JOHN G. KELTON, MD, FRCP[C]; MORRIS A. BLAJCHMAN, MD, FRCP[C]
Platelets play a pivotal role in hemostasis by forming the initial hemostatic plug and augmenting the formation of the more permanent fibrin thrombus. Thrombocytopenia may lead to bleeding, which can be treated with therapeutic platelet transfusions or prevented with prophylactic transfusions. While many advances have been made in platelet transfusion technology, problems remain. These include the short storage life of liquid.stored platelets and the frequent development of alloantibodies (the refractory state) in patients receiving a number of transfusions. Significant progress, however, is being made in both areas. Les plaquettes jouent un r6le essentiel dans l'hemostase en formant le bouchon hemostatique initial et en augmentant Ia formation du thrombus de fibrine plus permanent. Une thrombocytopenie peut conduire a l'hemorragie, qui peut .tre traitee par des transfusions therapeutiques de plaquettes ou prevenue grAce a des transfusions prophylactiques. Bien que de nombreux progres aient ete realises dans Ia technologie de Ia transfusion plaquettaire, des problemes persistent. Ceux-ci comprennent Ia courte periode de stockage des plaquettes gardees sous forme liquide et l'apparition frequentes d'alloanticorps (etat refractaire) chez les patients recevant de nombreuses transfusions. Dans les deux cas, toutefois, un progres important est enregistre.
Platelets play a fundamental role in hemostasis. They help maintain the integrity of the endothelial cell layer by donating membranes to this layer.1'2 Spontaneously occurring breaks in the endothelial lining of blood vessels expose collagen and induce platelets to adhere and aggregate, forming a temporary "plug".3 Platelets also assist in the formation of the more permanent hemostatic plug. Platelets provide a surface for the activation of coagulation factors, a function called platelet factor 3 activity, and also have specific receptors for activated From the departments of pathology and medicine, McMaster University Medical Centre and the Canadian Red Cross Blood Transfusion Service, Hamilton, Ont. Reprint requests to: Dr. John G. Kelton, Rm. 2N34, McMaster University Medical Centre, 1200 Main St. W, Hamilton, Ont. L8S 4J9
coagulation factors such as factor Thrombocytopenia may lead to bleeding varying in magnitude from petechiae (subepithelial collections of erythrocytes that have leaked through breaks in the capillary wall) to major hemorrhage. Although the mechanism by which thrombocytopenia led to bleeding was unknown, early investigators recognized the association. Therapeutic platelet transfusions were first suggested 70 years ago and the procedure was first attempted 30 years ago. In 1910 Duke6 proposed that the prolonged bleeding time in thrombocytopenic patients might be corrected by platelet transfusion. In 1952 Hirsch and Gardner7 gave thrombocytopenic patients plateletrich plasma from polycythemic patients. We now recognize that platelets from polycythemic patients are not optimal since they may be dys-
functional.8'9 Since that time considerable progress has been made in the preparation and storage of platelet concentrates, but important problems remain, most notably the short storage life of liquid-suspended platelets and the treatment of thrombocytopenic patients who have produced alloantibodies to platelets and do not have increments in the platelet count following transfusion (the refractory state).10 Indications for platelet transfusion
Thrombocytopenia does not usually produce serious bleeding unless the platelet count is less than 20 x I 0./l except if there is a platelet function defect, a coagulation defect or a local cause for bleeding. In a retrospective study of leukemic patients it was found that the frequency of bleeding rose dramatically when the platelet count fell below 20 x 109/1.11 In patients with aregenerative thrombocytopenia there is a close inverse correlation between the template bleeding time and the platelet count. The bleeding time is disproportionately prolonged if there is an associated platelet function defect and is disproportionately shortened if the thrombocytopenia is associated with increased platelet turnover.1214 Platelet transfusions may be given either prophylactically or therapeutically. Prophylactic platelet transfusions should be .onsidered in either thrombocytopenic patients or patients with platelet function defects who require an
CMA JOURNAL/NOVEMBER 17, 1979/VOL. 121
1353
operation or a biopsy or have sustained serious trauma. In addition, prophylactic platelet transfusions should be considered in patients with rapidly reversible severe thrombocytopenia during the period of hemorrhagic risk. Patients in this category include those with a platelet count of 20 x 1 O./l or less who have any of the following diagnoses: * Acute thrombocytopenia presumed to be drug-induced. * Acute leukemia either at the time of presentation or while receiving chemotherapy. * Thrombocytopenia associated with cytotoxic chemotherapy for malignant disease. * Thrombocytopenia associated with "massive" transfusions. * Thrombocytopenia associated with the use of an extracorporeal pump. The clinical data upon which these recommendations are based are largely anecdotal or retrospective since there have been few prospective studies investigating the efficacy of prophylactic platelet transfusions. One study demonstrated a decrease in the frequency of bleeding complications when thrombocytopenic leukemic patients were prophylactically treated with platelets in comparison with a control group given plasma.15 Prophylactic platelet transfusions are not indicated in patients with lifelong or chronic thrombocytopenia. Multiple transfusions induce alloimmunization and make it difficult to elevate the platelet count should the patient bleed. Prophylactic platelet transfusions are also unlikely to be of benefit in patients whose thrombocytopenia is associated with increased platelet destruction since the transfused platelets are also rapidly destroyed. The exceptions are patients with severe thrombocytopenia associated with septicemia or drug-induced immune thrombocytopenia since platelet transfusion may result in a rise in the platelet count in these patients.'6'17 Prophylactic platelet transfusions are not indicated in patients with chronic immune thrombocytopenia, thrombocytopenia associated with splenic pooling and post-transfusional purpura (platelet transfusions may aggravate the latter).'6 Platelet transfusions
may be of use in infants with severe neonatal thrombocytopenia; in this syndrome maternal platelets should be used since they lack the specific antigen against which the alloantibodies are directed.'9 Therapeutic platelet transfusions are indicated in any thrombocytopenic patient, including those with disorders caused by increased platelet destruction if there is severe and potentially life-threatening bleeding. Although the platelet count may not rise, hemostasis may be improved. Platelet transfusions should not be used to treat trivial bleeding.
