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Red blood cell transfusion in sickle cell disease


Authors
Michael R DeBaun, MD, MPH
Elliott P Vichinsky, MD
Section Editors
Stanley L Schrier, MD
Donald H Mahoney, Jr, MD
Deputy Editor
Jennifer S Tirnauer, MD
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Feb 2015. | This topic last updated: Feb 17, 2015.
INTRODUCTION Individuals with sickle cell disease (SCD) have chronic anemia that can
worsen abruptly (eg, from splenic sequestration or transient red cell aplasia), and they are at
risk of vasoocclusive events (eg, stroke) due to the high concentration of sickle hemoglobin
(HgbS) associated with their condition. Transfusion of red blood cells (RBCs) can be lifesaving in these settings.
However, transfusion carries risks, many of which are greater in individuals with SCD than in
the general population. The approach to transfusion in SCD 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 and transfusion complications in SCD. The
clinical manifestations of SCD, other aspects of SCD management, and more extensive
discussions of transfusion-related excessive iron stores are presented separately:
(See "Overview of the clinical manifestations of sickle cell disease".)
(See "Overview of the management and prognosis of sickle cell disease".)
(See "Routine comprehensive care for children with sickle cell disease".)
(See "Hydroxyurea and other disease-modifying therapies in sickle cell disease".)
(See "Cerebrovascular complications of sickle cell disease".)
(See "Vasoocclusion in sickle cell disease".)
(See "Pregnancy in women with sickle cell disease".)
(See "Hepatic iron concentration and hepatic iron index in the diagnosis of iron
overload and hereditary hemochromatosis".)
(See "Chelation therapy for thalassemia and other iron overload states".)
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 (HbSS; sickle cell anemia) or by compound heterozygosity
for the sickle mutation and a second beta globin gene mutation (eg, sickle-beta

thalassemia, HbSC disease). In either HbSS or compound heterozygotes, the majority


of Hgb is sickle Hgb (HgbS; ie, >50 percent). (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
apheresis (also called cytapheresis or hemapheresis) using an extracorporeal
continuous flow device.
DUAL ROLES OF TRANSFUSION Blood transfusion therapy in SCD differs from other
conditions. In patients with SCD, blood transfusion does more than simply raise the
hemoglobin (Hgb) level for oxygen delivery; transfusion also lowers the percentage of sickle
Hgb (HgbS) and increases Hgb oxygen saturation, both of which decrease the propensity for
vasoocclusion. (See "Vasoocclusion in sickle cell disease".)
At least four mechanisms contribute to the benefit of blood transfusion therapy in treating
vasoocclusive events and preventing SCD-related complications [1,2]:
Dilution of HgbS-containing RBCs via the addition of HgbA-containing cells from the
blood of normal donors
Suppression of erythropoietin release caused by the rise in Hgb, thereby reducing the
production of new HgbS-containing cells
Decrease in percentage of HgbS-containing cells due to the longer circulating lifespan
of HgbA-containing cells
Increase in Hgb oxygen saturation levels by approximately 1 to 6 percent, which
increases oxygen delivery to the tissues [3,4]
Transfusion has been shown to reduce morbidity related to some types of vasoocclusive
events and in the perioperative setting, but not for uncomplicated pain episodes without
symptomatic anemia. These findings inform our recommendations regarding when to
transfuse individuals with SCD. (See 'Indications for transfusion' below.)
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 and pain events).
The largest misuse of blood transfusion therapy is simple transfusion in an adult with SCD
admitted to the hospital for an uncomplicated vasoocclusive 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.
However, for more complex cases, in which pain occurs in the setting severe or symptomatic
anemia, transfusion may be appropriate. In such cases, it is important to note that 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 pain management in adults with sickle
cell disease" and "Routine comprehensive care for children with sickle cell disease", section
on 'Painful crises or events' and "Evaluation and management of pain in children".)

