Plasmapheresis: Basic Principles

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

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. 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.

9. Plasma removal is affected by: • Qb • Hct • Pore Size • TMP =Plasma effluent Qb 100-150 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

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 TPECategory 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 TPECategory 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 TPECategory 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 TPECategory 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 (adisintegrin 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. Suspected TTP vWF-Cleaving Protease Low Mixing Study Correction No Correction Deficiency Inhibitor Management for TTP 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;336:1587-94.) • 49 yo female with TTP developed TRALI during plasmapheresis. (Case 40 NEJM 1998;339:2005-12.)

26. Case 19 NEJM 1995;332:1700-7. • 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;326:1123-9.

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. Complications – 3 • Dilutional coagulopathy, when albumin is used.

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.