Plasma Exchange: Why We Do What We Do

Mark E. Brecher*

Department of Pathology and Laboratory Medicine, Transfusion Medicine Service, University of North Carolina at Chapel Hill

INTRODUCTION2

Since the introduction of automated cell separatorsin the 1970s, we have been witness to an explosion ininterest and application of therapeutic apheresis. Al-though therapeutic apheresis currently encompasses awide variety of procedural types, the majority ofprocedures (70.1%) performed are plasma exchangeswith or without plasma for replacement (Fig. 1) [1].Today, plasma exchange therapy is the standard ofcare for a diversity of diseases. It has, in fact, becomeso accepted and commonplace that we take forgranted many of the parameters of treatment (e.g., thevolume exchanged, the choice of replacement, and thetiming of treatment). The basis for these commonlyused parameters, or ‘‘why we do what we do’’ in thecase of plasma exchange, is explored in this review.

VOLUME EXCHANGED

The choice of a volume of blood to be exchanged isbased on the kinetics of apheresis therapy. Models ofapheresis removal of a blood component (or a soluteof interest) typically assume that the component orsolute being removed is neither synthesized nor de-graded substantially during the procedure, that it re-mains within the intravascular compartment and thatthere is instantaneous mixing. Such assumptions arelargely valid for solutes or cells located predomi-nantly within the intravascular space such as IgM(76% within the intravascular space) or red cells, butapply less well with solutes such as IgG, IgA, andalbumin, which have intravascular distributions ofapproximately 45, 42, and 40%, respectively [2].

For continuous flow plasma exchange, the removalof plasma or solute can be described by the samedifferential equation that applies to isovolemic he-modilution [2,3]:

dS

dVex¼ �S

PVð1Þ

where: S ¼ solute concentration, Vex ¼ Volume ex-changed, and PV ¼ Plasma Volume

This equation can be integrated and rearranged(where Sl ¼ the initial solute concentration and Sf¼ the final solute concentration) to yield:

Fraction remaining ¼ Sf=Si ¼ e�Vex=PV

Alternatively, the volume to be removed to achievea specific fraction of a solute is given by the followingequation:

Vex ¼ PV� lnðSi=SfÞ

For intermittent flow, if the replacement is givenafter the removal of the plasma, after N repetitions ofremoval the remaining fraction of the solute inquestion is given by the following equation [2]:

Fraction remaining ¼ fðplasma volume

� volume removed)/plasma volumegN

If the replacement is given before the removal ofthe plasma, after N repetitions of plasma removal, theremaining fraction of the analyte in question is givenby the equation:

Fraction remaining ¼ fplasma volume

/(plasma volume+volume removed)gN

Because of the initial hemodilution that occurs ifthe replacement is given before the removal of theplasma, for each cycle of plasma removal, the fractionremaining is less than if the replacement had onlybeen given after each repetition of plasma removal.

A comparison of continuous vs. intermittent flowexchange nd the percent removal is illustrated inFigure 2.

TIMING

The timing of exchanges is generally chosen basedupon a balancing of the need to allow the solute or

From the Proceedings of the 23rd Annual Meeting of the AmericanSociety for Apheresis*Correspondence to: Mark1 E. Brecher, Department of Pathologyand Laboratory Medicine, Transfusion Medicine Service, CB7600, University of North Carolina Hospitals, 101 ManningDrive, Chapel Hill, NC 27514. E-mail: brecher@med.unc.edu

Received 22 August 2002; Accepted 22 September 2002

Published online in Wiley Interscience(www.interscience.wiley.com)DOI: 10.1002/jca.10041

Journal of Clinical Apheresis 17:207–211 (2002)

� 2002 Wiley-Liss, Inc.

cell of interest to re-equilibrate into the vascular spaceand the desire to minimize the risk of bleeding thatcan be seen with dilutional coagulopathy.

EFFICIENCY OF IMMUNOGLOBULIN REMOVAL

In the case of IgG, where only 45% of the IgG lieswithin the intravascular space, a 1 plasma volumeexchange would be expected to remove 63.2% of theintravascular IgG but only 28.4% of the total bodyIgG (0.632 · 0.45 · 100). Re-equilibration of the in-travascular IgG with extravascular IgG typically oc-curs within 2 days and results in a substantial increasein the intravascular IgG level. For example, a patient

with an IgG level of 10 g/L would have their intra-vascular IgG level reduced to 3.68 g/L, but followingequilibration this level would be expected to rise to7.16 g/L. Increasing the volume of plasma exchangedfrom 1 plasma volume to 1.5 plasma volumes is as-sociated with only a modest increase in IgG removal(Fig. 3). Frequently, a 70–85% reduction of IgG istaken as a goal of therapy. A short-term reduction of70% in the titer of anti-acetylcholine receptor inmyasthenia gravis patients is generally associatedwith clinical improvement [5].

To achieve a 70–85% reduction in intravascularIgG (following re-equilibration and ignoring synthesisand catabolism), one would in theory require 4 one-

Fig. 1. Relative frequency of therapeutic procedures by type, based on data from 18 institutions in the United States encompassing3,421 procedures [1].

