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Apheresis in the ICU 

Apheresis in the ICU
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Apheresis in the ICU
Author(s):

Marion Sternbach

DOI:
10.1093/med/9780199600830.003.0268
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Key points

  • Apheresis means selective removal of either cellular or harmful molecular elements from blood.

  • Instruments are based mostly on density centrifugation, less on specific column adsorption or membrane filtration.

  • Plasmapheresis for noxious molecules uses albumin 5% most frequently. Fresh frozen plasma (FFP) is used therapeutically only in thrombotic micro-angiopathies.

  • Critical care therapies may interfere or be interfered by plasmapheresis. Careful monitoring during and after apheresis cannot be over emphasized.

  • Indication for plasmapheresis in haematological disorders proved as effective by RCT are only for thrombotic micro-angiopathies.

Definition

Apheresis is derived from Greek and means ‘to remove’. Initially, it was used in situations like life-threatening neutropenia or hyperviscosity states. It involves separation of blood cellular elements or plasma from cellular elements, and occasionally removing harmful molecules from the plasma, returning purified plasma to the patient.

Instrumentation

Most apheresis machines are based on the principle of continuous or intermittent density centrifugation. Some instruments have attached devices for selective column adsorption or membrane filtration for specific molecules, like antibodies or antigen-antibody complexes.

Physical and biochemical principles of therapeutic plasma exchange

Plasma exchange removes harmful molecules from the circulation, but stimulates their resynthesis through feedback to lymphocytes and plasma cells. Therefore, plasma exchange has to be performed repeatedly. The rate of synthesis of some molecules can decrease if appropriate therapy is administered following plasma exchange. For steady equilibrium, 1 or 1.5 plasma volume removal will effectively deplete the body of ≥2/3 of the targeted molecule and 100% is removed by the fourth session [1]‌. Ions re-equilibrate very fast, while most non-immunoglobulin proteins recover within 72 hours [1].

Blood and plasma volume calculations

These can be calculated from a person’s weight, gender, red cell volume, and muscle mass. Muscular people have a higher total blood volume (TBV) than obese persons.

During apheresis procedures extracorporeal blood volume should never exceed 15% of TBV to avoid hypovolaemia. Different instruments have different extracorporeal volumes varying between 150 and 500 mL. Therefore, small persons and children may not be able to tolerate a large extracorporeal volume. In such cases, the instruments can be primed with albumin 5% or a colloid solution.

Replacement fluids for plasma exchange

Albumin 5% with saline is the most common fluid. Fresh frozen plasma (FFP) or cryo-poor plasma are used only for thrombotic thrombocytopenic purpura (TTP), haemolytic uraemic syndrome (HUS), and for hypofibrinogenaemia. Hypocalcaemia due to citrate and albumin infusion is an important consideration. Adverse effects of hypocalcaemia, depending on its level, are far reaching from inhibition of haemostasis to neuromuscular symptoms and signs up to seizures and cardiac arrhythmias [2]‌. Citrate levels will rise in addition to anticoagulation at ratios 1 part citrate to 10–14 parts of blood, by infusion of FFP containing citrate (CPD). On the other hand albumin will bind Ca2+ too. The body’s parathormone will try to compensate by elevating Ca2+ levels. It rises fast, levels off, and decreases later during the procedure [3,4]. Higher concentration of citrate, as well as rate of its infusion and duration of the procedure will worsen hypocalcaemia.

Pathophysiology of apheresis

Therapeutic plasma exchange (TPE) depletes the body of immunoglobulins and coagulation factors. However, rapid resynthesis occurs due to negative feedback.

During thrombapheresis lymphocyte depletion also occurs because of their vicinity during density centrifugation. Lymphocytes that are long lived are not easily replaced by the lymphatic system.

