thrombosis of major veins
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TOPIC 12. THROMBOSIS OF MAJOR VEINS.
DEEP VENOUS THROMBOSIS
Introduction of acute deep venous thrombosis
Deep venous thrombosis (DVT) most commonly involves the deep veins
of the leg or arm, often resulting in potentially life-threatening emboli to the
lungs or debilitating venous alular dysfunction and chronic leg swelling. Deep
venous thrombosis (DVT) is also one of the most prevalent medical problems
today, with an annual incidence of 117 cases per 100,000. Each year in the
United States, more than 200,000 people develop venous thrombosis; of those,
50,000 cases are complicated by pulmonary embolism.1 Early recognition and
appropriate treatment of deep venous thrombosis (DVT) and its complications
can save many lives.
Pathophysiology
Over a century ago, Rudolf Virchow described 3 factors that are
critically important in the development of venous thrombosis: (1) venous
stasis, (2) activation of blood coagulation, and (3) vein damage. Over time,
refinements have been made in their description and importance to the
development of venous thrombosis. The origin of venous thrombosis is
frequently multifactorial, with components of the triad of variable importance
in individual patients.
Studies have shown that low flow sites, such as the soleal sinuses,
behind venous valve pockets, and at venous confluences, are at most risk for
the development of venous thrombi. However, stasis alone is not enough to
facilitate the development of venous thrombosis. Experimental ligation of
rabbit jugular veins for periods of up to 60 minutes have failed to consistently
cause venous thrombosis. Although, patients that are immobilized for long
periods of time seem to be at high risk for the development of venous
thrombosis, an additional stimulus is required to develop deep venous
thrombosis (DVTs).
Mechanical injury to the vein wall appears to provide an added stimulus
for venous thrombosis. Hip arthroplasty patients with the associated femoral
vein manipulation represent a high-risk group that cannot be explained by just
immobilization, with 57% of thrombi originating in the affected femoral vein
rather than the usual site of stasis in the calf.6 Endothelial injury can convert
the normally antithrombogenic endothelium to become prothrombotic by
stimulating the production of tissue factor, von Willebrand factor, and
fibronectin.
Genetic mutations within the blood’s coagulation cascade represent
those at highest risk for the development of venous thrombosis (See Table 1).
Table 1. Relative Risk for Venous Thrombosis
Primary deficiencies of coagulation inhibitors antithrombin, protein C,
and protein S are associated with 5-10% of all thrombotic events. Resistance of
procoagulant factors to an intact anticoagulation system has also recently been
described with the recognition of factor V Leiden mutation, representing 10-
65% of patients with deep venous thrombosis (DVT).8 In the setting of venous
stasis, these factors are allowed to accumulate in thrombosis prone sites, where
mechanical vessel injury has occurred, stimulating the endothelium to become
prothrombotic.
Components of the Virchow triad are of variable importance in
individual patients, but the end result is early thrombus interaction with the
endothelium. This interaction stimulates local cytokine production and
facilitates leukocyte adhesion to the endothelium, both of which promote
venous thrombosis. Depending on the relative balance between activated
coagulation and thrombolysis, thrombus propagation occurs.
Over time, thrombus organization begins with the infiltration of
inflammatory cells into the clot. This results in a fibroelastic intimal thickening
at the site of thrombus attachment in most patients and a fibrous synechiae in
up to 11%. In many patients, this interaction between vessel wall and thrombus
leads to alular dysfunction and overall vein wall fibrosis. Histological
examination of vein wall remodeling after venous thrombosis has demonstrated
an imbalance in connective tissue matrix regulation and a loss of regulatory
venous contractility that contributes to the development of chronic venous
insufficiency.
Risk factors
Many factors have been identified as known risk factors for the
development of venous thrombosis. The single most powerful risk marker
remains a prior history of DVT with up to 25% of acute venous thrombosis
occurring in such patients. Pathologically, remnants of previous thrombi are
often seen within the specimens of new acute thrombi. However, recurrent
thrombosis may actually be the result of primary hypercoagulable states.
Abnormalities within the coagulation cascade are the direct result of discrete
genetic mutations within the coagulation cascade. Deficiencies of protein C,
protein S, or antithrombin III account for approximately 5-10% of all cases of
deep venous thrombosis (DVT).
Age has been well studied as an independent risk factor for venous
thrombosis development. Although a 30-fold increase in incidence is noted
from age 30 to age 80, the effect appears to be multifactorial, with more
thrombogenic risk factors occurring in the elderly than in those younger than
40 years. Venous stasis, as seen in immobilized patients and paralyzed limbs,
also contributes to the development of venous thrombosis. Autopsy studies
parallel the duration of bed rest to the incidence of venous thrombosis, with
15% of patients in those studies dying within 7 days of bedrest to greater than
80% in those dying after 12 weeks.2 Within stroke patients, deep venous
thrombosis (DVT) is found in 53% of paralyzed limbs, compared with only 7%
on the nonaffected side.
Malignancy is noted in up to 30% of patients with venous thrombosis.
The thrombogenic mechanisms involve abnormal coagulation, as evidenced by
90% of cancer patients having some abnormal coagulation factors.18
Chemotherapy may increase the risk of venous thrombosis by affecting the
vascular endothelium, coagulation cascades, and tumor cell lysis. The
incidence has been shown to increase in those patients undergoing longer
courses of therapy for breast cancer, from 4.9% for 12 weeks of treatment to
8.8% for 36 weeks. Additionally, deep venous thrombosis (DVT) complicates
29% of surgical procedures done for malignancy.
Postoperative venous thrombosis varies depending on a multitude of
patient factors, including the type of surgery undertaken. Without prophylaxis,
general surgery operations typically have an incidence of deep venous
thrombosis (DVT) around 20%, while orthopedic hip surgery can occur in up
to 50% of patients. Based on radioactive labeled fibrinogen, about half of lower
extremity thrombi develop intraoperatively. Perioperative immobilization,
coagulation abnormalities, and venous injury all contribute to the development
of surgical venous thrombosis.
Other clinical settings commonly reported as risk factors have also been
identified and are shown in Table 2, 3
Table 2. Risk Factors for Venous Thromboemobolic Disease
Table 3. Risk Factors for Venous Thromboembolism
Clinical and diagnostic evaluation
The clinical diagnosis of deep venous thrombosis (DVT) is difficult and
fraught with uncertainty. The classic signs and symptoms of deep venous
thrombosis (DVT) are those associated with obstruction to venous drainage and
include pain, tenderness, and unilateral leg swelling. Other associated
nonspecific findings are warmth, erythema, a palpable cord, and pain upon
passive dorsiflexion of the foot (Homan sign). However, even with patients
with classic symptoms, up to 46% have negative venograms. Furthermore, up
to 50% of those with image-documented venous thrombosis lack any specific
symptom. Deep venous thrombosis (DVT) simply cannot be diagnosed or
excluded based on clinical findings; thus, diagnostic tests must be performed
whenever the diagnosis of deep venous thrombosis (DVT) is being considered.
When a patient has deep venous thrombosis (DVT), symptoms may be
present or absent, unilateral or bilateral, or mild or severe. Thrombus that does
not cause a net venous outflow obstruction is often asymptomatic. Thrombus
that involves the iliac bifurcation, the pelvic veins, or the vena cava produces
leg edema that is usually bilateral rather than unilateral. High partial
obstruction often produces mild bilateral edema that is mistaken for the
dependent edema of right-sided heart failure, fluid overload, or hepatic or renal
insufficiency.
Severe venous congestion produces a clinical appearance that can be
indistinguishable from the appearance of cellulitis. Patients with a warm,
swollen, tender leg should be evaluated for both cellulitis and deep venous
thrombosis (DVT) because patients with primary deep venous thrombosis
(DVT) often develop a secondary cellulitis, while patients with primary
cellulitis often develop a secondary deep venous thrombosis (DVT).
Superficial thrombophlebitis, likewise, is often associated with a clinically
inapparent underlying DVT.
If a patient is thought to have pulmonary embolism (PE) or has
documented PE, the absence of tenderness, erythema, edema, or a palpable
cord upon examination of the lower extremities does not rule out
thrombophlebitis, nor does it imply a source other than a leg vein. More than
two thirds of patients with proven PE lack any clinically evident phlebitis.
