Review Article Role of therapeutic apheresis and phlebotomy techniques in anaesthesia and critical care

Address for correspondence: Neeta Bose, Hitendra Kanzariya1 Dr. Neeta Bose, Department of Anesthesia, Gujarat Medical Education and Research Society, Gotri, Vadodara, 1Department 7, Laxminarayan Duplex, of Anaesthesia, PSMC, Karamsad, Anand, Gujarat, India Opp. Vipul Vatika, Nr Rajesh Towers, Ellora Park, Vadodara ‑ 390 023, ABSTRACT Gujarat, India. E‑mail: neetabosenayak@ Therapeutic transfusion techniques such as apheresis and phlebotomy are frequently used in hotmail.com intensive care units. Use of the apheresis technique for the treatment of various diseases in critically ill patients is growing day by day. There are increasing evidences for using apheresis Access this article online as a primary therapy or as an adjunct to other therapies for various diseases such as thrombotic

Website: www.ijaweb.org thrombocytopenic purpura, haemolytic uremic syndrome, drug toxicities, autoimmune disease, sepsis and fulminant hepatic failure. Apheresis is an invasive procedure. It has significant DOI: 10.4103/0019-5049.144685 physiologic consequences, so the care of these patients requires continuous supervision. Quick response code Phlebotomy is performed as an intervention for some disease management. Its use is nowadays restricted to conditions such as polycythaemia, haemochromatosis and porphyria cutanea tarda. In this review, we have looked at various indications, procedure and complications of apheresis and phlebotomy in critical care unit.

Key words: Apheresis, phlebotomy, plasmapheresis

INTRODUCTION [Table 1] This allows disease resolution or decrease in morbidity.[1,2] The procedure was first Therapeutic transfusion techniques consist of successfully used for the treatment of Waldenstrőm removal of a blood component from a patient macroglobulinemia in 1959.[3,4] Since then, the using apheresis technology for removing defective efficacy of plasmapheresis has been documented in cells or disease mediators. The terminology numerous diseases of various organ systems. “Apheresis” stems from Greek verb apairesos or Roman aphairesis meaning to take away by force Sixty three articles were reviewed using keywords or withdraw.[1] Apheresis (or Haemapheresis) is the such as, therapeutic apheresis, plasmapheresis and collection of blood from a donor or patient followed therapeutic plasma exchange (TPE), starting from 1952 by separation and removal of a cellular component(s) till date, accessed through search engines PubMed, and/or plasma and return of the remaining blood Google, Google scholar and Medscape. components to the donor or patient. Cytapheresis is the procedure by which cellular elements of the Role in intensive care unit blood, platelets, leucocytes, lymphocytes, red blood Apheresis therapy like plasma exchange and plasma cells (RBC’s), are selectively removed from the adsorption is emerging as a therapeutic tool in blood. Plasmapheresis is a process in which plasma critical care. Apheresis therapy frequently used in is selectively removed. It is used to collect plasma intensive care unit (ICU) patients for thrombotic from healthy donor (without any fluid replacement) or to exchange plasma from a patient to remove thrombocytopaenic purpura (TTP), haemolytic a constituent (antibody, immune complexes, uraemic syndrome (HUS), autoimmune disease and inflammatory mediator, paraproteins, lipoproteins sepsis. Apheresis therapy is also useful in patients with and toxins, excess cells) which is causing harm. fulminant hepatic failure for artificial liver support.[2]

How to cite this article: Bose N, Kanzariya H. Role of therapeutic apheresis and phlebotomy techniques in anaesthesia and critical care. Indian J Anaesth 2014;58:672-8.

672 Indian Journal of Anaesthesia | Vol. 58 | Issue 5 | Sep-Oct 2014 Bose and Kanzariya: Therapeutic transfusion techniques

