IN THE NAME OF

1. IN THE NAME OF GOD

2. Plasmapheresis DR KAMRAN FAZEL.MD.FCCM

3. Since antiquity, mankind has hypothesized there are bad substances called “humors” that accumulate in the blood of sick patients and that the removal of these humors would . make patients feel better

4. Bloodletting, the practice of draining blood from sick patients,hasbeen around since the Egyptians, dating back 1000 years BC. The practice of bloodletting peaked in the 18th century and evolves with modern technology to this day.

5. Apheresis is a procedure that is used in the treatment of patients with a variety of illnesses. The term apheresis comes from the Greek origin meaning “removal of”. All apheresis procedures involve removing components from the blood. Efficient apheresis procedures have been developed over the last 15 years.

6. Blood has 4 major components: red blood cells, white blood cells, platelets, and plasma. With modern machinery, blood can be separated into each of these 4 components. Thus, if a particular blood component is causing harm, it can be selectively removed and replaced with the same blood component from healthy donors.

7. History of modern plasmapheresis • 1909 Fleig / France • Auto & heterotransfusion of washed corpuscles • 1914 Abel / U.S. • Use the term of Plasmapheresis in his paper • Prolonged the life of dog with bilateral nephrectomy by plasmapheresis • 1959Michael Rubinstein was the first person to use plasmapheresis to treat an immune-related disorder when he "saved the life of an adolescent boy with thrombotic thrombocytopenic purpura (TTP) at the old Cedars of Lebanon Hospital in Los Angeles 1970-Invention of cell separator machine

9. Apheresis in Clinical Practice Sickle Cell Dis. Malaria Thrombocytosis RBC WBC PLT Plasma Leukemias Cell Therapies TTP Guillain Barre Syn. Myasthenia Gravis Goodpasture’s Syn. Waldenstrom’s

10. Plasmapheresis is an apheresis procedure that separates and removes the plasma component from a patient. Plasma exchange is when plasmapheresis is followed by replacement with fresh frozen plasma infusion

11. To apply this treatment to patients appropriately it is essential to understand: 1-the methods to remove plasma 2- its effects on normal plasma constituents 3-the role of replacement fluids in the treatment 4-and the risks associated with the procedure.

12. Mechanism of action of plasma exchange • Removes pathologic substances such as pathologic Abs, immune complexes,and cytokines is the major mechanism of action of TPE • TPE may have an immunomodulatory effect beyond the removal of Ig: • Reported effects of TPE on immune function include: • T-cell modulation with a shift from in the Th1/Th2 balance with a shift toward Th2 • suppression of IL-2 and IFN- γ production

13. Possible mechanisms of TPE

15. TECHNIQUES OF SEPARATING PLASMA FROM WHOLE BLOOD Plasmapheresis is performed by 2 fundamentally different techniques: Devices separating based on density: centrifugation or Devices separating based on size:filtration

16. centrifugation apheresis whole blood is spun so that the 4 major blood components are separated out into layers by their different densities. Centrifugation apheresis is commonly .performed by blood bankers

17. centrifugation apheresis Advantages: 1-Capable of performing cytapheresis 2-No heparin requirement 3-More efficient removal of all plasma components Disadvantages: 1-Expensive 2-Requires citrate anticoagulation 3-loss of platelets 4-usually requires a consultation to another service such as a blood banker

18. Centrifugal Separation

19. Filtration plasmapheresis whole blood passes through a filter to separate the plasma components from the larger cellular components of red blood cells, white blood cells,and platelets. commonly performed by nephrologists and intensivist

20. Membrane apheresis Advantages: 1-fast and efficient 2-No citrate requirements Disadvantages: 1-Removal of substances limited by sieving coefficient of membrane 2-Unable to perform cytapheresis 3-Requires high blood flows , central venous access, heparin 4-Limiting use in bleeding disorders

21. Membrane Separation

22. Dialysis & Transplantation 2009 February: 1-4

23. 2010, ASFA published its updated comprehensive “Guidelines • Category I: “Disorder for which apheresis is accepted as first-line therapy,either as a primary stand-alone treatment or in conjunction with other modes of treatment.” • Category II: “Disorders for which apheresis is accepted as second-line therapy,either as a stand-alone treatment or in conjunction with other modes of treatment.” • Category III: “Optimum role of apheresis therapy is not established. Decision -making should be individualized.” • Category IV: “Disorders in which published evidence demonstrates or suggests apheresisto be ineffective or harmful. Internal Review Board approval is desirable if apheresis treatment is undertaken in these circumstances.”

