Plasmapheresis: Basic Principles

Stuart L. GoldsteinAssistant Professor of Pediatrics

Baylor College of MedicineAdministrative Director, Pheresis Service,

Texas Children’s Hospital

Acknowledgements

• Jun Teruya, MD, Medical Director, Pheresis Service, Texas Children’s Hospital

• Jean Haas, Gambro (TPE membrane slides)

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.

Continuous vs. Intermittent

• Continuous: COBE Spectra, Fenwall CS3000

• Intermittent: Haemonetics

PlasmaPlatelets

Lymphocytes

Monocytes

GranulocytesNeocytes

Erythrocytes

Blood Components Separated by Centrifugation

Plasma Exchange

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

TPE: Available techniques

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.

Qb 100-150

Hct 25-45%

TMP <50 mmHg

=Plasma effluent

Plasma removal is affected by:• Qb• Hct• Pore Size• TMP

Pore Size

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.

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

Plasma Volume Exchange

Plasma Volume Exchange

Percent Removed

0 100%

0.5 39.3%

1.0 63.2%

1.5 77.7%

2.0 86.5%

2.5 91.8%

3.0 95.0%

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.

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.

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

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

Indication of TPECategory 3: Inconclusive evidence of

efficacy or uncertain risk/benefit ratio.

TPE can be considered for the following occasions:

1. Standard therapies have failed.2. Disease is active or progressive.3. There is a marker to follow.4. It is agreed that it is a trial of TPE and

when to stop.5. Possibility of no efficacy is understood by

the patient.

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

Replacement Fluid

• Fresh frozen plasma – TTP, liver failure, coagulopathy with inhibitors, patients with coagulopathy, immediate post surgery.

• Cryopoor plasma – TTP• 5% albumin – Most cases.

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).

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.

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.

Management for TTP

FFP Transfusion Plasma Exchange

Suspected TTP

vWF-Cleaving Protease

Low

Mixing Study

Correction No Correction

Deficiency Inhibitor

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%.

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.)

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 g/mL, LDH 3,525 U/L, uric acid 9.7 mg/dL

• Anatomical diagnosis: pulmonary embolic and lymphangitic carcinomatosis of breast origin.

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.

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.

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.

• 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

Complications - 2

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

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

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.