Table 1: TPE this procedure by one or more blood volumes, a Plasmapheresis TPE significant amount of pathologic components is Removal of plasma without Removal of a large proportion of removed. Anticoagulation of the circuit is required. fluid replacement patient plasma that is replaced with crystalloid, colloid fluids, FFP or This includes the collection of Centrifugation apheresis instruments use either a plasma from normal donors occasionally with coagulation factors TPE – Therapeutic plasma exchange; FFP – Fresh frozen plasma continuous or an intermittent flow method to drive the blood to the separation device. Continuous flow Description of apheresis methods draw blood into the extracorporeal circuit, Apheresis consists of the following: separate blood into components in the centrifugation • Circulating blood components can be chamber, channelizes the unwanted portion into a removed, either cells (cytapheresis) or plasma collection bag, and thereafter return the nonpathologic solutes (plasmapheresis). elements back to the patient without interruption. • Circulating substances responsible for certain Dual venous access is required for this. Intermittent diseases are removed. Some cells and plasma flow methods have the same steps but with a discrete components are mobilized from their tissue volume of blood at a time. This takes a longer time but depots and removed. requires only single venous access.[5] • Lymphocytes from the spleen and lymph nodes in chronic lymphocytic leukaemia THERAPEUTIC CYTAPHERESIS • Low‑density lipoproteins (LDLs) in familial hypercholesterolaemia. The purpose was to deplete over‑abundant or abnormal • Removal of platelets and lymphocytes. cellular components. • Reinfusion of a deficient plasma factor as in TTP. Common indications are as follows: • Increases clearance of immune complexes by • Erythrocytapheresis (the patient’s RBCs are the spleen, in certain autoimmune disorders. removed and replacement with donor red cells if required) Types of apheresis • Sickle cell disease: Goal of exchanging the • Collection of components for transfusion: sickle red cells for red cells containing • Platelets - Plateletpheresis haemoglobin A is to interrupt the vicious • Leucocytes - Leucocytapheresis cycle of stasis, sickling and hypoxia. • Plasma - Plasmapheresis This procedure has also been used • Peripheral blood stem cells (PBSCs) prophylactically in pregnancy with sickle • Removal of pathological components, that is, cell disease and prior to general anaesthesia therapeutic apheresis: in these patients[6] • Therapeutic cytapheresis • Hyperparasitaemia: To lower parasite loads • TPE. in Malaria, Babesiosis. • Leucocytapheresis The procedure involved in apheresis is more • Leukaemia with hyperleucocytosis extensively used to harvest platelets and plasma from syndrome: Leukostasis results from healthy donors than as a therapeutic modality. As a microvascular obstruction and therapeutic procedure, it is not curative and does not may lead to endothelial injury, change the natural course of the disease; however, it thrombosis and/or haemorrhage. can be life‑saving in many situations and buys time to affect more definitive therapy. The main emphasis Once total leucocyte count is above 3 in this article is on various aspects of therapeutic 200,000/mm in acute myeloid leukaemia 3 apheresis. and above 300,000/mm in chronic myeloid leukaemia, organ dysfunction is likely: TECHNICAL ASPECT OF APHERESIS • Pulmonary dysfunction (hypoxemia, diffuse lung infiltrates) Apheresis instruments separate the blood into • Cerebral dysfunction (confusion, components, then selectively remove one component mental status changes, altered level of and return the remaining to the patient. By running consciousness).

