Hyperhaemolysis Syndrome in Sickle Cell Disease

Review Article

Ann Hematol Oncol. 2019; 6(7): 1258.

Hyperhaemolysis Syndrome in Sickle Cell Disease

Win N*

NHS Blood and Transplant, UK

*Corresponding author: Nay Win, NHS Blood and Transplant, 75 Cranmer Terrace, London SW17 ORB, UK

Received: April 12, 2019; Accepted: July 04, 2019;Published: July 11, 2019


Hyperhaemolysis Syndrome (HHS) is a potentially life-threatening complication of blood transfusion. It is a distinct complex syndrome resulting destruction of both the transfused and patient’s own RBC [1]. Although less common compared to patients with Sickle Cell Disease (SCD), HHS has also been reported in thalassaemia patients and patients with other haematological disorders. Fatal cases have been reported as a result of additional blood transfusion in patients with SCD [2,3] and a patient with underlying Myelofibrosis [4]. Therefore, correct diagnosis and prompt treatment is important.

Keywords: Hyperhaemolysis syndrome; Sickle cell disease


The term “syndrome” was coined by Petz et al, [1] reported as “the sickle cell haemolytic transfusion reaction syndrome in 1997. At that time of writing, they have concluded that the pathogenesis is multifactorial and more definite data is required. New evidences added and updated the findings in this review article. The diagnostic criteria of HHS consists of four unusual features of haemolysis described by Petz et al, [1].

Firstly: “it may manifest as acute or delayed Haemolytic Transfusion Reactions (HTR), serological studies may not provide an explanation for the HTR. In some patients no alloantibodies are demonstrable or patients may have alloantibodies for which antigen-negative RBCs are readily obtainable. Even RBCs that are phenotypically matched with multiple patient antigens may be haemolysed”. These findings contradicted the basic principle of immunohematology. Providing cross matched compatible RBC units is to achieve a desired Hb increment and to avoid HTR. Following this, HHS is classified into acute and delayed forms, based on analysing 28 cases from 7 different publications in a review article published in 2008 (15 classified as acute and 13 as delayed form) [5].

Acute PTHS: occurs less than 7 days’ post-transfusion. The Direct Antiglobulin Test (DAT) is negative. There are no new red cell alloantibodies detected in follow-up serological investigations.

Delayed PTHS: usually occurs more than 7 days’ post-transfusion, (DAT) is positive. New alloantibodies identified [5].

Secondly: Petz [1] reported “that the patient developed a more severe anemia after transfusion and suggested that not only the transfused cells were haemolysed, but destruction of patient’s own RBC may play a role resulting in significant decrease in Hb level. King et al, [6] also proposed that sequential quantitation of HbA% and HbS% in the patient’s blood sample assist to capture the trajectory of haemolysis. Destruction of transfused and patient’s RBC was substantiated by serial analysis of urine by High Performance Liquid Chromatography (HPLC) demonstrating both the HbS (patient’s) and HbA (transfused RBC) in the urine by Win et al, [7] in 2001.

Thirdly: Petz at al, [1] observed a marked reticulocytopenia (a significant decrease from the patient’s usual absolute reticulocyte level) and recovery manifested by reticulocytosis and gradual improvement in Hb level. This is an unusual finding as a reticulocytosis is common presenting features of haemolysis (compensatory mechanism).

Fourthly: Not like classical Delayed Haemolytic Transfusion Reaction (DHTR) additional transfusion may further exacerbate haemolysis [1] and may become life-threatening or even may cause death [2-4].

Fifthly: After a recovery period, similar symptoms may recur following subsequent transfusion in some patients [1].

These unusual findings highlight the complexities of HHS and should be recognised as “syndrome” as defined by” Petz et al [1].

When describing HHS: Majority used the term “hyperhaemolysis syndrome” [4,5,8-16], followed by “hyperhaemolysis” [2,17-22] and

“(DHTR)” [23-28] the term DHTR / hyperhaemolysis syndrome [29,30] have also been used. Classical DHTR, [3,26] is a wellestablished complication of blood transfusion and it occurs as a result of immune destruction of the transfused RBC by red cell antibodies. Any recipient may develop classical DHTR. In general, it occurs between 2 to 21 days’ post-transfusion. Usually the DAT is positive with identification of red cell allo-antibodies that are not detected in the pre-transfusion sample. This is due to an anamnestic immune response as a result of re-exposure to red cell antigen which has previously been sensitized by transfusion, pregnancy or transplant. Reticulocytosis is common reflecting compensatory bone marrow erythropoiesis and subsequent transfusion with an antigen-negative unit may correct the anemia.

The incidence of HHS is not known and not all the patients who received blood developed HHS. Mwesigwa et al, reported a prevalence of 5% in SCD patients and commented that there is a potential role of recipient genetics in the susceptibility of HHS [31]. There is a striking difference in the clinical course, management and outcome between classical DHTR and HHS therefore it is crucial to distinguish between them. Some have commented that “there is no consensus definition of DHTR” when describing HHS [32] and even used the term “alloantibody –negative DHTR” without providing definite evidence [32]. Some described HHS as a subtype of DHTR [17]. Using the term DHTR when describing HHS in the literature is somewhat loose and confused. In our institution when describing HHS, we strictly adhere the “syndrome criteria“laid down by Petz et al, [1].