Nearly one third of patients with proven PE have no identifiable source of deep
venous thrombosis (DVT), despite a thorough investigation. Autopsy studies
suggest that even when the source is clinically inapparent, it lies undetected
within the deep venous system of the lower extremity and pelvis in 90% of
cases.
Vascular Lab and Radiologic Evaluation
Duplex Ultrasound
DUS is now the most commonly performed test for the detection of
infrainguinal DVT, both above and below the knee, and has a sensitivity and
specificity of >95% in symptomatic patients. DUS combines real-time B-mode
ultrasound with pulsed Doppler capability. Color flow imaging is useful in
more technically difficult examinations, such as in the evaluation of possible
calf vein DVT. This combination offers the ability to noninvasively visualize
the venous anatomy, detect occluded and partially occluded venous segments,
and demonstrate physiologic flow characteristics using a mobile self-contained
device.
In the supine patient, normal lower extremity venous flow is phasic (Fig.
1), decreasing with inspiration in response to increased intra-abdominal
pressure with the descent of the diaphragm and then increasing with expiration.
When the patient is upright, the decrease in intra-abdominal pressure with
expiration cannot overcome the hydrostatic column of pressure existing
between the right atrium and the calf. Muscular contractions of the calf, along
with the one-way venous valves, are then required to promote venous return to
the heart. Flow also can be increased by leg elevation or compression and
decreased by sudden elevation of intra-abdominal pressure (Valsalva's
maneuver). In a venous DUS examination performed with the patient supine,
spontaneous flow, variation of flow with respiration, and response of flow to
Valsalva's maneuver are all assessed. However, the primary method of
detecting DVT with ultrasound is demonstration of the lack of compressibility
of the vein with probe pressure on B-mode imaging. Normally, in transverse
section, the vein walls should coapt with pressure. Lack of coaptation indicates
thrombus.
Fig. 1. Duplex ultrasound scan of a normal femoral vein with phasic
flow signals.
The examination begins at the ankle and continues proximally to the
groin. Each vein is visualized, and the flow signal is assessed with distal and
proximal compression. Lower extremity DVT can be diagnosed by any of the
following DUS findings: lack of spontaneous flow (Fig. 2), inability to
compress the vein (Fig. 3), absence of color filling of the lumen by color flow
DUS, loss of respiratory flow variation, and venous distention. Again, lack of
venous compression on B-mode imaging is the primary diagnostic variable.
Several studies comparing B-mode ultrasound to venography for the detection
of femoropopliteal DVT in patients clinically suspected to have DVT report
sensitivities of >91% and specificities of >97%. The ability of DUS to assess
isolated calf vein DVT varies greatly, with sensitivities ranging from 50 to
93% and specificities approaching 100%.
Fig. 2. Duplex ultrasound of a femoral vein containing thrombus
demonstrating no flow within the femoral vein
Fig. 3. B-mode ultrasound of the femoral vein in cross-section. The
femoral vein does not collapse with external compression
Impedance Plethysmography
Impedance plethysmography (IPG) was the primary noninvasive method
of diagnosing DVT before the widespread use of DUS but is infrequently used
today. IPG is based on the principle that resistance to the flow of electricity
between two electrodes, or electrical impedance, occurs as the volume of the
extremity changes in response to blood flow. Two pairs of electrodes
containing aluminum strips are placed circumferentially around the leg
approximately 10 cm apart and a low-level current is delivered to the two outer
electrodes. A pneumatic cuff is inflated over the thigh for venous outflow
obstruction and then rapidly deflated. Changes in electrical resistance resulting
from lower extremity blood volume changes are quantified. IPG is less
accurate than DUS for the detection of proximal DVT, with an 83% sensitivity
in symptomatic patients. It is a poor detector of calf vein DVT.
Iodine 125 Fibrinogen Uptake
Iodine 125 fibrinogen uptake (FUT) is a seldom used technique that
involves IV administration of radioactive fibrinogen and monitoring for
increased uptake in fibrin clots. An increase of 20% or more in one area of a
limb indicates an area of thrombus.23 FUT can detect DVT in the calf, but high
background radiation from the pelvis and the urinary tract limits its ability to
detect proximal DVT. It also cannot be used in an extremity that has recently
undergone surgery or has active inflammation. In a prospective study, FUT had
a sensitivity of 73% and specificity of 71% for identification of DVT in a
group of symptomatic and asymptomatic patients. Currently, FUT is primarily
a research tool of historic interest.
Venography
Venography is the most definitive test for the diagnosis of DVT in both
symptomatic and asymptomatic patients. It is the gold standard to which other
modalities are compared. This procedure involves placement of a small
catheter in the dorsum of the foot and injection of a radiopaque contrast agent.
Radiographs are obtained in at least two projections. A positive study result is
failure to fill the deep system with passage of the contrast medium into the
superficial system or demonstration of discrete filling defects (Fig. 4). A
normal study result virtually excludes the presence of DVT. In a study of 160
patients with a normal venogram followed for 3 months, only two patients
(1.3%) subsequently developed DVT and no patients experienced symptoms of
PE.
Fig. 4. Venogram showing a filling defect in the popliteal vein (arrows).
Venography is not routinely used for the evaluation of lower extremity
DVT because of the associated complications discussed previously. Currently,
venography is reserved for imaging before operative venous reconstruction and
catheter-based therapy. It does, however, remain the procedure of choice in
research studies evaluating methods of prophylaxis for DVT.
Laboratory analysis has also been used in aiding the diagnosis of venous
thrombosis. D-dimers are degradation products of cross-linked fibrin by
plasmin that are detected by diagnostic assays. Although highly sensitive, up to
97%, elevated levels are not specific with rates as low as 35%.27 Many other
clinical situations can result in elevated D-dimer levels, including infection,
trauma, postoperative states, and malignancy.28 Additional blood work should
include coagulation studies to evaluate for a hypercoagulable state, if clinically
indicated. A prolonged prothrombin time or activated partial thromboplastin
time does not imply a lower risk of new thrombosis. Progression of deep
venous thrombosis (DVT) and PE can occur despite full therapeutic
anticoagulation in 13% of patients.
Treatment
Once the diagnosis of VTE has been made, antithrombotic therapy
should be initiated promptly. If clinical suspicion for VTE is high, it may be
prudent to start treatment while the diagnosis is being objectively confirmed.
The theoretic goals of VTE treatment are the prevention of mortality and
morbidity associated with PE and the prevention of the postphlebitic syndrome.
However, the only proven benefit of anticoagulant treatment for DVT is the
prevention of death from PE. Treatment regimens may include antithrombotic
therapy, vena caval interruption, catheter-directed or systemic thrombolytic
therapy, and operative thrombectomy.
Antithrombotic Therapy
Antithrombotic therapy may be initiated with IV or SC unfractionated
heparin, SC low molecular weight heparin, or SC fondaparinux (a synthetic
pentasaccharide). This initial therapy usually is continued for at least 5 days,
while oral vitamin K antagonists are being simultaneously administered. The
initial therapy typically is discontinued when the international normalized ratio
(INR) is ≥2.0 for 24 hours.
Unfractionated heparin (UFH) binds to antithrombin via a specific 18-
saccharide sequence, which increases its activity over 1000-fold. This
antithrombin-heparin complex primarily inhibits factor IIa (thrombin) and
factor Xa and, to a lesser degree, factors IXa, XIa, and XIIa. In addition, UFH
also binds to tissue factor pathway inhibitor, which inhibits the conversion of
factor X to Xa, and factor IX to IXa. Finally, UFH catalyzes the inhibition of
thrombin by heparin cofactor II via a mechanism that is independent of
antithrombin.
UFH therapy is most commonly administered with an initial IV bolus of
80 units/kg or 5000 units. Weight-based UFH dosages have been shown to be
more effective than standard fixed boluses in rapidly achieving therapeutic
levels. The initial bolus is followed by a continuous IV drip, initially at 18
units/kg per hour or 1300 units per hour. The half-life of IV UFH ranges from
45 to 90 minutes and is dose dependent. The level of antithrombotic therapy
should be monitored every 6 hours using the activated partial thromboplastin
time (aPTT), with the goal range of 1.5 to 2.5 times control values. This should
correspond with plasma heparin anti-Xa activity levels of 0.3 to 0.7 IU/mL.
