Blood transfusion has always been an integral part of
surgical practice. From William Harveys discovery of blood circulation in
1628, several practitioners reported success in transfusing animals throughout
that century; however, the first successful human blood transfusion was not
performed until 1795 by Philadelphian Philip Syng Physick, who never published
In 1818, English obstetrician James Blundell published on successful
transfusion for postpartum hemorrhage. Blood transfusion history continued to
evolve with Austrian physician Karl Landsteiners discovery of the ABO
blood grouping system in 1902 and the Rhesus factor in 1939, for which he and
his group received, the Nobel Prize.
The field of transfusion medicine was honored with another Nobel Prize
in 1912, when French surgeon Alexis Carrel anastomosed a donor vein to the
artery of a patient to transfuse the patient. Although this effort proved
unsuccessful as a treatment, it paved the way for successful organ
The explosion in open heart surgery in the 1950s coupled with two world
wars increased demand for blood, and this led to the institution of
blood banks around the world. The first reported blood bank
was set up in 1932 in a Leningrad hospital. War and conflict during the 20th
century has led to a greater understanding of trauma surgery and, hence,
transfusion medicine. Isodor Ravidin, another Philadelphia surgeon, first used
albumin infusions during the Pearl Harbor conflict as a plasma expander, and
the concept of shock management was born.
Blood transfusion has always been controversial, particularly with
contaminated products and poor donor screening. Many viruses have been
transmitted to donors in the latter part of the 20th century due to inadequate
screening techniques; HIV, HTLV, hepatitis B/C and vCJD have all resulted in
unnecessary recipient morbidity. Thankfully, screening techniques have improved
and the risks of these infections in now minimal.
The two primary transfusion methods used in orthopedic practice today
are autologous and allogenic transfusions. Despite their successes, several
issues have recently come to light regarding the safety of allogenic blood
products, a major one of which in infection.
Risk of infection
Reports from several authors have highlighted the risk of infection
associated with the use of allogenic products. The infection risk has been seen
in both elective and trauma orthopedic procedures. Koval and colleagues
reported an infection rate of 27% as opposed to 15% in transfused vs.
nontransfused patients undergoing open reduction and internal fixation for hip
fracture, out of a cohort of 687 patients. Similarly, Bierbaum and colleagues,
in a multicenter study on 9,482 patients undergoing elective joint
arthroplasty, noted an infection rate of 7% in patients who were transfused vs.
3% in nontransfused patients.
Increased postoperative infection associated with blood transfusion has
also been seen in other surgical disciplines after cardiac bypass and
colorectal surgeries, and the effect was found to be proportional to the number
of blood units transfused. Despite the statistical strength, criticisms have
been put forth regarding the conclusions of these studies, including their
retrospective nature, absence of risk stratification for disease severity and,
most importantly, the possibility that blood transfusion may act as a surrogate
for other confounding variables such as increased operative time. Their
inability to dissociate a predisposition to infection from underlying disease
severity acts as a strong confounding factor and must be considered when
interpreting these results. Interestingly, the incidence of urinary tract
infection is also considerably higher in patients undergoing orthopedic
procedures and receiving blood transfusion, pointing to the possible
transfusion-induced immunomodulation (TRIM).
The term TRIM was coined after observations that patients receiving
blood transfusion were at increased risk of any type of infection. The first
observations were made when increased renal graft survival was seen in patients
receiving allogenic blood transfusion after the transplant. These
immunosuppressive effects of blood transfusion was fully exploited
to maximize the survival of transplant tissues before introduction of
immunosuppressive agents such as cyclosporine.
Many other observations such as improvements in autoimmune diseases
status such as
Crohns disease, a decrease in repetitive spontaneous
abortions and increase in recurrence of solid tumors, all confirm the adverse
effect of allogenic transfusion on cell mediated immunity. The exact mechanism
by which allogenic transfusion modulates cell mediated immunity is unknown.
Initially, the presence of leukocytes in transfused whole blood was considered
as the culprit, and the usage of leuko-depleted products was introduced to
abrogate this effect. In recent years, other hypotheses have been proposed.
Part of the cellular immunity involves the maturation of Th0 cells into
TH1, 2 and 3 with immune activity. It is believed that release of
immunosuppressive cytokines occurs after allogenic blood transfusions that
suppress cell mediated immunity. Kirkley and colleagues have shown that the
transfusion of allogenic blood in total hip arthroplasty results in release of
IL 4 and IL10, which in turn results in suppression of Th1 response.
