Adverse reactions to platelet transfusion such as febrile reactions, alloimmunization and immune associated refractoriness to platelet transfusion have generally been thought to be associated with patients forming antibodies to donors' leukocytes which contaminate the transfused platelet products. In an attempt to prevent such reactions many clinicians have committed to using leukocyte reduction filters at the bedside. In fact, Lane et al¹ concluded in a 1992 Annals of Internal Medicine review that leukocyte reduction of red cell and platelet products should be indicated for patients likely to receive long term transfusion support to prevent recurrent febrile reactions and to prevent or delay alloimmunization to leukocyte antigens. This advice seems to have proven effective for alloimmunization. While bedside leukocyte reduction has been shown to significantly reduce the rate of febrile reactions associated with platelet transfusion, some patients continue to have reactions.² Furthermore, there are reports of reactions to platelet transfusion such as hypotension sometimes accompanied by nausea, chills, and tachycardia that are unexplained. The pathophysiology as well as the frequency and nature of febrile and these other adverse reactions to platelet transfusion have had limited investigation and review.

It is possible that sensitization to donor leukocytes is but one cause of febrile reactions associated with platelet transfusion. Other causes such as leukocyte released cytokines, and other biological mediators released into the plasma during platelet storage may be associated with febrile reactions and hypotensive and anaphylactic reactions to platelets, as recently reported.

The purpose of this monograph is to present a review of the literature to evaluate the likelihood that leukocyte released or breakdown products are associated with adverse reactions to platelets and that the timing of leukocyte reduction prestorage vs. poststorage should be considered.

Platelet transfusion reactions can vary from nonhemolytic febrile transfusion reactions, chills and rigors to allergic reactions characterized by urticaria, pruritus, erythema, bronchospasm and/or laryngeal edema, gastrointestinal symptoms, hypotension and tachycardia and respiratory and cardiac arrest. When these allergic reactions are known to be mediated by IgE, they are identified as anaphylactic reactions. For the remaining reactions that mimic anaphylactic reactions, the term "immediate generalized reactions" can be used as an umbrella term⁶, See Table 1.

The increased use of aggressive chemotherapy for malignant diseases and the increasing use of bone marrow transplantation for malignancies have led to significant increases in platelet usage. Concurrent with this increased use of platelet transfusion, Buck et al⁷ noted an increase at their institution in allergic reactions to platelet transfusion. Their retrospective review noted that 94 patients had 301 platelet transfusion reactions. Fifty-six reactions (19%) were urticarial, 199 (66%) were febrile, and 46 (15%) were severely allergic with or without anaphylaxis.⁷

Wilhelm et al reported their analysis of 57 nonhemolytic transfusion reactions to platelet transfusion and found that 29 (51%) of these reactions were allergic, followed by 18 (32%) febrile reactions and 10 (17%) were classified as circulatory distress. In describing the reactions, Wilhelm et al noted that the first NHFTR to platelet transfusion was often mild (rash, itching) but after repeated transfusion, reactions occurred almost immediately and with an increasing severity (i.e. shock). They found that 93% of all patients experiencing allergic transfusion reactions had IgE antibodies.⁸

Since these transfusion reactions occur with different frequencies in red cells and platelet components^3,4,5 and can occur virtually with the onset of transfusion in patients not previously transfused or pregnant⁴ and can vary with the age and content of the product suggests that multiple causes may be responsible for these patient symptoms. In the subsequent sections of this review, we will bring together literature reports on some of the cited potential causes of anaphylactic and immediate generalized reactions.

Red cell components and platelet components may be collected and stored differently yielding different cohorts of cellular components. Red cells are stored at 4 degrees Celsius. In the U.S. red cells in additive solutions such as AS-1 and AS-3 are stored for 42 days, while red cells in acid citrate preservative solutions such as CPDA-1 are stored for 35 days. Red cells are generally processed in a single centrifugation step with either a soft or hard spin. Red cells undergo physical changes in storage such as shape changes and biochemical changes such as a decline in 2,3 - DPG levels.¹⁷

