Hemapheresis

Principles of Apheresis

The principal objective of apheresis is efficient removal of some circulating blood component, either cells (cytapheresis) or some plasma solute (plasmapheresis). For most disorders, the treatment goal is to deplete the circulating cell or substance directly responsible for the disease process. Apheresis can also mobilize cells and plasma components from tissue depots. For example, lymphocytes may be mobilized from the spleen and lymph nodes of some patients with chronic lymphocytic leukemia (CLL), and low-density lipoproteins (LDLs) can be removed from tissue stores in patients with familial hypercholesterolemia. The apheresis procedure itself mobilizes CD34 ⁺ cells from extravascular depots during peripheral blood HSPC donation, resulting in collection of more than twice as many CD34 ⁺ cells than estimated based on preapheresis peripheral blood cell counts ( Fig. 116.1 ). Apheresis may have other, less obvious effects. Lymphocyte depletion may modify immune responsiveness in some disease states, possibly by disturbing the control mechanisms of cellular immune regulation. Plasmapheresis enhances splenic clearance of immune complexes in certain autoimmune disorders. When therapeutic effect is judged by clinical improvement rather than by efficiency of solute removal, apheresis is more often a helpful adjunct than a form of first-line therapy.

Several mathematical models formulated for different clinical conditions describe the kinetics of apheresis. Removal of most blood constituents follows a logarithmic curve ( Fig. 116.2 ). This model assumes that the substance removed is neither synthesized nor degraded substantially during the procedure, remains within the intravascular compartment, and mixes instantaneously and completely with any plasma replacement solution. When the goal of plasmapheresis is to supply a deficient substance, for example, the cleavase ADAM metallopeptidase with thrombospondin type 1 motif 13 (ADAMTS13) in the treatment of thrombotic thrombocytopenic purpura (TTP), replacement follows logarithmic kinetics similar to those developed for solute removal. Removal of 1.5 to 2.0 volumes will reduce an intravascular substance by approximately 80% (see Fig. 116.2 ); processing larger volumes results in little additional gain. Specific cell removal with centrifugal automated cell separators depend on the number of cells available, the volume of blood processed, the efficiency of the particular instrument, and the separation characteristics of the different cells. Most commercially available instruments remove platelets and lymphocytes extremely efficiently. Granulocytes and other mononuclear cells, including HSPCs from peripheral blood, cannot be cleanly separated from other cells by standard centrifugal apheresis equipment ( Fig. 116.3 ). Optimal harvesting of these cells requires special techniques such as stimulating the donor with corticosteroids, cytokines or chemokine receptor antagonists, or adding sedimenting agents to enhance cell separation.

Whereas this model accurately estimates removal of cells and large proteins such as fibrinogen and immunoglobulin (Ig) M, removal of smaller solutes such as IgG and albumin-bound drugs are less efficient. Transfer of these moieties from the extravascular to the intravascular compartment depends both on diffusion along a concentration gradient and on active transport. The rate of clearance can be calculated using diffusion coefficients, sieving coefficients, and lymphatic flow rate, although in practice this degree of accuracy is rarely necessary.

Technology and Techniques

Over 100 years ago, animal experiments formed the theoretical and practical basis for all modern extracorporeal blood purification methods. The plasmapheresis technique that originated in the animal laboratory required manual resuspension of RBCs and posed a substantial risk of microbial contamination of the components being reinfused. With the introduction of sterile, disposable, interconnected plastic blood bags, plasmapheresis became relatively safe and easy. However, manual apheresis proved too inefficient and labor intensive for collecting large component volumes, and raised concerns that the separated units of RBCs might be reinfused accidentally into the wrong donor or patient. The introduction of automated online blood cell separators solved these problems. Automated apheresis instruments use microprocessor technology to draw and anticoagulate blood, separate components either by centrifugation or by filtration, collect the desired component, recombine the remaining components for return to the patient or donor, and document procedure data. The equipment contains disposable plastic software in the blood path and uses anticoagulants containing citrate or combinations of citrate and heparin that do not result in clinical anticoagulation of the patient or donor. Most instruments function well at blood flow rates of 30 to 80 mL/min, and can operate from peripheral venous access or from a variety of multilumen central venous catheters. Newer therapeutic apheresis devices are smaller and more automated, allowing for implementation of more safety functions and improved portability. In large-volume leukapheresis (LVL) procedures, prophylactic intravenous calcium supplementation minimizes the risk of hypocalcemia due to the citrate anticoagulant used.

