Plasmapheresis

Plasmapheresis is a term used to refer to a broad range of procedures in which extracorporeal separation of blood components results in a filtered plasma product.[1, 2]

The filtering of plasma from whole blood can be accomplished via centrifugation or the use of semipermeable membranes.[3] Centrifugation takes advantage of the different specific gravities inherent to various blood products, such as red blood cells (RBCs), white blood cells (WBCs), platelets, and plasma.[4] Membrane plasma separation uses differences in particle size to filter plasma from the cellular components of blood.[3]

Traditionally, in the United States, most plasmapheresis has been done with automated centrifuge-based technology.[5] In certain instances—in particular, in patients already undergoing hemodialysis—plasmapheresis can be carried out using semipermeable membranes to filter plasma.[4]

In therapeutic plasma exchange, using an automated centrifuge, filtered plasma is discarded and RBCs along with replacement colloid (eg, donor plasma or albumin) are returned to the patient.

In membrane plasma filtration, secondary membrane plasma fractionation can selectively remove undesired macromolecules, which then allows return of the processed plasma to the patient instead of donor plasma or albumin. Examples of secondary membrane plasma fractionation include cascade filtration,[6] thermofiltration, cryofiltration,[7] and low-density lipoprotein pheresis.

Plasmapheresis is currently employed as a therapeutic modality in a wide array of conditions.[2, 8] Generally, it is used when a substance in the plasma (eg, immunoglobulin) is acutely toxic and can be efficiently removed. Myriad conditions that fall into this category (including neurologic, hematologic, metabolic, dermatologic, rheumatologic, and renal diseases, as well as intoxications) can be treated with plasmapheresis.

The Apheresis Applications Committee of the American Society for Apheresis (ASFA) periodically evaluates potential indications for apheresis and categorizes them from I to IV in the basis of the available medical literature. The following are some of the indications, and their categorization, from the society’s guidelines.[2]

Category I indications (disorders for which apheresis is accepted as first-line therapy, either as a primary standalone treatment or in conjunction with other modes of treatment) include the following:

• Guillain-Barre syndrome
• Myasthenia gravis (acute short-term treatment)
• Chronic inflammatory demyelinating polyneuropathy
• Hyperviscosity in hypergammaglobulinemia
• Thrombotic thrombocytopenic purpura
• Goodpasture syndrome (unless it is dialysis-dependent and there is no diffuse alveolar hemorrhage)
• Thrombotic microangiopathy, complement mediated (autoantibody to factor H)
• Wilson disease, ^[9] fulminant

Category II indications (disorders for which apheresis is accepted as second-line therapy, either as a standalone treatment or in conjunction with other modes of treatment) include the following:

• Lambert-Eaton myasthenic syndrome
• Multiple sclerosis (acute central nervous system demyelination disease unresponsive to steroids ^[10] )
• Thyroid storm
• Mushroom poisoning
• Acute disseminated encephalomyelitis
• Autoimmune hemolytic anemia (severe cold agglutinin disease)
• Systemic lupus erythematosus (severe)
• Myeloma cast nephropathy

Category III indications (disorders for which the optimal role of apheresis therapy is not established; decision-making should be individualized) include the following:

• Posttransfusion purpura
• RBC alloimmunization in pregnancy
• Autoimmune hemolytic anemia (severe warm)
• Hypertriglyceridemic pancreatitis ^{[11, 12]}
• Thrombotic microangiopathy, complement mediated (complement factor mutations)
• Stiff person syndrome
• Drug overdose/poisoning
• Immune thrombocytopenia

Category IV indications (disorders in which published evidence demonstrates or suggests apheresis to be ineffective or harmful; institutional review board [IRB] approval is desirable if apheresis treatment is undertaken in these circumstances) include the following:

• HELLP syndrome (ante partum)
• Hemolytic uremic syndrome (typical diarrhea-associated)
• Multifocal motor neuropathy
• Idiopathic polyarteritis nodosa

