Transfusion Management of Patients With Sickle Cell Disease and Thalassemia

Introduction

Patients with hereditary hemoglobinopathies such as sickle cell disease (SCD) and thalassemia may require lifelong red blood cell (RBC) transfusion support, warranting special consideration by blood centers and transfusion services.

Sickle Cell Disease

SCD is usually caused not only by homozygosity for the hemoglobin (Hb) S mutation (sickle cell anemia) but is also caused by heterozygosity of HbS with a β-thalassemia or HbC. It affects not only African Americans (AA) but also people of Hispanic, Mediterranean, Middle Eastern, South Asian, and Caribbean descent. Approximately 100,000 Americans are affected. Despite improved childhood survival because of early detection and interventions, the median overall survival is ∼43 years.

Pathophysiology

Deoxygenated sickle Hb forms polymers within the erythrocyte that distort its shape and decrease its deformability, leading to increased blood viscosity, vasoocclusion, intravascular hemolysis, and subsequent anemia. Patients may have recurrent episodes of severe pain and other complications, such as acute chest syndrome and stroke. Organs with slow flow through sinusoids, such as spleen, liver, bone marrow, and penis, are especially vulnerable to occlusion. Repeated vasoocclusion/hemolysis over time causes widespread end-organ damage, including the brain, heart, lungs, and kidneys. Patients are also at increased risk of thrombotic events.

Red Blood Cell Transfusion

RBC transfusion improves oxygen delivery, suppresses endogenous erythropoiesis, and also reduces vasoocclusion, hemolysis, and blood viscosity by decreasing the fraction of HbS-containing RBCs. RBC transfusion may be indicated either acutely or chronically, with simple (allogeneic RBCs transfused without autologous RBC removal) or exchange (autologous RBCs removed and replaced with allogeneic RBCs) transfusion performed depending on clinical presentation and feasibility. The end hematocrit (Hct) goal of transfusion should generally be ≤30% (≤36% appropriate in chronic stroke prophylaxis and possibly other chronic transfusion indications) to minimize increased blood viscosity.

With simple transfusion, achieving a therapeutic HbS reduction to ≤30%–50% may not be possible without increasing the patient Hct to a point that risks circulatory overload or significantly increases blood viscosity. In contrast, red cell exchange (RCE) allows the achievement of a low HbS level without increasing total blood volume or Hct, if desired. The risk of transfusional iron overload is also less with RCE compared with simple transfusion. RCE is usually performed using an automated apheresis instrument but can be performed manually when apheresis is unavailable or in infants with small total blood volumes. Drawbacks of RCE compared to simple transfusion include an increased number of RBC units transfused and thus possibly increased risk of alloimmunization, venous access requirements (two large-bore peripheral needles or a dialysis-type central venous catheter), and increased cost. A modified automated RCE, where RBC depletion by isovolemic hemodilution is performed before RCE, can be performed to decrease the number of RBC units needed or alternatively increase the time interval between procedures because of a greater reduction in HbS. Table 52.1 describes recommended transfusion management for various complications that arise in SCD patients.

