic and required inotropic support. He developed an adult respiratory distress syndrome (ARDS)-like picture, acute heart and respiratory failure and was intubated but he went on to 4 cardiac arrests over six hours and last time could not be resuscitated.

Table 1 Laboratory values at different time points of HDTR episode

Hemolytic transfusion reactions complicate as many as 3% of all transfusions given to patients with SCD [4]. The vast majority occur several days after transfusion as delayed hemolytic transfusion reactions, related to alloantibodies against non-ABO antigens. This delayed reaction typically occurs 4-14 days following RBCs transfusion in a patient who has been alloimmunized to a minor blood group antigen during a previous transfusion. Following the initial alloim- munization, antibody levels decline and may become undetectable. However, re-exposure to that antigen during the transfusion will cause an anamnestic response, with accelerated antibody production and hemolysis several days later [5].

HDTR sometimes referred to as bystander hemolysis [6], can be associated with delayed transfusion reactions and has been reported with pain [7]. Several case reports were published demonstrating the severity and sometimes fatality of HDTR in SCD [3,5,7-17]. It is defined as severe hemolysis following transfusion to a hemoglobin level lower than the initial value prior to transfusion with a marked reticulocytosis. Retrospective investigation sometimes shows that an antibody would have been detectable if other serological methods had been used, but at other times the antibody is only found in the serum after resolution of the HDTR. Rarely, an alloantibody responsible for the HDTR remains unidentified, even after careful serological investi- gation [2]. Chadebech et al hypothesized that hemolysis may be due to excessive eryptosis or suicidal RBC death with the

plasma factors responsible for phosphatidylserine expression on transfused RBCs which remain unknown [18].

Seeyave et al reported on a fatal HDTR in a SCD patient with Serratia marcescens sepsis. They discussed that it was possible that patient’s anemia was caused or exacerbated by an infection-induced Hemophagocytic Syndrome [5]. In our patient blood culture drawn prior and after blood transfusion did not show any growth. Aygun et al reported on severe HDTR in 3 patients (2 children and 1 adult) among 52 SCD patients who received transfusion (5.8%). In a similar case scenario one developed ARDS and expired [19].

Treatment of this sickle cell HDTR syndrome has been described but not well studied. Transfusion, even with phenotypically matched red cell units, can lead to more severe hemolysis and life-threatening anemia [20]. Corti- costeroids have been used with a good outcome. Intrave- nous gamma globulin has also been successful. Steroids and/or intravenous immune globulin may reduce hemolysis should additional transfusions be necessary, and these agents, along with erythropoietin, may have a role in stabilizing hemoglobin and helping to avoid the need for future transfusion [21]. In light of the associated reticulo- cytopenia, erythropoietin has been advocated as an adjunct to treatment. Stem cells from patients with SCD are, in general, hyper-responsive to erythropoietin, and remark- ably rapid recovery of Hemoglobin levels has been reported in this setting [20]. If significant hemoglobinuria is present during an episode of HDTR, an alkaline diuresis should be induced with bicarbonate and diuretics to reduce the risk of pigment nephropathy [11]. Despite the increased risk of transfusion-related complications in patients with HDTR, RBCs transfusion will still be necessary in those with significant Hemodynamic compromise due to anemia, such as our patient.

Our patient had evidence of anemic cardiac failure and respiratory failure. Exchange transfusion would have allowed for an isovolumetric increase in hemoglobin and potentially would have had the additional benefit of removing alloantibodies. We did not perform an exchange transfusion because our patient was hypotensive, acidotic and required inotropic support. Also, an exchange transfu- sion would have required a relatively large volume of blood; at the time of our patient’s admission to the intensive care unit, only a few compatible RBCs units were available. There are additional concerns regarding exchange transfu- sion in patients with HDTR as during exchange, the patient’s own RBCs are removed and replaced with donor cells. While there may be a component of autohemolysis in these patients, transfused cells may be at greater risk of destruction than the patient’s own red cells. Removal of a large volume of autologous cells by exchange transfusion may put the patient at risk for the development of an even more Severe anemia should accelerated destruction of the transfused cells occur [21].

Patients with sickle cell disease SCD exhibit high plasma levels of markers of thrombin generation, depletion of natural anticoagulant proteins, abnormal activation of the fibrinolytic system, and increased tissue factor expres- sion, even in the non-crisis steady state. In addition, plate- lets and other cellular elements are chronically activated in the non-crisis state. As a result of these findings, SCD is frequently referred to as a “Hypercoagulable state[22]. This may have contributed to severity of DIC. Bayazit and Kilinc previously reported that DIC is more apparent during the crisis period than in the steady state and this may be associated with thrombosis of large vessels in an advanced stage [23].

To date, a careful study of options to avoid alloimmuniza- tion has not been performed in SCD patients. Nevertheless, it is generally regarded as good policy to fully phenotype the RBCs of all patients with SCD. Phenotyping early becomes especially important when a multiply transfused patient later develops an apparent hemolytic transfusion reaction, and the need for identification of the offending antibody or antibodies and the provision of compatible blood is urgent [24].

Although blood transfusion has been felt to be a beneficial therapy for SCD, associated complications limits this therapy for these patients. The increased use of transfusions may ultimately be balanced by hydroxyurea and other newer therapies; however, RBCs transfusion is still the most accepted therapy for most acute and many chronic complications of SCD. Physicians caring for patients with SCD should be aware of the unique complications and transfusion requirements in this population. HDTR is one of these potentially Life-threatening complications. Finally, it is of paramount importance that when a patient presents with symptoms of a painful episode with worsening anemia and has a history of recent transfusion, the clinician be alert to the possibility of a HDTR.

Amr El-Husseini MD Texas Tech University Health Sciences CenterPermian Basin Odessa, TX 79762, USA

E-mail address: [email protected]

Alaa Sabry

Urology & Nephrology Center

Mansoura University Mansoura, Egypt

doi:10.1016/j.ajem.2010.01.032

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