The storage medium of platelets is autologous citrated plasma. There are two general types of platelet concentrate used. Random donor platelet concentrate harvested as a by-product of whole blood donations is prepared using the light spin/hard spin technique of centrifugation. A single unit, generally 50cc, is either combined with other platelet concentrates, usually 4 to 10 per transfusion, or in some instances is administered sequentially at the bedside. Single donor platelets are collected by a variety of apheresis procedures to give an equivalent of 4 to 8 random donor platelet concentrates or more. The storage volumes of the single donor units are 200 to 400mls. It should be noted that when platelets are transfused as random donor pools or single donor products, significant amounts of plasma are also transfused. Because, platelets are stored at 20-24 degrees Celsius/room temperature leukocytes will breakdown and release substances into the plasma⁹ and contaminating bacteria will proliferate.^{43 44 45}

At a 1991 Symposium of The Cellular and Molecular Basis of the Platelet Storage Lesion, Aster commented on what happens to platelets during storage:

"....We know that things go wrong with platelet concentrates during storage even under what seem to be optimal conditions. We know that activation occurs in the process of concentrating and resuspending platelets. Platelets do not like to come in contact with foreign surface or with each other. We know that there is release of granule contents and modifications of platelet membrane components during the storage period. The process of concentrating platelets at high G forces and resuspending them, in itself, induces changes...".⁹

Heddle et al reported that blood product age predicted transfusion reactions. Transfusion reactions were fivefold greater in platelets and the older the platelet product and the higher the white cell count the more likely upon transfusion a reaction would occur.³ Similar observations were reported by Muylle et al.¹⁰ In a retrospective study, Muylle and Peetermans found an increased incidence and severity of reactions to platelet transfusion concurrent with the use of plastic bags allowing 5 day platelet storage. They found these reactions to include bronchospasm, wheezing and dyspnea and to be related to the length of the storage time and the white cell content of the platelet concentrate.¹⁰

In subsequent studies Muylle et al¹¹ tested their hypothesis that transfusion reactions to platelet transfusion were more frequent and more severe after storage of the platelets for 3 days. Random donor platelet concentrates prepared from whole blood by the platelet rich plasma method were pooled and depleted of leukocytes by centrifugation immediately prior to transfusion. The incidence and severity of reactions in 74 patients receiving 570 leukocyte poor platelet transfusions was studied. While the overall transfusion reaction rate was 13.7%, the reaction rate to platelets stored for 3 days or more was 17.6% or twice the reaction rate found with platelets stored for less than 3 days. It was also noted that minor reactions as well as moderate and severe reactions were more frequent with the transfusion of platelets stored for 3 days or more. The severe reactions included wheezing, dyspnea and cyanosis as noted above and represented 5.1% of all reactions.¹¹

The symptoms that Muylle et al observed in the severe reactions also meet the description of the signs and symptoms of immediate generalized reactions to plasma and plasma containing products described by Greenberger.⁶ Muylle et al theorized that during the storage of platelet concentrates pyrogenic and vasoactive substances were accumulated in the plasma of the concentrate causing reactions when a critical dose was transfused to a patient.¹¹ See Table 2.

Patients to be transfused with platelet products may have circulating antibodies to leukocytes as we suggested earlier. The pathogenicity of leukocyte antibodies was demonstrated by an experiment reported by Brittingham and Chaplin. Fifty milliliters of blood containing a leukoagglutinin with a titre of 256 was transfused to one of the two authors. Within 45 minutes, the recipient developed a chill, severe hypotension with cyanosis and a respiratory rate of 60 per minute. His white cell count also fell from 9 x 10⁹/L to 2 x 10 ⁹/L. ^{12, 13}

This reaction would be classified as severe and as one that reflects the symptoms of immediate generalized reactions to plasma containing products.⁶ Payne has also reported that leukocyte antibodies were associated with febrile reactions. This generally has been assumed to be the cause of febrile reactions to platelets.¹³

What about other possibilities that might cause reactions such as that reported above, substances like histamine, cytokines, that can accumulate during platelet storage? What does the existing literature teach us?

