Plasmapheresis, also called plasma exchange (PE) or therapeutic plasma exchange (TPE) is a recognized medical procedure in which various techniques are used to separate and remove the plasma with undesirable blood elements. The term plasmapheresis is derived from the Greek words plasma (something moulded) and aphairesis (taking away). The procedure was first successfully used for the treatment of Waldenstrőm macroglobulinemia in the 50ties of the previous century [1, 2]. Since then the efficacy of plasmapheresis has been documented in numerous diseases of the nervous, respiratory, excretory, blood-forming systems, and in vascular diseases [3]. The procedure is widely used in intensive therapy units.

The main purpose of the procedure is to remove plasma with the substances responsible for the disease (autoantibodies, immunoglobulins, cytokines, etc.) from the patient`s blood; in some cases, it is also to supplement the lacking element by transfusion of fresh frozen plasma (FFP) [4]. The particles of harmful substances should be adequately large (≥ 15 kDa), or their half-life should be relatively long. Only in such cases, plasmapheresis is likely to be beneficial [5].

The amount of removed plasma should be based on the estimated plasma volume (EPV) in patient`s blood. The commonest method to determine EPV is the formula taking into account body weight (b.w.) and haemotocrit (Ht): EPV= ((0.065 x b.w. (kg) x (1-Ht)) [6]. In a patient weighing about 70 kg and with normal haemotocrit, this volume is about 2.5-2.7 litre or 35-40 mL kg-1. Harmful substances are present both in the intra- and extra-vascular space and plasmapheresis removes only those in the former. The higher the volume of removed plasma, the bigger the amount of a harmful substance removed. To remove 75% of a harmful substance, 1.4 of EPV should be exchanged during one procedure, i.e. about 2500-3500 mL. This volume should not be lower than EPV of a patient. After the procedure, due to re-synthesis of harmful substances, their transfer from the extra- to intra-vascular space and return with the lymph, this concentration re-increases. Therefore, plasmapheresis should be repeated (usually every 24-48 h). Generally, 4-5 exchanges are performed, which decreases the concentration of a harmful substance by about 90% compared to the baseline level depending on the sizes of particles removed, their half-life in plasma and rate of synthesis [5].

MODES OF PLASMAPHERESIS

TPE requires appropriate vascular access. In most cases, double-lumen catheters are placed in the central veins (internal jugular, subclavicular, femoral), which enable simultaneous collection and return of blood and fluids to the circulatory system. Irrespective of the type of procedure, effective anticoagulation with heparin or citrate is needed. Possible deficits of electrolytes, plasma or albumins are supplemented by the system supplying blood to the patient. 

Plasma is cleansed in an insernittent or continuous way.

The intermittent procedure is to separate the plasma from blood morphotic elements, to clean or remove plasma and to re-transfuse the morphotic substances to the patient`s body in the adequate volume of substitutive fluids (e.g. electrolytes, FFP, albumins). The limitation of this method is a transient marked decrease in blood volume. To use this method, a single-lumen vascular catheter is sufficient.

The continuous plasmapheresis involves simultaneous collection, cleansing and return of blood.

In both procedures, there are several methods of plasma cleansing [7]:

–  the sedimentation method based on spontaneous sedimentation of blood morphotic elements in accordance with the gravitational force,

–  the centrifugal method, in which blood fractions are separated using the centrifugal force,

–  the filtration method or membrane plasma separation (MPS) currently recommended: blood flows through special filters (of definite pore sizes) enabling the separation of the morphotic elements from plasma, which is removed with the filtered out particles and substances. The procedure requires the system of lines with pumps inducing the suitable blood flow rate, a filter for effective, selective removal of plasma and sensors measuring the pressure in the system,

– the cascade method (double filtration) - additional exposure of the separated plasma to further selective cleansing on a filter with smaller pores before it is returned to the patient`s circulatory system. Although it seems more effective, the method may cause adverse side effects, such as haemorrhagic complications induced by coagulopathy due to substantially decreased fibrinogen concentration or higher incidence of blood clotting on a filter [5].

