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Int J Crit Illn Inj Sci. 2013 Apr-Jun; 3(2): 143–151.
doi: 10.4103/2229-5151.114274
PMCID: PMC3743339
Prophylaxis and treatment of venous
thromboembolism in the critically ill
Sarah M Adriance and Claire V Murphy
Author information ► Copyright and License information ►
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Abstract
Venous thromboembolism (VTE) is a frequent complication in critically ill patients and is
associated with increased rates of morbidity and mortality. The use of thromboprophylaxis to
reduce the risk of VTE in this patient population is the standard of care. This review will
summarize the recommendations set forth in consensus guidelines for the prevention and
treatment of VTE across subgroups within the critically ill patient population. In addition, the
drug properties of the recommended pharmacologic agents for thromboprophylaxis will be
highlighted including their pharmacokinetics, dosing and complications. The critical care
practitioner may also encounter novel oral anticoagulants with increasing frequency. These
agents will be briefly reviewed in terms of their approved and investigational indications and
the clinical concerns related to their use will also be discussed.
Keywords: Anticoagulant, critical care, embolism, prophylaxis, thrombosis, venous
thromboembolism
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INTRODUCTION
Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary
embolism (PE), are frequent complications encountered in critically ill patients admitted to an
intensive care unit (ICU) leading to increased rates of morbidity and mortality within this
patient population.[1] Critically ill patients are at high-risk for developing a VTE for reasons
such as extended periods of immobilization, mechanical ventilation, and vascular injury or
surgery. The risk of developing a DVT can be as high as 81% in critically ill patients not
managed with thromboprophylaxis and can occur in approximately 44% of critically ill
patients despite some form of thromboprophylaxis.[1] However, VTE incidence can vary
markedly depending on mode of detection. Progression to a PE has been reported in
approximately 12% of patients with a documented DVT in the ICU despite
thromboprophylaxis.[2] The use of thromboprophylaxis to reduce rates of VTE in the ICU is
the standard of care.[1,3]
The 9th edition of the American College of Chest Physicians (ACCP) clinical practice
guidelines for prevention and treatment of VTE provide updated recommendations for
various subgroups of patients that emphasizes the evaluation of patient risk for VTE and
move clinical practice away from universal thromboprophylaxis for all patients.[3]
Prophylaxis with an anticoagulant is recommended in patients who have an elevated DVT
and PE risk, which includes the critically ill provided they are not at a high bleeding risk. The
use of anticoagulants in patients with an active gastroduodenal ulcer, bleeding history in the
three months prior to hospital admission or platelet count less than 50,000 K/uL may increase
the risk of hemorrhage. Clinicians may also reference specific recommendations set forth in
their respective specialty areas to guide their practice.
The focus of this review is to outline the specific pharmacologic profiles of the recommended
anticoagulants for VTE prophylaxis and treatment and provide a summary of current
recommendations for thromboprophylaxis across the distinct critically ill patient populations.
Also included is a discussion of novel oral anticoagulants that have or are currently
undergoing investigation for VTE prophylaxis and treatment in patients that clinicians may
encounter in intensive care units. Specific discussion of the underlying pathophysiology and
diagnosis of VTE is beyond the scope of this review.
Mechanical prophylaxis
Mechanical devices for thromboprophylaxis can be characterized as either static or
dynamic.[3,4] Static devices include graduated compression stockings (GCS) and placement
of an inferior vena cava (IVC) filter, which is an invasive procedure. Dynamic methods
include intermittent pneumatic compression devices (IPC) and arteriovenous foot pumps.