Basophils in the blood and mast cells in the tissue synthesize and store histamine. When histamine is released, it exerts its predominant effects by contracting the smooth muscles of the respiratory and gastrointestinal tract and dilating capillaries. The administration of a significant bolus of histamine can result in headache, flushing, hypotension, dyspnea, vomiting and diarrhea.¹⁵ Frewin et al reported the histamine content in red cells stored for 4 weeks reached concentrations more than 30 fold greater than their original level at the beginning of storage. They concluded that the quantity of histamine that accumulated in red cells was great enough to account for observed transfusion reactions.¹⁶ In subsequent studies Frewin et al found plasma histamine levels in excess of 1 mg/ml in a group of patients experiencing "anaphylactoid" reactions to the transfusion of older red cell units. Other patients in the same study who did not experience "anaphylacto id" reactions had mean plasma histamine concentrations below 0.50 mg/ml.¹⁶

Frewin et al was also able to correlate the increase in histamine content in stored blood with time and temperature.¹⁶

Frewin's observations are particularly relevant to the histamine content of platelets stored at 22 degrees Celsius. Muylle et al documented a similar progressive rise in histamine content during storage of platelet concentrates; however, the rise was far more rapid in the platelet concentrates. These authors theorized that a process of histamine release from leukocytes in the platelet concentrates accounted for this phenomena. Muylle et al suggested that a critical histamine threshold could be reached in a patient being transfused if stored platelets containing high levels of histamines were rapidly infused. This kind of event might result in symptoms such as bronchospasm and wheezing. Muylle et al documented levels as high as 22 mg/ml in single units of platelet concentrate stored for 5 days.¹⁷ This could account for a bolus infusion of approximately 6000 mg/ml of histamine in a 6 unit platelet pool. Both Frewin and Muylle suggest that the depletion of leukocytes from the r ed cell or platelet product shortly after collection would eliminate a large portion of the histamine and favorably influence the clinical outcome potentially eliminating or greatly reducing the number of severe transfusion reactions.^{16, 17}

Serotonin which is absorbed, concentrated and stored in dense granules in platelets can cause similar clinical effects to histamine.

Wiggins et al demonstrated in an animal model that profound hypotension can occur when platelet sequestration and platelet serotonin release occurs in response to the administration of dextran sulfate.¹⁸ This endogenous release phenomenon can be caused by serotonin released in vitro in stored platelet concentrate.¹⁹ During platelet storage, as Aster noted⁹ platelets release granule contents into the plasma in which the platelets are stored. Patients receiving chemotherapeutic drugs with strong emetogenic effects who require platelet transfusion therapy may be at particular risk of experiencing an adverse reaction to platelet transfusion. Cubeddu et al²⁰ have reported that these chemotherapeutic drugs stimulated the release of serotonin from enterochromaffin gut cells. The serotonin release has been reported to continue up to 8 hours after therapy. A patient could have, in conjunction with chemotherapy and transfusion of serotonin rich platelets expe rienced a cumulative effect increasing the likelihood of an immediate generalized reaction.

Several investigators have recently identified cytokines as possible important factors in certain transfusion reactions associated with the administration of platelet products. Cytokines are hormone-like substances secreted by a wide variety of cells such as lymphocytes, macrophages, fibroblasts and endothelial cells. They are a broad class of glycoproteins that regulate intercellular communication in normal and pathological situations.²¹ Since blood components all contain leukocytes which produce cytokines, it is not surprising that these hormone-like substances accumulate in products such as platelet concentrates during storage.

In light of earlier work where Muylle et al ¹¹ observed an increasing frequency and severity of transfusion reactions with increased storage time of platelet concentrates, these authors investigated cytokine levels in stored platelet concentrates and the relationship between these levels and transfusion reactions. Muylle and colleagues found increasing amounts of such cytokines as tumor necrosis factor (TNF), interleukin 1 (IL-1), and interleukin 6 in the plasma of stored platelet concentrates. These authors speculated that the source of these cytokines could be caused by damage to leukocytes in the platelet concentrate leading to leakage of cytokines and/or the activation of monocytes in the platelet concentrates. The activation of monocytes is possibly related to complement components causing the production of cytokines during storage. In their study platelet concentrates stored for 3 to 5 days contained total amounts of TNF and IL-1 close to 1000 mg/m 2 and 1 - 10 mg/kg respectively.²² In experimental clinical trials with recombinant TNF systemic toxicity including fever, chills, anorexia, and nausea were observed after TNF administration.²³

