Influence on the Immune System of Homologous Blood Transfusion and Autologous Blood Donation: Impact on the Routine Clinical Practice/Differences in Oncological and Non-tumour Surgery?

Patients with severe blood loss due to trauma, surgery and child-birth may require transfusion with blood components to maintain the overall hemodynamics, optimal tissue oxygenation and coagulation capacity. The potential risk of viral and bacterial transmission from donor to recipient has led to development of screening procedures - at least in the developed countries - to garantee the quality of blood components. At present transmission of HIV and Hepatitis viruses are very infrequent. Thereby transfusion with blood components is a well established treatment modality, witch often has beneficial impact on patient survival. When considering transfusion with blood components it should be kept in mind, however, that transfusion may also lead to acute side-effects such as recipient leucocytosis, febrile nonhemolytic transfusion reaction, acute haemolytic transfusion reaction, graft-versus-host disease, blood transfusion-related adult respiratory distress syndrome [1]; the overall frequency being œ - 2 %. Transfusion of homologous components may lead to recipient microchimerism, as Y-chromosomes may be detected in women months to years after recipience of male donor blood [2]. Viral infection due to transmission of virus sequences not found in the screening procedures may also still be a problem of vital interest [3] [4]. In addition, transfusion with components including the white cells should be considered as a mononuclear cell transplantation with expression of various tissue type antigens [5].

Transfusion of blood components cause recipient immunomodulation with stimulation of certain reactions and suppression of others, the overall net balance being impaired immune reaction [6]. Patients with Crohn's disease, patients undergoing organ transplantation and patients with recurrent rheumatoid arthritis may benefit of the blood transfusion-induced impaired immune reactions [1], while this may be of disadvantage for patients undergoing surgery, due to its relation to development of postoperative infectious complications [7]. However, interpretation of the association of blood transfusion and postoperative infectious complications may be complicated, because several other factors in addition to blood transfusion may play significant roles in development of postoperative infectious complications [6]. Thus, at least bacterial contamination, the circumstances under which the operation is performed (acute versus elective operation, etc.), the host immune competence, the nature of the disease, and alcohol abuse are factors to be considered [6] [8]. There are considerable differences between bacterial contamination in large bowel surgery and in hip or knee joint replacement surgery, with higher risk of infectious complications in large bowel surgery. Furthermore, patients undergoing emergency surgery for trauma or for large bowel disease have a much higher risk of developing infectious complications than patients with similar diseases undergoing elective surgery [8]. Therefore, the awareness of the association of blood transfusion with increased risk of postoperative infectious complications should be much differentiated, and related to the specific surgical situation considering pro's and contra's of perioperative blood component transfusion.

The debate of the association between perioperative blood component transfusion and reduced recurrence-free and long-term survival of patients with solid tumours has been running for decades without final consensus. At present, due to results from retrospective and prospective studies, it is well recognised that patients undergoing resection for colorectal cancer and receiving perioperative blood component transfusion have a poor prognosis compared to patients undergoing similar resections, but without receiving blood components [9]. However, results form clinical studies of patients with various other solid tumours are more difficult to be used in an overall evaluation of the significance of blood component transfusion and poor survival after resection. In some of these studies the association has been shown (including breast-, oesophageal-, liver-, lung-, and head & neck cancer), while results from other studies have been unable to confirm the association (including breast-, lung-, uterus-, and brain cancer). Very recent results from a major clinically controlled, prospective study including 740 patients undergoing elective resection for colorectal cancer have shown, that patients receiving perioperative blood component transfusion and who subsequently developed postoperative infectious complications (n = 134) had a significant and Dukes stage-independent reduced overall survival and reduced recurrence-free survival as well [10]. In a univariate statistical analysis followed by a multivariate statistical analysis including more that 150 pre-, intra- and postoperative variables the only other Dukes independent variable related to poor prognosis was tumour location in the rectum. In particular, patients receiving perioperative blood component transfusion without subsequent infectious complication development (n = 296) had a prognosis similar to non-transfused patients. These findings suggest that certain other factors than blood transfusion per se play a role in cancer recurrence related to blood component transfusion. In addition, the results may explain some of the discrepancies between results from different solid tumours with different risks of postoperative infectious complications.

