Transfusion and Apheresis Support for Sickle Cell Disease Patients

Hemodynamic Considerations

The interplay of mutations causative for SCD leading to hemoglobin (Hb) polymerization resulting in increased red cell rigidity are described elsewhere (see Chapter 42 ). One of the main features of SCD is the changes of red cell shape in response in part to delayed polymerization of HbS resulting in a sickle shaped cell. The abnormally shaped red cells are poor at oxygen delivery to tissues and prone to further cell membrane damage resulting in both intravascular and extravascular hemolysis. In addition, the combination of abnormally shaped and damaged cells together with products of hemolysis promotes vasculopathy through endothelial cell dysfunction and vessel occlusion, especially in the capillary vasculature but also in large blood vessels, resulting in ischemic tissue injury, inflammation, and immune dysregulation. The most significant factor that promotes the formation of sickled red cells in SCD is hypoxia, leading to an accumulation of cells in the capillary and venous vasculature. In addition to hypoxia, other factors promote red cell deformation and hemolysis including acidosis and oxidative stress. Moreover, endothelial damage that results from the cycles of ischemic and reperfusion injury results in an environment that promotes further red cell damage and hemolysis. The loss of RBC deformability in SCD is the main factor responsible for the disease morbidity associated VOE.

Blood flow is governed by many factors including hematocrit (Hct), red blood cell shape, oxygenation, plasma proteins, and vascular elasticity. Studies of blood flow (hemorheology) over the past half century have pointed to altered dynamics in patients with SCD, owing largely to increased blood viscosity. In turn, red cells, the largest cellular component of blood, largely govern viscosity with hematocrit and shape being the most important factors. A rise in Hct increases blood viscosity in all vessels and at all flow rates but is especially elevated in low flow vessels such as veins and capillaries. Increased viscosity produces increased resistance and pressure to blood flow, culminating in a drop of oxygen transport. While a drop in oxygen transport due to increased viscosity is seen at relatively high Hb concentrations (>20 g/dL) in cases of secondary polycythemia patients with normal red cells, patients with HbSS show a loss of oxygen delivery at a Hb concentration of about 10 to 12 g/dL. The viscosity of SCD patients is higher than that in patients with healthy red cells at the same hematocrit, which can further increase nearly ten-fold when deoxygenated. Deoxygenation of HbS containing red cells due to both a low flow state and a correspondingly longer time in a hypoxemic environment further promotes increased viscosity and irreversible sickling. Slower flow rates promote increased interactions between blood cells as well as between blood cells and endothelial cells that together with plasma proteins including coagulation and inflammatory factors lead to vaso-occlusion and tissue ischemia and injury. In fact, plasma viscosity increased in SCD is likely also due to these increased acute phase reactants and fibrinogen among other factors. Therefore, increased viscosity dramatically promotes irreversible sickling. However, blood viscosity (and similarly measures of this value alone) may not accurately represent all the forces that contribute to this pathologic process. Additional factors include shear rate, vessel size, and length of blood traversing small vessels. For these reasons, simple transfusion should be avoided in patients with Hb concentrations greater than 10 g/dL. Similarly, in SCD patients that receive transfusion and reach a higher than expected target Hb, phlebotomy to reduce the Hb concentration below 10 g/dL may be considered in some cases, especially in the setting of neurologic compromise.

A variety of additional factors alter the rheology of HbSS red cells, especially when additional genetic defects of Hb production are present. Alpha-thalassemia has been shown to ameliorate the complications seen in patients with HbSS disease, in part due to increased RBC deformability. In contrast, patients with Hb SC disease have increased blood viscosity but RBC deformability is not as severe as that found in SCD. Increased HbF concentrations, either through an inherited sequence modification (Hereditary Persistence of Fetal Hemoglobin [HPFH]), or pharmacologically (i.e., hydroxurea) significantly reduces the number of VOEs and improves the mortality of SCD. In vitro studies have shown that HbF inhibits HbS polymerization, which improves membrane deformability and thus prevents the formation of sickled cells. In addition to red cell intrinsic factors, others affecting the endothelium also adversely influence SCD hemorheology and include products of hemolysis, reactive oxygen species, and nitric oxide concentration. Taken together, one must consider all of these complex factors to plan for transfusion in order to balance the resultant increase of oxygen delivery with the possible increase in viscosity due to the remaining percentage of HbS containing cells.

Clinical Considerations for Transfusion

Transfusion of healthy donor RBC in SCD serves to both increase oxygen delivery to tissues and to dilute endogenous HbS containing cells. This can be done in an acute setting with the hope of improving end organ damage (e.g., acute chest syndrome, multi-organ failure) or in a prophylactic fashion (e.g., stroke prevention or perioperative settings). Transfusion, however, has not been shown to reverse uncomplicated VOEs consisting primarily of boney pain and correspondingly is not indicated in patients who do not have symptoms of anemia. In those latter cases, transfusion will not improve pain but may prevent further complications of the initial VOE. Clinical trials of when and how to transfuse patients with SCD are few and consequently most clinicians rely on consensus papers and clinical practice (see the box on Indications for Red Cell Transfusion ).

Acute Anemia

SCD is a chronic hemolytic anemia that is compensated by increased erythropoiesis and reticulocytosis. Red cell survival is significantly reduced in SCD with HbS cells lasting about two weeks and those with HbF up to 6 weeks. Therefore, stress erythropoiesis is already present even at steady state in untransfused patients with SCD. Any additional insult or burden on red cell production may result in a severe anemia. The net Hb concentration varies significantly among patients with SCD depending on the homeostatic factors controlling erythropoiesis (e.g., erythropoietin, B12, folate) and physiologic adaptation to anemia. Therefore, no single Hb concentration value can define acute anemia, which should be evaluated by comparing the historical peripheral blood Hb concentration of each patient together with a clinical assessment of symptoms of anemia. In addition to the variability of Hb concentrations among patients, each patient has their own variability over time based on factors including hydration, again denoting the need to correlate laboratory values with symptoms. Generally, most SCD patients have a Hb concentration of approximately 8 to 10 g/dL and a Hct of approximately 20% to 30% with reticulocytosis in the range of 3% to 15%. A drop of Hb of 2 to 3 g/dL without a corresponding reticulocytosis and with clinical signs of anemia would warrant transfusion. This is especially important in children where blood flow to the brain increases from birth to early childhood and decreases during adolescence. Children with SCD are at greater risk for silent ischemia that may lead to stroke; therefore, a lower trigger should be strongly considered for transfusion.

Causes of acute anemia include red cell aplasia secondary to parvovirus infection, splenic sequestration or rupture, bleeding, or accelerated hemolysis that may be associated with infection. One of the most important causes of acute anemia in recently transfused SCD patients is delayed hemolytic transfusion reaction (DHTR) (discussed later) that should be evaluated in all such patients. In these clinical settings, there should be prompt consideration to transfuse as it is unlikely that increased erythropoiesis can raise the Hb concentration.