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• Cutaneous T‑cell lymphoma (CTCL): In volumes beyond 1.5 plasma volumes removes smaller the leukaemic phase, also known as Sezary amounts of pathologic substance while prolonging syndrome, repeated leucocytapheresis reduces the procedure and exposing the patient to more circulating malignant cells (sezary cells).[7,8] replacement fluid and anticoagulant. • Extracorporeal photopheresis is also a type of leukopheresis in which the white blood The theoretical efficacy of TPE is shown in cells are exposed to ultraviolet A light to Table 2.[2] Role of plasmapheresis in various disease induce an immunomodulatory effect. It can conditions/syndromes are enlisted along with the achieve sustained remission in CTCL.[9] factors to be removed in each: • PBSC collection • Anti‑glomerular basement membrane (anti‑GBM) • Thrombocytapheresis: Acute management of disease[16] - Anti GBM antibody patients with symptomatic thrombocythaemia • Guillain-Barre syndrome (GBS) ‑ Antimyelin where a rapid reduction in platelet count is antibody[17] required. • Hyperviscosity syndrome - IgM • Thrombocytosis (platelet count > 450,000- • Cryoglobulinemia - Cryoglobulins 500,000/µl) like polycythaemia • Microangiopathic thrombocytopaenia (TTP/ vera (PV), essential thrombocythaemia, HUS) - Von Willebrand factor multimers/ idiopathic myelofibrosis or unclassified anti‑endothelial cell antigen[18‑20] myeloproliferative neoplasm, with • Homozygous familial hypercholesterolaemia ‑ an acute and severe thrombotic or LDL cholesterol[21] haemorrhagic event. Platelets are reduced • Myasthenia gravis (MG) crisis ‑ Ach receptor for symptomatic relief while waiting for antibody cytoreductive therapy to take effect. • Coagulation factor inhibitors ‑ Factor VIII • Useful in those who cannot tolerate drug inhibitor therapy such as e.g. hydroxyurea or • Haemolytic disease of newborn - IgM anagrelide.[10,11] • Overdose of certain drugs - e.g. digitalis (digitalis • Management of peri‑operative antibody) thrombohaemorrhagic complications in • Poisoning involving protein‑bound toxins ‑ e.g. patients with myeloproliferative neoplasms Amanita phalloides undergoing splenectomy.[12] • Pregnancy with thrombocythaemia, as In hyperviscosity syndrome, due to monoclonal drug therapy is contraindicated, and it gammopathies, TPE is particularly effective as IgM is prevents placental infarction and foetal largely distributed in the intravascular compartment. death.[13] Reduction in viscosity can be achieved even with the exchange of as little as 500-1000 ml of plasma Therapeutic plasma exchange by manual bag techniques, which relieves both A wide variety of diseases seen in different medical haemorrhagic and ischemic symptoms. specialties can be treated with TPE and it can be used as a first line of treatment in some diseases (example: Therapeutic plasma exchange is a therapy of choice TTP or as an adjunct to other therapies (example: for TTP, if not available temporarily, plasma infusion Goodpasture syndrome). TPE removes the can be given till transfer to an appropriate facility. pathogenic substances such as antibodies, immune Results with TPE are better due to two‑fold action complexes, monoclonal proteins, cryoglobulins, of TPE: Removal of IgM autoantibody which acts lipoproteins, protein‑bound toxins and cytokines. as a specific protease inhibitor and replacement of Additional evidence suggests that TPE may have an immunomodulatory effect beyond the removal Table 2: Plasma exchange: Theoretical efficiency of immunoglobulins (Igs).[14,15] In TPE, two plasma Number of plasma Percentage of the original volume exchanged plasma remaining volumes can be exchanged within 3 h and levels of 0.5 60 intravascular solutes can be lowered by 50-60% with 1.0 35 each exchange. Due to the dilution of the plasma, the 1.5 20 substance cannot be removed completely. Treating 2.0 12

674 Indian Journal of Anaesthesia | Vol. 58 | Issue 5 | Sep-Oct 2014 Bose and Kanzariya: Therapeutic transfusion techniques deficient factors.[18‑20] categorized by the American Society for Apheresis are enlisted in Appendix 1.[30] In familial hypercholesterolaemia, chronic TPE can reduce total plasma LDL levels and lead to regression PROCEDURE CONSIDERATIONS of atherosclerotic changes in blood vessels and promotes resorption of xanthomas and atheromas.[21] Replacement fluid LDL levels are reduced to more than 50%. VLDL In most cell collection and cell depletion procedures, and triglyceride levels are also reduced, but HDL no replacement fluid beyond the anticoagulant and is spared. In Refsum’s disease, removal of phytanic saline priming solution is required. But in plasma acid by TPE helps prevent or reverse the neurological exchange, 1-1.5 plasma volumes are typically manifestations.[22] In cold agglutinin‑induced removed, and replacement of intravascular volume autoimmune haemolytic anaemia (AIHA), TPE is is necessary. The main goal of replacement fluid is useful in a reduction of haemolysis as antibody to maintain intravascular volume, maintenance of titres falls. In warm antibody (IgG) AIHA, TPE is colloid oncotic pressure and electrolyte balance used as an adjunct to therapy with intravenous and restoration of deficient factors. The solutions Ig (IVIG) and/or cyclophosphamide in refractory used are 5% serum albumin, plasma, starches and cases. In haemophiliacs, development of both crystalloids. auto and allo‑antibodies is a major therapeutic challenge. These patients have to undergo surgery Vascular access after achieving adequate factor VIII levels which are Vascular access through peripheral vein is the difficult due to the presence of coagulation factor preferred route as it is associated with fewer infectious, inhibitors. TPE has an important role in removing haemorrhagic and thrombotic complications. When these. In ABO incompatible marrow transplants, frequent procedures over a prolonged period are the alloantibodies to RBCs can be removed by required, a double lumen central venous catheter [23] TPE. In Rh‑negative pregnant women, maternal designed for apheresis or haemodialysis should be IgG antibodies to the foetus can lead to destruction inserted. of foetal red cells. TPE can help remove these antibodies. COMPLICATIONS

