Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques

INTRODUCTION — Individuals with sickle cell disease (SCD) have chronic anemia that can worsen abruptly (eg, from splenic sequestration or transient red cell aplasia) and 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) remains a first-line therapy for many complications associated with SCD and can be life-saving.

Blood transfusion carries risks, many of which are greater in individuals with SCD than in the general population. 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 our approach to transfusion in children and adults with SCD. Complications of transfusion unique to this population, including high rates of alloimmunization and iron overload, are discussed separately. (See "Transfusion in sickle cell disease: Management of complications including iron overload".)

The clinical manifestations of SCD and other aspects of SCD management are presented separately:

●Clinical manifestations (overview) – (See "Overview of the clinical manifestations of sickle cell disease".)

●Management (specialist) – (See "Overview of the management and prognosis of sickle cell disease".)

●Management (general pediatrician) – (See "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance".)

●Hydroxyurea – (See "Hydroxyurea use in sickle cell disease".)

●Other disease-modifying therapies – (See "Disease-modifying therapies to prevent pain and other complications of sickle cell disease".)

●Stroke (management) – (See "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease".)

●Stroke (prevention) – (See "Prevention of stroke (initial or recurrent) in sickle cell disease".)

●Pain episodes – (See "Acute vaso-occlusive pain management in sickle cell disease".)

●Acute chest syndrome – (See "Acute chest syndrome (ACS) in sickle cell disease (adults and children)".)

●Pregnancy – (See "Sickle cell disease: Obstetric considerations".)

TERMINOLOGY

●Sickle cell disease – Sickle cell disease (SCD) refers to a group of inherited disorders characterized by sickled red blood cells (RBCs), caused either by homozygosity for the sickle hemoglobin mutation (Hb SS; sickle cell anemia) or by compound heterozygosity for the Hb S point mutation and a second beta globin gene variant (eg, sickle-beta thalassemia, Hb SC disease). In either Hb SS or compound heterozygotes, the majority (more than 50 percent) of hemoglobin (Hb) is sickle Hb (Hb S). (See "Diagnosis of sickle cell disorders", section on 'Terminology'.)

●Transfusion – Simple transfusion refers to transfusion of RBCs without removal of the patient's blood. Exchange transfusion involves transfusion of RBCs together with removal of the patient's blood. Exchange transfusion can be performed manually or via an automated apheresis using an extracorporeal continuous flow device (also called apheresis, cytapheresis, or hemapheresis).

RATIONALE FOR TRANSFUSION — Blood transfusion therapy in SCD can serve two roles, either for therapy (typically for life-threatening, SCD-related complications) or for prophylaxis, to decrease the incidence of specific SCD-related complications. In both cases, blood transfusion does more than simply raise the hemoglobin (Hb) level for oxygen delivery; transfusion also lowers the percentage of sickle Hb (Hb S) and increases Hb oxygen saturation, both of which decrease the propensity for vaso-occlusion. (See "Pathophysiology of sickle cell disease".)

At least four mechanisms contribute to the benefit of blood transfusion therapy in treating vaso-occlusive events and decreasing the incidence of SCD-related complications [1,2]:

●Dilution of Hb S-containing red blood cells (RBCs) via the addition of Hb A-containing cells from the blood of normal donors

●Suppression of erythropoietin release caused by the rise in Hgb, thereby reducing the production of new Hb S-containing cells

●Decrease in percentage of Hb S-containing cells due to the longer circulating lifespan of Hb A-containing cells

●Increase in Hgb oxygen saturation levels by approximately 1 to 6 percent, which increases oxygen delivery to the tissues [3,4]

These mechanisms, together with findings from trials in various clinical settings, inform our recommendations regarding when to transfuse individuals with SCD. (See 'Indications for transfusion' below.)

Reducing Hb S percentage — Prophylactic RBC transfusions, typically with a goal of reducing the maximum Hb S level to below 30 percent in individuals with homozygous sickle mutation (Hb SS), have been shown to reduce the incidence of vaso-occlusive pain and acute chest syndrome (ACS) events. In contrast, simple blood transfusion given at the time of an uncomplicated vaso-occlusive pain episode (eg, to raise the Hgb level to 10 g/dL) has not been demonstrated to hasten recovery, despite the chronic baseline anemia seen in SCD.

Increasing oxygenation — In the preoperative setting, simple blood transfusion with a goal Hb of approximately 10 g/dL is associated with a decreased incidence of postoperative vaso-occlusive events. In either a simple or exchange transfusion, the Hb S level is not required to be assessed, only because the goal is to successfully raise the hemoglobin to approximately 10 g/dL, or if already above 10 g/dL, to provide some normal hemoglobin. Simple blood transfusion to increase the hemoglobin level has not been demonstrated to hasten recovery in the setting of uncomplicated vaso-occlusive events.

INDICATIONS FOR TRANSFUSION

Overview of indications — We use red cell transfusion in clinical scenarios where there is strong or compelling evidence of the benefit of reduced morbidity (eg, stroke prevention, reduction of acute chest syndrome [ACS]).

The largest 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. 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 [5,6].

For more complex cases, in which pain occurs in the setting of severe or symptomatic anemia, transfusion may be appropriate. In such cases, blood transfusion should not be used as a substitute for acute and chronic pain management, and pain management should not be delayed while awaiting blood transfusion or an evaluation for the cause of anemia. (See "Overview of the management and prognosis of sickle cell disease", section on 'Pain management' and "Acute vaso-occlusive pain management in sickle cell disease" and "Pain in children: Approach to pain assessment and overview of management principles".)

Red blood cell (RBC) transfusion therapy for individuals with SCD can be categorized as therapeutic or prophylactic. Accepted indications for transfusion therapy in individuals with SCD include the following [7-10]:

●Acute therapeutic – Transfusions are used acutely for the treatment of hemodynamic compromise, ACS, acute cerebral infarct, transient ischemic attack, multiple organ failure, or acute single organ failure. Examples include:

•Acute stroke. (See "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease", section on 'TIA and ischemic stroke management'.)

•ACS. (See 'Acute chest syndrome treatment and prevention' below and "Acute chest syndrome (ACS) in sickle cell disease (adults and children)", section on 'Transfusion'.)

•Acute multi-organ failure. (See 'Multiorgan failure' below.)

•Acute symptomatic anemia (eg, onset of heart failure, dyspnea, hypotension, marked fatigue). (See 'Symptomatic or severe anemia' below.)

•A drop in baseline reticulocyte count (relative reticulocytopenia) with symptoms of acute hemodynamic compromise (increased pulse, decreased oxygen saturation, change in mental status, poor perfusion, orthostatic blood pressure changes). This indicates decreased red cell production, most commonly associated with parvovirus B19 infection, but it can occur with any infection. (See 'Symptomatic or severe anemia' below.)

•Hepatic or splenic sequestration, in which a large number of red cells become trapped in the spleen or liver resulting in a precipitous decline in hemoglobin level. (See 'Symptomatic or severe anemia' below.)

●Prophylaxis – Prophylactic transfusion is used to reduce perioperative complications in patients with SCD undergoing surgery and to reduce the incidence of a range of vaso-occlusive complications of SCD. (See 'Prophylactic preoperative transfusion' below and 'Prophylactic (regularly scheduled) transfusion' below.)

The potential benefit of transfusion therapy must be weighed against potential risks, including transfusion reactions, blood-borne viral infection, iron overload, and alloimmunization. (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Alloimmunization and hemolysis'.)

Symptomatic or severe anemia — SCD is characterized by chronic, compensated hemolytic anemia. Typically, symptoms of acute anemia develop when this compensation is impaired (eg, from bone marrow aplasia) or when the demand for RBCs increases (from splenic sequestration, bleeding, or accelerated hemolysis). (See "Overview of the clinical manifestations of sickle cell disease", section on 'Anemia'.)

As discussed separately, the possibility of a delayed hemolytic transfusion reaction (DHTR) should also be evaluated; in some individuals with SCD who have a DHTR, the direct antiglobulin (Coombs) test may be only weakly positive or negative. (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Alloimmunization and hemolysis'.)

