Transfusion in sickle cell disease: Management of complications including iron overload

INTRODUCTION — Individuals with sickle cell disease (SCD) have chronic anemia that can worsen abruptly for various reasons such as splenic sequestration or transient red cell aplasia, and they are at risk of vaso-occlusive events, including stroke, due to the high concentration of sickle hemoglobin (Hb S) associated with their condition. Transfusion of red blood cells (RBCs) can be life-saving in these settings.

Blood transfusion carries risks, many of which, especially alloimmunization and excess iron stores, are more likely and are typically more severe in individuals with SCD than in the general population. Excessive accumulation of iron is a serious problem that may not be detected because transfusion therapy may be irregular and episodic. The approach to transfusion must balance these benefits and risks, both in decisions regarding when to transfuse and in the practical aspects of how transfusions are administered.

Here we discuss complications of transfusion unique to this population, including high rates of alloimmunization and iron overload.

Separate topic reviews present an overview of the indications for transfusion and transfusion techniques in SCD, RBC antigens, and the general evaluation and management of transfusion reactions:

●Indications and techniques in SCD – (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques".)

●RBC antigens – (See "Red blood cell antigens and antibodies".)

●Evaluation of an acute transfusion reaction – (See "Approach to the patient with a suspected acute transfusion reaction".)

●Transfusion-associated circulatory overload – (See "Transfusion-associated circulatory overload (TACO)".)

●Transfusion-related acute lung injury – (See "Transfusion-related acute lung injury (TRALI)".)

●Hemolytic transfusion reactions – (See "Hemolytic transfusion reactions".)

●Allergic, anaphylactic, and febrile nonhemolytic reactions – (See "Immunologic transfusion reactions".)

●Transfusion-transmitted bacterial infection – (See "Transfusion-transmitted bacterial infection".)

LIMITING TRANSFUSIONS TO APPROPRIATE USE — Complications can be reduced by limiting transfusions to the appropriate clinical indications and using appropriate techniques, which are summarized here and discussed in more detail separately. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Indications for transfusion'.)

Appropriate indications — We use red cell transfusion in clinical scenarios where there is strong or compelling evidence of the benefit of reduced morbidity. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Indications for transfusion'.)

Transfusions are used acutely for the treatment of:

●Hemodynamic compromise

●Acute chest syndrome

●Acute cerebral infarction

●Transient ischemic attack

●Multiple organ failure

●An acute drop in hemoglobin without reticulocytosis

●Acute hepatic or splenic sequestration

●Priapism, if a urological procedure fails to produce detumescence

Transfusions are used prophylactically during pregnancy, perioperatively, and to reduce incidence of a range of vaso-occlusive complications of SCD including:

●Stroke

●Silent cerebral infarcts

●Recurrent acute chest syndrome

●Vaso-occlusive pain episodes that are severe and do not respond to medical therapies

●Recurrent priapism

●Pulmonary hypertension with progression

The most prominent misuse of blood transfusion therapy is simple transfusion in an adult or child with SCD admitted to the hospital for an uncomplicated vaso-occlusive pain episode without symptomatic anemia or vaso-occlusive pain without a significant change from the individual's baseline hemoglobin (typically <2 g/dL). In such a situation, there is no evidence that simple transfusion therapy will abate the pain episode, and there is a finite risk of transfusion-related complications, including the increased risk for alloimmunization [1].

For complicated vaso-occlusive pain episodes treated in the hospital, transfusion may be appropriate in the following instances:

●If the hemoglobin has decreased by ≥2 g/dL

●The person has developed pneumonia or acute chest syndrome with an increasing oxygen requirement to maintain oxygen saturation greater than 95 percent

In these situations, transfusion is used as an adjunct to (not a substitute for) pain management. (See "Evaluation of acute pain in sickle cell disease" and "Acute vaso-occlusive pain management in sickle cell disease" and "Disease-modifying therapies to prevent pain and other complications of sickle cell disease".)

Appropriate techniques — Appropriate use of red blood cell (RBC) antigen matching and exchange transfusion rather than simple transfusion in certain settings are important for reducing alloimmunization and iron overload, respectively. (See 'Alloimmunization and hemolysis' below and 'Excessive iron stores' below.)

Details are presented separately. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'RBC antigen matching' and "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Simple versus exchange transfusion'.)

ACUTE TRANSFUSION REACTIONS — As a general rule, acute transfusion reactions such as febrile nonhemolytic transfusion reactions (FNHTRs) and allergic reactions are low per unit transfusion in patients with SCD, perhaps due to the routine use of leukoreduction in this population and extended phenotypic matching in most institutions.

As an example, in the Silent Cerebral Infarct Transfusion (SIT) trial, there were 3236 transfusions administered; of these, nine participants had one reaction, six had two reactions, and one had four reactions [2]. Eight of 3236 transfusions (0.2 percent) were associated with a FNHTR and 13 of 3236 (0.4 percent) with an allergic reaction.

Patients with an acute transfusion reaction are generally treated similarly to individuals without SCD. (See "Approach to the patient with a suspected acute transfusion reaction".)

Anaphylactic and allergic reactions — Anaphylactic reactions to red blood cell (RBC) transfusions must be distinguished from severe hemolytic transfusion reactions due to antibodies formed against RBC antigens.

●The pathogenesis of anaphylactic and allergic reactions includes immune reactions against plasma proteins such as immunoglobulin (Ig) A, which is rare, as well as inflammatory cytokines in the product, passive antibody transfer, or both [3].

●Evaluation for the underlying cause of an anaphylactic reaction should at least consider IgA deficiency and haptoglobin deficiency if the patient has an anaphylactic reaction [3]. Elevated serum or plasma tryptase levels are supportive of an anaphylactic reaction [3].

●Treatment includes immediate cessation of transfusion and supportive care as needed, which might include oxygen supplementation, airway management, fluid resuscitation or vasopressors for hypotension, antihistamines, and epinephrine. We are unaware of the benefit of corticosteroids in this situation.

The evaluation and additional management of these reactions is discussed separately. (See "Immunologic transfusion reactions", section on 'Anaphylactic transfusion reactions' and "Immunologic transfusion reactions", section on 'Allergic reactions'.)

