sign in sign up
<<
Home , Blood bank, Blood type, Packed red blood cells, Plasmapheresis, Whole blood

Safety and Long-term Effects of

M. A. COHEN AND H. A. OHERMAN

From the Depnrttiient of , Uniuer.\ity of Michigan, Ann Arbor, Michigan

No consistent clinical or laboratory value ab- possible harmful effects which might be normalities were found during more than six induced by long-term intensive plasma- years of plaamapheresis of donors who gave as much aa the plasma equivalent of four units pheresis. This report presents data ac- of whole per week. Potential hazards to cumulated during the collection of more the plasmapheresis donor, including than 14,000 units of plasma by plasma- depletion, depletion, iron depletion, and misidentification of blood returned to the donor plieresis, during six years, from a relatively are discussed. In addition to affording an economic small group of donors in the of and efficient opportunity to expand component the University of Michigan Medical Center. therapy, repeated plasmapheresis of a small pool of preselected donors can provide a better quality Certain considerations germane to the product than that obtained from random donors. operation of a plasmapheresis program in a hospital blood bank also are discussed. INCREASEDdemand for plasma and plasma constituents in this country in Materials and Methods recent years largely has been met by plasmapheresis. Although first introduced Donors who participate in this program must fulfill the basic requirements established by in 1914,’ and the subject of limited ex- the American Association of Blood Banks for perimentation during World War II3 and all blood donors. They are predominantly in the early 1950’s,4 the technic was not medical or dental students, junior house staff, widely used until the advent of disposable or paramedical personnel. All donors are men with large and accessible antecubital closed plastic bag systems. veins. Informed consent is obtained from all Plasmapheresis (a+alpmrP, withdrawal) is donors. Entrance to the program is contingent employed commercially to obtain plasma upon donation of five units of , and plasma fractions, hyperimmune or six units of plasma, followed by a six-month plasma, and antihemophilic factors. With- waiting period to ascertain whether the pros- pective donor niay transmit hepatitis. Tests in a hospital, the technic is useful for lor irregular to red blood cells supplying , white blood cells, and must be negative. donors understand plasma factors, and also as a that they may be called to donate any time of mode of therapy for Waldenstrom’s macro- day or night. Plasmapheresis is performed on an appoint- globulinemia,7~16 congestive heart failure, iiient basis. Donors with similar names are and acute hepatic failure.11 not scheduled to donate at the same time. Previous reports have indicated the The methods used in our blood bank for safety of plasmapheresis for the donor, and preparation of platelet-rich plasma, platelet these have contributed to the exploitation Concentrate, or XHG- have heen described elsewhere.13 When double of the tec1inic.s-6- 1’. 1.1, 15 Nevertheless, plasmapheresis is performed, the first unit of many persons have reservations concerning must be returned to the donor before the second unit of whole I’resentcd in part at the 1969 Annual Meeting 1)lood is collected. Approximately 60 to 75 of the American Society of Clinical Pathologists, minutes are required for removal of two units September 17, 1969, , Ill. Received for publication December 16. 1969; ac- of plasma. The procedure may be repeated cepted January 26. 1970. after 72 hours, so that the maximum rate of 58 Transfusion Volume 10 Mar.-Apr. 1970 Number 2 Volume 10 PLASMAPHERESIS Number 2 59

Donor: B.M. ( PLATELET I

6.5 6.0

Donor: L.A. (PLATELET I 6.5 6.0 FIG. 1. Fluctuation of total protein levels LII1111 in four donors during early months of intensive Donor: W.B. (CRYO-PPT) plasmapheresis. Values plotted represent monthly averages. 6.5 6.0