In March 1993 Aye reported on the production of cytokines in platelet concentrates at the Canadian Red Cross Society Symposium on Leukodepletion. Aye found 7 of 16 platelet concentrates on day 5 contained significant amounts of IL-beta (range 170 to > 340 pg/ml). Four of 16 units had TNF- alpha concentrations above 100 pg/ml (range 120 - 400 pg/ml). Platelet units with the highest leukocyte counts tended to have the highest cytokine production. In a second series of experiments, three separate groups of random donor platelet concentrates were samples for IL-1 beta, TNF - alpha, Il 6, and IL 8 as well as two platelet derived compounds. In the first group sampled on day 5 and the second groups sampled on days 0, 1, 3, and 5, similar results to the first set of experiments showed increasing levels of the cytokines with increasing storage. In the third group the platelet concentrates were leukocyte depleted prior to storage and cytokine levels were undetectable even at day 5.²⁴

A third set of authors, Stack and Snyder, have also reported significant accumulations of IL-8, IL-1 beta, IL-6 and TNF - alpha in platelet concentrates during storage. These authors also found that leukocyte reduction by third generation filters at day 1 of storage prevented generation of IL-8, and IL-1 beta out to day 5 of storage.²⁵

Sacher et al reported significant increases in IL-6 levels in patients experiencing acute transfusion reactions.²⁶

These studies strongly suggest that transfusion reactions are not always the result of an antigen-antibody reaction but could be related to the administration of plasma containing large amounts of cytokines. These particular cytokines as reported on above participate in proinflammatory, chemotactic and white cell activations. Injections of these compounds could result in fever neutrophilia, and the acute phase reaction.²⁷ High doses or one cytokine synergistically combined with another could cause hypotension, shock, pulmonary hemorrhage and death.^27,28,29

Platelet-activating factor (PAF) is an endogenous phospholipid released by a variety of cells such as neutrophils, basophils, monocytes, platelets, and vascular endothelial cells. When given intravenously, PAF causes systemic hypotension in rats³⁰, guinea pigs, rabbits, pigs and dogs.^30,31 PAF like compounds are generated during the storage of cellular blood components including platelet concentrates^32,33 PAF has been linked to a role in ARDs and even transfusion-related acute lung injury (TRALI).³¹

Yamanaka et al described in some detail a two phase hypotensive effect of PAF in dogs. The first phase was a transient hypotension and the second phase was a prolonged hypotension. The transient hypotension was thought to result in a dilation of peripheral resistance vessels.^32.

With the reported progressive accumulation of PAF in platelet concentrates, as well as in other blood components, it is again not difficult to suggest a possible role for PAF in adverse transfusion reactions, including immediate generalized reactions to plasma containing products.

The literature clearly documents that the transfusion of blood components to IgA deficient patients brings the risk of anaphylactic transfusion reactions. In these incidents the anaphylaxis is due to an interaction between the donor's transfused IgA and the recipient's anti IgA, either class specific or of limited specificity.^34,35,36 For prevention of these particular problems, blood components can be obtained from IgA deficient donors. Cellular products washed relatively free of plasma can be administered or cellular components stored in artificial media can be transfused.^{34 35 36 37 38}

The Chido (Ch) and Rodgers (Rg) antigens are strictly plasma proteins that are secondarily adsorbed to cell membranes. Chido and Rodgers are actually allotypes of the C4d component of plasma complement.^39,40 About 5% of the recipient population lacks one of these phenotypes and can produce an anti-Ch or anti-Rg antibody.³⁹