Transfusion therapy for individuals with SCD can be categorized as therapeutic


or prophylactic/preventive. Accepted indications for transfusion therapy in individuals with
SCD include the following [5,6]:
Acute therapeutic Transfusions are used acutely for the treatment of vasoocclusive
phenomena accompanied by severe anemia that cannot be adequately compensated by
increased red cell production. Examples include:
Acute stroke. (See "Cerebrovascular complications of sickle cell disease", section
on 'Acute stroke management'.)
Acute chest syndrome (ACS). (See 'Acute chest syndrome treatment and
prevention' below and "Acute chest syndrome in adults with sickle cell disease",
section on 'Transfusion' and "The acute chest syndrome in children and
adolescents with sickle cell disease", 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 (ie, relative reticulocytopenia). 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.)
Preventive Preventive transfusion is used to prevent perioperative complications in
patients with SCD undergoing surgery, and to reduce morbidity from a variety of
vasoocclusive complications of SCD. (See 'Prophylactic preoperative transfusion' below
and 'Preventive (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 'Complications of RBC transfusion' below.)
After all transfusions, we perform a complete blood count (CBC) to check the total Hgb level
and measure the percent HgbS.
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 RBC increases (eg, from
splenic sequestration, bleeding, or accelerated hemolysis). (See "Overview of the clinical
manifestations of sickle cell disease", section on 'Anemia'.)
Given that symptomatic anemia will always be superimposed on chronic anemia, the baseline
Hgb 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 Hgb levels below an individual's baseline, it is also important to
distinguish between normal, day-to-day variability of biological anemia and a clinically
significant change.
In general, we suggest simple transfusion for children and adults if the Hgb level 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 Hgb 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 [7]. The potential consequences of severe
anemia in children with SCD are illustrated by reports of cerebral ischemia on magnetic
resonance imaging (MRI) [8]. Although high-quality data are lacking for absolute thresholds,
based on our clinical experience we transfuse all children with a Hgb <5.5 g/dL and all adults
with a Hgb <6 g/dL, unless there are major extenuating circumstances. (See 'Simple versus
exchange transfusion' below.)
Additional information regarding Hgb 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
indications' and "Indications and hemoglobin thresholds for red blood cell transfusion in the
adult", section on 'Transfusion thresholds'.)
We transfuse 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. However, with the exception of delayed or
hyper-acute hemolytic transfusion reactions, simple transfusion is likely to be appropriate
therapy, and 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 vasoocclusive pain or acute
chest syndrome (ACS), splenic sequestration, asymptomatic thrombocytopenia, and
acute kidney disease [9-11]. Although the aplasia is transient, the Hgb 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 Hgb 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 human 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 (eg, spleen, liver, lung),
acutely lowering the Hgb 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
'Hepatic sequestration crisis'.)
Acute bleeding Acute bleeding is often associated with surgery. An acute drop in
Hgb 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 SCDrelated 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, which should be suspected under the
following conditions (see"Transfusion-associated immune and non immune-mediated
hemolysis"):
Lower Hgb level after transfusion than before transfusion
Relative anemia noted at least five days after the transfusion
Anemia accompanied by associated vasoocclusive pain or ACS
Anemia accompanied by increased bilirubin, LDH, and hemoglobinuria (ie, urine
dipstick testing identifies the presence of heme, but microscopic evaluation does
not show RBCs)
Management of individuals with suspected delayed hemolytic transfusion reaction 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. If
transfusion is needed, avoidance of the implicated RBC antigen that caused the transfusion
reaction is critical; this requires coordination with the transfusion facility responsible for the
most recent transfusion, and previous facilities that have provided blood to the individual. Of
note, this communication between blood banks is critical because not all individuals with
delayed hemolytic transfusion reactions will have the offending allo-antibody detected.
Multiorgan failure Multiorgan failure is an incompletely understood complication typically
seen in the setting of severe acute painful episodes of SCD. (See "Overview of the clinical
manifestations of sickle cell disease", section on 'Multiorgan failure'.)
We recommend exchange transfusion in patients with multiorgan failure, based on data from
case reports that suggest improved clinical outcomes in this setting [12,13]. (See 'Exchange
blood transfusion' below.)
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 (eg, screening by transcranial Doppler
and prophylactic regularly scheduled transfusion for those with abnormal flow velocity) and
secondary stroke prevention (eg, chronic exchange transfusion, with a goal of reducing the
maximum fraction of HgbS to <30 percent of total Hgb and maintaining the total Hgb
>9 g/dL) are discussed in detail separately. (See"Cerebrovascular complications of sickle cell
disease".)
Acute chest syndrome treatment and prevention
Treatment of ACS Transfusion is an important component of the acute management
of acute chest syndrome (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 apheresis 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.
Details of the indications and parameters used for transfusion in treating ACS are
discussed separately. (See "The acute chest syndrome in children and adolescents with
sickle cell disease", section on 'Transfusion' and "Acute chest syndrome in adults with
sickle cell disease", section on 'Transfusion'.)
Prevention of ACS Transfusion can also be used as an adjunct to other measures
(eg, control of asthma, which is the greatest risk factor for ACS) to prevent ACS. We
typically initiate transfusions in patients who continue to have episodes of ACS
despite hydroxyurea therapy.
For children, we use prophylactic, regularly scheduled transfusion 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 "The acute chest syndrome in children and adolescents with sickle
cell disease", section on 'Long-term management'.)
For adults, we only initiate prophylactic, regularly scheduled transfusions if there
have been two or more episodes of moderate to very severe ACS in the past 24
months despite maximalhydroxyurea therapy. We perform exchange transfusions
either manually or by automated apheresis every four to six weeks to maintain a
maximum HgbS 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 in adults with sickle cell disease", section on 'Chronic transfusion
therapy'.)
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 [14]. The children randomized to chronic transfusion had reduced rates of
hospitalization for ACS compared with those randomized 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.
Our approach 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 [15]. 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.
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 (HbSS) undergoing major surgery.
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 HbSC disease depends on disease severity
and the clinical setting. (See 'Hemoglobin SC disease' below.)
Importantly, the patient's clinical history and perioperative management are major
determinants of anesthesia risk. Regardless of transfusion utilization 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
randomized 70 children and adults with SCD to no preoperative transfusion or preoperative
transfusion with a target Hgb level of 10 g/dL [16]. Patients were excluded if they had a Hgb
concentration <6.5 g/dL, transfusion during the preceding three months, acute chest
syndrome within the previous six months, oxygen saturation <90 percent, current renal
dialysis, or a history of stroke in children. The median Hgb 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 acute chest syndrome (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 would be expected to benefit from
prophylactic transfusion and/or a HgbS concentration of <30 percent.