There is some evidence that plasmapheresis can be successfully used in patients to alleviate infection-related symptoms associated with antibody-dependent enhancement (ADE) of bacterial disease.[13]

It has been suggested that plasmapheresis may be useful in the treatment of COVID-19 by removing cytokines and thus reducing the cytokine response.[14, 15]

Plasmapheresis is contraindicated in the following patients:

• Patients who cannot tolerate central line placement
• Patients who are in an actively septic state or are hemodynamically unstable - Although plasmapheresis can remove various mediators from the blood and so, in theory, would appear to be potentially useful in treating sepsis, patients in a septic state are often coagulopathic and hemodynamically unstable, which poses significant risks when catheters are inserted and connected to a mechanical circuit; there are some ongoing trials evaluating plasmapheresis in sepsis, but at present, there are no clear data to suggest that the clinical benefits of using plasmapheresis in this setting outweigh the risks associated with its use
• Patients who have allergies to fresh frozen plasma (FFP) or albumin, depending on the type of plasma exchange
• Patients with heparin allergies should not receive heparin as an anticoagulant during plasmapheresis
• Patients with hypocalcemia are at risk for worsening of their condition because citrate is commonly used to prevent clotting and can potentiate hypocalcemia
• Patients taking angiotensin-converting enzyme (ACE) inhibitors are advised to stop taking the medication for at least 24 hours before starting plasmapheresis

Terminology

Although the term plasmapheresis technically refers only to the removal of plasma, it is also widely used to encompass therapeutic plasma exchange in which a replacement product is transfused after removal of the plasma.[16]

As distinct from plasmapheresis, cytapheresis is the selective removal of RBCs, WBCs, or platelets and can be accomplished by using identical centrifuge-based equipment. Applications include the following:

• Erythrocytapheresis (selective removal of RBCs) is used in conditions such as sickle cell disease or malarial infection, in which RBCs are selectively removed and replaced with donor erythrocytes
• Leukapheresis (selective removal of WBCs) is used in conditions such as hyperleukocytosis, in which pathologically high number of white cells are present (as, for example, in leukemia); it can also be used to collect peripherally circulating stem cells that can then be infused in an autologous or allogeneic stem cell transplant
• Platelet apheresis (selective removal of platelets) can be used in conditions of thrombocytosis (eg, polycythemia vera)

Complication prevention

Having all the equipment and medications required for the procedure readily available at the start in order to minimize complications is important. Sterile technique is advised in order to reduce the likelihood of infection.

Premedication with acetaminophen, diphenhydramine, and hydrocortisone are often given if the patient is to receive any blood product, including priming the tubing with packed RBCs, in particular if a history exists of prior reaction to blood products.[17]

Plasmapheresis can be accomplished through centrifuge-based platforms such the Cobe Spectra, Fenwal Aurora, and the Fresenius COM.TEC series of devices. Patients require either a double-lumen central venous catheter or two large-bore antecubital peripheral lines.

Plasmapheresis can be performed using a semipermeable membrane–based device in combination with hemodialysis equipment. Central lines, as opposed to peripheral lines, are required for membrane-based plasmapheresis because of their higher flow rates of roughly 100-150 mL/min, as compared with 50-70 mL/min for centrifuge-based equipment.

Two types of membrane-based plasmapheresis technologies exist: hollow fiber and parallel plate. Hollow-fiber dialyzers consist of a bundle of capillaries potted (glued) at both ends into a plastic cylindrical shell. Parallel-plate dialyzers contain layers of stacked membranes with ridges and grooves. Both technologies allow for the separation of plasma from the cellular components of blood based on particle size as well as pressure gradients.

The major advantage of hollow-fiber dialyzers is that they are considered more gentle than parallel-plate technology and are therefore more commonly used in pediatrics. Parallel-plate dialyzers, on the other hand, require less blood volume and therefore less anticoagulant, thereby minimizing the side effects associated with citrate or heparin. Asahi Plasma-Flo is an example of hollow-fiber technology, and Cobe TPE is an example of parallel-plate technology.