Fig. 2. Fraction removed by plasma volume replaced (modified with permission from Brecher ME, editor. AABB Technical Manual,14th edition. Bethesda, MD: American Association of Blood Banks, 2002; p 136) [4].

208 Brecher

plasma-volume exchanges. Turnover of IgG is rela-tively slow with an approximate half-life of 21 days,but rapid rebound frequently occurs and sustainedreductions of IgG cannot be achieved unless plasmaexchange therapy is combined with immunosuppres-sion. In practice, a 70–85% reduction in IgG canfrequently be achieved with 5–6 plasma exchangesover14 days when combined with immunosuppression.Despite IgM’s more rapid synthesis (half-life of 5–6days), comparable reductions of IgM are seen withthe same number of exchanges and rapid total bodydepletion of IgM vs. IgG can be more effectivelyachieved with daily exchanges due to the predominantintravascular distribution of IgM.

Reductions of IgG beyond 70–85% are difficult toachieve as the absolute reduction in IgG with eachsubsequent plasma exchange is reduced (Fig. 3). For 6successive 1-plasma volume exchanges, the decreasein IgG (immediate pre to post procedure) in a patientwith an initial IgG level of 10 g/L would be 6.3, 4.5,3.2, 2.3, 1.7,3 and 1.2 g/L, respectively.

Thus, the number of exchanges performed takesinto account both the diminishing efficiency of re-moval associated with serial exchanges and the levelthat is generally associated with clinical efficacy.

EFFECT ON CLOTTING FOLLOWING PLASMAEXCHANGE

Therapeutic plasma exchange is generally associ-ated with the rapid (and repeated) removal of largequantities of plasma and its associated coagulantproteins. When non-coagulant containing replace-ment fluids such as albumin, saline, and colloidalstarches are used, one sees an acute fall in clotting

factor activity varying from 40–70% of baseline im-mediately following the exchange (Table I). This isgenerally associated with a small prolongation inmeasured PT and aPTT (albeit such values fre-quently remain within the normal range). Fibrino-gen, having a volume of distribution that is almostexclusively intravascular is the clotting factor mostdepleted. Clotting factor levels generally return tonormal within 1 to 2 days following exchange. Thegeneral consensus is that in the absence of an un-derlying hemostatic defect (e.g., liver disease), use ofclotting factor-free replacement solutions are ap-propriate.

An unintentional consequence of plasma removalis a reduction in circulating platelets. Mean reductionof platelets following a plasma exchange has beenvariably reported to range from 9.4 to 52.6% (TableII). This wide range likely reflects the differingamounts of plasma volumes processed, and the dif-ferent cell separators and settings employed. Largervolumes processed and low-rpm speeds (decreasedcentrifugal force) are associated with greater plateletloss. Despite mean decreases in platelet counts of52.6% following 1.6 plasma volume exchanges, Sultanet al. found that the platelets (as well as all clottingfactors measured with the exception of AT III) hadalmost reached or even exceeded their initial valuesafter 48 to 96 hours (just before the next plasma ex-change) [7]. We have also observed4 normal plateletcounts 48 hours after 1-plasma volume exchanges(just prior to the next plasma exchange).

In a hemostatically compromised patient or largevolume daily exchanges, hemostatic parametersshould be monitored and the replacement supple-mented with plasma or platelets as clinically indicated.

Fig. 3. Theoretical reduction of IgG following plasma exchange of 1, 1.25, and 1.5 plasma volumes and following re-equilibration oftotal body IgG. The solid line indicates a 85% reduction and the dashed line a 70% reduction. The absolute reduction in IgG is reducedwith each subsequent exchange. Calculations assume no degradation or synthesis of IgG, and re-equilibration of IgG at 2 days.

Plasma Exchange 209

In practice, plasma exchanges are frequently per-formed on a 3· per week schedule.

CHOICE OF REPLACEMENT SOLUTIONSFOR PLASMA EXCHANGE

Following the introduction of cell separators forplasma exchange 3 decades ago, it was commonpractice to replace plasma removed with stored allo-geneic plasma. Unfortunately, this early use of plas-ma led to unacceptable rates of viral contamination(particularly hepatitis) and citrate toxicity. As largeamounts of plasma protein were being removed, itseemed reasonable to replace the removed humanplasma protein with human-derived plasma protein inthe form of 5% albumin (which is �96% pure albu-min) or plasma protein fraction (�83% pure albu-min). These replacement solutions largely resolved theproblems of disease transmission and citrate toxicity.Subsequently, the introduction of partial saline re-placement was integrated into many program’s re-placement regimens [13,14]. In recent years, marketrecalls (due to Creutzfeld-Jacob disease or bacterialcontamination) decreasing availability, rising costs,recognition of drug interactions with albumin (i.e.,ACE inhibitors), and a fear of disease transmissionhave led several groups to the use of colloidal starches(hydroxethyl starches) as partial or full replacementfor plasma during plasma exchange [15–20]. Oneregimen currently in use includes 3%HES (6% hespan

diluted one to one with normal saline) at 110% re-placement for the initial replacement followed by afinal liter of replacement with 5% albumin at 100%replacement [19]. Alternatively, 10% pentastarch em-ployed for the first half of the colloid replacementfollowed by 5% albumin has also been a successfulreplacement strategy [20]. In some cases, 25% albu-min has been diluted to 5% albumin for use as re-placement. Hemolysis has occurred when hypotonicsolutions have been used as a diluent. Twenty-fivepercent albumin should be diluted with normal saline[21–23].