INDICATIONS FOR PLASMAPHERESIS

The indications for plasmapheresis are determined every several years by two American scientific associations: the American Association of Blood Banks (AABB) and American Society for Apheresis (ASA) [3, 8] based on available evidence of treatment efficacy in individual diseases. The guidelines use four categories of indications: I – TPE is considered standard therapy accepted as the first-line treatment; II – TPE is generally accepted to supplement the main treatment; III - there is not enough evidence to acknowledge the benefits of plasmapheresis and it should be considered only when standard management has failed; and IV – lack of effectiveness of TPE, which is considered a contraindication for such a procedure. The main uses of TPE according to the categories of indications are presented in Table 1.

Nephrology indications

1. Goodpasture’s disease, caused by anti-glomerular basement membrane (anti-GMB) antibodies inducing acute glomerulonephritis and pulmonary haemorrhage, accounts for 15% of rapidly progressive glomerulonephritis (RPGN). In some cases, anti-neutrophil cytoplasmic antibodies (ANCA) are also present, which enhance the basement membrane damage [3]. Generally, the disease progresses rapidly and leads to renal and respiratory failure requiring mechanical lung ventilation. It is treated with immunosuppressive therapy using steroids and cyclophosphamide combined with TPE. TPE should be instituted as early as possible before haemodialysis is necessary [3, 9].

2. A similar TPE indication is RPGN in the course of Wegener’s granulomatosis [3], in which ANCA are also generated.

Haematological indications

1. Thrombotic thrombocytopenic purpura (TTP) is thrombotic microangiopathy with thrombocytopenia caused by intravascular formation of platelet aggregates. TTP is usually an acquired disease (except for its genetically determined form, which is rare) induced by antibodies inhibiting ADAMTS-13, which breaks down the multimers of von Willenbrand factor, whose excess leads to enhanced adhesion, activation and aggregation of platelets [10]. The main symptoms include haemolytic anaemia, thrombocytopenia and ischaemia of many organs, including CNS. In untreated cases, the mortality is 90%; with TPE it decreases to <10% [11]. TPE should be instituted as soon as possible and used every day until the platelet count stabilizes at the level of at least 150 G L-1 [3, 12]. TPE should be used simultaneously with immunosuppressive therapy.

2. Waldenström macroglobulinemia – neoplastic proliferation of lymphocytes in the bone marrow, lymph nodes and spleen producing the IgM monoclonal protein. The symptoms are similar to those in multiple myeloma. Additionally, hepatomegaly, splenomegaly and enlarged lymph nodes are observed. Some patients develop symptoms related to hyperviscosity: mucous membrane bleeding, neurological manifestations and renal failure [13]. In such patients, TPE provides best outcomes [3].

Neurological indications

1. Acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barre syndrome) – an acquired disease of peripheral nerves of not fully clear etiology (most likely autoimmunological), which leads to progressive neurological symptoms, often precipitated by respiratory or alimentary infections [14]. Flaccid limb paresis and respiratory failure are likely to develop (25% of patients). When mechanical lung ventilation is needed, the mortality may reach even 20% [14, 15]. The treatment of choice is TPE or infusions of immunoglobulins. In general, 4-5 TPE procedures are applied, preferably during the first 2 weeks from the onset of symptoms. This enables to shorten mechanical lung ventilation and recovery [3]. During the procedures, special attention should be paid to arterial pressure fluctuations due to dysfunction of the vegetative system.

2. Chronic inflammatory demyelinating polyradiculopathy. The use of TPE in patients with this disease is also effective (category I) although its advantages over less expensive treatments with steroids and immunoglobulins have not been demonstrated [3, 16].

3. Myasthenia – an acquired autoimmune disease caused by autoantibodies against antigens of neuromuscular junctions, most commonly against the acetylcholine receptor. The disease is characterized by progressive myasthenia; muscles of eyeballs are first affected (diplopia), difficulty in biting and swallowing follows. The muscle weakness increases, which often leads to myasthenic crisis, exhaustion of respiratory muscles and respiratory failure requiring mechanical lung ventilation [15]. In such cases, TPE is the treatment of choice and once promptly instituted improves prognosis [17].