Table 52.1

Transfusion Management for Sickle Cell Disease (SCD) Complications

Indication	Description	Usual Method of Transfusion
Acute
Acute symptomatic anemia	Worsening of chronic anemia due to blood loss, increased hemolysis, viral suppression of erythropoiesis, or sequestration Treat if symptomatic	Simple
Aplastic crisis	Decreased Hb with reticulocytopenia Usually caused by parvovirus B19 infection Erythropoietic arrest for >5 days may lead to marked anemia with compensatory expanded plasma volume and secondary heart failure	Simple
Acute sequestration	Splenic or hepatic sequestration occurs due to RBC trapping within the sinusoids Signs and symptoms include pain, symptomatic anemia, hypotension, organ enlargement Laboratory findings for hepatic sequestration include mild liver enzyme elevation and direct bilirubinemia. Splenic sequestration has a recurrence rate of ∼50%	Simple in most cases, but exchange transfusion may be indicated if hemodynamically stable and hyperviscosity is a concern With simple transfusion, hyperviscosity from the release of sequestered autologous RBCs may be avoided by transfusing RBCs in small aliquots (5 mL/kg) over 4 hours
Preoperative (moderate- to high-risk surgery using general anesthesia)	Pre-op transfusion to a Hb goal of 10 g/dL reduces the risk of perioperative SCD-related complications Perioperative treatment should also include hydration, body temperature maintenance, adequate oxygenation, and incentive spirometry.	Simple sufficient in many cases, but exchange transfusion is recommended with high-risk surgery or with baseline Hb > 9 g/dL ^a ^b
Acute multiorgan failure	Life-threatening complication resulting from widespread tissue infarction secondary to vasoocclusion Signs and symptoms include rapid drop in platelet counts, highly elevated, LDH, fever, and acute dysfunction in at least two organs, most commonly the lungs, liver, and kidney	Exchange preferable to simple, especially in a rapidly decompensating patient
Acute stroke	The incidence rate of ischemic stroke is greatest in children and older patients, whereas the incidence rate of hemorrhagic stroke, which has a high case-fatality rate, is greatest in patients in their twenties Stroke treatment should also follow standard recommendations for non-SCD stroke treatment	Exchange to a target HbS level of ≤30% is recommended for both ischemic and hemorrhagic stroke Simple transfusion to raise the Hb to 10 g/dL before RCE may be warranted if RCE cannot occur soon
Fat embolism syndrome	Caused by extensive bone marrow infarction and necrosis due to vasoocclusion in bone marrow sinusoids Signs and symptoms include hypoxemia, nonfocal encephalopathy, thrombocytopenia, and skin and mucosal petechiae	Exchange
Severe hepatic crisis/intrahepatic cholestasis	Massive vasoocclusion in the sinusoids leads to hepatic ischemia and dysfunction Signs and symptoms include tender hepatomegaly, liver enzyme elevation, coagulopathy, and markedly elevated bilirubinemia (often >50 mg/dL) May be recurrent and progress to chronic liver disease	Exchange
Acute chest syndrome	Develops in >30% of patients with SCD in their lifetime Leading cause of death Signs and symptoms include pulmonary infiltrate on chest X-ray, shortness of breath, chest pain, and/or fever May not be the presenting diagnosis; often develops during admission for pain crisis or following anesthesia Precipitants include fat embolism from bone marrow infarction, pulmonary infarction, pneumonia, asthma	Simple or exchange ^c Simple transfusion may be effective if instituted promptly RCE is recommended with rapid clinical deterioration or progressive hypoxemia/respiratory distress despite simple transfusion
Preoperative high-risk surgery	Transfusions to a Hb goal of 10 g/dL before surgery reduces the risk of perioperative sickle cell–related complications in surgeries requiring general anesthesia Perioperative treatment should also include hydration, body temperature maintenance, adequate oxygenation, and incentive spirometry	Simple or exchange ^d RCE may be warranted in high-risk surgeries such as major cardiothoracic, vascular, or neurosurgical procedures and in patients with HbSC to prevent hyperviscosity
Chronic prophylactic
Pregnancy	With fetal or maternal complications: indicated in patients with previous fetal/neonatal mortality or morbidity, current risk factors (e.g., multiple gestations), obstetric complications (e.g., preeclampsia), or SCD-related complications (pain crisis or acute chest syndrome; more common in the third trimester) Universal 3rd trimester prophylaxis is controversial	Simple or exchange Decision of which trimester to initiate chronic transfusion should be individualized per history and risk factors
Stroke prevention (overt and silent cerebral infarct)	Primary stroke prophylaxis: Prophylactic chronic transfusion in children with high stroke risk by transcranial Doppler (TCD) ≥200 cm/s reduces a first stroke risk of 10% of patients per year by 92% (STOP trial) ^e . Hydroxyurea is noninferior to transfusions for stroke prevention in high-risk (by TCD) children who have received at least 1 year of transfusions and have no MRA-defined severe vasculopathy (TWITCH trial) ^f . Transfusions should be continued indefinitely, however, in the absence of hydroxyurea due to an otherwise high risk of TCD reversion, stroke, and silent infarcts (STOP II trial) ^g Secondary stroke prevention: chronic transfusion is effective for prevention of recurrent stroke, decreasing overt stroke recurrence from ∼70% in the absence of chronic transfusion therapy to 20% for new overt stroke and 27% for silent cerebral infarcts ^h . Hydroxyurea is not as effective as transfusion for prevention of recurrent stroke (SWITCH trial) ⁱ Silent cerebral infarcts: in patients with silent cerebral infarct alone (normal TCD and no history of overt stroke), chronic transfusion therapy reduces the incidence of overt stroke and new/enlarging silent cerebral infarcts, which are associated with neurocognitive disability and poor academic achievement (SIT trial) ^j	Simple or exchange The goal of chronic transfusion therapy for both primary and secondary stroke prophylaxis is to maintain HbS ≤30% and Hb at 10 g/dL Some reports suggest that the HbS target can be raised to <50% after 3 years of stability, but strong evidence is lacking
Controversial indications
Recurrent pain episodes	STOP trial showed a significant decrease in frequency of severe pain episodes with chronic transfusion	Simple or exchange
Recurrent acute chest syndrome	Multiple episodes of ACS may contribute to chronic lung disease such as pulmonary fibrosis and pulmonary hypertension STOP trial showed a decrease in frequency of ACS with chronic transfusion	Simple or exchange
Recurrent splenic sequestration	Chronic transfusion to prevent recurrence or delay splenectomy	Simple
Priapism	Acute transfusion reasonable if symptoms persist despite initial treatment with hydration, analgesia, and urologic intervention Reports of ASPEN syndrome (Association of sickle cell disease, Priapism, exchange transfusion, and neurologic events) are related to acute increases in blood viscosity avoidable by targeting an end Hct close to the patient’s baseline.	Simple or exchange avoiding an end Hct > 30%
Leg ulcers	Chronic transfusion therapy reasonable in conjunction with local measures (surgical debridement or grafts) until ulcer healed	Simple or exchange
Possible future indications
Pulmonary hypertension ^k	Prevalent in 6%–10% of adult patients when confirmed by right heart catheterization Associated with increased mortality Nitric oxide depletion by hemolysis may be causal factor Agents approved for pulmonary hypertension in other disease populations are not yet proven beneficial in SCD patients
Chronic kidney disease ^l	Microalbuminuria is a risk factor for chronic kidney disease and is associated with low hemoglobin.
Congestive heart failure/diastolic dysfunction	Appears to be related to anemia for which transfusion may therefore assuage ^m ⁿ
Nonindications
Acute pain crisis	Main treatment is hydration, analgesia, and incentive spirometry
Avascular necrosis	Causative factors of AVN are still unclear; treatment is focused on local interventions such as core decompression.