For vascular access, peripheral antecubital veins are preferred as they typically permit a blood flow of 60–120 mL/min and completion of a TPE in about 3 hours. Major cell collections take longer and require more invasive access, such as subclavian or jugular vein with rigid double lumen catheters. Central venous catheters are considered potentially dangerous because of possible clotting and septic complications.

Bleeding due to apheresis is rare, unless one is facing underlying DIC with septicaemia, hepatic coagulopathies, or vitamin K depletion due to broad spectrum antibiotics and starvation. In such cases, replacement fluid may have to include FFP and vitamin K.

During and immediately following the procedure, the prothrombin time (PT) and partial thromboplastin time (PTT) may be prolonged, and platelets and fibrinogen may fall, but clinical haemorrhage is rare, and abnormalities usually resolve in 24 hours.

Adverse effects

Adverse events occur in 4–5% of cases, especially in first time procedures, as shown in a large US review [1]‌. These events include fluid overload or hypovolaemia, unintentional removal of drugs from the circulation, citrate-induced hypocalcaemia and alkalosis, vaso-vagal reactions, allergic reactions, and some specific drug interactions. Careful monitoring of fluid status and consideration of drug redosing are therefore important. To avoid hypocalcaemia, consider using the lowest ratio of citrate to blood that prevents clotting. With early signs or symptoms of hypocalcaemia, consider reducing the blood flow to 50 mL/min. Treatment with oral calcium may be useful, but more severe cases require intravenous (iv) calcium gluconate, and aphersis should be put on hold. Allergic reactions are typically to hydroxyethyl starch (HES), plasma or the ethylene dioxide in the tubing. Typical drug interactions relate to the blunting of physiological responses to volume shifts by drugs, such as beta blockers or calcium channel blockers.

Therapeutic plasma exchange in haematological disorders

TPE is most commonly indicated, and most clearly demonstrated to be efficacious, in select haematological disorders, such as thrombotic thrombocytopenic purpura (TTP)/haemolytic uraemic syndrome (HUS) [5]‌. Thrombotic micro-angiopathies present with micro-angiopathic haemolytic anaemia, thrombocytopenia, and microthrombi due to platelet aggregation in small arterioles in kidneys, brain, heart, and in pregnancy even in the liver.

They comprise TTP, HUS, and HELLP (haemolysis, elevated liver enzymes, low platelets in pregnancy). Depending on the predominance of the brain versus kidney, the disease is coined either TTP or HUS. In overlap symptomatology it is called TTP/HUS [6]‌. A similar micro-angiopathy occurs in pregnancy, usually in the third trimester, known as HELLP, life-threatening to both mother and fetus. Immediate delivery is here indicated. If the condition does not resolve spontaneously post-partum, TPE is indicated with FFP or cryo-poor plasma.

The pathogenesis of thrombotic micro-angiopathies has been elucidated to be due in part to deficiency of ADAMTS 13, a metalloprotease cleaving ultra large von Willebrand multimers, originating in the endothelium, causing microthrombi through platelet aggregation. This deficiency may be either congenital or acquired due to antibodies to ADAMTS 13. TPE with FFP replaces at least in part the deficient enzyme. TPE with cryo-poor FFP is devoid of von Willebrand multimers, which ought to make it more efficacious. This has not been proven unequivocally to date.

Moshkovwitz’s classic ‘pentad’ of haemolysis, low platelets, neurological symptoms and signs (from headaches to palsies and seizures), renal failure, and fever is not always present. The presence of micro-angiopathic haemolytic anaemia and thrombocytopenia establish the likely diagnosis of TTP/HUS and justify the start of TPE, since this disease has a very high mortality in the absence of plasma exchange. If TPE cannot be started right away, infusion of FFP should be considered. Renal involvement may start with proteinuria, haemoglobinuria and haematuria and may end up with dialysis dependent uraemia. Early TPE may prevent this latter. E. coli with enterotoxin or Shigella are frequent aetiologies of HUS. Laboratory features are schistocytes and fragmented red blood cells, thrombocytopenia, elevated lactate dehydrogenase and unconjugated bilirubin, elevated creatinine. Usually PT, PTT, fibrinogen, and thrombin time are within normal limits. Direct antiglobulin test (Direct Coombs’) is negative. These parameters need to be monitored before and after daily TPE of 1–1.5 volume.