Westhoff et al⁴⁰ reported severe anaphylactic reactions in a patient during platelet transfusion. The case report is particularly interesting. The patient was diagnosed with acute myelocytic leukemia and underwent chemotherapy. During the course of this treatment the patient required transfusion and received 10 units of CPDA-1 RBC's and 50 units of random donor platelets over a three week period with no adverse reactions. At this time anti-Ch was identified in the patient's serum. This patient had no previous transfusion prior to diagnosis but did report two pregnancies. Following this, the patient received, over a 6-week period, 10 additional units of CPDA-1 RBC's and experienced febrile and/or urticarial reactions to at least 3 of the units. No platelets were transfused during this period. More than a year later the patient received an additional 3 units of Adsol RBC's with no adverse effects. About nine months later the patient required reinduction chemotherapy because of a relapse of her disease. Platelet transfusion was required at that time. Ten units of random donor platelets from O, Rh-positive donors were irradiated and administered at the bedside with a leukocyte reduction filter (Pall PL100). Seven minutes after the initiation of this transfusion, after only 50 ml through the filter the patient experienced an immediate reaction consisting of dizziness and a drop in systolic blood pressure from 150 over 72 to 50 with undetectable diastolic, wheezing and diaphoresis. The transfusion was stopped and 100 mg of methylprednisolone sodium succinate (Solumedrol, The Upjohn Company, Kalamazoo, MI) was administered intravenously. In the 60 minutes following, the patient experienced nausea, 1 degree Fahrenheit temperature rise, itching of the extremities and had a flat red rash on the trunk. The symptoms abated in 3 hours.

Two days later an additional 10 units of irradiated platelets were transfused through a leukocyte reduction filter (Pall PL100). The patient was premedicated with 500 mg of Solumedrol. After 200 ml were transfused, the patient experienced a similar life threatening immediate generalized reaction as reported above.

Subsequently, the patient received 23 random donor (230) units, plasma reduced, saline suspended platelet pools over a 6-week period. All pools were transfused with a leukocyte reduction filter (Pall PL100) and the patient experienced only one mild febrile incident. The patient also received 22 units of Adsol RBC's without adverse reactions.

Westhoff, et al,⁴⁰ concluded that these severe immediate generalized reactions occurred in this patient following transfusion of large amount of plasma associated with 10 unit platelet pools with protein C4 to a patient with high titer anti-Ch. When more moderate amounts of plasma were transfused with CPDA-1 RBC's, urticarial reactions were observed. The authors also ruled out any reaction to filter material or sterilization process since no reactions occurred with filtration of 23 10-unit pools of plasma reduced, saline-suspended platelets. It was also not possible to conclusively prove these reactions were due to anti-Ch.⁴¹ It is clear, though, that plasma reduction contributed significantly to eliminating subsequent reactions.

Bacterial contamination of platelet products can lead to transfusion associated sepsis. Characteristic symptoms in transfusion associated sepsis include chills, fever, hypotension and hypoxia. Blood cultures drawn from the patient experiencing such reactions are found to be positive in less than half the episodes.⁴¹ Estimates of the incidence of bacterial contamination in platelet products range from a high of 10% of all platelet pools⁴² to more conservative estimates of 4 in every 1000 pools.^41,42,43

If the bacteria contaminating the platelet product are gram negative, there is an added risk of the infusion of endotoxins which can result in endotoxic shock. Clinical features associated with endotoxins include fever, chills, hypotension, respiratory failure and gastrointestinal symptoms, to mention a few.⁴⁴

It is not clear what intervention can prevent or reduce of the incidence of bacterial contamination in platelet products. While shortening the storage shelflife to three days has been considered, studies have shown this may be of little real value since bacteria can achieve log growth and relatively high concentrations by day 3 of storage.⁴⁵

Transfusion-related-acute lung injury (TRALI), a life threatening complication
of hemotherapy, has been associated with plasma containing blood products. Most of the TRALI reactions have involved either whole blood, RBCs stored in non protein poor additives, or FFP.⁴⁶ Platelet products, because of their plasma content, could certainly be associated with a TRALI event. TRALI is characterized by acute respiratory distress; severe, bilateral pulmonary edema; and severe hypoxemia. Fever and hypotension may also be associated with TRALI.⁴⁶ Unlike cytokines or serotonin where the onset of patient reaction may be at the initiation of the transfusion TRALI has generally been associated within 1- 6 hours of transfusion.⁴⁶

TRALI is thought to be associated with passive transfer of antibody from donors, often multiparous women, to the recipient. These donor antibodies may interact with the recipient's leukocytes in an unusual immune-mediated transfusion reaction.⁴⁶

What have we learned and what consistent themes emerge from this review? First, as reported by several authors^3,4,5, patients are at greater risk of an adverse reaction when receiving platelet products compared to red cells. Second, when adverse reactions to platelet transfusion occurring at their institutions were reviewed by Buck et al⁷ and Wilhelm et al⁸, they reported 15% of 300 were severe allergic reactions and 51% of 57 were allergic reactions respectively. Buck et al suggested the allergic reactions were likely due to sensitization to plasma proteins or plasma constituents.⁷ See Table 2.

