Joint ASH and AABB Educational Session
Lawrence T. Goodnough, Patricia E. Hewitt, and Christopher C. Silliman
In the vein-to-vein flow of blood from donor to body-medicated event, involving anti-HLA Class I
patient, the role of the transfusion medicine and Class II, or anti-granulocyte antibodies; and
specialist has become increasingly centered at a two-event model, which includes the clinical
the bedside. Three clinically centered issues in condition of the patient resulting in pulmonary
blood safety and in blood conservation are endothelial activation and neutrophil sequestra-
presented in this chapter. tion. The second event is the transfusion of a
In Section I, Dr. Patricia Hewitt presents the biologic response modifier (lipids or antibodies)
epidemiologic and clinical evidence regarding in the blood component that activates primed
new variant Creutzfeldt-Jakob disease (nvCJD) in neutrophils. Prevention, clinical treatment, and
the UK and its relevance to transfusion medicine. proposed definition of TRALI are discussed.
Lessons learned from the responses by the In Section III, Dr. Lawrence Goodnough and
National Blood Service to this crisis are dis- colleagues present a transfusion medicine
cussed, particularly in the context of recent service approach to the utilization of recombi-
evidence of a case of vCJD transmission by nant factor VIIa (rFVIIa) in non-approved clinical
blood transfusion and a second case of apparent settings. rFVIIa has a potential role as a hemo-
transmission of abnormal prion protein without static intervention in a variety of clinical settings,
development of clinical illness. yet few clinical trials have been completed to
In Section II, Dr. Christopher Silliman and his date to guide indications for its use. The policies
colleagues summarize recent knowledge gained presented here are those in place at the authors’
regarding transfusion-related acute lung injury medical center, and will undergo periodic review
(TRALI), which is now the leading cause of and revision as relevant new information and
transfusion-related mortality. Two different data are generated.
etiologies have been proposed: a single anti-
I. VCJD AND BLOOD TRANSFUSION: and limited geographical distribution, mean that care-
HOW REAL IS THE RISK? ful surveillance is crucial in acquiring knowledge about
the disease and possible consequences. This section fo-
Patricia E. Hewitt, MD* cuses on work over the last 8 years, with particular
reference to CJD surveillance and blood transfusion is-
The possibility that variant Creutzfeldt-Jakob disease sues in the UK, and highlights the joint work between
(vCJD) might present a risk to the blood supply has
been debated since the first description of cases by the
UK National CJD Surveillance Unit (NCJDSU) in 1996. * National Blood Service, Colindale Centre, Colindale Avenue,
Risk assessments, experimental work, and expert com- London NW9 5BG, UK
mittees all contribute to the debate. A disease that is
essentially limited to one European country has evoked The author wishes to acknowledge the following co-workers:
Professor R G Will, UK National CJD Surveillance Unit,
world-wide interest. The appearance of vCJD provoked
Edinburgh, UK; Jan Mackenzie, UK National CJD Surveillance
renewed interest in sporadic (“classical”) CJD, never Unit, Edinburgh, UK; Dr H J Ward, UK National CJD
previously of significant concern within the blood trans- Surveillance Unit, Edinburgh, UK; Dr C Llewelyn, National
fusion community. The small number of cases of vCJD, Blood Service, Cambridge Centre, UK
Hematology 2004 457
the NCJDSU and UK Blood Services (UKBS), culmi- an abnormality of the PRNP gene.
nating in the identification of the first case of possible Iatrogenic CJD has followed treatment with con-
transfusion transmission of vCJD. taminated human pituitary-derived growth hormone or
gonadotrophin, as well as dura mater grafts, corneal
Epidemiology of CJD transplants, neurosurgical instruments and electroen-
CJD is a rare and fatal human neurodegenerative con- cephalogram (EEG) electrodes. Although these poten-
dition. In common with other transmissible spongiform tial sources of infection have been recognized, and mea-
encephalopathies (TSEs), CJD is experimentally trans- sures taken to reduce (or abolish) the risk of such trans-
missible to animals. Affected animals show character- mission, the number of cases continues to increase due
istic spongiform change on microscopic examination to past exposure to these known risks.
of the brain. Workers at the NCJDSU first described 6 cases of
There are a number of forms of CJD. Globally, vCJD in the UK in 1996.1 There have now been 146
over 80% of cases occur as sporadic disease (sCJD). cases of confirmed/probable vCJD in the UK2 (Figure
Epidemiological studies indicate 1–2 cases of sCJD per 1) and small numbers in France (6 cases), Republic of
million population per year, worldwide. Other forms Ireland, Italy, US and Canada. All except the French
of CJD include various genetic forms, iatrogenic forms, and Italian cases resided in the UK between 1980 and
and vCJD. All these forms show much lower incidence 1996. All tested cases have been homozygous for me-
than sporadic CJD. In addition, incidence varies be- thionine at codon 129 of the PRNP gene.
tween countries. For example, iatrogenic CJD has been
associated with adminstration of human growth hor- What Is the Relationship Between BSE and vCJD?
mone (USA, UK and others between 1958 and 1985) The causal link between vCJD and BSE is based on
human gonadotrophin hormones (Australia, UK) and epidemiological, biochemical and transmission studies.
use of dura mater (Germany and others before 1992). A scientific consensus that BSE-contaminated food was
The main features of the different forms of CJD
are summarized in Table 1.
Sporadic CJD remains of unknown cause. In par-
ticular, there is no evidence of a link with naturally
occurring animal TSEs, such as scrapie, nor with bo-
vine spongiform encephalopathy (BSE). Most cases oc-
cur between the ages of 60 and 80 years. Clinical and
pathological features of sCJD are variable and influenced
by a naturally occurring polymorphism at codon 129 of
the gene encoding for the prion protein (PRNP gene).
The main type of genetic CJD is familial CJD. Other
inherited forms of CJD, such as fatal familial insom-
nia, are recognized. All are rare. Genetic CJD is ex- Figure 1. Number of onsets per annum of variant
pressed as an autosomal dominant trait associated with Creutzfeldt-Jakob disease (vCJD) (UK).
Table 1. Features of the different forms of Creutzfeldt-Jakob disease (CJD).