Therapeutic plasma exchange is used in the treatment The rate of complication is variable, and ranges of neuro‑immunological diseases such as GBS, chronic from 4% to 36% but most of the events are mild and inflammatory demyelinating polyneuropathy (CIDP), easily treatable. Estimated mortality is 3 in 10,000 MG and Lambert-Eaton syndrome. Antibodies procedures, and most reported deaths have been responsible for these diseases are effectively removed due to cardiac and respiratory causes in critically by TPE and help in the amelioration of the disease.[17,24] ill patients.[31] The most common adverse effect The efficacy of plasmapheresis or administration of of apheresis is symptomatic hypocalcaemia due IVIG appears to be equal in GBS, AIDP and CIDP.[25,26] to infusion calcium chelating citrate ions in the In MG, plasmapheresis is reserved for myasthenic anticoagulants. Hypotension occurs in 0.5-2.9% crisis and refractory cases. cases.[32] Citrate toxicity occurs in approximately [33] In Goodpasture syndrome, early institution of TPE and 0.8-1.2% cases. cyclophosphamide is very effective.[16] Plasmapheresis Complications related to vascular access account for causes removal of anti‑GBM antibodies after diagnosis by renal biopsy or detection of anti‑GBM about 1% and include haematoma, pneumothorax, antibodies.[27] Systemic lupus erythematosus with bleeding, thrombosis and infection. Haemostatic nephritis does not respond well by adding TPE to alterations and bleeding may occur in patients with cyclophosphamide.[28] TPE has been beneficial in baseline coagulopathy or severe thrombocytopaenia. rapidly progressive glomerulonephritis with dialysis Furthermore, there is depletion of coagulation factors dependent renal failure.[29] during large volume plasma exchanges, wherein depletion of approximately 25-45% can occur.[34] There The disease/disorders treated with TPE that have been is also depletion of platelets and fibrinogen.

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Other effects Haemochromatosis Additional substances removed include inhibitors of Phlebotomy does not improve haemochromatosis coagulation[32] and the pseudocholinesterase necessary clinically, but prevents complications in symptomatic for the metabolism of some drugs.[35] Removal of patients or those who have already developed inhibitors of coagulation could predispose patients to end‑organ damage, with a serum ferritin > 300 μg/L thrombosis. Prolongation of actions of neuromuscular for men or post‑menopausal women and >200 μg/L [42] blocking drugs has been seen due to reduced activity for pregnant females. Phlebotomy sessions are of the enzymes after TPE. It can also remove drugs continued until the serum ferritin concentration drops [43] which are highly protein bound. Hence, caution is to <50 ng/ml and transferrin saturation is <50%. adviced if patient is on life‑saving drugs. Porphyris cutanea tarda Porphyria cutanea tarda is caused by uroporphyrinogen PHLEBOTOMY decarboxylase deficiency leading to the accumulation of uroporphyrinogen. Therapeutic phlebotomy is the Phlebotomy (also known as bloodletting) means treatment of choice with hydroxychloroquine as a the removal of blood from the body. Therapeutic good alternative.[44] Phlebotomy sessions are repeated phlebotomy is the treatment of choice for blood every 2 weeks until the haemoglobin level is below disorders in which the removal of RBCs or serum 20 ng/ml.[45] Some studies showed potential for iron is the most efficient method of managing disease erythrocyte apheresis as a replacement for standard symptoms and complications. Currently, therapeutic phlebotomy.[46] phlebotomy is approved for three main indications: Haemochromatosis, polycythaemia and porphyria Therapeutic transfusion techniques such as cutanea tarda. therapeutic cytapheresis, plasmapheresis and phlebotomy are an integral part of ICU procedures, Polycythaemia which require intensive monitoring and supervision. Polycythaemia is a disorder where too many red cells There are numerous conditions where this procedure are produced in bone marrow, which increase the is performed, but decisions should be individualised blood volume and viscosity. There is also increase for optimum use of resources. in platelet and white cell production. Patient with polycythaemia tends to develop thrombotic events REFERENCES such as cerebrovascular, cardiovascular accidents 1. Nair V. Apheresis. In: Choudhry VP, Saxena R, Pati HP, editors. and arterial and venous thromboembolism. In Recent Advances in Haematology. Ch. 3. New Delhi: JayPee primary polycythaemia (PV), one of the major goals Brothers Medical Publishers (P) Ltd; 2004. p. 56‑9. of treatment is to reduce these thrombotic events. PV 2. Hirasawa H, Sugai T, Oda S, Shiga H, Matsuda K, Ueno H, et al. Efficacy and limitation of apheresis therapy in critical study group prospective trial suggests that patients care. Ther Apher 1997;1:228‑32. treated with phlebotomy had a lower incidence of 3. Solomon A, Fahey JL. Plasmapheresis therapy in macroglobulinemia. Ann Intern Med 1963;58:789‑800. haematological malignancies and solid tumours. Some 4. Adams WS, Blahd WH, Bassett SH. A method of human studies showed that patients maintained at a target plasmapheresis. Proc Soc Exp Biol Med 1952;80:377‑9. haematocrit of <45% had a significantly lower rate of 5. Burgstaler EA. Current instrumentation for apheresis. In: McLeod BC, Price TH, Weinstein R, editors. Apheresis: [36,37] cardiovascular morbidity and major thrombosis. Principle and Practice. 2nd ed. Bethesda, MD: AABB; 2003. p. 95‑130. Phlebotomy can be performed in hypoxic conditions 6. Koshy M, Weiner SJ, Miller ST, Sleeper LA, Vichinsky E, Brown AK, et al. Surgery and anesthesia in sickle cell such as chronic lung diseases and cyanotic heart disease. Cooperative Study of Sickle Cell Diseases. Blood disease. Patients with hypoxic pulmonary disease who 1995;86:3676‑84. 7. Edelson R, Facktor M, Andrews A, Lutzner M, Schein P. have hyperviscosity symptoms or a haematocrit >56% Successful management of the Sézary syndrome. Mobilization should have phlebotomy to reduce this to 50-52%,[38‑40] and removal of extravascular neoplastic T cells by AHA recommends performing therapeutic leukapheresis. N Engl J Med 1974;291:293‑4. 8. Bongiovanni MB, Katz RS, Tomaszewski JE, Ziselman EM, phlebotomy for symptomatic patients of cyanotic Goldwein MI, Wurzel HA. Cytapheresis in a patient with congenital heart disease like Eisenmenger’s syndrome Sezary syndrome. Transfusion 1981;21:332‑4. 9. Lim HW, Edelson RL. Photopheresis for the treatment of or tetralogy of Fallot with haemoglobin >20 g/dl and cutaneous T‑cell lymphoma. Hematol Oncol Clin North Am haematocrit >65%.[41] 1995;9:1117‑26.