Optimal regimen for preoperative transfusion For children and adults with HbSS or
HbS-beta0 thalassemia who are scheduled to undergo surgery, we suggest a simple
transfusion regimen to increase the Hgb to 10 g/dL, rather than an aggressive exchange
transfusion regimen to reduce the HgbS concentration 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 [16-20].
In one such study, individuals undergoing 604 operations were randomly assigned to receive
either an aggressive exchange transfusion regimen designed to reduce the HgbS level to <30
percent, or a conservative transfusion regimen designed only to increase the Hgb
concentration to 10 g/dL [17]. The incidence of serious complications (31 and 35 percent) and
acute chest syndrome (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 sicklerelated complications (acute chest syndrome and vasoocclusive events) [18].
Cholecystectomy 39 percent serious complications, 19 percent sickle-related
complications, and 10 percent transfusion-related complications [20]. 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 [19].
Hemoglobin SC disease Similar principles apply to many individuals with combined
heterozygosity for HbS and HbC (ie, HbSC disease, SCD-SC). In keeping with the less
severe nature of HbSC disease, affected individuals have lower rates of overall complications
(18 percent) and sickle-related complications (9 percent) than those with sickle cell anemia
(ie, HbSS) [21]. In uncontrolled observations, sickle-related complications occurred only in
individuals who were not transfused (35 percent) [21]. However, the value of transfusion in
such individuals remains to be proven.
Thus, our approach is to perform exchange transfusion in individuals with HbSC disease who
have had serious acute complications in the past or have concurrent morbid disease such as
asthma or strokes. Patients who are relatively asymptomatic and undergoing elective surgery
do not necessarily require preoperative transfusion therapy. Since Hgb levels in some
individuals with HbSC disease may be >10 g/dL, partial exchange transfusion may be
preferable to simple transfusion in the preoperative setting. When performing exchange
transfusion in individuals with HbSC disease, we aim for a HgbA of >50 percent or a HgbS
<30 percent [21]. (See 'Exchange blood transfusion' below.)
PREVENTIVE (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, Hgb, and percent HgbS.

Indications Regular transfusions are effective in reducing morbidity of most complications


of SCD. As discussed in separate topic reviews, regular transfusions are utilized in the
secondary prevention of stroke, acute chest syndrome (ACS), painful events, priapism, and
pulmonary hypertension [22,23].
Stroke (See "Cerebrovascular complications of sickle cell disease", section on
'Prevention of a first stroke' and "Cerebrovascular complications of sickle cell disease",
section on 'Prevention of recurrent stroke'.)
Recurrent acute chest syndrome despite hydroxyurea therapy in severely affected
individuals (See "Acute chest syndrome in adults with sickle cell disease", section on
'Prevention of ACS'and "The acute chest syndrome in children and adolescents with
sickle cell disease", section on 'Hematologic'.)
Vasoocclusive pain episodes that are severe, frequent, and not responsive to
maximum tolerated doses of hydroxyurea (See "Overview of the clinical
manifestations of sickle cell disease", section on 'Major clinical
manifestations' and "Hydroxyurea and other disease-modifying therapies in sickle cell
disease".)
Recurrent priapism (See "Diagnosis and management of priapism in sickle cell
disease", section on 'Regular blood transfusion'.)
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 (third trimester for most patients with HbSS and earlier for patients at higher
risk of complications) (See "Pregnancy in women with sickle cell disease", 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 [24]. Benefits included statistically significant decreases in the rates of
pain, acute chest syndrome, symptomatic avascular necrosis, and priapism.
The SIT trial also demonstrated the efficacy of regularly scheduled transfusion in reducing the
risk of cerebral infarct recurrence by over 50 percent, as discussed separately.
(See "Cerebrovascular complications of sickle cell disease", section on 'Prevention of a first
stroke'.) The decision to utilize chronic transfusion therapy initially or after 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 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 threshold to switch therapy requires clinical judgment; high
quality data and evidence-based guidelines to guide this decision are lacking. Data to support

concomitant use of transfusion therapy and hydroxyurea are very limited, and we do not use
these therapies concomitantly.
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, to limit iron
accumulation from transfusions. (See 'Simple versus exchange transfusion' below.)
For most patients, the goal of regularly scheduled transfusions is to maintain the percent
HgbS <30 percent of total Hgb, and the total Hgb >9 g/dL. We typically monitor the Hgb level,
the percent HgbS, serum ferritin, and reticulocyte count with every blood transfusion to define
trends and determine when the next transfusion should occur.
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. In contrast, for individuals who have been placed on
regular blood transfusion to abate a high frequency of vasoocclusive 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 blood transfusion therapy, the associated
management issues (eg, minor 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 "Routine
comprehensive care for children with sickle cell disease", 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 RBC antigens (C, E, and Kell) to
reduce the risk of alloimmunization; using a white blood cell filter to decrease the rate of
febrile non-hemolytic transfusion reactions; and chelation therapy if iron stores reach a select
threshold. (See 'Minor RBC antigen matching' below and 'Leukoreduction' below
and 'Excessive iron stores' below.)
Individuals with SCD should not receive blood transfusion therapy 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 (HgbS) in
blood from individuals with sickle cell trait will make it difficult for the physician to predict the
anticipated HgbS level 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.
Minor RBC antigen matching We use minor RBC antigen matching (eg, for C, E, and
Kell) to minimize the likelihood of alloimmunization (ie, immunization of the patient by donor
RBC antigens), which can occur after a single transfusion. Alloimmunization due to minor
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.
Alloimmunization to minor RBC antigens in those with SCD can be associated with
vasoocclusive episodes and life-threatening hemolysis. 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 'Hemolysis and alloimmunization' below.)
Individuals with SCD are more likely to be from ethnic minority groups in the United States,
and the vast majority of donors are from ethnic groups that have a low incidence of SCD. The
ethnic mismatch between donor and recipients increases the likelihood of alloimmunization
because the frequency of minor RBC antigens is heavily influenced by ethnic origin. Thus, we
perform extended crossmatching of RBC units for minor antigens, as do most hematologists
who provide lifelong care to individuals with SCD [25-32].
The most common minor RBC match is for C, E, and Kell antigens, regardless of patient age.
Some blood banks also match RBC units for individuals with SCD for additional minor
antigens, such as Duffy, Kidd, and S. In practice, matching for C, E, and Kell 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 "A primer of red blood cell antigens and
antibodies" and "Pretransfusion testing for red blood cell transfusion".)
Examples of the success of minor 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 Kell antigens
demonstrated a marked decrease in alloimmunization and transfusion reactions [33].
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 [34].
Alloimmunization was detected in seven patients, a rate of 0.1 percent.
To improve the yield of minor RBC antigen matching for individuals with SCD receiving
regular blood transfusion, some programs use directed donors to decrease donor exposures.
The use of directed donation from minority populations similar to the recipient with SCD has
not been shown to offer any advantage for reducing alloimmunization beyond matching minor
RBC antigens alone [35]. However, minority recruitment blood donor programs have improved
access to matched units. We encourage efforts to educate African American communities
about the importance of blood donation to diversify the blood transfusion therapy pool [36-38].
Genetic crossmatching Genetic crossmatching uses analysis of donor and patient DNA
to more finely map potential incompatibilities in blood group systems, and it improves the
ability to identify appropriate donors [39,40]. Although genetic cross matching appears to have
unique advantages, its routine use in clinical practice has not been well defined, and most
programs do not routinely perform genetic crossmatching.
Another benefit of DNA typing is its accuracy. DNA typing avoids the multiple discrepancies
that can occur with serologic matching, including the Rh, Fy, Jk, and MNS systems [41].
There is significant polymorphism of the Rh alleles in both patients and donors that leads to