vious 24 hours) is taken into a multiple transfusion pack containing citrate-phosphate-dextrose or acidcitrate-dextrose. After centrifugation the platelet-rich plasma is transferred into the second bag and centrifuged; the excess plasma is then removed and the platelet pellet resuspended in 50 ml of residual plasma." Platelets retain optimal hemostatic function when stored at 220C while undergoing continuous gentle agitation.""' For storage at 220C at least 50 ml of residual plasma is necessary to maintain the pH of the platelet suspension above 6.0. Storage of platelet suspensions at volumes less than 50 ml for 72 Administration of platelets hours will result in pHs of less than There are few prospective studies 6.0 and hemostatically ineffective to guide the clinician on the quan- platelets." tity of platelets required to prevent Another method for obtaining bleeding. In one study leukemic platelets is single donor plateletchildren were given either 0.03 or phoresis." Heparinized, citrated 0.06 units of platelets per pound blood from a donor flows into a of body weight. (A unit of platelets continuous centrifuge that separates represents approximately 70% of the blood into its components. The the platelets present in one unit of platelets are harvested and the fresh whole blood and contains ap- plasma and remaining cells are reproximately 7 x 1010 platelets). infused into the donor. The adThere was no significant difference vantage of this system is that it in the frequency of bleeding be- allows the potential use of a donor tween the two groups despite the of known HLA type (ideally idendemonstration that the children re- tical to that of the patient). This ceiving the smaller quantities did delays the development of platelet not have an increase in platelet alloantibodies and has the theoretcount.'4' Murphy2' recommended ical advantage of limiting the range that thrombocytopenic patients re- of platelet antigens to which the quiring prophylactic platelet trans- patient is exposed. fusions should receive 3 to 4 units! m' three times per week; however, Cryopreserved platelets other quantities and schedules have Despite improved methods in the been suggested."' liquid preservation of platelets, the Platelets should be infused as cells lose their hemostatic function rapidly as tolerated through a spe- rapidly and therefore must be discial platelet filter. Microaggregate carded after 72 hours of storage. filters should not be used as they This wastage may be theoretically remove platelets during infusion. alleviated by the use of cryopreIdeally in an adult patient the servation.'74' Autologous cryopreplatelet count should rise 10 x served platelets have been used suc1 0./l *m' per unit of fresh platelets cessfully in the management of administered. Less than optimal in- leukemic patients:'7 the platelets crements occur if the patient is were obtained when the leukemia febrile, bleeding, infected or allo- was in remission, were cryopreimmunized, or has splenomegaly. served and then were given back to the patients when relapse ocPreparation of platelet concentrates curred. While the use of cryopreserved platelets may prevent wastThere are several techniques for age, problems remain, particularly preparing platelet concentrates, with the less-than-optimal in vivo reserial centrifugation being the most covery following cryopreservation."' common. A unit of whole blood from a healthy donor (who has not Platelet antigens taken acetylsalicylic acid in the preDespite the passage of 30 years
1354 CMA JOURNAL/NOVEMBER 17, 1979/VOL. 121
since the first platelet transfusion, the technology (in contrast to that of red cell transfusions) has remained undeveloped. There are three reasons for this: * Unlike ABO red cell incompatibility reactions, in which a mismatched transfusion may have disastrous results in the recipient, mismatched platelet transfusions have few adverse effects. Thus, there has not been the same incentive to solve the problems of transfusion incompatibility with platelets as there has been with red cells?0 * Leukemia will often go into remission before the patient becomes refractory to platelet transfusions. * It has been difficult to study platelet antigens. This is related to problems in isolating platelets owing to their tendency to aggregate spontaneously. A number of immunologic assays may be useful to study platelet antigens. The early assays (chromium51 release, platelet factor 3 release and carbon-i 4-serotonin release) were based upon the observation that the binding of immunoglobulins to platelet antigens causes platelet release.33.' Unfortunately these assays are nonspecific (since nonimmune stimuli can lead to platelet release) and insensitive (since the antigen-antibody reaction on the platelet surface is not always associated with platelet release).37'38 Methods that directly quantitate immunoglobulins on the platelet surface may prove to be useful in studying platelet antigens. These include the antiglobulin consumption test, the fluorescent-labelled antibody test and the iodine-i 25labelled antibody test.3941 Several types of platelet antigens appear to be important following alloimmunization. First, the platelet-specific, or P1, antigens have been implicated in alloimmune neonatal thrombocytopenia and posttransfusion purpura. In these conditions the lack of PlAl antigens (present on the platelets of 98% of the population) leads to the formation of alloantibodies.19'42 The second category of platelet antigens are those shared with leukocytes the HLA antigens. Antibodies to these antigens may occasionally be responsible for neonatal alloimmune thrombocytopenia.19'42 The
recognition that platelets and leukocytes share HLA antigens has enabled HLA-matched platelets to be transfused to patients requiring multiple platelet transfusions. The use of HLA-matched platelets postpones but does not always prevent the development of the refractory state.43 Although it has been demonstrated in vitro that platelets share red cell ABO antigens,"46 the clinical significance of this observation is unknown. When ABO-incompatible platelets are given, the rise in platelet count after transfusion is less than expected, but the platelets remaining in the circulation have a normal survival.'7 Furthermore, HLA-matched but ABO-mismatched platelets have a normal survival in vivo.'8'" Complications of platelet tranfusion The refractory state Most patients receiving multiple platelet transfusions ultimately become refractory to further transfusions because of the development of alloantibodies to nonautologous platelets.5044 While the refractory state usually develops after 4 to 6 weeks of repeated transfusion, it may develop sooner in patients who have received previous whole blood transfusions containing platelet fragments55 or later in the immunosuppressed patient. Many methods have been used in an attempt to avoid or treat the refractory state. Cryopreserved autologous platelets obtained from patients with leukemia that is in remission can be reinfused during relapse, so that development of the refractory state is avoided; unfortunately, this form of treatment is applicable to only a small group of patients.27 Steroid administration or splenectomy is not an effective treatment once alloimmunization has occurred.56 Massive platelet transfusions may be given to refractory patients who are bleeding in an attempt to overcome the effect of circulating platelet antibodies; however, such large quantities of platelets are needed that the cardiovascular system may be overloaded from the plasma." Since treatment is difficult, attempts have been made to avoid the induction of the refractory state by giving matched platelets. The use of HLA-matched
