Therapeutic hemapheresis: indications and risks

Therapeutic hemapheresis is a non-organ blood purification technology that selectively removes plasma, blood cells, or macromolecules from the patient's bloodstream, then returns the remaining components with a replacement fluid. The goal is to quickly reduce the concentration of pathogenic factors: autoantibodies, immune complexes, cryoglobulins, lipoproteins, free hemoglobins, and other toxic substrates. [1]

The main methods include therapeutic plasma exchange, immunoadsorption, single or scheduled red blood cell exchanges, leukapheresis, platelet apheresis, lipoprotein apheresis, and extracorporeal photopheresis. Each method has its own clinical niches, regimens, and requirements for replacement solutions, anticoagulation, and monitoring. [2]

The defining source of clinical indications are professional society guidelines, where each condition is assigned a category of use and a recommendation grade based on the quality of evidence. The most widely cited are publications of the American Apheresis Society, which reflect the current evidence base for dozens of nosologies. [3]

Procedures are performed using centrifuge or membrane systems, under the control of vital parameters, electrolytes, and coagulation. Key technical decisions include the choice of vascular access, anticoagulant, and calculation of the volume of plasma exchanged to achieve the desired therapeutic effect in a minimum number of sessions. [4]

Table 1. Main methods of hemapheresis and target “targets”

Method	What does it remove?	Typical clinical use
Therapeutic plasma exchange	Soluble pathogens: autoantibodies, immune complexes, paraproteins	Thrombotic thrombocytopenic purpura, hyperviscosity, antibody-dependent glomerulonephritis
Immunoadsorption	Selective removal of immunoglobulins	Preparation for transplantation, autoimmune diseases
Red blood cell metabolism	Red blood cells with abnormal hemoglobin	Sickle cell disease: stroke, acute chest syndrome
Lipoprotein apheresis	Atherogenic low-density lipoproteins and lipoprotein A	Severe forms of familial hypercholesterolemia
Extracorporeal photopheresis	Immunomodulation through leukocyte processing	Transplant rejection, cutaneous T-cell lymphomas

Background: Reviews and guidelines on the clinical use of apheresis. [5]

How to Read Categories and Levels of Evidence: The Logic of Guidelines

The American Apheresis Society guidelines assign each clinical situation a category from I to IV, ranging from first-line therapy to conditions where the method is considered ineffective or potentially harmful. This format, first formulated over 10 years ago, is regularly updated and helps standardize the use of procedures. [6]

The ninth edition (2023) describes more than 160 specific indications in the form of "passports" by nosology, including new lists and revisions of categories based on recent research. The document remains the reference for apheresis units in routine clinical practice. [7]

Category I means the method is recognized as first-line therapy for this condition and should be prescribed without delay where appropriate. Category II means it is an effective second-line or adjunct to basic therapy. Category III means the role is uncertain, and decisions are individualized. Category IV means there is no evidence of benefit or there is evidence of harm. [8]

In addition to the category, the strength of the recommendation is given according to the evidence quality assessment system. The higher the strength of the recommendation, the more stringent the adherence to protocols and the less room for variability in regimens, volumes, and choice of replacement media. [9]

Table 2. Explanation of application categories according to guidelines

Category	Meaning	Example of nosology
I	First-line therapy	Immune thrombotic thrombocytopenic purpura
II	Second line or addition	Myasthenia gravis in crisis, sickle cell disease for a number of situations
III	Role not defined	Certain rare autoimmune conditions
IV	Ineffective or harmful	Conditions with proven uselessness of the method

Reason: Review of categories and grading schemes. [10]

Highly Evidence-Based Indications: What Definitely Works

Immune thrombotic thrombocytopenic purpura. Therapeutic plasma exchange with fresh frozen plasma replacement is first-line therapy for the immediate removal of inhibitory antibodies to the metalloprotease ADAMTS13 and replenishment of the deficient enzyme. Current tactics include combination with glucocorticoids, early rituximab, and the anti-von Willebrand factor caplacizumab to accelerate remission and reduce the need for sessions. [11]