With respect to the platelet products themselves, numerous authors commented on the room temperature storage of platelets and the occurrence of cytokine^22,24,25, histamine¹⁷, serotonin¹⁹, PAF³³ accumulation in platelet products with increasing storage. See Table 3. Infusion of these substances in high enough concentration could as noted by several authors elicit adverse reactions characterized as immediate generalized reactions or reactions that mimic anaphylactic reactions. In conjunction, with this potential accumulation of substances in platelet products, it is also interesting to note that Heddle et al³ and Muylle et al¹¹ reported a high occurrence of adverse transfusion reactions with older platelets or platelets beyond day 3 of storage. Muylle et al also found moderate to severe reactions were more frequent when platelet products transfused were stored for more than 3 days. It should also be n oted that leukocytes that are in the platelet products as contaminants were identified as the source of accumulating histamine, cytokines and PAF in the platelet products. Several authors reported that leukocyte depletion of the platelets after processing and prior to storage would prevent the accumulation of the above substances.^{24, 25}

During transfusion, the variables most likely to contribute to transfusion reactions or immediate generalized reactions are donor related factors, the final state of the platelet product itself and some set of predisposing factors in the patient. In these kinds of circumstances a discernable pattern of patient reaction may be difficult to identify.

Since several authors^{24, 25} suggested a prestorage leukocyte reduction of the platelets would prevent or significantly reduce cytokine and other kinds of accumulation in platelets, we will conclude with two reports from Dzik et al^{47, 48} on a new method of component preparation that is capable of producing a leukocyte reduced platelet concentrate from whole blood. In this new method, the platelet-rich-plasma (PRP) is leukocyte reduced by filtration (Pall Biomedical Products Co.) prior to the second spin of component preparation. Dzik et al reported leukocyte residuals of <6 x 10⁴ per platelet concentrate with 95% of the platelets passing the filter. The platelet concentrates and plasma fractions were of standard volumes.(47,48) This simple and effective technique may hold great promise for addressing adverse reactions to platelet transfusion with a PRP pre storage leukocyte reduction.

TABLE 1:  Examples of Some Clinical Manifestations of Immediate Generalized Reactions from transfusions of Blood Products

1. Apprehension, feeling of doom, etc . 2. Generalized pruritus, flushing, and erythema . 3. Generalized utricaria or angiodema . 4. Dyspnea . 5. Gastrointestinal symptoms . 6. Hypotension and tachycardia . 7. Respiratory and cardiac arrest .

 

 

 

 

 

 

 

From: (6) Greenberger, P. A., Plasma anaphylaxis and immediate time reactions. In: Principles of Transfusion Medicine. ed. Rossi, E.C., Simon T.L., Mass G.S., Williams and Wilkins, Baltimore, MD, 1991.

TABLE 2:  Frequency of Immediate Generalized Reactions/or Severe Transfusion Reactions Mimicing Anaphylactic Reaction

Authors	Severe Reactions	Total Number of Reactions
Buck et al(7) (1987) . Wilhelm et al(8) (1993) . Chambers et al(4) 1990 . . Muylle et al(11) (1992) 95% WBC removed by centrifugation* .	46/15% . 10/17% . 53/42% 19/51% . 4/5.1% . .	301* . 57* . 125 (pooled Rd)* 37 (single dN)* . 78 . .

* Note all reactions reported are in unmodified or non leukoreduced platelets
** WBC residual 0.7 +/- 0.7 x 10⁸

TABLE 3: Substances Accumulated from WBCs in Platelet Products that could be Associated
with Immediate Generalized Reactions

Authors	Substance	Source	Symptoms
Muylle et al(17) (1988) . . . Muylle et al(22) (1993) . . . . Aye, M.T(24) (1994) . . . . . . Stack and Snyder(25) (1994) . . . . . . Silliman et al(33) . .	Histamine . . . Cytokines TNF IL-1 . . Cytokines IL-1 TNF IL-6 IL-8 . . Cytokines IL-8 IL-1 IL-6 TNF . . PAF . .	Released by WBC during storage . . Released by WBC during storage . . . Released by WBC during storage . . . . . Released by WBC during storage . . . . . Released by WBC during storage .	Erythema, dyspnea, wheezing, bronchospasm, hypotension . . Fever, Neutrophilia, Acute phase reaction, hypotension, shock, pulmonary hemorrhage . . Fever, Neutrophilia, Acute phase reaction, hypotension, shock, pulmonary hemorrhage . . . . Fever, Neutrophilia, Acute phase reaction, hypotension, shock, pulmonary hemorrhage . . . . Hypotension vasodilatory actions, lung tissue damage .