Initial anticoagulation with UFH may be administered SC, although this
route is less commonly used. Adjusted-dose therapeutic SC UFH is initiated
with 17,500 units, followed by 250 units/kg twice daily, and dosing is adjusted
to an aPTT goal range similar to that for IV UFH. Fixed-dose unmonitored SC
UFH is started with a bolus of 333 units/kg, followed by 250 units/kg twice
daily.
Hemorrhage is the primary complication of UFH therapy. The rate of
major hemorrhage (fatal, intracranial, retroperitoneal, or requiring transfusion
of >2 units of packed red blood cells) is approximately 5% in hospitalized
patients undergoing UFH therapy (1% in medical patients and 8% in surgical
patients).27 For patients with UFH-related bleeding complications, cessation of
UFH is required, and anticoagulation may be reversed with protamine sulfate.
Protamine sulfate binds to UFH and forms an inactive salt compound. Each
milligram of protamine neutralizes 90 to 115 units of heparin, and the dosage
should not exceed 50 mg IV over any 10-minute period. Side effects of
protamine sulfate include hypotension, pulmonary edema, and anaphylaxis.
Patients with prior exposure to protamine-containing insulin (NPH) and
patients with allergy to fish may have an increased risk of hypersensitivity,
although no direct relationship has been established. The protamine infusion
should be terminated if any side effects occur.
In addition to hemorrhage, heparin also has unique complications.
Heparin-induced thrombocytopenia (HIT) results from heparin-associated
antiplatelet antibodies (HAAbs) directed against platelet factor 4 complexed
with heparin. HIT occurs in 1 to 5% of patients being treated with heparin. In
patients with repeat heparin exposure (such as vascular surgery patients), the
incidence of HAAb may be as high as 21%.HIT occurs most frequently in the
second week of therapy and may lead to disastrous venous or arterial
thrombotic complications. Therefore, platelet counts should be monitored
periodically in patients receiving continuous heparin therapy. All forms of
heparin should be stopped if there is a high clinical suspicion or confirmation
of HIT [usually accompanied by an unexplained thrombocytopenia (<100,000/
L) or platelet count decrease of 30 to 50%]. Fortunately, direct thrombin
inhibitors (recombinant hirudin, argatroban, bivalirudin) now are available as
alternative antithrombotic agents (see later). Another complication of
prolonged high-dose heparin therapy is osteopenia, which results from
impairment of bone formation and enhancement of bone resorption by heparin.
Low molecular weight heparins (LMWHs) are derived from the
depolymerization of porcine UFH. Like UFH, LMWHs bind to antithrombin
via a specific pentasaccharide sequence to expose an active site for the
neutralization of factor Xa. However, LMWHs lack the sufficient number of
additional saccharide units (18 or more), which results in less inactivation of
thrombin (factor IIa). In comparison to UFH, LMWHs have increased
bioavailability (>90% after SC injection), longer half-lives (approximately 4 to
6 hours), and more predictable elimination rates. Weight-based once- or twice-
daily SC LMWH injections, for which no monitoring is needed, provide a
distinct advantage over continuous IV infusions of UFH for treatment of VTE.
Most patients who receive therapeutic LMWH do not require
monitoring. Patients who do require monitoring include those with significant
renal insufficiency or failure, pediatric patients, obese patients of >120 kg, and
patients who are pregnant. Monitoring may be performed using anti-Xa activity
assays. However, the therapeutic anti-Xa goal range will depend on the type of
LMWH and the frequency of dosing. Numerous LMWHs are commercially
available. The various preparations differ in their anti-Xa and anti-IIa activities,
and the treatment dosing for one LMWH cannot be extrapolated for use with
another. The action of LMWHs may be partially reversed (approximately 60%)
with protamine sulfate.
Numerous well-designed trials comparing SC LMWH with IV and SC
UFH for the treatment of DVT have been critically evaluated in several meta-
analyses. The more recent studies demonstrate a decrease in thrombotic
complications, bleeding, and mortality with LMWHs. LMWHs also are
associated with a decreased rate of HAAb formation and HIT (<2%) compared
with UFH (at least in prophylactic doses). However, patients with established
HIT should not subsequently receive LMWHs due to significant rates of cross
reactivity. A major benefit of LMWHs is the ability to treat patients with VTE
as outpatients. In a randomized study comparing IV UFH and the LMWH
nadroparin calcium, there was no significant difference in recurrent
thromboembolism (8.6% for UFH vs. 6.9% for LMWH) or major bleeding
complications (2.0% for UFH vs. 0.5% for LMWH). There was a 67%
reduction in mean days in the hospital for the LMWH group.
A patient with VTE should meet several criteria before receiving
outpatient LMWH therapy. First, the patient should not require hospitalization
for any associated conditions. The patient should not require monitoring of the
LMWH therapy (which is necessary in patients with severe renal insufficiency,
pediatric patients, obese patients, and pregnant patients). The patient should be
hemodynamically stable with a low suspicion of PE and have a low bleeding
risk. An established outpatient system to administer LMWH and warfarin, as
well as to monitor for recurrent VTE and bleeding complications, should be
present. In addition, the patient's symptoms of pain and edema should be
controllable at home.
Fondaparinux currently is the only synthetic pentasaccharide that has
been approved by the U.S. Food and Drug Administration (FDA) for the initial
treatment of DVT and PE. Its five-polysaccharide sequence binds and activates
antithrombin, causing specific inhibition of factor Xa. In two large
noninferiority trials, fondaparinux was compared with the LMWH enoxaparin
for the initial treatment of DVT and with IV UFH for the initial treatment of
PE.The rates of recurrent VTE ranged from 3.8 to 5%, with rates of major
bleeding of 2 to 2.6%, for all treatment arms. The drug is administered SC once
daily with a weight-based dosing protocol: 5 mg, 7.5 mg, or 10 mg for patients
weighing <50 kg, 50 to 100 kg, or >100 kg, respectively. The half-life of
fondaparinux is approximately 17 hours in patients with normal renal function.
There are rare case reports of fondaparinux-induced thrombocytopenia.
Direct-thrombin inhibitors (DTIs) include recombinant hirudin,
argatroban, and bivalirudin. These antithrombotic agents bind to thrombin,
inhibiting the conversion of fibrinogen to fibrin as well as thrombin-induced
platelet activation. These actions are independent of antithrombin. The direct
thrombin inhibitors should be reserved for (a) patients in whom there is a high
clinical suspicion or confirmation of HIT, and (b) patients who have a history
of HIT or test positive for heparin-associated antibodies. In patients with
established HIT, DTIs should be administered for at least 7 days, or until the
platelet count normalizes. Warfarin may then be introduced slowly,
overlapping therapy with a DTI for at least 5 days.41 Because bivalirudin is
approved primarily for patients with or without HIT who undergo percutaneous
coronary intervention, it is not discussed here in further detail.
Commercially available hirudin is manufactured using recombinant
DNA technology. It is indicated for the prophylaxis and treatment of patients
with HIT. In patients with normal renal function, recombinant hirudin is
administered in an IV bolus dose of 0.4 mg/kg, followed by a continuous IV
infusion of 0.15 mg/kg per hour. The half-life ranges from 30 to 60 minutes.
The aPTT is monitored, starting approximately 4 hours after initiation of
therapy, and dosage is adjusted to maintain an aPTT of 1.5 to 2.5 times the
laboratory normal value. The less commonly used ecarin clotting time is an
alternative method of monitoring. Because recombinant hirudin is eliminated
via renal excretion, significant dosage adjustments are required in patients with
renal insufficiency.
Argatroban is indicated for the prophylaxis and treatment of thrombosis
in HIT. It also is approved for patients with, or at risk for, HIT who undergo
percutaneous coronary intervention. Antithrombotic prophylaxis and therapy
are initiated with a continuous IV infusion of 2 g/kg per minute, without the
need for a bolus. The half-life ranges from 39 to 51 minutes, and the dosage is
adjusted to maintain an aPTT of 1.5 to 3 times normal. Large initial boluses
and higher rates of continuous infusion are reserved for patients with coronary
artery thrombosis and myocardial infarction. In these patients, therapy is
monitored using the activated clotting time. Argatroban is metabolized by the
liver, and the majority is excreted via the biliary tract. Significant dosage
adjustments are needed in patients with hepatic impairment. There is no
reversal agent for argatroban.