In specific clinical settings, patients may requirereplacement of a specific plasma protein (such asVWB metalloprotease in TTP) or clotting factors inpatients at increased risk for bleeding (e.g., Good-pasture’s syndrome with pulmonary hemorrhage). Insuch cases, plasma or modified plasma (such as sol-vent detergent treated plasma or cryo-reduced plasmasupernatant) may be indicated as full or partial re-placement. Alternatively, the use of albumin for thefirst half of the replacement followed by plasma hasalso been shown to be effective. The use of a combi-nation of albumin and plasma may be of particularadvantage in the case of limited supplies of ABO-compatible plasma such as with a group AB patient[24].

CONCLUSION

As one might hope, there is reason to the madness.Choices of plasma volume, frequency, and replace-ment solutions are based upon theoretical consider-ations, efficiencies, practical observations, risk andcost issues. What is standard today, may not bestandard tomorrow.

REFERENCES

1. McLeod BC, Sniecinski I, Ciavarella D, Owen H, Price TH,Randels MJ, Smith JW. Frequency of immediate adverse ef-

TABLE I. Representative Decreases and Recoveries of Clotting Factors Reported Following Plasma Exchange [6–10]*

Decrease from baseline24 hours after plasma

exchange48–96 hours afterplasma exchange

V 50–71 RTB RTBVII 69–82 62 RTBVIII 50–82 62% of baseline, RTB RTBIX 26–55 RTB RTBX 67–84 RTB RTBXI 50–66 RTBXII 66 RTBAntithrombin III 58–84 70% of baseline, RTB 82% of baseline, RTBFibrinogen 50–78.3 60 63% of baseline, RTB

*RTB = return to baseline.

TABLE II. Representative Decreases and Recoveries of Platelets

Reported Following Plasma Exchange

Plasmavolume % decrease

Post 24/48 hourspercent of normal References

1.2 33 [8]50.1 85/100 [10]

1.6 52.6 [7]1.3–2.1 30 [1]2 14.2 [11]1.59 33 70/ [9]1 9.4 [12]

210 Brecher

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3. Bourke DL, Smith TC. Estimating allowable hemodilution.Anesthesiology 1974;41:609–612.

4. Brecher ME, editor. AABB Technical Manual. Bethesda, MD:American Association of Blood Banks, 14th edition, 2002.

5. Dau PC. Plasmapheresis5 therapy in myasthenia gravis. MuscleNerve 1980;3:468–482.

6. Chirnside A, Uraniak SJ, Powse CV, Keller AJ. Coagulationabnormalties following intensive plasma exchangeon the cellseparator, II: Effects on factors I, II, V, VII, VIII, IX, X andantithrombin III. Br J Haematol 1981;48:627–634.

7. Sultan Y, Bussel A, Maisonneuve P, et al. Potential danger ofthrombosis after plasma exchange in the treatment of patientswith immune disease. Transfusion 1979;19:588–93

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16. Brecher ME, Owen HG. Washout kinetics of colloidal starchas a partial or full replacement for plasma exchange. J ClinApheresis 1996;11:123–126.

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19. Owen HG, Brecher ME, Howard JF, Bandarenko N. Mini-mizing hypovolemic reactions with 3% hetastarch replacementduring therapeutic plasma exchange. J Clin Apheresis 14:91(abstr).

20. Gross AG, Weinstein R. Pentastarch as partial replacementfluid for therapeutic plasma exchange: Effect on plasma pro-teins, adverse events during treatment, and serum ionizedcalcium. J Clin Apheresis 1999;14:114–121

21. Steinmuller DR. A dangerous error in the dilution of 25 per-cent albumin. N Engl J Med 1998;338:1226–1227 (letter).

22. Pierce LR, Gaines A, Varricchio F, Epstein J. Hemolysis andrenal failure associated with the inappropriate use of sterilewater to dilute human albumin 25%. N Engl J Med 1998;338:1226–1227

23. Pierce LR, Gaines A, Finlayson JS, Varricchio F, Epstein JS.Hemolysis and acute renal failure due to the administration ofalbumin diluted in sterile water [letter]. Transfusion. 1999;39:110–111.

24. Bandarenko N, Brecher ME. United States thromboticthrombocytopenic purpura apheresis study group (US TTPASG): Multicenter survey and retrospective analysis of currentefficacy of therapeutic plasma exchange. J Clin Apheresis1998;13:133–141.

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