Donor: R B (CRYO- PPT) :::EL :::EL 6.0 @u Months plasma removed is the plasma equivalent to Studies performed on all donors in this that in four units of whole blood per week. study consisted of a donor history, total serum During the platelet-rich protein level (automated biuret method), plasma may be centrifuged a second time to , and repeated tests for prepare platelet concentrate, and the platelet- and development of irregular erythrocyte anti- poor plasma then may be used to resuspend bodies with every plasma donation. In addi- the packed red blood cells before they are tion, at the initial donation and at every 20th returned to the donor. However, we find it double-plasmapheresis donation the following efficient and economical for the blood bank to laboratory tests were performed: serum pro- retain the unit of platelet-poor plasma for tein electrophoresis (cellulose acetate strips treatment of patients with hemophilia B or in barbital buffer, pH 8.6), serum iron and for volume expansion. iron-binding capacity (sulfonated bathophen- All donors in the cryoprecipitate program anthroline method), serum glutamic pyruvic are type AB and lack atypical antibodies, there- transaminase (diazonium salt method), leuko- by obviating the need for a minor cross-match cyte count with differential, platelet count either for this product or the residual super- (hemocytometer), total serum bilirubin, serum natant plasma. In addition, these donors must have and maintain Factor VIII activity in hemoglobin (benzidene method), and serum excess of 100 per cent as determined by the cholesterol level (p-toluene sulfonic acid prothrombin activation rate. Factor VIII cqo- method). Quantitative immunoglobulins by precipitate donors are expected to be available radial diffusion and serum protein immuno- for at least one year after entering the pro- electrophoresis on agar-gel coated glass micro- gram. The by-product from this procedure, scope slides were performed every 60th AHG-poor type AB plasma is a safe and donation. The VDRL test for was versatile product.9 performed at least once a month. COHEN AND OBERMAN Transfusion 60 Mar.-Apr. 1970

Results One donor (H. B.), early in 1963, gave 250 units of plasma in a ten-month period, during Since the plasmapheresis program for Factor which time his average total serum protein VIII cryoprecipitate was initiated in 1963, level was 5.8 g per 100 ml. When donations more than 5,200 units of plasma have been were restricted to four units per week, his collected. Eleven donors provided 4,500 of total serum protein level rose to an average these units; moreover, four donors accounted of 6.5 g per 100 ml, and this level was main- for 2,550 of the units. The maximum dona- tained with but minor brief deviations for tion by one subject (B. B.) was 931 units over almost four years of plasmapheresis. four years. Although in 1963 several donors Whereas monthly averages of total serum gave at rates up to 21 units per month, from protein levels, as demonstrated in Fig. 1, 1964 to the present time the maximum rate illustrate the usual response to plasmapheresis, of donation has been held to four units (two determinations performed at each donation double-plasmapheresis procedures) per week. (Table 1) indicate the inability of some donors With the exception of infrequent brief “rests,” to maintain serum protein levels greater than all donors on this program have given at this 6.0 g per 100 ml without decreasing the rate for the duration of their participation. frequency of donation. The use of plasmapheresis as a source of Although peaks found by serum protein platelets was instituted at the University of electrophoresis cannot be used to evaluate Michigan Medical Center in 1965. More than accurately, all donors but one have 8,600 units have been collected which account had normal serum protein separations. Per- for 90 per cent of the platelets provided by centages of y-globulin tended to be in the the blood bank to the clinical services during low range of normal for donors giving at the this time. Although almost 170 donors have rate of four units of plasma each week (Table participated in the platelet plasmapheresis 2). One donor (J. W.) gave almost 100 units program, 15 donors have provided more than of plasma in six months, at which time his 2,300 units. The maximum donation by one average total serum protein level fell to 5.8 g subject in this program is 220 units in 2.5 per 100 ml and the y-globulin to 5.3 per cent years. The maximum rate of donation (four (300 mg per 100 ml). IgM and IgG levels units per week) for the major duration of their were also low at that time. These values participation in the program has been main- remained depressed during three additional tained by six donors. months of plasmapheresis at the same rate, Serum Proteins and did not return to normal until after three Eighty-five per cent of donors manifested additional months of less frequent donation. a decrease in total serum protein level of from Since that time his protein levels have been 0.5 to 1.5 g per 100 ml within one to three stable and he has provided more than 400 months after beginning plasmapheresis at the units of plasma (Fig. 2). rate of four units per week (Fig. 1). Three do- For all other donors, serum protein im- nors, giving at this rate, did not exhibit this munoelectrophoresis and immunoglobulin as says have revealed no consistent abnormalities decline until up to seven months (or after do- nating 60 units) had elapsed. Seventy per cent of resulting from plasmapheresis. Transferrin donors manifested this same decline within and ceruloplasmin arcs were present in every one to two months after resuming plasma- case. Quantitative inimunogloliulin data are pheresis following a rest period of from one presented in Table 3. to three months. Eight donors exhibited a Hematologic Findings spontaneous rise in their total serum protein Fluctuations in the of donors to somewhat higher levels after the initial have not been observed. Leukocyte counts, fall, but no donor’s total serum protein level differentials, and platelet couiits have remained was as high as his preplasmapheresis level while donating at the rate of four units per normal for all donors, regardless of the intensity or duration of plasmapheresis (Fig. 3). week. Four of five donors who had donated at a submaximal rate for one or more months Similarly, leukocyte differential counts have at the beginning of their program, manifested been normal. a decline in total serum proteins of the same Serum hemoglobin levels have ranged from magnitude, and in the same time, as those who less than one to 49 mg per 100 ml, with an donated at the rate of four units per week average of 7.5 mg per 100 ml for 100 determi- from the outset. nations on 16 random donors. This slightly Volume 10 PLASMAPHERESIS Number 2 61

