Apheresis refers to the removal of a component of the blood and is performed using a group of medical technologies in which peripheral blood is processed by an instrument that separates the various components. The selected component is isolated while the remainder is returned to the patient. The rationale behind therapeutic apheresis is to remove the pathogenic components from the circulation. Apheresis is also used for peripheral hematopoietic progenitor cell collection. The procedure can be safely performed in most children with modifications to account for smaller pediatric blood volumes.
Key points
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During apheresis, peripheral blood components are separated from each other. The selected component is isolated while the remainder is returned to the donor or patient.
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Apheresis is performed for a wide variety of medical indications. It is also used for peripheral hematopoietic progenitor cell collection.
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The decision to perform apheresis on pediatric patients is largely extrapolated from the adult experience.
Introduction/Background
Apheresis refers to a group of medical technologies in which peripheral blood is processed by an instrument that separates blood into components. The selected component is isolated while the remainder is returned to the donor or patient. Modern apheresis instruments are fully automated and separation can be performed on the basis of density, size, and/or differential adsorption. Most apheresis instruments rely on density differences to separate blood into components by centrifugation. A notable exception is low-density lipoprotein (LDL) apheresis, in which LDL is selectively removed from plasma through filtration and/or adsorption.
Most forms of therapeutic apheresis are designed to remove the pathogenic components from the circulation. The therapeutic efficacy depends many factors including the importance of the substance removed in the pathophysiology of the disease, efficiency of removal of the pathogenic substance, and the presence of other complementary/adjunctive therapies. Therapeutic plasma exchange (TPE) or plasmapheresis is usually performed to remove toxic antibodies from the circulation. Cytapheresis is used to deplete leukocytes in the setting of hyperleukocytosis and leukostasis (specifically, leukapheresis) or platelets (plateletpheresis) in the setting of thrombocytosis and increased thrombotic or hemorrhagic risk. Leukapheresis is also used to collect peripheral hematopoietic progenitor cells (HPCs). Pathogenic red blood cells (RBCs) containing sickle hemoglobin can be removed and “exchanged” for donor RBCs with normal hemoglobin. Unlike other forms of therapeutic apheresis, the component removed during extracorporeal photopheresis (ECP), peripheral blood mononuclear cells, may not directly contribute to the disease process. During ECP the mononuclear cells are subjected to ultraviolet A light in the presence of psoralen and then reinfused to the patient.
The decision to perform apheresis on pediatric patients is often based on results of adult studies. The American Society for Apheresis (ASFA) guidelines, which assigns disease entities to 1 of 4 categories according to the strength of recommendations and quality of published evidence, does not distinguish between pediatric or adult-onset disease. The limited use of therapeutic apheresis in pediatric patients may be attributed to the lack of generally accepted indications and treatment course, as well as technical difficulty. Modifications of adult procedures to factor in smaller total blood volume and limit potential fluid shifts in pediatric patients, procedural anticoagulation regimens that minimize hypocalcemia, and improved options for vascular access have made therapeutic apheresis procedures safe to perform in most children.
Vascular Access
Peripheral access may be possible for older children with adequate vein size. If adequate peripheral access cannot be obtained (ie, 18-gauge or larger steel needle placed in the antecubital vein for the draw and a 22-gauge or larger needle placed in peripheral vein of opposite arm for return), central venous access is necessary. Catheters should be able to withstand negative pressure from blood withdrawal at high flow rates. Hence, most peripherally inserted central catheters (ie, most PICC lines) are not compatible to use for drawing but may be used for returning. Some institutions have had success with specific PICC lines designed to tolerate the flows and pressures of apheresis (eg, Power PICC). Femoral venous catheters are placed in urgent situations and are usually restricted for patients requiring only a few procedures or for temporary use until alternate central venous access is obtained. Femoral catheters are assumed to be associated with a higher risk of infection or thrombosis than other routes of access, although these beliefs have recently been challenged.
Procedural Risks
The major risks of apheresis are related to the need for peripheral access and include pain, infection, bleeding, and thrombosis. Complications associated with central venous access include pneumothorax, hemothorax, cardiac arrhythmias, and central vein stenosis. Sedation may be required for placement of the access device. In addition, femoral catheters impair the patient’s mobility. Because of small pediatric total blood volumes, procedure-related fluid shifts, intraprocedural anemia, and iron deficiency anemia with chronic apheresis therapy are of a greater concern in children than adult patients.
