1. Plasmapheresis: Basic Principles
Stuart L. Goldstein
Assistant Professor of Pediatrics
Baylor College of Medicine
Administrative Director, Pheresis Service,
Texas Children’s Hospital

2. Acknowledgements
Jun Teruya, MD, Medical Director, Pheresis Service, Texas Children’s Hospital
Jean Haas, Gambro (TPE membrane slides)

3. Membrane vs. Centrifugation
In the US, most TPE is performed by centrifugation.  One machine can do all apheresis procedures.
Double filtration method: first membrane separates plasma from cellular portion and second membrane separates globulin from albumin.
LDL apheresis: using membrane coated with antibody to LDL, only LDL cholesterol can be removed.

4. Continuous vs. Intermittent
Continuous: COBE Spectra, Fenwall CS3000
Intermittent: Haemonetics

5. Blood Components Separated by Centrifugation
Plasma
Platelets
Lymphocytes
Monocytes
Granulocytes
Neocytes
Erythrocytes

6. Plasma Exchange

7. TPE: Available techniques... TPE: Available techniques
Cascade or secondary filtration: Separated blood is perfused through a plasma filter (1) to remove certain plasma elements. The second column (2) (cascade) absorbs the element and the plasma is returned to the patient.
Please, read the definition above. This method has been utilized to adsorb immune antibody substances found in Multiple Sclerosis and mediators of Sepsis, among a couple of things. The second column can be an adsorptive column, containing a special resin to adsorb certain constituents like inflammatory mediators. Recently phase I trials have been completed utilizing this technique, and showed almost a 100% removal of Interleukin-6 and TNF-alpha. You can find more on this in my notes from the CRRT Conference. 1 2
PATIENT

8. Membrane Filtration
Use semi permeable membrane to separate the smallest component (plasma) from larger one (cells)
A negative pressure is applied via the effluent pump to remove plasma from the blood side of the membrane.
During TPE utilizing PRISMA, the effluent pump of Prisma creates a negative pressure to pull plasma across the membrane from the blood compartment.
There is really only one plasma filter being used in abundance: The Asahi plasma filter. The membrane used in this filter is made of cellulose diacetate and has a blood volume of 65 ml.
The PRISMA TPE filter is made of Polypropylene and has a volume of 41 ml.
Membrane biocompatibility is not as large a concern with TPE as it is with dialysis and CRRT membranes. I will discuss this more, when I send a primer on equipment and supplies.

9. Plasma removal is affected by: Qb Hct Pore Size TMP
=Plasma effluent Qb
The efficacy of plasmafiltration depends on Qb, pore size, TMP, hematocrit (hct), and blood viscosity. Unlike CRRT, where TMP is driven, sometimes quite high, to achieve adequate ultrafiltration, TPE needs to be performed at a TMP of <50 mmHG to prevent hemolysis. Plasma removal is more dependent on Qb and hct. Qb must be >50 ml/min to avoid clotting with the ideal rate being ml/min. The hematocrit will affect blood viscosity and plasma removal, too. The higher the hematocrit, the lower the rate of plasma removal at a given blood flow rate.
The seiving coefficient (pore size) of the membrane will determine how effectively a substance will be removed. Most plasma filter membranes are able to remove >80% of very large complexes, such as IgM and 90% of others such as IgG, which weigh about 1 million daltons.
Hct 25-45%
TMP <50 mmHg
Pore Size

10. Rationale of Plasma Exchange
The existence of a known pathogenic substance in the plasma.
IgG, IgM, phytanic acid, cytokines (?)
The possibility of removing this substance more rapidly than it can be renewed in the body.

11. Efficiency of removal is greatest early in the procedure and diminishes progressively during the exchange.

12. Plasma Volume Exchange
Percent Removed
100%
0.5
39.3%
1.0
63.2%
1.5
77.7%
2.0
86.5%
2.5
91.8%
3.0
95.0%

13. Small vs. Large Volume Exchange
1.0 plasma volume exchange: minimizes time required for each procedure but may need more frequent procedures.
2.0 – 3.0 plasma volume exchange: greater initial diminution of pathologic substance but requiring considerably more time to perform the procedure.

14. Mechanical Removal of Antibodies
When antibody is rapidly and massively decreased by TPE, antibody synthesis increases rapidly.
This rebound response complicates treatment of autoimmune diseases.
It is usually combined with immune suppressive therapy.

15. Indication of TPE Category 1: Standard acceptable therapy
Chronic idiopathic demyelinating polyneuropathy (CIDP), cryoglobulinemia, Goodpasture’s syndrome, Guillain-Barre syndrome, focal segmental glomerulonephritis, hyperviscosity, myasthenia gravis, post transfusion purpura, Refsum’s disease, TTP

16. Indication of TPE Category 2: Sufficient evidence to suggest efficacy usually as adjunctive therapy
ABO incompatible organ transplant, bullous pemphigoid, coagulation factor inhibitors, drug overdose and poisoning (protein bound), Eaton-Lambert syndrome, HUS, monoclonal gammopahty of undetermined significance with neuropathy, pediatric autoimmune neuropsychiatric disorder associated with streptococcus, RPGN, systemic vasculitis

17. Indication of TPE Category 3: Inconclusive evidence of efficacy or uncertain risk/benefit ratio.
TPE can be considered for the following occasions:
Standard therapies have failed.
Disease is active or progressive.
There is a marker to follow.
It is agreed that it is a trial of TPE and when to stop.
Possibility of no efficacy is understood by the patient.