Due to the risks of transmission of virus from donor to recipient, postoperative infectious complications, cancer recurrence, microchimerism, exposure to foreign tissue type antigens, etc. by transfusion of homologous components, preoperative autologous blood deposition has been considered and introduced in certain European countries. In elective hip and knee surgery for benign diseases this approach has reduced the overall infectious complication rates significantly from approximately 7 % to 4 % [11]. In surgery for solid, malignant tumours, however, results from studies comparing homologous blood component with predeposit autologous blood transfusion indicate, that patients receiving autologous blood have similar poor prognosis as patients receiving homologous blood [12] [13]. Blood deposit may lead to preoperative impaired natural killer cell function in patients with malignancy, and patients receiving transfusion of predeposit autologous blood have similar impaired postoperative immune reactions as patients receiving homologous transfusions [1]. Febrile nonhemolytic transfusion reactions, acute haemolytic transfusion reactions, graft-versus-host disease, and transfusion-associated lung complications are observed as frequently with autologous as with homologous transfusions [14]. Moreover, potential beneficial effects of predeposit of autologous blood may be overshadowed by the fact that more than 50 % of the predeposit autologous blood donations are not transfused. Such blood has to be discharged, because surgical patients with various benign or malignant diseases do not fulfil requirements for normal blood donors. Therefore, the economy in such approaches may be limiting its general use particularly in surgery for malignant diseases, but also to a certain extent in surgery for benign disease [15].

As indicated, side effects associated to blood component transfusion may be similar using homologous and autologous blood components. Therefore, various leukocyte- and platelet-derived bioactive substances well known as being involved in post-trauma complications, postoperative infectious complications and cancer cell growth should be considered to play a similar role after homologous and autologous blood component transfusion [1] [6]. In particular, substances such as tumour necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, activated complement factor-3 (C 3 a), histamine, serotonin, myeloperoxidase (MPO), eosinophil cationic protein (ECP) and eosinophil protein-X (EPX) may play a major role in infectious and septic complications [1] [16] [17] [18]. Substances such as histamine, MPO, plasminogen activator inhibitor-1 (PAI-1) and vascular endothelial growth factor (VEGF) may be involved in regulation of cancer growth and dissemination [1] [19] [20] [21]. The substances have been shown to accumulate extracellularly in a preparation- and storage time-dependent manner in various blood components for transfusion, including whole-blood, SAGM (saline-adenine-glucose-mannitol) blood, plasma-reduced whole-blood, fresh frozen plasma, single-donor platelets, platelet concentrates and platelets collected by the apheresis method [17] [22] [23] [24] [25] [26] [27] [28]. Indeed this area of transfusion medicine attracts specific interest, because recent data indicate blood transfusion-associated side-effects as being related to storage time of the blood components [1] [29] [30] [31] [32]. Thus, the results may change the attitude to blood component transfusion-associated side-effects, and future studies should include storage time as an independent new parameter. Moreover, blood component preparation has to be reconsidered, as recent results indicate a beneficial effect of leukocyte reduction by filtration on patient outcome in elective surgery and in burn trauma surgery as well [1] [18]. The optimal timing of leukocyte filtration has to be further evaluated, but recent results suggest that filtration performed at room temperature with specific filters within hours after donation (prestorage filtration) is superior to filtration performed at the time of actual transfusion (bedside filtration) [33] [34]. This suggestion has been further underlined by experimental results showing blood component transfusion-associated impaired immune reaction [35] and stimulated in vivo cancer cell growth being attenuated by prestorage leukofiltered blood components [36], while the effect of bedside leukofiltered was similar to non-filtered blood components. Introduction of general leukocyte filtration may at first sight increase the economic requirements, but reduction of the frequency of infectious complications, cancer recurrence and other severe side-effects may be beneficial for the patients in particular, and for the health budget as well. In addition, changed transfusion strategy with reduction in overuse of blood components particularly in surgery [37] may per se be beneficial for the patients. Recent reports have indicated that transfusion of blood components can be significantly reduced in trauma surgery [38] and in fracture surgery even in elderly patients [39].