Given that symptomatic anemia will always be superimposed on chronic anemia, the baseline hemoglobin (Hb) level and reticulocyte count are critical information in determining whether the symptoms are caused by a drop in the Hgb level and thus whether transfusion is needed. When evaluating reductions in Hb levels below an individual's baseline, it is also important to distinguish between normal, day-to-day variability of biologic anemia and a clinically significant change.

We typically suggest simple transfusion for children and adults if the Hgb level is at least 2 g/dL below the patient's baseline and there are new signs or symptoms of anemia, or if there is a progressive trend for a decreasing Hb over several days without a compensatory increase in reticulocyte count. Symptoms may include tachycardia, postural hypotension, dizziness, mental status change, dyspnea, or congestive heart failure [11].

Children with SCD who have severe anemia (hemoglobin <5.5 g/dL) are at significant risk for brain ischemia on magnetic resonance imaging (MRI) [12]. Although high-quality data are lacking for absolute thresholds, based on our clinical experience, we transfuse all children with Hgb <6 g/dL, unless there are major extenuating circumstances. (See 'Simple versus exchange transfusion' below.)

For adults, the threshold to transfuse is more complicated and should be based on the chronicity of the severe anemia, the underlying co-morbidities, and clinical symptoms. For adults with acute symptoms, we would typically transfuse if the hemoglobin is at least 2 g/dL below their baseline, with acute clinical symptoms, signs of hemodynamic compromise, or increased respiratory effort or oxygen requirement to keep the oxygen saturation above 92 percent.

Additional information regarding Hb thresholds used for simple transfusion in children and adults with severe anemia (without SCD) is presented separately. (See "Red blood cell transfusion in infants and children: Indications", section on 'General principles' and "Indications and hemoglobin thresholds for RBC transfusion in adults", section on 'Overview of our approach'.)

We transfuse one or two units of RBCs for adults and a volume based on weight for children. (See 'Blood transfusion volumes' below.)

Many individuals with SCD receiving blood transfusion therapy for acute management of their disease may also be receiving hydroxyurea. In this situation, no adjustment needs to be made other than to determine whether the requirement for blood transfusion therapy is secondary to reticulocytopenia associated with hydroxyurea therapy.

The following common causes of acute anemia in individuals with SCD can be distinguished based on clinical assessment at the bedside. Simple transfusion is likely to be appropriate therapy, and with the exception of delayed transfusion reactions or hyperhemolysis, transfusion should not be withheld while the cause of the anemia is being determined.

●Red cell aplasia – Parvovirus B19 infection is common in individuals with SCD and can lead to bone marrow aplasia characterized by worsening anemia without a compensatory increase in reticulocyte count. Parvovirus infection may be associated with a number of comorbidities, including and not limited to vaso-occlusive pain or ACS, splenic sequestration, asymptomatic thrombocytopenia, acute strokes, silent cerebral infarcts (silent strokes), and acute kidney disease [13-17]. Although the bone marrow aplasia is transient, the Hb can become dangerously low, and transfusion is required until the infection is cleared (typically a few days to weeks).

Individuals with decreases in both the Hb and reticulocyte count should be considered to have a parvovirus infection until proven otherwise. Once a diagnosis of parvovirus has been confirmed, repeat infection does not occur. (See "Clinical manifestations and diagnosis of parvovirus B19 infection" and "Treatment and prevention of parvovirus B19 infection".)

●Splenic or hepatic sequestration – An acute sequestration episode can occur when a large portion of the patient's blood volume pools in an organ such as the spleen, liver, or lung, acutely lowering the Hb level and potentially causing hypovolemic shock. The diagnosis and management of this complication is discussed separately. (See "Overview of the management and prognosis of sickle cell disease", section on 'Splenic and hepatic sequestration' and "Hepatic manifestations of sickle cell disease", section on 'Acute hepatic sequestration'.)

●Acute bleeding – Acute bleeding is often associated with surgery. An acute drop in Hb in an individual with SCD should prompt an evaluation for bleeding as it would in any individual without SCD. Postoperatively, acute bleeding with concomitant increases in respiratory rate and pulse must be differentiated from acute postoperative or SCD-related pain, as the former requires acute surgical management and the latter requires better pain management. In general, a rapid rise in the pulse is more likely to be associated with blood loss than SCD-related pain, and bleeding should be excluded in the setting of rapid increase in pulse, especially postoperatively.

If an individual with SCD is severely anemic and hypovolemic, RBC transfusion can be used if performed promptly (eg, within minutes); however, volume replacement should not be delayed while awaiting transfusion. (See "Overview of the management and prognosis of sickle cell disease", section on 'Hydration'.)

●Accelerated hemolysis – Accelerated hemolysis in individuals with SCD is often due to a delayed hemolytic transfusion reaction (DHTR), which should be suspected under the following conditions (see "Hemolytic transfusion reactions", section on 'Delayed hemolytic transfusion reactions and delayed serologic transfusion reactions'):

•Significant drop in Hb within 21 to 28 days of transfusion, without an alternative cause

•Accelerated increase in the Hb S percentage with a concomitant fall in the Hb A percentage post-transfusion

•Anemia accompanied by associated vaso-occlusive pain or ACS

•Anemia accompanied by increased bilirubin, lactate dehydrogenase (LDH), and hemoglobinuria (urine dipstick identifies the presence of heme, but microscopic evaluation does not show RBCs)

Management of individuals with suspected DHTR can involve observation if the anemia is not severe and the reticulocyte count is appropriately elevated. However, some individuals may require transfusion for severe or symptomatic anemia, especially if they develop hyperhemolysis. In some cases, concurrent treatment with glucocorticoids, intravenous immune globulin (IVIG), or a complement inhibitor may be indicated. (See "Overview of the clinical manifestations of sickle cell disease", section on 'Hyperhemolytic crisis'.)

If transfusion is needed, avoidance of the implicated RBC antigen that caused the transfusion reaction is critical. Communication between the transfusion services or blood banks responsible for the most recent transfusion, as well as previous facilities that have provided blood to the individual, is critical because not all individuals with DHTRs will have the offending alloantibody detected.

Multiorgan failure — Multiorgan failure is an incompletely understood complication typically seen in the setting of severe acute painful episodes of SCD.

Case reports and case series suggest improved outcomes with exchange transfusion in patients with multiorgan failure [18,19]. However, a randomized trial is not likely to be performed in multiorgan failure comparing simple blood transfusion therapy to RBC exchange, since this is a relatively rare complication, and RBC exchange remains a Category III indication according to the American Society for Apheresis (ASFA), since the data are limited and the role for apheresis not established [20]. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology", section on 'ASFA therapeutic categories'.)

Decision-making regarding transfusion for multiorgan failure should be individualized. The decision is time-sensitive because of rapid clinical deterioration and the complexity of the procedure, requiring coordination of multiple services. In the absence of a randomized trial, we recommend RBC exchange for a patient with multiorgan failure, due to the high mortality rate. A simple transfusion may be provided in the interim if mobilization of the apheresis service, need for a central line, or obtaining sufficient units of compatible RBCs would delay the RBC exchange. (See 'Exchange blood transfusion' below.)

For patients with multiorgan failure unresponsive to RBC exchange, two case series have reported therapeutic benefit from plasma exchange therapy [21,22]. The mechanism may involve circulating heme detoxification or removal of inflammatory cytokines.

Primary and secondary stroke prevention — Stroke is a leading cause of death in SCD, and stroke prevention is one of the major goals of comprehensive care for individuals with SCD. The approaches to primary stroke prevention (screening by transcranial Doppler and prophylactic, regularly scheduled transfusion for those with abnormal flow velocity [hydroxyurea in selected cases]) and secondary stroke prevention (chronic simple or exchange transfusion, with a goal of reducing the maximum fraction of Hb S to <30 percent of total Hb and maintaining the total Hb >9 g/dL) are discussed in detail separately. (See "Prevention of stroke (initial or recurrent) in sickle cell disease".)