Form of CJD Distribution Age Duration of illness Clinical features
Sporadic CJD Worldwide 60–80 Median 4 months; Rapidly progressive dementia
rarely greater than 2 years Impaired movement
Variant CJD Predominantly UK Median age 27 Median 14 months Early psychiatric symptoms
(range 12–74) (range 6–40) Unpleasant sensory symptoms
Familial (genetic) CJD Worldwide 30–50 Variable; Varies with underlying mutation;
may be up to 5 years may resemble sporadic CJD, or a
progressive cerebellar ataxia
Iatrogenic CJD Worldwide Any 2–18 months, occasionally Depends upon route of infection.
some years Intramuscular route: progressive
Neurological route: rapidly
458 American Society of Hematology
the main route of exposure of the human population with vCJD is much more limited, but there is now evi-
was reached by a Joint World Health Organization/Food dence of possible transmission of vCJD through blood
and Agriculture Organization/Office International des transfusion.9
Epizooties Technical Consultation on BSE in 2001.3
Cattle and their products and by-products are traded The Transfusion Medicine Epidemiology Review
worldwide, so that the risk of BSE (and therefore vCJD) The Transfusion Medicine Epidemiology Review
is a global risk. (TMER) is a collaborative project between the UK
NCJDSU and UKBS, investigating whether there is any
Clinical Features of vCJD evidence that CJD or vCJD have been transmitted by
The median age of onset is 28 years (range 12–74). blood. Cases of CJD (all types) and controls who have
Whereas sCJD typically presents with rapidly progres- acted as blood donors or have themselves received trans-
sive, clearly neurological symptoms, vCJD presenta- fusion are identified by NCJDSU. Details are provided
tion tends toward behavioral/psychiatric symptoms and to the UKBS in a blinded study. The UKBS traces
with slower progression. It may initially be difficult to records relating to donors and looks back to identify
determine that there is a neurological illness.3 Features recipient(s), whose details are provided to NCJDSU.
of depression are common and patients may initially be For blood recipients who have developed CJD, and their
referred to psychiatry services. Nearly half the patients controls, the UKBS obtains details of the transfused
are affected by sensory symptoms. At some point other blood components from the hospital in which the trans-
neurological features appear, with definite neurologi- fusion took place. The UKBS identifies the donors, and
cal abnormality developing at around 6 months from forwards details to NCJDSU. Identified recipients and
first symptoms. Ataxia is often prominent. Eventually, donors are checked with the CJD database; copies of
the picture is of a dementia with multiple neurological death certificates are obtained.
features including myoclonus. The illness duration has Because of regulatory requirements relating to vCJD
a median of 14 months (range 6–40). The differential and plasma products, all vCJD cases (definite and
diagnosis of a progressive neuropsychiatric disorder in probables) are notified to the UKBS by NCJDSU to
relative youth is potentially wide. It may be difficult or establish whether any have acted as donors. To date, 27
impossible to make a diagnosis of vCJD in the early of 146 vCJD cases were reported to have been blood
stages. donors. Records for 18 have been traced: 16 had do-
nated blood, producing 57 blood components issued to
Risk of Transmission of CJD by Blood Transfusion hospitals. Of these, 7 components were not traced, and
Infectivity can be demonstrated in the blood of rodents 50 recipients were identified. In addition, 23 plasma
experimentally infected with TSE agents, including the components were fractionated into plasma products. One
BSE agent. In these animal models, infectivity can be of the blood component recipients was identified, in
demonstrated in both cellular and plasma components.4 retrospect, as developing symptoms of vCJD 6½ years
Infectivity has also been demonstrated in primates ex- after receiving a transfusion of red cells donated 3½
perimentally infected with BSE and in whole blood years before the donor developed symptoms of vCJD .
and buffy coat of sheep with scrapie. The donor was in the typical age range for vCJD; the
A transfusion study in sheep has demonstrated trans- recipient was the second oldest case to date. The older
mission of experimentally produced BSE.5,6 Sheep from age may have accounted for the lack of a clinical diag-
flocks free of scrapie and BSE were fed BSE-infected nosis of vCJD before death. A second recipient, of a
food. Blood from infected and control (non-infected) different donor who had died of vCJD, remained
donor sheep was transfused to uninfected animals. Re- asymptomatic from the neurological viewpoint until
cipient sheep of infected donors have developed ill- death. Prion protein was detected in the spleen and in
ness. Further work aimed at investigating how long one cervical lymph node at autopsy, but not in the brain
during the incubation period infectivity is present, and or gut-associated lymphoid tissue.10 The linking of these
the effect of leukodepletion, is awaited with interest. two cases, through the the TMER, to cases of vCJD in
There has been no evidence of transfusion trans- two different donors is the first evidence of possible
mission of sCJD (or familial CJD) despite epidemio- transmission of vCJD through blood transfusion.
logical studies and case investigations.7 In particular, There is currently no evidence of vCJD in the other
hemophiliacs exposed to plasma-derived coagulation 18 surviving recipients in the TMER study. In the re-
factors have no increased prevalence of CJD, and stud- verse study, 9 vCJD cases were reported to have them-
ies involving examination of brain tissue post-mortem selves received blood transfusions, but only 5 had records
have not demonstrated any evidence of CJD.8 Experience of transfusion. These 5 individuals had received 122
Hematology 2004 459
components of blood (103 components to 1 recipient), tions. The UKBS asked for advice on the management
which have been traced to 120 named donors (includ- of recipients of blood components donated by individu-
ing the vCJD donor described above ). The donors of 2 als who later developed vCJD. A further risk assess-
components are not traceable. None of the donors has ment was commissioned in 200213 and used to formu-
been reported to develop vCJD. late the advice of the Panel and incorporated in a Frame-
work Document.14 The advice indicated that these indi-
Measures to Reduce the Risk of Transmission viduals should be notified, but this required a mecha-
of vCJD Through Blood Components nism for notification and support. That work was pro-
and Plasma Products gressing when the TMER demonstrated a link between
A number of donor selection criteria are aimed at ex- a donor and recipient. As a result, the Secretary of State
cluding donors at risk of CJD.11 This includes a family announced in December 2003 that other recipients of
history of CJD, treatment with pituitary-derived hor- blood components donated by individuals who later
mones and a history of neurosurgical procedures. Mea- developed vCJD would be notified (as already advised
sures to protect against vCJD are more difficult. Many by the Clinical Incident Panel).
countries have introduced restrictions for donors who Notification was carried out through local Health
have lived in the UK between 1980 to 1996, when BSE Protection Teams (HPTs). Local Consultants in Com-
was a concern through the food chain. Recall of plasma municable Disease Control (CsCDC) worked with oth-
products produced from pools containing donations from ers to satisfy themselves that the correct recipient had
donors who later developed vCJD were introduced in been identified (usually by reviewing medical records)
Europe in 1999.12 before contacting General Practitioners with a view to
Risk reduction measures within the UK are more notifying the recipients. Although the timing was less
problematical. All adults (except strict vegetarians) are than ideal, notification of all living recipients was
considered to have been at risk of vCJD through the achieved within a short space of time.
food chain. An early risk assessment (February 1999) The updated risk assessment has been applied to
made two firm recommendations on risk reduction.13 fractionated plasma products now known to have con-
The switch to non-UK plasma for fractionation was tained plasma from donors who later developed vCJD.