In conclusion, it should be considered that transfusion with homologous and predeposit autologous blood components leads to equal side-effects, which cannot be explained by the well known blood transfusion-induced immunomodulation. In particular, the relation between blood transfusion-associated immunomodulation and cancer recurrence after radical resection needs reconsideration. Most of the studied types of solid tumours are non-immunogenic; the incidence is not increased among immune-compromised patients [1], and therapy with immune modulating drugs has only a small, insignificant influence on survival of patients with these tumours, etc. [1] [6]. Storage of various blood components may lead to extracellular accumulation of leukocyte- and platelet-derived bioactive substances, which are involved in development of post-trauma complications, development of postoperative infectious complications and cancer cell growth. Recent data indicate that side-effects to blood transfusion are related to storage time of the blood components, as well as to the methods used for preparation. Reduction of the frequency of severe side-effects may be achieved by introduction of general leukocyte filtration of homologous blood components, and of predeposit autologous whole-blood as well. But the patients may further benefit in terms of reduced post-trauma morbidity and mortality by simultaneous reduction in the overuse of blood components.

References

• 1 Nielsen H J. Clinical impact of bioactive substances in blood components: Implications for leukocyte filtration.  Infuther Transfusion Med.. 1998;  25 296-304
• 2 Lee T H, Paglieroni T, Ohto H, Holland P V, Busch M P. Survival of donor leukocyte subpopulations in immunocompetent transfusion recipients: Frequent long-term microchimerism in severe trauma patients.  Blood. 1999;  93 3127-3139
• 3 Busch M P, Lee T H. Role of donor leukocytes and leukodepletion in transfusion-associated viral infections. In: Sweeney J, Heaton A (eds). Clinical benefits of leukodepleted blood products. R.G.Landers Company, New York 1995: 97-112
• 4 Holmgren L, Szeles A, Rajnavolgyi E. et al . Horizontal transfer of DNA by uptake of apoptotic bodies.  Blood. 1999;  93 3956-3963
• 5 Nusbacher J. Blood transfusion is mononuclear cell transplantation.  Transfusion. 1994;  34 1002-1006
• 6 Nielsen H J. Detrimental effect of perioperative blood transfusion.  Br. J. Surg.. 1995;  82 582-587
• 7 Agarwal N, Murphy J G, Cayton C G, Stahl W M. Blood transfusion increases the risk of infection after trauma.  Arch. Surg.. 1993;  128 171-177
• 8 Meakins J L. Surgeons, surgery and immunomodulation.  Arch. Surg.. 1991;  126 494-498
• 9 Amato A C, Pescatori M. Effect of perioperative blood transfusions on recurrence of colorectal cancer. Meta-analysis stratified on risk factors.  Dis. Colon. Rectum.. 1998;  41 570-585
• 10 Mynster T, Christensen I J, Nielsen H J. Blood transfusion-related postoperative infections and prognosis after elective colorectal cancer surgery. Br J Surg 2000 (in press)
• 11 Carson J L, Altman D G, Duff A. et al . Risk of bacterial infection associated with allogeneic blood transfusion among patients undergoing hip fracture repair.  Transfusion. 1999;  39 694-700
• 12 Ness P M, Walsh P C, Zahurak M, Baldwin M L, Piantadosi S. Prostate cancer recurrence in radical surgery patients receiving autologous or homologous blood.  Transfusion. 1992;  32 31-36
• 13 Busch O RC, Hop W CJ, Hoynch van Papendrecht M AW, Marquet R L, Jeekle J. Blood transfusion and prognosis in colorectal cancer.  N. Engl. J. Med.. 1993;  328 1372-1376
• 14 Domen R E. Adverse reactions associated with autologous blood transfusion: evaluation and incidence at a large academic hospital.  Transfusion. 1998;  38 296-300
• 15 Etchason J, Petz L, Keeler E. et al . The cost effectiveness of preoperative autologous blood donation.  N. Engl. J. Med.. 1995;  32 719-724
• 16 Allen S. The role of leucocytes in the systemic inflammatory response and the potential impact of leucocyte reduction.  Cardiovasc Engineering. 1997;  2 34-54