Potential concerns about meperidine — Meperidine can sometimes be used to treat transfusion-associated rigors, which can be severe and may make the patient, family, or caregivers very uncomfortable. Short-term use of meperidine (<24 hours) to treat rigors is acceptable, as long as the patient has normal kidney function and no previous history of seizures [4,5]. However, meperidine is metabolized to normeperidine, which has a half-life of 18 hours. When used for multiple days, normeperidine can cause anxiety, tremors, myoclonus, and seizures [4,6]. (See "Acute vaso-occlusive pain management in sickle cell disease", section on 'Therapies we do not use'.)

Rather than using diphenhydramine, which is sedating, we use a nonsedating histamine 1 (H1)-receptor antagonist to treat an acute reaction with rigors. (See "Immunologic transfusion reactions", section on 'Febrile nonhemolytic transfusion reactions'.)

Rigors associated with FNHTR are acute and self-limited; if there are any signs that suggest possible bacterial infection, the patient should be evaluated and treated accordingly, as patients with SCD are functionally asplenic and at risk of serious morbidities and mortality from sepsis. (See "Evaluation and management of fever in children and adults with sickle cell disease", section on 'Risk of life-threatening infection' and "Transfusion-transmitted bacterial infection", section on 'Immediate interventions'.)

In contrast to using a single dose of meperidine for rigors, we avoid meperidine for treating acute vaso-occlusive pain events in SCD because of potential toxicities of use for >24 to 48 hours (due to production of a toxic metabolite, normeperidine).

ALLOIMMUNIZATION AND HEMOLYSIS — Individuals with SCD have a high risk of alloimmunization (development of antibodies to red blood cell [RBC] antigens) typically due to a mismatch in minor RBC antigens between the donor pool and patients with SCD. The higher rate of alloimmunization can lead to difficulty in future crossmatching, which in turn reduces eligibility for chronic transfusion therapy and decreases access to compatible blood needed in the treatment of acute events [7]. Alloimmunization can also lead to hemolytic transfusion reactions if the implicated antigen is not excluded from future transfusions.

Likelihood of alloimmunization — Standard transfusion practice includes crossmatching RBC units for ABO and RhD antigens. (See "Pretransfusion testing for red blood cell transfusion", section on 'Compatibility testing (crossmatch)'.)

As discussed separately, matching for additional Rh antigens (C, E, or C/c, E/e) and the Kell blood group antigen K is also recommended for individuals with SCD and has been demonstrated to reduce alloimmunization rates significantly [8]. (See "Red blood cell antigens and antibodies" and "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'RBC antigen matching'.)

Direct comparison of the prevalence of alloimmunization in individuals with and without SCD is challenging because individuals with SCD receive more blood transfusions compared to individuals without SCD. Individuals with SCD are one of the most frequently transfused and heavily alloimmunized groups of patients, with the prevalence ranging from 7 to 59 percent Patients with SCD are one of the most frequently transfused and heavily alloimmunized groups of patients, with the prevalence ranging from 7 to 59 percent [7,9]. This compares with a prevalence of 2 to 3 percent of transfused patients in general hospital populations [10,11]. In the absence of Rh (C, E or C/c, E/e) and K antigen matching, alloimmunization occurs in approximately 30 percent of individuals with SCD who are transfused at least intermittently [12].

Instead of the prevalence of alloimmunization, the incidence rate of new alloantibodies per 100 units of RBCs transfused should be used, so that reasonable comparisons can be made from one study to another. Even when using the alloimmunization incidence per 100 units of RBCs, the true incidence may be biased unless the entire transfusion history is taken into account. Two randomized controlled trials conducted in children with SCD provided an estimate of the alloimmunization incidence rates, because relatively few children received transfusions prior to the entry into the trial, and the trial protocols intended for all units to be matched for Rh antigens C and E, and Kell antigen K:

●In the SIT Trial, in which children with silent cerebral infarcts were randomly allocated to receive regular blood transfusion therapy or standard care for three years of observation, a total of 3236 transfusions were administered in the transfusion group, and nine alloantibodies were detected in four participants: anti-C (in two participants), anti-V (in two participants), anti-FyA, anti-e, anti-S, anti-Jk^b, and anti-Wra, for an alloimmunization rate of 0.278 per 100 units of RBCs [2].

●In the STOP Trial, in which children with abnormal transcranial Doppler measurements were randomly allocated to receive regular blood transfusions or observation, a total of 1830 units were transfused, and the alloimmunization rate was 0.5 per 100 units of RBCs [13].

These trials indicate that when RBCs are prophylactically matched at a minimum for C, E, and K, the expected alloimmunization rate is low, between 0.28 and 0.5 per 100 units transfused.

Prevalence of DHTRs — Alloimmunization can lead to hemolysis. Typically, this manifests as a delayed hemolytic transfusion reaction (DHTR). (See "Hemolytic transfusion reactions", section on 'Delayed hemolytic transfusion reactions and delayed serologic transfusion reactions'.)

DHTRs are not always recognized, since their presentations are sometimes subtle. When specifically evaluated, the prevalence of DHTRs in individuals with SCD appears to be between 5 and 10 percent or higher.

●In a 2017 prospective study of 694 transfusion episodes in 311 patients over a 30-month period, the incidence of DHTR was approximately 5 percent [14].

●In a 2015 retrospective review of 220 individuals with SCD receiving transfusions over a five-year period, 17 experienced a DHTR (8 percent); this represented 23 of 2158 (1 percent) of transfusions [15]. Of note, 11 of these reactions (48 percent) were not appreciated at the time; most were misdiagnosed as a vaso-occlusive event.

Under-recognition of DHTRs was notable in a 2019 retrospective study in a cohort of 624 transfused individuals with SCD [16]. The study found laboratory evidence of DHTR based on total hemoglobin (Hb) and sickle hemoglobin (Hb S) levels, with 54 of 178 antibodies (30.3 percent); of these, fewer than half were recognized by the patient or provider at the time of the event.

The higher frequency of DHTRs in individuals with SCD is thought to primarily be due to the higher frequency of transfusions in which blood group incompatibilities exist between the donor population, which is predominantly White individuals, and the recipient SCD population, which is predominantly of African descent [12,17,18].

Antibodies against the Rh (D, C/c, E/e), Kell (K), Duffy (Fy^a, Fy^b), and Kidd (Jk^a, Jk^b) antigens present the greatest problem in transfusing these individuals [12,17,19]. (See "Red blood cell antigens and antibodies", section on 'Rh antigens' and "Red blood cell antigens and antibodies", section on 'Kidd antigens' and "Red blood cell antigens and antibodies", section on 'Duffy antigens' and "Red blood cell antigens and antibodies", section on 'Kell antigens'.)

