Transfusion medicine

Therapeutic apheresis

Red blood cell exchange


Editorial Board Member: Kyle Annen, D.O.
Deputy Editor-in-Chief: Patricia Tsang, M.D., M.B.A.
Timothy Carll, M.D.
Geoffrey Wool, M.D., Ph.D.

Last author update: 14 February 2022
Last staff update: 14 February 2022

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PubMed Search: Red blood cell exchange[TI] OR erythrocytapheresis "free full text"[SB]

Timothy Carll, M.D.
Geoffrey Wool, M.D., Ph.D.
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Cite this page: Carll T, Wool G. Red blood cell exchange. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/transfusionmedrbcexchange.html. Accessed February 3rd, 2023.
Definition / general
  • Automated technique that separates red blood cells (RBCs) from whole blood and replaces with replacement fluid
    • When replacement fluid is donor packed red blood cells (pRBCs), the procedure is referred to as red blood cell exchange (RBCX)
    • When replacement fluid is crystalloid or colloid solution, the technique is referred to as erythrocytapheresis (Greek: aphaíresis, "taking away")
Essential features
  • Therapeutic technique directed at correcting disease driven by congenital or acquired abnormality of red blood cells
  • Sickle cell disease (SCD) is the most common indication; American Society for Apheresis (ASFA) category I indications for RBCX in SCD include treatment of acute stroke and chronic prevention of stroke
    • Other indications include parasitemias, such as babesiosis and malaria
  • Red blood cell exchange requires donor pRBCs; having valid antibody screen testing on the patient is crucial and blood should be antigenically matched in sickle cell patients
  • Hereditary hemochromatosis (HH) and polycythemia vera (PV) are ASFA category I indications for erythrocytapheresis, with modest efficacy advantages over simple therapeutic phlebotomy
Terminology
  • Total blood volume (TBV):
    • Estimated from patient height, weight and sex
    • Preferred method is Nadler formula
  • Red blood cell volume (mass) (RBCV):
    • Calculated by multiplying total blood volume and hematocrit (Hct)
  • Hemoglobin S as a percentage of blood hemoglobin (HbS%):
    • Marker of disease severity in sickle cell disease best measured by high performance liquid chromatography (HPLC)
  • Fraction of cells remaining (FCR):
    • Fraction of residual patient red blood cells following exchange, a marker of procedure performance
    • 1.0 would indicate no replacement of patient cells, 0.0 would reflect complete replacement
  • Whole blood to anticoagulant ratio (WB:AC):
    • Inversely reflects degree of anticoagulation in extracorporeal circuit
    • Ratios of 10:1 to 15:1 are commonly used for un-anticoagulated patients
  • Inlet rate:
    • Refers to volume of whole blood drawn per unit time from patient
    • Directly affects procedure runtime
American Society for Apheresis (ASFA) guidelines
  • Published triennially (every 3 years)
  • Categories published based on best evidence; organized into 4:
    • Category I: disorders for which apheresis is accepted as first line therapy
    • Category II: disorders for which apheresis is accepted as second line therapy
    • Category III: optimum role of apheresis therapy is not established; decision making should be individualized
    • Category IV: disorders in which published evidence demonstrates or suggests apheresis to be ineffective or harmful
  • Reference: J Clin Apher 2019;34:171
Indications for red blood cell exchange
  • Sickle cell disease:
    • Congenital hemoglobinopathy caused by beta globin mutation
    • Disease can be caused by homozygous HbS or compound heterozygotes (HbSC, HbS beta thalassemia)
    • In HbSS patients with acute exacerbation, goal of RBCX is generally to reduce HbS to 30% or lower
      • Homozygotic patients with no HbS% data available can generally be assumed to have 90 - 100% HbS unless transfused within past 100 days
    • In patients with HbSC disease or other symptomatic compound heterozygous sickling disorder, goal of RBCX is generally to increase HbA to 70% or higher (i.e. the combined fraction of [HbS + HbX] is 30% or less)
    • Acute indications
      • Acute stroke: category I
      • Acute chest syndrome, severe: category II
      • Other complications (vaso-occlusive crisis, dactylitis, priapism, sequestration): category III
    • In patients with prior stroke or other severe sequelae of SCD or to prevent complication of pregnancy / surgery, goal of RBCX is to maintain HbS < 30 - 50%; HbS% data is generally necessary for procedure planning
      • Note: simple transfusion of pRBCs may be indicated as a temporizing measure while vascular access is obtained and blood is procured
    • Chronic indications
      • Chronic stroke prophylaxis (primary or secondary): category I
      • Pregnancy: category II
      • Recurrent veno-occlusive crises: category II
      • Preoperative management: category III
  • Parasitemias:
    • Severe infection by intraerythrocytic parasites, typically Plasmodium or Babesia
    • Diagnosis requires laboratory evidence of hemolysis and blood smear examination demonstrating organisms
    • RBCX is generally adjunctive to antiparasitic therapy when > 10% parasitemia with severe symptoms
      • 2 times RBC volume exchange is standard
    • Babesiosis: category II
    • Malaria: category III
  • ABO incompatibility:
    • Prevention / amelioration of hemolysis in major ABO incompatibility may be achievable through RBCX
    • Major ABO incompatible red cell transfusion:
      • Rationale is to remove incompatible transfused cells before total hemolysis occurs
      • In practice, cells hemolyze rapidly and practice is not recommended
      • Note: plasma exchange could be considered for removal of excess free hemoglobin to treat moderate to severe nephrotoxicity caused by hemolysis of incompatible RBCs
    • Red cell alloimmunization:
      • Usually to prevent immunization to RhD by RhD negative women in setting of accidental or emergency exposure to RhD positive cells or massive hemorrhage by RhD positive pregnancy
      • Category III
    • Minor ABO incompatible hematopoietic stem cell transplantation:
      • To prevent hemolysis of recipient RBCs by donor isohemagglutinins
      • Effectively accelerates patient ABO conversion
      • Category III
  • Reference: J Clin Apher 2019;34:171
Indications for erythrocytapheresis
  • Hereditary hemochromatosis:
    • Treat iron overload by removal of RBC mass, goal ferritin < 50 ng/mL
    • Erythrocytapheresis can more rapidly correct hyperferritinemia than therapeutic phlebotomy but incurs a higher procedure cost
    • Category I
  • Polycythemia vera:
    • Treat polycythemia by removal of RBC mass, goal hematocrit ≤ 45%
    • Erythrocytapheresis can more rapidly correct polycythemia than therapeutic phlebotomy and may be preferred in hemodynamically unstable patients
    • Category I
  • Reference: J Clin Apher 2019;34:171
Replacement fluid
  • For RBCX, obtain type and screen and procure donor pRBCs for replacement fluid, if needed
  • Patients with sickle cell disease require prophylactic antigen matching per National Heart, Lung and Blood Institute (NHLBI) guidelines
    • Procuring antigen negative compatible blood may cause delay
  • ABO, RH group and K recommended for sickle cell patients which no prior history of antibody formation
  • Extended matching (ABO, RH group, K, Duffy, Kidd and Ss systems) recommended for patients with a history of antibody formation
  • Reference: JAMA 2014;312:1033
Exchange volume
  • Removal of pathogenic substances in apheresis follows decay equation: Y/Yo = e-X
    • Y = residual pathogenic substance (note: fraction of cells remaining = Y/Yo)
    • Yo = initial pathogenic substance
    • X = number of volumes exchanged (in RBCX, red blood cell volume equivalents)
  • Determine the required number of volumes to exchange and convert into donor pRBC volume
    • Recall that most pRBC units are stored with additive solution and have a hematocrit of approximately 60%
    • Prediction of RBCX efficiency is optimized by accurate knowledge of pRBC unit hematocrit
  • Example:
    • Patient with 5 L total blood volume and 30% hematocrit has 90% HbS
    • RBCX is requested with an end goal of 30%
    • Goal fraction of cells remaining is (30/90) = 33%
    • Solving for X indicates that ~1.1 times the RBC volume should be exchanged
    • Patient's RBC volume is (5,000 mL x 0.3) = 1,500 mL
    • 1,650 mL of red cell mass should be exchanged or (1,650/0.60) = 2,750 mL of pRBCs
    • Exchange should be performed with 9 - 10 units of pRBCs
  • Automated calculator mobile app is available for free from TerumoBCT
  • Note that exchange becomes less efficient with higher volumes; most acute procedures tend to exchange about 1.0 times RBC volume
  • Note: end procedure patient hematocrit can be programmed; increasing patient hematocrit in this fashion requires further pRBCS but may improve symptoms and reduce reticulocytosis
    • Keep in mind that increasing end hematocrit will increase patient iron load and serum ferritin
    • End hematocrit should generally be ≤ 33% (and never higher than 36%) to avoid hyperviscosity in SCD; end hematocrit of 30% is typical
  • Reference: Transfusion 2018;58:1965
Simple exchange, depletion and depletion / exchange
  • In simple exchange, donor pRBCs are transfused to patient in an isovolemic fashion to offset removal of diseased RBCs
  • In depletion, crystalloid or colloid replacement is infused instead of donor pRBCs; this process is standard in erythrocytapheresis for polycythemia vera or hereditary hemochromatosis
  • Hybrid depletion / exchange can be performed, wherein a brief depletion phase is followed by exchange with donor pRBCs
    • This marginally improves procedure efficiency and may have implications on iron homeostasis (contested)
  • Reference: Transfusion 2018;58:1965
Vascular access
  • In adults, choice of vascular access should be able to support inlet rate of 30 mL/min or ideally up to and above 60 mL/min
    • Generally, procedure is performed continuously with 2 points of intravenous access
  • Peripheral IVs:
    • Least invasive
    • Should be considered in patients with adequate veins for peripheral access before resorting to central lines
  • Central venous catheters:
    • Femoral access confers higher infection rate but fewer placement complications (e.g. pneumothorax) than internal jugular or subclavian access and does not require imaging to confirm placement
    • Nontunneled lines are appropriate for short term inpatient exchange in patients who fail peripheral access
    • Tunneled lines (Permcath) can be used for intermediate duration of procedures on outpatient basis
    • Peripherally inserted central catheters (PICCs) generally cannot sustain required inlet rates and are inappropriate for apheresis procedures
  • Ports:
    • Appropriate for patients requiring chronic exchange on outpatient basis
    • Note required inlet rates; standard infusion ports are not adequate