Vitamin K antagonists, which include warfarin and other coumarin
derivatives, are the mainstay of long-term antithrombotic therapy in patients
with VTE. Warfarin inhibits the -carboxylation of vitamin K–dependent
procoagulants (factors II, VII, IX, X) and anticoagulants (proteins C and S),
which results in the formation of less functional proteins. Warfarin usually
requires several days to achieve its full effect, because normal circulating
coagulation proteins must first undergo their normal degradation. Factors X
and II have the longest half-lives, in the range of 36 and 72 hours, respectively.
In addition, the steady-state concentration of warfarin is usually not reached for
4 to 5 days.
Warfarin therapy usually is monitored by measuring the INR, calculated
using the following equation:
where ISI is the international sensitivity index. The ISI describes the
strength of the thromboplastin that is added to activate the extrinsic coagulation
pathway. The therapeutic target INR range is usually 2.0 to 3.0, but the
response to warfarin is variable and depends on liver function, diet, age, and
concomitant medications. In patients receiving anticoagulation therapy without
concomitant thrombolysis or venous thrombectomy, the vitamin K antagonist
may be started on the same day as the initial parenteral anticoagulant, usually
at doses ranging from 5 to 10 mg. Smaller initial doses may be needed in older
and malnourished patients, in those with liver disease or congestive heart
failure, and in those who have recently undergone major surgery.
The recommended duration of warfarin antithrombotic therapy is
increasingly being stratified based on whether the DVT was provoked or
unprovoked, whether it was the first or a recurrent episode, where the DVT is
located, and whether malignancy is present. Current American College of
Chest Physicians (ACCP) recommendations for duration of warfarin therapy
are summarized in Table 24-3. In patients with proximal DVT, several
randomized clinical trials have demonstrated that shorter-term antithrombotic
therapy (4 to 6 weeks) is associated with a higher rate of recurrence than 3 to 6
months of anticoagulation. In these trials, most of the patients with transient
risk factors had a low rate of recurrent VTE; most of the recurrences were in
patients with continuing risk factors. These studies support the ACCP
recommendation that 3 months of anticoagulation is sufficient to prevent
recurrent VTE in patients whose DVT occurred around the time of a transient
risk factor (e.g., hospitalization, orthopedic or major general surgery).
Table 4. Summary of American College of Chest Physicians
Recommendations Regarding Duration of Long-Term Antithrombotic Therapy
for Deep Vein Thrombosis (DVT)
LMWH = low molecular weight heparin; VKA = vitamin K antagonist.
Source: Adapted with permission from Kearon C, Kahn SR, Agnelli G,
et al: Antithrombotic therapy for venous thromboembolic disease: American
College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th
edition). Chest 133:454S, 2008.
In contrast to patients with thrombosis related to transient risk factors,
patients with idiopathic VTE are much more likely to develop recurrence (rates
as high as 40% at 10 years). In this latter group of patients, numerous clinical
trials have compared 3 to 6 months of anticoagulation therapy with extended-
duration warfarin therapy, both at low intensity (INR of 1.5 to 2.0) and at
conventional intensity (INR of 2.0 to 3.0). In patients with idiopathic DVT,
extended-duration antithrombotic therapy is associated with a relative
reduction in the rate of recurrent VTE by 75% to >90%. In addition,
conventional-intensity warfarin reduces the risk even further compared with
low-intensity warfarin (0.7 events per 100 person-years vs. 1.9 events per 100
person-years), but the rate of bleeding complications is no different.
In patients with VTE in association with a hypercoagulable condition,
the optimal duration of anticoagulation therapy is influenced more by the
clinical circumstances at the time of the VTE (idiopathic vs. secondary) than
by the actual presence or absence of the more common thrombophilic
conditions. In patients with VTE related to malignancy, increasing evidence
suggests that longer-term therapy with LMWH (up to 6 months) is associated
with a lower VTE recurrence rate than treatment using conventional vitamin K
antagonists.
The primary complication of warfarin therapy is hemorrhage, and the
risk is related to the magnitude of INR prolongation. Depending on the INR
and the presence of bleeding, warfarin anticoagulation may be reversed by (a)
omitting or decreasing subsequent dosages, (b) administering oral or parenteral
vitamin K, or (c) administering fresh-frozen plasma, prothrombin complex
concentrate, or recombinant factor VIIa. Warfarin therapy rarely may be
associated with the development of skin necrosis and limb gangrene. These
conditions occur more commonly in women (4:1), and the most commonly
affected areas are the breast, buttocks, and thighs. This complication, which
usually occurs in the first days of therapy, is occasionally, but not exclusively,
associated with protein C or S deficiency and malignancy. Patients who require
continued anticoagulation may restart low-dose warfarin (2 mg) while
receiving concomitant therapeutic heparin. The warfarin dosage is then
gradually increased over a 1- to 2-week period.
Systemic and Catheter-Directed Thrombolysis
Patients with extensive proximal DVT may benefit from systemic
thrombolysis or catheter-directed thrombolysis, which can potentially reduce
acute symptoms more rapidly than anticoagulation alone. These techniques
also may decrease the development of postthrombotic syndrome. Several
thrombolysis preparations are available, including streptokinase, urokinase,
alteplase (recombinant tissue plasminogen activator), reteplase, and
tenecteplase. All these agents share the ability to convert plasminogen to
plasmin, which leads to the degradation of fibrin. They differ with regard to
their half-lives, their potential for inducing fibrinogenolysis (generalized lytic
state), their potential for antigenicity, and their FDA-approved indications for
use.
Streptokinase is purified from beta-hemolytic Streptococcus and is
approved for the treatment of acute myocardial infarction, PE, DVT, arterial
thromboembolism, and occluded central lines and arteriovenous shunts. It is
not specific for fibrin-bound plasminogen, however, and its use is limited by its
significant rates of antigenicity. Fevers and shivering occur in 1 to 4% of
patients. Urokinase is derived from human neonatal kidney cells, grown in
tissue culture. Currently, it is only approved for lysis of massive PE or PE
associated with unstable hemodynamics. Alteplase, reteplase, and tenecteplase
all are recombinant variants of tissue plasminogen activator. Alteplase is
indicated for the treatment of acute myocardial infarction, acute ischemic
stroke, and acute massive PE. However, it often is used for catheter-directed
thrombolysis of DVT. Reteplase and tenecteplase are indicated only for the
treatment of acute myocardial infarction.
Systemic thrombolysis was evaluated in numerous older prospective and
randomized clinical trials, and its efficacy was summarized in a recent
Cochrane Review. In 12 studies involving over 700 patients, systemic
thrombolysis was associated with significantly more clot lysis [relative risk
(RR) 0.24 to 0.37] and significantly less postthrombotic syndrome (RR 0.66).
However, venous function was not significantly improved. In addition, more
bleeding complications did occur (RR 1.73), but the incidence appears to have
decreased in later studies, probably due to improved patient selection.
In an effort to minimize bleeding complications and increase efficacy,
catheter-directed thrombolytic techniques have been developed for the
treatment of symptomatic DVT. With catheter-directed therapy, venous access
may be achieved through percutaneous catheterization of the ipsilateral
popliteal vein, retrograde catheterization through the contralateral femoral vein,
or retrograde cannulation from the internal jugular vein. Multi–side-hole
infusion catheters, with or without infusion wires, are used to deliver the lytic
agent directly into the thrombus.
The efficacy of catheter-directed urokinase for the treatment of
symptomatic lower extremity DVT has been reported in a large multicenter
registry. Two hundred twenty-one patients with iliofemoral DVT and 79
patients with femoropopliteal DVT were treated with catheter-directed
urokinase for a mean of 53 hours. Complete lysis was seen in 31% of the
limbs, 50 to 99% lysis in 52% of the limbs, and <50% lysis in 17%. Overall, 1-
year primary patency was 60%. Patency was higher in patients with iliofemoral
DVT than in patients with femoropopliteal DVT (64% vs. 47%, P <.01). In
addition, patients with acute symptoms (≤10 days) had a greater likelihood of
complete lysis (34%) than patients with chronic symptoms (>10 days; 19%).