An advantage of membrane-based plasmapheresis is that multiple cycles of filtration and ultrafiltration can take place, potentially allowing for the return of beneficial plasma elements while discarding the pathogenic components.[5]

Anesthesia

Anesthesia is occasionally used during central line placement in preparation for plasmapheresis if the patient does not already have a central line. However, anesthesia is rarely used during the plasmapheresis session itself. In pediatrics, opioids such as morphine and benzodiazepines such as lorazepam are occasionally used for temporary pain relief and anxiety control, respectively.

Positioning

The patient is placed in the supine position. The head of the bed is flat or elevated to a reverse Trendelenburg position in accordance with the patient's comfort. If an internal jugular line is being used, the patient's neck may have to be repositioned to permit proper flow.

Vital signs are monitored every 15 minutes, particularly for signs of volume depletion (eg, tachycardia and hypotension). Signs and symptoms of hypocalcemia (eg, numbness or tingling of the fingers, nose, or tongue) are also checked carefully. In pediatric patients, symptoms of hypocalcemia can include abdominal pain, nausea, or vomiting.

Long-term monitoring

Delayed transfusion reactions can be seen several days after the transfusion ends, and patients should be alerted to the signs and symptoms so that they can seek medical attention.

Infection related to the use of central venous catheter is a potential complication. Sterile technique can minimize the likelihood of this possibility. Infection related to the use of blood products is another potential complication that should be raised as part of the initial consent.

Steps in therapeutic plasma exchange

The following is an example of the steps involved in performing therapeutic plasma exchange using centrifugation-based equipment such as the Spectra Auto PBSC:

• Any heparin that may be present in each of the two lumina of a central venous catheter is removed
• A waste of 3 mL is then discarded
• Laboratory studies, including complete blood count (CBC), calcium, and fibrinogen, are ordered and specimens sent from the draw lumen
• A flush with 10 mL of normal saline is placed in the draw lumen
• The draw and return lumina are then connected to the tubing, which is previously primed with normal saline; however, if a patient weighs less than 20 kg, then the draw and return tubing are primed with packed red blood cells (RBCs) instead of normal saline
• Height and weight are then entered into the system to allow estimation of total blood volume (TBV)
• Plasma volume is then calculated as follows: TBV × (1 – hematocrit)
• A replacement product is chosen
• The total volume of the desired replacement product is entered—usually either 1 plasma volume (40 mL/kg) or 1.5 plasma volume (60 mL/kg)
• A centrifuge speed is determined by the software on the basis of the data entered
• The device then draws whole blood through the draw lumen to the centrifuge
• Plasma is separated by the centrifuge and collected for discard
• RBCs are also separated by the centrifuge, then returned to the patient along with the previously selected colloid of either albumin or fresh frozen plasma (FFP)
• After the desired amount of plasma is removed, the machine is disconnected from the patient, and heparin is instilled into each catheter lumen to prevent clotting until the lumen is accessed again
• A post–plasma exchange fibrinogen level is checked if albumin was used as the replacement product (albumin does not contain fibrinogen, as opposed to FFP) to assess whether the patient has become severely hypofibrinogenemic

Replacement products

Options for replacement fluid during plasma exchange include albumin, electrolyte solutions, hydroxyethyl starch, FFP, and purified protein products such as individual clotting factors or antithrombin III.[18] Deciding which replacement product to use is based on the underlying condition and the risks and benefits associated with each replacement product. In general, albumin is the most common replacement product because of its low side-effect profile and broad availability.[18]

Symptomatic adjustments

If signs of hypocalcemia are present, replacement calcium can be administered either intravenously (IV) or orally. Additionally, the whole blood–to–citrate ratio can be titrated to minimize hypocalcemic symptoms, which are usually related to the amount of citrate being used as an anticoagulant.[19]

If signs of hypomagnesemia are present, replacement magnesium can be administered IV.