Acute chest syndrome treatment and prevention

●Treatment of ACS – Transfusion is an important component of the acute management of ACS, which is one of the most common causes of mortality in adults with SCD. The severity and rate of clinical decline in pulmonary function, and the corresponding increased need for respiratory support, determines the need for simple versus exchange transfusion. In general, exchange transfusion rather than simple transfusion is required for those with more severe decline in respiratory function (eg, rapid increase in oxygen requirement or work of breathing over the course of hours [not days], along with abnormalities on chest radiography and declining oxygen saturation).

In the event that the facility does not have the capacity for exchange transfusion (red blood cell automated or manual exchange), consideration should be made for transferring the patient to a facility that does have this capacity, because decisions to perform exchange transfusion are often time-sensitive and may result in a dramatic improvement in the patient's clinical course. In cases where red cell exchange is delayed, a simple transfusion should be provided if the patient's Hb is below 9 g/dL while waiting to initiate the exchange.

Details of the indications and parameters used for transfusion in treating ACS are discussed separately. (See "Acute chest syndrome (ACS) in sickle cell disease (adults and children)", section on 'Transfusion'.)

●Prevention of ACS – Transfusion can also be used as an adjunct to other measures to prevent ACS, including control of asthma, which is the greatest risk factor for ACS. We typically initiate transfusions in patients who continue to have episodes of life-threatening ACS despite hydroxyurea therapy.

•For children with ACS, we may use prophylactic, regularly scheduled transfusion, especially if there are repeated episodes of severe ACS despite hydroxyurea therapy and optimal management of asthma. Short-term therapy (eg, less than six months) is often used during high-risk periods, such as winter months, with increased frequency of respiratory illness, or during transition to hydroxyurea therapy. Long-term therapy (greater than six months) is used for children with year-round severe ACS episodes. (See "Acute chest syndrome (ACS) in sickle cell disease (adults and children)", section on 'Prevention'.)

•For adults, we generally reserve prophylactic, regularly scheduled transfusions for individuals with two or more episodes of moderate to very severe ACS in the past 24 months despite maximal hydroxyurea therapy. Simple or exchange transfusion, either manually or by automated apheresis, is provided every three to six weeks to maintain a maximum Hb S percentage <30 percent. Chronic transfusion therapy is continued for one to two years. Thereafter, the decision to continue transfusion therapy is based on a re-examination of the risk-to-benefit ratio accounting for factors such as iron overload, alloimmunization, and recent clinical course. (See "Acute chest syndrome (ACS) in sickle cell disease (adults and children)", section on 'Prevention'.)

Despite the absence of randomized trials documenting the benefit of regularly scheduled blood transfusion therapy to prevent ACS, our approach is supported by the secondary analysis from the 130 children in the Stroke Prevention Trial (STOP), which randomly assigned children with SCD to chronic transfusion or observation for primary stroke prevention [23]. The children assigned to regular blood transfusion had reduced rates of hospitalization for ACS compared with those assigned to observation (4.8 versus 15.3 per 100 patient years). If analyzed according to the treatment received, the hospitalization rates for ACS were 2.2 versus 15.7 per 100 patient years.

Similarly, in the Silent Cerebral Infarct Transfusion (SIT) trial, which randomly assigned children 5 to 15 years old with sickle hemoglobin mutation (Hb SS) and silent cerebral infarcts to receive regular blood transfusion therapy (goal Hb S <30 percent) versus observation for 36 months for stroke prevention, the annual incidence of ACS was reduced dramatically (1.3 percent for regular transfusions versus 14.4 percent for observation) [24].

Our approach of preferring hydroxyurea therapy for first-line therapy for reducing the incidence of ACS is also supported by the secondary analysis of the Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) trial, which randomly assigned 133 children with SCD to continuation of regularly scheduled transfusions plus iron chelation versus switching to hydroxyurea and regular phlebotomy for stroke prevention and control of iron overload [25]. Secondary analysis of this study showed a trend towards reduced rates of ACS in those receiving transfusion compared with hydroxyurea that did not reach statistical significance (6 versus 10 percent).

Prophylactic preoperative transfusion — Individuals with SCD have a high frequency of serious perioperative complications, some of which may be ameliorated by preoperative RBC transfusion. Preoperative transfusion therapy does not replace the requirement for preoperative preparation and postoperative monitoring. In addition to the type of surgical procedure, the patient's medical history, age, and American Society of Anesthesiologists (ASA) score should be taken into account in determining the patient's risk for surgery.

Indications for preoperative transfusion — For most patients with SCD undergoing surgery, we recommend preoperative transfusion.

●Preoperative transfusion is standard of care in children and adults with sickle cell anemia (Hb SS) undergoing surgery that requires anesthesia for more than 30 to 60 minutes. Preoperative transfusion therapy is generally indicated in all procedures, with the exception of minor procedures such as imaging, skin biopsies, or myringotomies. The procedures for which preoperative transfusion is appropriate include those considered low risk (eg, inguinal hernia repair), moderate risk (eg, abdominal and thoracic surgery [cholecystectomy]), and high risk (eg, intracranial or cardiac surgery). Our approach to eye surgery depends on the procedure. Repair of strabismus is low-risk surgery, in contrast to retinal or vitreous procedures, which are of moderate risk.

Several procedures have not been adequately studied for the risk-benefit of no transfusions, conservative transfusions, or aggressive transfusions. Overall, unless contraindicated, transfusion therapy is the standard of care in patients undergoing non-minor procedures.

●Preoperative transfusion may not be necessary in children and adults undergoing elective, minor, low-risk surgery such as myringotomy, anesthesia associated with imaging, and skin biopsies.

●Preoperative transfusion in individuals with Hb SC disease depends on disease severity and the clinical setting. (See 'Hemoglobin SC disease or other compound heterozygous SCD conditions' below.)

Importantly, the patient's clinical history and perioperative management are major determinants of anesthesia risk. Regardless of transfusion use or type of surgical procedure, attention to the following is necessary to minimize surgical risk:

●Preoperative hydration

●Incentive spirometry

●Optimal management of reactive airway or other underlying chronic lung disease

●Maintenance of oxygenation during postoperative sedation

Support for the use of perioperative transfusion in most patients with SCD comes from the Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) trial, which randomly assigned 70 children and adults with SCD to no preoperative transfusion or preoperative transfusion with a target Hb level of 10 g/dL [26]. Patients were excluded if they had a Hgb concentration <6.5 g/dL, transfusion during the preceding three months, ACS within the previous six months, oxygen saturation <90 percent, current renal dialysis, or a history of stroke in children. The median Hb at entry was 7.7 to 8.0 g/dL, and most patients underwent intermediate-risk surgery. The study was terminated early due to an increased incidence of serious adverse events in the no-transfusion arm. Compared with no transfusion, those who received preoperative transfusion had the following outcomes:

●Fewer serious adverse events (3 versus 30 percent; several caused prolonged hospital stays or led to readmission)

●Fewer episodes of ACS (3 versus 27 percent)

●More transfusions received (2.1 versus 1.2 units)

●A similar length of hospital stay

●A lower overall cost of resources

●Alloimmunization in one patient (versus none in the no-transfusion group)

This study excluded patients undergoing high-risk surgery such as cardiovascular or brain surgery. However, patients undergoing high-risk surgery may receive an additional benefit from prophylactic transfusion and/or a Hb S concentration of <30 percent. Trials in this setting are needed.

Optimal regimen for preoperative transfusion — For children and adults with Hb SS or Hb S-beta⁰ thalassemia who are scheduled to undergo surgery, we suggest a simple transfusion regimen to increase the Hb to 10 g/dL, rather than an aggressive exchange transfusion regimen to reduce the Hb S concentration to <30 percent in the perioperative period. Compared with an aggressive regimen, a conservative approach provides equivalent outcomes, similar rates of major complications, and fewer transfusion-related complications. These findings have been demonstrated in several multicenter cooperative studies performed by the National Preoperative Transfusion in Sickle Cell Disease Study Group [26-30].

