Transfusion of patients undergoing bone marrow transplantation

Transfusion of Patients Undergoing Bone Marrow Transplantation PHYLLIS I. WARKENTIN, MD Bone marrow transplant recipients require intensive transfusion support preceding the marrow infusion, because o f their underlying disease or the chemotherapeutic agents administered, and for 14 days or more post-transplantation until engraftment has occurred and marrow function has returned. Red blood ceils, plasma, and platelets are the usual c o m p o n e n t s transfused; granulocyte concentrates are occasionally required. Marrow transplantation across ABO and Rh barriers is performed routinely and requires careful, knowledgeable attention to the blood group of components chosen throughout the transplantation process to ensure effective transfusion support. This paper is a rev i e w o f the g e n e r a l p r i n c i p l e s g o v e r n i n g pre- and posttransplantation transfusion support, potential indications for the transfusion of various blood components in the marrow transplant setting, and the recommended blood groups o f these comp o n e n t s w h e n A B O i n c o m p a t i b i l i t i e s exist. H u m Pathol 14:261-266, 1983.

Bone marrow transplantation is the treatment of choice for patients with s e v e r e c o m b i n e d immunodeficiency I and severe aplastic anemia, z and is increasingly successful in the t h e r a p y o f acute leukemia, ~'~ other hematologic malignancies) nonmalignant stem cell defects, 6 and various hereditary metabolic disorders. 7'8 The prospect for the future is f u r t h e r e x t e n s i o n to many o t h e r d i s o r d e r s o f marrow-derived cells. Most bone marrow donors have been siblings identical to the recipient for the antigens of the major histocompatibility loci HLA-A and -B and HLA-D as determined by the mixed lymphocyte culture, because of the major role o f such identity in determining transplant outcome. A few successful transplantations involving partially matched, related donors 'J or unrelated donors ~~ have stimulated interest in expansion o f the marrow transplantation . potential) z Marrow transplant recipients are usually treated immediately prior to transplantation with chemotherapy, with or without radiation therapy, to 1) immunosuppress the host to prevent graft rejection, 2) create space within the hematopoietic microenvironment to permit transplanted stem cells to repopulate, and 3) eradicate residual host malignant cells. The precise preparative regimen depends on the recipient's underlying disease and the degree of histocompatibility between d o n o r and recipient. Optimal transfusion support also varies with the underlying disease, the preparative regimen, and the patient's Received from the D~partments of Laboratory Medicine and Pathology and Pediatrics, University of Minnesota, Minneapolis, Minnesota. Address correspondence and reprint requests to Dr. Warkentin: Blood Services, Northern Ohio Region, American Red Cross, 3950 Chester Ave, Cleveland, OH 44114.

stage in the transplantation process. The transfusion guidelines described here have been derived from animal experimentation, clinical experience and judgment, and empirical use. PRETRANSPLANTATION TRANSFUSION THERAPY

Severe Aplastic Anemia Sensitization to HLA or non-HLA antigens.via blood transfusion is an important factor determining the transplant outcome of patients with severe aplastic anemia. Various factors account for the likelihood of sensitization following blood, transfusion: 1) Most patients with aplastic anemia are immunologically competent. 2) Repeated and prolonged exposure to blood products is usual since autologous marrow recovery is unlikely. 3) The pretransplantation chemotherapeutic regimen is usually less intensive than that utilized in patients with malignancy. Since its purpose is only immunosuppression, not eradication of a malignant cell population, less intensive regimens are used to minimize acute toxicity and the potentially increased risk of malignancy following radiation therapy. 13 T h e d e l e t e r i o u s effect o f n u m e r o u s b l o o d transfnsions on marrow transplantation outcome can be observed in animal experimentation and in clinical transplantation. The canine model, in which marrow transplantation is performed between DLA-identical littermates, has been used extensively. ~4-~z Pertinent results and conclusions include the following: 1) Successful engraftment of littermate bone marrow occurs in 98.3 per cent of untransfused animals. 2) Among dogs given one or three pretransplantation whole blood transfusions from their marrow donors, 82 to 100 per cent subsequently rejected their marrow grafts. This suggests that cells in transfused blood express the antigens responsible for sensitization and graft rejection. 3) The 100 per cent graft rejection rate can be significantly decreased by transfusing leukocyte-poor platelets (leukocyte count less than 106/platelet concentrate; rejection, 47 per cent; leukocyte-poor red cells (leukocyte count less tlmn 10Vred cell unit; rejection, 36 p e r cent); ~~ o r granulocytes free of mononuclear cells 2~ rather than whole blood. Thus, antigens responsible for sensitization are absent from platelets, mature red cells, and mature granulocytes, but are present on mononuclear cells (monocytes and macrophages). 4) When unrelated dogs were utilized as donors for pretransplantation whole blood transfusions, 30 per cent of muhiply-transfused dogs subsequently rejected their littermate marrow graft, suggesting that tim risk of 261

