Red cell transfusion and alloimmunization in sickle cell disease

Red cell transfusion remains a critical component of care for acute and chronic complications of sickle cell disease. Randomized clinical trials demonstrated the benefits of transfusion therapy for prevention of primary and secondary strokes and postoperative acute chest syndrome. Transfusion for splenic sequestration, acute chest syndrome, and acute stroke are guided by expert consensus recommendations. Despite overall improvements in blood inventory safety, adverse effects of transfusion are prevalent among patients with sickle cell disease and include alloimmunization, acute and delayed hemolytic transfusion reactions, and iron overload. Judicious use of red cell transfusions, optimization of red cell antigen matching, and the use of erythrocytapheresis and iron chelation can minimize adverse effects. Early recognition and management of hemolytic transfusion reactions can avert poor clinical outcomes. In this review, we discuss transfusion methods, indications, and complications in sickle cell disease with an emphasis on alloimmunization.     

Red blood cell alloimmunization in sickle cell disease: pathophysiology, risk factors, and transfusion management

Red blood cell transfusions have reduced morbidity and mortality for patients with sickle cell disease. Transfusions can lead to erythrocyte alloimmunization, however, with serious complications for the patient including life-threatening delayed hemolytic transfusion reactions and difficulty in finding compatible units, which can cause transfusion delays. In this review, we discuss the risk factors associated with alloimmunization with emphasis on possible mechanisms that can trigger delayed hemolytic transfusion reactions in sickle cell disease, and we describe the challenges in transfusion management of these patients, including opportunities and emerging approaches for minimizing this life-threatening complication.     

Risk of alloimmunization and delayed hemolytic transfusion reactions in patients with sickle cell disease

Blood transfusion is an integral part of the supportive care of patients with sickle cell diseases. The hazards of red blood cell alloimmunization and delayed hemolytic transfusion reactions (DHTRs) complicate the treatment of patients with sickle cell diseases, particularly since such reactions may be misinterpreted as a pain crisis, and, as a result, specific transfusion serologic studies may not be performed. The frequency of alloimmunization in this population has been the subject of several reports; however, the frequency of DHTRs is unknown. To determine the frequency of this event, we retrospectively reviewed the medical and transfusion service records of all adult patients with sickle cell diseases transfused during the six-year period from January 1980 to December 1985. Seventy-three adult patients with sickle cell diseases received transfusions. The prevalence of recognized DHTR was three (4%) of 73. Red blood cell alloimmunization was seen in 22 (30%) of 73 of the patients. The calculated risk of alloimmunization was 3.1% per unit of blood. These observations suggest that alloimmunization and clinically apparent DHTRs occur more frequently in patients with sickle cell diseases and support pretransfusion testing for at least Rh and Kell red blood cell antigens in patients who are at high risk of such events (patients who have formed an alloantibody or who are being enrolled in a transfusion program).     

Delayed hemolytic transfusion reaction in children with sickle cell disease

Background

Transfusion is a cornerstone of the management of sickle cell disease but carries a high risk of hemolytic transfusion reaction, probably because of differences in erythrocyte antigens between blood donors of European descent and patients of African descent. Patients may experience hemolytic transfusion reactions that are delayed by from a few days to two weeks and manifest as acute hemolysis (hemoglobinuria, jaundice, and pallor), symptoms suggesting severe vaso-occlusive crisis (pain, fever, and acute chest syndrome), and profound anemia, often with reticulocytopenia. This case-series study aims to describe the main characteristics of this syndrome, to discuss its pathophysiology, and to propose a management strategy.

Design and Methods

We identified 8 pediatric cases of delayed hemolytic transfusion reactions between 2006 and 2009 in the database of the Necker Hospital, France. All patients had received cross-matched red cell units compatible in the ABO, RH, and KEL systems. We reviewed the medical charts in the computerized blood transfusion databases. All patients were admitted to the intensive care unit. We progressively adopted the following strategy: intravenous immunoglobulins, and darbopoietin alpha when the reticulocyte count was below 150×10⁹/L, without further blood transfusion during the acute episode unless absolutely necessary.

Results

The median time between the transfusion and the diagnosis of delayed hemolytic transfusion reaction was six days. All patients had severe bone pain; all but one had a high-grade fever. Five patients had hemoglobin levels less than than 4g/dL and 3 had reticulocytopenia. In 5 patients, no new antibody was found; one patient had weakly reactive antibodies. Only 2 patients had new allo-antibodies possibly responsible for the delayed hemolytic reaction.