This underscores the importance of prophylactic Rh (C, E, or C/c, E/e) and K antigen matching. Finding sufficient compatible donors requires recruitment of donors from the same ethnic backgrounds. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'RBC antigen matching'.)

Other forms of immune hemolysis — Other forms of immune hemolysis can also occur:

●Autoimmune hemolysis – Autoantibodies (antibodies that recognize the patient's own RBCs) have been reported in 7 to 47 percent of patients with SCD receiving transfusions [13,20]. An autoantibody is more likely to develop in patients who have already been alloimmunized. Some patients have a nonspecific, transient, weakly positive direct antiglobulin (Coombs) test (DAT) that has no specificity and is not associated with hemolysis. However, a new autoantibody can cause marked hemolysis (albeit rarely) and should undergo reference laboratory evaluation.

●AHTRs – Acute hemolytic transfusion reactions (AHTRs) can also occur. AHTRs are typically caused by clerical error with transfusion of the wrong ABO group blood, but in patients with SCD, these reactions often occur due to antibodies against non-ABO blood group antigens. An AHTR is a medical emergency. (See 'Acute transfusion reactions' above and "Hemolytic transfusion reactions", section on 'Acute hemolytic transfusion reactions'.)

●Hyperhemolysis – Hyperhemolysis refers to alloimmune hemolysis accompanied by bystander hemolysis of the patient's own RBCs. The mechanism is poorly understood. The degree of hemolysis can be severe. (See "Overview of the clinical manifestations of sickle cell disease", section on 'Hyperhemolytic crisis'.)

Clinical features of immune hemolysis — DHTRs generally occur 3 to 14 days after a transfusion. Patients with SCD who develop a DHTR may present with worsening anemia, increased fatigue, jaundice, dark urine, fever, and/or pain [21,22]. Importantly, a DHTR can be difficult to diagnose as the DAT may be negative or weak, and new antibody formation is not always detectable at the time of symptomatic presentation [16,22,23]. (See "Hemolytic transfusion reactions", section on 'Delayed hemolytic transfusion reactions and delayed serologic transfusion reactions'.)

The patient often has pain with evidence of hemolysis but a low reticulocyte count. Hemoglobin analysis typically demonstrates the disappearance of the transfused, Hb A-containing RBCs. Individuals with SCD have hemolysis at baseline, so hemolytic markers may be less helpful, and the evaluation should focus on the identification of new alloantibodies. (See "Pretransfusion testing for red blood cell transfusion", section on 'Antibody screen'.)

In some cases, Hb analysis may suggest "bystander" hemolysis of the patient's Hb S-containing RBCs, also referred to as hyperhemolysis or hyperhemolytic crisis. Hyperhemolysis events are serious and can be life-threatening [24]. (See "Overview of the clinical manifestations of sickle cell disease", section on 'Hyperhemolytic crisis'.)

In some cases, there will be multiple alloantibodies, making it difficult to obtain compatible RBCs for transfusion. In a 2016 analysis of 99 DHTRs in SCD, the overall mortality was 6 percent, and these DHTRs were often associated with pain events and secondary acute chest syndrome [25]. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Symptomatic or severe anemia' and "Pretransfusion testing for red blood cell transfusion", section on 'Sickle cell disease or thalassemia'.)

Evaluation of immune hemolysis — Testing for immune hemolysis includes hemoglobin (Hb) quantification, bilirubin, reticulocyte count, and lactate dehydrogenase (LDH). Any patient who has any one or a combination of findings of hemolysis, including a rapid decrease in Hb level and proportion of Hb A after the transfusion, jaundice with increased bilirubin, hemoglobinuria, or increased reticulocyte percentage (table 1) should be evaluated with a DAT. A low reticulocyte may also be seen [21]. (See "Approach to the patient with a suspected acute transfusion reaction", section on 'Suspected acute hemolytic reaction'.)

Any patient with a positive DAT should undergo evaluation to identify the antibody specificity (antibody identification) to avoid this antigen in future transfusions. Since these events are more likely following transfusion for an acute complication of SCD, any patient who has been recently transfused and presents with symptoms of worsening anemia should be evaluated for a DHTR. (See "Hemolytic transfusion reactions", section on 'Evaluation of DHTR and DSTR'.)

Management of immune hemolysis

DHTRs — For an uncomplicated delayed hemolytic transfusion reaction (DHTR), we avoid further transfusion if possible. To manage the DHTR, we provide supportive care with hydration and pain control as needed. (See "Hemolytic transfusion reactions", section on 'Management of DHTR and DSTR' and "Evaluation of acute pain in sickle cell disease" and "Acute vaso-occlusive pain management in sickle cell disease".)

Hyperhemolysis is a serious but rare complication that may accompany a DHTR (see 'Hyperhemolysis' below and "Overview of the clinical manifestations of sickle cell disease", section on 'Hyperhemolytic crisis'). Since DHTRs with hyperhemolysis are uncommon, the role of immunosuppressive therapy is based on case reports, case series, and expertise. In the event that a patient with SCD and hyperhemolysis requires preparation for hematopoietic stem cell transplant, gene therapy, or gene editing, referral to a transplant center with local expertise in immunosuppressive therapy is appropriate.

If additional transfusions are required, at a minimum, the red cells should be matched for ABO, Rh (C, E or C/c, E/e) and K, and RBC units should lack any antigens identified in the DHTR evaluation [8]. We also attempt to provide extended matching for Jk^a/Jk^b, Fy^a/Fy^b, and S/s. However, there should be close communication with the blood bank about the availability of extended antigen-matched units, and any delays in transfusion must be weighed against the patient's clinical status and urgency with which further transfusion is needed. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Indications for transfusion'.)

Hyperhemolysis — Hyperhemolysis is a potentially life-threatening reaction in which accelerated hemolysis and worsening anemia occur following transfusion. The mechanism is poorly understood. (See "Overview of the clinical manifestations of sickle cell disease", section on 'Hyperhemolytic crisis'.)

Hyperhemolysis and other severe hemolytic reactions, defined as transfusion-associated hemolysis with a rapid hemoglobin decline to below the pretransfusion level and rapid decline of the post-transfusion Hb A level, require prompt intervention, but evidence to guide optimal therapy is limited [8].

We suggest prompt initiation of immunosuppressive therapy for patients with hyperhemolysis with a glucocorticoid, intravenous immune globulin (IVIG), or both, especially for those who require further transfusions. The choice between glucocorticoids, IVIG, or both is individualized [26].