The average number of apheresis procedures to achieve lasting remission is 16. Mortality has dropped from 80% to less than 20%, but relapses after 1 month to years amount to 20% [7]‌. There are also cases with refractory TTP/HUS in 10–22% of patients. They will require repeat plasma exchanges and may benefit from anti-platelet drugs and splenectomy [8], as well as immune suppressant drugs, like vincristine, cyclosporin A, cyclophosphamide and rituximab (anti-CD20 monoclonal antibody), most successful [9].

Platelet transfusions may be harmful in TTP, ‘fuelling the fire’ of thrombotic micro-angiopathy. However, red cell transfusions may become necessary in severe haemolytic anaemias, either during or following plasmapheresis. Rock et al. showed in a randomized controlled trial (RCT) [5]‌ comparing TPE with FFP infusion, the superiority of TPE with survivals of 78 versus 63%, respectively. The response rate was also faster in the TPE group by day 9, 82 versus 49% in the FFP infusion group. The average number of TPE required was 15.8, including tapering with five treatments over 2 weeks.

Adult HUS is more severe than the paediatric, epidemic variety associated with E. coli verotoxin (O-157 H:7) or Shigella with diarrhoea at the outset. Adults may suffer from enterocolitis, neurological manifestations, liver impairment, pancreatitis, and even cardiac ischaemia with severe renal failure, requiring dialysis. Histology of renal biopsies in these patients show platelet aggregates, with von Willebrand Factor, thrombin in the glomeruli with fibrin deposits and widening of the glomeruli. HUS has usually somewhat higher platelets, over 31,000/µl. TPE has not been established as the most efficacious treatment. ADAMTS 13 may be normal or somewhat reduced in HUS.

HELLP occurs in 10% of women with severe pre-eclampsia, but may appear also post-partum or continue after delivery. Presenting symptoms are abdominal pains, nausea, oedemas with haemolysis, thrombocytopenia, liver dysfunction. Maternal mortality is about 1%, infant mortality goes as high as 10–20% due to placental ischaemia and possible abruption. Delivery should be performed as soon as possible. Post-partum recovery occurs usually within 6 days. In the presence of severe ongoing thrombocytopenia and organ dysfunctions plasma exchange may be helpful and, occasionally, all abnormalities have reverted to normal after a couple of procedures. ADAMTS 13 is usually reduced in the third trimester of pregnancy and no useful marker.

Autoimmune haemolytic anaemia with warm antibodies

Plasma exchange is rarely first line therapy in this disease. Autoimmune haemolytic anaemia (AIHA) may be ‘idiopathic’, due to underlying autoimmune disease, like systemic lupus erythematosus or lymphoproliferative disorders. Its symptoms are fatigue and dyspnoea, conspicuous signs pallor, icterus, and splenomegaly. The peripheral blood film shows anaemia with spherocytosis, polychromasia, and investigations detect a positive direct antiglobulin test (DAT) or Direct Coombs’ test often directed against an Rh system component and an elevated unconjugated (indirect) bilirubin. Since warm antibodies (IgG = immunoglobulin G) are widely distributed intra- and extravascular, TPE is not very helpful and should only be used in cases of fulminant AIHA, where conventional therapy with steroids given intravenous immunoglobulin (IVIg), cyclophosphamide, and splenectomy have failed.