Conclusions

The initial symptoms of delayed hemolytic transfusion reaction were complex and mimicked other complications of sickle cell disease. In most of our cases, no new antibody was identified, which underlines the complexity of the pathophysiology of this syndrome.     

Delayed Haemolytic Transfusion Reaction Due to Simultaneous Appearance of Anti-Fya and Anti-Fy5

We report here the development of anti-Fy5 in a young Negro female with sickle cell disease. The antibody was responsible for a delayed hemolytic transfusion reaction. We believe this is the first report of such an antibody in Europe.     

Increased IgG molecules bound to the surface of red blood cells of patients with sickle cell anemia

We have used the complement-fixing antibody consumption ( CFAC ) test to detect small concentrations of IgG on red blood cells from patients with hemolytic anemias that are not thought to be caused by an immune mechanism. Although patients with hereditary spherocytosis, pyruvate kinase deficiency, and mechanical hemolytic anemias generally had normal concentrations of IgG bound to their red cells (less than 25 molecules IgG per red cell), we found that 39/62 (63%) patients with sickle cell anemia had elevated values. These 39 patients had a mean of 195 and a maximum of 890 molecules of IgG per red cell. None of the patients had been transfused within the previous 90 days, and some had never been transfused. Direct antiglobulin tests were positive in only two instances and autoantibodies were not found in the serum of any patient. However, eluates from the red cells of 6 of 23 patients demonstrated antibody activity against all of a panel of normal red cells by the indirect antiglobulin test. There was no correlation between the number of IgG molecules on patients' red cells and the severity of their anemia, the incidence of painful sickle cell crises, the reticulocyte count, or with blood transfusion history. We conclude that further study of immunohematologic abnormalities in patients with sickle cell anemia is warranted, especially in view of previous reports in this population of patients with red cell autoantibodies, autoimmune hemolytic anemia, hemolytic transfusion reactions without detectable alloantibodies, and an association of some episodes of pain crises with immunologically mediated red cell destruction.     

The Role of Red Blood Cell Exchange Transfusion in the Treatment and Prevention of Complications of Sickle Cell Disease

Abstract: Patients with sickle cell disease have abnormal red blood cells (RBCs). This can cause chronic hemolytic anemia and vaso‐occlusion leading to tissue hypoxemia and organ dysfunction. RBC exchange transfusion can, without increasing the whole‐blood viscosity, quickly replace abnormal erythrocytes with normal and raise the hematocrit resulting in improved delivery of oxygen to hypoxic tissues. Unfortunately, transfusion can also be associated with complications. This paper reviews the role of transfusion, both simple and exchange, in the treatment and prevention of sickle‐related complications. The benefits of exchange versus simple transfusion and transfusion versus alternative therapies are discussed.     

Current issues with blood transfusions in sickle cell disease

With increased recognition of the profound morbidity of sickle cell disease and with growing evidence of the efficacy of transfusion therapy in prevention and treatment of sickle cell complications, most patients now receive intermittent transfusion therapy. The purpose of this report is to review blood component therapy and its risks for sickle cell patients. Packed red cells are the preferred blood component. Leukocyte-reduced units should be standard because of their beneficial effects in reducing alloimmunization, transfusion reactions, platelet refractoriness, and infection transmission. The use of washed, frozen, or irradiated units is limited to specific problems. Sickle trait-positive units function normally, but because of difficulties with calculating hemoglobin S percentages and leukocyte filters, they are not routinely used. Transfusion-acquired infections have shown a marked decrease but still present a major risk. Viral hepatitis transmission is currently low, but at least 10% of adult sickle cell patients are hepatitis C positive, and they often have liver damage. Although bacterial infections are rare, they account for 16% of transfusion-related fatalities. Patients who are iron overloaded are particularly vulnerable to Yersina enterocolitica. Red cell alloimmunization is a serious problem that could potentially affect 50% of transfused patients. However, preventive phenotypic matching for common antigens can minimize alloimmunization; limited matching for at least E, C, and K has become the standard of care. Recently, more patients are being identified who have developed red cell autoantibodies, which can mask alloantibodies and occasionally are hemolytic. Careful laboratory evaluation of all cases is essential. Transfusions also may trigger sickle cell events, including pain crises, stroke, and acute pulmonary deterioration. In part, these are induced by blood viscosity and increased blood pressure. Diuretic therapy and close monitoring of transfusion volume and vital signs can minimize these events. In summary, transfusion therapy carries risks, but the routine use of leukocyte-reduced, phenotypically matched units in conjunction with close monitoring of patients can make transfusion therapy safer.     