HUMAN PATHOLOGY

Volume t4, No. 3 (March '1983)

sensitization also increases with increasing numbers of transfllsions from unrelated donors. Initial experience in human marrow transplantation in muhiply-transfused patients with severe aplastic anexnia who had received HLA-identical sibling bone marrow was consistent with that observed in the canine model. Graft rejection occurred in 25 to 60 per cent of cases, was frequently fatal, and was the most significant cause of transplantation failure? 8-2~ A strong correlation exists between rejection and a positive relative response index in mixed lymphocyte culture, ~9 presumably reflecting transfusion-induced sensitization of the recipient to minor histocompatibility antigens of the donor. In subsequent studies, graft rejection was decreased and post-transplantation survival increased when patients with aplastic anemia were transplanted prior to transfusion-induced sensitization. 2~ O f 30 patients not transfused until inunediately prior to pretransplantation chemotherapy, 90 per cent demonstrated sustained engraftment, and their actuarial long-term survival was 75 per cent, compared with a concurrent series of 81 multiply-transfused marrow recipients among whom only 65 per cent sustained engraftment and whose actuarial survival was 48 per cent. Some transplantation centers have utilized more intensive preparative regimens such as total lymphoid irradiation 22 to successfnlly overcome transfusioninduced sensitization, reduce rejection, and improve survival. The following management is recommended for newly diagnosed patients with severe aplastic anemia: 1) Early bone marrow transplantation shoukl be anticipated and a search for a suitable donor begun. 2) Pretransplantation transfilsions should be utilized only for an urgent medical necessity. 3) Pretransplantation transfusion from any family m e m b e r should be avoided. 4) Prior to the transplantation preparative regimen, red blood cells should be given as frozen-deglycerolized or washed cells or, in an emergency, leukocyte-poor cells, to minimize the risk of sensitization. 5) Prophylactic platelet transfilsions are generally recommended to maintain the peripheral blood platelet count greater than 20,000/mm3. 23 6) T h e use o f single-donor platelets collected by apheresis techniques should be considered. Although unproven, this component may delay alloimmuniz a t i o n . 24,25

Malignant Disorders Most patients with hematologic malignancy who will undergo bone marrow transplantation have had multiple prior transfusions, which were required during initial induction chemotherapy. However, they are less likely than aplastjc anemia patients to be sensitized to histocompatibility antigens, since they were markedly immunosuppressed during the period of transfilsion support. For example, HLA antibodies were found in 27 per cent of 100 cancer patients who had received a mean of 72 units of platelets, compared with 88 per 262

cent of aplastic anemia patients who had received a mean of only 44 units. 2G Similarly, 7.8 per cent of Rh-negative patients receiving immunosuppressive therapy and Rh-positive platelet transfusions developed antibody to Rho(D), compared with 60 to 80 per cent of normal Rh-negative volunteers given a similar stimulusY Sensitization is also reduced in patients with malignant disease, because the transplantation preparative regimen is extremely intensive, owing to the need to eradicate residual malignant cells. The following are guidelines for pretransplantation transfusion therapy for patients with malignancy: 1) Pretransplantation transfnsion should not be restricted to minimize antigenic exposure; transfusion support should be based on individual clinical criteria. 2) Red blood cells and pooled random donor platelets may be transfi~sed; no special preparations are necessary. 3) Family members should not serve as pretransplantation blood component donors. POST-TRANSPLANTATION TRANSFUSION THERAPY The following general transfusion guidelines apply to the four-week or longer period of posttransplantation pancytopenia. Patients with aplastic anemia and patients with malignancy are managed similarly.

