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418 E. Gonzalez and E. E. Moore
A conventional course of therapeutic anticoagulation for PE should be
started once risk of bleeding allows, even while IVC filter is still in place.
In addition, IVC filter placement may be considered in patients with a PE when
their underlying hemodynamic or respiratory compromise is severe enough
that another PE may be lethal, regardless of the initial mode of treatment.
• Catheter related VTE
In patients with a CVC related DVT, routine catheter removal is not rec-
ommended, provided it is needed, remains functional, and well-positioned.
A CVC-related DVT involving the axillary or more proximal veins should
be treated with anticoagulation.
When removing a catheter responsible for a CVC-related DVT, it has been
suggested that at least a brief period of therapeutic anticoagulation should
precede removal, in order to minimize risk of embolization. There is no
data to validate this concept.
Patients who have had prior UEDVT should be screened for patency of
the central veins prior to placement of a subsequent catheter.
Table 5 describes duration of CVC-related DVT therapy.
• Complications of VTE
Phlegmasia cerulea dolens
Venous gangrene resulting usually from an extensive proximal (e.g.,
ilio-femoral) DVT (can also occur in upper extremity).
Clinical diagnosis based on severe pain, tenderness, swelling, and
cyanosis.
Unilateral limb discoloration or cyanosis in a patient with a known or
suspected DVT is the hallmark sign.
Thrombolysis or thrombectomy along with anticoagulation should be
the first-line of therapy.
Delay in treatment may result in secondary arterial compromise,
development of compartment syndrome, or limb loss.
Post-thrombotic syndrome (PTS)
PTS is a frequently unrecognized chronic sequela of DVT developing
in 20–50% of patients, even when treated appropriately with anticoagulation.
Symptoms range from persistent swelling to severe pain, ulceration,
and venous claudication.
The underlying pathophysiology of PTS is lack of venous patency and
venous valve incompetency resulting in venous hypertension.
Prevention and Management of Venous Thromboembolism 419
Patients at highest risk are those with ilio-femoral DVT (90% inci-
dence) and those with recurrence of DVT in the same location,
justifying consideration of thrombolysis or thrombectomy rather than
anticoagulation alone as the initial treatment in these patients.
PTS can be prevented by decreasing DVT recurrence with adequate anti-
coagulation regimens, and with use of a graduated elastic compression
stocking or sleeve on the affected limb beginning at the time of diagnosis.
DVT can lead to paradoxical arterial embolizations in patients with a PFO
(27% of population), and has been reported as a cause of non-hemorrhagic
cryptogenic stroke in critically ill patients.
Chronic thromboembolic pulmonary hypertension (CTPH)
Characterized by persistence of thrombi and vascular remodeling in
the pulmonary circulation secondary to pulmonary embolism; diagnosed by V/Q scan and confirmed by right heart catheterization (mean
pulmonary artery pressure >25 mm Hg in the absence of an elevated
wedge pressure [<15 mm Hg]).
Three months after an acute PE, 19% of patients treated with antico-
agulation have some residual perfusion obstruction.
Patients at increased risk for CTPH are those with PE recurrence,
>50% amputation of pulmonary artery or main branch at time, and
unprovoked or idiopathic PE.
Patients present with chronic dyspnea and subsequently develop heart
failure.
Treated with surgical pulmonary endarterectomy.
• Special populations
Renal disease
Patients with renal disease experience both bleeding and thrombotic
complications, conditions that often overlap.
Renal disease leads to increased levels of fibrinogen, factor VIII, von-
Willebrand factor (vWF), and homocysteine, with decreased levels of
protein C and antithrombin, all of which favor thrombosis.
Risk of thrombosis is highest in those patients with end-stage renal
disease requiring hemodialysis.
Bleeding complications secondary to anticoagulation often result from
inadequate dosing or choice of medication based on renal function.
General guidelines for VTE prophylaxis should be followed with par-
ticular attention to dosing and choice of anticoagulant based on renal
function. UFH can be used in patients with renal disease.