If signs of general discomfort are present, the return rate can be adjusted downward.

If signs of hypotension are present, normal saline boluses can be administered.

If signs of a transfusion reaction are present, the product infusion is discontinued, and diphenhydramine and hydrocortisone are given. In cases of anaphylaxis or respiratory distress, epinephrine can be administered as well.

Special considerations in pediatric patients

Magnesium is not always given prophylactically, though the decision is physician-dependent.[20]

If a patient weighs less than 20 kg, the draw and return tubing are primed with packed RBCs instead of normal saline.

Return rates of blood product are on the order of 1.5 mL/kg/min, as opposed to the standard 70 mL/min flat rate used in adults.[21]

Patients may experience symptoms of hypocalcemia and or hypomagnesemia during and after the procedure, which can be treated with replacement calcium and magnesium, respectively.[22]

Patients frequently become hypothermic during the procedure, in which case they should be warmed appropriately.

Patients can experience transfusion-related reactions, in particular with FFP, and should be treated with diphenhydramine, hydrocortisone, and/or epinephrine, depending on the severity of the reaction. These reactions can occur during and after the transfusion.

Patients can experience hypotension as a result of rapid fluid shifts, and proper precautions should be taken to minimize complications such as unintended falls.

Patients can become thrombocytopenic and hypofibrinogenemic after plasmapheresis (especially if albumin is being used as a replacement product) and should be monitored for signs of bleeding.

Patients may also be at further risk for developing hypotension if they have a history of taking angiotensin-converting enzyme (ACE) inhibitors, in particular while undergoing column-based plasmapheresis.[23] The suspected mechanism is related to increased bradykinin levels caused by use of ACE inhibitors. This accumulation of kinins leads to hypotension, flushing, and gastrointestinal symptoms. Patients are therefore advised to stop all ACE inhibitors at least 24 hours before starting plasmapheresis.

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Class Summary

These agents are used for the treatment of thromboembolic disorders.

Heparin

Heparin augments activity of antithrombin III and prevents conversion of fibrinogen to fibrin. It does not actively lyse but is able to inhibit further thrombogenesis. It prevents reaccumulation of clot after spontaneous fibrinolysis.

Class Summary

These agents act by competitive inhibition of histamine at the H1 receptor. This mediates the wheal and flare reactions, bronchial constriction, mucous secretion, smooth muscle contraction, edema, hypotension, CNS depression, and cardiac arrhythmias.

Diphenhydramine (Anti-HIst, Aler-Dryl, Benadryl)

This is a first-generation antihistamine with anticholinergic effects that binds to H1 receptors in the CNS and the body. It competitively blocks histamine from binding to H1 receptors. It is used for symptomatic relief of symptoms caused by release of histamine in allergic reactions and may be used in patients that experience transfusion related reactions, in particular with FFP.

Class Summary

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. In addition, these agents modify the body's immune response to diverse stimuli.

Hydrocortisone (Solu-Cortef, Cortef)

Hydrocortisone decreases inflammation by suppressing the migration of polymorphonuclear leukocytes (PMNs) and reversing increased capillary permeability.

Class Summary

Adrenergic agonists cause vasoconstriction, reduce vascular permeability, and bronchodilation. They are vitally important in treating acute angioedema associated with allergic reactions affecting upper airways. Their benefit in other types of laryngeal edema (eg, acute hereditary angioedema [HAE]) is less certain.

Epinephrine (EpiPen, Adrenalin, Twinject)

Epinephrine is used in cases of laryngeal edema. It has alpha-agonist effects that include increased peripheral vascular resistance and reduced vascular permeability.

Class Summary

Pain control is essential to quality patient care. Analgesics ensure patient comfort, promote pulmonary toilet, and have sedating properties.

Acetaminophen (Tylenol, APAP 500, Mapap, Feverall)

Acetaminophen reduces fever by acting directly on hypothalamic heat-regulating centers, thereby bringing about increased dissipation of body heat with vasodilation and sweating.