In one such study, individuals undergoing 604 operations were randomly assigned to receive either an aggressive exchange transfusion regimen designed to reduce the Hb S to <30 percent, or a conservative transfusion regimen designed only to increase the Hb concentration to 10 g/dL [27]. The incidence of serious complications (31 and 35 percent) and ACS (10 percent) were not different in the two groups, although the aggressive transfusion group had a higher rate of transfusion-related complications (14 versus 7 percent).

Other studies have confirmed the equivalent outcomes in the two groups, although the serious complication rate varied with the type of surgery:

●Orthopedic surgery – 67 percent serious surgical complications and 17 percent sickle-related complications (ACS and vaso-occlusive events) [28].

●Cholecystectomy – 39 percent serious complications, 19 percent sickle-related complications, and 10 percent transfusion-related complications [30]. Patients who were not transfused in this study appeared to have a higher incidence of sickle-related complications (32 percent).

●Ear, nose, and throat surgery – 32 percent serious complications with tonsillectomy and adenoidectomy and 36 percent for myringotomy [29].

If the starting Hb is >10 g/dL, exchange transfusion with RBC apheresis is used. If apheresis is not available, 10 mL/kg of blood can be phlebotomized and an equivalent mass of allogeneic RBCs administered (typically, approximately 5 mL/kg of packed RBCs). This is done once in preparation for surgery.

Hemoglobin SC disease or other compound heterozygous SCD conditions — Similar preoperative transfusion principles as those discussed above apply to many individuals with combined heterozygosity for Hb S and Hb C (Hb SC disease) or other compound heterozygous SCD conditions. (See "Overview of compound sickle cell syndromes", section on 'Specific compound sickle cell syndromes'.)

In keeping with the perceived less-severe nature of Hb SC disease, affected individuals have lower rates of overall complications (18 percent) and sickle-related complications (9 percent) than those with sickle cell anemia (Hb SS) [31]. (See "Overview of compound sickle cell syndromes", section on 'Hb SC disease'.)

In uncontrolled observations, sickle-related complications occurred only in individuals who were not transfused (35 percent) [31]. However, the value of preoperative transfusion in individuals with hemoglobin levels >10 g/dL has not been demonstrated in a controlled trial.

●We perform exchange transfusion in individuals with Hb SC disease or other compound heterozygous SCD conditions who have had severe acute complications in the past, have concurrent co-morbid diseases such as asthma, stroke, or have acute medical complications requiring non-elective surgery.

●Patients who are relatively asymptomatic and undergoing elective surgery do not necessarily require preoperative transfusion therapy.

In all instances, the decision to transfuse a patient with SCD and hemoglobin >10 g/dL before or immediately after surgery must carefully weigh the risks and benefits. The shared decision to transfuse or not to transfuse should be discussed with the family/caregivers, hematologist, surgical team, and anesthesiologists to ensure optimal preoperative and postoperative care.

Since Hb levels in some individuals with compound heterozygous SCD may be >10 g/dL, automated red cell exchange or partial manual exchange transfusion is preferable to simple transfusion in the preoperative setting. When performing exchange transfusion in individuals with Hb SC disease or other compound heterozygous SCD conditions, we aim for a Hb A of >50 percent [31]. (See 'Exchange blood transfusion' below.)

Regardless of the decision to transfuse before surgery or immediately after surgery, all individuals with SCD who have elective or urgent/emergency surgery are at increased risk of postoperative complications, including acute chest syndrome and surgical complications that require close postoperative management with frequent assessment for respiratory status, fluid balance, and pain management.

For surgical procedures greater than low risk, we typically monitor these individuals overnight in the facility, with close outpatient follow-up that includes a clinical a visit within a week of discharge if any new health concerns occur.

PROPHYLACTIC (REGULARLY SCHEDULED) TRANSFUSION — Regularly scheduled blood transfusion therapy (also called chronic, prophylactic, or preventive transfusion) involves periodic transfusion of the patient at regularly scheduled intervals, with the frequency guided by the patient's symptoms, hemoglobin (Hb), and percent sickle Hb (Hb S).

Indications — Regular transfusions are effective in reducing morbidity of most complications of SCD. As discussed in separate topic reviews, regular transfusions are used in the secondary prevention of stroke, acute chest syndrome (ACS), painful events, priapism, and pulmonary hypertension [7,8,32-34].

●Stroke – (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Prevention of a first ischemic stroke (primary stroke prophylaxis)' and "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Prevention of recurrent ischemic stroke (secondary stroke prophylaxis)'.)

●Silent cerebral infarcts in children with sickle cell anemia (Hb SS) or Hb S-beta⁰ thalassemia – (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Prevention of a first ischemic stroke (primary stroke prophylaxis)' and "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Prevention of recurrent ischemic stroke (secondary stroke prophylaxis)'.)

●Recurrent ACS despite hydroxyurea therapy in severely affected individuals – (See "Acute chest syndrome (ACS) in sickle cell disease (adults and children)", section on 'Prevention'.)

●Vaso-occlusive pain episodes that are severe, frequent, and not responsive to maximum tolerated doses of hydroxyurea – (See "Acute vaso-occlusive pain management in sickle cell disease" and "Hydroxyurea use in sickle cell disease".)

●Recurrent priapism – (See "Priapism and erectile dysfunction in sickle cell disease", section on 'Regular red blood cell transfusions'.)

●Pulmonary hypertension (PH) with progressive clinical symptoms or increasing pulmonary artery pressure documented by right heart catheterization, in adults with right heart catheterization-confirmed PH who are not benefitting from (or not candidates for) hydroxyurea therapy – (See "Pulmonary hypertension associated with sickle cell disease", section on 'SCD-specific treatments'.)

●Pregnancy (transfusion when clinically indicated for a complication or Hb lower than baseline, or transfusion at regular intervals for patients who have a history of severe SCD-related complications prior to or during current pregnancy) – (See "Sickle cell disease: Obstetric considerations", section on 'Transfusion therapy'.)

The use of regular transfusions to mitigate other morbidities of SCD is evolving. As an example, in the silent infarct transfusion (SIT) trial, which randomly assigned children with SCD and silent cerebral infarcts to monthly transfusions versus observation for approximately three years, there was a significant improvement in quality of life in the cohort that received regular transfusions [35]. In the same trial, regular blood transfusion therapy also significantly decreased the incidence rates of pain, ACS, symptomatic avascular necrosis, and priapism.

The decision to use transfusion therapy initially or after a trial of hydroxyurea therapy depends on specific patient circumstances and risks and benefits of each therapy for the individual patient. Transfusion therapy has many more adverse consequences than hydroxyurea. However, transfusion may be appropriate in some patients based on other important factors such as severity of disease complications, urgency of beneficial effects of the intervention, and individual patient comorbid problems.

The benefits of transfusion therapy occur rapidly, especially in patients receiving red blood cell (RBC) exchange. In contrast, hydroxyurea requires dose titration and may take months to reach a response. Therefore, the decision to switch from hydroxyurea to transfusion therapy requires an adequate period of drug trial during which there has been lack of improvement or progression of the primary complication being monitored.

The TWiTCH trial (TCD With Transfusions Changing to Hydroxyurea) provides the most reliable approach to switch children who were receiving regular blood transfusion therapy to maximum tolerated dose (MTD) of hydroxyurea [36]. In general, the transition period requires approximately six months with close clinical monitoring. (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Chronic transfusion followed by transition to hydroxyurea'.)

The protocol involves initiation of hydroxyurea at a dose of 20 mg/kg daily with gradual escalation to MTD. Transfusions are slowly decreased in amount while the hydroxyurea dose is increased. When the MTD is reached, the transfusions are stopped. Additional details of the transition are available in the trial description and are discussed separately [36]. (See "Hydroxyurea use in sickle cell disease", section on 'Administration and dosing'.)

Technical aspects — When performing regularly scheduled transfusions to reduce complications of SCD, our preference is to use exchange transfusion therapy (either automated apheresis or manual exchange) rather than simple blood transfusion for the majority of patients, to limit iron accumulation from transfusions. This is consistent with the 2020 American Society of Hematology (ASH) guideline [9].

Chronic exchange transfusion is a complex therapy that requires significant advance planning and coordination among hospital services, as well as education of patients, families, and caregivers about the rationale and important components of the process [37].

