What are the guidelines for transfusion therapy in patients with sickle cell disease?

Transfusion Guidelines for Sickle Cell Disease

All patients with sickle cell disease receiving transfusions should receive prophylactic red cell antigen matching for Rh (C, E or C/c, E/e) and K antigens, with an extended red cell antigen profile obtained by genotype or serology at the earliest opportunity, optimally before the first transfusion. 1

Red Cell Antigen Matching and Alloimmunization Prevention

Extended Antigen Profiling

• Obtain an extended red cell antigen profile (C/c, E/e, K, Jka/Jkb, Fya/Fyb, M/N, S/s at minimum) by genotype or serology before the first transfusion whenever possible 1
• Genotyping is preferred over serologic phenotyping as it provides additional antigen information and increased accuracy for C antigen determination and Fyb antigen matching 1
• Serologic phenotyping may be inaccurate if the patient has been transfused in the last 3 months 1

Mandatory Antigen Matching

• Match for Rh (C, E or C/c, E/e) and K antigens for all transfusions (strong recommendation) 1
• Extended matching for Jka/Jkb, Fya/Fyb, and S/s provides further protection from alloimmunization 1
• Patients with GATA mutation in the ACKR1 gene are not at risk for anti-Fyb and do not require Fyb-negative red cells 1
• Patients with hybrid RHDDIIIa-CE (4-7)-D or RHCECeRN alleles encoding partial C antigen should receive C-negative red cells to prevent allo-anti-C development 1

Acute Complications Requiring Transfusion

Acute Chest Syndrome (ACS)

For severe ACS (bilateral infiltrates, rapidly progressive disease), automated or manual red cell exchange (RCE) is preferred over simple transfusion 1, 2

Severe ACS Management

• Automated RCE is preferred over manual RCE as it more rapidly reduces HbS levels 1, 2
• Target HbS reduction to <30% (ideally <20%) 2
• Consider RCE for patients who do not respond to initial simple transfusion or have high pretransfusion hemoglobin levels that preclude simple transfusion 1
• Pre- and post-procedure complete blood count and hemoglobin fractionation should be obtained 1

Moderate ACS Management

• Either automated RCE, manual RCE, or simple transfusions may be used for moderate ACS 1
• Simple transfusions were effective in more than 75% of ACS cases in recent observational data 3

Critical Pitfall: Do not delay exchange transfusion while waiting for simple transfusion to work in patients with bilateral infiltrates, as this represents severe disease requiring immediate HbS reduction 2

Hemolytic Transfusion Reactions

For patients with delayed hemolytic transfusion reaction and ongoing hyperhemolysis, immunosuppressive therapy (IVIg, steroids, rituximab, and/or eculizumab) is recommended over no immunosuppressive therapy 1, 4

Immunosuppressive Regimens

• IVIg: 0.4-1 g/kg/day for 3-5 days (up to total dose of 2 g/kg) 4
• High-dose steroids: Methylprednisolone or prednisone 1-4 mg/kg/day 4
• Rituximab: 375 mg/m² repeated after 2 weeks, primarily for prevention of additional alloantibody formation 4

Critical Management Principle

• Avoid further transfusion unless the patient is experiencing life-threatening anemia with ongoing hemolysis, as additional transfusions may worsen hemolysis and potentially induce multiorgan failure and death 4
• If transfusion is absolutely warranted for life-threatening anemia, use extended matched red cells (C/c, E/e, K, Jka/Jkb, Fya/Fyb, S/s) 4
• Initiate erythropoietin with or without IV iron in all patients 4

High-Risk Patients Requiring Acute Transfusion

For patients with an acute need for transfusion and at high risk for acute hemolytic transfusion reaction or with a history of multiple or life-threatening delayed hemolytic transfusion reactions, consider immunosuppressive therapy (IVIg, steroids, and/or rituximab) through shared decision-making between hematologist and transfusion medicine specialist 1, 4

Chronic Transfusion Therapy

Transfusion Modality Selection

Either red cell exchange with isovolemic hemodilution (IHD-RCE) or conventional RCE may be used for patients receiving chronic transfusions 1

• IHD-RCE involves red cell depletion with concurrent volume replacement (normal saline or 5% albumin) before the RCE to decrease the number of red cell units needed 1
• Consultation with a hematologist and transfusion medicine specialist is advised to assess safety for the individual patient and technical specifications 1
• Maintain sickle hemoglobin levels of less than 30% prior to the next transfusion during long-term transfusion therapy 5

Iron Overload Monitoring

Screen for iron overload by MRI for liver iron content rather than serial monitoring of ferritin levels alone in patients receiving chronic transfusion therapy 1

Liver Iron Monitoring

• Use validated R2, T2*, or R2* methods; if unavailable, refer to a specialized center 1
• Use the same method (R2, T2*, or R2*) over time 1
• If ferritin level is <1000 ng/mL and patient is receiving chronic transfusion by RCE with neutral or negative iron balance, MRI for liver iron content is likely not needed 1

Cardiac Iron Monitoring

• Routine cardiac T2 MRI screening is not recommended for all patients* 1
• Perform cardiac T2* MRI screening for patients with high iron burden (liver iron content >15 mg/g dry weight) for 2 years or more, evidence of end organ damage from transfusional iron overload, or evidence of cardiac dysfunction 1

Perioperative Transfusion

Preoperative transfusion is recommended over no preoperative transfusion for patients undergoing surgeries requiring general anesthesia and lasting more than 1 hour 1, 5

• Aim for total hemoglobin levels of more than 9 g/dL before surgery 1
• Preoperative transfusion therapy to increase hemoglobin levels to 10 g/dL is strongly recommended 5
• Decision-making should consider genotype, risk level of surgery, baseline total hemoglobin, complications with prior transfusions, and disease severity 1

Pregnancy

Either prophylactic transfusion at regular intervals or standard care (transfusion when clinically indicated for a complication or hemoglobin lower than baseline) may be used for pregnant patients with SCD 1

The evidence is equivocal, with very low certainty; therefore, in real-life clinical practice, the decision should be made based on disease severity, history of complications, and shared decision-making with the patient 1

Common Pitfalls and Caveats

• Do not use simple transfusion alone if the patient has high baseline hemoglobin, as this increases viscosity and worsens vaso-occlusion 2, 6
• Transfusions can paradoxically trigger sickle cell events, including pain crises and acute chest syndrome, due to increased blood viscosity 7, 6
• Alloimmunization rates in SCD patients range from 7-30%, making future transfusions more difficult 7, 8
• Patients with small total blood volumes require a red cell prime for automated RCE because of the extracorporeal volume of the apheresis machine 1
• Leukocyte-reduced units should be standard to reduce alloimmunization, transfusion reactions, platelet refractoriness, and infection transmission 6
• Monitor for bacterial infections, particularly Yersinia enterocolitica in iron-overloaded patients 6