TARLE 1. Va'nr-iationof Serial Total Serum Protein Levels in Four Plasma+?resis Donors

Units TSP Units TSP Date Donated @/lo0 ml) Date Donated (g/lOOml)

Donor S.W. 7/15/67 20 6.5 Donor R.B. 6/4/68 80 7.5 7/18 22 5.9 6/5 82 4.3 1/20 24 4.1 6/10 84 5.8 811 26 6.0 6/12 86 5 .O 813 28 5.8 7/29 88 6.9 818 30 6.6 8/14 96 6.5 81 19 98 5.8 8/21 100 5.4 8/26 102 6.1 Donor J.H. 1 1125 166 74 6.1 Donor J.W. 1112/66 90 6.4 11/28 76 5.7 11/4 92 5.4 121 1 78 5.6 1119 94 62 1215 80 6.3 11/11 96 5.5 1217 82 5.5 11/15 98 59 12/12 84 4.7 11/17 100 5.2 12/16 86 5.1 11/22 102 6.0 12/20 88 6.2 11129 104 6.3 12/27 90 6.2

elevated level is due presumably to hemoglobin plasma were obtained in a nine-month period, released from red blood cells damaged during during which time his SGPT consistently re- the process. mained in the upper range of normal for our Levels of serum iron less than 50 mg per laboratory. Although all other -function 100 ml were observed in three of the donors tests were normal, the donor was dropped who gave plasma regularly at the rate of four from the program because' a barely palpable units per week. However, in the absence of spleen was noted on physical examination. therapy or modification of frequency of During the subsequent two years he has been donation, normal values subsequently were in excellent health, and his spleen is no obtained in these men. Serum iron-binding longer palpable. capacities consistently were normal. No at- Repeatedly elevated totaI serum bilirubin tempt to evaluate tissue stores of iron has been levels, 1.2 to 2.5 mg per 100 ml, have been made. No donor has been given therapeutic noted in three donors, none of whom has iron, or advised to take iron. given plasma at the maximal rate. The sulfo- bromophthalein, SGPT, and alkaline phos Liuer Function Tests phatase levels have been normal in these Greater than normal values of serum glu- subjects. Nevertheless, two subjects were tamic pyruvic transaminase were encountered dropped from the program and a third was in only one donor. That donor (B.B.) was permitted to resume plasmapheresis only after hospitalized, after providing 781 units of plasma, an eight-month rest, after which time his total for treatment of a peptic ulcer. At that time serum bilirubin was 0.4 mg per 100 ml. his SGPT rose to 45 units and his highest One donor, giving at the rate of four units SGOT was 60 units. Sulfobromophthalein per week, consistently has had low-normal retention, alkaline phosphatase, bilirubin, and levels of serum cholesterol, ranging between prothrombin levels were normal in this donor. 140 and 150 mg per 100 ml. Elevated levels Plasmapheresis was resumed after a three- of cholesterol have not been observed in any month rest and an additional 150 units of of the donors. COHEN AND OBERMAN Transfusion Mar.-Apr. 1970