420 E. Gonzalez and E. E. Moore
LMWH, fondaparinux, dabigatran, rivaroxaban, and apixaban should
be avoided in patients with renal disease.
End stage renal disease patients who require hemodialysis are at high
risk of HIT, given the repeated exposure to heparin during dialysis and
vascular access procedures.
Patients with renal disease and HIT can receive treatment with either
argatroban (if liver function is normal) or bivalirudin (adjusted to renal
function).
In patients with HIT requiring hemodialysis, argatroban should be used as
an alternative to heparin in the filter and extracorporeal circuit. Catheters
should not be locked with heparin, alternatively citrate can be used.
Liver disease
The coagulopathy and thrombocytopenia seen in liver disease do not
necessarily protect these patients from thrombosis.
Because both pro-coagulant and anti-coagulant proteins are dimin-
ished in unpredictable ratios during liver disease, the predilection for
either bleeding or thrombosis is difficult to assess.
Hepatic dysfunction leads not only to decreased synthesis of fibrino-
gen and coagulation factors (II, VII, IX, and X), but also to decreased
levels of the anticoagulant proteins C, S, and antithrombin, as well as
plasminogen.
In cirrhosis, elevated levels of PAI-1, factor VIII, and vWF, are also
seen, potentially representing an endothelial response to inflammation.
Patients with cirrhosis are at increased risk of portal thrombosis; this
risk is highest when these patients experience sepsis, severe trauma,
and major surgery.
Patients with esophageal varices secondary to portal hypertension are
at the highest risk of bleeding secondary to anticoagulation.
Guidelines on indications for VTE prophylaxis of cirrhotic patients
are lacking based on the paucity of data.
Pharmacologic VTE prophylaxis should be started based on a patient-
specific bleeding vs. thrombosis risk assessment. Low-dose UFH and
LMWH can be used in patients with liver disease.
The effectiveness of anticoagulation in cirrhotic patients may be affected
by lower levels of antithrombin and a larger volume of drug distribution.
Dose adjustment to anti-Xa target levels is recommended whenever
prophylactic or therapeutic anticoagulation is indicated in critically ill
cirrhotic patients or those with acute liver failure. Anti-Xa traget
ranges are described in Table 3.
Prevention and Management of Venous Thromboembolism 421
Argatroban, dabigatran, rivaroxaban, and apixaban should be avoided
in patients with liver disease.
Patients with liver disease and HIT can receive treatment with either
fondaparinux (if renal function is normal) or bivalirudin.
Pediatric patients
The strongest acquired risk factors for a first-time VTE in children
are: CVC, malignancy, and trauma.
Ö Two-thirds of all pediatric VTE’s are associated with the use of
a CVC.
Two serious DVT complications are seen more often in children than
in adults:
Ö Intra-cardiac extension into the right atrium of a CVC-related DVT.
Ö Paradoxical embolization of a venous clot into the arterial circulation
given the prevalence of a patent foramen ovale and septal defects.
Given extensive venous collateralization, extremity swelling resulting
from a DVT is less common than in adults.
Often, marked dilation or visibility of superficial veins is the only sign
of a DVT.
For pediatric trauma patients, we recommend VTE prophylaxis with
LMWH for ≥14 y.o., given the lower VTE incidence in younger
patients.
Ö For patients <50 kg, prophylactic doses should be adjusted to an
anti-Xa levels described in Table 3.
Ö For patients ≥50 kg, adult prophylactic doses can be used and do
not require routine anti-Xa dose adjustments.
Initial treatment for acute VTE is recommended with intravenous
UFH.
Ö An initial bolus of 75 units/kg should be given, followed by con-
tinuous infusion at 18–20 units/kg/hr.
Ö Bolus can be withheld or reduced if significant bleeding risk
exists.
Ö Transition to dose-adjusted warfarin for post-VTE risk reduction
therapy should be similar to adult patients.
LMWH can also be used in pediatric patients.
When indicated, therapeutic doses of aspirin in children should be
used in the dose range of 1.0–2.0 mg/kg/day.