Irradiation Bone marrow transplant i'ecipients, like other severely immunodeficient or immunosuppressed patients, are at risk for developing graft-versus-host disease from viable lymphocytes present in transfused blood components. 28 No effective t r e a t m e n t for transfusion-related graft-versus-host disease has been found; however, prevention is possible by irradiating all blood components prior to transfi~sion. The radiation dosage required to suppress ailogeneic lymphocyte proliferation is controversial; dosages o f 1,500 to 5,000 rads have been used successfully to prevent lymphocyte blastogenesis without interrupting the normal function o f other cellular components in blood. 29 We utilize 3,000 rads for all blood components transfused to marrow transplant recipients. Irradiated blood products are required by marrow recipients during severe immunoincompetence. It is unknown precisely when a patient is sufficiently immunosuppressed to be at risk for graft-versus-host disease. Since transfused lymphocytes capable of in vitro response to phytohemagglutinin may circulate up to one week following transfusion, 3~ lymphocytes in pretransplantation transfusions could persist into the early post-transplantation period. Therefore, it is r e c o m m e n d e d that irradiated blood products be transfused beginning of the first day of the bone marrow transplantation preparative regimen (i.e., one to two weeks pretransplantation). This is also a convenient way to identify a specific time to begin irradiating the blood and components. Immunoin-

TRANSFUSIONIN BONEMARROWIRANSPLANTATION[Warkentin} TABLE 1. Blood Component Utilization in Fifty-three Allogeneic Bone Marrow Transplant Recipients Day of Last Transfusion Post-BMT

Number of Units (All Patients) Patients Transfused Red blood cells Fresh frozen plasma Cryoprecipitate Platelets (total)* Random donor units Apheresis units White blood cells

52 25 4 53 48 53 2

(98.1%) (47.2%) (07.5%) (100.0%) (90.6%) (100.0%) (03.8%)

Range 0-61 0-135 0 - 80 44-1843 0-1363 5-82 2-4

Mean

Median

Range

Median

12.2 8.0 2.1 252.0 80.0 21.5 0.11

9 0 0 144 21 15 0

0-+229 - l - + 123

+28

+ 17-+228

+31

+ 19; +29

* Total units o f platelets is the n u m b e r o f pooled random donor tmits plus apheresis units, assuming one apheresis unit equals eight random d o n o r units.

competence frequently persists six months or more post-transplantation? ~-33 Therefore, blood components should be irradiated t h r o u g h o u t the first post-transplantation year, and longer for those patients with chronic graft-versus-host disease. Bone marrow aspirated for transplantation is unavoidably contaminated with peripheral blood of the donor, including blood transfused during the marrow harvest. Any nonautologous blood component transfused to the marrow donor during donation should be irradiated, since a portion o f the transfused cells will ultimately be given with the marrow to the immunodeficient recipient. Blood Component Support

Blood components transferred to 53 consecutive allogeneic bone marrow transplant recipients at the University o f Minnesota during 1981 are summarized m table 1. The transplantation period was defined as two weeks pretransplantation until transfusions were no longer required. The 53 patients included nine with severe aplastic anemia, 31 with acute leukemia in remission, seven with chronic granulocytic leukemia in accelerated phase, two with neuroblastoma, and four with non-Hodgkin's lymphoma. Patients were 18 months to 41 years o f age (median, 11 years). Nineteen recipients had major ABOincompatible marrow donors (recipient antibody against donor red cells), and seven had minor ABOincompatible marrow donors (donor antibody against recipient red cells). Transplant recipients require red cell transfusion s u p p o r t until erythropoiesis by engrafted d o n o r marrow is adequate. Since recipients remain immunosuppressed immediately post-transplantation, alioimmunization is unlikely and ordinary red blood cells can be utilized to maintain hemoglobin levels around 10 to 12 g/dl.'Transfusion o f fresh frozen plasma is indicated in marrow transplant recipients, as in other patients, for coagulopathies. In addition, it is frequently part of the replacement fluid when plasma exchange is part of the transplantation preparation. In some cases (table 1) the pretransplantation plasma exchange (day - 1 ) is the only plasma required. Granulocyte concentrates may be transfused 263