Since up to 80% of ICU patient experience one or more episodes of minor or major bleeding,
mechanical thromboprophylaxis is often an attractive option to limit potential adverse
effects.[3] However, data evaluating their use alone or as an adjunct to pharmacologic
prophylaxis in critically ill patients is limited. At this time, there are no randomized studies
comparing mechanical prophylaxis to no prophylaxis in critically ill patients. Current
guidelines recommend mechanical prophylaxis for patients in whom pharmacologic
prophylaxis is contraindicated or in combination with pharmacologic thromboprophylaxis in
certain sub-populations at higher VTE risk.[3,5] IPCs are the preferred device although
arteriovenous foot pumps can be considered when IPCs are contraindicated due to external
fixation or casts.[3] As a general rule, guidelines recommend against the use of IVC filters as
thromboprophylaxis and should only be considered in specific circumstances.[3]
Pharmacologic prophylaxis
Options for pharmacologic thromboprophylaxis include low dose unfractionated heparin
(LDUH), low molecular weight heparins (LMWH) (i.e., enoxaparin and dalteparin), and
pentasaccharides (i.e., fondaparinux). Specific information for each agent including dosing
and monitoring recommendations is outlined in Table 1. Although there are few studies
evaluating pharmacologic prophylaxis for the critically ill patient, current guidelines
recommend the use of either LMWH or LDUH over no prophylaxis.[3] Selection of a
specific agent for prophylaxis can be challenging in these patients, as the clinician must
balance the risk of thrombosis and hemorrhage. Furthermore, one may need to take into
consideration additional published literature to support the selection of prophylaxis for
certain subgroups of critically ill patients.
Table 1
Agents for the prevention and treatment of venous thromboembolism[5,7,8]
Trauma
Major trauma patients who receive no thromboprophylaxis are reported to have increased
rates of asymptomatic VTE with an incidence as high as 58% detected by a single venogram
during hospital admission.[9] However, the use of a diagnostic test as a surrogate marker for
clinically relevant VTE events is criticized.[10] The risk of symptomatic VTE is estimated to
be 3% to 5% among major trauma patients. Thromboprophylaxis should include mechanical
methods, preferably IPC, or administration of LDUH or LMWH in major trauma patients.[3]
Traumatic injury to the spinal cord and brain and surgical intervention to the spine place the
trauma patient at higher risk for VTE, estimated to be 8% to 10%, and thromboprophylaxis
recommendations include both pharmacologic prevention with LDUH or LMWH and
mechanical prophylaxis with IPC if no lower extremity injury exists.[3] The Eastern
Association for the Surgery of Trauma (EAST) guidelines for trauma patients published in
2002 suggest LMWH over LDUH for VTE prevention in major trauma patients.[5] The use
of a pharmacologic agent to prevent VTE may be limited by relative contraindications for
chemical prophylaxis including severe head injury, non-operatively managed liver or spleen
injures, renal failure, spinal column fracture with epidural hematoma, severe
thrombocytopenia, and coagulopathy.[11]
Burn injury
The incidence of VTE in burn patients is fairly low in comparison to most ICU populations
ranging from 1% to 3% with no routine prophylaxis and approximately 2% with
pharmacologic prophylaxis.[12,13,14,15] As there are limited studies evaluating
pharmacologic prophylaxis in burn patients; consensus guidelines extrapolate data from other
populations to recommend routine prophylaxis with LDUH or LMWH in burn patients who
have additional risk factors for VTE.[11] Additional VTE risk factors in burn patients include
age, morbid obesity, extensive or lower-extremity burns, lower-extremity trauma, insertion of
a femoral venous catheter, and prolonged immobility.[16] A single retrospective analysis
compared the incidence of symptomatic DVT in burn patients receiving enoxaparin or
LDUH.[17] Symptomatic DVT was documented in 5 (0.45%) patients receiving LDUH and
none in the enoxaparin group (P = 0.07). However, patients receiving LDUH had more VTE
risk factors and primarily received heparin 5000 units subcutaneously every 12 hours,
potentially biasing the results. Two recent studies evaluated the impact of burn injury on
enoxaparin dosing for thromboprophylaxis. The results suggest that patients with large burns
and associated hypermetabolism may require doses above 30 mg every 12 hours of
enoxaparin to achieve a targeted anti-factor Xa range for prophylaxis.[16,18] However,
specific dosing for either LDUH or LMWH is not defined in this population, and clinical
correlation between anti-factor Xa levels and thrombosis risk has not been established.