Major bleeding occurred in 11%, but neurologic involvement and mortality
were rare (both 0.4%). Adjunctive stent placement to treat residual stenosis
and/or short segment occlusion was required in 103 limbs.
One small randomized trial and numerous other retrospective studies
have demonstrated similar rates of thrombolysis, with some also showing
improved valve preservation and quality of life. Combining thrombolysis with
percutaneous thrombus fragmentation and extraction has the added benefit of
decreasing the infusion time, the hospital stay, and the overall cost of
treatment. These studies, as well as the current ACCP guidelines, suggest that
catheter-directed thrombolysis (with adjunctive angioplasty, venous stenting,
and pharmacomechanical fragmentation and extraction) may be useful in
selected patients with extensive iliofemoral DVT. Patients should have a recent
onset of symptoms (<14 days), good functional status, decent life expectancy,
and low bleeding risk.
Inferior Vena Caval Filters
Since the introduction of the Kimray-Greenfield filter in the United
States in 1973, numerous vena caval filters have been developed. Although the
designs are variable, they all prevent pulmonary emboli, while allowing
continuation of venous blood flow through the IVC. Early filters were placed
surgically through the femoral vein. Currently, less invasive techniques allow
percutaneous filter placement through a femoral vein, internal jugular vein, or
small peripheral vein under fluoroscopic or ultrasound guidance.
Complications associated with IVC filter placement include insertion site
thrombosis, filter migration, erosion of the filter into the IVC wall, and IVC
thrombosis. The rate of fatal complications is <0.12%.
Placement of an IVC filter is indicated for patients who develop
recurrent DVT (significant propagation of the original thrombus or proximal
DVT at a new site) or PE despite adequate anticoagulation therapy and for
patients with pulmonary hypertension who experience recurrent PE. In patients
who receive IVC filters for these indications, therapeutic anticoagulation
should be continued. The duration of anticoagulation is determined by the
underlying VTE and not by the presence of the IVC filter itself. Practically
speaking, however, many patients who require an IVC filter for recurrent VTE
are the same ones who would benefit most from indefinite anticoagulation. The
other major indication for placement of an IVC filter is a contraindication to, or
complication of, anticoagulation therapy in the presence of an acute proximal
DVT. In patients who are not able to receive anticoagulants due to recent
surgery or trauma, the clinician should continually reassess if antithrombotic
agents may be started safely at a later date. Even some patients who develop
anticoagulation-associated bleeding complications may be able to restart
therapy at a lower intensity of anticoagulation later in the hospital course. As
before, the clinical circumstances surrounding the VTE should determine the
duration of anticoagulation.
Placement of permanent IVC filters has been evaluated as an adjunct to
routine anticoagulation in patients with proximal DVT. In this study, routine
IVC filter placement did not prolong early or late survival in patients with
proximal DVT but did decrease the rate of PE (hazard ratio, 0.22; 95%
confidence interval, 0.05 to 0.90). An increased rate of recurrent DVT was seen
in patients with IVC filters (hazard ratio, 1.87; 95% confidence interval, 1.10 to
3.20). More controversial indications for IVC filter placement include
prophylaxis against PE in patients receiving catheter-directed thrombolysis and
in high-risk patients without established DVT or PE.
Hypercoagulability States
Certain patients seem to have a tendency to clot spontaneously. So-
called hypercoagulability states were long thought to exist, but they were
difficult to document except on clinical grounds. Currently, however, these
clotting tendencies are better understood, thanks in large part to recognition of
the role of antithrombins. If an antithrombin deficiency exists and clotting goes
unchecked, activation of a clotting cascade could theoretically progress to
clotting throughout the entire vasculature. Another important development was
the recognition that deficiencies of certain natural clot-removing substances in
the blood may lead to a clinical thrombotic tendency. Both types of deficiency
can be either acquired or congenital.
Screening
When the etiology of a clotting episode is unclear, the family history
should be reviewed for evidence of a congenital disorder. Even if the history is
negative, the patient should be screened for both acquired and congenital
disorders (table 6).
Acquired Clotting Conditions
Screening for acquired clotting conditions [see Table 7] is based on the
history, physical examination, and laboratory assessment. The history should
include medications, diseases, and surgical procedures or other
injuries.Examination may disclose causes of hypercoagulability. Soft tissue
injury, for example, is a potent activator of the coagulation system. If the injury
is severe enough, it may be capable of causing a severe acquired coagulopathy.
The problem is usually obvious, but on occasion, detailed study may be
necessary to identify tissue damage or ischemic injury to bowel or extremities.
Hypovolemia”especially hypovolemic shock—markedly reduces clotting
time: blood from a patient in profound shock may clot instantaneously in the
syringe as it is being drawn. The breakdown of red cells in a hemolytic
transfusion reaction can cause clotting. Severe infection, especially from gram-
negative organisms, is a potent activator of coagulation.
Table 7. Etiology of Acquired Hypercoagulability
Of the acquired hypercoagulability syndromes, Trousseau syndrome is a
particularly important condition for surgeons to recognize because it occurs in
the surgical population (cancer patients) and must be treated with heparin (it is
unresponsive to warfarin). It occurs when an adenocarcinoma secretes a protein
recognized by the body as tissue factor, resulting in multiple episodes of
venous thromboembolism over time (migratory thrombophlebitis). Simple
depletion of vitamin K-dependent factors is ineffective. Patients should receive
therapeutic-dose heparin indefinitely or until the cancer is brought into
remission.
Laboratory screening may facilitate diagnosis. A complete blood count
may document the presence of polycythemia or leukemia. Thrombocythemia
may be a manifestation of a hypercoagulable disorder, and thrombocytopenia
after the administration of heparin raises the possibility of intravascular platelet
aggregation. A prolonged aPTT is suggestive of lupuslike anticoagulant.
Increased levels of D-dimers, fibrin degradation products (FDPs), or fibrin
monomers in the plasma may reflect low-grade intravascular coagulation.
Congenital Clotting Conditions
Congenital clotting tendencies can result from deficiencies in inhibitors
of thrombosis (antithrombin, proteins C and S, and possibly heparin cofactor
II), dysfibrinogenemias, or dysfibrinolysis [see Table 8]. Most congenital
clotting defects are transmitted as an autosomal dominant trait. A negative
family history does not preclude inherited thrombophilia, because the defects
have a low penetrance, and fresh mutations may have occurred.
Table 8. Congenital Clotting Disorders
INITIAL LABORATORY ASSESSMENT
Initial evaluation of a patient with an unexplained thrombotic episode
should be directed at the most common causes of hypercoagulability. Acquired
causes of clotting are more commonly seen by surgeons than congenital causes
and therefore must be excluded first. If a clotting disorder is determined to be
congenital, a laboratory workup should be undertaken. Several of the relevant
assays ”specifically, the functional assaysв”should be performed after the acute
phase of the disorder has passed. If they are performed during the acute phase,
levels of several antithrombotics (e.g., antithrombin and proteins C and S) will
be misleadingly low not because deficiencies of these substances caused the
underlying thrombotic process but because they were consumed in that
process.
Specific Causes Of Thrombotic Tendency
The most common congenital causes of accelerated clotting are
mutations of prothrombin (prothrombin G20210A mutation) and factor V
(Leiden mutation, or activated protein C resistance).The prevalence of each of
these ranges from 1% to 5% in the general population and may be much higher
in specific ethnic subpopulations.1 Each mutation may be identified
conclusively by means of polymerase chain reaction (PCR) techniques.
Detection of these mutations, unlike assays for antithrombin and proteins C and
S, is not dependent on the patient's current inflammatory state. It must be
remembered that the presence of one of these mutations, especially in the
heterozygous form, does not imply that it is the sole cause of thrombosis. In
many patients, a second precipitating factor must be present for the pathologic
genetic thrombotic potential to be manifested.
Prothrombin G20210A Mutation
The prothrombin G20210A mutation is known to involve a single amino
acid substitution in the prothrombin gene, but precisely how this increases the
risk of venous thromboembolism is unclear. The one apparent manifestation of
the mutation is a 15% to 40% increase in circulating prothrombin. Regardless
of the mechanism at work, patients who are at least heterozygous for the trait
are at two- to sixfold greater risk for venous thromboembolism than those
without the mutation.