●First-line agents include glucocorticoids (prednisone at 1 to 4 mg/kg daily or equivalent dose methylprednisolone) or IVIG (0.4 to 1 g/kg per day for three to five days) [8]. Glucocorticoids may be given first and IVIG added if hemolysis is especially severe or continues despite glucocorticoids.

Evidence for the benefit of glucocorticoids is largely indirect, based on its efficacy in autoimmune hemolysis (see "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Glucocorticoids with or without rituximab as first-line agents') and from small case series or case reports of individuals with SCD showing good outcomes [27-32]. The use of glucocorticoids must be balanced against the known association with severe acute vaso-occlusive pain episodes and possibly fat emboli [33-37]. However, evidence from case reports suggests that hyperhemolysis almost always favors treatment with glucocorticoids.

●Depending on the length of the glucocorticoid therapy, regardless of the dose or duration of glucocorticoids, severe acute vaso-occlusive pain may be temporally related to the administration, typically within five days of treatment [34,35,38-40]. We are unaware of data that indicate whether a slow steroid taper or an abrupt cessation of the steroid will be more likely to reduce the risk of acute rebound vaso-occlusive pain.

●Eculizumab, a monoclonal antibody that targets the C5 component of complement, is generally reserved as a second-line agent if hemolysis does not respond to glucocorticoids and IVIG [7,41-43]. Prescribing information for eculizumab carries a Boxed Warning regarding the risk of meningococcal infections and need to vaccinate [44]. The Advisory Committee on Immunization Practices (ACIP) also encourages clinicians to consider anti-meningococcal prophylaxis for the duration of eculizumab treatment [45]. This subject is discussed in detail separately. (See "Treatment and prevention of meningococcal infection", section on 'Patients receiving C5 inhibitors'.)

●For patients in whom further transfusion is likely, rituximab can be considered [46]. However, rituximab can produce varying degrees of immunosuppression that may persist beyond the initial course of therapy, which is of potential concern in SCD due to coexisting functional asplenia. (See "Secondary immunodeficiency induced by biologic therapies", section on 'Rituximab'.)

●The use of tocilizumab, a monoclonal antibody against the IL-6 receptor that blocks macrophage activation, has been described for salvage treatment of severe DHTRs and hyperhemolysis [47-50]. In these reports, administration of one to four doses of 8 mg/kg daily was associated with good clinical responses and evidence of decreased hemolysis. Adverse events were limited to one patient who had seizures; the individual also had methemoglobinemia due to a hemoglobin-based oxygen carrier.

We also administer erythropoietin as a means of reducing the need for further transfusions, although transfusions may be required if the patient is experiencing life-threatening anemia [8]. Case reports and small series have demonstrated erythropoietin to be associated with good outcomes without major serious adverse events [27,51]. Doses in the range of 4000 international units subcutaneously once per day for 7 to 14 days have been used [27].

Voxelotor has been used in severe cases (baseline Hb <6 g/dL), but data supporting safety and efficacy are lacking. Voxelotor has also been used in individuals who decline blood transfusion, have a Hb <9 g/dL, and require surgery with general anesthesia [52]. (See "Investigational therapies for sickle cell disease", section on 'FDA-approved agents' and "Approach to the patient who declines blood transfusion", section on 'Jehovah's Witnesses'.)

INFECTION — Consequences of transfusion-related infection may be more serious in individuals with SCD compared to the general population:

●Viral infections that may reduce bone marrow production of red blood cells (RBCs) could lead to more severe acute anemia when superimposed on the chronic hemolytic anemia of SCD. In the United States, transfusion-transmission of serious viral infections is very rare except for parvovirus. (See 'Parvovirus' below.)

●Bacterial infections, especially with encapsulated organisms, poses a greater risk because individuals with SCD are functionally asplenic due to splenic infarction early in life and are at risk for bacterial sepsis. (See 'Bacterial infection' below.)

Parvovirus — Parvovirus is not eliminated by standard blood screening, and it is not inactivated by viral inactivation processes used for plasma products (see "Pathogen inactivation of blood products"). Unlike the general population, for whom parvovirus infection often does not cause severe anemia, patients with SCD who are infected with parvovirus can become symptomatic from an acute anemia caused by transient bone marrow red cell aplasia. This is because most individuals in the general population can easily tolerate a brief period of reduced RBC production and can compensate by increasing the reticulocyte count, whereas those with SCD are already in a state of compensated hemolytic anemia and cannot easily increase RBC production in the setting of transiently reduced RBC production. (See "Clinical manifestations and diagnosis of parvovirus B19 infection", section on 'Transient aplastic crisis'.)

Management of parvovirus-induced anemia is supportive with transfusions as needed. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Symptomatic or severe anemia'.)

The infection typically resolves after several days or in some cases weeks. For the rare patient with chronic infection and chronic hemolysis, intravenous immune globulin (IVIG) can be administered. (See "Treatment and prevention of parvovirus B19 infection", section on 'Transient aplastic crisis' and "Treatment and prevention of parvovirus B19 infection", section on 'Chronic infection with anemia'.)

CMV — The presence of antibodies to cytomegalovirus (CMV) is a nonspecific assay for CMV infectivity, and 30 to 70 percent of blood donors, depending upon geographic region, test positive for the presence of CMV antibodies. Leukoreduced RBCs also provide "CMV-safe" blood. Leukoreduced blood contains <5 million leukocytes per unit and is routinely performed prestorage with an RBC filter. (See "Blood donor screening: Laboratory testing", section on 'Cytomegalovirus' and "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Leukoreduction'.)

Prestorage leukoreduction of RBCs is also a means of preventing febrile nonhemolytic transfusion reactions (FNHTRs). (See "Immunologic transfusion reactions", section on 'Febrile nonhemolytic transfusion reactions'.)

Other viruses — Transfusion transmission of HIV, human T-lymphotropic virus type I (HTLV-I), and hepatitis B and C has diminished markedly with improved screening of banked units of blood (table 2). However, individuals with SCD who have immigrated to the United States may have previously received units of blood with the potential to transmit these viruses, and should be screened for viral hepatitis and HIV. (See "Blood donor screening: Laboratory testing", section on 'Infectious disease screening and surveillance'.)

