'THERAPEUTIC PLASMA EXCHANGE 23rd Nov' with you.pptx

Plasma exchange

1. Dr. Himadri Koley (SR) Moderator- Dr. Dipesh Kumar Dhoot Assistant Professor Department of Nephrology AIIMS, Rishikesh THERAPEUTIC PLASMA EXCHANGE

2. 2 Jeffrey L. Winters; Plasma exchange: concepts, mechanisms, and an overview of the American Society for Apheresis guidelines.  Hematology Am Soc Hematol Educ Program  2012; 2012 (1): 7–12

3. First used therapeutically to control hyperviscosity in multiple myeloma (1952) Lockwood et al. (1975) used plasmapheresis and immunosuppression to successfully treat pulmonary hemorrhage and renal failure in Goodpasture syndrome 3

4. Ideal target molecule characteristics for therapeutic PLEX 1. Identified etiologic agent or toxic substance 2. High molecular mass (> 15,000 D) 3. Slow rate of formation 4. Prolonged half life 5. Low volume of distribution Clin J Am Soc Nephrol 9: 181-190, 2014 4

5. 5 Figure- Effectiveness of extracorporeal therapies in relationship to the size of target substances. Molecular masses (in kD ) are as indicated Clin J Am Soc Nephrol 9: 181-190, 2014

6. Pharmacokinetics of Ig removal Removal of the molecule is determined by its- t ½ Volume of distribution Equilibration rate 6

7. IgM- largely intravascular with a t ½ of 5days  can be removed with a few daily treatment IgG- only 45% is intravascular with t ½ of 21d  needs more treatment with reasonable interval John T. Daugirdas . Handbook of Dialysis. 5 th edition 7

8. E xtravascular- to-intravascular equilibration is relatively slow T he kinetics of Ig removal by plasma exchange can be calculated by using first-order kinetics X 1 = X 0e – V e / EPV [ X 1 = final plasma concentration X 0e = initial concentration V e = the volume exchanged EPV= Estimated plasma volume] 8

9. CJASN 15: 1364-1370, 2020 John T. Daugirdas . Handbook of Dialysis. 5 th edition Fig- Relationship of plasma volume exchanged ( Ve ), estimated plasma volume (EPV), and percentage reduction in initial concentration for pathogenic molecules removed during therapeutic PLEX (MRR- molecular reduction ratio) 9

10. Exchange of > 1.5 X estimated plasma volume during one single session provides only minimal additional removal of molecules Increases treatment time and cost 1.0–1.5 plasma volume equivalents ( V e / V p ) are exchanged during a plasmapheresis session 10

11. Figure- Progressive decline in IgG levels after three consecutive PLEX (1 plasma volume each) Inter-treatment increase= extravascular to intravascular redistribution + variable amount of new IgG synthesis Slow extravascular to intravascular re-equilibration (1-3% per hour)  several consecutive treatment separated by 24-48hr each Endogenous production of IgG in Anti-GBM disease  Daily PLEX Kaplan AA: Therapeutic plasma exchange: A technical and operational review. J Clin Apher 28: 3–10, 2013 11

12. EPV= [0.065 X wt (kg)] X [1-Hct] U seful rule of thumb: EPV= ~ 35–40 mL/kg of lean body weight Lower number (35ml/kg) for normal Hct values Higher number (40ml/kg) for low Hct values 12

13. Two fundamentally different technological approaches: Centrifugal apheresis Membrane plasma separation 13

14. Centrifugal Apheresis Functional unit- Centrifuge Spins at2000-2500 rpm Based on specific gravity or density of various components of blood Non-selective plasma removal by layering of plasma near the axis of rotation 14

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16. Membrane Plasma Separation 25-years after the first centrifugal PLEX procedure in a patient with multiple myeloma in 1952, the membrane separation technique was introduced in 1978 Resembles Hemodialysis procedure run in isolated Ultrafiltration mode Flat parallel plate membrane ( Centry TPE; Cobe ) was the first membrane separation plasma exchange filter approved in the United States by the FDA in 1982 More advanced hollow fiber membranes evolved and replaced the parallel plates 16 CJASN 15: 1364-1370, 2020