platelets57 has led to the observation that certain HLA antigens (such as HLA-2), if not possessed by the recipient, rapidly induce refractoriness, while others (such as HLA12) are less important.58 Unfortunately, even HLA-matched platelets may ultimately lead to the development of alloantibodies.59 Furthermore, in 15% to 40% of refractory patients the transfusion of HLA-matched platelets does not result in an increment in the platelet count. This is not unexpected since platelets have antigens that are not shared by leukocytes and therefore would not be identified by HLA matching.0 The lack of success in HLA matching has led to the development of other "crossmatching" techniques. The use of platelet aggregometry as an index of compatibility appeared promising, but subsequent studies have given disappointing results.6143 More sensitive methods that quantitate antibody binding are now being applied to platelet crossmatching techniques. A fluorescent assay for platelet antibodies has been reported to provide better identification of patients who will respond to platelet transfusions than did HLA typing.60 While the results of such studies are promising, they must be confirmed. However, it is possible that platelet crossmatching prior to transfusion may become feasible and as routine as the crossmatching of red cells. Red cell alloimmunization Red cell alloimmunization due to contamination of the platelet transfusion by red cells and hemolytic reactions to the donor plasma has been reported." Since units of platelets contain significant amounts of red cells (approximately 0.4 ml per unit) Rh immunization by contaminating red cells is a potential problem. If platelets from an Rhpositive donor have to be given to an Rh-negative woman of childbearing age, it is recommended that Rh immunoglobulin be administered shortly after the platelet transfusion, while the platelets are hemostatically effective. Fever Fever occurring immediately or several hours following platelet transfusion is often due to allo-
CMA JOURNAL/NOVEMBER 17, 1979/VOL. 121
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antibodies to the leukocytes present in the platelet preparation.50 This is often encountered when the platelets are obtained by plateletphoresis. Premedication with antihistamines and additional centrifugation of the platelet preparation may help to decrease the frequency of this complication *50 Fever occurring several hours after the platelet transfusion may signify bacterial contamination of the platelet preparation (often with enterobacteria, staphylococci or pseudomonads) .51,65 Viral and protozoal infections transmitted by platelet transfusions have also been reported.66 Granulocytopenia Granulocytopenia, presumably on an immune basis, occasionally may follow platelet transfusion.67 This is potentially a serious problem in the leukemic or aplastic patient who has a depressed leukocyte count prior to the transfusion. Past-transfusion purpura While post-transfusion purpura is not a complication of platelet transfusion, it deserves emphasis since platelet transfusions given to patients with this problem can result in significant illness. This uncommon syndrome of severe thrombocytopenia usually occurs in women 1 week after a blood transfusion, and the recipient's platelets are usually negative to PlAl. The condition has been managed with plasmapheresis and corticosteroid therapy.68 Platelet transfusions should not be given. We thank Drs. J. Hirsh, M.C. Brain and W.E.C. Wilson for their thoughtful comments during the preparation of this manuscript. References
5. WALSH PN, CAMP E, DENDE D:
Different requirements for intrinsic factor-Xa forming activity and platelet factor 3 activity and their relationship to platelet aggregation and secretion. Br J Haematol 40: 311, 1978 6. DUKE WW: The relation of blood platelets to hemorrhagic disease. JAMA 55: 1185, 1910 7. HIRSCH EO, GARDNER FH: The transfusion of human blood platelets
with a note on the transfusion of granulocytes. J Lab Clin Med 39: 556, 1952 8. CARDAMONE JM, EDSON JR, McARTHUR JR, et al: Abnormalities of platelet function in the myeloproliferative disorders. JAMA 221: 270,
1972
4. GIDDINGs JC, SHEARN SAM, BLOOM
AL: Platelet-associated coagulation factors: immunological detection and the effect of calcium. Br J Haernatol 39: 569, 1978
25. BECKER GA, TUCCELLI M, KUNICKI
J, et al: Studies of platelet concentrates stored at 22 C and 4 C. Transfusion 13: 61, 1973 26. WIEcKowIcz M: Single donor platelet transfusions - scientific, legal, and ethical considerations. Transfusion 16: 193, 1976 27. SCHIFFER CA, AISNER J, WIERNIK PH: Frozen autologous platelet
transfusion for patients with leukemia. N Engi J Med 299: 7, 1978
9. GERRARD JM, STODDARD SF, SHAPIRO
28. MURPHY 5, SAYER SN, ABDOU NL,
RS, et al: Platelet storage pool deficiency and prostaglandin synthesis in
et al: Platelet preservation by freezing. Use of dimethylsulfoxide as cryoprotective agent. Transfusion 14: 139, 1974 29. DAYIAN G, ROWE AW: Cryopreservation of human platelets for transfusion. A glycerol-glucose, moderate rate cooling procedure. Cryobiology 13: 1, 1976
chronic granulocytic leukaemia. Br
J Haematol 40: 597, 1978 10. HOAK JC, KOEPKE JA: Platelet transfusions. Gun Haematol 5: 69,
1976 11. GAYDOS LA, FREIREICH EJ, MANTEL
N: The quantitative relation between platelet count and hemorrhage in patients with acute leukemia. N Engi J Med 266: 905, 1962 12. HARKER
LA,
SLICHTER
SJ:
The
bleeding time as a screening test for evaluation of platelet function. N Engi J Med 287: 155, 1972 13. The bleeding-time (E). Lancet 2: 579, 1972 14. COPLEY AL: Bleeding time, other in vivo hemostasis tests and the arrest of hemorrhage. Thrornb Res 4: 1, 1974 15. HIOBY DJ, COHEN E, HOLLAND JF,
et al: The prophylactic treatment of thrombocytopenic leukemic patients
with platelets: a double blind study. Transfusion 14: 440, 1974 16. KELTON JG, NEAME PB, GAIJLDIE J, et al: Elevated platelet-associated IgG in the thrombocytopenia of septicemia. N Engi J Med 300: 760,
1979 17. Moss RA, CASTRO 0: Platelet transfusion for quinidine-induced thrombocytopenia (C). N Engi J Med 288:
522, 1973 18. ABRAMSON N, EISENBERG PD, ASTER RH: Post-transfusion purpura: immunologic aspects and therapy. N
Engi J Med 291: 1163, 1974 1. HENRY RL: Platelet function. Semin Thromb Hemostas 4: 93, 1977 2. KITCHENS CS, WEIss L: Ultrastructural changes of endothelium associated with thrombocytopenia. Blood 46: 567, 1975 3. JOHNSON SA (ed): Endothelial supporting function of platelets, in The Circulating Platelet, Acad Pr, New York, 1971, p 284
23. FILIP DJ, ASTER RH: Relative hemostatic effectiveness of human platelets stored at 4-degrees-C and 22-degrees-C. J Lab Clin Med 91: 618, 1978 24. FRATANTONI JC: Status report on methods of platelet preservation. Transfusion 16: 1, 1976
19. PEARSON HA, SHULMAN NR, MAR-
DER VJ, et al: Isoimmune neonatal thrombocytopenic purpura. Clinical and therapeutic considerations. Blood
23: 154, 1964 20. Roy AJ, JAFFE N, DJERASSI I: Prophylactic platelet transfusions in children with acute leukemia: a dose response study. Transfusion 13: 283, 1973 21. MURPHY
5:
Platelet
transfusion.