Rh alloimmunization [35]. Another advantage of genotyping is that it can be performed after


transfusions, if needed, to determine sources of incompatibility.
Leukoreduction All blood administered to patients with SCD should be leukoreduced to
decrease the incidence of febrile non-hemolytic transfusion reactions, because fever may
necessitate admission to the hospital due to the increased risk of serious infections in
individuals with SCD. (See "Immunologic blood transfusion reactions", section on 'Febrile
nonhemolytic 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 in the blood bank at the time of
blood collection, but leukoreduction can also be done at the bedside. Some institutions
routinely leukoreduce all blood, 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. (See "Leukoreduction to prevent
complications of blood transfusion".)
VENOUS ACCESS DEVICES 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.
However, 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 [42-45].
CVC-related thromboembolism occurs in up to 30 percent of individuals with SCD who have a
CVC [43]; this may present as acute chest syndrome or other sickle-related events (eg,
vasoocclusive pain episodes). CVC-related bacteremia is a major cause of bloodstream
infections in individuals with SCD [42,46]. 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) [46]. 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 [42]. 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 "Complications of central venous catheters and their
prevention".)
In determining whether a CVC should be placed, we evaluate whether (and why) the patient
and family want a CVC, and whether the patient, family, 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 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 utilization of nurse
specialists for expert placement of peripheral access in the apheresis transfusion unit.
Fever (eg, temperature >38.3C [101F]) 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.

The type of CVC chosen requires an understanding of the patient's and family's preferences,
and the way in which the catheter will be used. The decision between port versus an
externalized catheter may also depend on the specific expertise at the nearest emergency
facility (eg, whether the clinicians are familiar with the specialized needles to access certain
ports and/or the care of an externalized catheter).
Catheters with externalized access offer the benefit of direct access without requiring
placement of a specialized access needle through the skin, which can be painful.
However, external catheters require much more maintenance by the
patient and/or family (eg, line flushing using sterile technique; site care).
Subcutaneous ports do not require preventative intervention by the family. In addition,
the catheter is not exposed outside the skin, which is important to many patients for
cosmetic reasons or sports (eg, swimming). A patient who previously had an
externalized CVC and developed an infection with a line-associated organism (eg,
coagulase-negative Staphylococcus) might also benefit from a subcutaneous port and
avoidance of preventive interventions.
The number of lumens 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 (eg, for exchange transfusion) requires a catheter that can
support higher flow rates and has at least two lumens. Apheresis can be performed
with single-lumen catheter, but this requires an additional form of peripheral
venous access, which is not ideal. Thus, our approach in patients undergoing
apheresis for exchange transfusion is to utilize double lumen catheters that allow
the apheresis equipment to withdraw from the lumen without collapsing the line
(eg, double-lumen apheresis port, Vortex port). These stiff ports accommodate
high-flow states required for apheresis, and can also be accessed with standard
needles for IV fluids and pain management.
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 prior to placement. (See "Overview of central venous
access" and"Complications of central venous catheters and their prevention".)
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 (Hgb) to increase the oxygen carrying capacity in
the setting of severe anemia. In individuals with severe anemia (ie, Hgb <5 g/dL), simple
transfusion may also be effective in lowering the HgbS level without increasing the red cell
viscosity.
We use simple blood transfusion therapy for the following situations in individuals with SCD:

An uncomplicated drop in Hgb levels resulting in signs or symptoms of decreased


oxygen delivery (eg, 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 Hgb is <5 g/dL and the patient is critically ill, simple transfusion can be used with
a goal to increase the Hgb level 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 red blood cell transfusion in the adult".)
Preoperative transfusion to reduce complications of surgery, 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 Hgb is
near baseline (typically 7 to 9 g/dL), because simple transfusions do not rapidly reduce the
percentage of HgbS 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 Hgb, percent HgbS, blood flow rate, white
blood cell count, and other parameters. As the blood viscosity increases beyond a threshold,
oxygen delivery decreases (even if the Hgb 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 HgbS. Baseline
HgbS levels in individuals with SCD are at least 90 percent of total Hgb, and typically after
simple transfusion, the percentage of HgbS remains >75 percent. In contrast, an exchange
transfusion can lower the HgbS levels to <30 percent. The higher HgbS levels that remain
following simple transfusion contribute significantly to higher blood viscosity [47].
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 "Cerebrovascular
complications of sickle cell disease".)
There is no general consensus regarding how to manage individuals with SCD at risk for
hyperviscosity (ie, with Hgb above 10 g/dL and HgbS >50 percent of total Hgb). 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
Hgb >10 g/dL and a HgbS percentage >50 percent of total Hgb.
If a patient's Hgb has been inadvertently raised above 12 g/dL with simple transfusions
and the HgbS levels are >50 percent of total Hgb, we use phlebotomy to decrease the
Hgb level closer to 10 g/dL.
We use phlebotomy for all patients with a post-transfusion Hgb 13.0 and HgbS >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
HgbS 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 HgbS levels (ie, to <30
percent of total Hgb). The lessened effects on viscosity for a given Hgb level are critical in
potentially reversing vasoocclusion and improving blood flow. (See "Vasoocclusion in sickle
cell disease", section on 'Multiple pathway model'.)
Exchange transfusion therapy can involve full blood volume exchange by manual or
automated apheresis. A full exchange transfusion allows for rapid lowering of the HgbS level
to 30 percent or less, and correction of anemia. Partial exchange transfusion refers to a
limited exchange transfusion that is less effective in lowering the HgbS level but is more
easily performed. In order to lower the HgbS below 30 percent, repeat partial exchange
transfusions may be necessary.
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 [48],
respiratory failure, and multi-organ failure [12]. We employ exchange transfusions in the
following situations:
For acute emergencies, when the patient is acutely ill and deteriorating quickly (eg,
multi-organ failure, suspected stroke, respiratory compromise, acute chest syndrome);
of note, hypotension is not a contraindication to exchange transfusion.
For regularly scheduled transfusions used in the prevention of stroke, acute chest
syndrome, and recurrent painful episodes.
In general, automated apheresis is preferred over manual exchange because it can be done
faster and causes fewer volume shifts [49]. In clinical situations where the exchange may be
considered as part of standard care (acute chest syndrome, 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.
With acute organ deterioration, such as respiratory failure, stroke, or multi-organ failure, we
suggest lowering the HgbS level into the range of 15 to 20 percent, and raising the total Hgb
to the range of 10 to 12 g/dL. Although strong evidence-based data confirming that a HgbS of
15 to 20 percent is better than 30 percent are lacking, the rationale for this approach is
twofold. First, in critically ill patients, this approach is thought to minimize sickling
complications. Second, the HgbS level is unlikely to increase above a threshold of 30 percent
within four weeks. Thus, this HgbS target decreases the likelihood of requiring another
exchange blood transfusion for at least three weeks to keep the HgbS level <30 percent.
A further benefit of RBC apheresis over simple transfusion is the prevention or minimization of
positive iron balance. RBC apheresis decreases positive iron balance when compared with
simple blood transfusion therapy and may delay, or in few cases eliminate, the need for
chelation therapy [50-52]. 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 [53]. (See 'Excessive iron
stores' below.)

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 cc/kg will increase
the Hgb 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
Hgb concentration by approximately 1 g/dL and the hematocrit by 3 percentage points.
[54,55].
The following formulas are used for estimation of simple transfusion and partial exchange
transfusion volumes [56]:
Packed RBC volume for simple transfusion (mL) =
([dHCT - iHCT] x TBV) rpHCT
Manual partial exchange volume (mL) =
([dHCT - iHCT] x TBV) (rpHCT - [(iHCT + dHCT) 2])
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 women, 70 mL/kg in adult men, 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).
As examples:
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 [57].
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)] 75 = 480;
rounded to 500 mL).
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 720 cc of
blood (ie, [(30 20) x (60 x 60)] [75 (30 + 20)/2]).
The maximum amount of blood phlebotomized should not exceed two units. Rounding
the volume up or down to the nearest RBC unit is acceptable in adults so as not to
discard blood.
COMPLICATIONS OF RBC TRANSFUSION The most common and most concerning
complications of RBC transfusion may be more likely and/or more severe in individuals with
SCD compared with individuals receiving RBC transfusions for other conditions.