General surgery
Approximately 1/3 of the 150,000 to 200,000 VTE-attributed deaths in the United States
reported annually occur after surgery.[19] The probability of thrombosis depends on the
surgical procedure and associated post-operative course, as well as underlying patient
characteristics.[11] In addition, surgical complications including post-operative infections
(pneumonia, urinary tract infection, and sepsis), acute renal failure and need for transfusion
have also been linked with an increased risk of VTE after surgery.[11] Due to the
complicated nature of determining risk of VTE in surgical patients, several models have been
developed to estimate total risk related to patient and procedural factors. For example, the
Caprini model scores risk of VTE based on a variety of risk factors and classifies patients as
very low (0-1 point), low (2 points), moderate (3-4 points) and high (≥5 points).[20,21] This
model has been validated in general surgery, vascular, urologic, plastic and reconstructive
surgery patients and is used in the current surgical VTE prevention guidelines.[11] Specific
recommendations based on VTE risk and surgical populations are outlined in Table 2.
Table 2
Recommendations for pharmacologic venous thromboembolism prophylaxis based on
surgical population[11]
Neurocritical care
The neurocritical care patient population encompasses a diverse group of underlying
pathologies, including neurosurgery, stroke (hemorrhagic and ischemic), traumatic brain
injury (TBI) and spinal cord injury (SCI). Thromboprophylaxis in this patient population
remains controversial with sparse high quality data in certain subgroups and considerable
differences in clinical practice, particularly with the timing of therapy initiation.[22] Timing
of initiation will vary based on underlying pathology and risk of hemorrhagic complications,
particularly with intracerebral hemorrhage. There is no uniform anticoagulant for
thromboprophylaxis agent recommended across the subsets of neurocritical care patients and
intermittent compression devices in general are the method of choice [Table 3]. No consensus
guidelines are available for patients with subarachnoid hemorrhage or brain tumors.
Table 3
Recommendations for venous thromboembolism prophylaxis in neurocritical care
Medical
Compared to other critically ill patient populations there are fewer studies involving patients
in the medical ICU regarding prevention of VTE. The incidence of asymptomatic DVT in
patients not receiving thromboprophylaxis among medical and medical-surgical ICU patients
ranges from 9% to 32% depending on screening method and 7% to 13% in those receiving
heparin products.[26,27,28] Only one symptomatic PE was reported in a single study among
100 patients.[26] In general, the ACCP guideline recommendations for critically ill patients
may be referenced in this patient population.[3] These recommendations include
pharmacologic prevention with a LMWH or LDUH. Mechanical prophylaxis with GCS or
IPC should be used if bleeding risk is present and pharmacologic prophylaxis should be reevaluated when the risk of bleeding subsides.
Pregnancy
Pregnancy is associated with a significantly increased thrombotic risk, with a 3 to 4-fold
higher risk throughout pregnancy.[29] Postpartum, the risk increases further to 20-fold, and
returns towards baseline 6-8 weeks after delivery.[29,30,31] The primary reason for increased
thrombotic risk is hormonally induced hypercoagulability as a result of increased venous
capacitance, decreased outflow, and increased production of factors VII, VIII, X and von
Willebrand factor.[30,31,32] In addition, mechanical obstruction due to the gravid uterus,
decreased mobility, and vascular injury during delivery may also increase risk of
VTE.[32,33] In deciding which patients require anticoagulation for prevention of VTE, risk
and benefit to both mother and fetus must be weighed. Although there is little data to guide
therapy in this population, current guidelines recommend LMWH as the preferred agent for
both prophylaxis and treatment of VTE during pregnancy.[34] However, neither heparin nor
LMWH cross the placenta and are both considered safe.[30,34] Based on limited data
supporting fetal safety, pentasaccharides (i.e., fondaparinux) and direct thrombin inhibitors
(DTIs) are not recommended during pregnancy.[34] Postpartum after cesarean section,
patients with at least one major or two minor risk factors should receive either LMWH or
mechanical prophylaxis.[34]
Malignancy
Patients with cancer who are critically ill or have undergone surgery are at significantly
higher risk of VTE compared to those without cancer.[35] The increased risk associated with
cancer is based on alterations in all three components of Virchow's triad as a result of the
underlying malignancy and associated management (chemotherapy and surgery) as well as
the presence of additional risk factors for thrombosis (i.e., prior VTE, obesity,
immobility).[35,36] VTE in cancer patients is associated with significant morbidity and
mortality, and is the 2nd most common cause of death in hospitalized patients with cancer.[36]
The majority of studies evaluating thromboprophylaxis in cancer patients focus on
perioperative management in patients undergoing surgical interventions. Based on these
studies, current guidelines recommend an extended duration (i.e., 4 weeks) of
thromboprophylaxis with LMWH for high VTE risk patients admitted for abdominal or
pelvic surgery for cancer.[11] If a patient is at increased risk for bleeding, mechanical devices
should be used until pharmacologic thromboprophylaxis can be initiated.