Prog Heinost Thrornb 3: 289, 1976 22. SLICHTER SJ, HARKER LA: Preparation and storage of platelet concen-
trates. Transfusion 16: 8, 1976
1356 CMA JOURNAL/NOVEMBER 17, 1979/VOL. 121
30. ROWE AW, LENNY LL, REICH LM:
Studies on chromium-Si labelling on human platelets cryopreserved by the glycerol/glucose method and the DMSO method. Cryobiology 15: 698, 1978 31. VoGIN EE, CARSON 5, CANNON G, et al: Chronic toxicity of DMSO in
primates. Toxicol Appi Pharmacol 16: 606, 1970 32. WooD DC, WEBER FS, PALMQUIST
MA: Continued studies in the toxicology of dimethyl sulfoxide (DMSO). J Pharmacol Exp Ther 177: 520, 1971 33. Nii.wiARowsKi 5: Proteins secreted by the platelet. Thromb Haemost 38: 924, 1977 34. CIMo PL, PIsCIoTTA AV, DEsAI RG, et al: Detection of drug-dependent antibodies by the 51Cr platelet lysis test: documentation of immune thrombocytopenia induced by diphenylhydantoin, diazepam, and sulfisoxazole. Am J Hematol 2: 65, 1977 35. KARPATKIN 5, STRICK N, KARPATKIN
MB, et al: Cumulative experience in the detection of antiplatelet antibody in 234 patients with idiopathic thrombocytopenic purpura, systemic lupus erythematosus and other clinical disorders. Am J Med 52: 776, 1972 36. HIRSCHMAN RJ, SHULMAN NR: The
use of platelet serotonin release as a sensitive method for detecting antiplatelet antibodies and a plasma anti-platelet factor in patients with idiopathic thrombocytopenic purpura. Br J Haematol 24: 793, 1973 37. MUELLER-ECKHARDT
C,
MERSCH-
BAUMERT K: The problem of platelet autoantibodies. I. Evaluation of the platelet factor 3 availability test for their detection. Vox Sang 33: 221, 1977
38. MUELLER-ECKHARDT C, MAYSER B,
HEINRICH D: The problem of platelet autoantibodies. II. The applicability of the 14C-serotonin release test. Ibid, p 234 39. KELTON JG, NEAME PB, BISHOP J,
et al: The direct assay for plateletassociated IgG (PAIgG) - lack of association between antibody level and platelet size. Blood 53: 73, 1979 40. VON DEM BORNE AEG, VERHEUGT
FWA, OOSTERHOF F, et al: A simple immunofluorescence test for the detection of platelet antibodies. Br J Haematol 39: 195, 1978 41. MCMILLAN R, LONGMIRE RL, YE-
LENOSKY R, et al: Quantitation of platelet-binding IgG produced in vitro by spleens from patients with idiopathic thrombocytopenic purpura. N Engi J Med 291: 812, 1974 42. SHULMAN NR, MARDER VJ, HILLER
MC, et al: Platelet and leukocyte isoantigens and their antibodies: serologic, physiologic and clinical studies. Frog Hematol 4: 222, 1964 43. BUCHER U, DE WECK A, SPLENGLER
H, et al: Platelet transfusions: shortened survival of HL-A-identical platelets and failure of in vitro detection of anti-platelet antibodies after multiple transfusions. Vox Sang 25: 187, 1973 44. GUREvITCH J, NELKEN D:
ABO
groups in blood platelets. Nature (Lond) 173: 356, 1954 45. Idem: Studies on platelet antigens.
II. A1 and A2 subgroups in blood platelets. J Lab Clin Med 46: 530, 1955 46. Idem: Studies on platelet antigens.
III. Rh-Hr antigens in platelets. Vox Sang 2: 342, 1957 47. ASTER RH: Effect of anticoagulant and ABO incompatibility on recovery of transfused human platelets. Blood 26: 732, 1965 48. LOHRMANN H-P, BULL MI, DECTER JA, et al: Platelet transfusions from
HL-A compatible unrelated donors to alloimmunized patients. Ann Intern Med 80: 9, 1974 49. SCHIFFER
CA,
LICHTENFELD
JL,
WIERNIK PH, et al: Antibody response in patients with acute nonlymphocytic leukemia. Cancer 37: 2177, 1976 50. HERZIG RH, HERZIG GP, BULL MI, et al: Correction of poor platelet
transfusion responses with leukocytepoor HL-A-matched platelet concen-
trates. Blood 46: 743, 1975 51. BUCHHOLZ DH, YOUNG VM, FRIEDMAN NR, et al: Detection and quan-
titation of bacteria in platelet products stored at ambient temperature. Transfusion 13: 268, 1973 52. GARDNER FH: Use of platelet trans-
fusions. Br J Haematol 27: 537, 1974 53. SCHIFFER CA: Some aspects of recent advances in the use of blood cell components. Br J Haematol 39: 289, 1978 1358
54. NAGASAWA T, KIM BK, BALDINI MG: Temporary suppression of circulating antiplatelet alloantibodies by the massive infusion of fresh, stored, or lyophilized platelets. Transfusion 18: 429, 1978 55. MCNAMARA JJ, ANDERSON BS, HAYA-
SHI T: Stored blood platelets and microaggregate formation. Surg Gynecol Obstet 147: 507, 1978 56. GRUMET FC, YANKEE RA: Long-
term platelet support of patients with aplastic anemia: effect of splenectomy and steroid therapy. Ann Intern Med 73: 1, 1970 57. MITTAL KK, RUDER EA, GREEN D: Matching of histocompatibility (HL-
A) antigens for platelet transfusion. Blood 47: 31, 1976 58. DUQUESNOY RJ, FILIP DJ, ASTER RH: Influence of HLA-A2 on the effectiveness of platelet transfusion
in alloimmunized thrombocytopenic patients. Blood 50: 407, 1977 59. HOWARD JE, PERKINS HA: The natural history of alloimmunization to
platelets. Transfusion 18: 496, 1978 60. BRAND A, VAN LEEUWEN A, ERNISSE JG, et al: Platelet transfusion therapy - optimal donor selection with a combination of lymphocytotoxicity and platelet fluorescence tests. Blood