a Howard, J., Malfroy, M., Llewelyn, C., Choo, L., Hodge, R., Johnson, T., et al. (2013). The transfusion alternatives preoperatively in sickle cell disease (TAPS) study: A randomized, controlled, multicentre clinical trial. Lancet (Lond Engl), 381 (9870), 930–938.

b Vichinsky, E. P., Haberkern, C. M., Neumayr, L., Earles, A. N., Black, D., Koshy, M., et al. (1995). A comparison of conservative and aggressive transfusion regimens in the perioperative management of sickle cell disease. The Preoperative Transfusion in Sickle Cell Disease Study Group. N Engl J Med, 333 (4), 206–213.

c Adams, R. J., McKie, V. C., Hsu, L., Files, B., Vichinsky, E., Pegelow, C., et al. (1998). Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med, 339 (1), 5–11.

d Ware, R. E., Davis, B. R., Schultz, W. H., Brown, R. C., Aygun, B., Sarnaik, S., et al. (2016). Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anemia-TCD with transfusions changing to hydroxyurea (TWiTCH): A multicentre, open-label, phase 3, noninferiority trial. Lancet (Lond Engl), 387 (10019), 661–670.

e Abboud, M. R., Yim, E., Musallam, K. M., & Adams, R. J. (2011). Discontinuing prophylactic transfusions increases the risk of silent brain infarction in children with sickle cell disease: data from STOP II. Blood, 118 (4), 894–898.

f Hulbert, M. L., McKinstry, R. C., Lacey, J. L., Moran, C. J., Panepinto, J. A., Thompson, A. A, et al. (2011). Silent cerebral infarcts occur despite regular blood transfusion therapy after first strokes in children with sickle cell disease. Blood, 117 (3), 772–779.

g Estcourt, L. J., Fortin, P. M., Hopewell, S., Trivella, M., Hambleton, I. R., & Cho, G. (2016). Regular long-term red blood cell transfusions for managing chronic chest complications in sickle cell disease. Cochrane Database Syst Rev , (5), Cd008360.

h Hirst, C., & Williamson, L. (2012). Preoperative blood transfusions for sickle cell disease. Cochrane Database Syst Rev, 1 , Cd003149.