Citrate and/or heparin prevent clotting of blood in the apheresis circuit. Citrate chelates calcium ions, thus preventing the calcium-dependent coagulation cascade. Citrate has a short half-life and is metabolized by the liver and excreted by the kidneys. Patients with renal or hepatic impairment undergoing lengthy procedures or receiving replacement fluids containing additional citrate (ie, plasma or RBCs) are at risk for developing symptomatic hypocalcemia. Signs and symptoms of hypocalcemia in adults begin with perioral or digital paresthesias and may progress to include nausea, vomiting, anxiety, diarrhea, lightheadedness, tremors, and muscle cramps. QT prolongation can occur, and in severe cases, the patient may develop tetany, seizures, and cardiac arrhythmias. Pediatric patients may not be able to communicate symptoms of hypocalcemia, which may present differently from adults, with abdominal pain, vomiting, pallor, and/or hypotension. Indeed, hypotension, which can be due to both hypocalcemia and hypovolemia, is one of the leading adverse events in pediatric apheresis. To avoid the complications of hypocalcemia, heparin can be used for anticoagulation in pediatric apheresis, although prophylactic administration of divalent cations such as calcium and magnesium can prevent most citrate-related toxicities. If blood products are used to prime the apheresis circuit and/or as replacement fluid, there will be additional risks related to blood component transfusion.
The remainder of the article provides an overview of the commonly encountered indications for apheresis and refers to ASFA categories. ASFA category I includes diseases in which therapeutic apheresis is primary or adjunct first-line therapy; category II denotes diseases for which apheresis is supportive or adjunctive therapy; category III includes diseases for which the existing evidence is insufficient to establish the efficacy of therapy; and category IV indicates disorders for which controlled trials have shown no benefit or anecdotal reports are discouraging.
Introduction/Background
Apheresis refers to a group of medical technologies in which peripheral blood is processed by an instrument that separates blood into components. The selected component is isolated while the remainder is returned to the donor or patient. Modern apheresis instruments are fully automated and separation can be performed on the basis of density, size, and/or differential adsorption. Most apheresis instruments rely on density differences to separate blood into components by centrifugation. A notable exception is low-density lipoprotein (LDL) apheresis, in which LDL is selectively removed from plasma through filtration and/or adsorption.
Most forms of therapeutic apheresis are designed to remove the pathogenic components from the circulation. The therapeutic efficacy depends many factors including the importance of the substance removed in the pathophysiology of the disease, efficiency of removal of the pathogenic substance, and the presence of other complementary/adjunctive therapies. Therapeutic plasma exchange (TPE) or plasmapheresis is usually performed to remove toxic antibodies from the circulation. Cytapheresis is used to deplete leukocytes in the setting of hyperleukocytosis and leukostasis (specifically, leukapheresis) or platelets (plateletpheresis) in the setting of thrombocytosis and increased thrombotic or hemorrhagic risk. Leukapheresis is also used to collect peripheral hematopoietic progenitor cells (HPCs). Pathogenic red blood cells (RBCs) containing sickle hemoglobin can be removed and “exchanged” for donor RBCs with normal hemoglobin. Unlike other forms of therapeutic apheresis, the component removed during extracorporeal photopheresis (ECP), peripheral blood mononuclear cells, may not directly contribute to the disease process. During ECP the mononuclear cells are subjected to ultraviolet A light in the presence of psoralen and then reinfused to the patient.
The decision to perform apheresis on pediatric patients is often based on results of adult studies. The American Society for Apheresis (ASFA) guidelines, which assigns disease entities to 1 of 4 categories according to the strength of recommendations and quality of published evidence, does not distinguish between pediatric or adult-onset disease. The limited use of therapeutic apheresis in pediatric patients may be attributed to the lack of generally accepted indications and treatment course, as well as technical difficulty. Modifications of adult procedures to factor in smaller total blood volume and limit potential fluid shifts in pediatric patients, procedural anticoagulation regimens that minimize hypocalcemia, and improved options for vascular access have made therapeutic apheresis procedures safe to perform in most children.