1. Lane, T.A., Anderson, K.C., Goodnough, L.T., Kurtz, S., Moroff, G. Pisciotto, P.T., Sayers, M. Silberstein, L.E., Leukocyte Reduction in Blood Component Therapy. Annals of Internal Medicine 117: 151-162, 1992.

2. Mangano, M.M., Chambers, L.A., Kruskall, M.S., Limited Efficacy of Leukopoor Platelets for A Prevention of Febrile Transfusion Reactions, Am. J. Clin. Pathol., 95: 733-738, 1991.

3. Heddle N.M., Klama L.N., Griffith R., Roberta R., Shulka G., Kelton J.G., A prospective study to identify the risk factors associated with acute reactions to platelet and red cell transfusion. Transfusion 33: 794-97, 1993.

4. Chambers L.A., Kruskoll M.S., Pacini D.G., Donovan L.M., Febrile reactions after platelet transfusion: the effect of single versus multiple donors. Transfusion 30: 219-21, 1990.

5. Riccardi D., Raspollini G., Rossini G., Porretti S., Cordini A., Parravicini A., Rebulla P., Sirchia G., Reactions reported to red blood cells without buffy coat and platelet concentrates prepared from buffy coats. 46th annual meeting of the American Association of Blood Banks, Oct. 1993, Miami, FL (5106).

6. Greenberger P.A.., Plasma anaphylaxis and immediate type reactions. In Principles of Transfusion Medicine. ed. Rossi E.C., Simon T.L., Mass G.S., Williams and Wilkins, Baltimore, MD, 1991.

7. Buck S.A., Kickler T.S., McGuire M., Braine H.G., Ness P.M., The utility of platelet washing using an automated procedure for severe platelet allergic reactions. Transfusion 27: 391-393, 1987.

8. Wilhelm D., Klauche M., Fiebelkon A., Gorg S., Kluter H., Kirchner H., Non-hemolytic transfusion reactions after platelet substitution. Lancet 7 August: 364 (L), 1993.

9. Aster R., Platelet storage lesion. Proceedings from: Symposium on: The cellular and molecular basis of the platelet storage lesion. April 9-10, 1991, Bethesda, MD.

10. Muylle L., Peetermans M.E., Transfusion reactions to platelet concentrates: effect of preparation and storage time. In: Abstracts of the Eighth Meeting of the International Society of Hematology, European and African Division, 177, 1985.

11. Muylle L., Wouters E., DeBock R., Peetermans M.E., Reactions to platelet transfusion, the effect of the storage time of the concentrate, Transfusion Medicine, 2, 289-293, 1992.

12. Mollison P.L., Englelfreit C.P., Contreras M., Some unfavorable effects of transfusion, Chapter 16, pp. 723-763, in: Blood Transfusion in Clinical Medicine, 8th Ed. by the above authors, Blackwell Scientific Publications, Oxford, 1983.

13. Brittingham T.E. and Chaplin H. Jr., Febrile Transfusion Reactions caused by sensitivity to donor leukocytes and platelets. J. American Med. Assn. 165, 819, 1957.

14. Payne, R., The association of febrile transfusion reactions with leukoagglutinins, Vox Sang. 2, 233, 1957.

15. Douglas W.W., Autocoids, In: The pharmacological basis of therapeutics, 7th edition. eds. Goodman Gilman A., Goodman L.S., Rall T.W., Murad F., MacMillan , N. Y., N. Y., 1985.

16. Frewin D.B., Jansson J.R., Head R.J., Russell W.J., Beal R.W., Histamine levels in stored blood. Transfusion, 24: 502-4, 1984.