51: 781, 1978 61. Wu KK, HOAK JC, ThOMPSON iS, et al: Use of platelet aggregometry
in selection of compatible platelet donors. N Engi J Med 292: 130, 1975 62. Wu KK, HOAK JC, KOEPKE JA, et
al: Selection of compatible platelet donors - prospective evaluation of
3 cross-matching techniques. Transfusion 17: 638, 1977 63. DUQUESNOY RJ, FILIP Di, RODEY
GE, et al: Successful transfusion of platelets "mismatched" for HLA antigens to alloimmunized thrombocytopenic patients. Am J Hematol 2: 219, 1977 64. ZoES C, DUnE VE, MILLER HJ, et al: Anti-Al in plasma of platelet concentrates causing a hemolytic reaction. Transfusion 17: 29, 1977 65. BUCHHOLZ DH, YOUNG VM, FRIEDMAN NR, et al: Bacterial proliferation in platelet products stored at room temperature: transfusion-induced enterobacter sepsis. N Engi J Med 285: 429, 1971 66. GARFIELD MD, ERSHLER WB, MAKI DG: Malaria transmission by platelet concentrate transfusion. JA MA 240: 2285, 1978 67. HERZIG RH, POPLACK DG, YANKEE RA: Prolonged granulocytopenia from incompatible platelet transfu-
sion. N Engi J Med 290: 1220, 1974 68. SEIDENFELD AM, OWEN i, GLYNN
MFX, et al: Post-transfusion purpura cured by steroid therapy in a man. Can Med Assoc J 118: 1285, 1978
CMA JOURNAL/NOVEMBER 17, 1979/VOL. 121
I BOOKS This list is an acknowledgement of books received. It does not preclude review at a later date. CLINICAL GENETICS. A Source Book for Physicians. Edited by Laird G. Jackson and R. Neil Schimke. 652 pp. Illust. John Wiley & Sons, Inc., Somerset, New Jersey, 1979. $35. ISBN 0-47101943-7 ENTERAL HYPERALIMENTATION WITH CHEMICALLY DEFINED ELEMENTAL DIETS: A SOURCE BOOK. 2nd ed. Compiled by Dennis B. Worthen and Joan R. Lorimer. 376 pp. Information Services, Research Department, Scientific Affairs, Norwich-Eaton Pharmaceuticals, Norwich, New York, 1979. $9.95, paperbound 1st SUPPLEMENT to the four volumes on the "Topographic Positions of the Measurement Points in Electro-Acupuncture (EAV)". Reinhold Voll. Translated and fully revised by Hartwig Schuldt. 49 pp. Illust. International Scholarly Book Services, Inc., Forest Grove, Oregon, 1978. $35, paperbound. ISBN 3-88136-063-8 THE FIRST YEAR OF LIFE. The Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke. Janet B. Hardy, Joseph S. Drage and Esther C. Jackson. 336 pp. lIlust. The Johns Hopkins University Press, Baltimore, 1979. $25. ISBN 0-8018-2167-3 HANDBOOK OF NONPRESCRIPTION DRUGS. 6th ed. Richard P. Penna, Project Director; L. Luan Corrigan, Managing Editor; Joan Welsh, Project Editor; and others. 488 pp. IlIust. American Pharmaceutical Association, Washington, DC, 1979. $20. ISBN 0-91733027-7 HAVENS OF REFUGE. A History of Leprosy in Western Australia. W.S. Davidson. 188 pp. lIlust. University of Western Australia Press for the Public Health Department; International Scholarly Book Services Inc., Forest Grove, Oregon, 1978. $24. ISBN 0-85564-141-X HEALTH GUIDE FOR TRAVELLERS TO WARM CLIMATES. 2nd ed. Stanley 5K. Seah. 89 pp. IlIust. The Canadian Public Health Association, Ottawa, 1979. $2.50 (single copies), paperbound HEALTH IN DANGER. The Crisis in the National Health Service. David Widgery. 178 pp. The Shoe String Press, Inc., Hamden, Connecticut, 1979. $17.50. ISBN 0-208-01759-3 HYPOTHALAMIC RELEASING FACTORS. Volume 3. Wayne B. Watkins. 130 pp. Eden Press Inc., Montreal, 1979. $20. ISBN 0-88831-046-3 IMMUNOPATHOGENESIS OF RHEUMATOID ARTHRITIS. Proceedings of the International Symposium held at Guy's Hospital, London in November 1978. Edited by G.S. Panayi and P.M. Johnson. 163 pp. IlIust. Reedbooks Ltd., Chertsey, Surrey, 1979. Price not stated, paperbound. ISBN 0-906544-02-5
continued on page 1380
Platelets play a pivotal role in hemostasis by forming the initial hemostatic plug and augmenting the formation of the more permanent fibrin thrombus. Thrombocytopenia may lead to bleeding, which can be treated with therapeutic platelet transfusions or prevented with prophylactic transfusions. While many advances have been made in platelet transfusion technology, problems remain. These include the short storage life of liquid.stored platelets and the frequent development of alloantibodies (the refractory state) in patients receiving a number of transfusions. Significant progress, however, is being made in both areas. Les plaquettes jouent un r6le essentiel dans l'hemostase en formant le bouchon hemostatique initial et en augmentant Ia formation du thrombus de fibrine plus permanent. Une thrombocytopenie peut conduire a l'hemorragie, qui peut .tre traitee par des transfusions therapeutiques de plaquettes ou prevenue grAce a des transfusions prophylactiques. Bien que de nombreux progres aient ete realises dans Ia technologie de Ia transfusion plaquettaire, des problemes persistent. Ceux-ci comprennent Ia courte periode de stockage des plaquettes gardees sous forme liquide et l'apparition frequentes d'alloanticorps (etat refractaire) chez les patients recevant de nombreuses transfusions. Dans les deux cas, toutefois, un progres important est enregistre.