Additional Data per day; losses in excess of this amount were Factor VIII levels have remained at above- reflected in depression of total serum pro- normal levels in all of the Factor VIII cryo- teins to levels approximating 5.0 g per precipitate plasrnapheresis donors. Direct questioning reveals no loss of exercise toler- 100 ml. Recovery from such depletion may ance, appetite, or sexual libido, and no in- take from two to four weeks for albumin creased incidence of or minor and total protein levels, but from one to respiratory illness in these donors. Some donors three months for 7-globulin. noted slight weight gain. With the exception These data suggest that the liver is cap of donor B. B., cited above, none has devel- oped enlargement of liver, spleen, or lymph able of responding to plasmapheresis by nodes. a fivefold increase in synthesis of albumin and other hepatic plasma proteins, but Discussion that the longer recovery for 7-globulin is Inasmuch as all but approximately 2 ml dependent upon decreased catabolism. The of the erythrocyte mass removed from each persistence of transferrin and ceruloplasmin donor is returned, and consistent abnor- arcs, noted in tmhis study, as well as the ob- malities in serum iron and hematocrit levels servation by Meling that the prothrombin have not been observed, the physiologic complex and haptoglobin, also of hepatic limiting factor in plasmapheresis is the origin, remain at normal levels further capacity of the donor to restore his plasma indicate the resistance to protein depletion proteins. The normal adult male at the rate of plasma withdrawal used in replaces approximately 10 g of plasma these donors. albumin, and 2 g of plasma 7-globulin When less than two liters of plasma are per day.10 Gamma-globulin, approximately removed per week by plasmapheresis, sig- half of the P-globulins, and a small frac- nificant depression of total serum proteins tion of the a-globulins arise in lymphoid was not observed by Kliman et aZ.6 This tissue; all other plasma proteins are of generally is in accord with our findings. hepatic origin.10- 17 Although total serum protein levels in Reversible depletion of plasma proteins our donors fell to a slightly subnormal is seen in the childhood nephrotic syndrome range for a short time, especially during in which remission of the results in the first six months of donation, for the corresponding elevation of plasma proteins ensuing period of long-term plasmapheresis and replenishment of wasted tissue. Similar total serum protein and y-globulin was findings are seen with intensive plasma- maintained at low-normal ranges. Never- pheresis in the dog and in man.6- 18 theless, individual variation in response to Andersen and Rossing2 observed an in- plasmapheresis, even at the rate of four creased rate of synthesis and decreased rate units of plasma per week, is evident in the of catabolism of albumin in one human data presented. Some donors could not subject undergoing intense plasmapheresis maintain normal levels of serum proteins (30 units of plasma in one month). In at that rate, and required a longer interval this subject there was a shift of albumin between donations. For this reason, sub- from the interstitial to the vascular com- jects undergoing a program of plasma- partment, a decreased rate of y-globulin pheresis should be monitored frequently catabolism, but no increased rate of syn- by determining levels of total serum pro- thesis of y-globulin. During intensive tein and protein fractions seen on plasmapheresis (five liters of plasma in five elec troplioresis. days in five human donors), Kliman ct a1.G Although plasmapheresis at the rate of noted that up to 49 g protein was replaced four units per week usually does not result TABLE2. Variation of Sei-uiii Proteins in Plasmabheresis Donors z<

No. Units Donor D.M. Donor J. 1%'. Donor R.B. Donor J.H. Donor T.S. Donor R.T. $2 Drawn TSP Alb G.G. TSP Alb G.G. TSP Alb G.G. TSP Alb G.G. TSP Alb G.G. TSP Alb G.G. "Z

0 5.1 64 13 6.5 65 11 5.1 63 13 6.i 61 14 6.8 63 11 6.6 54 20 100 6.3 69 11 5.8 69 6.4 6.5 62 16 6.1 66 11 6.3 67 9.1 6.4 58 9.0 200 6.2 55 15 6.3 62 8.6 6.6 56 17 6.5 60 12 6.5 6i 8.3 6.4 55 I3 300 6.5 64 12 6.5 62 11 6.6 62 16 6.3 56 13 6.6 61 12 6.2 52 19 400 6.3 61 16 6.2 G3 8.0 6.5 66 12 500 6.7 61 9.2 6.1 58 11 600 6.5 58 14 700 6.7 57 13

TSP-Total serum protein (grams per 100 ml) . Alb-Albumin (per cent protein by electrophoresis). G.G.-Gamma-globulin (per cent protein by electrophoresis)