Cold antibody haemolytic anaemia

This may be also ‘idiopathic’, associated with lymphoproliferative disorders, Mycoplasma pneumonia, viral diseases, like Hepatitis B, infectious mononucleosis or Varicella. Symptoms and signs are due to red blood cell (RBC) sludging coated by IGM antibodies with acral cyanosis of fingers, toes, ears and nose. Haemolysis occurs largely intravascularly, since IGM fixes complement. The specificity of the antibody is usually anti-I, occasionally IH or IGM dissociates itself in a warmer environment at 37°C from the RBC. The C3b-coated RBCs flowing through the liver, fix C3d (which is a C3b inhibitor), emerging more resistant to haemolysis. Thermal amplitude of these IGM antibodies determines the severity of the clinical manifestations. Cold antibody haemolytic anaemia CAHA respond poorly or not at all to steroids. Immune suppression by cyclophosphamide, azathioprine recently to rituximab (anti-CD20 monoclonal Antibody) [4,10] have been more successful.

IGM, a very large molecule is mostly intravascular and lends itself to very efficient removal by plasma exchange. One to one-and-a-half plasma volume removed, will remove up to 90% of the circulating IGM, provided the blood and fluids are maintained at 37°C, using a blood warming coil.

Immune thrombocytopenia

Is in adults a similar autoimmune disease to AIHA, starting out insidiously—in children it may follow viral infections. The auto-antibody is directed against the membrane glycoproteins on the platelet GIIb IIIa and less to GIb9. It presents with haemorrhagic symptoms of different degrees, petechiae, purpura, ecchymoses, and often active bleeding. The blood film shows scant platelets, but large, often giant young ones. The bone marrow is replete of megakaryocytes, young, and hypoploid with no pathology. TPE is not included in the newest guidelines of the American Society of Hematology (ASH) being currently developed for immune thrombocytopenia (ITP). Correct therapy of ITP in adults includes steroids, followed by IVIg 1.0 g/kg. If that fails, immune suppression with rituximab before or after splenectomy has shown success. If all fails TPE has been used by Bussell followed by large dose IVIg in a few refractory cases [11].

Post-transfusion purpura

This is a rare syndrome, more frequently seen in females, presenting as severe thrombocytopenia, 10,000–20,000/µl within 5–14 days usually following red cell transfusion. The pathogenesis is due to previous sensitization to a specific platelet antigen PLA1 during pregnancy, which persists in the recipient. The antigen, absent in the recipient is being transfused with the red cells, adsorbed to the recipient’s platelets and then reacting with the specific (Immunoglobulin G (IgG) antibody to PLA1. Thus the platelets are destroyed as ‘innocent bystanders’. Post-transfusion purpura PTP responds usually dramatically to IVIg [4]‌. TPE has been used successfully in cases of failure due to IVIg [12]. Haemostasis should be closely monitored during and after plasmapheresis, since dilutional coagulopathies may occur and FFP may have to be used as replacement fluid.

Coagulation factor inhibitors (allo- and autoantibodies)

Allo-antibodies against Factor VIII in haemophiliacs occur in 15–20% of this population. Autoantibodies against this appear spontaneously in SLE, pregnancy, and may be a presenting symptom or sign in lymphoproliferative disorders. Immune suppressive therapy with corticosteroids, cyclophosphamide, and rituximab have been used for eradication of the autoantibody. ‘Bypassing coagulation factors’ with activated Factor VII, have been used in severe, life-threatening haemorrhage. Porcine Factor VIII can be used successfully, though cross-reacting antibodies with the porcine Factor VIII may also develop.

Slocombe described successful plasma exchange in a haemophiliac with alloantibodies to Factor VIII and post-operative haemorrhage: fourteen daily 4.0 l. exchanges reduced the antibody by 90% [13]. TPE followed by immune suppression with steroids, and cyclophosphamide and Factor VIII infusion resulted in good control of haemorrhage [14]. Central catheters in such bleeding patients should be, if possible, avoided. Currently anti-Factor VIII inhibitors can be successfully treated by column adsorption.