Class Summary

Calcium and vitamin D are essential to increase bone density. Vitamin D repletion is essential for calcium absorption. Calcium supplements are used to increase calcium levels. Adequate calcium intake is essential to attain peak bone mass and for continued maintenance of bone health.

Calcium citrate (Cal-Citrate, Cal-Cee, Cal-C-Caps)

Calcium is the primary component of skeletal tissue, providing structural integrity and support for individual growth. Bone undergoes constant remodeling and turnover. Combination of supplemental calcium and vitamin D can potentially lower the incidence of fractures. Calcium citrate is absorbed equally well when taken with or without food.

Calcium carbonate (Caltrate 600, Calcarb 600, Oysco 500, Super Calcium 600, Tums Ultra)

Calcium intake is essential in the prevention and treatment of osteoporosis. Calcium carbonate is generally more inexpensive and requires fewer tablets. Because of its dependence on stomach acid for absorption, calcium carbonate is absorbed most efficiently when taken with food.

Calcium chloride

Calcium chloride moderates nerve and muscle performance by regulating the action potential excitation threshold. This form of calcium is preferred for patients in cardiac arrest and in other serious cases.. The 10% IV solution provides 100 mg/mL of calcium chloride equaling 27.2 mg/mL (1.4 mEq/mL) of elemental calcium (ie, 10 mL of calcium chloride 10% solution contains 272 mg of elemental calcium).

Class Summary

Serum potassium levels can fall during therapy. Therefore, potassium supplements may be indicated.

Potassium Chloride (K-Tab, Klor-Con, Micro-K, Epiklor)

Essential for transmission of nerve impulses, contraction of cardiac muscle, maintenance of intracellular tonicity, skeletal and smooth muscles, and maintenance of normal renal function.

Class Summary

Correction of acute anemia often requires blood and/or blood products. With significant ongoing hemorrhage or hemolysis, transfusion of blood alone is insufficient. Nonetheless, providing timely transfusion to restore hemoglobin to safe levels can prevent major complications of acute anemia.

Packed red blood cells

Packed red blood cells (PRBCs) are used preferentially to whole blood, since they limit volume, immune, and storage complications. PRBCs have 80% less plasma, are less immunogenic, and can be stored about 40 days (versus 35 d for whole blood). PRBCs are obtained after centrifugation of whole blood. Leukocyte-poor PRBCs are used in patients who are transplant candidates/recipients and in those with prior febrile transfusion reactions. Washed or frozen PRBCs are used in individuals with hypersensitivity transfusion reactions.

Fresh frozen plasma

Fresh frozen plasma (FFP) contains coagulation factors, as well as protein C and protein S. Its uses include the treatment of coagulopathies and TTP and the reversal of Coumadin. FFP does not transmit infections.

Albumin 5% (Albuminar, Buminate, Kedbumin)

Albumin is used for treatment of certain types of shock or impending shock. It is useful for plasma volume expansion and maintenance of cardiac output. A solution of NS and 5% albumin is available for volume resuscitation.

Class Summary

Isotonic sodium chloride (normal saline [NS]) is a standard crystalloid intravenous (IV) fluid used for initial volume resuscitation. It expands the intravascular and interstitial fluid spaces. Typically, about 30% of administered isotonic fluid stays intravascular; therefore, large quantities may be required to maintain adequate circulating volume.

Normal saline (NS, 0.9% NaCl)

NS restores interstitial and intravascular volume. It is used in initial volume resuscitation.

Class Summary

Magnesium can be administered either orally in an oxide or gluconate form or parenterally as a sulfate salt.

Magnesium oxide (Mag-Ox, MagGel 600, Uro-Mag)

This agent is used for the treatment of magnesium deficiencies or magnesium depletion from malnutrition, restricted diet, alcoholism, or magnesium-depleting drugs.

Magnesium gluconate (Magtrate, Mag-G, Magonate)

Five hundred milligrams of magnesium gluconate contain 27 mg of elemental magnesium.