Vascular Access
Peripheral access may be possible for older children with adequate vein size. If adequate peripheral access cannot be obtained (ie, 18-gauge or larger steel needle placed in the antecubital vein for the draw and a 22-gauge or larger needle placed in peripheral vein of opposite arm for return), central venous access is necessary. Catheters should be able to withstand negative pressure from blood withdrawal at high flow rates. Hence, most peripherally inserted central catheters (ie, most PICC lines) are not compatible to use for drawing but may be used for returning. Some institutions have had success with specific PICC lines designed to tolerate the flows and pressures of apheresis (eg, Power PICC). Femoral venous catheters are placed in urgent situations and are usually restricted for patients requiring only a few procedures or for temporary use until alternate central venous access is obtained. Femoral catheters are assumed to be associated with a higher risk of infection or thrombosis than other routes of access, although these beliefs have recently been challenged.
Procedural Risks
The major risks of apheresis are related to the need for peripheral access and include pain, infection, bleeding, and thrombosis. Complications associated with central venous access include pneumothorax, hemothorax, cardiac arrhythmias, and central vein stenosis. Sedation may be required for placement of the access device. In addition, femoral catheters impair the patient’s mobility. Because of small pediatric total blood volumes, procedure-related fluid shifts, intraprocedural anemia, and iron deficiency anemia with chronic apheresis therapy are of a greater concern in children than adult patients.
Citrate and/or heparin prevent clotting of blood in the apheresis circuit. Citrate chelates calcium ions, thus preventing the calcium-dependent coagulation cascade. Citrate has a short half-life and is metabolized by the liver and excreted by the kidneys. Patients with renal or hepatic impairment undergoing lengthy procedures or receiving replacement fluids containing additional citrate (ie, plasma or RBCs) are at risk for developing symptomatic hypocalcemia. Signs and symptoms of hypocalcemia in adults begin with perioral or digital paresthesias and may progress to include nausea, vomiting, anxiety, diarrhea, lightheadedness, tremors, and muscle cramps. QT prolongation can occur, and in severe cases, the patient may develop tetany, seizures, and cardiac arrhythmias. Pediatric patients may not be able to communicate symptoms of hypocalcemia, which may present differently from adults, with abdominal pain, vomiting, pallor, and/or hypotension. Indeed, hypotension, which can be due to both hypocalcemia and hypovolemia, is one of the leading adverse events in pediatric apheresis. To avoid the complications of hypocalcemia, heparin can be used for anticoagulation in pediatric apheresis, although prophylactic administration of divalent cations such as calcium and magnesium can prevent most citrate-related toxicities. If blood products are used to prime the apheresis circuit and/or as replacement fluid, there will be additional risks related to blood component transfusion.
The remainder of the article provides an overview of the commonly encountered indications for apheresis and refers to ASFA categories. ASFA category I includes diseases in which therapeutic apheresis is primary or adjunct first-line therapy; category II denotes diseases for which apheresis is supportive or adjunctive therapy; category III includes diseases for which the existing evidence is insufficient to establish the efficacy of therapy; and category IV indicates disorders for which controlled trials have shown no benefit or anecdotal reports are discouraging.
Indications
Hematologic
Hemoglobinopathies
RBC exchange is a procedure in which patient red cells are exchanged for donor red cells. RBC exchange in sickle cell disease or other heterozygous compound hemoglobinopathies (ie, HbSC disease) is performed to replace pathogenic RBCs for donor RBCs with wild-type hemoglobin, hence improving oxygen-carrying capacity, decreasing blood viscosity, and suppressing endogenous erythropoiesis. Advantages of RBC exchange over simple transfusion include rapid decrease in percentage of hemoglobin S (HbS), ability to more precisely control posttreatment hematocrit, and reduced risk of fluid overload. In sickle cell disease, RBC exchange associated with benefits of transfusion and also minimized tissue iron loading. Disadvantages of RBC exchange include exposure to more blood units and increased venous access requirements. The increased number of transfused RBC units with RBC exchanges may increase alloimmunization but one report suggests this is not the case.
Acute chest syndrome, which is defined by new radiographic infiltrate accompanied by respiratory signs and symptoms, is the second leading cause of sickle cell–associated mortality in children. In acute chest syndrome both simple and exchange transfusion (ASFA category II) can rapidly improve oxygenation. Exchange transfusion should be reserved for patients whose hematocrit is so high that simple transfusion would dangerously increase viscosity, with more severe hypoxia requiring mechanical ventilation, and/or failure to improve with simple transfusion.