    • Vortex (AngioDynamics) or PowerFlow (Becton-Dickinson) ports are recommended
  • Reference: Transfusion 2018;58:569
Anticoagulation
  • Majority of apheresis procedures use citrate to anticoagulate extracorporeal circuit
    • Patients who are systemically anticoagulated (e.g. high dose heparin therapy) may require less or even no anticoagulation
    • Citrate prevents clotting by binding calcium that is required for secondary hemostasis
  • Default whole blood to anticoagulant ratio is 12:1; increasing the ratio decreases the anticoagulation dose to patient and slightly increases speed of procedure at risk of extracorporeal clot formation
  • Reference: Transfus Apher Sci 2019;58:132
Circuit priming
  • Extracorporeal circuit must be purged of air; saline is used for initial purge as part of standard kit operation
  • When exchanging patients with low total blood volume (infants or small children) or at risk of severe intraprocedural anemia, circuit may then be primed with pRBCs (1 unit is sufficient)
    • pRBC prime if extracorporeal volume (ECV) exceeds 15% of patient total blood volume
    • Spectra Optia therapeutic kit ECV is 185 mL plus blood warmer tubing volume or other circuit dead volume
  • Rinseback refers to end of procedure purging of circuit back to patient
    • If pRBCs were used for prime, rinseback may be modified, as rinseback would result in net transfusion of the unit used for priming
Adverse events
  • Use of a blood warmer is recommended for prevention of hypothermia
  • Citrate toxicity:
    • Most frequent adverse effect, related to hypocalcemia
    • Often limited to paresthesias or numbness
    • Severe complications include nausea / vomiting, muscle spasms or cardiac arrhythmias
    • Severe citrate toxicity in red blood cell exchange is rare; oral calcium repletion is generally sufficient to resolve mild symptoms
  • Transfusion reactions:
    • Apheresis provider should evaluate for acute reactions to donor pRBCs, including allergic reaction, transfusion related acute lung injury (TRALI) and acute hemolysis
    • Apheresis and other patient providers should be alert to delayed transfusion reactions that occur 24 hours to 28 days later, such as delayed hemolysis or transfusion transmitted infection
  • Line and procedural related complications:
    • Improper line placement or pneumothorax following internal jugular or subclavian line placement must be ruled out with plain film chest Xray
    • Hypotension during apheresis is common due to fluid shifts but is a known complication in setting of ACE inhibitor use due to contact activation of bradykinin in extracorporeal circuit
    • Line infection and bacteremia may present as fever during procedure and should be prevented by proper line care
  • Reference: Transfusion 1999;39:282
Sample assessment & plan
  • Assessment and plan: John Doe is a 25 year old man with history of sickle cell disease (HbSS) who is admitted for leg and back pain consistent with veno-occlusive crisis. He is normally treated with Hydrea as an outpatient. His baseline hemoglobin is 10 g/dL and his current hemoglobin is also 10 g/dL. He has not been transfused this admission. 2 days into admission, he developed shortness of breath and an oxygen requirement (saturating 86% on room air). Chest plain film imaging shows bilateral opacities concerning for acute chest syndrome. Apheresis service is consulted for urgent red cell exchange by the inpatient Heme / Onc consulting team. A central line is currently being placed.
  • Severe acute chest syndrome is a category II (grade 1C) indication for red cell exchange according to 2019 ASFA guidelines (J Clin Apher 2019;34:171). Emergent exchange is indicated for acute chest syndrome with severe features (SaO2 < 90%). The apheresis service will perform inpatient red cell exchange to reduce his HbS to < 30% and to effect an acute change in his respiratory condition with the following parameters:
    • Height: 69 inches / 175 centimeters
    • Weight: 165 pounds / 75 kilograms
    • Hematocrit: 30% per most recent CBC
    • TBV: ~5,000 mL
    • RBCV: ~1,500 mL
    • Current HbS%: currently unknown (no Hb eval sent), assume 90%
    • Goal HbS%: < 30%
    • Goal FCR: 33.3%
  • Type & screen drawn on admission is negative. All past antibody screens are negative. Patient is group A positive. STAT order placed with blood supplier for 10 units group A pRBC as below.
  • Primary team to verify appropriate line placement and vascular access.
  • Nurse to perform simple red cell exchange with 10 units of antigen negative, crossmatch compatible pRBCs, negative for C, E, K antigens and negative for HbS (SickleDex).
  • Set start and end hematocrit both to 30%. Set WB:AC ratio to 12.
  • Nurse to monitor for signs and symptoms of hypocalcemia. 2 g PO calcium carbonate ordered PRN. Page blood bank physician on call for any issues or patient reactions.
  • Postprocedure:
    • Patient tolerated red cell exchange well. During the visit, he was comfortable and did not complain of itching, numbness or paresthesias. No adverse reactions were noted by nursing. Per Optia instrument, the final FCR was 29%; therefore, residual HbS% is expected to be approximately 26%.
    • Primary team: Please draw hemoglobin electrophoresis to assess HbS%.
  • This patient has been seen by and discussed with the attending blood bank physician. Their written attestation is to follow.
Board review style question #1
Which of the following conditions is considered an American Society for Apheresis (ASFA) category I indication for red cell exchange?