422 E. Gonzalez and E. E. Moore
Pregnancy
Pregnancy is associated with an increased risk of thrombosis that may
be due in part to obstruction of venous return by the enlarged uterus,
as well as a hypercoagulable state associated with pregnancy.
Estimates of the age-adjusted incidence of VTE range from 5 to
50 times higher in pregnant versus non-pregnant women.
Hypercoagulability seen during pregnancy occurs in part because of
activated protein C resistance, and increased levels of fibrinogen,
factors V, VII, VIII, IX, X, and PAI-1.
LMWH is the preferred agent, over UFH, for prophylaxis and VTE
treatment when indicated (mostly due significant variability in doseresponse to UFH given increase in heparin-binding proteins and
plasma volume changes seen in pregnancy, as well as higher incidence
of osteoporosis with long-term use of UFH).
85% of pregnancy-related DVT occur during pregnancy (incidence
highest in the third trimester), while 85% of PE occur in the post-partum
period (incidence highest in those undergoing cesarean delivery).
90% of pregnancy-related DVT occur in the left lower extremity, and
the majority involve a proximal vein.
Post-VTE risk reduction therapy should be performed with LMWH
and can be transitioned to dose-adjusted warfarin post-partum, with
a minimum total anti-coagulation period of three months, and at least
six weeks of post-partum anti-coagulation.
Anticoagulation should be held 24 hours prior to induction of labor or
cesarean section, and re-started at 12 h post-operatively if hemostasis
is adequate.
All patients with a history of a prior VTE, those with factor V Leiden,
prothrombin 20210A mutation, or a first-degree relative with a VTE,
should undergo post-partum prophylaxis with LMWH for six weeks.
Low-dose UFH and LMWH do not cross placenta.
Warfarin crosses placenta and has the potential to cause fetal wastage,
bleeding in the fetus, and teratogenicity.
Oral direct thrombin and Xa inhibitors should be avoided during preg-
nancy. Fondaparinux is restricted for pregnant patients with HIT or
severe allergic reactions to heparin. Experience with argatroban and
bivalirudin during pregnancy is limited.
Use of thrombolytics to manage PE is associated with a 15% incidence
of fetal loss and 30% of pre-term labor. This should not preclude the
use of thrombolytics, when indicated, for a life-threatening PE.
Prevention and Management of Venous Thromboembolism 423
Neuraxial anesthesia.
Neuraxial anesthesia can be used with pharmacologic prophylaxis with
cautious patient selection as follows: avoiding patients with known
clotting disorders, avoiding patients receiving thienopyridine platelet
inhibitors (clopidogrel and ticlodipine) within two weeks of placement,
waiting until trough blood levels for those already receiving pharmacologic prophylaxis, delaying prophylaxis (at least 24 h) if a hemorrhagic
aspirate is performed, and monitoring for symptoms of spinal hematoma when using spinal anesthesia and pharmacologic prophylaxis.
Spinal catheter placement or removal should be delayed from last
administered dose: 2 h for i.v. UFH (normal PTT should be documented), 4 h for low-dose UFH, 12 h for LMWH.
After spinal catheter placement or removal, the next dose should be
given at least 2h after for intravenous or subcutaneous UFH, and 6 h
for LMWH.
Given increased risk of bleeding, patients on therapeutic dose LMWH,
q12 h prophylactic dose LMWH, and fondaparinux, should not receive
neuraxial anesthesia, or should transition to UFH or daily LMWH
dosing prior to placement.
Patients receiving more than one medication affecting hemostasis
(including NSAID’s) should generally not receive neuraxial anesthesia.
Patients receiving aspirin can have spinal catheters placed or removed
without delaying dosing, as long as they are not receiving, or expected
to receive, another medication affecting hemostasis while the spinal
catheter is in place.
• Heparin induced thrombocytopenia (HIT)
Generation of IgG antibodies directed against circulating complexes of
platelet factor-4 (PF4) bound to heparin resulting in thrombocytopenia
and in some patients, thrombosis.
PF4 is a cytokine released by alpha-granules when platelets are acti-
vated that inhibits endogenous heparinoids on the endothelial surface,
and consequently has a high affinity for exogenous heparin.