17. Membrane Plasma Separation Large pore (0.3-0.5 µm) Easily rejecting smallest cellular component- Platelet (3 µm) Removal rate depends on- Plasma filtration rate Sieving coefficient (ratio of a given plasma protein or solute concentration between the filtrate and the blood side of the membrane) Not able to perform Cytapheresis 17 CJASN 15: 1364-1370, 2020

18. 18 CJASN 15: 1364-1370, 2020

19. 19 CJASN 15: 1364-1370, 2020 Apparatus- Fresenius 4008/5008 Kit -Plasma flux P2S/bloodlines

20. Filters for membrane plasma separation 20

21. Operational contrasts between centrifuge and membrane apheresis procedures Characteristic Centrifuge Therapeutic Plasma Exchange Membrane Therapeutic Plasma Exchange Mechanism Centrifugal force Capillary membrane filter Blood flow rate (ml/min) 10-150 (can be performed at low flow ~ 40-50) 100-150 Plasma extraction (%) 80% 30-35% (to avoid filter clogging) Plasma removal (ml/min) Variable 30 Anticoagulation Citrate Heparin Mechanism of separation Specific gravity Molecular Size Molecular weight cut off (D) NA 3 million Sterilization ƴ Irradiation or ethylene oxide Steam/ Ethylene oxide Fluid replacement Albumin, FFP Albumin, FFP 21 Clin J Am Soc Nephrol 9: 181-190, 2014

22. Comparison of Membrane Plasma Separation and Centrifugal Apheresis 22 John T. Daugirdas . Handbook of Dialysis. 5 th edition

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24. n= 21 Germany M embrane filtration by the Plasmaflo filter compared with the centrifugal separation by the Spectra Optia apheresis system 24

25. Figure- Comparison between efficacy of membrane separation therapeutic plasma exchange ( mTPE ) and centrifugation therapeutic plasma exchange ( cTPE )- SIMILAR EFFICACY 25

26. Treatment time of mTPE was 10.4 % longer than for cTPE Platelet loss during mTPE was nearly twice as much as with cTPE cTPE as compared to mTPE provided a comparable treatment quality in a shorter period of time 26

27. Vascular Access Large peripheral vein (antecubital vein)- can be used in centrifugal technique ( Qb 40-50ml/min is required) For membrane separation PLEX- Central venous access IJV access in centrifugal PLEX: Citrate infusion  reduction in ionized calcium cardiac arrhythmia Needs continuous cardiac monitoring 27

28. Anticoagulation Unfractionated Heparin: In Membrane separation TPE Single bolus of 40-60 U/Kg Followed by 1000 U/h 28 CJASN 15: 1364-1370, 2020

29. Citrate Normal ionized calcium levels range from 1.1-1.4 mmol /L Citrate concentrations of 15-24 mmol /L in extracorporeal circuit reduce ionized Ca2+ levels sufficiently (to 0.2-0.3 mmol /L) to produce an anticoagulant effect Two commonly used formulation: ACD-A= 3% citrate (used commonly) ACD-B= 2% citrate 29 Lee G, Arepally GM. Anticoagulation techniques in apheresis: from heparin to citrate and beyond.  J Clin Apher . 2012;27(3):117-125.

30. Current instruments use the total blood volume (TBV) to calculate citrate infusion rate delivered to the patient (ml/min/L of TBV) Citrate infusion rate - 1.0 to 1.8 mg/kg/min 30 Lee G, Arepally GM. Anticoagulation techniques in apheresis: from heparin to citrate and beyond.  J Clin Apher . 2012;27(3):117-125.

31. Procedural settings and influence on systemic citrate concentrations 31 Lee G, Arepally GM. Anticoagulation techniques in apheresis: from heparin to citrate and beyond.  J Clin Apher . 2012;27(3):117-125.