to marrow transplant recipients during severe neut r o p e n i a for d o c u m e n t e d septicemia or severe localized infection unresponsive to appropriate antibiotic therapy. Granulocytes are most commonly obtained from donors who are ABO and Rh compatible with the intended recipient, because of their large volume of red blood cells. Only two o f the 53 patients (table 1) received granulocyte transfusions. Prophylactic granulocyte transfusions are not recommended during severe neutropenia. Although they significantly decrease the incidence of bacterial septicemia, overall survival is not improved. 34 This is presumably because of the effectiveness of newer antibiotics and the variety o f other potentially fatal complications that are not affected by prophylactic granulocytes (e.g., graft-versus-hos t disease and leukemic relapse). 3a In addition, two studies have shown a higher incidence of cytomegalovirus in recipients o f p r o p h y l a c t i c g r a n u l o c y t e s and, in seronegative recipients of seropositive granulocytes, higher mortality from cytomegalovirus pneumonitis? 5,36 Virtually all marrow transplant recipients require platelet transfusion (table l).3z The precise indications for platelet transfilsion and the donor source of this c o m p o n e n t vary a m o n g transplantation centers. Commonly, platelets are transfused prophylactically to maintain the platelet count greater than 20,000l mm 3. This practice is based on the known association between prolonged bleeding time and thrombocytopenia,3~ a few studies in which prophylactic transfusions have reportedly decreased the incidence of bleeding, 39 and anecdotal clinical experience. Random donors supply most of these platelets, whether pooled from single-unit whole blood donations or collected by plateletpheresisY Donations from family members, particularly the bone marrow donor, or from unrelated, HLA-matched donors may be required if refractoriness to platelet transfusion develops. It is apparent from table 1 that the magnitude of blood support in allogeneic transplantation is great and that the range in the number of components required per patient is extremely large. Individual patrent differences, especially in infection and alloimmunization, are probably the most important determinants of transfusion support requirement. 3~ This -.

HUMAN PATHOLOGY

BEGIN BMT PREPARATIVE REGIMEN

Volume 14, No. 3 [March t983]

ABO ANTIBODY TO DONOR TYPE UNDETECTABLE AND DAT NEGATIVE

BMT

RECIPIENT TYPE RED CELLS UNDETECTABLE

ABO MAJOR INCOMPATIBILITY Red Cells Plasma and Platelets ~ . . ABO MINOR INCOMPATIBILITY n

Red Cells Plasma and Platelets

"////////////~ "//'///,~

ABO MAJOR AND MINOR INCOMPATIBILITY Red Cells

,.....

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Plasma and P l a t e l e t s ~ FIGURE 1. Recommended blood groups for blood component transfusion, throughout the transplantation process, to recipients of ABO-incompatible bone marrow transplants. Granulocyte concentrates, when necessary, should b e of the same ABO group as recommended for red ceils because of the large volume of red cells present in white cell concentrates. When a patient requires both granulocytes and platelets, both may b e of the recommended red cell type to allow a single apheresis donor to provide both components. [Hatched areas = recipient type; back areas : donor type; stippled areas = group O; crosshatched areas = group AB.]

support, however, is required for a finite period. Approximately half of marrow recipients require blood component transfusion for less than one month (table 1).

S P E C I A L C O N S I D E R A T I O N S IN A B O - I N C O M P A T I B L E BONE MARROW TRANSPLANTATION

ABO incompatibility between bone marrow donor and recipient does not adversely affect transplant outcome, incidence of graft rejection, failure of engraftment, or the incidence or severity of graftversus-host disease? ~ This is expected from in vitro studies suggesting that ABH antigens are not present on hematopoietic stem cells, a~ However, the management of the infusion of incompatible marrow and the selection of the appropriate ABO group of components reqtfire careful consideration. ~IAJOR ABO INCOMI'ATIBILITY (Recipient has Antibody Directed Against Donor). Bone marrow harvested for transplantation contains approximately tile same red cell concentration as whole blood, and the volume transfllsed is at least 10 ml/kg of recipient body weight. Thus, the marrow inoculum contains a sufficient volume of mature red cells to initiate, in the presence of appropriate isoagglutinin, an immediate hemolytic transfusion reactiofi with the potential risks o f renal failure and d i s s e m i n a t e d intravascular coagulation. Three general methods have successfully minimized this risk: large volume plasma exchange of the recipient pretransplantation to remove antibody,4~ transfusion of incompatible, donor-type red 264