Resistance to Activated Protein C (Factor V Leiden)
Resistance of human clotting factors to inactivation by activated protein
C is believed to be the most common inherited procoagulant disorder.114
Normally, activated factor V is degraded by activated protein C in the presence
of membrane surface as part of normal regulation of thrombosis. Activated
protein C resistance is caused by a single substitution mutation in the factor V
gene, which is passed in an autosomal dominant fashion. The mutant factor V
that results, termed factor V Leiden, is resistant to inactivation by activated
protein C and thus has a greater ability to activate thrombin and accelerate
clotting.
Two techniques are commonly used to diagnose this disorder. The first
is a functional assay that compares a standard aPTT to one performed in the
presence of exogenous activated protein C. If the latter aPTT does not exhibit
significant prolongation, the patient is probably resistant to activated protein C.
The results of this assay must be interpreted with caution if the patient is still in
the acute phase of the illness. The second technique, which is more reliable,
involves direct detection of the mutation via PCR analysis of DNA.
Antithrombin Deficiency
Antithrombin (once termed antithrombin III) is a 65 kd protein that
decelerates the coagulation system by inactivating activated
factors—primarily factor Xa and thrombin but also factors XII, XI, and IX.
Antithrombin therefore acts as a scavenger of activated clotting factors. Its
activity is enhanced 100-fold by the presence of heparans on the endothelial
surface and 1,000-fold by administration of exogenous heparin.
Congenital antithrombin deficiency occurs in approximately 0.01% to
0.05% of the general population and 2% to 4% of patients with venous
thrombosis. The trait is passed on as an autosomal dominant trait, with the
heterozygous genotype being incompatible with life. Antithrombin-deficient
patients are at increased risk for thromboembolism when their antithrombin
activity falls below 70% of normal.
Patients with congenital antithrombin deficiency frequently present after
a stressful event. They usually have DVT but sometimes have PE. If
anticoagulation is not contraindicated, the treatment of choice is heparin at a
dosage sufficient to raise the aPTT to the desired level, followed by warfarin. If
anticoagulation is contraindicated (as it is during the peripartum period),
antithrombin concentrate should be given to raise the antithrombin activity to
80% to 120% of normal during the period when anticoagulants cannot be
given.
Acquired antithrombin deficiency is a well-recognized entity. In most
patients undergoing severe systemic stress, antithrombin levels fall below
normal. Patients with classic risk factors for venous thromboembolism tend to
have the lowest levels.
Protein C and Protein S Deficiency
Protein C is a 62 kd glycoprotein with a half-life of 6 hours. Because it is
vitamin K dependent, a deficiency will develop in the absence of vitamin K.
Acquired protein C deficiency is seen in liver disease, malignancy, infection,
the postoperative state, and disseminated intravascular coagulation. Protein C
deficiency occurs in approximately 4% to 5% of patients younger than 40 to 45
years who present with unexplained venous thrombosis. It is transmitted as an
autosomal dominant trait, and the family history is usually positive for a
clotting tendency. Protein C levels range from 70% to 164% of normal in
patients without a clotting tendency; levels below 70% of normal are
associated with a thrombotic tendency. The most appropriate tests for
screening are functional assays; there are cases of dysfunctional protein C
deficiency in which protein C antigen levels are normal but protein C activity
is low, and these would not be detected by the usual immunoassays.
Protein S is a vitamin K-dependent protein that acts as a cofactor for
activated protein C by enhancing protein C-induced inactivation of activated
factor V. The incidence of protein S deficiency is similar to that of protein C
deficiency. It is transmitted as a dominant trait, and the family history is often
positive for a thrombotic tendency.
Hyperhomocysteinemia
Although hyperhomocysteinemia is more commonly associated with
cardiac disease and arterial thrombosis, it may also be associated with an
increased incidence of venous thromboembolism. This association is not as
strong as those already discussed. Accordingly, anticoagulation of
asymptomatic patients with elevated homocysteine levels is not currently
recommended.
Dysfibrinogenemia
More than 100 qualitative abnormalities of fibrinogen
(dysfibrinogenemias) have been reported. Dysfibrinogenemias are inherited in
an autosomal dominant manner, with most patients being heterozygous. Most
patients with dysfibrinogenemia have either no clinical symptoms or symptoms
of a bleeding disorder; a minority (about 11%) have clinical features of a
recurrent thromboembolic disorder. Congenital dysfibrinogenemias associated
with thrombosis account for about 1% of cases of unexplained venous
thrombosis occurring in young people. The most commonly observed
functional defect in such dysfibrinogenemias is abnormal fibrin monomer
polymerization combined with resistance to fibrinolysis. Decreased binding of
plasminogen and increased resistance to lysis by plasmin have been noted.
In addition to a prolonged TT, patients who have dysfibrinogenemia
associated with thromboembolism may have a prolonged INR. The diagnosis is
confirmed if the reptilase time is also prolonged. Measured with clotting
techniques, fibrinogen levels may be slightly or moderately low; measured
immunologically, levels may be normal or even increased.
Dysfibrinolysis
Fibrinolysis can be impaired by inherited deficiencies of plasminogen,
defective release of t-PA from the vascular endothelium, and high plasma
levels of regulatory proteins (e.g., t-PA inhibitors). In addition, factor XII
(contact factor) deficiency may induce failure of fibrinolysis activation.
Inherited plasminogen deficiency is probably only rarely responsible for
unexplained DVT in young patients. It is transmitted as an autosomal dominant
trait. In heterozygous persons with a thrombotic tendency, plasminogen
activity is about one half normal (3.9 to 8.4 Вµmol/ml). The euglobulin clot
lysis time is prolonged. Functional assays should be carried out, and there
should be full transformation of plasminogen into plasmin activators.
The important role of t-PA inhibitors I and II in the regulation of
fibrinolysis is well defined.In normal plasma, t-PA inhibitor I is the primary
inhibitor for both t-PA and urokinase. Release of t-PA inhibitor I by platelets
results in locally increased concentrations where platelets accumulate. The
ensuing local inhibition of fibrinolysis may help stabilize the hemostatic plug.
t-PA inhibitor II is present in and secreted by monocytes and macrophages.
Factor XII deficiency is a rare cause of impaired fibrinolysis. Initial
contact activation of factor XII not only results in activation of the clotting
cascade and of the inflammatory response but also leads to plasmin generation.
This intrinsic activation of fibrinolysis requires factor XII, prekallikrein, and
high-molecular-weight kininogen. Patients with factor XII deficiencies can be
identified by a prolonged aPTT in the absence of clinical bleeding.
Operative Venous Thrombectomy
In patients with acute iliofemoral DVT, surgical therapy is generally
reserved for patients who worsen with anticoagulation therapy and those with
phlegmasia cerulea dolens and impending venous gangrene. If the patient has
phlegmasia cerulea dolens, a fasciotomy of the calf compartments is first
performed. In iliofemoral DVT, a longitudinal venotomy is made in the
common femoral vein and a venous balloon embolectomy catheter is passed
through the thrombus into the IVC and pulled back several times until no
further thrombus can be extracted. The distal thrombus in the leg is removed by
manual pressure beginning in the foot. This is accomplished by application of a
tight rubber elastic wrap beginning at the foot and extending to the thigh. If the
thrombus in the femoral vein is old and cannot be extracted, the vein is ligated.
For a thrombus that extends into the IVC, the IVC is exposed transperitoneally
and the IVC is controlled below the renal veins. The IVC is opened and the
thrombus is removed by gentle massage. An intraoperative completion
venogram is obtained to determine if any residual thrombus or stenosis is
present. If a residual iliac vein stenosis is present, intraoperative angioplasty
and stenting can be performed. In most cases, an arteriovenous fistula is then
created by anastomosing the great saphenous vein (GSV) end to side with the
superficial femoral artery in an effort to maintain patency of the
thrombectomized iliofemoral venous segment. Heparin is administered
postoperatively for several days. Warfarin anticoagulation is maintained for at
least 6 months after thrombectomy. Complications of iliofemoral
thrombectomy include PE in up to 20% of patients and death in <1% of
patients.