Antibodies against the heparin/PF4 complex appear in serum at a
median of 4 days from a first-time heparin exposure.
A pro-thrombotic state occurs when platelets are activated by the Fc
region of the antibody bound to the heparin/PF4 complex, this also
causes the platelets to release pro-coagulant microparticles that promote thrombin generation.
424 E. Gonzalez and E. E. Moore
Platelets with these antibody complexes attached are then cleared by
macrophages and the reticuloendothelial system.
HIT occurs in 5% of patients exposed to heparin, regardless of the dose,
schedule, or route of administration.
The frequency of HIT is variable and influenced by the type of patient
population: cardiac surgery>vascular surgery>trauma>medical>obstetri
cal, sex: female>male, type of heparin used: bovine unfractionated>porcine
unfractionated>LMWH>fondaparinux, duration of exposure: the risk
decreases if it has not occurred at 10–14 days of continuous exposure,
timing of exposure in relation to surgery post-operative>pre-operative,
and BMI: high BMI>low BMI.
The highest incidence of HIT is seen in patients on extracorporeal
circulatory support and with ventricular assist devices receiving
heparin (10%).
Thrombocytopenia is the most common finding of HIT, and typically
occurs between 5–10 days from beginning of heparin exposure.
In patients who have been exposed to heparin within the last 3 months,
thrombocytopenia can occur in <24 h with heparin re-exposure.
A platelet count drop of >50% of baseline is typical, the mean nadir is
a count of 60 × 109, and counts rarely decrease <20 × 109.
The pro-thrombotic state induced by HIT leads to a 50% incidence of
thrombotic complications in serologically confirmed HIT:
DVT (50%), PE (25%), aorto-iliac thrombosis (10%), thrombotic
stroke (7%), adrenal hemorrhagic infarction from adrenal vein
thrombosis (3%), cerebral sinus thrombosis (3%), mesenteric thrombosis (3%).
Skin necrosis (typically seen at subcutaneous injection sites) is common
in patients with HIT, and should prompt an evaluation for HIT when noted
in high-risk patients.
Acute systemic reactions to heparin (most commonly seen with a heparin
bolus) are common in patients with HIT, and range from mild allergic
reactions to anaphylaxis with cardiopulmonary collapse. Acute systemic
reactions to heparin should prompt an evaluation for HIT when noted in
high-risk patients.
Clinical suspicion of HIT should be followed by serologic testing if there
is an intermediate or high pretest probability. Table 6 describes the 4T
pre-test probability model.
Prevention and Management of Venous Thromboembolism 425
A low pretest probability represents a minimal possibility of HIT, and
does not require serologic testing, however monitoring of platelet counts
and for clinical findings of thrombosis should continue.
Serologic testing for PF4/heparin antibodies (PF4-ELISA) (reported in
optical density, OD) has a strong negative predictive value, however it has
low specificity.
An OD value ≤0.4 has a ≤0.5% risk of HIT and can exclude this diag-
nosis.
An OD value ≥2.0 has a ≥90% risk of HIT and does not require further
testing.
0.5–1.9 OD values are considered indeterminate and require a platelet
activation assay (serotonin-release assay, SRA) to confirm diagnosis.
There is a high degree of false positivity post-cardiopulmonary bypass
or aortic balloon pump.
A presumptive diagnosis of HIT based on clinical findings (moderate or
high 4T score) should be treated for HIT while awaiting serologic confirmation. Presumptive treatment includes the following:
All forms of heparin should be discontinued (including LMWH,
heparin flushes, and heparin-bonded catheters).
Because of the high risk of thrombosis associated with HIT, therapeu-
tic anticoagulation with a non-heparin anticoagulant should be
initiated (unless contraindicated by bleeding risk), even if the original
indication for anticoagulation no longer exists.
Ö Patients with normal renal and hepatic function can receive fonda-
parinux (subcutaneous), argatroban (intravenous), or bivalirudin
(intravenous).
Ö Patients with renal dysfunction can be treated with argatroban.