17. Muylle L., Laekeman G., Herman A.G., Peetermans M.E., Histamine levels in stored platelet concentrate. Relationship to white cell content. Transfusion 28: 226-228, 1988.

18. Wiggins R.C., Glatfelter A., Campbell A.M., Kunkel R.G., Ulevitch R.J. Acute hypotension due to platelet serotonin induced chemoreflexes after intravenous injection of dextran sulfate in the rabbit. Circ Res. 57: 262-77, 1985.

19. Holmsen H., Ostvold A.C., Day H.J. Behaviour of endogenous and newly absorbed serotonin in the platelet release reaction. Biochem Pharacol. 22: 2599-608; 1973.

20. Cubeddu, L.X., Hoffman I.S., Fuenmayor N.T, Malove J.J. Changes in Serotonin metabolism in cancer patients: its relationship to nausea and vomiting induced by chemotherapeutic drugs, Br. J. Cancer. 66: 198-203, 1992.

21. Blajchman M., Cytokines in transfusion medicine, Transfusion 33, 1-3, 1993.

22. Muylle L., Joss M., Wouters E., DeBock R., Peetermans M.E., Increased tumor necrosis factor a(TNF a), interleukin 1, and interleukin 6 (IL 6) levels in the plasma of stored platelet concentrates: relationship between TNF a and IL - 6 levels and febrile transfusion reactions, Transfusion 33, 195-199, 1993.

23. Spriggs D.R., Sherman M.L., Frei E.III, Kufe D.W., Clinical studies with tumor necrosis factor. In: Tumor necrosis factor and related cytotoxins, 131st Ciba Foundation Symposium, Chichester, U.K., Wiley, 206-207, 1987.

24. Aye M.T., Production of Cytokines in Platelet Concentrates, In: Canadian Red Cross Society Symposium on Leukodepletion: Report of Proceedings to be published, 1994.

25. Stack G., Snyder E.L., Cytokine Generation in Stored Platelet Concentrates, Transfusion 34, 20-25, 1994.

26. Sacher, R.A., Boyle, L., Freter, C.E., High circulating interleukin and levels associated with acute transfusion reaction: cause or effect, Transfusion 33, 962, 1993.

27. Smith J., Urba W., Steis R., et al., Interleukin -1 alpha: results of a phase 1 toxicity and immunomodulatory trial. Am. Soc. Clin. Oncol. 9: 717, 1990.

28. Butler L.D., Lagman N.K., Coin R.L., et al.: Interleukin -1 induced pathophysiology: induction of cytokines development of histopathological changes, and immunopharmacological intervention. Clin. Immunol. Immunopatol. 53: 400-21, 1989.

29. O'Kusaiva S., Gelfond J.A., Ikejima T., Connoly R.J., Dinarello C.A., Interleukin -1 induces a shock-like state in rabbits. Synergism with tumor necrosis factor and the effect of cyclooxygenase inhibition. J. Clin. Invest.
81: 162-172, 1988.

30. Siren A. Feuerstein G. Effects of PAF and BN52021 on cardiac function and regional blood flow in conscious rats. Am. J. Physiol. 257, H25-H32, 1989.

31. Tanaka S., Kasuya K., Masuda Y., Shigenobu K. Studies on the hypotensive effects of platelet activating factor (PAF, 1-0-alkyl-2-acetyl-sn-glyceryl-3-phasphacylcholine) in rats, guinea pigs, rabbits and dogs. J. Pharmacobrodyn 6, 866-873, 1983.

32. Yamanaka S. Miura K, Yukimura T., Okumura M. and Yamamoto K., Putative mechanism of hypotensive action of platelet-activating factor in dogs.Circulation research 70, 893 - 901, 1992.

33. Silliman C.C., Thurman G.W., Ambruso D.R., Stored Blood Components contain agents that prime the neutrophil NADPH Oxidase through the Platelet activating factor receptor. Vox Sang. 63: 133-136, 1992.

34. Vyas G.N., Perkins H.A., Fudenberg H.H, Anaphylactoid transfusion reactions associated with anti-IgA. Lancet 2:312-315, 1969.

35. Pineda A.A., Taswell H.F., Transfusion Reactions Associated with anti-IgA
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