Common adverse events include transfusion-associated hemolytic anemia caused by


immunologic reactions. (See 'Hemolysis and alloimmunization' below.)
Infectious complications are uncommon, but include sepsis from intravenous catheters or
transfusion-transmitted bacterial infections, and transmission of viral illness such as hepatitis
and HIV. In the United States, transmission of serious viral infections is very rare except for
parvovirus. (See 'Infection' below.)
Excessive accumulation of iron is a serious problem and may be undetected because
transfusion therapy may be irregular and episodic. (See 'Excessive iron stores' below.)
Hemolysis and alloimmunization Individuals with SCD have a high risk of
alloimmunization, which can lead to difficulty in future crossmatching, which in turn reduces
eligibility for chronic transfusion therapy, and/or access to compatible blood needed in the
treatment of acute events.
In the absence of minor RBC antigen matching, alloimmunization occurs in approximately 30
percent of individuals with SCD who are transfused at least intermittently [25]; this is much
higher than the 5 percent rate in individuals with other forms of anemia, a difference primarily
due to minor blood group incompatibilities between the donor population, which is
predominantly white, and the recipient SCD population, which is predominantly of African
descent [25,36,58]. Antibodies against the Rh (E, C), Kell (K), Duffy (Fya, Fyb), and Kidd (Jk)
antigens present the greatest problem in transfusing these individuals [25,58,59]. (See 'Minor
RBC antigen matching' above and "The incompatible crossmatch", section on 'Sickle cell
disease'.)
Alloimmunization also can cause immune-mediated hemolysis, typically as a delayed
hemolytic transfusion reaction. This can lead to shortened RBC survival, worsening anemia,
and exacerbation of SCD complications. Acute hemolytic transfusion reactions, which are a
medical emergency due to rapid intravascular lysis of RBCs, can also occur.
(See "Transfusion-associated immune and non immune-mediated hemolysis".)
Any patient who has findings of hemolysis, including a rapid decrease in Hgb level, jaundice
with increased bilirubin, reduced or absent haptoglobin, and/or increased reticulocyte
percentage, should have a direct antiglobulin test (Coombs test); and any patient with a
positive direct antiglobulin test should undergo evaluation for the type of antibody in order to
avoid this antigen in future transfusions.
Most transfusion-associated hemolysis in individuals with SCD occurs as a delayed hemolytic
transfusion reaction due to alloantibodies, but other forms of immune hemolysis can also
occur.
Autoantibody-mediated hemolysis Autoantibodies (ie, antibodies that recognize
the patient's own RBCs) have been reported in 7 to 47 percent of patients receiving
transfusions [32,33]. An autoantibody is more likely to develop in patients who have
already been alloimmunized. Some patients have a nonspecific, transient, weakly
positive direct antiglobulin test that has no specificity and no hemolysis. However, a new
autoantibody can cause marked hemolysis and should undergo reference laboratory
evaluation.
Coombs-negative hemolysis Individuals with SCD are also prone to develop direct
antiglobulin negative (ie, Coombs-negative) hyperhemolysis that acts as an autoimmune
hemolytic transfusion reaction. Patients with severe autoimmune transfusion reactions

may respond to immunosuppressive therapy with intravenous gammaglobulin, steroids,


or rituximab.
Infection Transfusion-related infection may have more serious consequences in
individuals with SCD. Viral infections that may reduce bone marrow production of RBCs (eg,
parvovirus) could lead to more severe acute anemia when superimposed on the chronic
hemolytic anemia of SCD. Bacterial infection from intravenous catheters is especially
concerning because individuals with SCD are functionally asplenic and at risk for bacterial
sepsis.
Parvovirus Parvovirus is not eliminated by standard blood screening, and it is not
inactivated by viral inactivation processes used for plasma products. Unlike those
without underlying hemolysis, 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.
(See "Blood donor screening: Laboratory testing" and "Pathogen inactivation of blood
products" and 'Symptomatic or severe anemia' above.)
Bacterial infection The risk of sepsis from intravenous catheters or transfusiontransmitted bacterial infection 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 "Prevention of intravascular catheter-related
infections" and "Overview of the management and prognosis of sickle cell
disease" and 'Indications for transfusion' above.)
HIV, HTLV-I, hepatitis Transfusion transmission of HIV, HTLV-I, and hepatitis B and
C has diminished markedly with improved screening of banked units of blood (table 1).
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 "Transfusion transmitted HIV
infection and AIDS".)
CMV Given that the presence of antibodies to cytomegalovirus (CMV) is a
nonspecific assay for CMV infectivity, and that 30 to 70 percent of blood donors,
depending upon geographic region, test positive for the presence of CMV antibodies,
much effort has gone into finding another method of providing "CMV-safe" blood to
individuals with SCD. Blood depleted of leukocytes below a level of five million per unit
of blood is an acceptable alternative; leukocyte depletion using filters is routinely used
for individuals with SCD to prevent febrile transfusion reactions.
(See'Leukoreduction' above and "Leukoreduction to prevent complications of blood
transfusion", section on 'Viral diseases'.)
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. A high degree of suspicion is needed for
early detection [60,61]. (See "Blood donor screening: Laboratory testing", section on
'Emerging infectious disease agents'.)
EXCESSIVE IRON STORES Despite limiting transfusion to appropriate indications, many
patients with SCD will develop excessive iron stores if chelation therapy is not used. Excess
iron is a cause of significant morbidity in patients with SCD, especially as the longevity of
individuals with SCD continues to increase with improved management and use
of hydroxyurea [54,62,63]. Hepatic fibrosis and death from hemosiderosis-related cirrhosis of