i Ware, R. E., Schultz, W. H., Yovetich, N., Mortier, N. A., Alvarez, O., Hilliard, L., et al. (2011). Stroke with transfusions changing to hydroxyurea (SWiTCH): A phase III randomized clinical trial for treatment of children with sickle cell anemia, stroke, and iron overload. Pediatr Blood Cancer, 57 (6), 1011–1017.

j DeBaun, M. R., Gordon, M., McKinstry, R.C., Noetzel, M. J., White, D.A., Sarnaik, S. A., et al. (2014). Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia. N Engl J Med, 371 (8), 699–710.

k Detterich, J. A., Kato, R. M., Rabai, M., Meiselman, H. J., Coates, T. D., & Wood, J. C. (2015). Chronic transfusion therapy improves but does not normalize systemic and pulmonary vasculopathy in sickle cell disease. Blood, 126 (6), 703–710.

l Alvarez, O., Montane, B., Lopez, G., Wilkinson, J., & Miller, T. (2006). Early blood transfusions protect against microalbuminuria in children with sickle cell disease. Pediatr Blood Cancer, 47 (1), 71–76.

m Westwood, M. A., Shah, F., Anderson, L. J., Strange, J. W., Tanner, M. A., Maceira, A. M., et al. (2007). Myocardial tissue characterization and the role of chronic anemia in sickle cell cardiomyopathy. J Magn Reson Imaging, 26 (3), 564–568.

n Niss, O., Fleck, R., Makue, F., Alsaied, T., Desai, P., Towbin, J. A., et al. (2017). Association between diffuse myocardial fibrosis and diastolic dysfunction in sickle cell anemia. Blood, 130 (2), 205–213.

For automated RCE procedures, the apheresis instrument will calculate the required volume of RBC replacement based on patient and target parameters. Use of the RBCX Calculation Tool app developed by TerumoBCT is recommended (see Chapter 76 ). If unavailable, a simple way to estimate the number of units to order, which assumes that the patient has 100% HbS-containing RBCs, is provided in Table 52.2 . Performance of manual RCE is outlined in Table 52.3 . Chapter 49 includes the dosing calculation for simple RBC transfusion in pediatric patients.

Table 52.2

Estimation for Number of Red Blood Cell (RBC) Units to Order for Automated Red Cell Exchange (RCE) ^a

1.
RBC volume (mL) = current Hct × total blood volume
2.
Number of RBC units to maintain current Hct = RBC volume/180 mL
3.
Number of RBC units to raise current Hct to desired Hct = (desired Hct − current Hct)/3
4.
Total number of RBC units to order = Equation 3 + Equation 4 (roundup)

a Assumes the patient’s RBC Volume is 100% HbS-containing RBCs.

Table 52.3

Manual RCE Procedure ^a

Adults

1.
Phlebotomize 500 mL whole blood, infuse 500 mL normal saline
2.
Phlebotomize 500 mL whole blood, infuse 2 RBC units
3.
Repeat Steps 1 and 2 until the total blood volume exchanged equals 1.5 times the patient’s RBC volume

Infants

1.
Calculate RBC product volume to prepare for transfusion based on formula in Table 50.4
2.
Phlebotomize 5–10 mL/kg, infuse an equivalent volume of RBC product
3.
Repeat Step 2 until 1–2 times the patient’s total blood volume has been exchanged

a Utilizing stopcocks for whole blood removal and infusion of RBC product is helpful.

Red Blood Cell Product Selection

RBC products are typically matched for DCE and K RBC antigens, leukocyte-reduced, and HbS-negative to decrease the risk of RBC and HLA alloimmunization and accurately assess HbS percentage.

Antigen Matched

All SCD patients should have an extended antigen genotype or phenotype (ABO, Rh, Kell, Kidd, Duffy, Lewis, and MNS system antigens) on record to better manage alloimmunization risk. Molecular genotyping is preferable to serologic phenotyping due to likely history of recent transfusion, its ability to detect Rh variants (D, CEe), and type for antigens for which there are no serologic reagents.

Prophylactic RBC matching for C, E, K antigens decreases the risk of RBC alloimmunization, and more extensive prophylaxis that includes Duffy, Kidd, and S antigens can be initiated, especially if alloantibodies to Kidd, Duffy, S, or Dombrock antigens have formed. Limitations to prophylactic matching include increased cost, inventory management, and procurement delays, so urgently needed RBC transfusion should not be delayed for the purpose of prophylactic matching (in contrast to matching for already formed RBC alloantibodies).

Risks of Transfusion

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