cells to absorb residual antibody prior to transplantation, a~'a2 and in vitro removal of red cells from the marrow prior to its transfusionW '4~'45 Blood components transfused near the time of transplantation should be of an ABO group compatible with both the recipient and the donor. Severe hemolysis has occurred occasionally following transfusion of incompatible cells. 4~ Figure 1 illustrates recommended blood groups for transfilsion throughout the transplantation procedure, regardless of the methods used to accomplish the marrow infusion. Plasma and plasma products (including platelets) should be of donor type once tile transplantation procedure has begun to minimize tbe amount of passively administered antibody directed against the red cells that are, or soon will be, produced by the engrafted marrow. The beginning of the preparative chemotherapy is a convenient time to begin this. Red cells, and components containing a large volume or red cells, should be of recipient original type until that time post-transplantation when there is no l o n g e r detectable antibody to donor-type red cells circulating in tile recipient's serum or on red cells (i.e., direct antiglobulin test negative). Red blood cell units, which contain only about 100 ml of plasma, are suitable for most recipients. In very small recipients, or in other patients in whom it is necessary to avoid transfusion of any antibody, frozen-thawed or washed red cells may be transfi~sed. MiNoR ABO INCOMPATIBILIT'," (Donor has antibody directed against recipient). The marrow inoculum also contains nearly the same proportion of d o n o r plasma as is present in whole blood. T h e

TRANSFUSION IN BONE MARROW TRANSPLANTATION (Warkentinj

alnottnt and type of antibody (IgG or IgM) varies, as it does among donors. If the donor isoagghttinin titer is ltigh or the volume of plasma to be transfused with the marrow is large relative to tile recipient's plasma vohtme, hemolysis of recipient red ceils is possible. Centrifugation of the marrow inoculnm prior to transfusion allows reduction of tim plasma vohime by greater than 70 per cent wlfile retaining more than 99 per cent of tlte original nucleated cells and more titan 95 pet- cent of CFU-C activity/~ The recommended ABO groups of blood components for transfusion to tltese patients are shown in figure 1. Significant morbidity, including hemolysis, occurred in a recipient transfused with a large volunte o f donor-type incompatible plasmaW T h e r e f o r e , plasma and platelets should be of the recipient's original type until recipient-type red cells are no longer detectable in the circulation. Red cells may be of donor type to decrease ttte time to disappearance of recipient-type red cells. Ordinary red blood cell units are appropriate for most recipients. COEXISTENCE OF MAJOR AND M I N O R A B e

3.

4. 5.

6. 7. 8.

9.

IN-

com>A'rJmi.rr~'. This relatively u n c o m m o n circumstance requires application o f the principles o f botlt major and minor incompatibility. If tim marrow recipient tmdergoes plasma exchange to remove antibody directed against donor red cells, the marrow inocuhim sbould also be centrifuged to remove donor antibody to recipient red cells. Marrow processing to remove red cells will also remove most of tim incompatible plasnm. To transfuse components compatible witli both donor and recipient, group O red cells are required until antibody to donor-type red cells is undetectable, and group AB plasma and platelets are reqnired nntil recipient-type red cells are nndetectable, t f t h e supply o f AB plasma products, particularly platelets, is limited, an alternative type compatible witlt tim majority o f red cells circulating in tire recipient at that time should be selected. RII-MISMATCnED TRANSPLANTATION. Tim effect o f Rh mismatch between d o n o r and recipient in marrow transplantation has not been studied extensively. At least one Rh-negative recipient with anti-D was successfully grafted with an Rli-positive inarrow/s Rh-positive recipients whose donors were Rhnegative may develop attti-D owing to transfusion of Rh-positive c o m p o n e n t s d u r i n g the early posttransplautation period; 4~ however, these antibodies probably do not affect the well-being of the patients. Potentially, such antibodies could be avoided by t r a n s f u s i n g only Rh-negative c o m p o n e n t s . Tim theoretical complication o f failure of red cell engraftment has never been reported.

10. I 1. 12.

13. 14. 15.

16.

17.

18.

19. 20. 21.

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23.