Hyperviscosity syndromes

Occur in lymphoproliferative disorders with IGM monoclonal antibody hyperproduction. These are large molecules of 900,000 Dalton present in 50–70% of patients with Waldenstrom’s macroglobulinaemia. These large, intravascular molecules cause hypervolaemia due to their colloid osmotic pressure. They also surround and coat the red cells lowering their ‘zeta’ (electro-negative repealing) potential, thus causing sludging in the microcirculation in the brain and eyes. Symptoms consist of headaches, dizziness, somnolence, nystagmus, stupor, and if untreated, lead to coma. Eye grounds show sausage-shaped veins, poor pulsations, haemorrhages, and retinal exudates. When plasma viscosity reaches four times that of water (Ostwald units), symptoms may appear, over 8 Ostwald units, manifestations become severe. Impaired platelet function and fibrin polymerization may result in a coagulopathy. TPE results in immediate and dramatic improvement of symptoms, since one volume exchange removes 90% of the intravascular immunoglobulin. Chemotherapy is very important as mainstay, since TPE stimulates through its IGM removal ‘feedback’ resynthesis of IGM by lymphocytes. ASFA and AABB classify hyperviscosity as category II indication for TPE.

Myeloma with renal failure

Myeloma is classified by the WHO as a lymphoplasmacytoid lymphoproliferative disease, often evolving from a monoclonal gammopathy at a rate of 1% per year. Its characteristics are a monoclonal immunoglobulin expansion due to neoplastic plasma cell proliferation, which cause through osteoclastic activity very painful osteolytic lesions. Anaemia due mostly to bone marrow infiltration by plasma cells, but often, in part, also due to the accompanying renal failure.

Renal impairment progressing to severe renal failure requiring haemodialysis is multifactorial. Good hydration and occasional haemodialysis may be required to reverse or improve renal failure to enable appropriate chemotherapy. TPE has been used in myeloma renal disease in RCT with variable success. Where TPE was compared with its absence, but where one arm consisted of TPE, chemotherapy, and haemodialysis, while the control arm had no TPE, but peritoneal dialysis the outcomes were good favouring TPE significantly with improved renal function (creatinine < 2.5 mg/dL), marked decrease of light chain proteinuria and significantly improved survival, 66% in the TPE group, versus 28% in the control arm [15]. TPE was not shown to be superior to conventional chemotherapy in a small study of patients with multiple myeloma [16].

Cryoglobulinaemia

Encompasses diverse groups of immunoglobulins with a low thermal amplitude, which causes their precipitation at even room temperature:

  • Type 1: monoclonal proteins seen with myeloma.

  • Type 2: mixed cryoglobulins, monoclonal IGM, and polyclonal IGG, as seen in autoimmune diseases, like rheumatoid arthritis, scleroderma, or leucocytoclastic vasculitis.

  • Type 3: antigen-polyclonal immunoglobulin complexes, associated with glomerulonephritis, polyarthralgias, and skin ulcerations.

Pathogenetic therapy comprises steroids, (except in hepatitis C) and immune suppression [17]. TPE as adjuvant therapy has a salutary effect on symptoms, clinical signs and a protective effect on renal function [18].

Cytapheresis in the critical care setting

Cytapheresis implies selective removal of blood cell types from the buffy coat, separable by density centrifugation. This has become possible over the years through highly sophisticated cell separators, electronic cell size recognition and computerized programming. Centrifugal force and speed in the separation chamber allows for collection of platelets from the upper most layer of the buffy coat, mononuclear cells (MNC): lymphocytes, blasts, monocytes from the lower layer and polymorphonuclears (PMN) from the deepest layer of the buffy coat. This latter can be enhanced by hydroxyethyl starch (HES), causing rouleaux formation of red cells, thus separating the PMN more visibly from the RBCs and harvesting larger numbers.

The intended number of cells to be removed is not easily predictable:

  • Blood volumes calculated may be underestimated.

  • Cells may be recruited also from bone marrow and large spleens.