Patient size is a limitation for young children, and if a central indwelling catheter is required for exchange transfusion, the risks and benefits must be weighed. (See 'Simple versus exchange transfusion' below.)

For most patients, the goal of regularly scheduled transfusions is to maintain the percent Hb S at <30 percent of total Hgb, and the total Hb >9 g/dL. We typically monitor the total Hb, percent Hb S, and reticulocyte count with every blood transfusion to define trends and determine when the next transfusion should occur.

Serum ferritin levels are obtained every one to three months to monitor changes and provide direct feedback to the family/caregivers about iron store trends.

Decisions regarding discontinuation of a regular transfusion program depend on the reason for the therapy:

●We continue regularly scheduled transfusion indefinitely when it is used for primary or secondary stroke prevention. As one exception for primary stroke prevention, for individuals without severe or progressive vasculopathy, we discuss with families, caregivers, and affected individuals the pros and cons of transition to MTD hydroxyurea after a period of chronic transfusion, based on findings from the TWiTCH (TCD With Transfusions Changing to Hydroxyurea) trial [36]. (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Chronic transfusion followed by transition to hydroxyurea'.)

●For individuals who have been placed on regular transfusions to abate a high frequency of vaso-occlusive pain or ACS events, we may consider therapy for 6 to 24 months depending on the actual benefit to the patient.

Regardless of the indication for regularly scheduled transfusion therapy, the associated management issues (RBC antigen matching, leukoreduction, monitoring of iron burden) should be incorporated into a patient care plan to ensure that designated providers review the results and make decisions on an ongoing basis. Likewise, other components of a comprehensive care plan (eg, assessing symptoms of stroke or pain) can be incorporated into the patient encounters during visits for regularly scheduled transfusions. (See "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance", section on 'Care plans' and "Overview of the management and prognosis of sickle cell disease".)

TRANSFUSION TECHNIQUES

Overview of transfusion techniques — Most individuals with SCD will receive multiple transfusions over their lifetimes and are thus at risk for transfusion complications. In addition to avoiding unnecessary transfusions, we employ evidence-based strategies to minimize transfusion complications, including:

●Matching for minor red blood cell (RBC) antigens (C, E, and K) to reduce the risk of alloimmunization. (See 'RBC antigen matching' below and "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Alloimmunization and hemolysis'.)

●Using pre-storage leukoreduction and, if pre-storage leukoreduction is not done, a bedside white blood cell (WBC) filter to decrease the rate of febrile non-hemolytic transfusion reactions (FNHTRs). (See 'Leukoreduction' below and "Immunologic transfusion reactions", section on 'Febrile nonhemolytic transfusion reactions'.)

●Chelation therapy if iron stores reach a high enough threshold. (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Excessive iron stores'.)

Individuals with SCD should not receive donor blood from individuals with sickle cell trait as a component of a regular transfusion therapy program. The receipt of blood from individuals with sickle cell trait is of no consequence for those without SCD, but for those with SCD, receipt of sickle cell trait blood is problematic because sickle hemoglobin (Hb S) in blood from individuals with sickle cell trait will make it difficult for the clinician to predict the anticipated Hb S percentage after the transfusion. While we routinely screen for and use sickle cell trait-negative blood for individuals receiving regular blood transfusion therapy, obtaining sickle cell trait-negative blood should not delay transfusion in the setting of acute anemia.

RBC antigen matching

Rationale and approach — Alloimmunization due to RBC antigen mismatch is of greater concern in individuals with SCD than in the general population because individuals with SCD may require ongoing transfusions throughout their lifetimes and are at higher risk of alloantibody formation than other transfused populations. Alloimmunization occurs rapidly after the initiation of transfusions without Rh and K matching (see "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Alloimmunization and hemolysis'). Therefore, Rh (C, E, or C/e, E/e) and K matching should be provided to all patients with SCD who require a transfusion [8,9,38,39].

Individuals with SCD in the United States are more likely to have Hispanic ethnicity or African ancestry, and the vast majority of donors have White European ancestry and may have different RBC antigens patterns. The RBC antigen mismatch between donor and recipients increases the likelihood of alloimmunization because the frequency of RBC antigens is heavily influenced by race.

Occasionally, for individuals with SCD, transfusion services also match RBC units for additional antigens, such as Duffy (Fy^a/Fy^b), Kidd (Jk^a/Jk^b), and S. In practice, matching for Rh (C, E, or C/e, E/e) and K increases the likelihood that the unit will also be compatible for Duffy and Kidd because these antigens are highly related to the patient's race. (See "Red blood cell antigens and antibodies" and "Pretransfusion testing for red blood cell transfusion".)

Our approach is as follows, consistent with guidelines such as those from the American Society of Hematology (ASH) [9]:

●We recommend obtaining an extended RBC antigen profile by genotype or serology for all individuals with SCD at the earliest opportunity, such as their first outpatient hematology visit. The extended RBC antigen profile should include C/c, E/e, K, Fy^a/Fy^b, Jk^a/Jk^b, M/N, and S/s at a minimum [9]. We prefer genetic antigen typing if possible, recognizing that this method will not be available at all centers. (See 'Genetic RBC antigen typing' below.)

●Prophylactic RBC antigen matching for Rh (C, E, or C/c, E/e) and K should be provided to all individuals with SCD requiring transfusion to minimize alloimmunization (ie, immunization of the patient by donor RBC antigens), which can occur after a single transfusion.

●While extended antigen matching beyond Rh (C, E, or C/c, E/e) and K, to include Fy^a/Fy^b, Jk^a/Jk^b, and S/s, can further reduce alloantibody formation, identifying sufficient numbers of matched units would be challenging [40]. We typically reserve extended matching for patients with a history of multiple alloantibodies or delayed hemolytic transfusion reactions, and/or those with hyperhemolysis requiring further transfusion.

This practice is also consistent with that of most hematologists who provide lifelong care to individuals with SCD [41-48].

Some programs use directed donors to decrease donor exposures. Donors with similar ancestry or ethnic background as the recipient with SCD has not been shown to offer any advantage for reducing alloimmunization beyond matching for Rh and K antigens alone, with an alloimmunization rate of 0.3 percent in chronically transfused patients [49]. However, blood donor recruitment programs from diverse populations have improved access to matched units. We encourage efforts to educate African American communities about the importance of blood donation to diversify the blood donor pool [50-52].

Alloimmunization in individuals with SCD can be associated with delayed hemolytic transfusion reactions, accompanying vaso-occlusive episodes, and life-threatening anemia. Equally important, alloimmunization can result in a greater risk of future transfusion reactions and greater difficulty identifying compatible units of blood, thus delaying the only therapy for many life-threatening conditions in SCD. (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Alloimmunization and hemolysis'.)

Supporting evidence for RBC antigen matching — Examples of the success of prophylactic RBC antigen matching in reducing transfusion-associated hemolysis due to alloimmunization include the following:

●In one study, 61 children who received a total of 1830 units of leukoreduced red cells (average 35 units per patient) that were matched for C, E, and K antigens demonstrated a marked decrease in alloimmunization and transfusion reactions [53]. The alloimmunization rate was 0.5 percent compared with 3 percent in historical controls, and hemolytic transfusion reactions were 0.1 percent compared with 1 percent in historical controls.

●A retrospective study evaluated the risk of alloimmunization for 99 patients with SCD who were transfused with 6946 RBC units matched for 20 blood group antigens [40]. Seven alloantibodies were detected in seven patients, and the alloimmunization rate was 0.1 percent.

●A systematic review determined the incidence rate of alloimmunization by pooling data from studies that reported the incidence of alloimmunization for different extents of matching [9]:

•ABO and RhD only (six studies) – 1.94 alloantibodies per 100 units transfused

•Prophylactic matching for Rh (C, E or C/c, E/e) and K (nine studies) – 0.40 alloantibodies per 100 units

•Prophylactic extended matching for Rh, K, Jk, Fy, and Ss (five studies) – 0.25 alloantibodies per 100 units

Genetic RBC antigen typing — Most blood group antigens other than ABO and RhD result from single nucleotide changes, making design and interpretation of genotyping approaches relatively straightforward.