4. Lambert-Eaton syndrome (symptoms similar to myasthenia). TPE is used in most severe conditions (category II). Simultaneously, urgent diagnostic procedures to detect any neoplastic disease are necessary; once detected, the adequate treatment should be instituted [3, 8].

Autoimmunological indications

Cryoglobulinemia. Immunoglobulins or their complexes, which precipitate at a low temperature, may occur in various types of infections, lymphoproliferative disorders and autoimmune diseases. Precipitation in fine vessels may induce tissue damage by excessive activation of complement components and migration of leucocytes. The manifestations vary from very mild to life threatening, e.g. glomerulonephritis, neuropathies and systemic vasculitis. The treatment should be targeted at the underlying disease and TPE, as the supportive therapy, is clinically extremely effective in relieving the symptoms [3, 19].

MONITORING OF VITAL FUNCTIONS

Considering the patient`s severe condition and marked interference in homeostasis, strict monitoring of vital functions is necessary during the procedure and perioperative period. Continuous observation improves the safety of the entire procedure thanks to early detection of adverse effects [20].

A prerequisite of the properly administered procedure is:

– control of blood test results before and after the procedure, particularly haemoglobin, haemotocrit, platelet count, clotting parameters (INR, APTT, fibrinogen), electrolytes  (potassium, sodium, calcium) and bilirubin. Additionally, prior to the first procedure, concentrations of plasma proteins with immunoglobulins should be determined; if possible, the levels of pathogenic substances which are to be removed [21],

– during the procedure, since high doses of heparin are used, the activated clotting time (ACT) should be monitored and maintained within the range of 1.5-2.5 times (in the majority of cases between 160 - 200 s) [22, 23],

– monitoring of vital parameters during the procedure (HR, SAP/DAP, CVP, SpO2, f, body temperature). Since the arterial pressure may be decreased during the procedure, CVP should be maintained within the range of 8-12 cm H2O (0.78 – 1.18 kPa). The vascular bed filling before the procedure enables to reduce the risk of adverse effects such as reduced systemic arterial pressure,

– observation of the patient  to detect possible skin changes – pruritus, erythema or rash as symptoms of allergic reactions to transfused substitutive fluids (mainly FFP).

Besides, clinical status monitoring, control of technical parameters during the procedure is relevant:

– blood flow - the target value depends on the membranes used and should be 50-150 mL min-1. Too big flow poses the risk of haemolysis [21],

– transmembrane pressure – depends on the kind of membrane and should be 50-100 mm Hg (6.67-13.33 kPa). Too high pressure may cause erythrocyte haemolysis or penetration of erythrocytes through the filtration membrane [20],

– ultrafiltration – optimal amount of removed plasma is 800-1000 mL h-1. Too fast plasma exchange is likely to induce side effects, e.g. decreased arterial blood pressure,

– temperature of substitutive fluid should be about 370 C.

COMPLICATIONS

Complications during TPE are rare (3.9-4.75%) [24, 25] and are usually easily reversible. They mainly include limb paresthesias and muscle contractions (caused by decreased levels of calcium), urticaria, dizziness, nausea, vomiting and hypotonia [26]. Life-threatening complications constitute only 0.025-0.2% and are commonly associated with extremely severe conditions of patients before the procedure rather than the procedure itself [5].

TPE-related complications most commonly concern central vein cannulation, transfusion of blood preparations and other substitutive fluids, anticoagulation or the procedure technique and depend on the experience of the team. The commonest complications are compiled in Table 2.

One of the commonest complications during the procedure is a decrease in blood calcium concentration. Hypocalcaemia induces abnormalities in the threshold of excitability of neuromuscular structures, which may result in symptoms of tetany or its equivalents. Moreover, limb paresthesias, enhanced ligamentous reflexes, seizures, reduced arterial blood pressure, decreased cardiac output and ventricular arrhythmias are observed. Hypocalcaemia results from the use of sodium citrate (during FFP production) – an anticoagulant binding calcium ions; therefore, during the procedure prophylactic supplementation of calcium ions should be administered (gluconate), which markedly prevents this complication [27].

