Coagulation Abnormalities Made Easy
Susan S. Yoo, MD, and Linda L. Liu, MD
Department of Anesthesia and Perioperative Care
University of California, San Francisco
San Francisco, California
he coagulation cascade was first described in the
T 1960s as consisting of two distinct pathways, the
intrinsic and extrinsic, joined to a common pathway.
Figure 1 shows this simplified version, known as the
waterfall/cascade model of the coagulation system. Since
then, our understanding of hemostasis has greatly ex-
panded, revealing an extremely complex, intertwined
system of clotting factors, proteins, anticoagulant/fibrino-
lytic pathways, and platelets intricately checked by a
multitude of feedback loops. The modern view of
coagulation now is largely cell-based and organizes clot
formation into initiation, amplification, and propagation.1
Still, the simple old two-pathway model is beneficial in
terms of helping us understand what abnormal coagula-
tion tests mean. This chapter will use the waterfall/cascade
model to describe and examine several causes of perio-
perative coagulopathy, and discuss the drugs used to treat
these abnormalities.
PREOPERATIVE PERIOD
The main concern during the preoperative period is to ac-
curately screen patients for a preexisting bleeding disorder
before surgery. Patients can have congenital abnormalities
or acquired bleeding disorders from coexisting diseases,
transfusions, medications, or herbal remedies. The best
means of detecting a hemorrhagic diathesis is by a thor-
ough history and physical. Some screening preoperative
questions that may help elucidate a bleeding disorder are
listed in Table 1.
Most patients with congenital coagulation abnormal-
ities are identified early in life, and present for surgery with
128
established diagnoses. Patients with hemophilia, von
Willebrand disease, and platelet disorders usually need
treatment before, during, and after surgery. As hematolo-
gists are often involved with their care, treatment for these
abnormalities will not be discussed in this chapter.
The more pressing question is: what does an abnormal
coagulation test mean for the patient scheduled for surgery
tomorrow? Preoperative bleeding abnormalities are best
classified based on the abnormal laboratory value: pro-
thrombin time (PT) or activated partial thromboplastin
time (aPTT). PT abnormalities are associated with factors
involved in the extrinsic and common pathways, which
include FII, FV, FVII, FX, or fibrinogen. These factor
deficiencies are associated with liver disease, vitamin K
deficiency, or warfarin effect. Activated PTT abnormalities
can be associated with deficiencies or inhibitors of factors
in the intrinsic pathway, which include FVIII, FIX, FX,
FXI, or FXII. Diseases often associated with these defi-
ciencies include hemophilia A (VIII), hemophilia B (IX),
lupus anticoagulant (LA), or heparin effect (Figure 1).
These laboratory values, wheres frequently helpful for
diagnosis, are not good predictors of intraoperative
bleeding. For instance, although it is clear that deficiencies
of each of the factors in the intrinsic pathway could have
equally long aPTT values, there are dramatically different
hemorrhagic risks for each. Deficiencies of FXII are not
associated with significant hemorrhage, whereas defi-
ciencies of FXI might or might not be associated with
hemorrhage,2 and deficiencies of FVIII and FIX are
consistently associated with hemorrhage. To confuse mat-
ters more, the LA frequently leads to an increased aPTT,
but the clinical presentation is typically that of thrombosis
Coagulation Abnormalities Made Easy 129

aPTT PT
Table 1. Preoperative Questions to Help Elucidate a prolonged prolonged
Bleeding Disorder
(1) Is there a family history of bleeding abnormalities?
(2) Is there a history of bleeding after procedures? (i.e., biopsy, tooth Check for Lupus
extraction, minor surgery)? Anticoagulant >15.6 sec
(LA) repeated
(3) Do you experience recurrent nosebleeds, gingival bleeds, easy
bruising, and/or prolonged bleeding after cuts or scrapes (shaving)?
(4) Have you experienced recurrent joint or muscle bleeds in the LA negative
absence of trauma? If so, what is the frequency and duration of LA
these recurrent bleeds? Look for FII, FV,
positive FVII, FX, fibrinogen
Look for FVIII, FIX,
(5) For females, do or did you experience heavy periods (10 pads/d  4 deficiency or
FXI deficiency or
days)? inhibitor
inhibitor
(6) What other medical problems do you have? (Liver diseases, renal
disease, malignancy, vitamin K or C deficiency) Levels Levels Levels
normal low normal
(7) What prescription, over-the-counter, and herbal medicines do you
regularly take? Proceed Hematology Proceed
to surgery consult to surgery

Figure 2. Algorithm for work-up of an abnormal preoperative PT or aPTT.

aPTT ¼ activated partial thromboplastin time; PT ¼ prothrombin time.

as opposed to bleeding. Owing to this lack of predictability INTRAOPERATIVE PERIOD

for bleeding, preoperative coagulation tests are not
recommended for healthy ASA I or ASA II patients with
negative bleeding histories.3
An algorithm for further preoperative work-up for an
abnormal PT or aPTT, and a positive bleeding history is
shown in Figure 2. If the work-up for LA is positive, then
the patient may proceed to the operating room, but he-
matology should be involved postoperatively due to the
increased risk for thrombosis. Patients with elevated PT or
aPTT with negative LA need to undergo work-up for factor
inhibitors or deficiencies. If levels are low or an inhibitor is
present, then further hematology work-up is required. Pa-
tients with a positive bleeding history, but normal PT and
aPTT, should have a more extensive hematology con-
sultation. In this instance, low or dysfunctional platelets,
mild deficiency of von Willebrand factor, vascular dis-
orders, and, rarely, FXIII deficiency should be considered.
Intrinsic Pathway
(aPTT)
Kallikrein Extrinsic Pathway
(PT)
fXII
Tissue Factor
fXI
There are really only two major causes of intraoperative
bleeding. The first and most common is bleeding at the op-
erative site, which needs to be corrected surgically. The second
is nonsurgical or medical bleeding, or failure of the hemostatic
pathways. Causes for this failure are shown in Table 2.
The mainstays of massive blood loss management in-
clude replacement of red cells, platelets, clotting factors,
and fibrinogen. Avoidance of hypothermia, correction of
acidosis/shock, and frequent checking of laboratory va-
lues, to help guide transfusions and electrolyte replace-
ments, are necessary. A basic laboratory profile in the
operating room should include hematocrit, platelet count,
PT, aPTT, and fibrinogen level.
For trauma patients, the evaluation should also focus on the
degree of shock or tissue hypoperfusion. Although the classical
teaching of acute traumatic coagulopathy focused on
consumption, dilution, and hypothermia, more recent findings
strongly support the central role of shock, which can lead to
activation of protein C, systemic anticoagulation, and hy-
perfibrinolysis.4,5 Brohi et al.,4 found that trauma patients with
base deficits greater than 6 mEq/L had a 20% chance of de-
veloping coagulopathy, compared with 2% risk for patients
with base deficits less than 6 mEq/L.

fIX fVIII fVII Table 2. Nonsurgical Causes of Intraoperative

Bleeding
fX Causes for the Failure of the Hemostatic Pathways
fV Undetected preexisting bleeding disorder
fII
Hemodilution of coagulation factors
Common Pathway
Fibrinolysis induced by surgical procedure (prostatectomy, liver
Fibrin transplant, or foreign graft material)
Disseminated intravascular coagulation (sepsis, cardiopulmonary
Figure 1. Waterfall/cascade model of the coagulation cascade. aPTT ¼ acti- bypass, or transfusion reaction)
vated partial thromboplastin time; PT ¼ prothrombin time.
130
Current management of acute traumatic coagulopathy
focuses on early blood products and replacement of coagula-
tion proteins rather than crystalloid resuscitation. The ratio of
fresh frozen plasma (FFP) and packed red blood cells (PRBC)
is of particular importance. Duchesne et al.,6 showed, in a
retrospective review of 2746 trauma patients, that a 1:1 ratio
of FFP:PRBC had a significantly (Po 0.0001) decreased risk
of mortality as compared with a 1:4 ratio. Borgman et al.,7
reviewed 246 massive transfusion patients. They supported
the results by showing a significant decrease in mortality when
the ratio stayed closer to 1:1 as compared with 1:2.5 or 1:8.
Other factors that may be of importance include the ratio of
platelets to PRBC. Holcomb et al.8 showed improved 30-day
survival with high FFP:RBC ratios and high platelet:RBC
ratios. The patients in the high ratio groups had decreased
intensive care unit stay, ventilator days, and hospital stay.
Whether we should apply the same transfusion ratios for sur-
gical patients in the operating room remains to be determined,
but the underlying pathophysiologic concerns seem similar.
Other than hemodilution, hypothermia, and acidosis, the
remaining causes of medical bleeding are fibrinolysis and dis-
seminated intravascular coagulation (DIC). DIC is a derange-
ment of the coagulation system leading to clotting and then
fibrinolysis. This is difficult to diagnose during surgery, parti-
cularly since there is no pathognomonic laboratory test. Sur-
gical bleeding alone can cause an elevated PT, low fibrinogen
levels, and low platelet counts. Distinguishing between
primary fibrinolysis and DIC by laboratory values in-
traoperatively is challenging. The diagnosis will often depend
on the clinical scenario. D-dimers can be ordered, but the re-
sults will not be available quickly. The first goal in treatment of
DIC is to correct the primary disorder, if possible, and then
replace fibrinogen, platelets, and coagulation factors as
necessary. Heparin therapy is not universally accepted in
the treatment of DIC. The decision to use heparin, especially
intraoperatively, should be discussed with the surgical team
and the hematologists.
Treatment
Fortunately, there are some pharmacologic interventions
available for use during massive blood loss. These can be
divided mainly into two categories: drugs that increase
clotting and drugs that decrease clot breakdown. Overall,
although it appears that the medications may reduce blood
loss, there has been lack of evidence showing improved
mortality and morbidity.
Recombinant Factor VIIa
Recombinant factor (rFVIIa, Novoseven) was originally
developed for the treatment of patients with hemophilia A or B
with antibodies to FVIII and FIX, respectively.9 Now, wider
applications of this drug also include treatment of patients
with other factor deficiencies (FVII, FV, FXI), and patients
with qualitative or quantitative platelet defects (Glanzmann
thrombasthenia, Bernard-Soulier syndrome).10
Recombinant FVIIa enhances hemostasis due to the
additional generation of thrombin (Figure 3). In the tissue
Yo o a n d L i u
factor-dependent or extrinsic system, rFVIIa binds to tissue
factor at the site of vessel injury, causing activation of FX.
In the tissue factor-independent or intrinsic system, rFVIIa
binds to the surface of the activated platelet, directly acti-
vating FX. This explains why rFVIIa can overcome FVIII
and FIX deficiencies in patients with hemophilia. Both
mechanisms result in a ‘‘burst’’ of thrombin and fibrin
generation, which leads to clot formation. A key point,
however, is that there must be sufficient platelets and
fibrinogen for rFVIIa to effectively generate the thrombin
burst. Other important factors that should also be cor-
rected are temperature, acid/base status, and calcium to
improve the responsiveness to the drug.10
A growing number of case reports suggest that this agent
may be effective in various ‘‘off-label’’ indications. It has
been used to control intractable bleeding when other ef-
forts have failed to work. Its use has also progressed from
rescue therapy to prophylactic therapy in surgical situa-
tions with expected heavy blood loss, such as complex
cardiac surgeries or liver transplantations.
In a randomized controlled trial (RCT) involving 36
patients undergoing radical prostatectomy, patients were
randomized to placebo, rFVIIa at 20, or 40 mcg/kg.11 Pa-
tients receiving rFVIIa had a mean blood loss that was
statistically significantly lower than the control group. In
trauma patients, the use of rFVIIa reduced the need for
massive blood transfusions (defined as 4 20 units) from
33% in the control group down to 14% in the treatment
group.12 Although the results for penetrating trauma were
also promising, the data did not reach statistical sig-
nificance. Efficacy, dosage, and safety of rFVIIa use during
cardiac surgery remain unclear, particularly considering
the higher risk and catastrophic result of thromboembolic
events in this patient population.10
Researchers have also gained experience with the use of
rFVlIa in intracranial hemorrhages. So far, the data show
that the drug decreases the size of the hemorrhage as as-
sessed by volume on serial head computed tomographic
scans.13 The study was repeated in a phase 3 trial.14 There,
again, was decreased growth in the volume of the in-
tracranial hemorrhage, but mortality was similar in both
groups, and the incidence of severe disability at 90 days
was not improved in the treatment groups.
Intrinsic Pathway Extrinsic Pathway
Activated Tissue
rFVIIa
Platelet Factor
fX
Common
Pathway
fII
CLOT
Fibrinogen Fibrin
Figure 3. Mechanism of action of rFVIIa.
Coagulation Abnormalities Made Easy
Two meta-analyses and one Cochrane report have at-
tempted to summarize all the data.15–17 Depending on in-
clusion criteria, most included between 7 and 13 trials. All
together, only about 700 patients have been enrolled in
trials involving the prophylactic use of rFVIIa during liver
transplantation, liver resection, prostatectomy, repair of
pelvic trauma, and cardiac surgery. Approximately, 1200
patients have been enrolled in studies looking at the ther-
apeutic use of rFVIIa. The underlying etiologies for the
therapeutic use of rFVIIa have been quite varied, and in-
clude stem-cell transplant, dengue fever, trauma, upper
gastrointestinal bleeding, and intracranial hemorrhage. If
all the trials are analyzed together, there is a slight reduc-
tion in the number of patients that needed PRBC transfu-
sions with the prophylactic use of rFVIIa. The effect is
mostly from the use of high dose rFVlIa (450 mcg/kg) and
not low dose treatments. In the studies that looked at the
use of rFVIIa therapeutically, there was no significant dif-
ference in the number of patients transfused between the
treated and not treated groups.
Aside from reduced transfusion needs, the endpoints of
real interest should be morbidity and mortality. Mortality
data have been unclear, since often rFVIIa is used as a last
ditch effort. In the meta-analysis, there were only 14
deaths out of 507 patients.15–17 With so few deaths, the
confidence interval was quite wide, and so there appeared
to be no statistically significant decrease in mortality.
At this point, the data does not favor
the prophylactic use of rFVlla, but also
cannot show definitive harm from
its use.
As the use of rFVlla increases, there have been more
reports of morbidity from thromboses. O’Connell et al.18
looked at the Food and Drug Administration (FDA) ad-
verse event database, a voluntary reporting system. From
the 431 reports involving rFVIIa, 168 described thrombo-
tic complications. ‘‘Off label’’ usage accounted for 151 of
these reports. Thirty-six of the 50 deaths reported were
attributed to the thromboembolic event. The rate of com-
plication is still uncertain because the denominator is
unclear. Patients with procoagulant diseases (cancer, in-
fections, h/o thromboembolic events, and receiving pro-
coagulant drugs) were usually excluded from the studies,
so the actual risk of thromboembolic events could poten-
tially be higher as drug use increases in the general surgical
and critically ill patient population. From the intracranial
hemorrhage data,13,14 the incidence of thrombosis was
higher, especially for arterial events (myocardial infarc-
tions and cerebrovascular accidents), in patients who
received 80 mcg/kg of rFVIIa.
131
At this point, the data does not favor the prophylactic
use of rFVlla, but also cannot show definitive harm from
its use. Considering that no RCT has been able to de-
monstrate a significant benefit in terms of intensive care
unit stay, hospital stay, or mortality, the financial burden of
this drug needs to be weighed against the cost/benefit of
transfusing fewer blood products. Each clinician will have
to consider the risk of thromboembolic events against
continued bleeding for each individual patient. More
RCTs are necessary before a definitive statement can be
made about the efficacy, safety, and dosage recommenda-
tions of rFVIla.
Antifibrinolytics
Antifibrinolytics, like aprotinin, tranexamic acid, and ep-
silon-aminocaproic acid, fall into the category of drugs
that decrease clot breakdown. These can be given if fi-
brinogen levels remain low, and a mechanism for primary
fibrinolysis seems likely. Both tranexamic acid and epsilon-
aminocaproic acid are synthetic lysine derivatives that re-
versibly bind to plasminogen, preventing fibrinolysis.19
Aprotinin is a serine protease inhibitor, and was widely
used in cardiopulmonary bypass cases to reduce blood loss
and transfusions. However, it is no longer available (except
by special request) due to the data attributing higher risks
of stroke, myocardial infarction, renal failure, and death to
this drug.20
Antifibrinolytic drugs have been recommended in car-
diac surgery to reduce blood loss during and following
cardiopulmonary bypass. These drugs have also gained
popularity in noncardiac surgeries. Although blood loss is
reduced in most studies, data showing a decrease in the
number of blood transfusions is inconsistent. Some of the
heterogeneity is due to different dosing schedules; the trials
have a three-fold difference in loading dose. These drugs
may also have efficacy in liver transplantation and ortho-
pedic surgery, but the trials are small. Kagoma et al.19
published a systematic review of randomized trials evalu-
ating the use of antifibrinolytics (tranexamic acid, epsilon
aminocaproic acid, and aprotinin) in total knee and total
hip replacement surgeries. This analysis, however, in-
cluded great variability in the type and dose of anti-
fibrinolytics across the studies, so a definitive conclusion
was not possible. More adequately powered studies are
necessary to elucidate the role of antifibrinolytics in these
operations.
POSTOPERATIVE CAUSES OF ABNORMAL
COAGULATION
In the postoperative period, usually the deficiency of clot-
ting factors, platelets, and red cells begin to resolve, unless
there is ongoing surgical blood loss. Now, the imbalance of
procoagulant and anticoagulant agents increases the risk
for prothrombotic complications. Standard of care is to
institute thromboembolic prophylaxis in surgical patients.
132
Heparin is the usual drug of choice, but it has many
drawbacks. It is an indirect thrombin inhibitor and,
therefore, is effective on free thrombin only, and has lim-
ited inhibition of clot-bound thrombin. It requires anti-
thrombin as a cofactor, which leads to wide interindividual
variability. The most devastating side effect of heparin is its
ability to form a complex with platelet factor 4 (PF4),
which can then generate formation of heparin-PF4 anti-
bodies. In a subset of patients, the immunoglobulin
G (IgG) antibodies can bind to the Fc receptor on the
platelets, which leads to activation and consumption of
platelets, and thrombus generation21 (Figure 4). This can
lead to heparin-induced thrombocytopenia (HIT) with
thrombosis, the most dangerous manifestation.
The diagnosis of HIT depends on a high clinical suspi-
cion. Clinical suspicion should be increased if there is a
moderate platelet decline more than 5 days after first ex-
posure to heparin, because it takes about 5 days to generate
the IgG antibodies. The time frame can be much shorter on
heparin reexposure since the patient already has antibodies.
Patients are unlikely to have HIT if platelet counts are very
low (o 15  109/L). Risk factors for HIT are duration of
therapy more than 5-7 days, unfractionated heparin versus
low molecular weight heparin use (5% vs. 0.5%, respec-
tively), surgical patients more than medical patients, bovine
heparin rather than porcine heparin, and female patients
more frequently than male patients.22
Detection of HIT antibodies (enzyme-linked immuno-
sorbent assay) is not sufficient for the diagnosis of HIT. A
functional assay must be performed to detect the presence
of plasma antibodies that result in platelet activation. The
serotonin-release assay takes donor platelets with radi-
olabeled serotonin and adds them to patient plasma. The
addition of heparin results in platelet activation and release
of radiolabeled serotonin if HIT is present. While awaiting
test results, heparin should be discontinued and a non-
heparin anticoagulant instituted, even though there is
thrombocytopenia. Simple discontinuation of heparin,
without the provision of alternate anticoagulants has been
associated with subsequent severe and fatal thrombotic
complications if the patient has HIT with thrombosis.
Warfarin should be avoided as the first agent due to
HIT Pathophysiology
PF4
Heparin
Platelet
IgG
Fc Receptor
Immune
Complex
Activated
Platelet
Figure 4. Heparin-induced thrombocytopenia pathophysiology.
Yo o a n d L i u
the initial drop in protein C, which makes the patient
hypercoagulable. Platelet transfusions should also be
avoided unless there is active bleeding, as it just adds more
‘‘fuel to the fire.’’21,22
Direct Thrombin Inhibitors (DTIs)
DTIs, initially isolated from the saliva of leeches, have been
developed for use as anticoagulants in patients with HIT.
Most DTIs are relatively short acting and predictable.
DTIs inhibit free and clot-bound thrombin, and are in-
dependent of antithrombin. The drugs are not bound to
plasma proteins nor neutralized by PF4. Dosing can be
monitored by following PTT or activated clotting time
(ACT) in the operating room.23 The drawback for these
drugs is that there are no specific reversal agents. Dialysis
may be effective, and rFVIla has shown some efficacy in
animals and in healthy volunteers ex vivo.24 One DTI,
melagatran, and its oral formulation, ximelagatran, were
removed from the market due to hepatotoxicity.
Lepirudin
The first drug approved by the FDA was lepirudin. It can
lead to frequent bleeding complications, and its elimina-
tion is dependent on renal function. Half-life can be pro-
longed to 4-5 days in dialysis-dependent patients. There is
no reversal agent like protamine for lepirudin. Hemodia-
lysis and hemofiltration may be effective, but the data are
limited. More than half the patients treated with lepirudin
for more than 5 days develop antihirudin antibodies. These
are not neutralizing antibodies, but may actually enhance
drug potency, perhaps by delaying its clearance from the
circulation. As a result, the aPTT needs to be monitored on
a regular basis in these patients. Severe anaphylaxis is rare,
but has been reported, and appears to be more common in
patients with previous exposure.
Argatroban
Argatroban has a 45-minute half-life, and it is cleared by
the liver, so no dose adjustments are needed in patients
with low glomerular filtration rate. It is less immunogenic
than lepirudin, but it does increase the international nor-
malized ratio, which may be a factor when initiating
Coumadin. Like all DTIs, dose should be titrated to aPTT
(1.5–3  normal) or ACT. The FDA approved this drug as
an anticoagulant for prophylaxis or treatment of throm-
bosis in patients with HIT and for percutaneous coronary
intervention in patients with or at risk for HIT. There are
also a few reports of the successful use of argatroban in
ischemic stroke, hemodialysis, continuous renal replace-
ment therapy, and peripheral vascular surgery.25–27
Bivalirudin
Bivalirudin has a 25-minute half-life, and it is 80% cleared
by proteolysis and 20% renally cleared. Unlike arga-
troban, it needs to be dosed for glomerular filtration rate,
Coagulation Abnormalities Made Easy
and it only causes a slight increase in international
normalized ratio. The dose should be titrated to aPTT
(1.5–3  normal) or ACT. The FDA approved this drug as
an anticoagulant for percutaneous transluminal coronary
angioplasty in patients with unstable angina28 and for
percutaneous coronary intervention. Other reported uses
of bivalirudin include cardiopulmonary bypass, vascular
surgery, and neuroendocrine procedures. Table 3 sum-
marizes a comparison between the different DTIs.
Regional Anesthesia
There is not much data on the use of these new anti-
coagulants with regional anesthesia. Only a few case re-
ports relating to spontaneous intracranial hemorrhages
have been published in the literature. Broad clinical ex-
perience with these drugs and neuraxial techniques does
not exist. Most recommendations, if there are any, are
based exclusively on the pharmacokinetics of the drugs
themselves.29 In fact, the American Society of Regional
Anesthesia and Pain Management at their last consensus
conference declined to make a statement regarding the use
of epidural catheters for patients receiving DTIs due to the
lack of information.30
SUMMARY
The modern view of coagulation is of a highly complex
system with multiple cofactors and enzymes divided into the
initiation, amplification, and propagation phase of clot for-
mation. The older view of an intrinsic and extrinsic pathway,
although greatly simplified, is still useful because it illustrates
what the coagulation tests (PT/PTT) are measuring. Bleeding
diatheses in the perioperative period are easier to discuss
when we divide the differential into the preoperative, in-
traoperative, or postoperative periods. Several new drugs
that either increase clotting or increase anticoagulation have
been introduced, and many more are due on the market. It
is the responsibility of anesthesiologists to understand
the mechanisms of action of these agents and know how
to safely use them in the perioperative period.
Table 3. DTI Comparisons
Lepirudin Argatroban Bivalirudin
FDA indications HIT HIT/PCI PCI
Half-life 1.3 hours 40-50 minutes 25 minutes
Elimination Renal Hepatic Plasma/renal
Monitoring PTT/ACT PTT/ACT PTT/ACT
Stop before surgery 8 hours 4-6 hours 2-3 hours
ACT ¼ activated clotting time; FDA ¼ Food and Drug Administration; HIT ¼
heparin-induced thrombocytopenia; PCI ¼ percutaneous coronary intervention;
PTT ¼ partial thromboplastin time.
133
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