18. Indication of TPE Category 4: Lack of efficacy in controlled trials.
Examples: AIDS, amyotrophic lateral sclerosis, lupus nephritis, psoriasis, renal transplant rejection, schizophrenia, rheumatoid arthritis

19. Replacement Fluid
Fresh frozen plasma – TTP, liver failure, coagulopathy with inhibitors, patients with coagulopathy, immediate post surgery.
Cryopoor plasma – TTP
5% albumin – Most cases.

20. Thrombotic Thrombocytopenic Purpura (TTP)
Pentad: Thrombocytopenia, microhemangiopathic hemolytic anemia, renal dysfunction, CNS symptoms, fever
Etiology: Platelet activation by unusually large multimers of von Willebrand factor (vWF). vWF cannot be cleaved due to the absence of cleaving enzyme, metalloprotease = ADAMTS 13 (a disintegrin and metalloprotease, with thrombospondin-1-like domains).

21. TTP vs. DIC TTP - platelet activation
Platelet activating factor is unusually large vWF.
Platelet aggregates stain for vWF.
DIC - coagulation activation
Platelet aggregates stain for fibrinogen.
Hypercoagulability and consumption coagulopathy.
No primary DIC.

22. Congenital TTP vs. Primary TTP
Congenital TTP: Hereditary deficiency of metalloprotease.  Transfusion of FFP every 2-3 weeks.
Primary TTP: Autoantibody against metalloprotease.  Removal of the antibody and replacement with cryopoor plasma or FFP.

23. Management for TTP FFP Transfusion Plasma Exchange Suspected TTP
vWF-Cleaving Protease
Low
Mixing Study
Correction
No Correction
Deficiency
Inhibitor
FFP Transfusion
Plasma Exchange

24. TPE for Primary TTP Medical emergency.
DDx: Malignant hypertension, DIC
1.3 plasma volume exchange everyday until 3-5 days after normal platelet count and normal LDH.
Replacement fluid: cryopoor plasma, FFP
Overall response 81% (182/224), refractory 19% (42/224), early relapse 27%, late relapse 10%.

25. Cases of TTP in CPC, NEJM
41 yo female received platelet transfusion for hematuria. She developed acute myocardial infarction during TPE and died. (Case 33 NEJM 1994;331:661-7.)
67 yo female developed bloody diarrhea after vacation in Italy. (Case 17 NEJM 1997;336: )
49 yo female with TTP developed TRALI during plasmapheresis. (Case 40 NEJM 1998;339: )

26. Case 19 NEJM 1995;332:
55 yo female with history of breast carcinoma developed acute respiratory distress and thrombocytopenia. Requested for TPE.
Hct 37%, schistocytes 2-5, WBC 13,800, PLT 34,000, PT 13.2 sec, PTT 32.1 sec, D-dimer 2-4 mg/mL, LDH 3,525 U/L, uric acid 9.7 mg/dL
Anatomical diagnosis: pulmonary embolic and lymphangitic carcinomatosis of breast origin.

27. Guillain-Barre Syndrome
Acute inflammatory demyelinating polyneuropathy.
Positive anti peripheral nerve myelin in most patients.
Triggered by common cold or vaccination.
Indication for TPE: progressive disease, an inability to ambulate, decreased respiratory capacity, bulbar symptoms.

28. TPE for Acute GBS 1.3 plasma volume exchange 6 times over 1-2 weeks.
85% patients respond, 10% left with severe disability, 5% death.
IVIG or TPE is controversial.
Dutch Guillain-Barre Group. A randomized trial comparing IVIG and plasma exchange in GBS. N Engl J Med 1992;326:

29. Complications - 1
Death: >50 deaths have been associated with apheresis (<3/10,000 procedures)
Cardiac arrhythmias, respiratory distress syndrome, pulmonary edema.
Hypotention, hypovolemia, hypervolemia, anemia
Association of ACE inhibitor and hypotension and anaphylaxis has been reported.

30. Complications - 2 Effects on the circulation
Tiredness and malaise, presumably due to the shifts in fluid balance and extracorporeal circulation.
Citrate toxicity (most common)
Plasma protein levels
Decrease in immunoglobulins, cholesterol, C3, alkaline phosphatase, AST
Alteration of pharmacodynamics
Restlessness, agitation

31. Post 1.3 Plasma Volume Exchange
Complications – 3
Dilutional coagulopathy, when albumin is used.
Pre
Post 1.3 Plasma Volume Exchange PT
14.2 sec
26.7 sec
PTT
29.9 sec
64.9 sec
Fibrinogen
159 mg/dL
55 mg/dL

32. Physician’s Procedure Note
Reviewed and evaluated the pertinent clinical lab data relevant to the treatment of the patient that day.
Made decision to perform the procedure on the day.
Saw and evaluated the patient during the procedure.
Remained available to respond in person to emergencies or other situations throughout the procedure.