the liver can occur [64-68]. For those who receive multiple transfusions, iron chelation therapy
is an important component of the transfusion program because it prevents complications of
iron deposition in organs (eg, liver, heart).
While long-term efficacy and safety studies on the effects of chelation on morbidity and
mortality in individuals with SCD have not been completed, existing data and multiple
consensus reports recommend iron chelation therapy for transfusion iron overload [69,70].
Chelation therapy in SCD is managed similarly to that for other chronically transfused, ironoverloaded individuals (eg, beta thalassemia major). However, it is important to note that in
thalassemia the optimal iron levels and guidelines for initiation of chelation therapy are
evolving toward maintenance of lower iron stores, based on decreasing the long-term, ironinduced organ dysfunction observed in thalassemia. The clinical interaction of SCD
pathophysiology and iron overload alters iron deposition and tissue injury in SCD, and these
more aggressive chelation recommendations for thalassemia should not be adopted for SCD
until further risk/benefit studies are completed [71,72].
In contrast to chelation, phlebotomy cannot be used to remove iron in transfusion-dependent
subjects and is useful only in the rare individual with SCD and a high Hgb. In such cases,
automated apheresis is effective in decreasing the iron burden and may prevent the need for
chelation [6,50,52].
Monitoring iron stores The serum ferritin concentration is a useful test to monitor the
status of iron stores, particularly in the first few years of transfusion therapy. Ferritin levels
need to be serially measured at least every three to four months, and must be drawn in the
steady state (ie, separate from acute inflammatory or vasoocclusive events). We prefer to
draw the ferritin levels with each blood draw so that we can easily monitor the trend for the
individual, which is likely to be more important than a single measure. 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 for maintaining a serum ferritin value no greater than 1000 to 1500 ng/mL (1000 to
1500 mcg/L), based on the assumption that minimizing iron stores is likely to be associated
with similar benefit as in patients with beta thalassemia [68,69]. However, inflammation alters
serum ferritin levels, and periodic monitoring of quantitative liver iron is recommended.
Optimal management of iron overload in SCD requires periodic correlation of ferritin with
tissue iron stores (eg, liver, heart).
Liver We measure liver iron stores noninvasively at the initiation of chelation therapy,
and annually in chronically transfused patients. More frequent monitoring may be used if
a potential decision is to be made about stopping chelation therapy. We use noninvasive quantitative MRI to assess liver iron; regionally, different techniques to
quantitate iron stores may be available. Quantitative MRI utilizing 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 'MRI and
SQUID techniques'.)
We prefer to use MRI rather than liver biopsy for a number of reasons, including the lack
of a clear correlation of plasma steady state ferritin levels with hepatic iron stores [64,7375]. At least two studies found a poor correlation of plasma ferritin with hepatic iron

stores as determined by liver biopsy in patients who were receiving chronic transfusions
[64,75]. 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 [76].
We reserve liver biopsy for 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 we want to assess histology of the liver. (See "Hepatic iron
concentration and hepatic iron index in the diagnosis of iron overload and hereditary
hemochromatosis".)
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 initiated cardiac iron monitoring using
T2* MRI of the heart in patients who have undergone five to eight years of transfusion
therapy, or earlier in patients with markedly elevated ferritin and/or liver iron levels [7779]. (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 the iron overload needs to be addressed by a multidisciplinary team.
Serious iron overload results from noncompliance. Factors causing noncompliance,
including family support and home infrastructure, must be addressed in order to have
long-term improvement.
Chelation therapy The initiation of chelation therapy in individuals with SCD is dependent
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
[68,69,80]. 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 two years of transfusion in chronically transfused
individuals, or after approximately 120 mL of transfused RBCs per kilogram, and when the
serum ferritin exceeds at least 1000 to 1500 mcg/L (ng/mL) or the liver iron is >7 mg/g dry
weight. 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 [81]. The major challenge in using these criteria is that when exchange transfusion
rather than simple transfusion is used, the ferritin 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.
Choice of chelating agent Three available iron chelators
exist: 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 (DFX; Exjade) is an orally-available iron chelator that appears to have
efficacy similar to deferoxamine in decreasing liver iron concentration [82,83]. The side
effect profile of deferasirox appears to be tolerable in individuals with SCD. Diarrhea,
nausea and vomiting, and abdominal pain are common side effects, but these are
usually mild and decrease with time. In multicenter trials, laboratory abnormalities
include dose-dependent rise in serum creatinine, which is reversible, and occasional
liver dysfunction. Long term follow-up studies of five years have shown a clinically

acceptable safety profile with no evidence of progressive or irreversible renal or liver


injury [84].
Post-marketing surveillance in subjects taking deferasirox has identified hepatic failure
as a complication in high risk individuals, such as patients with pre-existing liver failure
and hepatitis C. Accordingly, serum transaminases and bilirubin should be monitored
twice during the first month in individuals at high risk (ie, those with hepatitis C or liver
failure) after initiation of therapy with deferasirox, and monthly afterward.
In addition, rare reports of renal failure and Fanconi syndrome have occurred,
particularly in patients not having dose adjustments for renal function abnormalities [8587]. (See "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular
acidosis", section on 'Proximal (type 2) RTA'.)
Deferiprone (DFP; Ferriprox) is orally active; it was approved for use in thalassemia in
the United States in 2011 and has been utilized worldwide for many years. US Food and
Drug Administration (FDA) approval for use in SCD is pending the results of ongoing
SCD trials. 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 [83].
Deferoxamine (DFO; Desferal) is effective and available, but requires daily
subcutaneous infusions, which often result in poor compliance. 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 upon response and organ function over
time. As examples:
In general, in stable patients 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.
The starting dose for oral deferasirox 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 standard dose of deferiprone is 75 mg/kg three times a day. After six months, it
may be increased up to 100 mg/kg/day in non-responding or high risk patients.
Deferoxamine with deferiprone, sequentially or in combination, has been routinely used in
high risk patients [89]. In addition, the safety and efficacy of combining deferasirox and
deferoxamine for severely affected individuals appears promising [90]. (See "Chelation
therapy for thalassemia and other iron overload states", section on 'Deferoxamine plus
deferasirox'.)