Commercial DNA arrays that predict phenotype for 35 to 37 antigens have been licensed by the US Food and Drug Administration; these can identify patient-donor antigen incompatibilities and ultimately improve RBC matching [54-56]. The development of automated high-throughput genotyping and the growing evidence that alloimmunization increases morbidity and mortality has led several large programs with chronically transfused patients to use RBC antigen genotyping in individuals with SCD [57,58].

Recognizing the resources needed to obtain insurance pre-authorization, we prefer to obtain the RBC genotype rather than serology, since expanded antigen information is provided for the same cost of serologic phenotyping and with greater accuracy [59].

However, while genetic RBC matching would likely be advantageous if applied broadly, its routine use in clinical practice is hampered by the regulated environment of transfusion medicine practice and the lack of a coordinated information system infrastructure to share patient and donor RBC genotypes among different hospital systems and blood centers [60].

Advantages of DNA typing include:

●Greater accuracy than serologic typing.

●Avoidance of the multiple discrepancies that can occur with serologic typing and matching, including the Rh, Fy, Jk, and MNS systems [61].

●Ability to test for antigens for which there are no serologic reagents.

●Ability to identify variant antigens, particularly in the Rh system.

●Avoidance of interference from transfused RBCs or bound IgG (ie, patient with a warm autoantibody).

●Ability to address significant polymorphism of the RH alleles in both patients and donors that can lead to Rh alloimmunization [49,62]. Knowledge of a patient's RH genotype can facilitate complex Rh antibody identification, help distinguish alloantibodies from autoantibodies, and further inform RBC matching for transfusion [63]. Testing for RH variants requires comprehensive RH genotyping assays that are offered by reference immunogenetics laboratories.

We suggest comprehensive RH genotyping for any patient who forms an Rh antibody after receiving serologic Rh (C, E, or C/c, E/e) matched transfusion to determine if the patient has RH variants. At one author's institution, we perform comprehensive RH genotyping when we obtain the extended RBC antigen profile by genotype for all individuals with SCD. We provide prophylactic RhD or C negative RBCs to patients whose RH genotype predicts expression of partial RhD or C antigen without the corresponding conventional antigen, since these individuals are at higher risk of anti-D or anti-C alloimmunization [64,65].

Leukoreduction — All blood administered to patients with SCD should be leukoreduced to decrease the incidence of febrile non-hemolytic transfusion reactions (FNHTRs) because fever may necessitate admission to the hospital due to the increased risk of serious infections in individuals with SCD. (See "Immunologic transfusion reactions", section on 'Febrile nonhemolytic transfusion reactions'.)

Leukoreduction removes most of the white blood cells (WBC) present in the unit of RBCs, by passing the blood through a filter. It is typically performed at the donor center at the time of blood collection (pre-storage leukoreduction), but leukoreduction can also be done at the bedside. (See "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion", section on 'Pre-storage leukoreduction'.)

Some institutions routinely leukoreduce all RBC units, while others do so only for certain indications. Clinicians caring for patients with SCD should know the practices of their institution so that they can request leukoreduction if it is not done routinely, and patients should be educated regarding this issue in case they are hospitalized elsewhere.

Storage time and irradiation — Information on the effects of RBC storage injuries in SCD is limited. Increased alloimmunization rates, shortened RBC survival, and other complications have been suggested; however, a retrospective study of 131 children with SCD and acute chest syndrome (ACS) did not find any association between RBC storage duration and patient outcomes [66-68].

Despite the lack of high-quality data, a survey of transfusion services indicated that several programs have policies for limiting the storage duration of RBCs given to individuals with SCD, using units less than 15 days old [69]. We use units less than 21 days old for all patients requiring chronic transfusion therapy [70]. Additional discussions and evidence of the effect of storage time on clinical outcomes in the general population is presented separately. (See "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion", section on 'RBC age/storage duration effect on clinical outcomes'.)

Some centers do not use irradiated RBCs in individuals with SCD because irradiation shortens cell survival and increases cost [71,72]. However, some centers, particularly pediatric institutions, irradiate almost all blood products as a universal precaution to prevent transfusion-associated graft-versus-host-disease (ta-GVHD) in susceptible patients receiving transfusion. This subject is discussed in more detail separately. (See "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion", section on 'Irradiation'.)

In contrast to routine transfusion settings, irradiation of blood products is required for all patients undergoing hematopoietic cell transplantation (HCT). (See "Hematopoietic stem cell transplantation in sickle cell disease".)

VENOUS ACCESS DEVICES

Decision to place a central venous catheter — A peripheral venous catheter is always preferable for transfusion if feasible. However, lack of venous access becomes a serious problem in many chronically transfused patients, and venous access devices (eg, central venous catheters [CVCs]) are frequently required for individuals with SCD who receive chronic transfusions [37].

The CVC-associated risks of infection and thrombosis are particularly concerning in individuals with SCD, who are already at increased risk for thrombosis and bacteremia due to their underlying disease [73-76].

●CVC-related thromboembolism occurs in up to 30 percent of individuals with SCD who have a CVC [74]; this may present as acute chest syndrome (ACS) or other sickle-related events (eg, vaso-occlusive pain episodes).

●CVC-related bacteremia is a major cause of bloodstream infections in individuals with SCD [73,77]. As examples, a retrospective analysis of 900 adults with SCD found that bacteremia associated with venous catheters accounted for 41 percent of bloodstream infections (compared with 10 percent for pneumococcal infections) [77]. In an analysis of 815 children with SCD, there appeared to be a shift over time in the cause of bacteremia, with line-associated infections increasing and pneumococcal and Haemophilus influenzae decreasing [73]. Over the 10-year period, central venous access bacteremia accounted for 23 percent of all cases of bacteremia. Additional details of CVC complications are presented separately. (See "Central venous catheters: Overview of complications and prevention in adults".)

In determining whether a CVC should be placed, we evaluate whether (and why) the patient and family/caregivers want a CVC, and whether the patient, family/caregivers, and closest emergency facility can adequately respond to signs and symptoms of CVC thrombosis and/or infection.

●Patients with a history of frequent thromboses and/or infections may have a stronger incentive to avoid CVC placement.

●Some patient and family/caregiver concerns may be addressed by other means besides insertion of a CVC. As an example, if a child is experiencing increasingly more difficult peripheral line placement attempts, this may be addressed through increased use of nurse specialists for expert placement of peripheral access in the apheresis transfusion unit. Training our apheresis nurses on ultrasound-guided peripheral line placement has minimized the number of new CVCs placed for patients on chronic red cell exchange and has even allowed CVC removal for some individuals.

●Fever (eg, temperature >38.3°C [>101°F]) requires immediate evaluation, and patients who do not have adequate access to an emergency facility may need to address this issue before a CVC is placed.

Type of central venous catheter — A peripheral intravenous line (large-bore) is always preferred for transfusion; however, in many cases intravenous access will not be adequate for individuals receiving chronic RBC transfusions or RBC exchange. For children and adults with SCD who require regular blood transfusion therapy, including red cell exchange, a subcutaneous CVC, also called a subcutaneous port, is strongly preferred when compared with an externalized CVC. In select situations, peripheral intravenous catheters can be used. (See 'Decision to place a central venous catheter' above.)

●Subcutaneous ports do not require preventive intervention by the family/caregiver. In addition, the catheter is not exposed outside the skin, which is important to many patients for cosmetic reasons or sports such as swimming. We recommend subcutaneous ports for patients requiring chronic transfusions.

●External catheters require much more maintenance by the patient and/or family/caregivers (line flushing using sterile technique; site care). We typically do not recommend these for long-term use in patients requiring chronic transfusions.

●The number of lumens and the type of port depends on whether simple transfusions or exchange transfusions with apheresis will be used.

•Simple transfusion and blood draws only require a single-lumen catheter.