Study of Anti-Fya in Five Black Fy(a-b-) Patients

Fya antibodies were detected in 5 Fy(a-b-) black patients during a 5-year period. The Duffy phenotype was confirmed using anti-Fya, anti-Fyb, and anti-Fy3 by an adsorption-elution technique. These 5 patients had sickle cell disease and had received multiple blood transfusions. The antibodies were all found during the investigation of a hemolytic transfusion reaction or failure to achieve the desired red cell increments after transfusion.     

Blood transfusion in sickle cell disease

Sickle cell anemia is an inherited disease that causes chronic hemolytic anemia. Its pathognomonic signs and symptoms are caused by hemoglobin (Hb) S, which results from a single nucleotide substitution in the β-globin gene that places the amino acid valine with glutamic acid at codon 6 of the β-globin chain. Hb S is an insoluble Hb that crystalizes at low oxygen tension and other precipitating conditions leading to rigidity of red cells and clumping in small blood vessels. Patients with sickle cell disease have a variable Hb level that may range from 7.0 to 11.0 g/dL in their steady state condition. The most common cause of hospital presentation is due to acute painful crisis that results from vaso-occlusion by sickled cells. These episodes are treated with hydration and analgesia and do not require blood transfusion. Blood transfusion should be aimed to increase tissue delivery of oxygen. Hb S is known to be a low affinity Hb and so delivers oxygen at a lower partial pressure of oxygen compared to Hb A. Even with adequate pre transfusion testing and precautions, blood transfusion is never totally safe and short or long term complications may occur. Blood transfusion in patients with sickle cell disease has only limited indications such as acute hemolytic, aplastic or sequestration crises. Chronic transfusion protocols are implemented in cases of strokes or high cerebral blood flow ultrasonic studies as a prophylactic measure. Exchange blood transfusion is used in some complications of the disease such as acute chest syndrome (ACS), priapism or peri operatively. Once it is decided to transfuse blood, the transfused blood should be Hb S negative, Rh and Kell antigen matched.     

Blood Transfusion in Sickle Cell Disease

Sickle cell anemia is an inherited disease that causes chronic hemolytic anemia. Its pathognomonic signs and symptoms are caused by hemoglobin (Hb) S, which results from a single nucleotide substitution in the β-globin gene that places the amino acid valine with glutamic acid at codon 6 of the β-globin chain. Hb S is an insoluble Hb that crystalizes at low oxygen tension and other precipitating conditions leading to rigidity of red cells and clumping in small blood vessels.

Patients with sickle cell disease have a variable Hb level that may range from 7.0 to 11.0 g/dL in their steady state condition. The most common cause of hospital presentation is due to acute painful crisis that results from vaso-occlusion by sickled cells. These episodes are treated with hydration and analgesia and do not require blood transfusion. Blood transfusion should be aimed to increase tissue delivery of oxygen. Hb S is known to be a low affinity Hb and so delivers oxygen at a lower partial pressure of oxygen compared to Hb A. Even with adequate pre transfusion testing and precautions, blood transfusion is never totally safe and short or long term complications may occur.

Blood transfusion in patients with sickle cell disease has only limited indications such as acute hemolytic, aplastic or sequestration crises. Chronic transfusion protocols are implemented in cases of strokes or high cerebral blood flow ultrasonic studies as a prophylactic measure. Exchange blood transfusion is used in some complications of the disease such as acute chest syndrome (ACS), priapism or peri operatively. Once it is decided to transfuse blood, the transfused blood should be Hb S negative, Rh and Kell antigen matched.     