32. Citrate is not used in membrane separation TPE: Higher volumes of blood are processed in mTPE  increased citrate exposure  toxicity 80% of citrate infused in mTPE is retained due to reduced removal (plasma extraction ratio is 20-30% compared with 80% in centrifugal exchanges) 32 CJASN 15: 1364-1370, 2020

33. Prevention of low ionized calcium levels during citrate anticoagulation Limiting the rate of citrate delivery to the patient: High blood flow rates should not be used (amount of citrate infused is proportional to Qb ) FFP contains up to 14% citrate by volume When FFP is used as the replacement fluid, the total citrate infusion rate should include the citrate in FFP 33 John T. Daugirdas . Handbook of Dialysis. 5 th edition

34. Prevention of low ionized calcium levels during citrate anticoagulation Providing additional calcium during the plasmapheresis : IV Infusion of calcium gluconate 10% (10 mL of calcium gluconate solution per liter of replacement fluid) Intravenous boluses of calcium – whenever symptoms of hypocalcemia become manifest 34 John T. Daugirdas . Handbook of Dialysis. 5 th edition

35. Replacement Fluid Replacement by colloidal agent - essential to maintain hemodynamic stability Combination of Crystalloid and colloid To replace the initial 20%–30% of the removed plasma volume with crystalloid and then substitute the rest with colloid 35

36. FFP Urticaria, Anaphylaxis Infusion of IgA-containing FFP to a patient with selective IgA deficiency Risk of hypocalcemia (FFP contains 14% citrate by volume) Specific indication for FFP use: TTP-HUS At risk for bleeding (pre- or post-surgery, thrombocytopenia) Low pretreatment serum fibrinogen level (<125 mg/ dL ) 36

37. Human Albumin 5% albumin solution at a concentration of 5 g/ dL 5% Albumin is isosmotic 0.9% saline - as diluent Use of water as a diluent - severe hyponatremia and hemolysis 37

38. Choice of Replacement Solution 38 John T. Daugirdas . Handbook of Dialysis. 5 th edition

39. Complications Related to Vascular Access Hematoma Pneumothorax Local or systemic infection 39

40. Hypocalcemia (iCa 2+ <1.1 mmol /L) 40 Lee G, Arepally GM. Anticoagulation techniques in apheresis: from heparin to citrate and beyond.  J Clin Apher . 2012;27(3):117-125.

41. Hypotension: (2% overall incidence) Externalization of blood in the extracorporeal circuit Decreased intravascular oncotic pressure Vasovagal episodes Delayed or inadequate volume replacement Anaphylaxis (FFP) Cardiac arrhythmia (hypocalcemia, hypokalemia ) 41 John T. Daugirdas . Handbook of Dialysis. 5 th edition

42. Hematologic complication Bleeding from reduction in plasma levels of coagulation factors After a single plasma exchange- Serum fibrinogen level falls by 80% Prothrombin and other clotting factor levels fall by about 50%–70% aPTT increases by 100% Recovery of plasma levels of coagulation factors =biphasic [rapid initial increase up to 4 hours postapheresis and followed by a slower increase 4–24 hours postexchange ] Fibrinogen level require 48–72 hours for complete recovery 42 John T. Daugirdas . Handbook of Dialysis. 5 th edition

43. Multiple treatments performed over a short period (three or more exchanges over a week)  depletion in clotting factors is more pronounced Replace 2 units of FFP at the end of each treatment Thrombocytopenia- due to entrapment in the membrane filter 43 John T. Daugirdas . Handbook of Dialysis. 5 th edition

44. Metabolic alkalosis from citrate Anaphylaxis - FFP Hypokalemia 25% reduction in serum K in immediate post TPE when replacement solution is albumin in saline To add 4 mmol of potassium per Liter of replacement fluid 44 John T. Daugirdas . Handbook of Dialysis. 5 th edition

45. Infection: Immunosuppression + TPE compared to those treated with immunosuppressive therapy alone  studies have failed to show an increased infection in the TPE arm If severe infection develops in the immediate post–TPE period  a single infusion of IVIG (100–400 mg/kg) 45 John T. Daugirdas . Handbook of Dialysis. 5 th edition

46. INDICATIONS 46

47. 47 American Society For Apheresis (ASFA) J Clin Apher . 2019;34:171–354

48. Category Definitions for Therapeutic Apheresis 48 J Clin Apher . 2019;34:171–354.

49. 49 Figure- The 6 most common renal indications for plasma exchange therapy in 2014 [Canadian Apheresis Group 2014] Clark WF, Huang SS, Walsh MW, Farah M, Hildebrand AM, Sontrop JM. Plasmapheresis for the treatment of kidney diseases. Kidney Int. 2016 Nov;90(5):974-984