•Automated apheresis for red cell exchange transfusion may require an apheresis catheter that can support higher flow rates. The preference is to use peripheral intravenous access whenever possible, which may be facilitated by ultrasound-guided insertion by an apheresis nurse. For those who require a catheter, options include a double-lumen apheresis port, two single-lumen ports, or a single-lumen port for withdrawal and a peripheral intravenous line for the infusion. The stiff ports accommodate high-flow states required for apheresis and can also be accessed for intravenous fluids and pain medications.

Multiple studies have demonstrated the clinical utility of peripheral intravenous access for red cell exchange transfusion programs [78-81]

•In general, complications appear lower with continuous flow apheresis equipment, but intermittent flow devices can be used for apheresis in selected cases and when a continuous flow device is unavailable. Intermittent flow devices have more restrictions and complications than continuous flow devices, and they require that larger volumes of blood be removed compared with continuous apheresis devices. This often results in patients requiring a transfusion or fluid load prior to apheresis initiation.

Discussion of the appropriate line placement and the size of the catheter should occur with the surgeon or invasive radiologist and the apheresis team prior to placement. (See "Central venous access in adults: General principles" and "Routine care and maintenance of intravenous devices" and "Central venous catheters: Overview of complications and prevention in adults".)

SIMPLE VERSUS EXCHANGE TRANSFUSION

Uses of simple blood transfusion — Simple blood transfusion involves transfusion of one or more units of blood without removal of the patient's blood. Simple blood transfusions may provide sufficient increase in hemoglobin (Hb) to increase the oxygen carrying capacity in the setting of severe anemia. In individuals with severe anemia (Hb <5 g/dL), simple transfusion may also be effective in lowering the sickle Hb (Hb S) level without increasing the red cell viscosity.

We use simple blood transfusion therapy for the following situations in individuals with SCD [9]:

●An uncomplicated drop in Hb levels resulting in signs or symptoms of decreased oxygen delivery (tachycardia, hypotension, mild respiratory distress), where the immediate need is to restore oxygen carrying capacity rather than to decrease sickling. (See 'Symptomatic or severe anemia' above.)

●If the Hb is <5 g/dL and the patient is critically ill, simple transfusion can be used with a goal to increase the Hb to 10 to 11 g/dL. Since the percentage of blood volume replaced by simple transfusion in this scenario will be high, exchange transfusion generally will not be needed in such patients. (See "Indications and hemoglobin thresholds for RBC transfusion in adults".)

●Preoperative transfusion to reduce complications of surgery, if the Hb is <9 to 10 g/dL, based on clinical trial data in which simple transfusion was found to be effective. (See 'Prophylactic preoperative transfusion' above.)

Simple transfusions may not be optimal for a patient with SCD complications whose Hb is near baseline (typically 7 to 9 g/dL), because simple transfusions do not rapidly reduce the percentage of Hb S containing cells. In addition, simple transfusions may increase the blood viscosity, while exchange transfusions do not. (See 'Risk of hyperviscosity syndrome from simple transfusion' below.)

Risk of hyperviscosity syndrome from simple transfusion — Blood viscosity is determined by an interrelationship between total Hb, percent 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). (See "Neonatal polycythemia", section on 'Hyperviscosity'.)

Simple blood transfusions can cause hyperviscosity syndrome in children or adults with SCD because they raise the Hgb but only marginally lower the percentage of Hb S. Baseline Hb S levels in individuals with SCD are 80 to 90 percent of total Hgb, and typically after simple transfusion, the percentage of Hb S remains >70 percent. In contrast, an exchange transfusion can lower the Hb S to <30 percent. The higher Hb S percentages that remain following simple transfusion contribute significantly to higher blood viscosity [82].

Symptoms of hyperviscosity are non-specific and related to the affected vascular bed. Central nervous system hyperviscosity can cause signs of acute neurologic injury and can be associated with central venous thrombosis or cerebral infarcts. (See "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease".)

There is no general consensus regarding how to manage individuals with SCD at risk for hyperviscosity (such as those with Hb >10 g/dL and Hb S >50 percent). With increased use of disease-modifying therapies such as hydroxyurea, which induces Hb F and increases total Hb levels, and voxelotor, which inhibits Hb S polymerization, individual assessment of risk is critical. Based on our experience, we use the following strategies to prevent hyperviscosity syndrome:

●We minimize the use of simple blood transfusion therapy in individuals who have a Hb >10 g/dL and a Hb S percentage >50 percent.

●If a patient's Hb has been inadvertently raised above 12 g/dL with simple transfusions and the Hb S is >50 percent, we use phlebotomy to decrease the Hb level closer to 10 g/dL.

●We use phlebotomy for all patients with a post-transfusion Hb ≥13.0 and Hb S >50 percent.

Exchange blood transfusion — Exchange transfusion involves removing some of the patient's own blood and transfusing allogeneic blood, thereby lowering the concentration of Hb S through dilution. A cardinal principle in transfusing individuals with SCD who are critically ill is that exchange transfusion provides greater benefit compared with simple transfusion because only exchange transfusion can significantly lower Hb S levels (to <30 percent). The lessened effects on viscosity for a given Hb level are critical in potentially reversing vaso-occlusion and improving blood flow. (See "Pathophysiology of sickle cell disease", section on 'Vaso-occlusion'.)

Exchange transfusion therapy can involve at least one blood volume exchange by manual or automated apheresis. Automated RBC exchange transfusion allows for rapid lowering of the Hb S level to 30 percent or less, and correction of anemia. Manual exchange transfusion typically results in a limited exchange transfusion that is less effective in lowering the Hb S but does not require an apheresis device. To lower the Hb S to <30 percent, repeat partial manual exchange transfusions may be necessary.

Enhanced availability of pre-transfusion Hb S percentage values before RBC exchange can facilitate calculation of precise donor unit numbers required to achieve the target post-exchange Hb S percentage in advance of each procedure.

Randomized trials analyzing the benefit of simple versus exchange transfusion for treating specific complications in SCD have not been performed. Clinical experience coupled with several limited observational studies suggests that exchange transfusion, either automated apheresis or manual, is superior to simple blood transfusion in suspected stroke [83], respiratory failure, and multi-organ failure [18]. Over time, for individuals who require chronic transfusions, exchange transfusion reduces the risk of iron overload significantly over simple transfusions, as illustrated in the figure (figure 1).

We employ exchange transfusions in the following situations:

●For acute emergencies, when the patient is acutely ill and deteriorating quickly (multi-organ failure, suspected stroke, respiratory compromise, acute chest syndrome [ACS]). Hypotension is not a contraindication to exchange transfusion.

●For regularly scheduled transfusions used in the prevention of stroke, ACS, and recurrent painful episodes.

For young children requiring chronic transfusion therapy, we prefer simple transfusion combined with iron chelation to avoid the need for central venous catheter (CVC) placement. Once they reach the age of 10 years or the weight of 30 kg, we discuss whether to place a CVC or use peripheral venous access for red cell exchange. (See 'Venous access devices' above.)

Modified exchange transfusion requires a dedicated team with experience and ability to perform ongoing surveillance for adverse events.

In general, automated apheresis is preferred over manual exchange because it can be done faster and causes fewer volume shifts [9,84]. It is typically programmed by the desired post-procedure hematocrit and Hb S level. (See 'Blood transfusion volumes' below.)

A study that compared automated versus manual methods in 39 children receiving chronic transfusion for stroke prevention (1353 total transfusion sessions) found both methods were effective and well tolerated, with a median reduction in the percentage of Hb S by approximately 20 percent with both methods [85]. Importantly, manual exchange should be performed by a dedicated team with experience in the procedure and using quality controls and adverse event monitoring.

In clinical situations where the exchange may be considered as part of standard care (ACS, multi-organ failure, or strokes) without availability of apheresis or local expertise to perform a manual exchange, the patient should be transferred to a facility to perform apheresis or manual exchange, as these decisions are often time sensitive. In cases where red cell exchange is delayed, a simple transfusion should be provided if the patient's Hb is <9 g/dL while waiting for red cell exchange. (See 'Uses of simple blood transfusion' above.)

With acute organ deterioration, such as respiratory failure, stroke, or multi-organ failure, we suggest lowering the Hb S to approximately 15 percent and raising the total Hb to the range of 10 to 12 g/dL. Although strong evidence-based data confirming that a Hb S of 15 percent is better than 30 percent are lacking, the rationale for this approach is twofold.