Bacterial infection — The risk of sepsis from intravenous catheters or transfusion-transmitted bacterial infection (TTBI) can be reduced by appropriate catheter care and disease management that lessens the need for transfusions and limits transfusions to indications for which they are likely to be helpful. (See "Overview of the management and prognosis of sickle cell disease" and "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Indications for transfusion' and "Routine care and maintenance of intravenous devices".)

Evaluation and management of TTBI is discussed separately. (See "Transfusion-transmitted bacterial infection".)

The combination of iron overload, chelation therapy (which mobilizes iron), and immunosuppression (from functional asplenia and treatment with glucocorticoids) increases risk for iron-avid organisms such as Yersinia enterocolitica [53]. (See 'Excessive iron stores' below and "Evaluation and management of fever in children and adults with sickle cell disease", section on 'Risk of life-threatening infection'.)

Emerging infections — Transfused individuals with SCD may be at particular risk for emerging transfusion-associated infections including babesiosis and malaria, for which specific laboratory testing is not performed (or performed on a limited basis). A high degree of suspicion is needed for early detection [54,55]. (See "Blood donor screening: Laboratory testing", section on 'Emerging infectious disease agents'.)

HYPERVISCOSITY FOLLOWING SIMPLE TRANSFUSION — Blood viscosity is determined by an interrelationship between total hemoglobin (Hb), percent sickle hemoglobin (Hb S), blood flow rate, white blood cell count, and other parameters. As the blood viscosity increases beyond a threshold, oxygen delivery decreases (even if the Hb level has been increased).

Hyperviscosity is a risk in some individuals receiving simple transfusions; this is because simple transfusion can raise the total Hb but only marginally lower the percentage of Hb S. In SCD, there is an optimal balance of increasing Hb levels and viscosity while also increasing oxygen delivery.

With a simple transfusion in individuals with SCD, increasing the Hb level will result in an increase in oxygen delivery up to a certain threshold, after which there is a decrease in the oxygen delivery with further increases in Hb. Based on in vitro studies and experts' clinical experience, the risk of decreased oxygen delivery is considered to be highest when the total Hb is >10 g/dL and the Hb S is >50 percent of total Hb [8,56].

Symptoms of hyperviscosity are nonspecific and related to the affected vascular bed. The literature does not describe many cases of hyperviscosity syndrome, in part because hyperviscosity syndrome complications in SCD are often unintended and potentially avoidable consequences of a transfusion therapy. Central nervous system-related injury is the most severe hyperviscosity sequela in children and adults with SCD. Hyperviscosity in SCD can be associated with the following complications:

●Dural venous thrombosis [57]

●Cerebral infarcts

●Cerebral hemorrhage [58]

●Seizures with hypertension [59]

●Death [58,60]

The major strategies for preventing hyperviscosity include using exchange transfusion rather than simple transfusion for individuals with Hb >10 g/dL and Hb S >50 percent of total Hb, and using phlebotomy for those with a post-transfusion Hb above 12 to 13 g/dL and Hb S >50 percent. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Simple versus exchange transfusion'.)

EXCESSIVE IRON STORES

Scope of the problem — Despite limiting transfusion to appropriate indications, many patients with SCD will develop excessive iron stores if chelation therapy or red blood cell (RBC) exchange transfusion is not used. Excess iron is a cause of significant morbidity in patients with SCD, especially as their longevity continues to increase with improved management and use of hydroxyurea [61-63]. Hepatic fibrosis and death from hemosiderosis-related cirrhosis of the liver can occur [64-68].

Prevention — Preventing accumulation of excess iron is critical to prevent serious morbidity and mortality.

The preferred method to attenuate excessive iron stores is automated RBC exchange, or to a lesser degree, manual exchange. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Simple versus exchange transfusion'.)

The American Society of Hematology (ASH) guidelines for SCD and transfusion support suggests using automated RBC exchange over simple transfusion or manual RBC exchange in patients receiving chronic transfusions [8]. A shared decision-making model with the patient and family is recommended; this should consider patient age, patient preferences, need for a central venous access device, iron overload status, adherence with iron chelation, and the availability of compatible RBCs, especially in heavily alloimmunized individuals.

Compared with simple transfusion, automated RBC exchange results in a smaller increase in ferritin. This was illustrated in a secondary analysis of the Silent Cerebral Infarct Trial (SIT), a stroke prevention trial that compared regular transfusions versus standard of care [69]. The method of regular transfusion (simple transfusion, manual exchange transfusion, or automated exchange transfusion) was determined by the site investigators based on local resources and patient characteristics. A secondary analysis involving 83 participants who received monthly blood transfusion therapy for one year analyzed the effect of the transfusion method on ferritin levels (figure 1). Baseline ferritin levels were similar in all three groups, at approximately 100 to 200 ng/mL. After one year of transfusions, the median ferritin levels (and interquartile ranges [IQR]) were as follows [69]:

●Simple transfusion – 1800 ng/mL (IQR, 1426 to 2204 ng/mL)

●Manual exchange – 1530 ng/mL (IQR, 1205 to 1805 ng/mL)

●Automated exchange – 355 ng/mL (IQR, 179 to 579 ng/mL)

Only 9 participants received automated exchange transfusion, and the analysis only covered one year of transfusion therapy [69]. Nevertheless, these data clearly show the benefit of automated exchange transfusion in attenuating iron overload compared with the other transfusion methods.

The center of one of the authors no longer offers simple transfusions to patients who require monthly blood transfusions to maintain Hb S levels <30 percent of total Hb. The patients receive either manual or automated exchange transfusions. Occasional patients will receive simple transfusions as a short-term measure or because a central line cannot be placed, but generally, they do not perform simple transfusions for >12 months. This practice is informed by several cases of premature death in adolescents with SCD who received simple transfusions for many years coupled with non-adherence to chelation therapy.

For those who receive regular, chronic simple transfusions, iron chelation therapy is an important component of the transfusion program because it prevents complications of iron deposition in organs, particularly in the liver. Long-term efficacy and safety studies on the effects of chelation on morbidity and mortality in individuals with SCD have not been completed, but existing data and multiple consensus reports recommend iron chelation therapy for transfusion iron overload [70,71]. (See 'Chelation therapy' below.)

In contrast to chelation, phlebotomy cannot be used to remove iron in transfusion-dependent individuals due to their baseline anemia; phlebotomy is useful only in the rare individual with SCD and a high baseline hemoglobin (Hb) concentration. In such cases, automated apheresis is effective in minimizing the iron burden and may prevent the need for chelation [72-74]. Excess iron can be removed by phlebotomy following hematopoietic stem cell transplant, provided the post-transplant Hb concentration is sufficiently high to allow for a transient further decrease in Hb. (See "Hematopoietic stem cell transplantation in sickle cell disease".)