achieved over the second half of 1998. Leukodepletion As no UK-derived plasma has been used for manufac-
was achieved in a progressive program completed by 1 ture since late 1998, these batches were transfused years
November 1999, although the bulk of components were ago. In general, “at risk” recipients have received mul-
leukodepleted well before that date. tiple doses of certain products, in particular coagula-
Other suggested risk reduction measures included tion factors and intravenous immunoglobulin. The ear-
the appropriate use of blood, consideration of blood liest cases of vCJD in former blood donors triggered
conservation strategies including autologous donation notification exercises in 1998 and 2000. Some albumin
and cell salvage, reduction in the volume of plasma in products had been provided outside the UK and used as
red cell and platelet components, use of imported (non- excipients (more or less inert substances used as a ve-
UK) plasma instead of fresh frozen plasma from UK hicle for medicinal agents) in other products. The noti-
donors, and exclusion of donors who have themselves fication therefore had repercussions outside the UK and
received a blood transfusion. The 2004 report of pos- led to many recipients, exposed to minute quantities of
sible transmission of vCJD by blood transfusion led to the affected product, being informed that they had been
a further investigation of these possibilities. Exclusion put at risk of vCJD. The current risk assessment would
of donors who had themselves received a blood trans- not put such individuals in a risk group. On the other
fusion in the UK since 1980 was implemented in April hand, many hemophiliacs have been exposed to coagula-
2004. Approximately 2%–3% of donors have been ex- tion factor treatment from one or more affected batches.
cluded by this measure. The impact has been minimized Others may have been exposed to batches not yet identi-
by careful advance planning and recruitment campaigns, fied as a risk. Hemophiliacs, as a group, will be consid-
but places a further pressure on an already diminishing ered “at risk” and treated accordingly when requiring sur-
donor base. gery. Individuals can elect to be told specifically if they
have received treatment from affected batches.
Notification of Recipients of The vCJD epidemic in the UK appears to be in
Affected Components and Products decline.15 Nevertheless, experts warn against compla-
The CJD Clinical Incident Panel was set up in 2000 to cency, since cases seen between 1996 and 2004 might
advise on management of incidents where patients might reflect only early onset cases. There could be later cases
have been put at risk of CJD through clinical interven- representing a longer incubation period of disease. The
460 American Society of Hematology
epidemic in cattle has not so far demonstrated any re- brane oxygenation (ECMO) for a particularly severe
surgence in the UK, but vCJD represents a TSE that clinical presentation.5,7,9,10
has crossed the species barrier and may not behave in The mortality from TRALI is 5%–25%, with lower
the same way as naturally occurring TSEs. UKBS are rates being more common.3,5,10,11 Most patients recover
preparing themselves for the possibility of a blood test within 72 hours; however, the data regarding TRALI
to detect individuals who might be infected with vCJD. are limited, and its attendant morbidity and mortality
The potential problems of such a test, such as sensitiv- may be underappreciated due to lack of recognition and
ity, specificity and predictive value, are already recog- underreporting.3,5,10,11 In addition, in epidemiological
nized. A facility to provide panels of blood samples for studies of ARDS, blood transfusion was implicated as
assessment of such tests is in progress. Other interven- the most common risk factor for the genesis of ARDS,
tions, such as prion removal filters, are already on the and a number of these cases may represent severe cases
horizon. For the United Kingdom, at least, the “pre- of TRALI.12
cautionary principle” (application of proportionate
measures to remove or reduce threats of serious harm, Differential Diagnosis
even in the absence of scientific proof) will operate for The differential diagnosis of patients who have pulmo-
some time to come. nary insufficiency following transfusion must include
circulatory overload, anaphylactic transfusion reactions,
II. TRANSFUSION-RELATED ACUTE LUNG INJURY and transfusion of blood products contaminated with
(TRALI) bacteria.5,10,11 Transfusion-associated circulatory over-
load (TACO) presents within minutes to hours of the
Christopher C. Silliman, MD, PhD* transfusion as respiratory distress with tachypnea, ta-
chycardia, hypertension, and cyanosis.13 All blood com-
Transfusion-related acute lung injury (TRALI) was not ponents have been implicated in TACO, and it rapidly
recognized as a distinct clinical entity until the 1980s responds to aggressive diuresis and ventilatory support.14
with the report of a series of 36 patients.1 TRALI has Anaphylactic transfusion reactions involve respiratory
since become recognized as a not uncommon clinical distress related to bronchospasm manifested by tachy-
complication of transfusion and over the past two re- pnea, wheezing, cyanosis, and severe hypotension.15 Fa-
porting years has become the leading cause of transfu- cial and truncal erythema and edema are common, with
sion-related death in the US.2 urticaria characteristically involving the head, neck, and
trunk.15 The respiratory distress from anaphylactic trans-
Clinical Presentation and Treatment fusion reactions is related to laryngeal edema rather
While TRALI can occur within 6 hours of transfusion, than pulmonary edema as in TRALI.15 These reactions
the majority of cases present either during the transfu- occur rapidly during the transfusion of any type of pro-
sion or within the first 1–2 hours.1,3,4 TRALI is clini- tein containing blood component and may occur fol-
cally identical to the acute respiratory distress syndrome lowing the transfusion of very small volumes of blood.15
(ARDS) with the insidious onset of acute pulmonary Lastly, bacterial contamination manifests as fever, hy-
distress temporally related to transfusion.1,3,4 The clini- potension, and vascular collapse, which may include
cal findings of TRALI consist of the rapid onset of respiratory distress, although pulmonary involvement
tachypnea, cyanosis, dyspnea and fever (≥ 1°C).1,5 Aus- is not a consistent finding.16 Bacterial contamination is
cultation of the lungs reveals diffuse crackles and de- most frequent in platelet concentrates and packed red
creased breath sounds, especially in dependent areas.1,5 blood cells (PRBCs) and must be considered in patients
The physiologic findings include acute hypoxemia, with who become acutely ill following transfusion of these
PaO2/FiO2 < 300 mm Hg, and decreased pulmonary com- components.16
pliance despite normal cardiac function.1,4-6 Radio-
graphic examination reveals diffuse, fluffy infiltrates
consistent with pulmonary edema.1,5 Treatment consists
of aggressive respiratory support including supplemen-
tal oxygen and mechanical ventilation.1,4,5 Milder forms
of TRALI have been described that require prompt de- * University of Colorado School of Medicine, Bonfils Blood
Center, 717 Yosemite Street, Denver CO 80230
livery of supplemental oxygen alone.3,4,7,8 As with acute
lung injury (ALI) and ARDS, there is no role for treat- This work was supported in part by Bonfils Blood Center, grant
ment with corticosteroids or diuretics, although one #HL59355 from NHLBI, and the Departments of Pediatrics and
infant was successfully treated with extracorporeal mem- Surgery University of Colorado School of Medicine
Hematology 2004 461
Incidence and Patient Predisposition reversal and patients with thrombotic thrombocytopenic
In North America the reported incidence of TRALI is purpura (TTP) who have widespread endothelial cell
1/5000–1/1323 transfusions.1,3,4 The incidence in Eu- activation (personal communications from Patricia M.
rope is markedly lower, 1/7980, but the true incidence Kopko, MD and Richard Benjamin, MD).
of TRALI remains unknown, and it is unlikely to be
determined until a consensus definition can be reached.11 Implicated Blood Components
Although no specific patient groups are predisposed In published series of TRALI, plasma-containing blood
to TRALI, Van Buren et al first postulated that the clini- components are most commonly implicated, with whole
cal status of the patient played a significant role in the blood–derived platelet concentrates (WB-PLTs) hav-
genesis of TRALI.17 In a retrospective series of 10 ing caused the largest number of these reactions (Table
TRALI patients compared to 10 patients with uncom- 2).4,5,10 Although the plasma fraction of blood or blood
plicated febrile or urticarial transfusion reactions, in- components rather than the cellular constituents appears
vestigators hypothesized that TRALI was the result of to be etiologic in TRALI, two of the most frequently
two independent insults because every patient in the implicated products (WB-PLTs and PRBCs) do not con-
TRALI group (10/10) had an antecedent “first event” tain large amounts of plasma.
(such as recent major surgery, active infection, or mas-
sive transfusion); only 2/10 patients in the control group Pathogenesis
had such a predisposing clinical condition.3 These first Two basic mechanisms have been proposed for the patho-
events may have predisposed these patients to TRALI genesis of TRALI. The first hypothesis is that TRALI
through activation of the pulmonary endothelium re- is antibody-mediated and is caused by either the pas-
sulting in neutrophil (polymorphonuclear leukocyte sive infusion of donor antibodies directed against re-
[PMN]) sequestration in the lungs.3 Transfusion repre- cipient antigens or the infusion of donor leukocytes into
sented the second event that activated the PMNs in the a recipient who has antibodies directed against these
lung causing endothelial damage and capillary leak, donor leukocytes.5,7 The second hypothesis is that
culminating in TRALI.3 A prospective, epidemiologic TRALI is caused by at least two independent events.3,4,10,19
study demonstrated that two patient groups were at par- The first event relates to the underlying clinical condi-
ticular risk for developing TRALI, those patients in the tion of the patient such that this individual has pulmo-
induction phase of treatment for hematological malig- nary endothelial activation resulting in pulmonary se-
nancies and patients with cardiovascular disease who questration of neutrophils.3,4,10,19 The second event is
required bypass surgery.4 A recent report implicated the infusion of specific antibodies, directed against the
massive transfusion as a risk factor for TRALI in pa- adherent PMNs in the lung, or other biologic response
tients receiving solid organ transplants.18 Moreover, modifiers (including lipophilic compounds) that cause
follow-up information from the Mayo Clinic group in activation of these primed, adherent PMNs resulting in
their series of 36 TRALI patients revealed that all of activation of the microbicidal arsenal of PMNs leading
these patients had had recent surgery.1,10 In addition, to endothelial damage, capillary leak, and acute lung
two other patient groups appear to be at risk for TRALI, injury.3,4,10,19
patients receiving fresh frozen plasma for coumadin
Antibody-mediated TRALI due to HLA class I
and antigranulocyte antibodies
Table 2. Clinical criteria for the diagnosis of acute lung In 1985, Popovsky and Moore proposed the infusion of
injury (ALI) and transfusion-related ALI (TRALI).35 donor antibodies to explain TRALI.1 They documented
donor antibodies to granulocytes in 89% of these cases
1. Insidious, acute onset of pulmonary insufficiency and antibodies to HLA antigens in 72% of cases exam-
2. Profound hypoxemia PaO2/FiO2 < 300 mmHg* ined.1 Most of the granulocyte antibodies did not ex-
3. Chest radiograph: hibit specificity, but 59% of the HLA class I antibodies
bilateral fluffy infiltrates consistent with pulmonary edema did.1 These findings have been confirmed by a number
4. Cardiac: of other groups, and approximately 50% of donor
Pulmonary artery wedge pressure ≤ 18 mm Hg†
No clinical evidence of left atrial hypertension
antileukocyte antibodies display specific reactivity to
recipient antigens. 5,17,20,21 The infusion of leuko-
agglutinins is postulated to cause complement activa-
*For patients without an arterial blood gas, pulse oximetry less
than 90% meets the criteria for hypoxemia. tion resulting in PMN influx into the lung followed by
†Irrespective of the pulmonary end expiratory pressure activation of these PMNs and release of cytotoxic agents,
(PEEP). resulting in endothelial damage, capillary leak and pul-
462 American Society of Hematology
monary damage.1,5,21 In addition, TRALI can be caused demonstrated in vitro that HLA class II antibodies im-
by the binding of recipient antibodies to discrete anti- plicated in TRALI could activate circulating monocytes
gens on transfused donor granulocytes; however, the that expressed these antigens causing synthesis of sig-
number of viable PMNs is an issue and such a mecha- nificant amounts of tumor necrosis factor alpha (TNFα),
nism represents only 10% of TRALI cases.5,22 Impor- interleukin (IL)-1β and tissue factor over a 4-hour time
tantly, this mechanism has particular relevance to pa- period as compared to monocytes incubated with con-
tients receiving granulocyte transfusions and must be trol sera.27 In addition, because HLA class II antigens
taken into account for these individuals.22 also are expressed on endothelial cells, these investiga-
tors questioned whether infusion of class II antibodies
Animal models of antibody-mediated TRALI into a recipient with cognate antigen expression on the
The relevance of these observations was reported in an pulmonary endothelium could manifest TRALI due to
ex vivo rabbit model of TRALI in which lungs were endothelial activation, changes in cellular shape, fenes-
isolated from rabbits and perfused with human PMNs, tration, and capillary leak.27
antibodies directed against specific PMN antigens or The infusion of class II HLA antibodies into patients
not, and rabbit plasma as a complement source. These who express the cognate antigens represents an attractive
experiments demonstrated that acute lung injury, char- model for TRALI but raises a number of questions. First,
acterized by severe pulmonary edema, resulted from although the synthesis of cytokines by circulating mono-
the infusion of a mixture of human PMNs [HNA-3a+ cytes is interesting, there is a significant time delay for
(5b+)], human HNA-3a antibodies, and a complement the production of these inflammatory mediators; more-
source.23 In this ex vivo model pulmonary edema oc- over, in these studies these cytokines were intracellular
curred 3–6 hours following the infusion of the admix- and were not released into the supernatant.27 Second, this
ture.23 However, if any one of the three components model has relevance only if the infused antibody specifi-
were deleted pulmonary edema did not occur.23 Fur- cally recognizes a recipient antigen.27
thermore, if immunoglobulins with indeterminate anti-
gen specificity were infused together with complement The two-event model of TRALI
and human PMNs, lung injury was not observed.23 Re- All proposed models of TRALI implicate the PMN as
cently, Bux et al have demonstrated that employing anti- the effector cell, and both TRALI and ARDS are clini-
granulocyte antibodies and PMNs that have the cognate cally identical.1,3,4,7,10,19 Thus, it is important to under-
antigens may cause pulmonary edema without the ad- stand PMN physiology, especially the interaction of
dition of a complement source.24 PMNs with pulmonary vascular endothelium (Figure
Although antibodies to HLA class I or granulocyte 2) and PMN-mediated cell damage leading to acute lung
antigens explain many TRALI cases, a number of prob- injury (Figure 3). Moreover, the underlying clinical
lems with this mechanism remain. In the original de- condition of the patient is important as demonstrated in
scription, only 59% of the immunoglobulins identified three “look back” studies; those of Van Buren with a
demonstrated antigen specificity and in published se- donor with HNA-2b antibodies, Kopko with a donor
ries of TRALI only about 50% of the implicated anti- with HNA-3a antibodies and Toy with a donor with
bodies demonstrate specificity for recipient antigens.1,5 multiple HLA class I and II antibodies8,17 (P. Toy, per-
Since such “non-specific antibodies” did not cause sonal communication). These studies demonstrated that
TRALI in the ex vivo animal model, the significance the majority of transfused patients did not develop
of these immunoglobulins, especially in the context of TRALI even though their leukocytes contained the cog-
TRALI, is undefined.23 The precise mechanism for an- nate antigens 8,17 (P. Toy, personal communication).
tibody-mediated TRALI is not known; moreover, there
are a number of cases of TRALI in which an antibody The accumulation of PMN priming activity
either in the donor or in the recipient is not present, and in stored blood
recently a case of autologous TRALI has been re- During routine storage of cellular components, an ef-
ported.1,3-5,10 fective PMN priming activity accumulates that is lipo-
philic as determined by its solubility in chloroform.28,29
TRALI secondary to the infusion of Separation and characterization of this activity in WB,
class II HLA antibodies PRBCs and platelet concentrates demonstrated that this
Recently Kopko et al postulated that TRALI is due to activity consisted of a mixture of lysophosphatidyl-
the infusion of HLA class II antibodies with specificity cholines (lyso-PCs).28,29 These compounds effectively
for class II antigens in the recipient, and these findings prime the PMN oxidative burst and can activate primed
have been confirmed.7,25,26 Furthermore, Kopko et al adherent PMNs both in vitro.28-31 In addition an in vitro
Hematology 2004 463
Figure 2. Normal polymorphonuclear leukocyte (PMN) emigration from the vasculature to the site of infection in the
In response to an infection in the tissues, inflammatory signals (arrows) diffuse to the vasculature and activate the vascular
endothelium causing release of chemokines (4-pointed stars), which attract PMNs to the endothelial surface. Attraction is followed
by selectin-mediated PMN rolling and β2-integrin:ICAM-1 mediated firm adhesion of PMNs to endothelial cells (ECs).10 These
PMNs, which have undergone a change from a non-adhesive to an adhesive phenotype are now primed.10,31 Priming of PMNs
enhances the microbicidal function of PMNs to a subsequent stimulus and changes the activity of PMNs such that stimuli that
normally do not cause activation of quiescent neutrophils are able to activate primed PMNs.10,31 It is important to note that priming
is part of the orderly process of PMN transmigration to the tissues, and although there are benefits to enhanced PMN function
including efficient destruction of pathogens, it is clear priming may be detrimental to the host leading to PMN-mediated organ injury,
especially acute respiratory distress syndrome (ARDS).10,31 The PMNs then diapedese through the endothelial layer, chemotax to
the site of infection and phagocytize and destroy the bacterial invaders.10
Figure 3. Polymorphonuclear leukocyte (PMN)–mediated tissue injury.
If the orderly process of PMN transmigration is altered by a stimulus coming from the intravascular space (arrows) rather than the
tissues, these intravascular stimuli activate vascular endothelial cells (ECs) and cause attraction, firm adhesion and priming of
PMNs. As shown the vascular endothelium is activated causing the release of chemokines (stars) that attract PMNs to the
endothelial surface followed by selectin-mediated tethering and firm adhesion through the ICAM-1:β2-integrin interaction. However,
since there are not signals to cause diapedesis and PMN chemotaxis into the tissues, the PMNs become sequestered, and these
primed, hyper-reactive leukocytes may be activated by stimuli that normally have no effect including antibodies directed against
specific leukocyte antigens or the lipids that accumulate during routine storage of cellular blood components. Activation of these
adherent PMNs causes endothelial damage (ECs with diagonal lines), capillary leak (the large arrow), and organ injury.10
464 American Society of Hematology
model of TRALI that employed human pulmonary mi- penic patients. Hypotheses regarding these reactions
crovascular endothelial cells (HMVECs) as targets dem- have included the infusion of permeability factors in-
onstrated that two events were required for PMN cyto- cluding venule endothelial growth factor (VEGF) or
toxicity.31 The first was HMVEC activation, which dem- class II HLA antibodies that may recognize antigens on
onstrated PMN adherence to the HMVEC surface that pulmonary ECs and cause EC fenestration.7,34
required chemokines for PMN attraction and firm ad-
herence via the PMN β2-integrins and the ICAM-1 on Relevance of the two-event model to clinical TRALI
HMVECs.31 The second event, introduction of lyso- A retrospective clinical study of TRALI patients dem-
PCs from stored blood, could then activate these PMNs, onstrated that there was an effective PMN priming ac-
causing HMVEC death, and this PMN cytotoxicity could tivity, which was a lipid, in the patients’ plasma at the
be abrogated by inhibitors of the respiratory burst.31 time that TRALI was recognized, which was not in the
patient’s pre-transfusion typing serum, and postulated
The two-event animal model of TRALI that the clinical condition of the patient was important
The two-event model of TRALI has been verified in an as a first event.3 In this study, patients with uncompli-
animal model.19,32 Rats were treated with endotoxin (lipo- cated febrile and urticarial reactions comprised a con-
polysaccharide [LPS]) for 2 hours to approximate ac- trol group that did not demonstrate PMN priming ac-
tive infection, one of the predisposing clinical condi- tivity in their post-reaction blood samples.3 Importantly,
tions associated with TRALI.19,32 LPS activated the pul- two of the predisposing conditions postulated by this
monary vascular endothelium resulting in pulmonary study to be involved with the two-event pathogenesis
sequestration of PMNs, which was confirmed by the of TRALI, massive transfusion and recent major sur-
pulmonary histology.19,32 The lungs were then isolated gery, have since been implicated by other groups as
and perfused with buffer controls or 5% heat-treated predisposing conditions for TRALI.3,10,18
plasma from fresh (day 0) or stored (day 5 or day 42) In a prospective analysis of TRALI, the role of
plasma from platelet concentrates (apheresis platelet cytotoxic HLA class I, class II and anti-granulocyte
concentrates [A-PLTs] or whole blood–derived plate- antibodies were examined.4 Of the donors tested, only
let concentrates [WB-PLTs]) or PRBCs, respectively.19,32 1/28 exhibited an antibody with specificity (HLA A26)
The plasma fraction of PRBCs and platelet concentrates similar to positive controls.4 The implicated blood prod-
were taken from the same units so that the only vari- ucts demonstrated significant plasma PMN priming ac-
able among the different plasma fractions was storage tivity as compared to similar products from the same
time.19,32 The lungs isolated from buffer pretreated ani- facility and identical storage time that did not cause
mals did not evidence ALI with any of the perfusates.19,32 transfusion reactions.4 There was lipid priming activity
In addition, the lungs from LPS-treated animals per- in all TRALI patients at the time of recognition, which
fused with fresh (day 0) blood components also did not consisted of two classes of lipids: neutral lipids and
evidence acute lung injury. However, lungs from LPS lyso-PCs.4 In addition, the roles of IL-6 and IL-8 were
pretreated animals, perfused with plasma from stored examined and both increased during storage, but only
components (day 42 PRBCs or day 5 platelet concen- IL-6 was significantly increased in the TRALI patients
trates) caused ALI as documented by pulmonary edema, versus the pre-transfusion sample.4 Thus, in this series
lung histology, and increased leukotriene concentrations TRALI was due to two events: the first was the clinical
in the perfusate.19,32 In addition, both the lipid fraction condition of the patient, and the second was the infu-
and purified lipids from stored, but not fresh, PRBCs, sion of bioactive lipids in the stored blood component.4
WB-PLTs, and A-PLTs caused TRALI.19,32 Thus, both
the plasma and lipids from stored blood products caused Prevention
TRALI in this model.19,32 Decreasing blood usage will diminish TRALI. In addi-
Apparently healthy patients who experience TRALI tion, all donors who have been implicated in TRALI
would seem to disprove the two-event model. How- reactions should be temporarily disqualified from do-
ever, by definition, patients who require transfusion are nation until leukocyte antibody testing can be completed.
not healthy. Moreover, a study of the appearance and If these donors have antibodies to high frequency leu-
activity of PMNs from “healthy” donors indicated that kocyte antigens, they should be disqualified from plasma
the donors were in fact not well; all evidenced infec- or platelet donation; otherwise, if these studies are nega-
tions, 2 with sinusitis and 3 with viral syndromes, over tive, they should be returned to the donor pool. Current
the next 24 hours.33 Thus, it may be difficult to deter- data do not support the disqualification of multiparous,
mine if transfused patients are indeed healthy. It is no- female donors at this time, and such disqualification
table that TRALI has occurred, albeit rarely, in neutro- may be disastrous to blood centers in which these indi-
Hematology 2004 465
Table 3. Blood products implicated in transfusion-related Table 4. Definition of transfusion-related acute lung injury
acute lung injury (TRALI).* (TRALI).
• Whole blood–derived platelet concentrates (WB-PLTs) 1. TRALI in patients with clinical risk factors for ALI:
• Fresh frozen plasma (FFP) a. New ALI temporally related to transfusion.*
• Packed red blood cells (PRBCs) b. The new ALI is thought to be mechanistically related to
• Whole blood (WB) the transfusion. †
• Apheresis platelet concentrates (A-PLTs) c. Worsening of pre-existing pulmonary insufficiency
temporally related to transfusion.
2. TRALI without clinical risk factors for ALI:
• Stem cell preparations
a. New ALI temporally related to transfusion.*
• Intravenous gamma globulin
b. Worsening of pre-existing pulmonary insufficiency
• Cryoprecipitate temporally related to transfusion.
* The implicated blood products are listed in the order of *During or within 6 hours of the completion of the transfusion.
numbers of published cases of TRALI. †Recognition by the clinical care team that ALI is most likely
due to the transfusion.
Abbreviations: ALI, acute lung injury
viduals make up 20%–30% of the donor pool. For high- may have the early stages of an acute illness whose
risk surgical procedures requiring transfusions, wash- presentation is sub-clinical. As stated previously, it is
ing of cellular components removes both antibodies and often difficult to assess patients who may have early
lipids from the plasma fraction. Fresher products may phases of acute infection.33
be used to obviate the effects of lipids in high-risk pa-
tients who are not neutropenic such that the use of PRBCs III. UTILIZATION OF RECOMBINANT FACTOR VIIA
< 21 days and platelet concentrates < 3 days will avoid (RFVIIA) IN NON-APPROVED SETTINGS
much of the effects of these compounds that accumu-
late during storage. Lawrence T. Goodnough, MD*
Definition Recombinant FVIIa (rFVIIa) has been approved for
Because of the increase in TRALI cases in the United treatment of bleeding in hemophilia patients with in-
States, a working group was convened in May of 2003 hibitors. It has also been successfully used in non-
by the National Heart, Lung, and Blood Institute, Na- hemophilia patients with acquired antibodies against
tional Institutes of Health (NIH), to arrive at a consen- FVIII (acquired hemophilia). Pharmacological doses
sus definition. TRALI was also the subject of a two- of rFVIIa have been found to enhance the thrombin
day Canadian Consensus Conference sponsored by Ca- generation on already activated platelets and, therefore,
nadian Blood Services and Héma-Quebec, and a num- may also likely be of benefit in providing hemostasis in
ber of European groups, including the British and the other (non-approved) situations characterized by pro-
Dutch, are currently developing a consensus definition fuse bleeding and impaired thrombin generation,1 such
of this life-threatening adverse event. TRALI is acute as patients with thrombocytopenia and in those with
lung injury, as the name implies, and should be consid- functional platelet defects.2,3 Additionally, it has been
ered in all cases of respiratory distress with profound used successfully in a variety of less well-characterized
hypoxemia (PaO2/FiO2 < 300 mm Hg) temporally re- surgical bleeding situations4-6 as well as in patients with
lated to a transfusion (Table 3). TRALI may occur with impaired liver function.7
the presence of risk factors for ALI or not as long as To date, case reports, anecdotal experience, and lim-
the observed ALI is temporally related to the transfu- ited clinical trials describe these uses; data from ran-
sion (Table 4). Risk factors for ALI should not exclude domized clinical trials are limited. Because of the re-
TRALI, for it is a form of ALI that has a two-event cent trends in rFVIIa usage in non-approved settings
etiology, with the second event related to factors present
within the transfused component(s). Moreover, wors-
* Transfusion Medicine Service, Washington University
ening pulmonary function following transfusion in a Medical School and Barnes-Jewish Hospital, St. Louis MO
patient with compromised respiratory status should also
be considered TRALI. Patients who are transfused are Current address: Stanford Medical Center, 300 Pasteur Drive,
not healthy; even though patients who appear healthy H-1402, Stanford CA 94304-5626
466 American Society of Hematology
among physicians from various disciplines, significant ommended to be a 4.8 mg vial, which for an adult pa-
concerns about its safety, efficacy, and costs have arisen. tient is a dose range of 50–100 µg/kg for a body weight
Additionally, dosing of rFVIIa for these potentially range of 100–50 kg (Table 5). One or two administra-
broad clinical applications is not standardized. The de- tions seem to be enough to decrease the bleeding sig-
cision to use rFVIIa for patients with uncontrolled bleed- nificantly. Controlled randomized studies are, however,
ing continues to be one that is made by individual phy- required to prove any beneficial effect of rFVIIa in
sicians, assisted by their hospital pharmacotherapeutics these patients.
or transfusion committees.8
The transfusion medicine service of Barnes-Jewish Congenital FVII deficiency
Hospital in St. Louis, Missouri, therefore undertook a In a randomized study, 17 FVII-deficient patients were
review of the currently available data and experience treated with rFVIIa,11 ranging from 21 to 27 µg/kg based
regarding rFVIIa therapy in non-approved settings and on the dose capable of normalizing the prothrombin
developed educational guidelines and policies for its time (PT) 15 minutes after injection. The treatment
potential use in these areas. These elements were ap- resulted in excellent resolution of all hemarthroses
proved by our hospital transfusion committee and pub- treated. An infant with severe FVII deficiency and
lished in our Laboratory Medicine Newsletter. These massive intracranial hemorrhage was evaluated after
policies for rFVIIa therapy undergo periodic review administration of rFVIIa at three dose levels: 15 µg/kg,
and revision as relevant new information and data are 22 µg/kg, and 30 µg/kg.12 FVII levels were > 100%
generated, and are presented here. between 30 and 180 minutes after each infusion, with
mean trough levels above 25% at all three dose levels.
Experience with rFVIIa in Non-Approved Settings The recommended dosage at the Transfusion Medicine
Service at Washington University for rFVIIa replace-
Complex surgery and traumas resulting ment therapy in congenital FVII deficiency is therefore
in profuse bleeding 20 µg/kg (Table 5).
A hemostatic effect has been demonstrated following
the administration of rFVIIa in a limited number of Patients receiving oral anticoagulant therapy
patients after trauma and bleeding.5,6 Seven trauma pa- One report describes the use of rFVIIa in 7 adult pa-
tients treated with rFVIIa after failure of conventional tients with prolonged INR, 3 of whom required sur-
measures to achieve hemostasis6 reported cessation of gery. The doses administered ranged from 20 µg/kg to
diffuse bleeding and correction of abnormal coagula- 90 µg/kg, and all patients were reported to have a posi-
tion assays; 3 of the 7 patients died of reasons other tive outcome.13 These observations indicate that rFVIIa
than bleeding or of thromboembolism. may be used to reverse the effect of warfarin or other
Anecdotal case reports have been published that vitamin K-antagonist therapy in cases in which the ad-
describe the successful use of rFVIIa in patients with ministration of vitamin K alone has been found to be
substantial perisurgical bleeding.4 A prospective, ran- insufficient. Two published reports of 15 total patients
domized study of rFVIIa (20 µg/kg or 40 µg/kg) versus treated with rFVIIa for reversal of excessive antico-
placebo perioperatively in 36 patients undergoing radi- agulation with coumadin support a dosage of 20 µg/kg,
cal retropubic prostatectomy found that the cohorts re- or 1.2 mg for an adult patient.14,15 A recent review of 19
ceiving rFVIIa had substantially less median operative patients with acute warfarin-associated intracranial hem-
blood loss compared to placebo (1235 mL, 1089 mL, orrhage over this same time period at our institution,
and 2688 mL, respectively).9 who received rFVIIa (30–135 µg/kg) as well as vita-
Nine patients with coagulopathy and urgent neuro- min K (10 mg/D × 3) and FFP (1307 ± 652 mL) for
surgical intervention were reviewed after receiving pre- treatment, found that treatment was associated with rapid
operative rFVIIa (40–90 µg/kg).10 Post-rFVIIa coagu- correction of INR and that single doses appeared safe
lation parameters normalized as early as 20 minutes in this high-risk population.16
after infusion, with no noted procedural or operative
complications. No associated thromboembolic compli- Patients with impaired liver function
cations were observed. A hemostatic effect of rFVIIa has been proven in a
The experience of rFVIIa use in trauma with ex- limited number of liver disease patients.7 In one clinical
cessive bleeding as well as in postoperative profuse trial, 10 cirrhotic patients whose PT did not correct to
bleeding, based largely on case reports, indicates a he- within 2 seconds above the control reference value were
mostatic effect of rFVIIa given in doses of 20–120 µg/ given three successive dosages of rFVIIa (5, 20, or 80
kg. Initial dosage approval for administration is rec- µg/kg) during a 3-week period in a randomized study.17
Hematology 2004 467
Table 5. Recombinant factor VIIa (rFVIIa) dosing policies.*
Currently Approved Clinical Settings
1. Patients with factor VIII or IX inhibitor
A) Vigorous bleeding, impending compartment syndrome, or bleeding in critical location: 90 µg/kg q 2–3 hours until patient
hemostasis is achieved, then less frequently thereafter.
B) Persistent bleeding, not life or limb threatening: titrate both dose and interval to obtain adequate hemostasis.
C)Prior to invasive procedures: 90 µg/kg initially, subsequent doses, interval, and duration of treatment titrated to bleeding risk.
D)No signs of bleeding, stable Hgb: rFVIIa not indicated.
Currently Nonapproved Clinical Settings
1. Qualitative, quantitative platelet disorders and life threatening bleeding unresponsive to platelet transfusion.
A) Correct coagulopathy and anemia with platelets, FFP, cryoprecipitate, and red cell transfusions.
B) Administer DDAVP and Amicar.
C)Dialyze if uremic.
D)rFVIIa 4.8 mg vial (50–100 µg/kg for 100–50 kg patient). If clinical response, titrate dose and interval to maintain adequate
2. Prolonged INR requiring rapid reversal
A) Minimal or no active bleeding
10 mg Vitamin K IV or SQ
B) Life or limb at risk
1.2 mg vial rFVIIa**, and
FFP 15–20 mL/kg, and
10 mg vitamin K, IV infused over 20 minutes
*20 µg/kg for a 70 kg patient; subsequent doses of rFVIIa indicated for clinical signs of persistent bleeding, not to
maintain a normal PT/INR.
3. Uncontrollable hemorrhage associated with trauma, surgery, and liver failure.
A) Replace consumed/diluted hemostatic factors with FFP, cryoprecipitate, platelet transfusion, red cell transfusions.
B) Periodically monitor PT, aPTT, fibrinogen, platelet count, hemoglobin.
C)If excessive bleeding continues without apparent response to adequate blood components and no identifiable surgical
source has been found, 4.8 mg vial rFVIIa (50–100 µg/kg for 100–50 kg patient). If bleeding does not diminish in 30–60
minutes, consider one more dose or surgical exploration.
D)Use rFVIIa with caution in patients at increased risk for thrombotic complications:
a. After cardiac surgery
b. Patients with history of coronary artery disease
c. Patients with history of venous or arterial thrombosis
d. Patients with DIC
e. Patients on ECMO or VAD
f. Patients with cerebral vascular disease
4. Congenital factor VII deficiency.
A) Factor VII activity > 25%, expectant management except neurologic, cardiothoracic, or ophthalmologic surgery/trauma.
B) Factor VII activity < 25% and minor trauma/surgery:
Initial treatment: 10–15 mL/kg FFP
Repeat 3–6 mL/kg at 6–8 hour intervals until hemostasis is achieved.
C)Factor VII activity < 25% and at risk for neuro, cardiothoracic, ophthalmologic bleeding:
a. Initial treatment: rFVIIa 1.2 mg vial (20 µg/kg for 70 kg patient) q 2 hours until hemostasis is achieved.
b. Titrate dose and interval to ongoing bleeding risk.
c. Combined treatment with FFP and rFVIIa at lower doses is a consideration, in patients who can tolerate volume
* Goodnough LT. Recombinant Factor 7a. Washington University Laboratory Medicine Newsletter 2003;9:1-4.
**Currently available in vials of 1.2 mg, 2.4 mg, and 4.8 mg.
Abbreviations: FFP, fresh frozen plasma; DDAVP, desmopressin acetate; DIC, disseminated intravascular coagulation; ECMO,
extracorporeal membrane oxygenation; VAD, vincristine, doxorubicin, and dexamethasone; INR, international normalized ratio; PT,
prothrombin time; aPTT, activated partial thromboplastin time
468 American Society of Hematology
Table 6. Recombinant factor VIIa (rFVIIa) utilization.
Series 2002 Jan-June 2002 July-Dec 2003 Jan-June 2003 July-Dec 2004 Jan-June Total
All patients (n) 5 14 26 47 38 130
# of doses 18 45 121 121 78 383
Mean total dose* 12.2 ± 9.1 12.0 ± 12.1 21.2 ± 50.5 10.4 ± 13.0 8.6 ± 13.5 12.5 ± 26.0
(mg) (range) (2.4–24) (2.4–48) (2.4–246) (1.2–60) (1.2–84) (1.2–246)
On-label – FVIII Inhibitors (n) 2 0 2 2 2 8
# of doses 9 0 79 12 26 126
Mean total dose* 14.4 ± 6.8 - 125 ± 121 57 ± 2.5 43.2 ± 57.7 75.7 ± 80.8
(mg) (range) (9.6–19.2) (4–246) (55.2–58.8) (2.4–84.0) (2.4–246)
Off-label (n) 3 14 24 45 36 122
# of doses 9 45 42 100 52 248
Mean total dose* 10.8 ± 11.6 12 ± 12.1 8.2 ± 4.8 8.3 ± 8.6 6.7 ± 5.2 8.3 ± 7.7
(mg) (range) (2.4–24) (2.4–48) (2.4–24.5) (1.2–60) (1.2–27.6) (1.2–60)
* Values expressed as means ± SD with range in parenthesis.
The PT transiently corrected to normal in all three dos- patients with FXII deficiency.18,19 The last of 10 patients
age groups. enrolled in an open-label, dose-escalation trial to pre-
A multicenter trial studied 71 patients with advanced vent rebleeding after subarachnoid hemorrhage devel-
liver disease who were undergoing laparoscopic liver oped middle cerebral artery thrombosis after receiving
biopsy.18 The patients were randomized to receive one rFVIIa.20 In a high-risk trauma population, 3 of 40
of four doses (5, 20, 80, or 120 µg/kg); 48 (74%) of 65 (7.5%) patients who were deemed at high risk for throm-
patients achieved hemostasis within 10 minutes. One bosis developed thrombotic complications after receiv-
thrombotic event and one case of disseminated intra- ing rFVIIa.21
vascular coagulation (DIC) were reported, not felt by We reported a patient who had a fatal thrombosis
the authors to be related to rFVIIa therapy. Despite these after administration of activated prothrombin complex
complications, the authors concluded that laparoscopic concentrate (APCC), who had also received two doses
liver biopsy can be performed safely and reliably by of rFVIIa more than 6 hours earlier, while supported
using rFVIIa in patients in whom the standard proce- by extracorporeal membrane oxygenation.22 Because of
dure might be contraindicated because of coagulopathy. this experience, we recommend that patients should not
receive combination therapy with both APCC and
Of the more than 170,000 standard doses of rFVIIa On the basis of these reports, use of activated fac-
given after its approval (almost all to patients with he- tor concentrates should be used with caution in patients
mophilia and inhibitors), only rare (< 1:11,300) throm- with known hypercoagulability (e.g., history of throm-
botic events have been reported.1 Five patients with botic complications, established thrombotic disorders
thromboembolic events have been reported. Six patients like factor V Leiden, antiphospholipid syndrome, etc.)
developed acute myocardial infarction in association or who have excessive bleeding in the setting of DIC or
with rFVIIa treatment. Five out of the 6 patients were other states of generalized activation of the hemostatic
over 70 years old, and 2 hemophilia patients had a his- system (e.g., after cardiac surgery, patients on extra-
tory of cardiovascular disease, which also was the case corporeal membrane oxygenation [ECMO] or ventricu-
in 2 patients with acquired hemophilia. Cerebrovascu- lar assist devices) based on the potential for develop-
lar disorders were reported in 4 patients, 3 of whom ment of localized or systemic intravascular thrombosis.
were more than 55 years old, 1 with hemophilia, and
the others having acquired hemophilia. Utilization
Thrombotic complications have also been reported A review of our transfusion service for 2002 to 2004
with rFVIIa therapy in patients without inhibitors to indicated that 122 patients received rFVIIa therapy for
FVIII or FIX. An acute cerebral vascular accident and non-approved indications (Table 6). The mean dose
death occurred in a clinical trial of rFVIIa (90 µg/kg) administered for all of these patients was 8.3 ± 7.7 mg
before and after minor surgery or dental procedures in (range 1.2–60 mg) at a mean cost of $7215 per patient.
Hematology 2004 469
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472 American Society of Hematology