Methods for VTE treatment in critically Ill
Management of VTE in critically ill patients can be especially difficult as the selection and
dosing of therapeutic anticoagulation may be affected by several aspects of critical illness
such as liver or kidney dysfunction [Table 1]. Furthermore, an ICU patient is subject to
invasive monitoring and surgical intervention that carry inherent bleeding risks, which can
complicate anticoagulant use. Nonetheless, therapeutic anticoagulation is appropriate for the
majority of critically ill patients experiencing a VTE and recommended for patients with a
high clinical suspicion while diagnostic tests are being carried out.[37] There are no specific
recommendations with respect to one anticoagulant over another in the critically ill patient.
Initial anticoagulation may include a LMWH, intravenous unfractionated heparin (UFH) or
fondaparinux. A critical care clinician may suggest UFH for VTE management in the
critically ill given that it is minimally affected by organ dysfunction, has a relatively shorter
half-life and is reversible with protamine. The administration of agents such as enoxaparin or
fondaparinux may not be appropriate for critically ill patients secondary to potential
interference with subcutaneous absorption.[38] Non-heparin anticoagulants may be used,
particularly in the setting of HIT such as bivalirudin, danaparoid, desirudin or argatroban.
Complications of VTE prevention and treatment
The complications associated with the prevention and treatment of VTE that are of utmost
concern in the ICU setting include hemorrhage and heparin induced thrombocytopenia (HIT)
[Table 1].[39] Bleeding complications with UFH and LMWH are due to the underlying
mechanism of action with inhibition of anti-thrombin III, whereas HIT is related to formation
of IgG antibodies that recognize complexes of platelet factor 4 (PF4) and heparin on the
surface of platelets.[39,40] Risk of hemorrhage depends on drug dosing and route of
administration, as well as patient specific characteristics (i.e., renal/liver dysfunction, age,
and underlying hematologic abnormalities) and treatment related variables (i.e., surgical
interventions and concomitant medications).[39] While major bleeds are the most concerning
adverse effect associated with VTE prevention and treatment, the risk of hemorrhage can be
minimized thorough risk/benefit assessment prior to initiation, and appropriate dosing and
monitoring. In addition, for the majority of traditional anticoagulants used for prevention and
treatment of VTE in the acute setting, agents for reversal exist [Table 1].
HIT is an antibody mediated adverse reaction primarily related to the use of UFH and
LMWH.[41] The incidence of HIT varies from 0.1-5% based on patient population, with the
highest risk reported in cardiovascular and orthopedic surgery and the lowest in non-critically
ill medical and obstetric patients.[40,42] In addition, choice of anticoagulant significantly
impacts risk as UFH has a 10-fold higher risk of HIT compared to LWMH.[40] The hallmark
characteristic of HIT is thrombocytopenia (<150 × 109/L or 30-50% reduction from baseline)
which is traditionally observed about 5 days after initiation of UFH or LMWH. Occasionally
thrombocytopenia can occur within 24 hours in patients with prior exposure or up to 3 weeks
after discontinuation of UFH or LMWH in delayed onset HIT.[40]
Treatment of HIT includes discontinuation of all forms of UFH or LMWH and initiation of a
DTI. Currently available DTIs include lepirudin, argatroban, bivalirudin and desirudin, and
guidelines recommend initiation of one of these agents rather than immediate initiation of
vitamin K antagonist therapy.[40] Lepirudin, danaparoid or argatroban are recommended for
patients with normal renal function, while argatroban is preferred for patients with renal
insufficiency. In patients requiring renal replacement therapy, both argatroban and
danaparoid are options. Although many institutions have implemented protocols for
bivalirudin for management of HIT, published data is limited primarily to patients
undergoing percutaneous intervention.[40,43,44] Data for desirudin is also currently lacking.