Although the first case of HHS was reported in 1993 in a SCD patient [2] uptill recently the pathogenesis still appears to be a subject of debate, [18] but most have cited the following hypotheses: i) marrow suppression, [1] ii) bystander mechanisms [6,18], and iii) macrophage activation [5,7,8]. The presenting symptoms are perplex and some commented that “bystander haemolysis and suppression erythropoiesis” occurs by unknown mechanism [33] and some suggested that reticulocytopenia is due to “accelerated destruction of reticulocytes as a result of selected antibody targeting of reticulocytes” [29].

Here we present the evidences related to the above three proposals and discuss the therapeutic intervention based on each of the theories and clinical outcome.

Firstly: “Marrow suppression theory”

One of the presenting features of HHS is relative reticulocytopenia and Petz et al, [1] have initially suggested that the apparent increase of the rate of haemolysis of autologous RBC was due to transfusion “suppression of erythropoiesis”.

They described [4] Delayed and one acute form of HHS. Each patient received additional transfusion of 7 to 8 units (mean 13 units) and were discharged on days [2,24,29,36] and [52] after the admission. As these patients received multiple transfusions over a certain period, it is possible that suppression of erythropoiesis might play some part in contributing to the worsening anemia. Despite providing cross matched compatible RBCs, there is an ongoing haemolysis and Petz et al, [1] recommended to withhold transfusion and to prescribe corticosteroid, as two recovered gradually with steroid therapy. In view of the reticulocytopenia, Erythropoietin (EPO) has been prescribed in HHS either as a single supportive therapy [6] or as a supplement to IVIG /steroids [17,26,29].

Response to steroids therapy contradicted the marrow suppression theory and it clearly indicates that another element may be involved in the pathogenesis of HHS. Therefore, in 2001 Win et al, [7] have proposed the alternative theory; that the “reticulocytes are destroyed by activated macrophage” (i.e. peripheral consumption). See subheading Macrophage activation theory.

Secondly: “Bystander mechanisms” [6,18]

Petz described bystander mechanism as ”Immune haemolysis of cells that are negative for the antigen against which the relevant antibody is directed” [34]. Therefore, in the process of antigen/ antibody reactions, implicated antibodies form immune complexes, complement activation, resulting reactive lysis for those RBCs lacking cognate antigen. Sickle RBCs show increased susceptibility to reactive lysis due to suggested functional defect of CD59. King et al, [6] reported 5 cases of HHS after receiving exchange transfusion of which 2 acute and 3 delayed forms. They conducted serial measurement of HbA and HbS levels in the peripheral blood and as a marker to document both the presence and absence of autologous destruction. Based on the evidence of autologous red cell destruction they have concluded “we have shown one patient with clinical evidence of bystander haemolysis complicating a DHTR”.6 No definite proof of laboratory evidence has been provided.

Bystander mechanism fails to cover or explain the following complex presenting symptoms of HHS:

i) As there was no antibody detected in acute HHS it is difficult to explain how the autologous RBCs were destroyed by bystander mechanism.

ii) In HHS despite providing antigen-matched crossmatchcompatible units (no potentiation for complement activation) haemolysis may occur.

iii) Petz et al, [1] have recommended”if possible to withhold further transfusion and to try oral prednisolone 1-2 mg/kg/day and to monitor closely.” It is obvious that steroid therapy will not resolve immune complex bystander mechanism of red cell destruction.

iv) Bystander theory fails to explain the reticulocytes findings in HHS; relative reticulocytopenia at presentation and a rise in reticulocyte count with recovery.

v) HHS has also been reported in Non SCD patients, who are not susceptible to reactive lysis.

“Anti-complement agent Eculizumab”. Eculizumab is a monoclonal antibody which inhibits complement activation by targeting C5, preventing progress into C5b-9 membrane complex. Sickle RBCs show increased susceptibility to reactive lysis due to suggested functional defect of CD59. Based on that, assumption has been made that bystander haemolysis might play a role in destruction of RBCs in HHS and Eculizumab has been tried. Gupta et al, [15] have tried Eculizumab in HHS and reported unresponsive to therapy. Dumas et al, [25] have tried Eculizumab as salvage therapy in patients with SCD. One received plasma exchange and another had liver transplantation. Delayed recovery was recorded in all cases and the authors have concluded that further assessments are required in prospective studies, taking into account the cost and possible side effects of this therapy.

Thirdly: ”Macrophage activation theory”

In acute HHS there is no evidence of red cell antibody mediated haemolysis and the activated macrophage theory focuses on the role of adhesion molecules, was proposed by Win et al. [5,7,8] depicted in (Figure 1) and (Figure 2) as follows:

Citation: Win N. Hyperhaemolysis Syndrome in Sickle Cell Disease. Ann Hematol Oncol. 2019; 6(7): 1258.