Platelets play a fundamental role in hemostasis. They help maintain the integrity of the endothelial cell layer by donating membranes to this layer.1'2 Spontaneously occurring breaks in the endothelial lining of blood vessels expose collagen and induce platelets to adhere and aggregate, forming a temporary "plug".3 Platelets also assist in the formation of the more permanent hemostatic plug. Platelets provide a surface for the activation of coagulation factors, a function called platelet factor 3 activity, and also have specific receptors for activated From the departments of pathology and medicine, McMaster University Medical Centre and the Canadian Red Cross Blood Transfusion Service, Hamilton, Ont. Reprint requests to: Dr. John G. Kelton, Rm. 2N34, McMaster University Medical Centre, 1200 Main St. W, Hamilton, Ont. L8S 4J9
coagulation factors such as factor Thrombocytopenia may lead to bleeding varying in magnitude from petechiae (subepithelial collections of erythrocytes that have leaked through breaks in the capillary wall) to major hemorrhage. Although the mechanism by which thrombocytopenia led to bleeding was unknown, early investigators recognized the association. Therapeutic platelet transfusions were first suggested 70 years ago and the procedure was first attempted 30 years ago. In 1910 Duke6 proposed that the prolonged bleeding time in thrombocytopenic patients might be corrected by platelet transfusion. In 1952 Hirsch and Gardner7 gave thrombocytopenic patients plateletrich plasma from polycythemic patients. We now recognize that platelets from polycythemic patients are not optimal since they may be dys-
functional.8'9 Since that time considerable progress has been made in the preparation and storage of platelet concentrates, but important problems remain, most notably the short storage life of liquid-suspended platelets and the treatment of thrombocytopenic patients who have produced alloantibodies to platelets and do not have increments in the platelet count following transfusion (the refractory state).10 Indications for platelet transfusion
Thrombocytopenia does not usually produce serious bleeding unless the platelet count is less than 20 x I 0./l except if there is a platelet function defect, a coagulation defect or a local cause for bleeding. In a retrospective study of leukemic patients it was found that the frequency of bleeding rose dramatically when the platelet count fell below 20 x 109/1.11 In patients with aregenerative thrombocytopenia there is a close inverse correlation between the template bleeding time and the platelet count. The bleeding time is disproportionately prolonged if there is an associated platelet function defect and is disproportionately shortened if the thrombocytopenia is associated with increased platelet turnover.1214 Platelet transfusions may be given either prophylactically or therapeutically. Prophylactic platelet transfusions should be .onsidered in either thrombocytopenic patients or patients with platelet function defects who require an
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operation or a biopsy or have sustained serious trauma. In addition, prophylactic platelet transfusions should be considered in patients with rapidly reversible severe thrombocytopenia during the period of hemorrhagic risk. Patients in this category include those with a platelet count of 20 x 1 O./l or less who have any of the following diagnoses: * Acute thrombocytopenia presumed to be drug-induced. * Acute leukemia either at the time of presentation or while receiving chemotherapy. * Thrombocytopenia associated with cytotoxic chemotherapy for malignant disease. * Thrombocytopenia associated with "massive" transfusions. * Thrombocytopenia associated with the use of an extracorporeal pump. The clinical data upon which these recommendations are based are largely anecdotal or retrospective since there have been few prospective studies investigating the efficacy of prophylactic platelet transfusions. One study demonstrated a decrease in the frequency of bleeding complications when thrombocytopenic leukemic patients were prophylactically treated with platelets in comparison with a control group given plasma.15 Prophylactic platelet transfusions are not indicated in patients with lifelong or chronic thrombocytopenia. Multiple transfusions induce alloimmunization and make it difficult to elevate the platelet count should the patient bleed. Prophylactic platelet transfusions are also unlikely to be of benefit in patients whose thrombocytopenia is associated with increased platelet destruction since the transfused platelets are also rapidly destroyed. The exceptions are patients with severe thrombocytopenia associated with septicemia or drug-induced immune thrombocytopenia since platelet transfusion may result in a rise in the platelet count in these patients.'6'17 Prophylactic platelet transfusions are not indicated in patients with chronic immune thrombocytopenia, thrombocytopenia associated with splenic pooling and post-transfusional purpura (platelet transfusions may aggravate the latter).'6 Platelet transfusions
may be of use in infants with severe neonatal thrombocytopenia; in this syndrome maternal platelets should be used since they lack the specific antigen against which the alloantibodies are directed.'9 Therapeutic platelet transfusions are indicated in any thrombocytopenic patient, including those with disorders caused by increased platelet destruction if there is severe and potentially life-threatening bleeding. Although the platelet count may not rise, hemostasis may be improved. Platelet transfusions should not be used to treat trivial bleeding.
vious 24 hours) is taken into a multiple transfusion pack containing citrate-phosphate-dextrose or acidcitrate-dextrose. After centrifugation the platelet-rich plasma is transferred into the second bag and centrifuged; the excess plasma is then removed and the platelet pellet resuspended in 50 ml of residual plasma." Platelets retain optimal hemostatic function when stored at 220C while undergoing continuous gentle agitation.""' For storage at 220C at least 50 ml of residual plasma is necessary to maintain the pH of the platelet suspension above 6.0. Storage of platelet suspensions at volumes less than 50 ml for 72 Administration of platelets hours will result in pHs of less than There are few prospective studies 6.0 and hemostatically ineffective to guide the clinician on the quan- platelets." tity of platelets required to prevent Another method for obtaining bleeding. In one study leukemic platelets is single donor plateletchildren were given either 0.03 or phoresis." Heparinized, citrated 0.06 units of platelets per pound blood from a donor flows into a of body weight. (A unit of platelets continuous centrifuge that separates represents approximately 70% of the blood into its components. The the platelets present in one unit of platelets are harvested and the fresh whole blood and contains ap- plasma and remaining cells are reproximately 7 x 1010 platelets). infused into the donor. The adThere was no significant difference vantage of this system is that it in the frequency of bleeding be- allows the potential use of a donor tween the two groups despite the of known HLA type (ideally idendemonstration that the children re- tical to that of the patient). This ceiving the smaller quantities did delays the development of platelet not have an increase in platelet alloantibodies and has the theoretcount.'4' Murphy2' recommended ical advantage of limiting the range that thrombocytopenic patients re- of platelet antigens to which the quiring prophylactic platelet trans- patient is exposed. fusions should receive 3 to 4 units! m' three times per week; however, Cryopreserved platelets other quantities and schedules have Despite improved methods in the been suggested."' liquid preservation of platelets, the Platelets should be infused as cells lose their hemostatic function rapidly as tolerated through a spe- rapidly and therefore must be discial platelet filter. Microaggregate carded after 72 hours of storage. filters should not be used as they This wastage may be theoretically remove platelets during infusion. alleviated by the use of cryopreIdeally in an adult patient the servation.'74' Autologous cryopreplatelet count should rise 10 x served platelets have been used suc1 0./l *m' per unit of fresh platelets cessfully in the management of administered. Less than optimal in- leukemic patients:'7 the platelets crements occur if the patient is were obtained when the leukemia febrile, bleeding, infected or allo- was in remission, were cryopreimmunized, or has splenomegaly. served and then were given back to the patients when relapse ocPreparation of platelet concentrates curred. While the use of cryopreserved platelets may prevent wastThere are several techniques for age, problems remain, particularly preparing platelet concentrates, with the less-than-optimal in vivo reserial centrifugation being the most covery following cryopreservation."' common. A unit of whole blood from a healthy donor (who has not Platelet antigens taken acetylsalicylic acid in the preDespite the passage of 30 years
1354 CMA JOURNAL/NOVEMBER 17, 1979/VOL. 121