24. Diseases and disorders treated with plasma exchange. ASFA categoryI • Acute inflammatory demyelinatingpolyradiculopathy (Guillain-Barré Syndrome) • ANCA-associated rapidly progressive glomerulonephritis/vasculitis • (Wegener granulomatosis) Dialysis independent Alveolar hemorrhage • Antiglomerular basement membrane disease (Goodpasture syndrome) Dialysis independent Alveolar hemorrhage

25. Diseases and disorders treated with plasma exchange. ASFA categoryI • Chronic inflammatory demyelinatingpolyradiculopathy • Cryoglobulinemia • Focal segmental glomerulosclerosis (recurrent) • Hemolytic uremic syndrome • Autoantibody to factor H • Hyperviscosity in monoclonal gamopathies • Symptomatic • Prophylactic for rituximab treatment

26. Diseases and disorders treated with plasma exchange. ASFA categoryI • Paraproteinemicpolyneuropathies • IgG/IgA • IgM • Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) • Renal transplantation, Ab-mediated rejection • Thrombotic thrombocytopenic purpura

27. TPE & removal of plasma Significant declines in factor V (FV), FVII, FVIII, FIX, FX, and VWF activity occurs. Activities of FVIII, FIX, and VWF return to normal within 4 hours after TPE whereas the remaining coagulation factors achieve pre-TPE activity levels by24 hours. The exception to this is fibrinogen, which reaches 66% of pre-apheresis levels by72 hours

28. Additional substances removed include: inhibitors of coagulation such as antithrombin and the pseudocholinesterasenecessary for metabolism of some drugs • Theoretically, the removal of inhibitors of coagulation could predispose patients to thrombosis, but this has not been demonstrated definitively • Reports of prolonged neuromuscular blockade due to decreased pseudocholinesterase activity have been reported

29. The removal of Abs from the patient can result in: false negative tests for: infectious diseases, autoantibodies, alloantibodies,andenzyme and coagulation factor activity. Samples for such testing should be collected before the initiation of TPE

30. Medications reportedly removed by TPE Basiliximab Ceftriaxone Ceftazidime Chloramphenicol Cisplatin Diltiazem α IFN- IVIG Palivizumab Propoxyphene Propranolol Rituximab Tobramycin Verapamil Vincristine American Society of Hematology 2012

31. For each 1-1.5 plasma volume exchanged, approximately 60%-70% of substances present in the plasma at the start of that .plasma volume will be removed routine practice is to exchange only 1-1.5 plasma volumes during a TPE. American Society of Hematology 2012

32. Treating volumes beyond 1.5 plasma volumes removes smaller, less clinically important amounts of pathologic substance present in the plasma while prolonging the procedure and exposing the patient to more replacement fluid and anticoagulant,increasing : risk of complications withoutincreasing benefit to the patient. American Society of Hematology 2012

33. one-third of the replacement fluid administered at the beginning of the TPE will be present by the end, with the majority having been removed. Administering plasma as a replacement fluid at the beginning of a TPE results in exposure of the patient to blood products without benefit.