50. TMA 50

51. 51 Clark WF, Huang SS, Walsh MW, Farah M, Hildebrand AM, Sontrop JM. Plasmapheresis for the treatment of kidney diseases. Kidney Int. 2016 Nov;90(5):974-984

52. 52 To initiate PLEX within 24 hour of presentation Exchanges of 1.0 to 1.5 plasma volumes per session (FFP as replacement fluid) performed daily until the platelet count is >150 × 10 9 /L, and LDH is near normal for 2-3 consecutive days J Clin Apher . 2019;34:171–354

53. Lengthy turnaround times needed at most centers for ADAMTS13 activity testing  unsuitable for real-time clinical decision making ADAMTS13 activity assay is unavailable in many developing countries Method to rapidly assess the likelihood of severe ADAMTS13 deficiency is needed 53

54. PLASMIC score Points Platelet count <30 × 10⁹ per L 1 Haemolysis variable (Reticulocyte count >2·5%, or haptoglobin undetectable, or indirect bilirubin >2·0 mg/ dL ) 1 No active cancer 1 No history of solid-organ or stem-cell transplant 1 MCV <90 fL 1 INR <1·5 1 Creatinine <2·0 mg/ dL 1 54 Bendapudi PK, Hurwitz S, Fry A, Marques MB, Waldo SW, Li A, Sun L, Upadhyay V, Hamdan A, Brunner AM, Gansner JM, Viswanathan S, Kaufman RM, Uhl L, Stowell CP, Dzik WH, Makar RS. Derivation and external validation of the PLASMIC score for rapid assessment of adults with thrombotic microangiopathies : a cohort study. Lancet Haematol . 2017 Apr;4(4):e157-e164 Score 0-4 Low risk of severe ADAMTS 13 deficiency Score 5 Intermediate risk Score 6-7 High risk

55. ASFA category aHUS (Factor H autoantibody) aHUS ( Complement factor gene mutations) I III STEC-HUS III TMA (transplant associated) III Ticlopidine I Clopidogrel III Gemcitabine IV 55 J Clin Apher . 2019;34:171–354

56. Goodpasteur Syndrome 56

57. Goodpasteur Syndrome Very rare (0.5-1.0 cases per million in general population) Anti-GBM is pathogenic The immunoassays for anti-GBM antibodies may be negative in up to 10% of patients (diagnosed with kidney biopsy only) No high quality RCT available 57

58. Recovery of kidney function is ~ 5% in high proportion of crescents (85%–100%) oliguria, and/or advanced kidney failure requiring initiation of dialysis High index of suspicion of anti-GBM disease- treatment should start without delay (within 24 hours), even before the diagnosis is confirmed with a kidney biopsy Antibodies are cleared in most patients treated with plasma exchange plus immunosuppression within 8 weeks 58

59. Plasma exchange and IS are not recommended : 59 Treated with dialysis at presentation 100% crescents >50% global glomerulosclerosis in an adequate biopsy sample, and Do not have pulmonary hemorrhage

60. 60 Ongoing production of antibody Daily plasma exchange plus Immunosuppression

61. 61 * at presentation, Cr ≥5.7 mg/dl indicates “dialysis-dependence” J Clin Apher . 2019;34:171–354.

62. Dosing and duration of PLEX Dose Duration of treatment Plasma exchange 40-50ml/kg ideal body weight exchange daily against 5% albumin Add FFP at the end of plasma exchange if alveolar hemorrhage and/or after kidney biopsy Until circulating anti-GBM antibody can no longer be detected; usually 14days 62

63. ANCA associated vasculitis 63

64. ANCA associated vasculitis- MEPEX trial 64

65. ANCA associated vasculitis-PEXIVAS trial 65

66. MEPEX trial PEXIVAS trial PLEX- Significantly reduced the risk of progression to kidney failure at 12 months Patient survival was not affected PLEX- Did not reduce the incidence of death or ESRD Subgroup of patients with baseline serum creatinine >5.6 mg/dl or undergoing dialysis (29%) No significant beneficial effect of PLEX Subgroup of 191 patients (27%) with pulmonary hemorrhage [61 (9%)= severe]  In neither subgroup, PLEX had a statistically significant effect on the primary outcome of kidney failure or death from any cause Because the numbers of patients in these subgroups were already small, it is highly unlikely that further analysis of the PEXIVAS data will shed more light 66 An S. De Vriese , Fernando C.  Fervenza Clin . The End of Plasmapheresis for ANCA-Associated Vasculitis? J Am Soc Nephrol .  Feb 2021, 16 (2) 307-309