265

stud)" o f androgens and bonc InalToW lr, lll~lJlalllaliOil l l l l treatment of s0vere aplastic allenli,i. Blood 53:,'50t, 1979 Johnson FL, Whonlas El), Clark BS, el al: A colnp,iris, lll .I inarrow transplantation with chemotherapy for children with acute I)'mphoblastic lenkemia in second or sullsequenl remission. N Engl J Mcd 305:840, 1981 Thomas ED, Buckner CD, Clift RA, et al: Marrow Ir,nlsplanration for acute nonl)'mphoblastic leukemia in Ihst renlission. N E n g l J Mcd 301:579, 1979 Fefer A, Cheerer MA, Grcenberg PD, et al: Treatment of chronic granulocytic leukenaia with chemoradiolhcrap) +and transplanlalion n f nlarrow from identical twins. N Ellgl .I Med 505:63, I982 Ghlckman E, Devergie A, Schaison G, et al: Bone marrow transplantation in fanconl anaemia. B r J llaematol 45:557, 1980 Coccia I'F, Krivit W, CervenkaJ, et al: Successlul bone marrow transplantation for intantile malignant ostcopetrosis. N Eng[ J Med 302:701, 1980 Hobbs JR, Barrett AJ, Chambers D, et aS: Reversal of clinical features o f Hurler's disease and biochemical improvement after treatment b)' bone marrow transplantation. Lancet 2:709, 1981 Hansen JA, Clift RA, Mickclson EM, et al: Marrow transplantation from donors other th.in HI.A idenlical siblings, lluul h n n m n o l 1:31, 1981 O'Reilly RJ, Dupont B, Phawa S, et al: Rcconstitulion in severe combined imniunodeficiency by transplantalioti o f marrow from an unrelated donor. N Engl J.Med 297:1311, 1977 Hansen JA, Clift RA, Thomas El), et al: Transplantation of marrow from an unrelated d o n o r to a patient with acute leukenlia. N E n g l J Med 303:565, 1980 McCullough J, Bach FH, Coccia P, et al: Bone marrow transplantation from unrelated vohmteer donors: summary of a conference on scientific, ethical, legal, tinancial, and other practical issues. Transfiision 22:78, 1982 Deeg HJ, Storb R, Prentice R, et al: Increased cancer risk in canine radiation chimeras. Blood 55:233, 1980 Storb R, Epstein RB, Rudolph RIt, et al" T h e effect of prior transfusion on m a r r o w grafts between histocompatil)le canine sibliligs. J h n n l u n o l 105:627, 1970 Slorb R, Rudolph RH, Grahanl TC, et al: T h e inllnence of lransfuslon from unrelated donors upon marrow grafts b e t w e e n h i s t o c o m p a t i b l e c a n i n e siblings, j | m m u n o l 107:409, 1971 Storb R, Weiden PL, Deeg HJ, et al: Rejection of marrow lrom DLA-identical canine littermates given transfusions before grafting: antigens involved are expressed on leukocytes and skin epithelial cells but not on platelets and red blood cells. Blood 54:477, 1979 Deeg HJ, Torok-Storb B, Storb R, et al: Rejection of DI.Aidentical caniue l i n e r m a t e s m a r r o w a f t e r t r a n s f n s i o n induced sensitization: antigens invoh.ed are expressed on COtton-wool adherent but not o n n o n a d h e r e l i i nloil()nucle~lr cells, grauuloc)'tes, or thoracic duct lyniphocytes. In Bauul SJ, Ledney GD, Khan A (eds): Experimental ttcmatology Today, 1981. New York, S. Karger, 1981, p 31 Berlin MM, Gale RP, Rimm A A (for the Advisor)' Conlmiitee of tim haternational Bone Marrow Transpkmt Registry): A[logeneic bone marrow transplantation for 144 patients with severe aplastic anemia. JAMA 245:1132, 198 ! Storb R, Prentice RL, T h o m a s ED: Marrmr transplantation for treatment of aplastic anemia: an analysis o f factors associated with grail rejection. N Engl J Med 296:61, 1977 UCLA Bone Marrow Transplant Team: Bone-marrow transplantation in severe aplastic anemia. Lancet 2:921, 19711 Storb R, Thonms ED, Buckner CD, et al: Marrow translfl:mmtion in thirty "'untransfused'" patients with severe apl.islic aneniia. Ann Intern Med 92:30, 1980 Ramsay NKC, Kim T, Nesbit ME, et al: T , lal lynlphoid irradiation and c)'clophosphamide as prepmalion li,i" bolit, m:lrrow transplantation in severe aplaslic anemia, llh,.d 55:3~14, 1980 Gay/|os LA, Freireich EJ, Mamel N: ']'lie quzltllha~i~c relalh,I