Baxter Healthcare Corporation also recently announced the decision to discontinue
production of lepirudin in 2012 and Organon, Inc. also discontinued manufacturing
danaparoid in the United States in 2002, leaving argatroban as the only guideline supported
DTI for management of HIT in some countries. Further studies are needed to evaluate the
efficacy and safety of bivalirudin and desirudin for management of HIT in critically ill
patients. Specific information regarding each DTI is summarized in Table 4.
Table 4
Intravenous direct thrombin inhibitors for heparin-induced thrombocytopenia with or without
thrombosis[40,43,44,45]
Like standard therapies for VTE prophylaxis and treatment, DTIs are associated with a
significant risk of bleeding. However, the incidence and risk factors for bleeding with these
agents are not fully established. In addition, unlike traditional anticoagulant therapies there
are no available reversal agents for bleeding associated with DTIs and the optimal strategy
for restoring hemostasis is not clear.[7]
Novel anticoagulants
Oral DTIs and direct factor Xa inhibitors comprise two novel therapeutic classes of
anticoagulants that differ pharmacologically from traditional agents used to prevent and treat
VTE. At this time dabigatran and rivaroxaban have approved use in and outside of the United
States, while apixaban has only entered the international market. There are numerous agents
that remain under investigation (i.e., edoxaban, betrixaban), including two subcutaneous
indirect factor Xa inhibitors, idrabiotaparinux and semuloparin.
Clinical indications for the novel anticoagulants vary but their primary use is for stroke
prevention in the setting of atrial fibrillation and for VTE prevention after hip or knee
replacement surgery [Table 5]. Unfortunately, there is lack of readily available monitoring for
these agents and a specific antidote to reverse their action, of particular concern in emergent
situations such as a severely injured trauma patient.[60,61,62,63] Dialysis is suggested in the
product labeling to reduce serum concentrations of dabigatran over several hours but this
option has its limitations in the unstable bleeding patient.[62] Procoagulant products such as
activated prothrombin complex concentrates (i.e., FEIBA) may aid in the reversal of
dabigatran and rivaroxaban as reversal of laboratory markers have been demonstrated but
clinical correlation is still needed.[61,64]
Table 5
Novel oral anticoagulants and venous thromboembolism related research
In the setting of acute and critical illness the irreversibility and lack of monitoring to
determine the degree of anticoagulation of the novel oral anticoagulants lends great concern
for this complex patient population. Furthermore, questions remain about appropriate dosing
in the elderly population and in severe renal or liver impairment, and experience with these
agents in critically ill patients is not available at this time.
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CONCLUSION
The critically ill encompasses a diverse group of patients who are considered high-risk for
developing a DVT and PE. Routine thromboprophylaxis is standard of care in this patient
population using mechanical methods, pharmacologic prophylaxis, or both. The latest edition
of the ACCP guidelines on the management of VTE recommend the use of IPC combined
with a LDUH or LMWH for the thromboprophylaxis in the critically ill if no bleeding risk is
present. Reference to specific literature published within certain subgroups of patients may
provide additional guidance in the selection of prophylaxis. In the setting of an active VTE,
therapeutic anticoagulation is generally indicated but no specific pharmacologic class is
recommended. Selection of an anticoagulant for VTE prevention or treatment in a critically
ill patient may be based on several factors including the pharmacology of the anticoagulant,
anticipated complications of therapy, the renal or hepatic function of the patient, and the
underlying needs of the patient. Being familiar with specific drug properties of traditional
anticoagulants and emerging agents, as well as the evidence to support their use is important
for clinicians involved in the selection of a pharmacologic agent for VTE prevention,
treatment or for the management of complications such as bleeding and HIT.
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Footnotes
Source of Support: Nil
Conflict of Interest: None declared.
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