67. Indications: S.Cr > 5.7mg/dl requiring dialysis or rapidly increasing S.Cr Diffuse alveolar hemorrhage who have hypoxemia Double positivity for ANCA and anti-GBM [5% of ANCA are anti-GBM positive, 32% of anti-GBM are ANCA positive] 67 Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4S):S1–S276

68. 68 *Cr ≥5.7 mg/dl includes “on dialysis”. J Clin Apher . 2019;34:171–354.

69. Plasma exchange dosing & frequency ANCA vasculitis with severe kidney disease Vasculitis with DAH Vasculitis in association with anti-GBM antibody 7- treatments over a period of maximum of 14 days , 60ml/kg volume replacement, Albumin substitution Daily until bleeding stops To use FFP as replacement fluid Daily for 14 days or until anti-GBM antibodies are undetectable 69 Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4S):S1–S276

70. FOCAL SEGMENTAL GLOMERULOSCLEROSIS 70

71. FOCAL SEGMENTAL GLOMERULOSCLEROSIS Severe proteinuria recurs in 30-55% of patients post-transplant (often within hour or days of grafting) Role of plasma factor- soluble urokinase -type Plasminogen Activating Receptor ( suPAR ) Daily proteinuria testing for ≥ 14 days after transplantation Treated with PLEX within 2 weeks of recurrence have higher likelihood of remission of proteinuria 71 Clark WF, Huang SS, Walsh MW, Farah M, Hildebrand AM, Sontrop JM. Plasmapheresis for the treatment of kidney diseases. Kidney Int. 2016 Nov;90(5):974-984

72. 72 J Clin Apher . 2019;34:171–354. Remission rate is 50-70%

73. 3 daily exchanges followed by 6 or more in the subsequent 2 weeks , for a minimum of 9 PLEX with concomitant immunosuppression treatment 73 Clark WF, Huang SS, Walsh MW, Farah M, Hildebrand AM, Sontrop JM. Plasmapheresis for the treatment of kidney diseases. Kidney Int. 2016 Nov;90(5):974-984

74. Multiple Myeloma 74

75. Multiple Myeloma Renal involvement in up to 50% of patients with multiple myeloma Myeloma kidney (cast nephropathy) accounts for about 30-80% of such cases Patients with cast nephropathy have poor 1-year survival Co-precipitation of filtered free light chains with Tamm– Horsfall protein in the distal tubules 75 J Clin Apher . 2019;34:171–354.

76. 76 Ann Intern Med. 2005;143:777-784

77. Limitations of the study by Clark et al. (2005) Small study The power was compromised by the use of a composite outcome, which considered death of any cause and eGFR <30 ml/min/1.73m2 a failure No evidence to suggest that an eGFR of <30 ml min1 1.73m2 is associated with poorer prognosis in myeloma patients Lack of renal disease confirmation by renal biopsy Lack of therapeutic marker ( sFLC not measured) 77 Leung N, Gertz MA, Zeldenrust SR, Rajkumar SV, Dispenzieri A, Fervenza FC, Kumar S, Lacy MQ, Lust JA, Greipp PR, Witzig TE, Hayman SR, Russell SJ, Kyle RA, Winters JL. Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains. Kidney Int. 2008 Jun;73(11):1282-1288.

78. 78 Kidney International (2008) 73, 1282–1288

79. 40 patients Average number of PLEX performed= 6 PLEX was found to be effective at reversing renal failure if it was due to- Cast Nephropathy (biopsy proven)and sFLC levels reduced by at least 50% Renal function improved in 78% of the patients when both criteria met 79

80. In patients with other renal pathology, the recovery of renal function did not depend on sFLC reduction 80 3- LCDD 1- Diabetic nephropathy with ATN 1- CN precipitated by IV contrast 1- CN with tubulointerstitial nephritis & fibrosis

81. 81 Ther Apher Dial. 2018 Feb;22(1):79-86

82. 24-month retrospective, longitudinal follow-up study 29 patients Myeloma and acute kidney injury Significant decrease of FLCs in patients treated with TPE compared to the Bortezomib group Significantly higher decrease of FLCs in TPE group Longer survival in patients treated with 3 or more TPEs than patients treated with 2 TPEs 82 Ther Apher Dial. 2018 Feb;22(1):79-86