●In critically ill patients, this approach is thought to minimize sickling complications.

●Hb S is unlikely to increase above a threshold of 30 percent within four weeks.

Thus, this Hb S target decreases the likelihood of requiring another exchange blood transfusion for at least three weeks to keep the Hb S level <30 percent.

A major benefit of red cell exchange over simple transfusion is prevention or minimization of excess iron stores. Red cell exchange decreases the degree of excess iron accumulation when compared with simple blood transfusion therapy and may delay, or in few cases eliminate, the need for chelation therapy [86-88]. (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Excessive iron stores'.)

For most patients who maintain a hematocrit of at least 27 percent, we can achieve a net zero red cell balance with automated apheresis, reducing the accumulation of excess iron. Regular manual modified exchange transfusion therapy has been shown to decrease net iron balance compared with regular simple blood transfusion therapy but with less benefit in net iron balance than RBC apheresis [89]. (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Excessive iron stores'.)

In the preoperative setting, randomized trials have found simple transfusion to be equivalent to exchange transfusion in preventing perioperative complications. (See 'Prophylactic preoperative transfusion' above.)

Blood transfusion volumes — The volumes required for simple and exchange transfusions can be estimated based on patient weight and hematocrit; these are particularly important for transfusing children.

●Children – In children, the general rule is that a transfusion of 10 mL/kg will increase the Hb 2.5 to 3.0 g/dL and the hematocrit by 7 to 9 percentage points.

●Adults – The general rule for adults is that each unit of RBC infused will increase the Hb concentration by approximately 1 g/dL and the hematocrit by 3 percentage points [90,91].

The following formulas are used for estimation of simple transfusion and partial exchange transfusion volumes [92]:

In the formulas above, dHCT is the desired hematocrit; iHCT is the initial hematocrit (both given as percent [eg, 40 percent]); TBV is the estimated total blood volume in mL (ie, 60 mL/kg in adult females, 70 mL/kg in adult males, 80 mL/kg in children, 100 mL/kg in infants); and rpHCT is the hematocrit of the replacement packed RBC (typical range, 55 to 60 percent). The volume of each unit of packed red blood cells (pRBCs) varies depending on the anticoagulant used in the collection bag; most units are approximately 300 to 400 mL.

The following are example calculations:

●Children – For simple transfusion of a 20 kg child to raise the hematocrit from 20 to 30 percent, one would transfuse 266 mL of blood (ie, [(30 – 20) x 1600] ÷ 60 = 266 mL).

To perform a manual exchange in the same scenario, one would provide 500 mL of normal saline, phlebotomize 458 mL and then transfuse 458 mL of blood (ie, [(30 – 20) x (80 x 20)] ÷ [60 – ([30+20]/2)]).

Rounding the volume up or down to the nearest RBC unit should be avoided in young children, and the maximum amount of blood phlebotomized is 500 mL [93].

●Adults – For simple transfusion of a 60 kg adult to raise the hematocrit from 20 to 30 percent, we would transfuse 500 mL of blood (ie, [(30 – 20) x (60 x 60)] ÷ 60 = 600; may round the volume up or down to 2 units).

To perform a manual exchange transfusion in the same scenario, we would infuse 500 mL of normal saline, phlebotomize up to 500 mL of blood, and then transfuse 1028 cc of blood (ie, [(30 – 20) x (60 x 60)] ÷ [60 – (30 + 20)/2]).

The maximum amount of blood phlebotomized is 500 mL and the maximum amount of blood transfused is typically two units, despite the requirement for additional blood transfusion based on the above calculation.

The total amount of blood infused should take into account the patient's ability to manage increased fluid volume without developing severe transfusion-associated circulatory overload (TACO), defined as occurrence of symptoms and signs of acute pulmonary edema within six hours after blood transfusion [94]. (See "Transfusion-associated circulatory overload (TACO)".)

Risk factors for severe TACO in one study (non-SCD population) included chronic renal failure (odds ratio [OR] 27, 95% CI 5.2-143), history of heart failure (OR 6.6, 95% CI 2.1-21), hemorrhagic shock (OR 113, 95% CI 14.1-903), number of blood products transfused (OR 1.11 per unit, 95% CI 1.01-1.22), and fluid balance per hour (OR 9.4 per liter, 95% CI 3.1-28) [95].

At least half-way through the infusion, immediately after, and several hours after the transfusion, the patient should be evaluated for TACO symptoms and evidence of fluid overload.

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".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

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)" and "Patient education: Blood transfusion (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

●Benefits – Blood transfusion in sickle cell disease (SCD) improves oxygen delivery and can lower the percentage of sickle hemoglobin (Hb S); the latter can decrease vaso-occlusion and reduce morbidity from some of the most severe complications of SCD (stroke, acute chest syndrome [ACS]). (See 'Rationale for transfusion' above.)

●Indications – Transfusions are indicated to treat severe uncompensated anemia and severe vaso-occlusive phenomena including multiorgan failure, acute stroke, and ACS; and preoperatively in most patients. The largest misuse of transfusion is for an adult with SCD with uncomplicated vaso-occlusive pain without symptomatic anemia, for which there is no evidence of benefit. Simple transfusion can increase oxygen carrying capacity in patients with severe anemia. Exchange transfusion provides greater benefit in critically ill patients and those with vaso-occlusion, by lowering Hb S without increasing blood viscosity; automated apheresis is generally preferred over manual exchange. Over time, chronic simple transfusion increases the risk of iron overload (figure 1). (See 'Overview of indications' above and 'Simple versus exchange transfusion' above.)

•Anemia – We suggest simple transfusion for individuals with SCD if the Hb is below the patient's baseline and there are new signs or symptoms of anemia, or if there is a progressive trend for a decreasing Hb over several days without a compensatory increase in reticulocyte count (Grade 2B). (See 'Symptomatic or severe anemia' above.)

•Multiorgan failure – We recommend exchange transfusion for acute multiorgan failure (Grade 1B). Hypotension is not a contraindication to exchange transfusion. (See 'Multiorgan failure' above.)

•Acute stroke and ACS – (See "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease", section on 'TIA and ischemic stroke management' and "Acute chest syndrome (ACS) in sickle cell disease (adults and children)", section on 'Transfusion'.)

•Preoperative – We recommend preoperative transfusion for most patients with SCD undergoing surgery (Grade 1B). For those with Hb SS or Hb S-beta⁰ thalassemia undergoing elective surgery, we suggest simple transfusion to increase the Hb to 10 g/dL rather than exchange transfusion (Grade 2B). Patients with Hb SC require an individualized approach based on disease severity. Individuals with SCD undergoing elective, minor, low-risk procedures may not require transfusion. (See 'Prophylactic preoperative transfusion' above.)

•Prophylactic – Regular prophylactic transfusions can reduce most complications of SCD; they are used for primary and secondary prevention of strokes (in children), silent cerebral infarcts, ACS, priapism, and pulmonary hypertension. The decision to use chronic transfusion initially or after a trial of hydroxyurea depends on evolving evidence and patient circumstances. (See 'Prophylactic (regularly scheduled) transfusion' above.)

●Antigen matching – We match Rh (D, C, E or C/c, E/e) and K to minimize alloimmunization. We use pre-storage leukoreduction to decrease febrile non-hemolytic transfusion reactions (FNHTRs). (See 'Transfusion techniques' above.)

●Central venous catheter – We consider several factors in decisions to place central venous catheters (patient preference, emergency facility expertise, type of transfusion program). (See 'Venous access devices' above.)

●Complications – Certain transfusion complications are more common and potentially more severe in individuals with SCD, including alloimmunization and excess iron stores. Prevention, and management are presented separately. (See "Transfusion in sickle cell disease: Management of complications including iron overload".)

ACKNOWLEDGMENTS

UpToDate gratefully acknowledges Stanley L Schrier, MD (deceased), who contributed as Section Editor on earlier versions of this topic review and was a founding Editor-in-Chief for UpToDate in Hematology.

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