Ö Patients with hepatic dysfunction can be treated with fondaparinux
or bivalirudin.
Ö Patients with renal and hepatic dysfunction can be treated with
bivalirudin (dose adjusted to renal function).
Ö Specific dosing for each agent is described in Table 3.
Warfarin should not be started until therapeutic anticoagulation has
9
been achieved, and the platelet count is ≥150 × 10
in order to avoid
the transient increase in hypercoagulability initially induced by warfarin (due to the rapid inhibition of protein C).
Warfarin should be dose-adjusted to a target INR of 2.5 (range 2.0–3.0).
426 E. Gonzalez and E. E. Moore
Optimal duration of anticoagulation with warfarin for HIT patients
has not been studied. It has been recommended that:
Ö Patients with serologically confirmed HIT, with no thrombotic
complications, should receive 1–3 months of anticoagulation.
Ö Patients with serologically confirmed HIT, who developed throm-
botic complications, should receive 3–6 months of anticoagulation.
Thrombocytopenia resolves in a median of 7 days from nadir (range
4–14 days).
If the diagnosis of HIT is excluded by serology, heparin can be resumed
(if the original indication for anticoagulation persists).
Practical Algorithm(s)/Diagrams
Table 1. Caprini venous thromboembolism risk assessment.
1 point
o Age 41-60 y
o Minor surgery
o BMI >25 kg/m2
o Swollen legs or varicose veins
o Pregnancy or postpartum
o History of unexplained or
recurrent spontaneous aborƟon
o Oral contracepƟves or hormone
replacement
o Sepsis (<1mo)
o Serious lung disease, including
pneumonia (<1mo)
o Abnormal pulmonary funcƟon
o Acute myocardial infarcƟon
o CongesƟve heart failure ( <1mo)
o History of inflammatory bowel
disease
o Medical paƟent at bed rest
score risk group
0 VERY LOW <0.5% early and frequent ambulaƟon
1-2 LOW 1.5% IPC and ambulaƟon
3-4 MODERATE 3.0%
≥5 HIGH ≥6.0%
* risk calculated from post-operave incidence of VTE’s in general surgery paents
Pharmacologic prophylaxis is preferred over intermient pneumac compression (IPC) only by Denver Health consensus
**
guidelines in the absence of significant bleeding risk
2 points 3 points 5 points
o Age 61-74y
o Arthroscopic surgery
o Major open surgery (>45min)
o Laparoscopic surgery (>45min)
o Malignancy
o Confined to bed ( >72h)
o Immobilizing plaster cast
o Indwelling central venous
catheter
risk of symptomaƟc VTE if no
o Age >75y
o History of VTE
o Family history of VTE
o Factor V Leiden
o Prothrombin gene mutaƟon
20210A
o Lupus anƟcoagulant
o AnƟcardiolipin anƟbodies
o Elevated serum homocysteine
o Heparin-induced
thrombocytopenia
o Other congenital or acquired
thrombophilia
prophylaxis used*
recommended prophylaxis
modality (ACCP 9
IPC
pharmacologic prophylaxis**
pharmacologic prophylaxis
AND
o Stroke (<1mo)
o ElecƟve arthroplasty
o Hip, pelvis, or leg fracture
o Acute spinal cord injury ( <1mo)
th
ed. 2012)
OR
IPC
Prevention and Management of Venous Thromboembolism 427
Table 2. Trauma venous thromboembolism risk assessment profile (RAP).
Points
Underlying condition
obesity 2
malignancy 2
coagulation disorder 2
previous VTE 3
Iatrogenic factors
femoral venous line 2
transfusion >4 units 2
operation >2h 3
major venous repair 3
Injury-related factors
chest AIS >22
abdomen AIS >22
head AIS >22
spinal fractures 3
GCS <83
severe lower extremity frac-ture 4
pelvic fracture 4
spinal cord injury 4
Age
40–59 2
60–74 3
>75 4
AIS: Abbreviated injury score, GCS: Glasgow coma scale
Adapted from Greenfield et al., J Trauma 1997;42:100–3.