83. 83 J Clin Apher . 2019; 34:171–354. Volume treated 1 – 1.5 TPV Replacement fluid 5% Albumin Frequency Daily or every other day Session 5

84. CRYOGLOBULINEMIA 84

85. Indications (life threatening or organ threatening complication): RPGN Severe neuritis Refractory cutaneous vasculitis Rapidly improve acute symptoms and serves as bridging therapy prior to treatment with immunosuppressive drugs No correlation between the severity of disease and cryocrit Cryocrit is not to be used as criteria to initiate or discontinue TPE 85 J Clin Apher . 2019; 34:171–354.

86. 86 J Clin Apher . 2019; 34:171–354.

87. Exchange 1-1.5 TPV Replacement with 5% Albumin 3 time per week for 2-3 weeks To check clinical response to guide subsequent therapy The room, lines, and replacement fluid should be warmed to prevent precipitation of circulating cryoglobulins 87 Clark WF, Huang SS, Walsh MW, Farah M, Hildebrand AM, Sontrop JM. Plasmapheresis for the treatment of kidney diseases. Kidney Int. 2016 Nov;90(5):974-984

88. RENAL TRANSPLANTATION 88

89. ABO COMPATIBLE (HLA-sensitized transplant recipients) HLA sensitization: Pregnancy Transfusion Previous transplantation Increased risk for graft loss Elevated HLA antibody screen (high PRA) - difficulty finding HLA compatible donors and remain on the transplantation list 89

90. PLEX (in combination with IS- IVIG/Rituximab)- Pretransplantation desensitization protocols patients with living donors Incompatible crossmatch because of DSA Anti-HLA antibody titers rebound within a few weeks after treatment stops Transplantation within 1 week of the last desensitization treatment is recommended Post-transplantation monitoring and rapid treatment of antibody-mediated rejection 90 Clark WF, Huang SS, Walsh MW, Farah M, Hildebrand AM, Sontrop JM. Plasmapheresis for the treatment of kidney diseases. Kidney Int. 2016 Nov;90(5):974-984

91. 91 TPE in combination with immunosuppressive drugs pre-transplant until crossmatch is negative 1-1.5 TPV exchange Daily or every other day Continued postoperatively and re-initiated if AMR occurs J Clin Apher . 2019; 34:171–354.

92. Whether HLA-incompatible kidney transplantation, after desensitization, conferred a survival advantage relative to waiting for a compatible transplant ??? 92

93. 93 N Engl J Med 2016;374:940-50 Significant survival benefit as compared with the other options available to sensitized patients

94. RENAL TRANSPLANT -ABO INCOMPATIBLE Major ABOi exists in ~ 35% of random donor-recipient pairs Risk of Hyperacute rejection and ABMR To reduce anti-A and/or anti-B titers to less than a specific critical threshold prior to transplantation  TPE + IS Threshold titer varies with center-specific titration methods and techniques No RCTs, abundance of supportive evidence exists 94

95. 95 1-1.5 TPV Albumin, FFP FFP should be compatible with both the recipient and donor ABO type Daily or every other day FFP in the immediate pre- & post-surgical period J Clin Apher . 2019; 34:171–354

96. Nephrology consultation for membrane separation TPE Indications for Plasma exchange are not limited to kidney diseases Nephrology consultation is sought by other specialties (Hematology, Neurology, Gastroenterology) for Membrane separation TPE Collaboration with other specialties Valid indication (ASFA 2019) 96

97. Myasthenia gravis (Acute, short-term treatment) Acute liver failure GB syndrome Wilson disease (fulminant) Chronic inflammatory Demyelinating polyradiculoneuropathy (CIDP) Cutaneous T cell lymphoma ( Erythrodermic ) N-methyl-D-aspartate receptor antibody encephalitis Hyperviscosity in hypergammaglobulinemia Paraproteinemic demyelinating Neuropathies ( IgG /IgA/ IgM ) Catastrophic antiphospholipid syndrome (CAPS) 97 J Clin Apher . 2019; 34:171–354.

98. THANK YOU 98