Other means of minimizing iron burden include [8]:

●Restricting transfusions to appropriate indications. (See 'Appropriate indications' above and "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Indications for transfusion'.)

●Optimal use of disease-modifying therapies. (See "Hydroxyurea use in sickle cell disease", section on 'Indications and appropriate age to start therapy' and "Investigational therapies for sickle cell disease", section on 'FDA-approved agents'.)

Monitoring iron stores

Serum ferritin concentration — The serum ferritin concentration is a useful test to monitor the status of iron stores, particularly by following the trend. Ferritin levels need to be serially measured at least every three to four months and must be drawn in the steady-state, separate from acute inflammatory or vaso-occlusive events. Ferritin is an acute-phase reactant and will become elevated during acute inflammatory events.

We prefer to draw the ferritin levels with each blood draw at routine outpatient visits to monitor the trend for the individual, which is more representative of iron stores than a single ferritin measurement. Patients receiving chelation therapy have monitoring of serum ferritin level at every transfusion. Since the ferritin fluctuates, it is important to average three to five serial ferritin measurements before determining the direction in change of iron stores.

We aim to maintain a serum ferritin value no greater than 1000 to 1500 ng/mL (no greater than 1000 to 1500 mcg/L). However, periodic monitoring of quantitative liver iron is important, as discussed below. (See 'Liver' below.)

Tissue iron stores — Optimal management of iron overload in SCD requires the periodic correlation of ferritin with tissue iron stores in the liver and sometimes the heart. (See 'Liver' below and 'Heart' below.)

Additional evaluations for endocrine dysfunction may be appropriate (thyroid function, FSH and LH in females, testosterone in males).

Liver — We measure liver iron stores noninvasively using magnetic resonance imaging (MRI) at the initiation of chelation therapy and every one to two years in chronically transfused patients [8]. More frequent monitoring may be used if a potential decision is to be made about stopping chelation therapy. Conversely, in patients receiving chronic transfusion by red blood cell (RBC) exchange with a neutral or negative RBC balance and have a ferritin less than 1000 ng/mL, measurement of liver iron content every one to two years is not needed [8]. We use non-invasive quantitative MRI to assess liver iron; regionally, different techniques to quantitate iron stores may be available. Quantitative MRI using R2 or R2* relaxometry or biomagnetic liver susceptometry (Ferritometer) are acceptable. The Ferriscan is a standardized, validated MRI method using R2 MRI that utilizes locally acquired data analyzed at a centralized facility that can be adapted to most MRI scanners. (See "Approach to the patient with suspected iron overload", section on 'Noninvasive imaging (MRI)'.)

We prefer to use MRI to monitor iron status and adjust chelation for a number of reasons, including the lack of a clear correlation of steady-state ferritin levels with hepatic iron stores and the desire to avoid an invasive procedure [64,75-77]. At least two studies found a poor correlation of serum ferritin with hepatic iron stores as determined by liver biopsy in patients who were receiving chronic transfusions [64,77]. Furthermore, significant variability of the liver iron content may occur within the liver, such that a single needle biopsy may not be representative of the total liver iron content [78].

We reserve liver biopsy for rare individuals with SCD in whom the MRI-based estimate of the liver iron content is inconsistent with the transfusion history or where there is concern regarding liver function (and assessment of liver histology is needed). Some curative therapy protocols may require a liver biopsy to assess for bridging fibrosis. However, the clinical utility of this indication for a liver biopsy is unclear, particularly in individuals with low liver iron content. (See "Methods to determine hepatic iron content".)

Heart — Patients with SCD accumulate cardiac iron at a lower rate than patients with thalassemia but remain at risk for cardiac hemosiderosis. Cardiac iron cannot be predicted solely by liver iron stores. We generally reserve cardiac iron monitoring using T2* MRI of the heart for patients with a high iron burden (liver iron content >15 mg/g dry weight for two years or more) or those with evidence of cardiac dysfunction or other end organ damage due to iron overload [8,79-81]. (See "Clinical utility of cardiovascular magnetic resonance imaging", section on 'Iron overload'.)

While improved chelation programs may stabilize patients with cardiac dysfunction, the root cause of excessive iron strokes must be addressed by a multidisciplinary team. Serious iron overload can result from nonadherence to therapy. Factors causing nonadherence, including lack of family/caregiver support and home infrastructure, must be addressed to have long-term improvement.

Chelation therapy

When to start chelation therapy — The initiation of chelation therapy in individuals with SCD depends upon the number of transfusions given, the degree of iron deposition in the liver and heart, the amount of hepatic and cardiac dysfunction present, and the type of transfusion regimen [68,70,82]. Management by a multidisciplinary team that includes at least a medical social worker and a nurse case manager is optimal and should include staff familiar with the toxicity and compliance issues associated with iron chelation and prevention of organ injury.

Generally, chelation therapy is started after one to two years of transfusion in chronically transfused individuals, when the serum ferritin exceeds at least 1000 to 1500 mcg/L (ng/mL) or the liver iron is >3 to 5 mg/g dry weight. Often this correlates with a total transfusion burden of approximately 120 to 200 mL of transfused RBCs per kilogram, although in practice, calculating this volume may not be very helpful. A quality-of-care indicator from the American Academy of Pediatrics suggests that children receive chelation therapy to maintain a ferritin <1500 ng/mL or liver iron <7 mg/g dry weight [83].

The major challenge in using these criteria is that when patients transition to exchange transfusion from simple transfusion, the ferritin level typically falls below 1000 ng/mL after 12 months, but the tissue iron stores may still be high. We prefer to use annual liver MRI and initiate chelation if the liver iron is >3 mg/g dry weight or if the serum ferritin is >1000 ng/mL on two consecutive measurements.

The targets used for iron chelation therapy are changing as better iron chelators become available. Studies addressing the long-term safety and efficacy of maintaining near normal iron stores have not been completed [84].

Baseline testing prior to starting chelation includes audiology, ophthalmology, and pregnancy test in females.

Choice of chelating agent — Three iron chelating agents are available: deferiprone, deferoxamine, and deferasirox. For most patients, we use deferasirox because it is orally active and has a good therapeutic index (eg, benefit to toxicity ratio).