Because the ideal method for treating disorders mediated by abnormal plasma components is to remove the offending substance selectively, a variety of online filtration and column adsorption techniques have been introduced or proposed. Ligands bound to a column matrix may be relatively nonspecific chemical sorbents, such as charcoal or heparin, or specific ligands, such as monoclonal antibodies and recombinant protein antigens. Two such columns are commercially available: one using staphylococcal protein A, and the other using negatively charged dextran sulfate cellulose beads. Staphylococcal protein A has high affinity for the Fc portion of IgG1, IgG2, and IgG4 and for immune complexes containing these IgG subtypes. The dextran sulfate cellulose columns selectively remove LDL, very-low-density lipoprotein, and lipoprotein, and have proved effective in managing patients with homozygous hypercholesterolemia who have not responded to diet and cholesterol-lowering drug therapy ( Fig. 116.4 ). A similar technique, heparin-induced extracorporeal lipoprotein precipitation, uses low pH and negatively charged heparin to precipitate lipoproteins and remove the precipitate by filtration online (H.E.L.P. Plasmat Futura, Braun Medical). Apheresis technology has also been adapted for extracorporeal phototherapy of patient leukocytes (photopheresis) to treat cutaneous T-cell lymphoma, and to modulate the pathologic immune response in graft-versus-host disease (GVHD), solid organ transplant.

Therapeutic Plasma Exchange (Plasmapheresis)

Common clinical indications for therapeutic plasma exchange (TPE), frequently referred to as plasmapheresis, are outlined in Table 116.1 . Most procedures are performed for treatment of immunologic and hematologic disorders. A course of plasmapheresis generally consists of five to seven exchanges of 1 to 1.5 plasma volumes each, either daily or with an interval of 1 to 2 days between procedures; the course of therapy varies depending on the specific disease indication and rate and duration of the response. Several expert committees have published practice guidelines for using plasmapheresis in a wide variety of disease states. Some of the least controversial indications for plasmapheresis are supported by small series of uncontrolled cases that rely on some objective clinical or laboratory measurement of patient improvement. In recent years, effective biologic and pharmacologic agents such as IVIg have rendered TPE a backup therapy for some indications.

Replacement Fluids for Plasma Exchange

The success of therapeutic apheresis procedures seldom depends on the composition of the replacement solution; the major exception is TTP for which plasma is indicated to replace the depleted ADAMTS13 protein. With therapeutic plasmapheresis for most other disorders, the primary function of the replacement solution is to maintain intravascular volume. Additional requirements include restoration of important plasma proteins, maintenance of colloid osmotic pressure, maintenance of electrolyte balance, and preservation of trace elements lost during a prolonged course of plasmapheresis procedures. For most conditions, it is acceptable to perform 1 to 1.5 plasma volume exchanges per procedure. A single plasma volume exchange in an average-sized adult uses approximately 3 L of replacement fluid. In moderately well-nourished patients, homeostatic mechanisms normally obviate the need for precise plasma replacement, and 5% albumin in normal saline or combinations of albumin and crystalloid are usually sufficient. Patients with clinical conditions such as hypotension, hypoalbuminemia, or preexisting coagulopathies should receive solutions prepared specifically to meet their individual requirements. Problems of decreased availability and high cost of albumin have led some centers to develop protocols for alternatives to plasma-derived volume expanders, such as hydroxyethyl starch (HES), for full- or partial-volume replacement with plasma exchange. One center has used a combination of 3% HES and 5% albumin mixture successfully, but patients did experience mild adverse events more frequently than did historical control subjects. Although such solutions are generally well tolerated, extensive replacement with HES in patients undergoing longer courses of plasmapheresis, especially those with impaired renal function, can result in diffuse tissue accumulation of the larger starch molecules (acquired lysosomal storage).