Invariably, physicians will identify a subgroup of children or adults with SCD with excessive
liver iron stores (eg, >15 mg/g dry weight, either by liver biopsy or MRI), 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. 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 [91-93]. (See "Acute iron
poisoning", section on 'Deferoxamine'.)
Monitoring 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 given 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 [94].
(See "Chelation therapy for thalassemia and other iron overload states", section on 'Side
effects'.)
Ophthalmology Visual loss has been most clearly linked to deferoxamine, especially
at high doses. An annual evaluation by an ophthalmologist should be performed.
Individuals should be routinely questioned about visual acuity, changes in color vision,
and visual fields.
Nephrology Creatinine/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 urineprotein/creatinine ratio is >0.6 mg/mg.
Hematologic Those on deferiprone require weekly complete blood count 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 re-analysis 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 [95].
Growth Growth can sometimes be affected by chelators. Ongoing measurements of
height and weight velocity, including sitting height, should be performed.
Liver function 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. Deferoxaminehas been associated with an acute respiratory distress that can mimic
acute chest syndrome. 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.
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 (eg, severity of the SCD
complication, severity of the chelator toxicity, availability of alternative agents).
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
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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 information: Sickle cell anemia (The Basics)" and "Patient
information: When your child has sickle cell disease (The Basics)".)
Beyond the basics topic (See "Patient information: Blood donation and transfusion
(Beyond the Basics)".)
SUMMARY AND RECOMMENDATIONS
Blood transfusion in sickle cell disease (SCD) improves oxygen delivery and can lower
the percentage of sickle Hgb; the latter can decrease the propensity for vasoocclusion
and reduce morbidity from some of the most severe complications of SCD (eg, stroke,
acute chest syndrome). (See 'Dual roles of transfusion' above.)
Transfusions are indicated to treat severe uncompensated anemia and severe
vasoocclusive phenomena including multiorgan failure, acute stroke, and acute chest
syndrome; and preoperatively in most patients. The largest misuse of blood transfusion
is for an adult with SCD with an uncomplicated vasoocclusive pain episode 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 vasoocclusion, by lowering
hemoglobin S levels without increasing blood viscosity; automated apheresis is
generally preferred over manual exchange. (See 'Overview of indications' above
and'Simple versus exchange transfusion' above.)
Anemia We suggest simple transfusion for individuals with SCD if the Hgb level
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 Hgb over several days without a
compensatory increase in reticulocyte count (Grade 2B). (See 'Symptomatic or
severe anemia' above.)

Details regarding treatment of more severe anemia in children and adults are
discussed separately. (See "Red blood cell transfusion in infants and children:
Indications", section on 'General indications' and "Indications and hemoglobin
thresholds for red blood cell transfusion in the adult", section on 'Transfusion
thresholds'.)
Multiorgan failure We recommend exchange transfusion for acute multiorgan
failure (Grade 1B). Of note, hypotension is not a contraindication to exchange
transfusion. (See 'Multiorgan failure' above.)
Acute stroke and acute chest syndrome The use of transfusion in the
treatment of stroke and acute chest syndrome (ACS) is discussed separately.
(See "Cerebrovascular complications of sickle cell disease", section on 'Acute
stroke management' and "Acute chest syndrome in adults with sickle cell disease",
section on 'Transfusion'.)
Preoperative We recommend preoperative transfusion for most patients with
SCD undergoing surgery (Grade 1B). For those with HbSS or HbSbeta0 thalassemia undergoing elective surgery, we suggest simple transfusion to
increase the Hgb to 10 g/dL rather than exchange transfusion (Grade 2B).
Patients with HbSC require an individualized approach and are managed
according to disease severity. Individuals with SCD undergoing elective, minor,
low-risk procedures may not require transfusion. (See 'Prophylactic preoperative
transfusion'above.)
Regular (preventive) transfusions are effective in reducing morbidity of most
complications of SCD; they are utilized in the secondary prevention of stroke, ACS,
painful events, priapism, and pulmonary hypertension. The decision to use chronic
transfusion initially or after a trial of hydroxyurea depends on specific patient
circumstances. (See 'Preventive (regularly scheduled) transfusion' above.)
We use minor RBC antigen matching (eg, for C, E, and Kell) to minimize
alloimmunization; and we use leukoreduction to decrease the incidence of febrile nonhemolytic transfusion reactions, which may necessitate hospital admission due to the
increased risk of serious infections. (See 'Transfusion techniques' above.)
We consider a variety of factors in decisions regarding insertion of central venous
catheters (eg, patient preference, emergency facility expertise, type of transfusion
program). (See 'Venous access devices' above.)
Major complications of transfusion include transfusion-associated hemolysis,
alloimmunization, transfusion-transmitted infection, and excessive iron stores. Simple
transfusion can increase blood viscosity and will increase iron burden more than
exchange transfusion. (See 'Complications of RBC transfusion' above and 'Risk of
hyperviscosity syndrome from simple transfusion' above and'Simple versus exchange
transfusion' above.)
For those who receive multiple transfusions, iron chelation therapy is an important
component of the transfusion program because it prevents complications of iron
deposition in organs (eg, liver, heart). Chelation is generally started after two years of
chronic transfusion or approximately 200 mL of transfused RBCs per kilogram, and
when the ferritin exceeds at least 1000 to 1500 g/L or the liver iron is >3 mg/g. We
use deferasirox for most patients because it is orally active and has a good benefit to
toxicity ratio. Serum ferritin level is monitored at every transfusion; liver iron is assessed
annually; and additional monitoring for drug toxicity is performed as indicated for the
specific chelator. (See 'Excessive iron stores' above.)

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