HUMAN PATHOLOGY

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Volume '14, No. 3 (March "1983)

between platelet count and hemorrhage in patients with acute leukemia. N Engl J Med 266:905, 1962 Sintnicolaas K, Sizoo W, Haije WG, et al: Delayed alloimmunisation by random single donor platelet transfusions. Lancet 1:750, 1981 Gmiir J, yon Fehen A, Frick P: Delayed HLA-alloimmunization by transfusions of random single-donor platelets instead of common m u l t i p l e - d o n o r platelet concentrates: a prospective study. Exp Hematol 8(suppl 7):56, 1980 Holohan TV, Terasaki PI, Deisseroth AB: Suppression of transfusion-related alloimmunization in intensively treated cancer patients. Blood 58:122, 1981 Goldfinger D, McGinnis MH: Rh-incompatible platelet transfusions: risks and consequences of sensitizing immunosuppressed patients. N EnglJ Med 284:942, 1971 vonFliedner V, Higby DJ, Kim U: Graft-versus-host reaction following blood product transfusion. Am J Med 72:951, 1982 Button LN, DeWolf WG, Newburger PE, et al: The effects of irradiation on blood components. Transfusion 21:419, 1981 Schechter GP, Whang-Peng J, McFarland W: Circulation of donor lymphocytes after blood transfusion in man. Blood 49:651, 1977 Witherspoon RP, Kopecky K, Storb RF, et al: Immunological recovery in 48 patients following syngeneic marrow transplantation for hematological malignancy. Transplantation 33:143, 1982 Witherspoon RP, Storb R, Ochg HD, et al: Recovery of antibody production in human allogeneic marrow graft recipients: influence of time posttransplantation, the presence or absence of chronic graft-versus-host disease, find antithymocyte globulin treatment. Blood 58:360, 1981 Pahwa SG, Pahwa RN, Friedrich W, et al: Abnormal humoral immune responses in peripheral blood lymphocyte cultures of bone marrow transplant recipients. Proc Natl Acad Sci USA 79:2663, 1982 Cliff RA, Sanders JE, Thomas ED, et al: Granulocyte transfusions for the prevention of infection in patients receiving bone-marrow transplants. N E n g l j Med 298:1052, 1978 Winston DJ, Ho WG, Young LS, et al: Prophylactic granulocyte transfusions during human bone marrow transplantation, Am J Med 68:893, 1980

266

36. Hersman .], Meyers JD, Thomas ED, et al: The effect of granulocyte transfusions on the incidence of cytomegalovirus infection after allogeneic marrow transplantation. Ann Intern Med 96:149, 1982 37. Weiden PL, Slichter SJ, Banaji M: Marrow transplantation for aplastic anemia and leukemia: review of results and blood product support required. In Jamieson GA, Greenwalt TJ (eds): The Blood Platelet in Transfusion Therapy. New York, Alan R. Liss, Inc, 1978, p 295 38. Harker LA, Slichter SJ: The bleeding time as a screening test for evaluation of platelet function. N Engl J Med 287:155, 1972 39. Higby DJ, Cohen E, Holland JF, et al: The prophylactic treatment of thrombocytopenic leukemia patients with platelets: a double blind study. Transfusion 14:440, 1974 40. Buckner CD, Clift RA, Sanders JE, et al: ABO-incompatible marrow transplants. Transplantation 26:233, 1978 41. Hershko C, Gale RP, Ho W, et al: ABH antigens and bone marrow transplantation. B r j Haematol 44:65, 1980 42. Lasky LC, Warkentin PI, Kersey JH, et al: Hemotherapy in patients undergoing blood group incompatible bone marrow transplantation. Transfusion, in press 43. Berkman EM, Caplan S, Kim CS: ABO-incompatible bone marrow transplantation: preparation by plasma exchange and in vivo antibody absorption. Transfusion 18:504, 1978 44. Ritchey BE, Petz LD, Spruce WE, et al: A new technique using differential centrifugation of bone marrow for ABOincompatible transplants. Transfusion 18:604, 1981 45. Reich LM, Self SZ, Mayer K: A simple technique to overcome ABH incompatibility in bone marrow transplants. Transfusion 20:640, 1980 46. Warkentin PI, Yomtovian R, Hurd D, et al: Severe delayed hemolytic transfusion reaction complicating an ABOincompatible bone marrow transplantation. Vox Sanguinis, in press 47. Yomtovian R, Swanson J, Quackenbush E, et al: Fatal hyaline membrane disorder in an ABO-incompatible bone marrow transplantation (BMT): the case for immune isohemagglutinin tissue fixation. Transfusion 21:604, 1981 48. Berkman EM, Caplan SN: Engraftment of Rh-positive marrow in a recipient with Rh antibody. Transplant Proc IX(suppl 1):215, 1977