Hyperviscosity in Waldenström's macroglobulinemia and other paraproteinemias. Plasma exchange quickly reduces viscosity and alleviates threatening symptoms, after which antitumor therapy is initiated. It is important to consider the risk of an immunoglobulin M surge with rituximab, so sequencing treatment and short-term plasma exchange before initiating systemic therapy are of practical value. [12]

Antiglomerular basement membrane disease. A combination of plasma exchange with the cytostatic agent cyclophosphamide and glucocorticoids is recommended until serum antibodies disappear, with an adjusted approach in patients undergoing dialysis without pulmonary hemorrhage. These recommendations are supported by the latest revision of nephrology guidelines. [13]

Acute neurological autoimmune conditions. In Guillain-Barré syndrome, plasma exchange accelerates recovery compared to supportive care and, in most cases, is comparable in effectiveness to intravenous immunoglobulin. In myasthenic crises, plasma exchange provides rapid relief of weakness and respiratory distress as a short-term measure, equivalent in clinical efficacy to immunoglobulin in some studies. [14]

Sickle cell disease. Programmed red blood cell exchange is used to prevent and treat vascular complications, including stroke and acute chest syndrome, with a targeted reduction in the proportion of abnormal hemoglobin S. Specialized guidelines recommend exchange as a preferred approach over simple transfusions in some patients in a number of clinical situations. [15]

Table 3. Recommended modes for key indications

Indication	Procedure regime	Replacement solution	Criteria for stopping or de-escalating
Immune thrombotic thrombocytopenic purpura	Daily, the volume is about 1-1.5 times the patient's plasma volume.	Fresh frozen plasma	Normalization of platelets and lactate dehydrogenase, sustainability of the effect
Hyperviscosity in Waldenstrom's macroglobulinemia	Repeated sessions at the clinic	Albumin or plasma as indicated	Relief of symptoms and reduction of viscosity, followed by systemic therapy
Anti-glomerular basement membrane disease	A series of sessions until antibodies are negative	Albumin with the addition of plasma as indicated	Negative antibodies, clinical stabilization
Guillain-Barre syndrome	Short course in the first weeks	Albumen	Improvement in weakness and breathing scales
Myasthenic crisis	A series of procedures over 1-2 weeks	Albumen	Clinical improvement, transfer to maintenance therapy
Sickle cell disease	Red blood cell exchange according to protocol	Red blood cell components	The proportion of hemoglobin S is below the target threshold

Basis: specialized guides and reviews. [16]

How the procedure is performed: calculations, replacement media, and anticoagulation

Classic plasma exchange is performed with volume calculated based on the patient's weight, height, and hematocrit. One session typically exchanges approximately one volume of plasma; in severe cases, up to one and a half volumes may be used to accelerate pathogen reduction. The frequency and duration of the course depend on the diagnosis and response dynamics. [17]

The choice of replacement solution determines the safety profile. Albumin is associated with a lower incidence of hypersensitivity and acute pulmonary complications, while fresh frozen plasma is necessary when factor replacement is required, as in immune thrombotic thrombocytopenic purpura. In registry studies, albumin predominates, with plasma used in a minority of cases for strict indications. [18]

Anticoagulation is most often based on sodium citrate, which effectively prevents clotting in the circuit and is rapidly metabolized. In patients at risk of bleeding, regional citrate anticoagulation shows a more favorable profile than systemic heparin, with comparable efficacy, as confirmed by meta-analyses and observational studies. [19]

Intra- and post-procedural monitoring includes pulse rate, blood pressure, oxygen saturation, temperature, calcium and acid-base balance monitoring, and, when using plasma, an assessment of the risk of immune reactions. For red blood cell metabolism, target hemoglobin and hemoglobin S levels are set and achieved by the device's software. [20]