since the first platelet transfusion, the technology (in contrast to that of red cell transfusions) has remained undeveloped. There are three reasons for this: * Unlike ABO red cell incompatibility reactions, in which a mismatched transfusion may have disastrous results in the recipient, mismatched platelet transfusions have few adverse effects. Thus, there has not been the same incentive to solve the problems of transfusion incompatibility with platelets as there has been with red cells?0 * Leukemia will often go into remission before the patient becomes refractory to platelet transfusions. * It has been difficult to study platelet antigens. This is related to problems in isolating platelets owing to their tendency to aggregate spontaneously. A number of immunologic assays may be useful to study platelet antigens. The early assays (chromium51 release, platelet factor 3 release and carbon-i 4-serotonin release) were based upon the observation that the binding of immunoglobulins to platelet antigens causes platelet release.33.' Unfortunately these assays are nonspecific (since nonimmune stimuli can lead to platelet release) and insensitive (since the antigen-antibody reaction on the platelet surface is not always associated with platelet release).37'38 Methods that directly quantitate immunoglobulins on the platelet surface may prove to be useful in studying platelet antigens. These include the antiglobulin consumption test, the fluorescent-labelled antibody test and the iodine-i 25labelled antibody test.3941 Several types of platelet antigens appear to be important following alloimmunization. First, the platelet-specific, or P1, antigens have been implicated in alloimmune neonatal thrombocytopenia and posttransfusion purpura. In these conditions the lack of PlAl antigens (present on the platelets of 98% of the population) leads to the formation of alloantibodies.19'42 The second category of platelet antigens are those shared with leukocytes the HLA antigens. Antibodies to these antigens may occasionally be responsible for neonatal alloimmune thrombocytopenia.19'42 The
recognition that platelets and leukocytes share HLA antigens has enabled HLA-matched platelets to be transfused to patients requiring multiple platelet transfusions. The use of HLA-matched platelets postpones but does not always prevent the development of the refractory state.43 Although it has been demonstrated in vitro that platelets share red cell ABO antigens,"46 the clinical significance of this observation is unknown. When ABO-incompatible platelets are given, the rise in platelet count after transfusion is less than expected, but the platelets remaining in the circulation have a normal survival.'7 Furthermore, HLA-matched but ABO-mismatched platelets have a normal survival in vivo.'8'" Complications of platelet tranfusion The refractory state Most patients receiving multiple platelet transfusions ultimately become refractory to further transfusions because of the development of alloantibodies to nonautologous platelets.5044 While the refractory state usually develops after 4 to 6 weeks of repeated transfusion, it may develop sooner in patients who have received previous whole blood transfusions containing platelet fragments55 or later in the immunosuppressed patient. Many methods have been used in an attempt to avoid or treat the refractory state. Cryopreserved autologous platelets obtained from patients with leukemia that is in remission can be reinfused during relapse, so that development of the refractory state is avoided; unfortunately, this form of treatment is applicable to only a small group of patients.27 Steroid administration or splenectomy is not an effective treatment once alloimmunization has occurred.56 Massive platelet transfusions may be given to refractory patients who are bleeding in an attempt to overcome the effect of circulating platelet antibodies; however, such large quantities of platelets are needed that the cardiovascular system may be overloaded from the plasma." Since treatment is difficult, attempts have been made to avoid the induction of the refractory state by giving matched platelets. The use of HLA-matched
platelets57 has led to the observation that certain HLA antigens (such as HLA-2), if not possessed by the recipient, rapidly induce refractoriness, while others (such as HLA12) are less important.58 Unfortunately, even HLA-matched platelets may ultimately lead to the development of alloantibodies.59 Furthermore, in 15% to 40% of refractory patients the transfusion of HLA-matched platelets does not result in an increment in the platelet count. This is not unexpected since platelets have antigens that are not shared by leukocytes and therefore would not be identified by HLA matching.0 The lack of success in HLA matching has led to the development of other "crossmatching" techniques. The use of platelet aggregometry as an index of compatibility appeared promising, but subsequent studies have given disappointing results.6143 More sensitive methods that quantitate antibody binding are now being applied to platelet crossmatching techniques. A fluorescent assay for platelet antibodies has been reported to provide better identification of patients who will respond to platelet transfusions than did HLA typing.60 While the results of such studies are promising, they must be confirmed. However, it is possible that platelet crossmatching prior to transfusion may become feasible and as routine as the crossmatching of red cells. Red cell alloimmunization Red cell alloimmunization due to contamination of the platelet transfusion by red cells and hemolytic reactions to the donor plasma has been reported." Since units of platelets contain significant amounts of red cells (approximately 0.4 ml per unit) Rh immunization by contaminating red cells is a potential problem. If platelets from an Rhpositive donor have to be given to an Rh-negative woman of childbearing age, it is recommended that Rh immunoglobulin be administered shortly after the platelet transfusion, while the platelets are hemostatically effective. Fever Fever occurring immediately or several hours following platelet transfusion is often due to allo-
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antibodies to the leukocytes present in the platelet preparation.50 This is often encountered when the platelets are obtained by plateletphoresis. Premedication with antihistamines and additional centrifugation of the platelet preparation may help to decrease the frequency of this complication *50 Fever occurring several hours after the platelet transfusion may signify bacterial contamination of the platelet preparation (often with enterobacteria, staphylococci or pseudomonads) .51,65 Viral and protozoal infections transmitted by platelet transfusions have also been reported.66 Granulocytopenia Granulocytopenia, presumably on an immune basis, occasionally may follow platelet transfusion.67 This is potentially a serious problem in the leukemic or aplastic patient who has a depressed leukocyte count prior to the transfusion. Past-transfusion purpura While post-transfusion purpura is not a complication of platelet transfusion, it deserves emphasis since platelet transfusions given to patients with this problem can result in significant illness. This uncommon syndrome of severe thrombocytopenia usually occurs in women 1 week after a blood transfusion, and the recipient's platelets are usually negative to PlAl. The condition has been managed with plasmapheresis and corticosteroid therapy.68 Platelet transfusions should not be given. We thank Drs. J. Hirsh, M.C. Brain and W.E.C. Wilson for their thoughtful comments during the preparation of this manuscript. References
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30. ROWE AW, LENNY LL, REICH LM:
Studies on chromium-Si labelling on human platelets cryopreserved by the glycerol/glucose method and the DMSO method. Cryobiology 15: 698, 1978 31. VoGIN EE, CARSON 5, CANNON G, et al: Chronic toxicity of DMSO in
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MB, et al: Cumulative experience in the detection of antiplatelet antibody in 234 patients with idiopathic thrombocytopenic purpura, systemic lupus erythematosus and other clinical disorders. Am J Med 52: 776, 1972 36. HIRSCHMAN RJ, SHULMAN NR: The
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HEINRICH D: The problem of platelet autoantibodies. II. The applicability of the 14C-serotonin release test. Ibid, p 234 39. KELTON JG, NEAME PB, BISHOP J,
et al: The direct assay for plateletassociated IgG (PAIgG) - lack of association between antibody level and platelet size. Blood 53: 73, 1979 40. VON DEM BORNE AEG, VERHEUGT
FWA, OOSTERHOF F, et al: A simple immunofluorescence test for the detection of platelet antibodies. Br J Haematol 39: 195, 1978 41. MCMILLAN R, LONGMIRE RL, YE-
LENOSKY R, et al: Quantitation of platelet-binding IgG produced in vitro by spleens from patients with idiopathic thrombocytopenic purpura. N Engi J Med 291: 812, 1974 42. SHULMAN NR, MARDER VJ, HILLER
MC, et al: Platelet and leukocyte isoantigens and their antibodies: serologic, physiologic and clinical studies. Frog Hematol 4: 222, 1964 43. BUCHER U, DE WECK A, SPLENGLER
H, et al: Platelet transfusions: shortened survival of HL-A-identical platelets and failure of in vitro detection of anti-platelet antibodies after multiple transfusions. Vox Sang 25: 187, 1973 44. GUREvITCH J, NELKEN D:
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II. A1 and A2 subgroups in blood platelets. J Lab Clin Med 46: 530, 1955 46. Idem: Studies on platelet antigens.