The pathophysiology, prevention, and treatment of stroke in sickle cell disease

PURPOSE OF REVIEW: Stroke is one of the most devastating complications of sickle cell disease, but current research has led to improved understanding of its pathogenesis and to new approaches in the prevention of both primary and secondary stroke. This review focuses on advances reported in the past 2 years. RECENT FINDINGS: New concepts in the pathophysiology of central nervous system events in sickle cell disease have centered around hemolytic anemia and nitric oxide metabolism. Genetic risk factors are now being explored. Major improvement in primary stroke prevention has occurred through transcranial Doppler ultrasonography screening, but utilization of this technique is far from optimal. Hydroxyurea is now being tested as an alternative approach to chronic transfusion for secondary stroke prevention through a multicenter trial. Other studies are addressing the management of silent infarcts and nocturnal hypoxemia. SUMMARY: Increased understanding of the etiology and pathogenesis of stroke in sickle cell disease should eventually lead to improved management of all central nervous system complications. Alternative secondary stroke prevention with hydroxyurea may allow patients to avoid dependence on life-long chronic transfusion. Primary stroke prevention through transcranial Doppler ultrasonography screening may ultimately yield a dramatic reduction in the incidence of stroke in sickle cell disease.     

Rituximab for prevention of delayed hemolytic transfusion reaction in sickle cell disease

Delayed hemolytic transfusion reaction (DHTR), a life-threatening transfusion complication in sickle cell disease (SCD), is characterized by a marked hemoglobin drop with destruction of both transfused and autologous red blood cells (RBCs) and exacerbation of SCD symptoms. One mechanism of RBCs destruction is auto-antibody production secondary to transfusion. As rituximab specifically targets circulating B cells, we thought that it could be beneficial in preventing this immune-mediated transfusion complication. We report the case of a SCD patient who previously experienced DHTR with auto-antibodies and who needed a new transfusion. DHTR recurrence was successfully prevented by rituximab administration prior transfusion, supporting the safe use of rituximab to prevent DHTR in SCD patients as a second line approach when other measures failed.     

Plasma Hemoglobin-Binding Capacity in Sickle Cell Disease

Studies of the capacity of plasma proteins to bind hemoglobin were madein patients with sickle cell anemia (SS), sickle cell trait (SA), hemoglobinC disease and in patients with hemolytic anemias. Hemoglobin binding wasquantitatively normal in sickle cell trait, but was greatly reduced or absentin sickle cell anemia, hemoglobin C disease and in other hemolytic disorders.These alterations have been attributed to a reduction in the level of hemoglobin-binding proteins in circulating plasma. The mechanism of this reduction was not established, but the observed changes were correlated with thepresence of increased hemolytic activity.

The binding of hemoglobin C and hemoglobin S by normal plasma wasquantitatively normal.

Submitted on October 25, 1958 Accepted on December 12, 1958     

Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes

Hemolysis, long discounted as a critical measure of sickle cell disease severity when compared with sickle vaso-occlusion, may be the proximate cause of some disease complications. New mechanistic information about hemolysis and its effects on nitric oxide (NO) biology and further examination of the subphenotypes of disease requires a reappraisal and deconstruction of the clinical features of sickle cell disease. The biology underlying clinical phenotypes linked to hemolysis may increase our understanding of the pathogenesis of other chronic hemolytic diseases while providing new insights into treating sickle cell disease. The pathophysiological roles of dysregulated NO homeostasis and sickle reticulocyte adherence have linked hemolysis and hemolytic rate to sickle vasculopathy. Nitric oxide binds soluble guanylate cyclase which converts GTP to cGMP, relaxing vascular smooth muscle and causing vasodilatation. When plasma hemoglobin liberated from intravascularly hemolyzed sickle erythrocytes consumes NO, the normal balance of vasoconstriction:vasodilation is skewed toward vasoconstriction. Pulmonary hypertension, priapism, leg ulceration and stroke, all subphenotypes of sickle cell disease, can be linked to the intensity of hemolysis. Hemolysis plays less of a role in the vaso-occlusive-viscosity complications of disease like the acute painful episode, osteonecrosis of bone and the acute chest syndrome. Agents that decrease hemolysis or restore NO bioavailability or responsiveness may have potential to reduce the incidence and severity of the hemolytic subphenotypes of sickle cell disease. Some of these drugs are now being studied in clinical trials.     

New pulmonary infiltrates in a 19 year-old with sickle cell crisis.