TABI.C3. Eflect of Phinapheresis on Iinniunoglobulins E

No. Donations mE Donor Fraction 0 50 100 200 300 400 500 600 100 800 900

~ ~ 197 122 223 98 89 115 588 665 945 210 190 118 165 46 iO9 42 55 800 100 555 580 1i0 li3 120 240 5.i 55 57 95 870 850 697 1,260 260 197 173 265 67 55 1,100 950 R50 m Values expressed in mg per 100 ml. w COHEN AND OBERMAN Transfusion Mar.-Apr. 1970

Donor. J.W. [CRYO- PPTj

1

a:vj 6.06.5 t q.'dx-j Lllllllllllll'llllll1 5/66 7 9 II 1/67 3 5 7 9 II 1/68 3 5 I 9 II 1/69 3 5 7 9 Months I I 1 I I 0 I00 200 300 400 500 Units of Plasma FIG.2. Monthly determinations of serum glutamic pyruvic transaminasc: leukocyte count, total serum protcin. per cent albumin and 7-globulin by scrum protcin clcctroplioresis in a donor during 40 months of plasmapheresis.

in protein depletion, a 48-hour interval blood donor who is limited to five dona- between donations of the plasma equivalent tions a year. It is for this reason that great to two units of blood is the minimal time care must be exercised in selecting donors necessary for the restoration of plasma for plasmapheresis programs. Use of a volume; we prefer to allow at least 72 small group of prescreened donors thus hours. Whether performed for cryoprecipi- provides the greatest safety possible to the tate or platelets, plasmapheresis did not recipient of these blood products. lower the leukocyte count or platelet count Although the safety of plasmaplieresis of donors. for the donor is apparent, many risks are Because a plasmapheresis donor may do- involved, some recognized, others, perhaps, nate more than 200 units of plasma a year, not yet known. For this reason informed his potential for transmitting hepatitis is consent from the donor, obtained by a 40 times greater than that of the whole- physician, is mandatory. An individual Volurlle 10 PLASMAPHEKESJS Number 2 65 about to enter the program should be in unexplained hypertransaminasemia is pre- excellent healtli and have normal baseline sumptive evidence of hepatitis, necessitating laboratory values. exclusion of the donor from the program. A protocol of laboratory studies for fol- Considerable loss of blood volume and lowings these donors must be maintained. liemoglobin results from removal of two Moreover, a thorough donor history must units of blood during double plasma- be reviewed at each visit. On the basis of pheresis if, for technical reasons, the two our experience, donors now providing units of red blood cells cannot be returned plasma at the rate of four units per week to the donors. Therefore we require that are followed minimally with total serum the second unit of blood be drawn only protein and hematocrit values and screen- after the first unit of packed red blood ing for unexpected at each do- cells has been rein fused successfully. nation, and bimonthly serologic test for Similarly, blood taken from the donor for sypliilis and serum protein electrophoresis, laboratory studies may amount to as much serum glutamic pyruvic transaminase as 1,500 ml per year. If, in addition, the (SGPT) or the result of other tests for donor is permitted to donate five units of hepatitis detection, and leukocyte counts, whole blood per year, up to 2.0 g iron may leukocyte differentials, and platelet counts. be lost. Despite enhanced absorption of If abnormal results are found, the patient dietary iron, iron loss at this rate results is referred to an appropriate physician and in depleted iron stores. Conservative corroborative tests are ordered. Otherwise, withdrawal of blood for laboratory studies,