  • Leukaemic blasts may have different sedimentation density than expected [19].

Therefore it is recommended to monitor harvested cell numbers during cytapheresis procedures until the desired number has been collected. In therapeutic cell depletions one should achieve optimally 30–50% collection of the harmful elements.

Therapeutic plateletpheresis (thrombapheresis)

Is indicated in rare cases of myeloproliferative neoplasias (MPN), such as chronic myelogenous leukaemia (CML) and essential thrombocythaemia (ET) with platelet counts of 100–10–9/L (over 1 million per µl) with clinical evidence of haemorrhagic or thrombosing tendency, and only until chemotherapeutic agents (e.g. hydroxyurea or anagrelide) have started to lower platelets. Thrombosis may be venous like in Budd–Chiari syndrome or arterial in stroke, gastrointestinal haemorrhages can be severe and life-threatening.

Therapeutic leukapheresis

This is performed in leukaemia with high blast counts of over 100,000/µl because of leucostasis, impending or ongoing tumour lysis syndrome and high mortality.

Table 268.1 ASFA and AABB indication categories for therapeutic apheresis in hematologic diseases and dysproteinemias

Disease

ASFA/AABB Category

ABO-incompatible marrow transplant

II

Aplastic Anemia

III

Autoimmune hemolytic anemia

III

Coagulation Factor Inhibitor

II

Cryoglobulinemia

II

HELLP syndrome (postpartum)

NR

Hemolytic uremic syndrome

III

Hyperviscosity syndrome/multiple myeloma

II

Immune Thrombocytopenic Purpura

II*

Posttransfusion purpura

I

Pure red cell aplasia

III

Red cell alloimmunization

III

Thrombotic thrombocytopenic purpura

I

* This disorder is only ranked in context of staphylococcal protein A immune adsorption. NR, Disorder not ranked by AABB or ASFA; HELLP, hemolysis, elevated liver enzymes, low platelets; Category I, standard acceptable therapy; Category II, available evidence suggests efficacy; Category III, available evidence inconclusive; Category IV, ineffective in controlled trials.

From: THERAPEUTIC APHERESIS, A Physician’s Handbook 1-st Edition 2005 AABB and ASFA,

Editor: Bruce C. McLeod, MD. Reproduced with permission of the Editor and Publishers.

Clinical leucostasis manifestations are microvascular sludging in brain and eyes, as well as in the pulmonary circulation in acute leukaemia. In CML priapism has been seen on occasion. The causes of leucostasis are multifactorial, of which hyperviscosity is the least important, while reduced deformability, cytokine secretion, inter-adherence of mostly myeloblasts are essential [19,20]. Hyperleucocytosis has a poor prognosis at presentation. It parallels hyperuricaemia and unless treated promptly, leads to tumour lysis syndrome. Therefore, it should be dealt with by apheresis, before initiating definitive chemotherapy, thus making it an urgent indication.

The risk of introducing a central venous line in patients with severe thrombocytopenia or even coagulopathies in acute promyelocytic leukaemia and acute monocytic leukaemia has to be weighed against the benefits of leukapheresis. The extent and number of leukapheresis procedures to prevent tumour lysis syndrome is unknown. Removal of large number of blasts, will also remove significant amounts of plasma, therefore fluid replacement is essential. Efficiency of cell removal is increased by HES addition as sedimenting agent and volume expander. Cell counts should be monitored, during procedures, as well as volume status and urinary output.