  1. Acute chest syndrome in sickle cell disease
  2. Babesiosis
  3. Prevention of hemolysis in ABO major incompatible packed red blood cell transfusion
  4. Stroke in sickle cell disease
  5. Thrombotic thrombocytopenic purpura
Board review style answer #1
D. Stroke in sickle cell disease. In sickle cell disease, acute treatment or prevention of stroke are both category I ASFA indications for red blood cell exchange. Thrombotic thrombocytopenic purpura is a category I indication for therapeutic plasma exchange (TPE). Severe acute chest syndrome is a category II indication for red blood cell exchange. Prevention of hemolysis in major incompatible transfusion is unlisted in the 2019 ASFA guidelines but is not recommended. Babesiosis is a category II indication for red blood cell exchange.

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Reference: Red blood cell exchange
Board review style question #2
A red cell exchange is requested for a 50 kg, 165 cm man with sickle cell disease with acute stroke. His hematocrit is 27% and his HbS is 90%. Because of antigen matching requirements, only 4 units of packed red blood cells (300 mL volume each, at 60% hematocrit) are immediately available. What is the expected postprocedural HbS if all 4 units are used and end hematocrit is left at 27%?

  1. 27%
  2. 30%
  3. 45%
  4. 50%
  5. 70%
Board review style answer #2
C. 45%. The available donor red cell mass to exchange is (300 mL x 0.60 x 4) = 720 mL. The patient's total blood volume is ~3,900 mL (via Nadler formula). At a hematocrit of 27%, his red blood cell volume is ~1,050 mL. Using all 4 units would amount to a (720/1,050) = 0.69 red blood cell volume exchange, with a resulting fraction of cells remaining of e-0.69 = 50%. If the patient's starting HbS is 90%, the expected postexchange HbS should be 45%.

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Reference: Red blood cell exchange
Board review style question #3
Which of the following vascular access methods is inappropriate for red cell exchange?

  1. Arteriovenous fistula
  2. Existing extracorporeal circuits (e.g. extracorporeal membrane oxygenation)
  3. Mahurkar catheter
  4. Nonpower single lumen port
  5. Quinton catheter
Board review style answer #3
D. Nonpower single lumen port. Most single lumen nonpower injectable ports, such as most standard chemo infusion ports, cannot support the pressure and inlet rates needed for apheresis procedures. Additionally, 2 access sites are necessary for continuous apheresis. Quinton and Mahurkar catheters are both central venous catheters (CVCs) generally used for hemodialysis and are adequate for apheresis. Special attention should be given to the catheter diameter and length to ensure flow rates of up to 60 mL/min or greater can be supported. For reference, typical inlet rates in hemodialysis may exceed 120 mL/min. Arteriovenous fistulas are acceptable for access but require training for safe access. Extracorporeal circuits are also acceptable for apheresis procedures but the additional extracorporeal volume should be factored into consideration and coordination with extracorporeal membrane oxygenation team is necessary.

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