the coag course
Managing patients with advanced sepsis has just gotten a little
bit easier. That’s the good news. The bad news? The task remains a
little on the order of skirting Niagara Falls in a canoe.
Physicians now have a drug—Eli Lilly’s Xigris, or drotrecogin
alfa (activated), also known as recombinant activated protein C—that
has been shown to significantly reduce mortality in patients with
severe sepsis. The drug, approved by the FDA last November, showed
an absolute reduction in the risk of death of 6.1 percent and a
reduction in the relative risk of death of 19.4 percent in a multicenter
clinical trial involving 1,690 randomized patients (Bernard GR,
et al. N Engl J Med. 2001;344:699-709).
The enthusiasm generated by the PROWESS study comes as no surprise.
Rick Dew, RPh, a pharmacist at Massachusetts General Hospital, Boston,
has seen more than his share of failed sepsis agents over the years.
"Historically, none of the other trials have worked. Over 30 of
them have failed. This is the first one to have shown a benefit
and made it onto the market. So it’s very exciting, after participating
in so many negative trials, to finally have something that works."
The real surprises lie elsewhere, in the largely unexpected links
between sepsis and inflammation, coagulation, and fibrinolysis.
Laboratories and clinicians must now take on a tangle of delicate
decisions as they try to puzzle out who will benefit from APC—and,
just as important, who won’t.
For starters, Xigris appears to be associated with an increased
risk of bleeding.
"People with severe sepsis who have a profound coagulopathy are
at a higher risk of bleeding, with or without Xigris. They’re also
at a higher risk of mortality," says John Brandt, MD, medical advisor
at Lilly and a member of the CAP’s Coagulation Resource Committee.
"So you’re caught in a little bit of a dilemma in that people with
a very marked coagulopathy are perhaps the ones who need the drug
most." Retrospective analysis of the data from the PROWESS trial
suggests that patients with more severe coagulopathy, if it is due
to the sepsis, may have a positive risk benefit.
Moreover, some patients, such as those with cirrhosis, may be
unable to upregulate the production of clotting factors and may
not be candidates for Xigris. "The risk of bleeding must be weighed
against the benefits of Xigris in each patient," Dew says.
In the clinical trial, notes Dew, a subset of less-sick patients,
as determined by APACHE II scores, actually had three percent higher
mortality when given the drug. "So the fear is that somebody who
is very clearly septic, but not septic enough, if you will, might
actually be harmed"—a concern that will be addressed in another
large clinical trial, Dr. Brandt reports.
Some septic patients actually get better without treatment. "You
don’t want to give them the drug and expose them to the risk of
bleeding," Dew says. Then there’s the expense of the treatment—about
[Interestingly, a front-page article in the Wall Street Journal
May 17 addressed the costliness of Xigris. The story, part of an
ongoing series on drug prices, noted that several studies, though
far from conclusive, have hinted that cheap, common steroids may
also halt sepsis, by normalizing the inflammatory process.
[One article, published in Chest (Meduri GU, et al. 1998;114:355b-360b),
proposed that low doses of glucocorticoid might be effective. Another,
published in JAMA (Meduri GU, et al. 1998;280:159-165), looked
at prolonged administration of methylprednisolone in patients with
acute respiratory distress syndrome, which can result from sepsis.
It should be noted that none of the studies have numbers anywhere
similar to those in the PROWESS study; the JAMA study, for
example, had only 24 patients.]
None of which diminishes the cheers that have greeted Xigris. Quite simply,
it saves lives. And, as Michael Laposata, MD, PhD, director of clinical labs
at Mass General, puts it: "Who would have thought that regulating coagulation
in a septic patient could be a life-saving maneuver?"
Consider the approval of APC to be the alpha, not
the omega, of understanding the pathophysiology of sepsis. No one
knows for sure why Xigris is effective, and the theories put forth
are rigorously debated. "We know that it has anticoagulant properties,"
Dr. Brandt says. "We believe it has significant anti-inflammatory
properties, and that it probably restores the fibrinolytic system
toward its normal state."
Are all three pathways important? "There are some of us who think
so," says Dr. Brandt. Though some suggest that Xigris’ anticoagulant
properties are the linchpin, Dr. Brandt hesitates.
"My personal opinion is that there must be something else additional
going on," he says. His reasoning: Heparin has been tried in severely
septic patients, particularly those with a coagulopathy, with no
effect on mortality. Granted, says Dr. Brandt, those clinical trials
took place in the 1970s and were not all that sophisticated; they
might not pass muster with today’s more rigorous trial standards.
"But there’s no suggestion that heparin as an anticoagulant had
an effect on mortality."
Tissue factor pathway inhibitor and antithrombin can also shut down coagulation,
but they too have failed to lower death risk in large phase III clinical trials.
So while the anticoagulant properties of Xigris are important, particularly
in controlling thrombosis in the smaller blood vessels and microvasculature,
"I think it [the drug] must be doing more than just that," Dr. Brandt says.
"That’s why I think the anti-inflammatory properties are of potential interest."
Until APC came along, the link between coagulation and
inflammation had not been seen as intense. "That was a surprise,"
says Dr. Laposata, former vice chair of the Coagulation Resource
Committee. "We knew that minimizing inflammation was important;
we didn’t know one of the ways to do it was to give an anticoagulant
In the past, the search for a sepsis agent had taken a different
tack, focusing on cytokines and other mediators of inflammation
to either eliminate the underlying organism or minimize the inflammatory
effects produced by the infection. "If anybody guessed what you
really need for sepsis, it would be something that kills the organism,
right? Or some major inflammatory drug," says Dr. Laposata.
Dew underscores that point, recalling the many years researchers
spent trying to manipulate the balance between pro- and anti-inflammatory
responses. One early hope was that blocking the endotoxin component
of gram-negative bacteria would shut down the proinflammatory response.
Another approach was to look at two proinflammatory cytokines,
interleukin-1 and tumor necrosis factor, which are released by gram-positive
bacteria. "We figured if we gave patients antagonists to that, it
would shut the whole thing down," says Dew. This approach didn’t
Researchers then turned their attention to the endothelial lining
and its role in transporting white blood cells. As it turned out,
upregulating tissue factor—which is not expressed on normal
endothelium—activates the coagulation pathway.
Most researchers were at first skeptical of proposals to replace
coagulation proteins. The original hypothesis was that activated
protein C would shut down the tissue factor-activated extrinsic
coagulation pathway, eliminating the fibrin clots responsible for
organ failure in severe sepsis cases. As studies continued, researchers
discovered that activated protein C also works to inhibit inflammation
as well as the coagulation pathway.
The latter is accomplished as APC binds to and shuts down factors
Va and VIIIa. Other factors that have failed in recent sepsis trials,
such as tissue factor pathway inhibitor and antithrombin, inhibit
coagulation, but at other points in the pathway. "So there might
be something special about inactivating factors Va and VIIIa that
makes this drug work where others have failed," Dr. Laposata proposes.
In addition, APC appears to enhance fibrinolysis (which is suppressed
in sepsis) by neutralizing plasminogen activator inhibitor and by
accelerating tissue plasminogen activator-dependent clot lysis.
These emerging links between coagulation, inflammation, and fibrinolysis
have launched new rounds of questions. Does inflammation start the
coagulation cascade, or vice versa? How do the three pathways fit
together? Moreover, the fibrinolysis genes in particular are becoming
targets for genomics and proteomics research aimed at sorting out
whether a genetic predisposition toward sepsis exists.
As if all this weren’t complicated enough: "I’ll tell you what—there’s
another biology on top of all this," says Liliana Tejidor, PhD, director of
research and development in hemostasis at bioMérieux. That would be apoptosis.
"People are starting to say, OK, this is not just the intersection of inflammation
and coagulation, but also cell death. And there are so many genes and so many
proteins involved in programming cells to die."
Not that everything is a complete muddle. Says Tim Hayes,
MD, DVM, chief of clinical pathology at Maine Medical Center, Portland:
"We realize coagulation is activated early on in this course. You
don’t have to go into septic shock before you’ve activated the coagulation
cascade." With Xigris moving off the shelf into clinical practice,
more answers will be forthcoming.
As of late April, Dr. Laposata and his colleagues at Massachusetts
General had experience with seven patients using Xigris. "We’re
seven for seven," says Dr. Laposata, explaining that all seven did
well on the drug. It’s unlikely, he adds, that any or all would
have improved without APC. "We estimate the risk of mortality was
on the order of 40 percent before the drug," he says. Indeed, the
death rate in sepsis patients is significant, between 30 and 50
percent by most estimates.
From these and other early patients, Dr. Laposata and his colleagues
are attempting to refine the use of activated protein C, which needs
to be treated with the healthy respect given to any anticoagulant.
The laboratory has taken a rather aggressive approach in monitoring
Xigris, measuring the full panel of coagulation factors each of
the four days the patient receives the drug and looking for major
changes that might indicate a predisposition to bleed. "We have
some early hints," is all Dr. Laposata will reveal.
Prior to a patient’s receiving the drug, the laboratory looks
at all the usual starting points—platelet count, PT, PTT,
D-dimer. Each measure has its own cutoff value, which would vary
among institutions. Says Dr. Laposata: "The bottom line is, there
are thresholds for the PT and the PTT above which we would say,
’No, the patient can’t get the drug, they’re already too compromised.’
And there’s a threshold for platelets below which we say, ’There
are not enough platelets, it is not safe to give the drug.’ Because
we realize we are going to compromise the coagulation even more,
and if they’re already predisposed to bleed, then that’s a problem."
A coagulation workup has not been routine in sepsis patients.
In phase III of the clinical trial, Lilly did do extensive coagulation
testing, Dr. Brandt reports, which demonstrated how common coagulopathies
were among patients with severe sepsis. Nearly everyone, for example,
had increased levels of D-dimer. "And these tended to be fairly
high levels of D-dimer," he says. More than 90 percent of patients
had prolonged PTs, and about two-thirds had prolonged APTTs. Thrombin-antithrombin
complex and prothrombin fragment 1.2 were also elevated.
The clinical trial had its own criteria for excluding patients
at high risk of bleeding: platelet count less than 30,000/µL, recent
surgery, recent trauma, history of intracranial pathology, congenital
bleeding disorder, and recent gastrointestinal bleeding. In the
real world, says Dew, caregivers have the flexibility to consider
stringent safety criteria without being restricted by them. "We
can correct for a lot of these things while they’re happening,"
he points out. "We can give them platelets, FFP, blood."
At the same time, says Dr. Laposata, "We are extremely cautious."
At Mass General, approval for the drug comes by way of a committee,
which consists of a pharmacist and a clinician, either an intensivist
or a pulmonary care physician. "These two people call the shots,"
he says. "If the patient qualifies, then they bring the rest of
Yet there is room for judgment. If a patient looks like a good
candidate despite a borderline platelet count, for example, the
committee will ask other members of the care team, including the
lab, to weigh in with their opinions. "This is where Dr. Laposata’s
expertise has really come into play," Dew says.
Since most intensivists don’t have extensive hematological backgrounds,
Dew says, the laboratory has stepped up to the plate, interpreting
the data in real-time to determine if a transfusion is needed, and,
if so, what kind. "It’s one thing to look at the data from a trial
in a population-based study," Dew says. "We’re arguing that this
drug can benefit some people who were probably excluded from the
trial—and we need the lab to help figure that out."
Other challenges lie in wait.
Laboratories don’t need to routinely monitor the drug’s administration,
says Dr. Brandt. "It’s administered as a constant-rate infusion,"
he explains. "The half-life, once you stop the infusion, is quite
short. And generally within two hours you can no longer measure
APC in the plasma from these patients." But activated protein C
does have an effect on the APTT, which is related to the concentration
of APC. The APTT is also dependent on the underlying coagulopathy
that affects so many of these patients. Another caveat: The APC
is gradually neutralized in the test tube between the time the sample
is drawn and the time it’s tested in the laboratory. Thus, the APTT
does not provide much helpful information on clinical samples. "If
someone were trying to follow the underlying coagulopathy, rather
than the drug effect, the prothrombin time would probably be a better
test to use," Dr. Brandt says. And given that factor VIII assays
are measured using the APTT, "You can get spurious results on a
factor VIII assay. It can be very problematic."
Laboratories may also be called on to help monitor the impact of the drug,
though the particulars are a question mark. "Certainly there is a great desire
to limit the severe consequences of an intracerebral hemorrhage, and the lab
may be able to help with that," says Dr. Laposata. "But we are not there yet."
The number of unknowns is hardly shocking, given that both
the definition of sepsis and the tests used to identify it are undergoing
"We’ve not had real sensitive tools. They’re kind of blunt instruments
to detect sepsis," says Maine Medical Center’s Dr. Hayes, pointing
to dropping platelet counts, a drop in fibrinogen, and elevated
fibrin degradation products and/or D-dimer.
At the same time, the definition of inflammation itself has changed
considerably in recent years, with efforts to grade the stages of
sepsis. "Up until now there were a lot of terms out there that were
poorly defined; now the intensivists and clinical doctors are using
the new criteria, and we’re finally starting to all speak the same
language," Dr. Hayes says.
SIRS, or systemic inflammatory response syndrome, is a cornerstone
of this new lingua franca. Patients must have two of the four criteria—abnormal
body temperature, either elevated or lowered; tachycardia; increased
respiratory rate; and an abnormal white count, either high or low—to
meet the definition of SIRS. Patients with SIRS plus a confirmed
infectious process meet the criteria for sepsis; those with sepsis
and organ failure, such as respiratory failure, hypotension, or
hypoperfusion, are considered to have severe sepsis. Nonresponsive
shock (hypotension despite fluid resuscitation) translates into
"It’s only in the last few years that we’ve begun to start understanding
the relationship between SIRS, and the various forms of it, and
coagulation," says Dr. Hayes. "We’ve always known that people who
have fulminant gram-negative sepsis often end up in DIC. What we’re
realizing now is that early on in sepsis we’re activating the coagulation
cascade. DIC is kind of the end stage of that process."
For that matter, perceptions of DIC are also evolving, Dr. Hayes
says. "Most of us, when we think of DIC, we’re thinking of patients
who are bleeding out—it looks like a hemorrhagic disorder."
The multitude of fibrin deposition microthromboses, which impair
organ perfusion and often lead to the multiorgan system failure,
have been less obvious.
"We’re finding out that before you can really see those changes, you oftentimes
have a severe derangement of the coagulation system," Dr. Hayes says. "When
you use more sensitive tools, like the thrombin-antithrombin complex, or some
of the activation peptides in prothrombin, we find these things are oftentimes
elevated very early on in sepsis. In a sense, they’re sort of subclinical, both
from a laboratory perspective and a clinical perspective. They’re really, really
It would be nice, says Dr. Hayes, if laboratories could
"go to clinicians before the cat’s out of the bag—before we’ve
got overt DIC—and give them a heads-up because we’ve got early
indicators of a pending disaster."
Some are turning a hopeful eye toward the biphasic waveform; bioMérieux
uses its Waveform Analysis Technology on its MDA analyzers to alert
the operator to the presence of this abnormal waveform. A flag,
called A2, is reported with the patient’s APTT clot time. Early
investigations of the biphasic waveform, done by Cheng Hok Toh,
MD, a hematologist with The Royal Liverpool University Hospitals
and the University of Liverpool, United Kingdom, showed a high correlation
between the biphasic waveform and DIC.
"I personally have found it useful, in cases where the diagnosis
is a little less clear," says Elizabeth Van Cott, MD, director of
the coagulation laboratory at Massachusetts General. "When the waveform
was strongly abnormal, it pushed our diagnostic decision-making
toward DIC." Her lab has started using the waveform in Xigris patients,
and she and her colleagues plan to continue evaluating the test.
Others who are familiar with the waveform offer similar anecdotal
information. Dr. Hayes weighs in with mixed findings.
"We’ve had some very interesting cases where the A2 flag was an
early predictor of bacterial infection. And the laboratory was aware
of it before the clinicians were. That’s very clear," he says.
"Interestingly, we’ve also seen some fulminant cases of meningococcal
sepsis that didn’t have an A2 flag, even though the patient was
in fulminant DIC," he continues. "We’re still trying to understand
the nuances of this tool." The questions are lining up: What is
its sensitivity? Specificity? What are the positive and negative
predictive values of the assay in the ER? The ICU? "A lot of this
is just trying to get the bugs out and understand the performance
characteristics in different settings," Dr. Hayes says.
The waveform’s first phase reflects the precipitation of a complex
between C-reactive protein and lipoproteins, primarily very low-density
lipoproteins; the second phase represents the clotting reaction.
The lipoprotein component is especially complicated, with the literature
offering no clear-cut answers about the precise role lipoproteins
play in sepsis and infection. "I think some of our understanding
has been limited by the technology used to measure the lipoproteins
and triglycerides," bioMérieux’s Dr. Tejidor says. "Perhaps the
measurement of the complex quantifies a unique subfraction of lipoproteins
that is clinically important." They have evidence, she says, that
suggests lipoproteins in patients with biphasic waveforms are qualitatively
different. "What we don’t know yet is whether these qualitative
differences can be attributed to the lipoproteins that form the
lipoprotein complexed CRP complex."
Dr. Brandt terms the waveform "an interesting biologic phenomenon—it’s
real. But how it’s going to be used is unclear. For example, would
a patient benefit from intervention therapy as soon as they develop
a positive A2 flag? I don’t have an answer to that."
No one does. But rest assured, they’re looking. Especially bioMérieux.
A multicenter clinical trial just getting underway will look prospectively
at the flag’s sensitivity and specificity for sepsis and infection
in the ICU setting, says Dr. Tejidor. This trial and others will
also clarify the waveform’s role as an early indicator of sepsis.
"We believe that the activated coagulation state and linked inflammatory
state, as a background, are the common denominators in the appearance
of the biphasic waveform and therefore can be seen in other disease
states," such as cancer and trauma, she says. It’s clear that the
specificity of the flag is not 100 percent for sepsis. But, Dr.
Tejidor contends, sepsis is the most common disease state associated
with the biphasic waveform.
There also seems to be a strong relationship between the ongoing
appearance of the biphasic waveform in ICU patients and mortality.
"One of the things we’re trying to sort out is, Is this just a marker
of death, or do you have time to do something for the patient?"
Dr. Tejidor says. "In our pilot trial, we were encouraged that the
answer is that we do have a window of time for the physician to
do something differently, to monitor the patient more closely, order
a blood culture, be more proactive even when they don’t suspect
The A2 flag was not part of the Xigris studies. "We want
to confirm its utility before we confirm the therapeutic side,"
says Dr. Tejidor. The flag does not currently have FDA approval
for any specific clinical claim.
However, it has been approved for reporting, and some laboratories
are doing just that.
Tai Po Tschang, MD, medical director of the laboratory at St.
Agnes Medical Center, Fresno, Calif., has been reporting the A2
flag for more than a year, noting "biphasic waveform present" in
the lab’s reports. Dr. Tschang calls the flag a value-added service
in conjunction with reporting PTT clotting times.
He and his colleagues began looking at the flag two years ago,
identifying 43 inpatients whose PTTs had one or more A2 flags. (When
the A2 flag function is turned on, it’s run automatically with any
panel that has a PTT component.) Out of that group, the mortality
rate was 42 percent. The diagnoses ran the gamut: CABG, chest pain,
pneumonia, fever, sepsis, pulmonary emboli, edema.
Impressed with those findings, the lab began regular reporting
about year and a half ago. In 2001, the lab performed 8,594 inpatient
PTTs; out of that group, 169 had an A2 flag present, approximately
a two percent incidence. In ER patients, 2,244 PTTs were performed,
with 14 A2 flags present (0.6 percent).
Dr. Tschang himself raises the obvious question: What does that
mean? "It’s difficult to answer," he says, launching into a mini-Socratic
musing. "It’s a bad prognostic sign. But nobody knows what to do
with it. Is it useful? Yes. Is it of great importance? At present,
the answer is ’No.’ We’re waiting for the research to catch up."
Bernard Fernandes, MD, offers a similar assessment. Dr. Fernandes,
associate professor of laboratory medicine at the University of
Toronto and head of hematopathology and blood transfusion service
at Mt. Sinai Hospital, Toronto, analyzed 100 biphasic waveforms
that occurred in 61 patients—40 of whom came from the ER.
As at St. Agnes, the flag appeared in a variety of primary diagnoses
and was associated with a high degree of mortality (42 percent).
A blood culture confirmed infection in 67 percent of these patients
and, though all had evidence of altered coagulation, only two met
the International Society for Thrombosis and Haemostasis proposed
criteria for overt DIC. The lab uses the flag to alert physicians
but does not regularly report it.
"This may be another piece of the puzzle, but much of it is speculation
at this point," Dr. Fernandes says.
The challenge now is to put all the pieces together, to understand
the true pathophysiology of sepsis. And to intervene, says Dr. Hayes,
"before the patient ends up in the autopsy suite."
Karen Titus is CAP TODAY contributing editor and co-managing