Cellular anergy theory
T cells when stimulated need co-factors to achieve their final goal,
ligands on their surface such as CD40 and CD80 act as accelerators, whereas
ligands such as CD152 act as suppressors. It has been suggested that the
storage process of allogenic blood releases such suppressors from leukocytes,
inducing T cell anergy.
Apoptotic cells are also immunosuppressive in nature. The presence of
donor antigen-presenting cells (APC) appears to be a prerequisite for
alloimmunization, and they must be both viable and capable of presenting a
co-stimulatory signal to induce IL-2 secretion and proliferation of responding
CD4 T cells. APCs presenting antigen, but no co-stimulatory signal, can induce
non-responsiveness in CD4 T cells, another possible mechanism of TRIM. APCs in
refrigerated blood continue to present antigen, but progressively lose their
ability to provide co-stimulation. By day 14, co-stimulatory capacity is
absent, and transfusion of such blood should not alloimmunize but could induce
some degree of immunosuppression. Further refrigerated storage in excess of 2
to 3 weeks leads to induction of apoptosis in contaminating leukocytes and may
further debilitate an already compromised transfusion recipient.
The exact mechanism of TRIM has yet to be fully elucidated and certain
questions still exist as we try to comprehend its effects on transfused
The immunocompromise that occurs with allogenic transfusion does not
explain the increased infection rates seen in trauma patients. Trauma inflicts
an immune challenge to patients, and their inflammatory response follows a
bimodal pattern with an initial hyperimmune response followed by an
immunocompromised state several days post-trauma. A blood transfusion
administered during surgery or within 24 hours of trauma should have a minimal
effect on blunting this immune response and should not theoretically lead to an
increased risk of infection.
There have been reports of patients with certain blood groups having an
increased risk of infection. This has been controversially discussed with
regard to blood group O and the higher incidence of Helicobacter colonization.
Authors have also maintained a link between blood groups B and AB lacking the
anti-B isohemagglutinin and, hence, predisposing such patients to infections.
Patients lacking the Lewis erythrocyte antigen are known as nonsecretors and
have been proven to be at a higher risk of urinary tract infection in a
pediatric population. Patients with the Lewis A antigen are at increased risk
of bacterial adhesion, particularly at mucosal interfaces.
The Lewis antigen, per se, is not routinely part of the cross matching
procedure, as hemolysis is not a recognized feature of a mismatch. Patients
negatively expressing such an antigen may be converted to positive expression
by transfusion. This facet of transfusion has not been extensively studied and
does merit further evaluation. Perhaps the issue may not be immunocompromise
due to TRIM but due to other factors such as antigens on transfused
erythrocytes inciting susceptibility to infection.
Despite a lack of clarity on its etiology, transfusion with allogenic
blood products does predispose patients to an increased risk of infection. With
improved handling and screening of blood products, infection now becomes the
leading associated risk of transfusing allogenic products. Auto-transfusion,
whether through autogenous pre-donation or operative cell salvage, offers a
realistic alternative. The practice of hemoglobin trigger levels has reduced
the need for transfusion and made liberal transfusion a thing of the past.
Alternatives to transfusion such as intravenous iron and erythropoietin analogs
are also being investigated, but have yet to gain widespread approval.
For more information:
Eoin Sheehan, MD, FRCS, and Javad Parvizi, MD, FRCS, can be reached at
Rothman Institute of Orthopaedics at Jefferson, 925 Chestnut St., 2nd Floor,
Philadelphia, PA 19107; 267-399-3617; e-mail:
Bierbaum BE, Callaghan JJ, Galante JO, et al. An analysis of blood
management in patients having a total hip or knee arthroplasty. J Bone
Joint Surg (Am). 1999;81(1):2-10.
Innwehofer P, Klingler A, Klimmer C, et al. Risk for postoperative
infection after transfusion of white blood cell-filtered allogeneic or
autologous blood components in orthopedic patients undergoing primary
arthroplasty. Transfusion. 2005;45(1):103-110
Kirkley SA, Cowles J, Pellegrini VD, et al. Increased T helper 2 (Th2)
type cytokine secretion in surgical patients receiving allogeneic transfusions.
Transfus Med. 1998;8:195204.
Koval KJ, Rosenberg AD, Zuckerman JD, et al. Does blood transfusion
increase the risk of infection after hip fracture? J Orthop
Trauma. 1997;11(4):260-265; discussion 265-266.
Opelz G, Sengar D P S, Mickey M R, Terasaki P I. Effect of blood
transfusions on subsequent kidney transplants. Transplant Proc.
Pulido L, Ghanem E, Joshi A, et al. Periprosthetic joint infection:
the incidence, timing, and predisposing factors. Clin Orthop Relat
Res. 2008; 466(7):1710-1715.