RBC exchange is first-line therapy for acute stroke (ASFA category I) and has been shown to be effective in decreasing both primary and secondary strokes in children while reducing iron overload (ASFA category II). RBC exchange (ASFA category III) may also be preferred over simple transfusion in the setting of acute multiorgan failure and higher hematocrit levels to avoid hyperviscosity while rapidly reducing HbS levels. RBC exchange may be indicated preoperatively in patients with high blood hemoglobin concentrations who are undergoing high-risk procedures. Transfusion therapy, whether simple or exchange, has not been shown to benefit patients with frequent pain episodes, acute pain crisis, prevention of pulmonary hypertension, or priapism.
Immune-mediated cytopenias
Autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura are caused by production of autoantibodies that result in RBC and platelet destruction, respectively. The efficacy of TPE in treating immune thrombocytopenic purpura and warm AIHA has not been proven by (ASFA categories IV and III, respectively). Although cold AIHA is primarily a disease of the elderly, it can be seen in children. Cold AIHA is due to immunoglobulin M antibodies, most of which reside intravascularly and can be effectively removed by plasmapheresis. Thus severe life-threatening cold AIHA is an ASFA category II indication. Thombotic thrombocytopenic purpura, an important indication for plasmapheresis, and hemolytic uremic syndrome are discussed in the article by Trachtman elsewhere in this issue.
Oncologic
Hyperleukocytosis with or without leukostasis
Hyperleukocytosis can cause significant morbidity and mortality through inducing tumor lysis syndrome, leukostasis, and/or disseminated intravascular coagulopathy. In leukostasis, occlusion of the microcirculation by leukocyte aggregates may lead to endothelial damage, thrombosis, and/or hemorrhage. Leukostasis of cerebral and pulmonary vasculature are most likely to cause immediate symptoms. In acute myelogenous leukemia, the white blood cell (WBC) count threshold for symptomatic leukostasis is typically greater than 100,000/μL, while it is often greater than 400,000/μL in acute lymphoblastic leukemia. Because the type of acute leukemia is often unknown at presentation, leukapheresis should be considered in all patients with new onset acute leukemia whose WBC is greater than 100,000/μL, especially if they are symptomatic. In addition to absolute WBC and blast count, blast-endothelial cell interactions likely play a role in the pathophysiology.
The management of hyperleukocytosis includes cytoreduction and supportive care. Mechanical cytoreduction by leukapheresis has been performed in the setting of symptomatic leukostasis as well as prophylaxis/bridge to definitive therapy. There is general consensus that symptomatic leukostasis is a valid indication for leukapheresis (ASFA category I). However, it is less clear whether prophylactic leukapheresis reduces complications of hyperleukocytosis. Although some analyses suggest that leukapheresis may reduce early mortality, this benefit does not extend to improvement in long-term prognosis. Hence, prophylaxis of hyperviscosity has been designated as a category III indication by ASFA guidelines. Leukapheresis is particularly at risk in patients with acute promyelocytic leukemia as it may worsen associated disseminated intravascular coagulation.
Peripheral hematopoietic progenitor cell collection
Hematopoietic progenitor cells are used for hematologic reconstitution following myeloablative chemotherapy to eradicate underlying disease. Such diseases include both hematological and nonhematological malignancies and inherited metabolic and immune disorders. There are 3 sources of HPC: bone marrow, peripheral blood, and umbilical cord blood. Most autologous HPC transplants are peripheral blood-derived. Pediatric allogeneic HPC transplants are mostly bone marrow- and umbilical cord blood-derived.
Peripheral blood-derived HPCs are collected by leukapheresis following mobilization to increase the number of circulating HPCs. HPCs from autologous donors can be mobilized with cytotoxic chemotherapeutic agents and/or growth factors such as granulocyte – colony stimulating factor (G-CSF) and/or an agent that disrupts the attraction of the HPCs to the bone marrow such as plerixafor. G-CSF is most commonly used to mobilize allogeneic HPC donors. Peripheral access is often sufficient to collect peripheral HPCs from older donors. In contrast, young, small pediatric patients often require central venous access because of inadequate peripheral vascular access.
Graft-versus-host disease
Acute graft-versus-host disease (GVHD) occurs in 20% to 50% of patients after allogeneic hematopoietic stem cell transplantation and chronic graft-versus-host disease (cGVHD) affects 30% to 50% of engrafted survivors. cGVHD usually occurs greater than 100 days posttransplant, with fibrosis and sclerosis predominating. The cause of GVHD includes donor T-cell alloreactivity to recipient human leukocyte antigens (HLA). GVHD frequently requires long-term systemic immunosuppression and ECP is useful as adjunctive therapy for refractory disease (cutaneous GVHD ASFA category II, noncutaneous GVHD ASFA category III). The exact mechanisms behind ECP are unclear, but murine studies indicate that ECP leads to induction of CD4+, CD25+, Foxp+ regulatory T-cells that mediate immunologic tolerance and human studies have demonstrated ECP allows for decreased steroid doses for patients with chronic cGVHD.