III. Rh-Hr antigens in platelets. Vox Sang 2: 342, 1957 47. ASTER RH: Effect of anticoagulant and ABO incompatibility on recovery of transfused human platelets. Blood 26: 732, 1965 48. LOHRMANN H-P, BULL MI, DECTER JA, et al: Platelet transfusions from
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term platelet support of patients with aplastic anemia: effect of splenectomy and steroid therapy. Ann Intern Med 73: 1, 1970 57. MITTAL KK, RUDER EA, GREEN D: Matching of histocompatibility (HL-
A) antigens for platelet transfusion. Blood 47: 31, 1976 58. DUQUESNOY RJ, FILIP DJ, ASTER RH: Influence of HLA-A2 on the effectiveness of platelet transfusion
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3 cross-matching techniques. Transfusion 17: 638, 1977 63. DUQUESNOY RJ, FILIP Di, RODEY
GE, et al: Successful transfusion of platelets "mismatched" for HLA antigens to alloimmunized thrombocytopenic patients. Am J Hematol 2: 219, 1977 64. ZoES C, DUnE VE, MILLER HJ, et al: Anti-Al in plasma of platelet concentrates causing a hemolytic reaction. Transfusion 17: 29, 1977 65. BUCHHOLZ DH, YOUNG VM, FRIEDMAN NR, et al: Bacterial proliferation in platelet products stored at room temperature: transfusion-induced enterobacter sepsis. N Engi J Med 285: 429, 1971 66. GARFIELD MD, ERSHLER WB, MAKI DG: Malaria transmission by platelet concentrate transfusion. JA MA 240: 2285, 1978 67. HERZIG RH, POPLACK DG, YANKEE RA: Prolonged granulocytopenia from incompatible platelet transfu-
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CMA JOURNAL/NOVEMBER 17, 1979/VOL. 121
I BOOKS This list is an acknowledgement of books received. It does not preclude review at a later date. CLINICAL GENETICS. A Source Book for Physicians. Edited by Laird G. Jackson and R. Neil Schimke. 652 pp. Illust. John Wiley & Sons, Inc., Somerset, New Jersey, 1979. $35. ISBN 0-47101943-7 ENTERAL HYPERALIMENTATION WITH CHEMICALLY DEFINED ELEMENTAL DIETS: A SOURCE BOOK. 2nd ed. Compiled by Dennis B. Worthen and Joan R. Lorimer. 376 pp. Information Services, Research Department, Scientific Affairs, Norwich-Eaton Pharmaceuticals, Norwich, New York, 1979. $9.95, paperbound 1st SUPPLEMENT to the four volumes on the "Topographic Positions of the Measurement Points in Electro-Acupuncture (EAV)". Reinhold Voll. Translated and fully revised by Hartwig Schuldt. 49 pp. Illust. International Scholarly Book Services, Inc., Forest Grove, Oregon, 1978. $35, paperbound. ISBN 3-88136-063-8 THE FIRST YEAR OF LIFE. The Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke. Janet B. Hardy, Joseph S. Drage and Esther C. Jackson. 336 pp. lIlust. The Johns Hopkins University Press, Baltimore, 1979. $25. ISBN 0-8018-2167-3 HANDBOOK OF NONPRESCRIPTION DRUGS. 6th ed. Richard P. Penna, Project Director; L. Luan Corrigan, Managing Editor; Joan Welsh, Project Editor; and others. 488 pp. IlIust. American Pharmaceutical Association, Washington, DC, 1979. $20. ISBN 0-91733027-7 HAVENS OF REFUGE. A History of Leprosy in Western Australia. W.S. Davidson. 188 pp. lIlust. University of Western Australia Press for the Public Health Department; International Scholarly Book Services Inc., Forest Grove, Oregon, 1978. $24. ISBN 0-85564-141-X HEALTH GUIDE FOR TRAVELLERS TO WARM CLIMATES. 2nd ed. Stanley 5K. Seah. 89 pp. IlIust. The Canadian Public Health Association, Ottawa, 1979. $2.50 (single copies), paperbound HEALTH IN DANGER. The Crisis in the National Health Service. David Widgery. 178 pp. The Shoe String Press, Inc., Hamden, Connecticut, 1979. $17.50. ISBN 0-208-01759-3 HYPOTHALAMIC RELEASING FACTORS. Volume 3. Wayne B. Watkins. 130 pp. Eden Press Inc., Montreal, 1979. $20. ISBN 0-88831-046-3 IMMUNOPATHOGENESIS OF RHEUMATOID ARTHRITIS. Proceedings of the International Symposium held at Guy's Hospital, London in November 1978. Edited by G.S. Panayi and P.M. Johnson. 163 pp. IlIust. Reedbooks Ltd., Chertsey, Surrey, 1979. Price not stated, paperbound. ISBN 0-906544-02-5
continued on page 1380
