EXPLANATION


Sickle cell anemia is an autosomal recessive genetic disorder affecting the beta-chain of hemoglobin located on chromosome 11, in which the substitution of valine by glutamine leads to a defective hemoglobin subtype, termed HbS. Patients with a homozygous genotype (HbSS), also known as sickle cell disease (SCD), typically have a fractional HbS concentration between 70 and 98%. Patients with the heterozygous genotype (HbAS), known as sickle cell trait (SCT), are generally asymptomatic and have a fractional HbS concentration below 50%. During a sickling crisis, HbS polymerizes and red blood cell (RBC) shape becomes distorted, thereby losing the ability to deform when passing through the microcirculation. This leads to widespread microvascular occlusion and inflammation of the vascular endothelium. These crises clinically manifest as acute chest syndrome or painful vaso-occlusive events due to tissue ischemia. Sickled RBCs have a shorter lifespan and are prone to hemolysis, resulting in anemia and the need for frequent RBC transfusions. Precipitating factors for sickling include hypoxia, acidosis, hypothermia, hypovolemia, infection, vascular stasis, stress, and inflammatory states. Repeated microvascular occlusion causes localized endothelial injury and inflammation, increasing the propensity for further RBC entrapment. When exposed to a partial pressure of oxygen (P_aO₂) below 40 mm Hg, HbSS RBCs undergo sickling, while the HbAS RBCs do not sickle until the P_aO₂ falls below 15 mmHg. Interestingly, fetal Hb (HbF) is protective against sickling. Thus, symptoms of SCD do not manifest until conversion from the fetal gamma-chain to the adult beta-chain is complete at approximately six months of age. Hydroxyurea has been the mainstay of therapy used to increase the percentage of HbF in patients with SCD. Recently, in December of 2023, the US Food and Drug Administration approved two cell-based gene therapies for the treatment of SCD called Casgevy and Lyfgenia. Both are approved for SCD in patients 12 years and older with recurrent vaso-occlusive crises. Casgevy modifies hematopoietic stem cells by genome editing technology, overall resulting in greater production of HbF. Lyfgenia is a cell-based gene therapy that genetically modifies hematopoietic stem cells to produce adult hemoglobin (HbA).


Patients with SCD undergoing cardiac surgery with cardiopulmonary bypass (CPB) encounter multiple triggers for sickling of RBCs. The perioperative goal is to reduce or prevent RBC sickling and vaso-occlusive crisis. Transfusion of RBCs is the main treatment toward this goal. RBC sickling is in part dependent on the proportion of HbS present, the patient’s disease phenotype and fragility, and the extent of exposure to triggers. Consensus perioperative recommendations from the American Society of Hematology state that for minor surgery, patients with a history of mild vaso-occlusive crises and low percentage of HbS should receive transfusion of allogenic RBCs to a target hemoglobin of 10 g/dL (without consideration of the proportion of circulating HbS). For major surgery, (i.e. cardiac and neurologic) recommendations center on decreasing the fractional concentration of HbS with the goal of less than 30% via exchange transfusion. The clinical reasoning for this approach is patients with a higher fractional concentration of HbS will benefit more from exchange transfusion, as simple transfusion alone will not significantly decrease the proportion of HbS.


During cardiac surgery with cardiopulmonary bypass (CPB), intraoperative exchange transfusion can be accomplished using the bypass circuit to minimize circulating HbS prior to initiating CPB. Whole blood from the patient is separated into components. The RBCs are discarded after separation, and platelets with the plasma are transfused back to the patient at the conclusion of CPB. Although exchange transfusion could be done preoperatively, the CPB circuit streamlines the process. The bypass circuit can be modified to facilitate an exchange transfusion by adding a shunt in the venous line to drain out volume while simultaneously delivering prime volume of washed RBCs and plasma. Other considerations for perfusion include modifications to the bypass circuit and strategies to reduce the risk of vaso-oclusive crisis. A hemoconcentrator can be added to the circuit to facilitate continuous ultrafiltration during CPB, which removes cytokines and increases the hematocrit while preserving plasma proteins and clotting factors. Use of hypothermia during bypass is controversial, but there are reports of successful utilization of hypothermia in this patient group. Although hypothermia is protective, it promotes in vivo sickling due to the vasoconstriction and vascular stasis. Avoidance of hypoxia is crucial to prevent a sickling crisis. Mixed venous oxygen saturation monitoring is a reliable marker for blood oxygenation during CPB. Other goals during CPB include higher pump flow and higher oxygen saturation.


The perioperative care of patients with SCD requires a multidisciplinary approach. A history of previous blood transfusions and transfusion reactions is particulary important as patients with SCD have a high rate of alloimmunization and are at increased likelihood of having a positive antibody screen. Performing standard ABO and RhD typing alone puts the patient at risk for delays in antibody identification, locating compatible donor units, and transfusion. Therefore, it is recommended to do an extended red cell antigen profile to facilitate antibody identification and expedite procurement of compatible blood.


The patient described in the stem is at high risk of perioperative RBC sickling and vaso-occlusive crisis due to several factors, including a past history of frequent sickle cell crises, high fractional concentration of HbS (85%) and high-risk surgery (cardiac surgery with CPB). Current consensus guidelines recommend exchange transfusion to HbS less than 30%. Patients undergoing minor procedures with a history of mild sickle crises should undergo transfusion to a target HB of 10 g/dL, which is not applicable to this patient. No transfusion would not be appropriate in this setting either. The patient should also undergo extended RBC antigen screening, in addition to the standard ABO and RhD typing, to expedite blood product procurement.


REFERENCES


Daaboul DG, Yuki K, Wesley MC, Dinardo JA. Anesthetic and cardiopulmonary bypass considerations for cardiac surgery in unique pediatric patient populations: sickle cell disease and cold agglutinin disease. World J Pediatr Congenit Heart Surg. 2011;2(3):364-370.


US Food and Drug Administration News Release. December 08, 2023. FDA approves first gene therapies to treat patients with sickle cell disease. Accessed December 19, 2023 at https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease


Smith MM, Renew JR, Nelson JA, Barbara DW. Red blood cell disorders: perioperative considerations for patients undergoing cardiac surgery. J Cardiothorac Vasc Anesth. 2019;33(5):1393-1406.


Mennes I, Van de Velde M, Missant C. Sickle cell anaemia and the consequences on the anaesthetic management of cardiac surgery. Acta Anaesthesiol Belg. 2012;63(2):81-89.


Chou ST, Alsawas M, Fasano RM, et al. American Society of Hematology 2020 guidelines for sickle cell disease: transfusion support. Blood Adv. 2020;4(2):327-355.


Bocchieri KA, Scheinerman SJ, Graver LM. Exchange transfusion before cardiopulmonary bypass in sickle cell disease. Ann Thorac Surg. 2010;90(1):323-324.