• 17 Hyllner M, Arnestad J P, Rydberg L, Bengtson A. Complement activation during storage of whole blood, red cells, plasma and buffy-coat.  Transfusion. 1997;  37 264-268
• 18 Nielsen H J, Krarup A L, Munk-Nielsen L. et al . Prestorage leukocyte filtration may reduce leukocyte-derived bioactive substances accumulation in patients operated for burn trauma.  Burns. 1999;  25 162-170
• 19 Nielsen H J. Histamine-2 receptor antagonist as immunomodulators - New therapeutic views?.  Ann. Med.. 1996;  28 107-113
• 20 Bajou K, Noël A, Gerred R. et al . Absence of host plasminogen activator inhibitor-1 prevents cancer invasion and neovascularisation.  Nature Med.. 1998;  4 923-928
• 21 Werther K, Brünner N, Christensen I J, Nielsen H J. The prognostic impact of perioperative blood transfusion and preoperative soluble VEGF in patients undergoing resection for primary colorectal cancer. Eur J Surg Oncol 2000 (in press)
• 22 Nielsen H J, Edvardsen L, Vangsgaard K, Dybjaer E, Skov R S. Time-dependent histamine release from stored human blood products.  Br. J. Surg.. 1996;  83 257-262
• 23 Nielsen H J, Reimert C M, Pedersen A N. et al . Time-dependent, spontaneous release of leukocyte- and platelet-derived bioactive substances from stored human blood.  Transfusion. 1996;  36 960-965
• 24 Edvardsen L, Nielsen H J, Dybkjaer E. et al . Leukocyte and platelet derived bioactive substances in stored standard platelet concentrates.  Eur. J. Haematol.. 1996;  56 185-187
• 25 Nielsen H J, REimert C M, Pedersen A N. et al . Leucocyte-derived bioactive substances in fresh frozen plasma.  Br. J. Anaesth.. 1997;  78 548-552
• 26 Edvardsen L, Taaning E, Mynster T, Pedersen A N, Drachman O, Nielsen H J. Bioactive substances in buffy-coat derived platelets pools stored in platelet additive solutions.  Br. J. Haematol.. 1998;  103 445-448
• 27 Nielsen H J, Werther K, Mynster T, Brünner N. Soluble vascular endothelial growth factor in various blood transfusion components. Transfusion 1999 39: 1078-1083
• 28 Edwardsen L, Taaning E, Gammelgaard B D, Dalh Christesen L, Mynster T, Nielsen H J. Extracellular accumulation of bioactive substances during preparation and storage of various platelet concentrates. Transfusion 1999 (still in press)
• 29 Purdy F R, Tweedale M G, Merrick P M. Association of mortality with age of blood transfused in septic ICU patients.  Can. J. Surg.. 1997;  44 1256-1261
• 30 Mynster T, Dybkjaer E, Kronborg G, Nielsen H J. Immunomodulating effect of blood transfusion. Is blood storage time important?.  Vox Sang. 1998;  74 176-181
• 31 Vamvakas E C, Carven J H. Transfusion and postoperative pneumonia in coronary artery bypass graft surgery: Effect of the lenght of storage of transfused red cells.  Transfusion. 1999;  39 701-710
• 32 Mynster T, Nielssen H J. The impact of storage time of transfused blood on postoperative infectious complications in rectal cancer surgery. Scand. J. Gastroenterol. 2000 35: 212-217
• 33 Hammer J H, Mynster T, Reimert C M. et al . The effect of active heating on accumulation of extracellular bioactive substances in transfused blood.  J. Trauma. 1997;  43 799-803
• 34 Hammer J H, Mynster T, Reimert C M, Brünner N, Nielsen H J. Reduction of bioactive substances in donor blood. Prestorage versus bedside leucofiltration.  Eur. J. Haematol.. 1999;  63 29-34
• 35 Mynster T, Hammer J H, Nielsen H J. Prestorage and bedside leukofiltration of whole blood modulates storage time dependent suppression of in vitro TNF-α release. Br. J. Haematol. 1999 106: 248-251
• 36 Bordin J O, Bardossy L, Blajchman M A. Growth enhancement of established tumors by allogeneic blood transfusion in experimental animals and its amelioration be leukodepletion.  Blood. 1994;  84 344-348
• 37 Sirchia G, Giovanetti A M, McClelland B, Fracchia G N. Safe and good use of blood in surgery (SANGUIS). Use of blood and artificial colloids in 43 European hospitals. Council of Europe Publishing 1994: 1-235
• 38 Hébert P C, Wells G, Blajchman M A. et al . A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care.  N. Engl. J. Med.. 1999;  340 409-417
• 39 Carson J L, Duff A, Berlin J A. et al . Perioperative blood transfusion and postoperative mortality.  JAMA. 1998;  279 199-205