Table 4. Substitution media: when albumin, and when plasma

Replacement environment	Advantages	Restrictions	Typical indications
Albumen	Lower risk of immune reactions and acute pulmonary complications	Does not replenish enzymes and clotting factors	Neurological autoimmune conditions, hyperviscosity after stabilization
Fresh frozen plasma	Replenishes deficient proteins and enzymes	Higher risk of allergies, congestion and pulmonary reactions	Immune thrombotic thrombocytopenic purpura, certain coagulopathies

Basis: educational guidelines and clinical practice data. [21]

Adverse events, drug interactions and their prevention

The most common adverse events are citrate-induced hypocalcemia, dizziness, paresthesia, hypotension, and allergic reactions to plasma. Most events are reversible with timely detection and correction, and the overall incidence of serious complications in recent publications is low. Standardized prophylaxis significantly reduces this risk. [22]

Hypocalcemia is prevented by prophylactic infusion of calcium solutions and titrated citrate infusion rates. Approaches to calcium support vary among centers, but prophylactic administration of calcium to the return line has been shown to be well tolerated and predictable. [23]

When using plasma, the risk of acute lung injury and volume overload must be considered, so albumin is preferred in vulnerable patients unless factor replacement is critical. The choice of medium and infusion rate are adapted to the specific risk profile and comorbidities. [24]

An important practical aspect is the removal of drugs during plasma exchange. A session can reduce the concentrations of antibiotics, immunosuppressants, and monoclonal antibodies, requiring adjustments in administration time, dosage, and level monitoring. This also applies to hemosorption, but its pharmacokinetic effects differ by mechanism. [25]

Table 5. Frequent complications and preventive measures

Complication	What to do for prevention
Hypocalcemia due to citrate	Prophylactic calcium infusion on the return line, monitoring of calcium ions
Hypotension	Speed control, adequate pre-hydration, positional assistance
Allergic reactions to plasma	Premedication as indicated, choice of albumin in the absence of a need for factors
Volume overload	Individualization of rate and volume, careful monitoring of diuresis and respiration
Reducing drug levels	Synchronization of doses with sessions, therapeutic drug monitoring

Basis: safety reviews, clinical guidelines and practice reviews. [26]

Special situations: pregnancy, children, intensive care and organizational issues

In obstetrics, plasma exchange is used for strict indications when the expected benefit outweighs the risks, for example, in the case of recurrent thrombotic thrombocytopenic purpura. Protocols take into account platelet dynamics, biochemical markers, and clinical findings, as well as interactions with anticoagulation and specific medications. [27]

In pediatrics, regimens are adjusted based on body weight and calcium metabolism physiology. Regional citrate anticoagulation is considered a safe alternative in children with a high risk of bleeding during membrane plasma exchange, as reflected in modern comparative studies. [28]

In intensive care units, plasma exchange is used as part of multidisciplinary protocols for life-threatening conditions requiring rapid control of pathogens or mediators. This emphasizes the need for an experienced team, clear stopping criteria, and thoughtful selection of the environment to minimize complications in critically ill patients. [29]

Organizational importance lies in vascular access planning, staff training in the prevention of vasovagal and citrate-related reactions, and patient routing between specialized services. Unified local protocols and checklists reduce practice variability and improve the predictability of outcomes. [30]

Table 6. Monitoring and target parameters by state

Situation	What to track	Practical target benchmarks
Immune thrombotic thrombocytopenic purpura	Platelets, lactate dehydrogenase, neurological status	Sustained normalization of platelets and hemolysis biomarkers
Hyperviscosity in Waldenstrom's macroglobulinemia	Symptoms, viscosity, immunoglobulin M	Rapid clinical improvement and viscosity reduction, then transition to systemic therapy
Anti-glomerular basement membrane disease	Antibody titer, creatinine, diuresis	Negative antibodies and stabilization of renal function
Guillain-Barre syndrome	Muscle strength scales, respiratory function	Improved functional performance and reduced need for ventilation
Sickle cell disease	Hemoglobin S fraction, hemoglobin	The proportion of hemoglobin S is below the target threshold according to the protocol

Basis: specialized guidelines and critical reviews. [31]