●Deferasirox – Deferasirox (DFX; Exjade, Jadenu) is an orally available iron chelator that appears to have efficacy similar to deferoxamine in decreasing liver iron concentration [85]. Exjade is a tablet that was approved in 2005 for individuals two years or older with iron overload. Jadenu is a powder formulation of the same drug that can be sprinkled on food, which is easier for young children. Concomitant use of hydroxyurea does not appear to alter the efficacy, safety, or pharmacokinetics of deferasirox [86]. The side effect profile of deferasirox appears to be tolerable in individuals with SCD. The major adverse events include gastrointestinal symptoms, a reversible, dose-dependent rise in serum creatinine, and occasional liver dysfunction. (See 'Monitoring for adverse events' below.)

●Deferiprone – Deferiprone (DFP; Ferriprox) is an orally active iron chelator that was approved for use in sickle cell disease in 2021 [87]. Its major side effect is the risk of agranulocytosis; therefore the FDA requires weekly neutrophil counts on all patients [88]. Patients may also experience arthralgia and gastrointestinal symptoms, and hepatotoxicity has been reported [89].

●Deferoxamine – Deferoxamine (DFO; Desferal) is effective and available but requires daily subcutaneous infusions that last for many hours, which often result in poor adherence to therapy. This agent can also be given intravenously for more rapid iron chelation. Since the half-life of DFO is extremely short (ie, minutes), the efficacy of DFO is determined by its duration of infusion as well as the dose.

Dosing — The optimal dose of the chelating agent is determined by the patient's age, iron stores, the frequency of transfusions, and the presence of organ dysfunction. Persistently low ferritin levels (eg, below 500 ng/mL) in the face of regular chelation are not optimal for growing children and may be associated with increased toxicity.

Most patients require modification of dosing based on response and organ function over time. As examples:

●Deferasirox – The starting dose for oral deferasirox as Exjade is 20 mg/kg/day once daily. The dose is increased by 5 to 10 mg every three to six months based on iron stores. Toxicities such as skin rash, nausea, and diarrhea are dose related. These adverse events may be decreased by giving the same total dose twice a day, rather than once a day, and accompanied with food. The dosing for deferasirox as Jadenu is approximately 30 percent lower (rounded to the nearest whole tablet or sachet of granules) than for Exjade because of greater bioavailability [90,91].

•Exjade requires dispersion in a liquid

•Jadenu tablets can be swallowed whole but cannot be made into a suspension

•Jadenu granules can be sprinkled on soft foods

●Deferiprone – The standard dose of deferiprone is 75 mg/kg/day, given as three doses of 25 mg/kg. After six months, it may be increased up to 100 mg/kg/day in non-responding or high-risk patients.

●Deferoxamine – In general, in individuals without iron-induced cardiac dysfunction, the starting dose of deferoxamine is 30 mg/kg given daily over 8 to 12 hours, five days per week. This can be modified by 5 to 10 mg every three to six months depending on the individual patient's transfusion burden and iron status.

Deferoxamine with deferiprone, sequentially or in combination, has been routinely used in high-risk patients with very high iron burden [92]. In addition, the safety and efficacy of combining deferasirox and deferoxamine for severely affected individuals appears promising [93-95]. (See "Iron chelators: Choice of agent, dosing, and adverse effects", section on 'Deferoxamine plus deferasirox'.)

Invariably, clinicians will identify a subgroup of children or adults with SCD with excessive liver iron stores (eg, >15 mg/g dry weight, either by MRI or liver biopsy), without evidence of immediate cardiac arrhythmias or left ventricular dysfunction. In such situations, considerations should be made for alternative strategies for aggressive chelation, including hospitalization for intravenous chelation therapy and combination chelation. Inpatient chelation should be managed by (or in consultation with) a clinician with experience in this approach. Example dosing includes deferoxamine 50 mg/kg over 24 hours for two days plus deferasirox 20 to 40 mg/kg daily for two days. Deferiprone may be added if heart failure or significant cardiac iron overload is present. Deferasirox may be added if liver iron content is very high.

In the event that the patient has evidence of life-threatening cardiac arrhythmias or left ventricular dysfunction, we recommend extended inpatient hospitalization for chelation therapy with long-term combination chelation therapy. Chelation regimens for the management of cardiac dysfunction have been established for patients with thalassemia [96-98]. (See "Acute iron poisoning", section on 'Deferoxamine'.)

Monitoring for adverse events — In addition to monitoring iron stores during chelation (see 'Monitoring iron stores' above), we also perform the following testing for toxicity of the chelating agents:

●Audiology – A formal audiology exam should be obtained prior to initiation of a chelator. A screening hearing exam should be performed in clinic every six months and a formal audiogram every 12 months. Those with new onset hearing loss or tinnitus should be evaluated. Hearing loss is most frequently identified with deferoxamine, especially at higher doses. Early detection of hearing loss followed by dose modification may result in reversal of damage. Irreversible hearing loss requiring hearing aids does occur [99]. (See "Iron chelators: Choice of agent, dosing, and adverse effects", section on 'Side effects'.)

●Ophthalmology – Visual loss has been most clearly linked to deferoxamine, especially at high doses. A baseline and annual evaluation by an ophthalmologist should be performed. Individuals should be routinely questioned about visual acuity, changes in color, vision, and visual fields.

●Nephrology – With deferasirox, there is a dose-dependent rise in serum creatinine, which is reversible. Long-term follow-up studies of deferasirox for five years have shown a clinically acceptable safety profile, with no evidence of progressive or irreversible renal injury [100]. Rare reports of renal failure and Fanconi syndrome have occurred in individuals receiving deferasirox, particularly in those not having dose adjustments for renal function abnormalities [101-103]. Deferasirox may increase urinary calcium loss [104].

Creatinine/blood urea nitrogen (BUN), serum chemistry, and urine protein and creatinine should be monitored monthly in individuals on deferasirox and every three months in those on deferoxamine. We discontinue therapy immediately if the serum creatinine is greater than two times the upper limit of normal. Any patient who experiences a serum creatinine increase >50 percent above baseline should have the dose held temporarily, and an increase in serum creatinine of 33 to 50 percent should prompt dose reduction. We temporarily hold the chelator if the urine protein/creatinine ratio is >0.6 mg/mg (>600 mg/g).

●Hematologic – Those on deferiprone require a weekly complete blood count (CBC) to detect serious neutropenia/agranulocytosis; a neutrophil count below 1000 cells/microL (calculator 1) requires stopping the drug and reassessing future use. All individuals with fever who are on deferiprone require an immediate evaluation of their white blood cell count.