References

1. McLeod BC. (2005). Therapeutic Apheresis: a Physician’s Handbook. Bethesda MD: AABB and ASFA.Find this resource:

    2. Strauss RG and McLeod BC. (2001). Complication of therapeutic apheresis In: Popovsky MA (ed.) Transfusion Reactions, 2nd edn, pp. 315–38. Bethesda MD: AABB Press.Find this resource:

      3. Bolan CD, Greer SE, Cecco SA, et al. (2001). Comprehensive analysis of citrate effects during platelet pheresis in normal donors. Transfusion, 41, 1165–71.Find this resource:

      4. Weinstein R. (2001). Hypocalcemic toxicity and atypical reaction in therapeutic plasma exchange. Journal of Clinical Apheresis, 16, 210–11.Find this resource:

      5. Rock GA, Shumak KH, Buskard NA, et al. (1991). Comparison of plasma exchange and plasma infusion in the treatment of thrombotic thrombocytopenic purpura. New England Journal of Medicine, 325, 393–7.Find this resource:

      6. Moake JL. (2002). Thrombotic micro-angiopathies. New England Journal of Medicine, 347, 589–600.Find this resource:

      7. Bondarenko N and Brecher ME. (1998). United States thrombotic thrombocytopenic purpura apheresis study group (US TTP ASG): multicenter survey and retrospective analysis of current efficacy of therapeutic plasma exchange. Journal of Clinical Apheresis, 13, 133–41.Find this resource:

      8. Crowther MA, Heddle N, Hayward CP, et al. (1996). Splenectomy done during hematologic remission to prevent relapse in patients with thrombotic thrombocytopenic purpura. Annals of Internal Medicine, 125, 294–6.Find this resource:

      9. Yomtovian R., Niklinski W, Silver B, et al. (2004). Rituximab for chronic recurring thrombotic thrombocytopenic purpura: a case report and review of the literature. British Journal of Haematology, 124, 787–95.Find this resource:

      10. Zaja F, Russo D, Fugo G, et al. (2001). Rituximab in a case of cold agglutinin disease. British Journal of Haematology, 115, 232–4.Find this resource:

      11. Bussel JB, Saal S, and Gordon B. (1998). Combined plasma exchange and intravenous gammaglobulin in the treatment of patients with refractory immune thrombocytopenic purpura. Transfusion, 28, 38–41.Find this resource:

      12. Cimo PL and Aster RH. (1972). Post-transfusion purpura: successful treatment by exchange transfusion. New England Journal of Medicine, 287, 290–2.Find this resource:

      13. Slocombe GW, Newland AC, Colvin MP, et al. (1981). The role of intensive plasma exchange in the prevention and management of haemorrhage in patients with inhibitors to factor VIII. British Journal of Haematology, 47, 577–85.Find this resource:

      14. Pintado T, Taswell HF, and Bowie EJW. (1975). Treatment of life threatening hemorrhage due to acquired factor VIII inhibitor. Blood, 46, 435–41.Find this resource:

        15 Zucchelli P, Pasquali S, Cagnoli L, and Ferrari G. (1988). Controlled plasma exchange trial in acute renal failure due to multiple myeloma. Kidney International, 33, 1175–80.Find this resource:

        16 Clark WF, Stewart K, Rock GA, et al. (2005). Plasma exchange when myeloma presents as acute renal failure. Annals of Internal Medicine, 143, 777–84.Find this resource:

        17. Berkman EM and Orlin JB. (1980). Use of plasmapheresis and partial plasma exchange in the management of patients with cryoglobulinemia. Transfusion, 20, 171–8.Find this resource:

        18. Geltner D, Kohn RW, Gorevic PD, et al. (1981). The effect of combination chemotherapy (steroids, immunosuppressives and plasmapheresis) on 5 mixed cryoglobulinemia patients with renal, neurologic and vascular involvement. Arthritis & Rheumatology, 24, 1121–7.Find this resource:

        19. Hester J. (2003). Therapeutic cell depletion. In: McLeod BC, Price TA, Weinstein R (eds) Apheresis: Principles and Practice, 2nd edn, 283–94. Bethesda MD: AABB Press.Find this resource:

          20. Porcu P, Cripe LD, Ng EW, et al. (2000). Hyperleukocytic leukemias: a review of pathophysiology, clinical presentation and management. Leukemia & Lymphoma, 39, 1–18.Find this resource: