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316
Fig. 26.2 Examples of a normal
TEG tracing ( a ) and a TEG-
based treatment algorithm for
abnormal values ( b ). Reaction
time ( R ) corresponds to the initia-
tion phase of clotting; angle ( α )
corresponds to the rate of clot
expansion and strengthening;
maximal amplitude ( MA ) corre-
sponds to the maximal clot
strength; lysis at 30 min (LY-30)
corresponds to the degree of
fi brinolysis at 30 min. CRYO
cryoprecipitate, FFP fresh frozen
plasma, PCC prothrombin com-
plex concentrate, PLT apharesis
platelet unit, TXA tranexamic
acid. Low Amicar dose is 5 g
IV × 1 followed by 1 g/h until
LY-30 <3 %. High Amicar dose is
10 g IV × 1 followed by 1 g/h
until LY-30 <3 %. *Check heparinase TEG; if R normalizes, heparin effect is present
a
R (min)
α
MA (mm)
Time (min)
LY-30 (%)
b
R a MA LY-30
10–14 min-->2 FFP <50°-->10 CRYO, 2 FFP,
or fibrinogen (60–70
mg/kg)
>14 min*-->4 FFP or PCC
40–50 mm-->1 PLT
<40 mm-->2 PLT >8 %-->High Amicar or
3–8 %-->Low Amicar or
TXA
TXA
J.W. Cannon
normal pooled plasma in a 1:1 ratio and then repeating the
abnormal study. If the study results return to normal, the
abnormality is likely due to a factor defi ciency. Conversely, if
the results do not normalize, this indicates that the abnormality is due to a coagulation inhibitor. Common examples of
such inhibitors include heparin and antiphospholipid antibodies (associated with both hyper-and hypocoagulable states).
Point of care testing (POCT) at or near the patient’s bedside is now available for many of these tests. Examples
include INR, ACT, and TEG/TEM [ 15 , 16 ]. A new INR test-
ing device has also recently been approved for home use with
excellent accuracy [ 17 , 18 ]. These tests require strict adher-
ence to quality control standards to assure study validity.
Common Acquired and Medication-Induced Coagulopathies in the ICU
Liver Disease
Critically ill patients with both acute liver failure and chronic
liver disease manifest signifi cant abnormalities in coagulation [
19 , 20 ]. Defi ciencies in both procoagulant and antico-
agulant factors, abnormal platelet numbers and function,
hyperfi brinolysis, and frequent episodes of infection result in
a mixed and dynamic picture of both hyper- and hypocoagulability in these patients. Patients with liver disease manifest
abnormal coagulation laboratory values and can present with
both acute hemorrhage (e.g., bleeding varices) and acute
thrombosis (e.g., portal vein thrombosis).
These patients should not be considered “auto-
anticoagulated” [
20 ]. To determine the status of coagulation
in a patient with liver disease, the following tests should be
obtained: platelet count, PT, aPTT, TT, fi brinogen, and
D-dimer. There is growing evidence that the INR varies signifi cantly among laboratories in the presence of liver disease,
thus calling the use of the MELD score (based on a locally
measured INR) for organ allocation into question [ 21 , 22 ].
TEG appears to have signifi cant utility in managing coagulopathy in liver disease [ 23 ].
Management of patients with liver disease who are bleeding or who are undergoing invasive procedures should be
guided by specifi c laboratory fi ndings where possible.
However, empiric therapy is required in some instances, such
as vitamin K defi ciency, as it is impossible to determine if the
observed abnormalities are due to lack of synthetic function
or lack of substrate. In general, blood products are overused
in patients with liver disease with little demonstrated benefi t
[ 24 ]. Alternatives to FFP infusion include more liberal use of
cryoprecipitate or fi brinogen concentrates (targeting a fi brin-
26 Coagulopathies and Anticoagulation
317
ogen level of ≥120 mg/dL), prothrombin complex concentrates (PCCs), antifi brinolytics (e.g., ε-aminocaproic acid or
tranexamic acid), and desmopressin. These agents, when
used judiciously, decrease the risk of volume overload while
more directly correcting the coagulopathic abnormality.
Cirrhotic patients with venous thromboembolism (VTE)
complications require careful consideration of the risks of
bleeding weighed against the risk of further clot propagation.
Portal vein thrombosis (PVT) signifi cantly worsens patient
outcomes. Consequently, PVT prophylaxis should be considered in at-risk patients [
25 ]. Furthermore, when PVT is
diagnosed, therapeutic anticoagulation should generally be
initiated [ 26 ]. Patients with liver disease also develop other
forms of VTE including deep venous thrombosis and pulmonary embolism. Prior to initiating therapeutic anticoagulation, an assessment for esophageal and gastric varices should
be performed. If these are present, the risk of bleeding on
therapeutic anticoagulation is considered high and should be
weighed against the risk of thrombus propagation or migration [ 27 ]. The ideal anticoagulation regimen in these patients
is debated due to the frequency of low levels of antithrombin
in patients with cirrhosis and the diffi culty in monitoring
warfarin therapy. In most cases, a LMWH regimen monitored with anti-Xa levels is safe and effective.
Acute Traumatic Coagulopathy
Acute traumatic coagulopathy (ATC) is precipitated by a
large soft tissue injury burden combined with hypoperfusion.
This results in activation of the protein C pathway, shedding
of the protective endothelial glycocalyx leading to “autoheparinization,” Weibel-Palade body degradation with release of
tissue plasminogen activator (tPA), and possibly platelet
hypofunction mediated by ADP [ 28 , 29 ]. ATC may be fur-
ther exacerbated by iatrogenic coagulopathy from indiscriminant crystalloid resuscitation.
Up to one third of severely injured patients present with
ATC. Clinically, patients with ATC have an elevated PT
(>18 s)/INR (>1.5) or aPTT (>60 s), low fi brinogen, and
some degree of fi brinolysis. Treatment of ATC often begins
empirically, however, based on patient risk factors or the
appearance of diffuse bleeding during damage control surgery [ 30 ]. This is done by activating the hospital’s massive
transfusion protocol (MTP) and administering predetermined blood product ratios (along with calcium repletement)
and select hemostatic adjuncts [ 31 ]. As laboratory results
begin to return during ongoing resuscitation, this empiric
therapy can be refi ned with specifi c product replacement.
[Of note, although many trauma centers are now advocating
the use of TEG/TEM to guide hemostatic resuscitation in
trauma patients [ 14 , 32 , 33 ], a recent Cochrane review con-
cluded that TEG/TEM should only be used in the context of
research [
34 ]]. Crystalloid infusions should be minimized
while hypothermia and acidosis are aggressively avoided as
all of these factors decrease the function of the coagulation
enzymes.
Need for MTP can be anticipated by using a number of
clinical and laboratory factors. These include INR >1.5, systolic blood pressure <90 mmHg, hemoglobin <11 g/dL, base
defi cit ≥6, FAST+, heart rate ≥120 beats/min, and penetrating mechanism. Of these, INR >1.5 has the highest positive
predictive value, and two or more positive triggers together
predict a need for MT with a sensitivity of 85 % [
35 ]. POCT
for INR in trauma patients may, thus, be justifi ed [ 16 ].
The ideal blood product ratio within an MTP has not been
precisely defi ned. The recently completed randomized, prospective PROPPR study found no difference in 24-h and
30-day mortality between bleeding trauma patients treated
with a 1:1:1 ratio of plasma:platelets:RBCs as compared to a
1:1:2 strategy [ 36 ]. However, the 1:1:1 group had fewer early
deaths due to exsanguination and no increase in complications
over the 1:1:2 group. Thus, one approach is to target as close
as possible to a 1:1:1 ratio and administer more hemostatic
blood products (i.e., plasma and platelets) generously early in
the resuscitation [ 37 ].
Hemostatic adjuncts such as tranexamic acid (TXA) and
recombinant VIIa (rVIIa, NovoSeven) should generally be
limited to those patients with signifi cant blood loss as indicated by a high probability of receiving a MT. The large
CRASH-2 study on TXA does not have clear applicability to
trauma care in established trauma centers [ 38 ] although mili-
tary data suggests a mortality data if given early to severely
injured patients [ 39 ]. No mortality benefi t has been found
with rVIIa [ 40 ]; however, it may reduce transfusion require-
ments in blunt trauma patients [ 41 ]. PCCs (e.g., Kcentra) are
indicated for the reversal of known warfarin therapy in
trauma patients who are bleeding [ 42 , 43 ].
Post Cardiopulmonary Bypass
Cardiopulmonary bypass activates platelets, the coagulation
cascade, and complement. Intraoperative anticoagulation
with heparin partially counteracts these effects. However,
residual activation of these complex systems along with
residual heparin effect, hypothermia, and hemodilution all
contributes to postoperative coagulopathy in cardiac surgery
patients [ 44 ]. About 30 % of patients require a postoperative
blood product transfusion, and about 10 % develop signifi cant bleeding which increases postoperative mortality [ 44 ,
45 ]. In such cases, sources of surgically correctable hemor-
rhage should always be considered and discussed with the
cardiac surgeon.
For the assessment of nonsurgical coagulopathic bleeding, essential laboratory testing in the postoperative
318
J.W. Cannon
cardiac patient includes a CBC, PT/INR, aPTT, TT, fi brinogen level, and a TEG/TEM. A prolonged aPTT and TT
suggests residual heparin effect which can be reversed
with protamine in a patient with excessive bleeding.
Elevated PT/INR indicates defi cient levels of vitamin
K-dependent factors including factor VII which can be
corrected with FFP. Fibrinogen levels less than 100–
150 mg/dL should be treated with FFP or cryoprecipitate.
Thrombocytopenia or evidence of depressed platelet function on a TEG (i.e., low MA) can be treated with platelet
transfusion. Further therapy should be guided by repeat
testing if bleeding continues.
Pregnancy
Pregnancy results in a hypercoagulable state which persists
for up to 3 months postpartum. This is due to an increase in
procoagulant proteins including factor VIII and von
Willebrand factor, a decrease in protein S activity, and the
mechanical compression of the gravid uterus primarily on
the left iliac venous system. Pregnant patients diagnosed
with VTE should be treated with weight-based LMWH or a
heparin infusion. LMWH should be dosed according to
actual weight rather than predicted or ideal body weight.
Treatment should continue a minimum of 6 weeks postpartum for a total duration of at least 3 months of therapy [
Warfarin can safely be used as treatment after delivery even
during breastfeeding.
46 ].
Antiphospholipid Syndrome
This is an acquired autoimmune syndrome typically characterized by a hypercoagulable state [ 47 ]. Patients with
antiphospholipid antibodies usually present with multiple
venous or arterial thrombotic events or with fetal loss.
Those with antiprothrombin antibodies present with
bleeding. A small subset of patients experience catastrophic antiphospholipid syndrome (CAPS) resulting in
multi-organ failure from diffuse microvascular
thrombosis.
The diagnosis of antiphospholipid syndrome (APS) is
made when antiphospholipid antibodies are detected in the
appropriate clinical setting [ 48 ]. Screening tests consistent
with the presence of an antiphospholipid antibody include a
prolonged aPTT and dilute Russell viper venom time.
Initial treatment of venous thrombotic events in these
patients consists of anticoagulation with heparin or LMWH
transitioned to warfarin. Duration of therapy depends on the
certainty of the APS diagnosis. Those patients with strongly
positive test results should be maintained on lifelong
anticoagulation.
Heparin and LMWH
“Iatrogenic coagulopathy” due to anticoagulant medications is very common in the management of surgical ICU
patients. Factors that increase bleeding risk in these patients
include high anticoagulation doses, combined therapy with
NSAIDS or antiplatelet agents, and underlying patient factors. For unfractionated heparin, a treatment protocol based
on aPTT or anti-Xa should be used to minimize wide
swings in heparin dosing. LMWH does not require monitoring except in unique circumstances (e.g., obesity or
pregnancy).
Patients receiving over 35,000 units/day of heparin to
achieve a therapeutic aPTT are considered heparin resistant
[ 49 ]. Causes of heparin resistance include antithrombin
(AT) defi ciency, increased elimination (e.g., aggressive
diuresis) and elevations in factor VIII. In such cases, monitoring heparin therapy with anti-Xa levels results in a lower
heparin dose with no difference in outcome [ 50 ]. If high
doses are still required, AT levels can be measured in many
large medical centers, and low levels (e.g., ≤60 % predicted) can be supplemented with FFP or AT concentrate.
Be aware that dosing AT concentrate carries a risk of bleeding if excessive doses are given; so consideration should be
given to consulting a hematologist if considering AT
repletion.
Management of bleeding on heparin or LMWH depends
on the severity of bleeding and the risk of discontinuing anticoagulation. If a patient on heparin or LMWH develops signifi cant bleeding (e.g., suspected hemorrhagic stroke,
hematemesis, hematochezia, or large blood loss from surgical or traumatic wounds), immediately discontinue the medication and send the standard battery of anticoagulation labs
(including TT and RT). To measure any underlying coagulopathy independent of heparin, a TEG with heparinase can
also be ordered.
Heparin has a very short half-life (30–60 min); so reversal
with protamine is generally not required. However, in
extreme circumstances, protamine can be given at a dose of
1 mg per 100 units residual heparin given slowly (e.g.,
<5 mg/min) [ 43 ]. If no heparin boluses have been given
recently, the amount of residual heparin can be roughly
approximated as the current heparin infusion rate (e.g., if a
patient is on a heparin infusion at 1,500 units/h, 15 mg IV
protamine will fully reverse the heparin). Alternatively, a
default dose of 25 mg protamine can be used. Protamine also
partially reverses LMWH but has no effect on the indirect Xa
inhibitor fondaparinux (Arixtra), other Xa-Is, or DTIs.
Patients on heparin or LMWH frequently undergo invasive bedside and surgical procedures. A full discussion on
the management of both prophylactic and therapeutic doses
of these medications in the periprocedural period is provided
below.
26 Coagulopathies and Anticoagulation
319
Warfarin
Warfarin inhibits the γ-carboxylation of the vitamin
K-dependent coagulation factors II (prothrombin), VII, IX,
and X, resulting in a prolonged PT and INR. Warfarin has a
narrow therapeutic window and variable absorption based on
diet and other patient factors. Consequently, warfarin dosing
can vary up to 50-fold between patients. Warfarin therapy
requires frequent monitoring with INR levels checked either
in a laboratory or at home.
A number of scenarios can arise in patients on warfarin
requiring intervention. The urgency of intervention is dictated by the INR relative to the patient’s upper therapeutic
range and whether the patient is bleeding (Table 26.3 ) [ 51 ,
52 ]. The FDA recently approved a four-factor PCC
(Kcentra) for urgent reversal of warfarin in adult patients
with acute bleeding. This is a pooled plasma product which
contains factors II, VII, IX, and X. It can be administered in
a low or standard dose depending on the INR. The advantage of this approach is that it achieves rapid reversal with
a very small volume infusion as compared to FFP. For inpatients who need to resume or start warfarin, all planned
invasive procedures should have been completed before
warfarin administration and the INR monitored daily until
a stable dose is achieved.
Novel Anticoagulants
A number of DTIs and Xa-I inhibitors have recently been
approved for use in cerebrovascular accident (CVA) prevention and treatment of VTE [ 53 ]. The IV DTI argatroban
is also used for prophylaxis and anticoagulation in patients
with heparin-induced thrombocytopenia (HIT). DTIs can
be monitored with aPTT with 1.5–3× the upper limit of
normal representing therapeutic anticoagulation. Xa inhibitors also prolong the aPTT and the anti-Xa assay. Oral DTIs
and Xa inhibitors do not generally require monitoring;
however, these assays can be used to determine the drug
effect level in patients who are bleeding or who cannot provide a reliable medication history.
Both DTIs and Xa inhibitors have long half-lives (rela-
tive to heparin) and only one (dabigatran) has a direct anti-
54 ]. This combination makes the management of
dote [
bleeding in patients on these medications especially challenging [
43 ]. The characteristics of the most common oral
novel anticoagulants and a recommended management
strategy for bleeding in these patients are presented in
Table 26.4 .
Inherited Coagulopathies in the ICU
Table 26.3 Management of bleeding in patients on warfarin based on
INR levels
INR Bleeding Management
>9 − Hold warfarin until INR
oral vitamin K (2.5–5 mg PO × 1)
+ Reverse with IV vitamin K (10 mg QDay ×
1–3 days given over 10 min); standard dose
4-factor PCC (50 units/kg IV × 1)
>5–9 − Hold warfarin until INR
+ Reverse with IV vitamin K (10 mg
>INR
2-INR
1.5–2 + Consider FFP or low-dose PCC if the
FFP fresh frozen plasma, INR international normalized ratio, INR
upper therapeutic limit for the patient, PCC prothrombin complex
concentrate
-5 − Reduce warfarin dose or hold warfarin until
THER
+ Consider reversal with vitamin K (10 mg IV
+ Low-dose 4-factor PCC (25 units/kg IV up
THER
consider oral vitamin K (1–2.5 mg PO × 1)
QDay × 1–3 days given over 10 min);
standard dose 4-factor PCC (50 units/kg IV
up to 5,000 units × 1)
and then reduce dose; no specifi c
INR
THER
reversal
QDay × 1–3 days over 10 min); standard
dose 4-factor PCC (50 units/kg IV up to
5,000 units ×1)
to 2,500 units × 1)
patient is volume sensitive
and re-assess;
THER
and re-assess;
THER
THER
Inherited disorders of coagulation are uncommon relative
to acquired and medication-induced coagulation abnormalities. Nonetheless, these abnormalities in coagulation
present signifi cant management challenges in critical care
and warrant specifi c discussion. The most common inherited coagulopathy is von Willebrand disease VWD. Other
factor defi ciencies (e.g., hemophilia A) are much less
common but present more signifi cant management challenges in critical illness. Although these conditions generally present early in life, acquired forms of these
conditions can present later in life with variable phenotypic manifestations.
Table 26.4 Characteristics of novel oral anticoagulants and the man-
agement of bleeding on these medications
Medication Class Half life Dialyzable Bleeding management
Dabigatran
(Pradaxa)
Rivaroxaban
(Xarelto)
Apixaban
(Eliquis)
DTI direct thrombin inhibitor, PCC prothrombin complex concentrate,
Xa-I direct factor Xa inhibitor
DTI 14–17 h Y Charcoal (within 2 h),
idarucizumab
(Praxbind), dialysis,
FEIBA
Xa-I 5–13 h N Charcoal (within 2 h),
PCC
Xa-I 8–15 h N Charcoal (within 3 h),
PCC
320
J.W. Cannon
Von Willebrand Disease
Primary hemostasis involving platelet adhesion is facilitated by von Willebrand factor. This factor also carries factor VIII, thereby protecting it from degradation. Decreased
levels or activity of this factor result in VWD which is the
most common inherited bleeding disorder, diagnosed by
laboratory criteria in up to 1 % of the population. However,
clinically signifi cant bleeding occurs in only 1 % of these
patients [ 55 ]. VWD is transmitted in an autosomal domi-
nant fashion and is divided into three disease types with
multiple subtypes. VWD can also be acquired and should
be considered in patients with a bleeding diathesis of
uncertain etiology [ 56 ], especially while on extracorporeal
therapy [ 57 ]. In patients with moderate to severe VWD,
aPTT and bleeding time may be prolonged. Further testing
for suspected VWD should consist of a von Willebrand
factor antigen, von Willebrand factor activity, and a factor
VIII activity.
Therapy depends on the type of VWD, the severity of
symptoms, and the planned procedure [ 58 ]. For minor proce-
dures in minimally symptomatic patients, IV or intranasal
desmopressin is the fi rst-line therapy for those who are desmopressin responsive. All others should be treated with a
von Willebrand factor concentrate. Adjuncts to this therapy
in patients with VWD include the use of oral or IV antifi brinolytics and topical hemostatic agents (e.g., thrombin-soaked
Gelfoam).
Hemophilia A and B
Factor VIII (hemophilia A) and factor IX (hemophilia B)
defi ciencies are inherited coagulopathies transmitted in an
X-linked recessive fashion. Mild forms of coagulopathy can
present in carrier females as well. Severity of disease depends
on the level of factor activity present. Prophylactic factor
replacement therapy is recommended for patients with severe
disease [ 59 ].
Perioperatively and following acute trauma with bleeding, emergent factor replacement to >50 % activity (and
ideally up to 100 %) is indicated [ 58 , 60 ]. Minor bleeding
can be treated with a low dose of factor concentrate except
in patients with mild hemophilia A where desmopressin is
the treatment of choice. In hemophiliac trauma patients,
joints should be monitored for hemarthrosis and extremities frequently assessed for deep hematomas that could
progress to compartment syndrome. Antifi brinolytics can
also be administered to further stabilize established clot.
Patients with factor inhibitors require alternative treatment strategies such as use of activated PCC (FEIBA) or
rVIIa [ 61 ].
Procoagulant Therapies
Transfusion therapy has long been the mainstay of managing
coagulopathic bleeding. Early and appropriate component
therapy with plasma, platelets, and cryoprecipitate can treat
coagulopathy effectively, and these remain important tools in
the armamentarium of critical care physicians [ 36 , 37 , 62 ,
63 ]. Furthermore, for severe bleeding, the use of these prod-
ucts in the context of an institutional MTP improves survival
[ 31 , 64 ].
Conversely, unscrupulous or inappropriate transfusion
must be avoided as treatment with blood products carries a
risk of bacterial or viral infection, transfusion reaction, fl uid
overload, and end-organ failure such as ARDS [ 65 , 66 ].
Thus, it is prudent to avoid transfusion for minor laboratory
abnormalities in a non-bleeding patient [ 67 , 68 ]. In some
cases, an alternative procoagulant therapy should be considered. A description of the important features of these alternative procoagulant therapies is provided in Table 26.5 .
Anticoagulation Management in the ICU
During a course of ICU treatment, patients are frequently
managed with VTE chemoprophylaxis. Some patients also
develop indications for therapeutic anticoagulation. In all
cases, a careful assessment of the risk of thrombosis must be
weighed against the risk of bleeding over days to weeks or
even months. Unfortunately, the risk of bleeding is poorly
quantifi ed which further complicates decision-making.
Recent guidelines by the American College of Chest
Physicians quantify the existing data on the risk of bleeding
vs. the risk of VTE events in the general postoperative patient
population [ 69 ]. Some specifi c scenarios of particular inter-
est are discussed in the subsequent paragraphs.
VTE Chemoprophylaxis or Full Anticoagulation in Patients with Blunt Solid Organ Injury
Patients with blunt solid organ injuries often have a number
of associated injuries and are at moderate to high risk for
both VTE and bleeding. The timing of initiating VTE chemoprophylaxis has been hotly debated over the years as the
rate of non-operative management in the adult population
has increased. Recent evidence suggests that the historic tendency has been to unnecessarily delay VTE chemoprophylaxis. Retrospective data further indicates that bleeding from
a solid organ injury is independent of VTE chemoprophylaxis initiation across all grades of solid organ injury [
Consequently, VTE prophylaxis should be considered early
in the patient’s course regardless of the organ injury grade.
70 ].
26 Coagulopathies and Anticoagulation
Table 26.5 Common hemostatic adjuncts used in treating coagulopathy
Agent Dose Indications Notes
Vitamin K 1–10 mg IV daily for 1–3 days Vitamin K defi ciency; prolonged
reversal of warfarin
4-factor prothrombin complex
concentrate (PCC, Kcentra)
Activated prothrombin complex
concentrate (factor VIII inhibitor
bypassing activity, FEIBA)
Fibrinogen concentrate (RiaSTAP) 60–70 mg/kg (each vial contains
rVIIa (NovoSeven) 90–120 mcg/kg IV Hemophilia; hemostatic adjunct
ε-Aminocaproic acid (Amicar) Low dose: 5 g IV bolus × 1
Tranexamic acid (TXA) 1 g IV bolus × 1 followed by a 1 g
25–50 units/kg Urgent-emergent reversal of
warfarin; treatment of bleeding
in patients on oral Xa inhibitors
12.5–25 units/kg Hemophilia prophylaxis;
treatment of bleeding in patients
on dabigitran
900–1,300 mg; so a full dose is
approximately 3–4 vials)
followed by a 1 g/h infusion for 8 h
or until hemostasis; high dose:
substitute 10 g IV bolus
IV infusion over 8 h
Fibrinogen repletion Pooled human product;
in trauma
Fibrinolysis; hemostatic adjunct
in VWD, hemophilia, liver
disease
Fibrinolysis; hemostatic adjunct
in trauma, VWD, hemophilia,
liver disease
Low risk of anaphylaxis from IV
dosing (3/100,000); it can be
safely given at a rate of 1 mg/min
Contains factors II, VII, IX and X
as well as protein C, protein S,
antithrombin and albumin;
warfarin reversal is FDA
approved; the use for bleeding in
patients on direct Xa inhibitors
has not been studied on a large
scale
Contains factors II, VIIa, IX, and
X; the use for bleeding in patients
on direct thrombin inhibitors has
not been studied on a large scale
lyophilized and treated for viral
attenuation
No survival benefi t in trauma;
dose will be ineffective in
acidemia (pH <7.1)
Not specifi cally studied in trauma
patients
Use within the fi rst 3 h of severe
injury; may lower the seizure
threshold
321
Full anticoagulation in patients with solid organ injury
has been examined in one small study limited to low-grade
liver and spleen injuries [ 71 ]. In this report of 20 patients
with both a blunt aortic injury and a grade 1 or 2 liver or
spleen injury, there were no failures of non-operative management despite undergoing operative aortic repair on partial
bypass with full anticoagulation. Thus, if full anticoagulation is required early post-injury (e.g., for management of a
blunt cerebrovascular injury), this can likely be initiated
safely in the setting of a low-grade solid organ injury. No
data exists to guide decision-making in higher-grade injuries. Practically speaking, if full anticoagulation is strongly
indicated, this should be started while the patient is under
close surveillance with angiographic and surgical resources
rapidly available.
VTE Chemoprophylaxis or Full Anticoagulation in Patients with Traumatic Brain Injury
One of the most contentious topics in all of critical care is the
anticoagulation of neurotrauma patients. Some centers have
created treatment guidelines with input from all the involved
specialties to guide therapy in these diffi cult situations. This
approach results in an institution-specifi c practice guideline
that can serve as a reference point for patient management
decisions at the bedside.
Based on the work of Norwood and Berne, there appear to
be specifi c TBI injury patterns with an increased risk for progression [
72 ], and VTE chemoprophylaxis may further
increase this risk [ 73 ]. At the same time, the risk of VTE
begins to increase signifi cantly at 72 h post- injury [ 74 ]. One
approach to the questions of (1) whether a given patient is a
candidate for VTE chemoprophylaxis and (2) when that prophylaxis can be initiated is shown in Fig. 26.3 . This approach
ensures collaborative review of the CT fi ndings to determine
the presence of moderate- or high- risk criteria upon which
both the neurosurgical and critical care teams can agree.
Results of the Delayed vs. Early Enoxaparin Prophylaxis
(DEEP) randomized, prospective study on patients in the
low-risk group found no increased risk of clinically signifi cant bleed progression with enoxaparin at 24 h post-injury
over placebo [ 75 ].
No data exists on the safety of therapeutic anticoagulation
in patients with acute traumatic brain injury. However, the
same risk factors for bleed progression as discussed above
can be applied to identify patients who should defi nitely not
be started on early therapeutic anticoagulation (i.e., those
with documented bleeding progression on CT, those with an
indwelling ICP monitor or extraventricular drain, and those
322
Fig. 26.3 Algorithm for risk
stratifying TBI patients for
VTE prophylaxis (Adapted
from Phelan [
angiography, ICP intracranial
pressure, IVC inferior vena
cava, IVH intraventricular
hemorrhage, SAH
subarachnoid hemorrhage
92 ]). CTA CT
No
Progression on repeat CT?
Clinical deterioration?
No
Low risk
ICP Monitor, Ventriculostomy
Craniotomy or Craniectomy
No
Subdural hematoma>8 mm
Epidural hematoma>8 mm
Contusion or IVH>2 cm
Multi-focal contusions
SAH with abnormal CTA
Yes
Yes
Moderate risk
Re-assess at 72 h
Consider repeat CT
Clinical deterioration?
No
Yes
J.W. Cannon
Yes
High risk
who have undergone a craniotomy or craniectomy). For
those with a stable interval CT either with or without risk
factors for bleeding progression, the timing of anticoagulation should be determined in consultation with neurosurgery.
The decision of whether and when to resume pre-injury anticoagulation for atrial fi brillation CVA prevention is discussed below.
Atrial Fibrillation ATE Prevention
Patients with a history of atrial fibrillation are at increased
risk of a thromboembolic CVA, while the recommended
stroke prevention strategy—oral anticoagulation—
increases the risk of bleeding, including intracranial
hemorrhage (ICH), which can be equally disabling. A
number of well-conducted studies and carefully considered guidelines have addressed this conundrum [ 76 ].
The risk of a thromboembolic CVA can be assessed with
the CHA 2 DS 2 -Vasc score which is an acronym for c ongestive
heart failure (CHF), h ypertension (HTN), a ge, d iabetes mel-
litus, s troke, s ex, and vasc ular disease. One point is assigned
for CHF, HTN, age 65–74, diabetes, and female gender
while two points are assigned for age ≥75 and stroke.
Patients with a score of 0 are considered low risk for CVA
(0.2 %/year), 1 intermediate risk (0.4 %/year), and ≥2 high
risk (2.2–13.2 %/year). Anticoagulation is generally not recommended for patients with a score of 0. A score of 1 is
more controversial with some recommending a nuanced
approach depending on the specifi c risk factor (e.g., age car-
Start chemoprophylaxis
Consider removable IVC filter
or serial ultrasound screen
ries a higher risk than gender). Thus some patients with a
score of 1 may not be anticoagulated [ 77 ]. Those with a
score ≥2 should be started on anticoagulation [ 78 ].
Traditionally, this is done with warfarin (following a heparin
bridge in higher risk patients) although DTIs and Xa-Is are
now used more commonly as they do not require monitoring
and appear to carry a comparable or even lower overall
bleeding risk compared to warfarin [ 79 , 80 ]. As noted above,
however, the anticoagulation effect of these agents cannot be
easily reversed.
Another scoring system called HAS-BLED can also
help estimate the risk of bleeding from anticoagulation.
This acronym stands for h ypertension, a bnormal renal
and/or liver function, s troke, b leeding history or predispo-
sition, l abile INR on warfarin, e lderly (age >65), and d rugs
(aspirin or NSAIDS; alcohol abuse). One point is assigned
for each risk factor (up to 2 for abnormal organ function
and up to 2 for drugs) [ 81 ]. A score of 0–2 represents a low
risk of bleeding (1–2 bleeding events per 100 patient years)
while a score of ≥3 is high risk (≥4 bleeding events per
100 patient years). Limitations include the wide range of
bleeding severity and the fact that this scoring system has
not been validated on surgical patients.
Patients on anticoagulation who have a major bleeding
complication, such as an intracranial bleed, bear special
mention. Following such a life-threatening complication,
the patient’s risk for future thromboembolism and bleeding
should be reassessed. Patients at high risk for a thromboembolic stroke and low risk for bleeding should be resumed
on anticoagulation following the establishment of hemosta-
26 Coagulopathies and Anticoagulation
323
sis. Those deemed high risk for recurrent bleeding may be
reluctant to resume anticoagulation. Unfortunately, aspirin
monotherapy affords minimal protection against CVA and
carries a moderate bleeding risk [ 77 ]. Dual antiplatelet
therapy with aspirin and clopidogrel offers slightly more
protection against CVA but at the expense of bleeding risk
that is comparable to full anticoagulation. A recent retrospective study of patients with an intracranial bleed on anticoagulation indicates that outcomes (mortality, CVA,
recurrent bleeding) are signifi cantly better in patients
resumed on anticoagulation (within a median of 31 days of
the index bleed) [
to confi rm these fi ndings, this study does provide some
guidance for discussing this issue with patients prior to
hospital discharge. If the patient is undecided on anticoagulation or the care team feels this presents excessive risk, a
short-term approach would be to start aspirin monotherapy
(81 mg PO daily) if the patient should otherwise be considered for primary prevention with ASA (e.g., a Framingham
Heart Study score of >10 %) with short-interval primary
care follow-up.
New-onset paroxysmal atrial fi brillation can present in
the postoperative cardiac patient, trauma patients, and noncardiac thoracic postoperative patients in the ICU. In addition to decisions about rate and rhythm control, the
intensivist must decide on the need for and timing of systemic anticoagulation in these patients. In general, anticoagulation should be started when atrial fi brillation persists
beyond 48 h [ 83 ], especially in patients with a CHA 2 DS 2 Vasc ≥2. Those with one or no risk factors may benefi t
from a more selective approach. One study in non-cardiac
thoracic surgical patients found no benefi t to nonselective
anticoagulation in patients with postoperative atrial fi brillation due to increased bleeding complications [ 84 ]. Closer
examination of these results indicates that selective anticoagulation in those with a CHADS 2 score ≥2 may have been
a safer strategy. If patients undergo electrical cardioversion, anticoagulation should be started prior to the procedure (time permitting) and continued thereafter.
82 ]. Although prospective data is needed
ICU Procedures in Patients with Coagulopathy and Therapeutic Anticoagulation
The timing of therapeutic procedures in a coagulopathic
patient and the management of anticoagulation in an ICU
patient undergoing a bedside procedure depends upon the
degree of coagulopathy or the indication for anticoagulation
and the urgency of the procedure. There is considerable practice variability among expert intensivists and no clear guidance from the literature on these issues [ 85 , 86 ]. Coagulopathic
patients should undergo resuscitation aimed at reversing
coagulopathy. Emergent monitoring and access procedures
should not be delayed but should be performed by experienced providers to minimize mechanical complications
which can lead to bleeding.
In the patient on therapeutic anticoagulation, a radial arterial line can be placed without holding or reversing the anticoagulation. Similarly, for a standard triple lumen central
venous catheter placed under ultrasound guidance, anticoagulation can generally be continued. For insertion of larger
catheters (e.g., hemodialysis access) on an elective basis,
heparin can be held for 1–6 h prior to insertion or one dose of
LMWH can be skipped with resumption of anticoagulation
after successful, hemostatic placement of the line (provided
the insertion was straightforward). Bedside percutaneous
dilational tracheostomy (PDT) and percutaneous endoscopic
gastrostomy (PEG) are elective procedures with a risk of
bleeding [ 87 ]. Consequently, anticoagulation should be
reduced or held around the time of these procedures. If this
cannot be done safely (e.g., recent pulmonary embolism with
right heart strain), the procedure should generally be deferred
although some choose to continue anticoagulation through
these procedures [ 88 ].
Mechanical Heart Valves
Guidelines for the perioperative management of anticoagulation for mechanical heart valves have been recently published [ 89 ]. Some minor procedures (e.g., cataract surgery
and diagnostic endoscopy) can be performed with a therapeutic INR and thus do not require any special anticoagulation management [ 90 ]. For cases where the INR should be
normal at the time of surgery, if the patient has a bileafl et
mechanical valve in the aortic position with no additional
risk factors for arterial thromboembolism (ATE), bridge
anticoagulation is not warranted. Warfarin should be held
for 5 days preoperatively, and an INR is checked the day
prior to surgery. If it is still elevated beyond the surgeon’s
comfort level, vitamin K (1 mg PO) can be given. Warfarin
can be restarted 12–24 h postoperatively once hemostasis is
assured. Patients with a bileafl et aortic valve and additional
thromboembolic risk factors are at moderate risk for ATE,
and the need for bridging anticoagulation should be tailored to the individual patient and the type of surgical procedure being considered. Those with a mechanical mitral
valve are at high risk for ATE and require bridge anticoagulation therapy with heparin or LMWH while warfarin is
held. If heparin is used for bridge anticoagulation, it should
be held 4–6 h before surgery. For bridge LMWH, the last
dose should be given 24 h prior to surgery. Bridging heparin or LMWH can be resumed at the preoperative dose once
hemostasis has been assured approximately 24 h after lowbleeding-risk surgery and 48–72 h after high-bleeding risk
surgery [
89 ].
324
J.W. Cannon
Pulmonary Embolism with an Absolute Contraindication to Anticoagulation
Patients with an absolute contraindication to anticoagulation
who develop a pulmonary arterial thrombosis or embolism
should be considered for a removable IVC fi lter [ 69 ]. Although
IVC fi lters increase the risk of DVT [
91 ], the patient may not
tolerate another VTE event. The IVC fi lter can be removed
once the patient is started on therapeutic anticoagulation. In
patients on bed rest or other causes of decreased mobility,
delayed removal until their mobility improves is also
reasonable.
Presumed Pulmonary Embolism in a Patient with Hemodynamic Instability or Cardiac Arrest
Patients who develop a massive pulmonary embolism with
hemodynamic compromise should be considered for thrombolysis [ 92 ]. Diagnostic imaging with CT angiography is often not
possible in these circumstances. If available, TTE or TEE should
be obtained to assess for right heart strain. In a patient with PEA
arrest or profound hypotension together with right heart strain,
thrombolysis should be administered. One convenient dosing
regimen is tPA 50 mg IV as a bolus followed by another 50 mg
bolus if the fi rst proves ineffective [ 93 ]. Anticoagulation should
then be continued in patients who are successfully resuscitated.
Summary
Management of coagulopathy and anticoagulation in the ICU
presents many nuanced challenges to the ICU physician. Early
recognition and treatment of hemorrhage is critical in the management of coagulopathic patients. Although empiric therapy is
sometimes required, laboratory analysis provides the most
appropriate therapeutic guidance. Specifi c management depends
on the patient’s condition and the available resources. Those
patients who present on anticoagulation or who develop a need
for anticoagulation require special consideration. Rapid reversal
in anticoagulated patients who are bleeding will minimize the
risk of complications. Novel anticoagulants present special challenges in this regard. Those patients who require resumption of
anticoagulation in the ICU or who need treatment for a VTE
should be evaluated in a multidisciplinary fashion to ensure the
patient’s care is optimized over both the short and long term.
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