Life-threatening complications include decreased cardiac output, hypotonia, anaphylactic reaction or sepsis.

Anaphylactic reactions are mainly associated with FFP transfusion and in the majority of cases occur in TTP patients treated with plasmapheresis [24]. Their manifestations are urticaria, pruritus, elevated body temperature, in severe cases – anaphylactic shock. The incidence of anaphylactic reactions is markedly lower when albumins are used for fluid supplementation [28]. Less severe anaphylactoid reactions develop in response to the contact of blood with the filter and system of lines sterilized with ethylene oxide. Their severity may be limited by suitable rinsing of the plasma-filter with saline.

Complications such as haemorrhagic diathesis or hypercoagulation result from clotting disturbances and are caused by the loss of clotting factors during TPE. In cases of total plasma exchange during one procedure, the levels of plasma clotting factors (V, VII, IX, X, fibrinogen) decrease by approximately 60% [5].

Haemorrhagic complications may also result from anticoagulation used (heparin, citrate) and manifest themselves as bleeding from the site of catheter placement or from nasal mucosa, vomiting with blood or coughing up of bloody bronchial secretion.

Transient decreased levels of antithrombin during the procedure may predispose to venous thromboembolic disease [5].

During everyday procedures of plasma exchange, the risk of infections increases. In extreme cases sepsis may develop caused by decreased concentrations of immunoglobulins and complement components C3 and C4.

Complications related to central vein cannulation are typical of this procedure and include pneumothorax, air embolus, injection site haemotoma, infection, and venous thrombosis.

Plasmapheresis is effective in many diseases, including life-threatening conditions treated in ITUs. In many cases, the decision about its institution saves the patient`s life. TPE-related adverse side effects are rare when the procedure is performed by experienced physicians and nurses trained according to the current standards.

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REFERENCES

1.    Solomon A, Fahey JL: Plasmapheresis therapy in macroglobulinemia. Ann Intern Med 1963; 58: 789-800.

2.    Adams WS, Blahd WH, Bassett SH: A method of human plasmapheresis. Proc Soc Exp Biol Med 1952; 80: 377-379.

3.    Szczepiórkowski ZM, Bandarenko N, Kim HC, Linenberger ML, Marques MB, Sarode R, Schwartz J, Shaz BH, Weinstein R, Wirk A, Winters JL: Guidelines on the use of therapeutic apheresis in clinical practice: evidence-based approach from the Apheresis Applications Committee of the American Society for Apheresis. J Clin Apher 2007; 22: 106-175.

4.    McLeod BC: Rationales for therapeutic apheresis. Hematology 2005; 10 (Suppl. l): 203-207.

5.    Kaplan AA: A practical guide to therapeutic plasma exchange. Blackwell Science, London 1999

6.    Inkley SR, Brooks L, Krieger H: A study of methods for the prediction of plasma volume. J Lab Clin Med 1955; 45: 841-850.

7.    Sawada K, Malchesky PS, Nose Y: Available removal systems: state of the art. Curr Stud Hematol Blood Transfus 1990; 57: 51-113.

8.    Smith JW, Weinstein R: Therapeutic apheresis: a summary of current indication categories endorsed by the AABB and the American Society for Apheresis. Transfusion 2003; 43: 820-822.

9.    Levy JB, Turner AN, Rees AJ, Pusey CD: Long-term outcome of anti-glomerular basement membrane antibody disease treated with plasma exchange and immunosuppression. Ann Intern Med 2001; 134: 1033-1042.

10.    Levy GG, Nichols WC, Lian EC, Foroud T, McClintick JN, McGee BM, Yang AY, Siemieniak DR, Stark KR, Gruppo R, Sarode R, Shurin SB, Chandrasekaran V, Stabler SP, Sabio H, Bouhassira EE, Upshaw JD, Jr., Ginsburg D, Tsai HM: Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 2001; 413: 488-494.