OBJECTIVE: Sickle cell anemia (SCA) is the most common inherited blood disorder. Sickle cell crisis is characterized by episodes of pain, chronic hemolytic anemia and severe infections, usually beginning in early childhood. Sickle cell disease primarily affects those of African descent and Hispanics of Caribbean ancestry, but the trait has also been found in those with Middle Eastern, Indian, Latin American, Native American, and Mediterranean heritage. Recent studies indicate that more than 12,500 people in England have sickle cell disorders. The acute chest syndrome is the leading cause of death and the second most common cause of hospitalization among patients with sickle cell disease. The acute chest syndrome (ACS) is characterized by chest pain with dyspnea and recent radiological abnormalities. Since its cause is largely unknown, rapid recognition and early institution of therapy is paramount as with timely and appropriate intervention majority of these patients survive. The treatment of ACS rests on controlled hydration, antibiotic therapy, oxygen therapy, controlled analgesic therapy, blood transfusion and exchange transfusion. A better understanding of the disease and a close collaborative approach between a primary care physician and a specialist may be the key to improve the quality of care rendered. METHODS: Research studies, review articles, and published scientific meeting abstracts were reviewed.     

Techniques for blood administration in sickle cell patients

Transfusion therapy provides many benefits to individuals with sickle cell disease but may lead to cardiovascular complications, alloimmunization, exposure to infection, and iron overload. Simple transfusion is used to increase oxygen-carrying capacity. Chronic simple transfusion is useful in preventing a number of complications in sickle cell disease. Acute erthrocyte exchange transfusion can reduce the percentage of cells containing sickle hemoglobin while decreasing volume overload and minimizing hyperviscosity. Chronic erythrocyte exchange transfusion reduces iron loading but increases donor exposure. Directed odnation may reduce alloimmunization and exposure to infection.     

Aplastic crisis in sickle cell disorders: bone marrow necrosis and human parvovirus infection

Aplastic crisis in patients with sickle cell disease who develop a parvovirus infection may be associated with extensive bone marrow necrosis as well as acute selective erythroblastopenia. This illness may be manifested by pyrexia, lymphadenopathy, bone tenderness and significant hypoxemia with minimal roentgenographic findings in the lungs. It is uncertain whether the hypoxemia is caused by the effects of the viral infection on the lungs or is secondary to sickling of red blood cells in the pulmonary vasculature or both. The hypoxia may be sufficiently severe to require treatment with both oxygen and transfusion. The physical damage to the bone marrow associated with bone marrow necrosis may be more important than selective acute erythroblastopenia in inducing aplastic crisis in patients with sickle cell disorders. Studies of bone marrow biopsy specimens collected during parvovirus-associated aplastic crisis in patients with nonsickle cell hemolytic disorders would be helpful in determining the pathophysiology of parvovirus-associated disorders.     

Intravenous immunoglobulin given to lymphoma patients with recurrent haemolytic transfusion reactions after transfusion of compatible blood

Accelerated destruction of red cells after transfusion of compatible blood has been reported in both sickle cell disease (SCD) and non-SCD patients. We report three patients with lymphoma, all of whom had recurrent haemolytic transfusion reactions after receiving compatible red cell units. The direct antiglobulin test (DAT) was negative and there were no detectable red cell alloantibodies in either pre-transfusion or post-transfusion samples. As there was no evidence of red cell antibody-mediated haemolysis and response to oral steroids, a trial of intravenous immunoglobulin (IVIg) was given. Immediate cessation of haemolysis with sustained haemoglobin level was achieved in all cases. The response to IVIg in these cases suggests that IVIg should be tried when recurrent non-antibody mediated haemolytic transfusion reactions occur in patients with a lymphoid malignancy.     

Intravenous immunoglobulin given to lymphoma patients with recurrent haemolytic transfusion reactions after transfusion of compatible blood

Accelerated destruction of red cells after transfusion of compatible blood has been reported in both sickle cell disease (SCD) and non-SCD patients. We report three patients with lymphoma, all of whom had recurrent haemolytic transfusion reactions after receiving compatible red cell units. The direct antiglobulin test (DAT) was negative and there were no detectable red cell alloantibodies in either pre-transfusion or post-transfusion samples. As there was no evidence of red cell antibody-mediated haemolysis and response to oral steroids, a trial of intravenous immunoglobulin (IVIg) was given. Immediate cessation of haemolysis with sustained haemoglobin level was achieved in all cases. The response to IVIg in these cases suggests that IVIg should be tried when recurrent non-antibody mediated haemolytic transfusion reactions occur in patients with a lymphoid malignancy.