Deferasirox has been associated with neutropenia, agranulocytosis, worsening anemia, and thrombocytopenia, including fatal events. We hold therapy with deferasirox in individuals who develop cytopenias until the cause of the cytopenias has been determined. Deferasirox is contraindicated in patients with platelet counts below 50,000/microL [105].

●Growth – Growth can sometimes be affected by chelators or confounded by excessive iron deposition [106]. Ongoing measurements of height and weight velocity, including sitting height, should be performed.

●Gastrointestinal and liver function – Diarrhea, nausea and vomiting, and abdominal pain are common side effects with deferasirox, but these are usually mild and decrease with time; these effects appear to be less with the Jadenu formulation. Liver dysfunction has been seen in multicenter trials with deferasirox. Long-term follow-up studies of five years have not shown evidence of progressive or irreversible liver injury with deferasirox [100]. However, post-marketing surveillance has identified hepatic failure as a complication in high-risk individuals, such as patients with pre-existing liver failure and hepatitis C.

For deferasirox, serum transaminases and bilirubin should be monitored twice during the first month in individuals at high risk of liver disease (ie, those with hepatitis C or liver failure) after initiation of therapy with deferasirox and monthly afterward. For standard-risk individuals, hepatic enzymes should be monitored monthly with deferasirox and every three months with other chelators. We hold chelation therapy if the serum alanine aminotransferase (ALT, formerly called SGPT) is greater than five times the upper limit of normal.

Other acute events that require immediate temporary withdrawal of chelation therapy include acute respiratory distress, Stevens-Johnson syndrome, and acute gastrointestinal bleeding. Deferoxamine has been associated with acute respiratory distress that can mimic acute chest syndrome. Gastrointestinal hemorrhage has been seen with deferasirox, especially in older adults with malignancies or thrombocytopenia [107].

Chelating agents may affect the growth of some microorganisms (eg, Yersinia enterocolitica) and should be held temporarily in patients with fever or active infection until the patient becomes afebrile. (See 'Bacterial infection' above.)

Decisions regarding discontinuation of the chelating agent or switching to a different chelator are made on a case-by-case basis depending on a variety of factors including the severity of the SCD complication, severity of the chelator toxicity, and availability and tolerability of alternative agents.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sickle cell disease and thalassemias".)

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (See "Patient education: Sickle cell disease (The Basics)" and "Patient education: When your child has sickle cell disease (The Basics)".)

●Beyond the basics topic (See "Patient education: Blood donation and transfusion (Beyond the Basics)".)

PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Sickle cell disease".)

SUMMARY AND RECOMMENDATIONS

●Avoiding complications – Alloimmunization and excess iron stores are more frequent and severe in individuals with sickle cell disease (SCD) than the general population. Complications can be reduced by limiting transfusions to appropriate indications and using appropriate techniques. (See 'Limiting transfusions to appropriate use' above and 'Prevention' above.)

●Alloimmunization

•For prevention, we match ABO, Rh (C, E, or C/e, E/e), and the Kell antigen K for all patients with SCD. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'RBC antigen matching'.)

•DHTRs may present with worsening anemia, fatigue, jaundice, dark urine, fever, and/or pain 3 to 14 days after transfusion. The direct antiglobulin test (DAT; Coombs test) may be negative or weakly positive. Evaluation for an antibody specificity should be performed. (See 'Clinical features of immune hemolysis' above and 'Evaluation of immune hemolysis' above.)

•For an uncomplicated DHTR, we avoid further transfusion if possible and provide hydration and pain control as needed. If transfusions are required, we provide matched blood that lacks antigens identified in the DHTR evaluation. In addition to antigens listed above, we match for Jk^a/Jk^b, Fy^a/Fy^b, and S/s if time permits. (See 'DHTRs' above.)

•Hyperhemolysis is a poorly understood form of bystander hemolysis that can cause life-threatening anemia. (See 'Hyperhemolysis' above.)

•For patients with SCD and severe DHTR or hyperhemolysis, we suggest immunosuppressive therapy (Grade 2C). Common therapies include prednisone and intravenous immune globulin (IVIG). Watchful waiting is an alternative for milder hemolysis. Eculizumab may be used if prednisone and IVIG are ineffective. We also suggest erythropoietin (Grade 2C).

●Infection – Parvovirus is not eliminated by screening or pathogen inactivation. Worsening anemia without reticulocytosis following transfusion is suggestive of parvovirus. Individuals with SCD are functionally asplenic and at risk for sepsis from bacterial infection. (See 'Infection' above.)

●Hyperviscosity – Hyperviscosity can occur if the hemoglobin (Hb) is >10 g/dL and sickle hemoglobin (Hb S) is >50 percent of total Hb. Prevention strategies include exchange transfusion rather than simple transfusion and phlebotomy if post-transfusion Hb is >12 to 13 g/dL and Hb S is >50 percent. (See 'Hyperviscosity following simple transfusion' above and "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Simple versus exchange transfusion'.)

●Excess iron – Transfusion of >15 to 20 RBC units (>10 units in small children) can cause clinically significant iron overload (figure 1). (See "Approach to the patient with suspected iron overload", section on 'Transfusional iron overload' and 'Scope of the problem' above.)

•Ferritin is measured between monthly and quarterly to provide immediate feedback about ferritin trends. We use liver magnetic resonance imaging (MRI)-based assessment of liver iron content to make a firm decision about clinical management. Liver MRI is done every one to two years in chronically transfused patients and before chelation. We generally reserve cardiac T2* MRI for patients with high iron burden, cardiac dysfunction, or other organ damage. (See 'Serum ferritin concentration' above and 'Tissue iron stores' above.)

•Chelation is generally started after one to two years of chronic transfusions and when the ferritin is >1000 to 1500 ng/mL or liver iron is >3 to 5 mg/g dry weight. (See 'Chelation therapy' above.)

-For most patients, we suggest deferasirox (Grade 2C). Deferasirox is orally active and has a good benefit-to-toxicity ratio. (See 'Choice of chelating agent' above.)

-Ferritin is monitored at every transfusion and liver iron every one to two years. Monitoring for drug toxicity is individualized and may include ophthalmologic, auditory, hematologic, kidney, and liver function testing. (See 'Monitoring for adverse events' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges extensive contributions of Donald H Mahoney, Jr, MD to earlier versions of this topic review.