11.    Bell WR, Braine HG, Ness PM, Kickler TS: Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients. N Engl J Med 1991; 325: 398-403.

12.    Jankowski M, Sznajd J, Szczeklik W, Maga P, Węgrzyn W, Królikowski W, Niżankowski R, Szczeklik A: Thrombotic thrombocytopenic purpura with myocardial ischaemia: two case reports. Kardiol Pol 2008; 66: 966-968.

13.    Fahey JL, Barth WF, Solomon A: Serum hyperviscosity syndrome. JAMA 1965; 192: 464-467.

14.    Hahn AF: Guillain-Barre syndrome. Lancet 1998; 352: 635-641.

15.    Szczeklik W, Jankowski M, Węgrzyn W, Królikowski W, Zwolińska G, Mitka I, Seczyńska B, Niżankowski R: Acute respiratory failure in patients with Guillain-Barre syndrome and myasthenic crisis treated with plasmapheresis in the intensive care unit. Pol Arch Med Wewn 2008; 118: 239-242.

16.    Koller H, Kieseier BC, Jander S, Hartung HP: Chronic inflammatory demyelinating polyneuropathy. N Engl J Med 2005; 352: 1343-1356.

17.    Gajdos P, Chevret S, Toyka K: Plasma exchange for myasthenia gravis. Cochrane Database Syst Rev 2002; CD002275.

18.    Newsom-Davis J. Lambert-Eaton: Myasthenic syndrome. Curr Treat Options Neurol 2001; 3: 127-131.

19.    Berkman EM, Orlin JB: Use of plasmapheresis and partial plasma exchange in the management of patients with cryoglobulinemia. Transfusion 1980; 20: 171-178.

20.    Chrzanowski W: Plazmafereza, immunoadsorpcja i ich kliniczne znaczenie. Gdańsk, MAKmedia; 2004.

21.    Wołyniec W, Urbaniak M: Plazmafereza lecznicza. Gdańsk, Viamedica; 2009.

22.    Daugirdas JT, lake PG, Ing TS: Handbook of dialysis. Lippincott Williams & Wilkins, London, 2007.

23.      Bambauer R, Latza R, Lentz MR: Therapeutic plasma exchange and selective plasma separation methods. Pabst Science Publishers, New York London, 2009.

24.    Basic-Jukic N, Kes P, Glavas-Boras S, Brunetta B, Bubic-Filipi L, Puretic Z: Complications of therapeutic plasma exchange: experience with 4857 treatments. Ther Apher Dial 2005; 9: 391-395.

25.    Kiprov DD, Golden P, Rohe R, Smith S, Hofmann J, Hunnicutt J: Adverse reactions associated with mobile therapeutic apheresis: analysis of 17,940 procedures. J Clin Apher 2001; 16: 130-133.

26.    McLeod BC, Sniecinski I, Ciavarella D, Owen H, Price TH, Randels MJ, Smith JW: Frequency of immediate adverse effects associated with therapeutic apheresis. Transfusion 1999; 39: 282-288.

27.    Kankirawatana S, Huang ST, Marques MB: Continuous infusion of calcium gluconate in 5% albumin is safe and prevents most hypocalcemic reactions during therapeutic plasma exchange. J Clin Apher 2007; 22: 265-269.

28.    Shemin D, Briggs D, Greenan M: Complications of therapeutic plasma exchange: a prospective study of 1,727 procedures. J Clin Apher 2007; 22: 270-276.

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address:

*Wojciech Szczeklik
Oddział Intensywnej Terapii
II Katedra Chorób Wewnętrznych
Collegium Medium Uniwersytetu Jagiellońskiego
ul. Skawińska 8, 31-066 Kraków
tel.:0-12 430 52 66, fax: 0-12 430 52 03
e-mail: wszczeklik@gmail.com

received: 28.12.2009
accepted: 28.02.2010