Neurologic
Acute inflammatory demyelinating polyneuropathy/Guillain-Barré syndrome
Acute inflammatory demyelinating polyneuropathy (AIDP)/Guillain-Barré syndrome is an acute progressive paralysis disorder resulting in both motor and sensory deficits. It is caused by antibodies against peripheral nerve myelin. Spontaneous recovery occurs in most cases, although severe cases may necessitate mechanical ventilation and intensive care. The efficacy of TPE has been demonstrated in randomized controlled trials and is an ASFA category I designation. Although randomized controlled trials have not been performed in children, case series or retrospective reviews have shown a beneficial effect of TPE in pediatric patients with AIDP. Intravenous immunoglobulin (IVIG) is equivalent to plasma exchange for patients with AIDP.
Chronic Inflammatory Demyelinating Polyneuropathy
Chronic inflammatory demyelinating polyneuropathy (CIDP) is a chronic demyelinating disorder of the peripheral nervous system resulting in motor and sensory deficits that is thought to be of an autoimmune nature and possibly antibody-mediated. TPE is effective in adults with CIDP (ASFA category I), is comparable to IVIG, and has been used in pediatric patients with CIDP.
Myasthenia Gravis
Myasthenia gravis is an autoimmune disorder typically caused by antibodies to the acetylcholine receptor that disrupts neuromuscular transmission resulting in muscle weakness. TPE is usually reserved for severe or refractory Myasthenia gravis, and is an ASFA category I indication in this setting.
Multiple Sclerosis and Neuromyelitis Optica
Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system (CNS) white matter. The relapsing-remitting form is the most common clinical pattern, although others include primary progressive, secondary progressive, and relapsing progressive forms. Neuromyelitis optica (NMO), which is related to but distinct from MS, specifically involves demyelination of the optic nerve and/or spinal cord, although the brain may be involved in a minority of cases. The pathogenesis of both disorders is unclear but is thought to be immune-mediated. The T-cell-rich CNS lesions of MS point to a cellular-mediated process, although oligoclonal immunoglobulin in the CSF of MS patients suggests an additional humoral component. Immunoglobulin G antibodies to aquaporin-4 (a molecule found on CNS astrocytes) have been found in most NMO patients, although its pathogenesis remains unproven.
TPE has been explored in both steroid-refractory MS and NMO. TPE was shown to be effective in a randomized, sham-controlled trial of 22 patients with steroid-refractory acute CNS demyelination. However, the study has been criticized because of the heterogeneous study population representing a variety of diagnoses (MS, NMO, transverse myelitis, acute disseminated encephalomyelitis) without subgroup analysis. There is general consensus that TPE has minimal benefit in treating chronic or progressive forms of MS, but may have a role in acute relapsing MS or NMO resistant to immunosuppressive therapies. Acute MS refractory to steroids and NMO are ASFA class II indications.
Acute Disseminated Encephalomyelitis
Acute disseminated encephalomyelitis is an acute inflammatory demyelinating disease of the CNS primarily affecting children and young adults postinfection or vaccination. It is thought to be due to an autoimmune response against CNS antigens. TPE may have a role in managing steroid-refractory cases (ASFA category II indication).
Chronic Focal Encephalitis (Rasmussens Encephalitis)
Rasmussen encephalitis is a rare acquired disorder resulting in seizures refractory to anticonvulsant drugs and progressive dementia and hemiparesis. The cause is unclear, but autoantibodies to the glutamate receptor GluR3 and glutamic acid decarboxylase 65 have been reported. TPE and IVIG have been used in refractory cases or in nonsurgical candidates (ASFA category II).
Phytanic Acid Storage Disease (Refsum Disease)
Refsum disease is an inherited deficiency of the enzyme that metabolizes phytanic acid, resulting in phytanic acid accumulation and neurologic deficits. Phytanic acid is a branched-chain fatty acid derived from dietary sources, and the mainstay of therapy is dietary control. TPE has been used to remove phytanic acid in severe disease and/or exacerbations (ASFA category II).
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