One study followed 77 limbs for a mean of 8.5 years after thrombectomy
for acute iliofemoral DVT. In limbs with successful thrombectomies, valvular
competence in the thrombectomized venous segment was 80% at 5 years and
56% at 10 years. More than 90% of patients had minimal or no symptoms of
postthrombotic syndrome. There were 12 (16%) early thrombectomy failures.
Patients were required to wear compression stockings for at least 1 year after
thrombectomy.
Survival rates for surgical pulmonary embolectomy have improved over
the past 20 years with the addition of cardiopulmonary bypass. Emergency
pulmonary embolectomy for acute PE is rarely indicated. Patients with
preterminal massive PE (Fig. 5) for whom thrombolysis has failed or who have
contraindications to thrombolytics may be candidates for this procedure. Open
pulmonary artery embolectomy is performed through a posterolateral
thoracotomy with direct visualization of the pulmonary arteries. Mortality rates
range between 20 and 40%.
Fig. 5. Autopsy specimen showing a massive pulmonary embolism.
Percutaneous catheter-based techniques for removal of a PE involve
mechanical thrombus fragmentation or embolectomy using suction devices.
Mechanical clot fragmentation is followed by catheter-directed thrombolysis.
Results of catheter-based fragmentation are based on small case series. In a
study in which a fragmentation device was used in 10 patients with acute
massive PE, fragmentation was successful in 7 patients with a mortality rate of
20%.65 Transvenous catheter pulmonary suction embolectomy has also been
performed for acute massive PE with a reported 76% successful extraction rate
and a 30-day survival of 70%.66
Prophylaxis
Patients who undergo major general surgical, gynecologic, urologic, and
neurosurgical procedures without thromboprophylaxis have a significant
incidence of perioperative DVT (15 to 40%). The incidence is even higher with
major trauma (40 to 80%), hip and knee replacement surgery (40 to 60%), and
spinal cord injury (60 to 80%). The goal of prophylaxis is to reduce the
mortality and morbidity associated with VTE. The first manifestation of VTE
may be a life-threatening PE (Fig. 6), and as indicated earlier, clinical
evaluation to detect DVT before PE is unreliable.
Fig. 6. Pulmonary angiogram showing a pulmonary embolism (arrow).
Effective methods of VTE prophylaxis involve the use of one or more
pharmacologic or mechanical modalities. Currently available pharmacologic
agents include low-dose UFH, LMWH, synthetic pentasaccharides, and
vitamin K antagonists. Mechanical methods include intermittent pneumatic
compression (IPC) and graduated compression stockings. Aspirin therapy
alone is not adequate for DVT prophylaxis. These prophylaxis methods vary
with regard to their efficacy, and the 2008 ACCP Clinical Practice Guidelines
stratify their uses according to the patient's level of risk (Table 6).
Table 6. Thromboembolism Risk and Recommended Thromboprophylaxis in
Surgical Patients
Complications
Complications after venous thrombosis can vary from life threatening to
chronically debilitating. Pulmonary embolism develops as venous thrombi
break off from their location of origin and travel through the right heart and
into the pulmonary artery, causing a ventilation perfusion defect and cardiac
strain. PE occurs in approximately 10% of patients with acute deep venous
thrombosis and can cause up to 10% of in hospital deaths.60,61 However, most
patients (up to 75%) are asymptomatic. Traditionally, proximal venous
thrombosis are thought to be at highest risk for causing pulmonary emboli;
however, the single largest autopsy series ever performed to specifically to
look for the source of fatal PE was performed by Havig in 1977, who found
that one third of the fatal emboli arose directly from the calf veins.6
PHLEGMASIA ALBA AND CERULEA DOLENS
More than 600,000 cases of venous thromboembolism are estimated to
occur each year in the United States. Pulmonary embolism (PE) complicates
approximately 50% of cases of untreated proximal deep venous thrombosis
(DVT) and contributes to 10-15% of all hospital deaths. Less frequent
manifestations of venous thrombosis include phlegmasia alba dolens,
phlegmasia cerulea dolens (PCD), and venous gangrene. These form a clinical
spectrum of the same disorder. All 3 manifestations result from acute massive
venous thrombosis and obstruction of the venous drainage of an extremity
History of the Procedure
In the 16th century, Fabricius Hildanus first described the clinical
syndrome of what is currently called PCD. In 1938, Gregoire made an
outstanding description of the condition and used the term PCD to differentiate
ischemia-associated massive venous thrombosis from phlegmasia alba dolens,
which describes fulminant venous thrombosis without ischemia.1 The exact
incidence of these disorders is not well reported.
In 1939, Leriche and Geissendorfer performed the first thrombectomy
for cases of PCD.2 Historically, surgical thrombectomy has been the procedure
of choice for PCD refractory to medical therapy and in patients with
established or impeding gangrene.
Frequency
More than 600,000 cases of venous thromboembolism are estimated to
occur annually in the United States. Phlegmasia alba dolens, PCD, and venous
gangrene occur at any age but are more common during the fifth and sixth
decades of life. Incidence is higher in females than in males.
Etiology
The main causative factor in phlegmasia is massive thrombosis and
occlusion of major venous channels with significantly compromised venous
outflow. Multiple triggering factors exist. Malignancy is the most common
triggering factor and is present in approximately 20-40% of patients with PCD.
Other associated risk factors include hypercoagulable syndrome, surgery,
trauma, ulcerative colitis, gastroenteritis, heart failure, mitral valve stenosis,
vena caval filter insertion, and May-Thurner syndrome (compression of the left
iliac vein by the right iliac artery). Pregnancy has often been associated with
phlegmasia alba dolens, especially during the third trimester when the uterus is
large enough to compress the left common iliac vein against the pelvic rim (ie,
milk leg syndrome). Finally, 10% of patients with phlegmasia have no apparent
risk factors.
Pathophysiology
In phlegmasia alba dolens, the thrombosis involves only major deep
venous channels of the extremity, therefore sparing collateral veins. The
venous drainage is decreased but still present; the lack of venous congestion
differentiates this entity from PCD.
In PCD, the thrombosis extends to collateral veins, resulting in venous
congestions with massive fluid sequestration and more significant edema.
Without established gangrene, these phases are reversible if proper measures
are taken.
Of PCD cases, 40-60% also have capillary involvement, which results in
irreversible venous gangrene that involves the skin, subcutaneous tissue, or
muscle. Under these conditions, the hydrostatic pressure in arterial and venous
capillaries exceeds the oncotic pressure, causing fluid sequestration in the
interstitium. Venous pressure may increase rapidly, as much as 16- to 17-fold
within 6 hours. Fluid sequestration may reach 6-10 L in the affected extremity
within days. Circulatory shock, which is present in about one third of patients,
and arterial insufficiency may ensue.
The exact mechanism for the compromised arterial circulation is
debatable but may involve shock, increased venous outflow resistance, and
collapse of arterioles due to increased interstitial pressure. Vasospasm of the
resistance vessels has also been hypothesized but has never been observed
experimentally or radiographically.
Presentation
In the lower extremities, left-sided involvement is more common by a
3:1 or 4:1 ratio. Involvement of upper extremities occurs in less than 5% of
patients with PCD. Manifestations may be gradual or fulminant. Of PCD cases,
50-60% are preceded by phlegmasia alba dolens, with symptoms of edema,
pain, and blanching (alba) without cyanosis. The blanching, which previously
was thought to be caused by arterial vasospasm, is caused by subcutaneous
edema, without venous congestion.
Patients with PCD present with the clinical triad of edema, agonizing
pain, and cyanosis. Massive fluid sequestration may lead to bleb and bullae
formation. The pain is constant, usually starting at the femoral triangle and then
progressing to the entire extremity. Cyanosis is the pathognomonic finding of
PCD, progressing from distal to proximal areas.
When venous gangrene occurs, it has a similar distribution with the
cyanosis. Arterial pulses may be present when the venous gangrene is
superficial; however, gangrene that involves the muscular compartment may
result in increased compartment pressures and a pulse deficit. In addition, the
pulses may be difficult to appreciate because of the significant edema. Various
degrees of shock may be present because of significant fluid loss.