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APPENDIX • ABO‑incompatible haematopoietic stem cell transplantation Appendix 1: Disease conditions enlisted as Category • ABO‑incompatible solid organ transplantation 1-4 (heart, kidney) Category 1 • Cold agglutinin autoimmune haemolytic Apheresis as primary therapy or first line adjunct to anaemia other therapy. • Catastrophic antiphospholipid Ab syndrome • Chronic focal encephalitis (Rasmussen Examples: encephalitis) • Thrombotic thrombocytopenic purpura • Multiple sclerosis • Haemolytic uraemic syndrome‑atypical • Phytanic acid storage disease (Refsum disease) • Acute inflammatory demyelinating • Red blood cell alloimmunization in pregnancy polyradiculopathy (Guillain- Barre syndrome) • Renal transplantation desensitization • Anti‑neutrophil cytoplasmic antibodies‑associated rapidly progressive Category 3 glomerulonephritis/vasculitis This includes diseases for which adequate role of • (Wegener granulomatosis) apheresis is not established, and treatment with • Antiglomerular basement membrane apheresis is individualized. disease (Goodpasture syndrome) • Chronic inflammatory demyelinating Examples: polyradiculopathy • Paraproteinemic demyelinating polyneuropathies ABO‑incompatible liver transplantation, aplastic (IgG, IgM, IgA) anaemia, warm agglutinin autoimmune haemolytic • Paediatric autoimmune neuropsychiatric anaemia, hypertriglyceridemic pancreatitis, multiple disorders associated with myeloma, sepsis with multiorgan failure, thyroid • Streptococcal infections (PANDAS) storm • Renal transplantation, Ab‑mediated rejection • Myasthenia gravis Category 4 • Polycythaemia vera This category includes diseases in which apheresis is • Sickle cell disease with acute stroke ineffective or harmful.

Category 2 Examples: Apheresis is used as second‑line therapy for some disease conditions. Dialysis dependent Goodpasture syndrome, scleroderma, amyloidosis, amyotrophic lateral Examples: sclerosis, polymyositis, psoriasis

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