I S. K. mO0" 3x 1 I I I I I I 0 I 2 3 4 5 6 Months 111'111111111111111111111 0 8 16 24 32 40 48 56 64 72 00 88 96 Units of Plasma FIG.3. Platelet and leukocyte counts in two donors during their initial six nionths of plasmapheresis. COHEN AND OBERMAN Transfusion 66 Mar.-Apr. 1970 restriction of the donor pool to men, and 6. , P. P. Carbone, L. A. Gaydos. and permitting whole- on a E. J. Freireich: Effects of intensive plasma- pheresis on normal blood donors. Blood 23: submaximal schedule prevents depletion of 647, 1964. tissue iron stores. 7. Lawson. N. S., J. S. Nosanchuk, H. A. Ober- The greatest risk to the plasmapheresis man, and M. C. Meyers: Therapeutic plasma- pheresis in treatment of patients with Wal- donor is receiving the packed red blood denstrom’s macroglobulinemia. Transfusion cells of another donor. Despite this minimal 8: 174, 1968. risk to our type AB donors, they are acutely 8. Melin. M.: Conference on Plasmapheresis, 20th aware of the problem and actively join the Scientific Meeting of Protein Foundation, Inc., Boston, Mass., April 7, 1966, pp. 78-79. technologist in proper identification of each 9. Oberman, H. A., and J. A. Penner: Utilization bag. Only technologists or nurses who of the residual plasma following preparation appreciate the seriousness of this step of Factor VIII cryoprecipitate. JAMA 205: should be permitted to function in any 819. 1968. plasmapheresis program. Undue levity and 10. Peters, T.: The Biosynthesis of Serum Pro- teins. In Serum Proteins and the Dysprotein- distraction in the donor room, especially emias, F. W.Sunderman and F. W. Sunder- among donors and technologists who are man Jr.. eds. Philadelphia, J. B. Lippincott familiar through repeated visits, must not Co., 1964, p. 9. 11. Sabin. S., and J. A. Merritt: Treatment of be permitted. Plasmapheresis donors are hepatic coma in cirrhosis by plasmapheresis also susceptible to other reactions uniquely and plasma infusion (plasma exchange). associated with the procedure, such as Ann. Intern. Med. 68: 1, 1968. -induced diuresis and syncope due 12. Simson, L. R.. D. M. Lien, C. L. Warner, and H. A. Oberman: The long-term effects of to rapid emptying of a distended urinary repeated plasmapheresis. Amer. J. Clin. bladder. Because of these dangers, a phy- Path. 45:367, 1966. sician must be available on the premises. 13. , D. M. Lien, and H. A. Oberman: Moreover, in therapeutic plasmapheresis Plasmapheresis: an innovation in procure- ment of blood components. Mich. Med. 65: in which sick patients are the “donors,” it 111, 1966. is especially important that a physician be 14. Smolens, I., J. Stokes, Jr., and A. B. Vogt: present in the donor room during the Humanplaimapheresis- and its effect on anti- procedure. bodies. J. lmmun. 79: 434, 1957. 5. -, J.Stokes, Jr., E. McGee, and V. Hunter: Feasibility and safety of frequent plasma- References pheresis of the same human donors. Proc. SOC. Exp. Biol. Med. 91:611, 1956. 1. Abel, ,J. J., L. G. Rowntree, and B. B. Turner: 6. Solomon, A,, and J. L. Fahey: Plasmapheresis Plasma removal with return of corpuscles therapy in macroglobulinemia. Ann. Intern. (plasmapheresis) , J. Pharmacol. Exp. Ther. Med. 58: 789, 1963. 5:625, 1914. 7. Wcissman. S. M.. R. D. Wochner, F. X. Mullins, 2. Andenen, S. B., and N. Rossing: Metabolism A. Wyngate, and T. A. Waldman: Synthesis of slbumin and gamma globulin during al- of plasma proteins by hepatectomized dogs. bumin infusions and during plasmapheresis. Amer. J. Phyriol. 210: 128, 1966. Scand. J. Clin. Lab. Invest. 20 183, 1967. B. IVhipple, G. H.: Protein production and ex- 3. Co Tui, F. C., F. C. Bartter, A. M. Wright, change in the body including hemoglobin, and R. B. Holt: Red re-infusion and the plasma protein and cell protein. Amer. J. frequency of plasma donations: preliminary Med. Sci. 196:609, 1938. report of multiple donations in eight weeks by each of six donors. JAMA 124: 331, 1944. Merrill A. Cohen, M.D., Resident IV, Department 4. -Lucas. J. A.: Use of plasmapheresis in of Pathology. blood donors. Brit. Med. J. 1: 854, 1952. Harold A. Oberman, M.D., Professor, Department 5. Kliman, A., and P. J. Schwab: Plasmapheresis of Pathology, and Medical Director, Blood Bank, with simple equipment. Amer. J. Clin. Path. University of Michigan Medical Center, 1335 East 36: 379, 1961. Catherine Strcet, Ann Arbor, Michigan 48104.