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,has been 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
1959 Michael 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
Mechanism of action
Disorders
Removal of autoantibody
Myasthenia gravis
Removal of alloantibody
Rh alloimmunization in preg.
Removal of immune complex
Systemic lupus erythemotosus
Removal of monoclonal protein
Hyperviscosity syndrome
Removal of toxin
Mushroom poisoning
Replacement of specific plasma factor
Thrombotic thrombocytopenic purpura

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 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 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 apheresis to 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 demyelinating polyradiculopathy
(Guillain-Barré Syndrome)
ANCA-associated rapidly progressive glomerulonephritis/vasculitis
(Wegener granulomatosis)
Dialysis independent
Alveolar hemorrhage
Antiglomerular basement membrane disease (Goodpasture syndrome)

25. Diseases and disorders treated with plasma exchange. ASFA categoryI
Chronic inflammatory demyelinating polyradiculopathy
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
Paraproteinemic polyneuropathies
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 by 24 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 pseudocholinesterase necessary 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,and enzyme 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

31. For each 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 plasma volumes during a TPE.
American Society of Hematology

32. risk of complications without increasing benefit to the patient.
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 without increasing benefit to the patient.
American Society of Hematology

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 Combination of saline and albumin FFP
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. FFP 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

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 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.
Hyperviscosity syn 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 pathophysiologic process :
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 proteolytic inactivators
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 proteolytic inactivators, and replenish ADAMTS-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 recommend consulting 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 .

51. Systemic Lupus Erythematosus
The ASFA gives a category II recommendation for TPE :in severe SLE such as with cerebritis or diffuse alveolar hemorrhage. The ASFA does not recommend TPE (category IV) for SLE-associated nephritis. TPE is thought to remove autoantibodies, complement, interferon alpha, and immune complexes. The recommended TPE replacement fluid is either plasma or albumin.

52. NEUROLOGIC DISORDERS
The ASFA gives a category I recommendation for TPE in acute inflammatory demyelinating polyneuropathy (Guillain-Barre syndrome), chronic inflammatory demyelinatingpolyradiculoneuropathy, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections and Sydenham’s chorea, multiple sclerosis, and myasthenia gravis

53. Frequency of procedures Duration of therapy
Anti- GBM disease :2 plasma volume daily for 7 consecutive days
TTP-HUS :1.5 plasma v. for first 3 treatments followed by 1 plasma v. until plt is normalized and LDH level below 400iu/l
Cryuoglobulinemia:1 plasma v. 3 times weekly for 2-3 weeks
RPGN: 4 days for the first week
Hyperviscosity syn: daily 1 plasma v for 2-5 days (HAND BOOK OF DIALYSIS 2007)

54. FUTURE VIEW
Hemophagocytic Lymphohistiocytosis: Pathologic Hyperactive Inflammation(HLH) HLH is a syndrome of pathologic hyperactive inflammation due to unchecked immune .activation

55. multiorgan failure with the following clinical criteria
(1) fever (2) splenomegaly (3) cytopenia (4) Hypertriglyceridemia (5) hemophagocytosis in bone marrow spleen, lymph nodes, or liver (6) low or absent NK-cell activity (7) ferritin greater than 500 ng/mL, and (8) elevated serum CD 25

56. Secondary HLH &familial/primary
Epstein-Barr virus is the most commonly recognized .infection associated with secondary HLH TPE has been reported in many small case series to be beneficial in calming the cytokine storm and to provide hematologic support in patients with primary and secondary HLH. Currently, the ASFA has not commented on the use of TPE in HLH.

57. THANKS