34. Exchange Fluids • 5% Albumin • Best choice • Dilute only with saline • Combination of saline and albumin • FFP • Cryopoor plasma

35. Albumin Advantages: 1-No risk of hepatitis 2-Stored at room temperature 3-Allergic reaction are rare 4-No concern about ABO blood group 5-Depletes inflammation mediators Disadvantages: 1-Expensive 2-No coagulation factors 3-No immunoglobulins

36. 70% albumin and 30% saline. majority of the albumin being given at the end of the procedure to avoid hypovolemia from redistribution of the crystalloid

37. Advantages: 1-Coagulation factors 2-Immunoglobulins Disadvantages: 1-Risk of hepatitis, HIV, transmission 2-Allergic reaction 3-Hemolytic reaction 4-Must be ABO compatible 5- citrate load FFP

38. vascular access ? central venous access Or peripheral vascular access

39. Studies examining the complication rates of apheresis procedures : the frequency of complications due to the placement of central venous catheters exceed the frequency of complications directly related to the procedure. (hemopneumothorax) Central venous access has also been identified as a major risk factor for complications of TPE in other studies

40. Complications of plasmapheresis • 4-25% • Minimal reactions 5% • Mod reactions 5-10% • Severe reactions <3% • Mortality rate 3-6 per 10000 procedures • The majority of deaths is anaphylaxis associated with FFP, PTE , vascular perforation

42. Indications for emergency plasmapheresis • Anti-GBM disease and /or/pulmonary hemorrhage in Goodpasture syn. • Hyperviscositysyn with signs and symptoms suggesting impending stroke or loss of vision • TTP/HUS • Factor 8 inhibitor in patients requiring surgery • Respiratory insufficiency in G-B syn • MG with respiratory distress not responding to medication • Acute poisoning

43. THROMBOTIC MICROANGIOPATHIES • Thrombotic thrombocytopenic purpura(TTP) • hemolytic uremic syndrome (HUS) • disseminated intravascular coagulation (DIC) • catastrophic antiphospholipid syndrome (CAPS)

44. ASFA category for TPE I for : TTP and atypical HUS due to autoantibody to factor H II for : CAPS III for : hematopoietic stem cell transplant–associated thrombotic microangiopathy

45. TTP classic “pentad” pathophysiologic process : deficiency ofADAMTS-13 (aka, von Willebrand factor[VWF]–cleaving proteinase) VWF- and platelet-rich microthrombi congenital and acquired ADAMTS-13 inhibitors and proteolyticinactivators including :interleukin-6, plasma-free hemoglobin, IgG autoantibody, Shiga toxin,plasmin, thrombin, and granulocyte elastase

46. TPE in TTP remove the large and ultra-large VWF - ADAMTS-13inhibitors and proteolyticinactivators, and replenishADAMTS-13. the recommended TPE replacement fluid is plasma or plasma with cryoprecipitate removed (ie, the plasma portion that is depleted with ultra-large VWF and large plasma VWF).

47. HUS:Typical&Atypical The “triad” of HUS is thrombocytopenia, microangiopathic hemolytic anemia, and .renalFailure In atypical HUS, in addition to the typical “triad” , .patients have neurologic abnormalities Currently, the ASFA does not recommend TPE (category IV) for typical HUS

48. We recommendconsulting nephrology and hematology to send the appropriate ADAMTS-13, VWF, and complement studies. In addition, TPE should be initiated until the results of biomarkers can differentiate the diagnoses. Because the underlying pathology is the deficiency of complement H activity, the recommended TPE replacement fluid is either plasma or albumin. We recommend plasma as the replacement fluid since it has normal factor H activity. Crit Care Clin 28 (2012) 453–468

49. DIC Many case series and observational studies suggest that TPE might have a beneficial effect in DIC. TPE is thought to normalize the blood coagulation to homeostasis milieu by removing tissue factor and plasminogen activator inhibitors type I and by replacing antithrombin III, protein C,and coagulation factors. Currently, the ASFA does not have a specific recommendation for TPE in DIC.

50. sepsis the ASFA gives a category III recommendation DIC has been shown to be one of the major contributing mechanisms to multiorgan failure in critically ill patients. Thus, there is a biologic plausibility that the beneficial treatment effect of TPE in sepsis with multiorgan failure could be from reversing DIC .