Indications
Historically, surgical thrombectomy has been the procedure of choice for
phlegmasia cerulea dolens (PCD) refractory to medical therapy and for patients
with established or impeding gangrene. The standard treatment of phlegmasia
and venous gangrene is evolving, but most clinicians attempt endovascular
approaches to thrombolysis, if possible.
Relevant Anatomy
The main causative factor in phlegmasia is massive deep venous
thrombosis (DVT) and occlusion of major venous channels with significantly
compromised venous outflow. In phlegmasia alba dolens, the thrombosis
involves only major deep venous channels of the extremity, therefore sparing
collateral veins and preserving some venous outflow from the limb. In
phlegmasia cerulea dolens (PCD), the thrombosis extends to collateral veins,
with complete obstruction of venous outflow, resulting in massive venous
congestion and fluid sequestration and more significant edema.
Contraindications
For phlegmasia alba dolens and mild nongangrenous forms of
phlegmasia cerulea dolens (PCD), conservative medical treatment, rather than
surgical thrombectomy, should be the initial course of therapy. Thrombolysis
may be initiated if conservative management does not elicit a response and if
the patient has no contraindication to lytic therapy.
Surgical thrombectomy cannot open the small venules that are affected
in venous gangrene, and it does not prevent valvular incompetence or
postphlebitic syndrome. For these reasons, thrombolysis seems to be an
attractive alternative in the management of PCD and venous gangrene.
Imaging Studies
The diagnoses of phlegmasia alba dolens, phlegmasia cerulea dolens
(PCD), and venous gangrene are established mainly via clinical criteria with
the assistance of contrast venography and duplex ultrasonography.
Although venography is considered the criterion standard for diagnosis,
technical difficulties may be encountered in as many as 20-25% of patients.
Attempts to perform ascending venography when extensive deep system
thrombosis is present may result in nonvisualization of the deep system and a
nondiagnostic study result. In these cases, descending venography via the
contralateral femoral vein or via the upper extremity veins may provide more
information about the iliocaval system and proximal extent of the thrombus.
Recent improvements in ultrasonography have made this modality a
more reliable and accurate way to assess for proximal deep venous thrombosis
(DVT) with less morbidity. In addition, duplex imaging may be repeated as
needed to monitor for thrombus propagation. Ultrasonography can also be
performed at the bedside in patients who are critically ill or unstable.
Ultrasonography is often used to guide the initial venipuncture for diagnostic
venography and initiation of thrombolytic therapy.
Magnetic resonance venography (MRV) is an evolving modality of
diagnostic imaging. Its principal advantage is its ability to easily reveal the
proximal and distal extent of thrombus with a single study. Its principal
disadvantage is the inability to image acutely ill patients with hemodynamic
instability or motion artifacts due to pain.
Medical Therapy
The standard treatment of phlegmasia and venous gangrene is still
evolving. The optimal therapeutic modality remains under debate. So far, the
results of treatment have been moderately successful. For phlegmasia alba
dolens and mild nongangrenous forms of phlegmasia cerulea dolens (PCD),
conservative medical treatment, such as steep limb elevation, anticoagulation
with intravenous administration of heparin, and fluid resuscitation, should be
the initial course of therapy.
Initiate heparin administration with an intravenous bolus of 80-100
U/kg, followed by a continuous infusion of 15-18 U/kg/h. Frequently monitor
the activated partial thromboplastin time (aPTT), with a goal range of 2-2.5
times the laboratory reference range. Frequently monitor platelet counts to
allow the early detection of heparin-induced thrombocytopenia.
The purpose of rapid heparin anticoagulation is to decrease the risk of
proximal clot propagation or thromboembolism. Heparin does not directly
affect limb swelling. The best nonsurgical method to decrease edema is steep
leg elevation.
Recent studies have demonstrated that low molecular weight heparins
are safe and effective in the treatment of proximal deep venous thrombosis
(DVT) and pulmonary embolism (PE); however, no good evidence supports
the use of these newer agents in phlegmasia and venous gangrene.
If heparin-induced thrombocytopenia occurs, immediately discontinue
the use of heparin and replace it with an alternative anticoagulant. Danaparoid
and lepirudin are effective alternative agents; however, heparin-associated
antibodies exhibit a 10-19% cross-reactivity with danaparoid. Thus, perform
cross-reactivity testing before the initiation of danaparoid in patients with these
antibodies. Lepirudin is a direct thrombin inhibitor that does not demonstrate
any cross-reactivity. The recommended dosage of lepirudin in patients without
renal failure is 0.4 mg/kg as an intravenous bolus followed by a continuous
infusion of 0.15 mg/kg/h. Use aPTT to monitor therapy, with a goal range of 2-
2.5 times the laboratory reference range.
Continue long-term anticoagulation with warfarin (or other coumarin
derivatives) for at least 6 months. Life-long anticoagulation is recommended in
patients with hypercoagulable states.
Patients should wear long-term prescription compression stockings with
at least 30-40 mm Hg of graded pressure. Many physicians erroneously have
the patient fitted for a prescription stocking while the limb is still severely
edematous. Instead, the patient may use nonprescription stockings or an elastic
bandage, in combination with elevation, to minimize edema prior to being fit
for a prescription stocking.
Surgical Therapy
Surgical thrombectomy performed through a femoral venotomy allows
instant decompression of the venous hypertension. An intraoperative
Trendelenburg position may be used to decrease the risk of PE.
Transabdominal cavotomy and thrombectomy is an alternative approach that
permits better control of the cava above the thrombus and, thus, provides
protection against PE. Procedures that have been performed in an effort to
decrease the rethrombosis rate include cross-pubic vein-to-vein reconstruction
with polytetrafluoroethylene (PTFE) or the greater saphenous vein (GSV) or
the creation of an arteriovenous fistula between the femoral artery and the
GSV. These adjuvant procedures may be especially beneficial in cases that
involve proximal iliofemoral vein constriction, damage, or external
compression.
Concomitant administration of heparin and long-term anticoagulation are
mandatory. Regardless, thrombectomy in patients with PCD is associated with
a high rate of rethrombosis. Surgical thrombectomy cannot open the small
venules that are affected in venous gangrene, and it does not prevent valvular
incompetence or postphlebitic syndrome. The incidence of postphlebitic
syndrome may be as high as 94% among survivors.
For the above reasons, thrombolysis seems to be an attractive alternative
in the management of PCD and venous gangrene. In 1970, Paquet was the first
to use thrombolysis for the treatment of PCD.4 Some authors propose catheter-
directed thrombolysis directly into the vein with high doses of urokinase or
tissue plasminogen activator (t-PA). Other authors support the method of intra-
arterial low-dose thrombolysis via the common femoral artery, reasoning that
the arterial route delivers the thrombolytic agent to the arterial capillaries and,
subsequently, to the venules. The intra-arterial approach seems to be more
effective in cases with venous gangrene. Systemic thrombolysis has also been
used. Many authors have strongly recommended the insertion of a vena caval
filter prior to initiation of thrombolytic therapy. Combine thrombolysis with
heparin administration and long-term oral anticoagulation.
Fasciotomy alone or in conjunction with thrombectomy or thrombolysis
reduces compartmental pressures; however, it significantly increases morbidity
because of the prolonged wound healing and the risk of infection.
Finally, if all efforts fail and amputation is required, delay the procedure
as long as possible. Take all precautions to reduce edema, allow venous
channels to recanalize, and allow necrotic tissue to demarcate.
Preoperative Details
Patients who require emergent venous thrombectomy should have
heparin continued throughout the perioperative period. Banked red blood cells
should be available. The proximal extent of the thrombosis must be defined
using a combination of venous ultrasonography for infrainguinal veins and
retrograde venography of the iliac veins and inferior vena cava using a jugular
or contralateral femoral approach. If the thrombosis extends into the iliac veins
and vena cava, preparations should be made to control the cava via a right
retroperitoneal incision. A high-quality fluoroscopy unit should be available to
aid in catheter manipulation and completion venography.
Intraoperative Details
Operative exposure depends on the proximal and distal extent of the
thrombus. The involved veins should be controlled proximally and distally
prior to venotomy.
Iliac venous thrombectomy should be performed with large-bore
thrombectomy balloon catheters (as large as 10F). Extension of the thrombus
into the inferior vena cava may require proximal control of the cava. The
anesthesiologist should apply positive airway pressure while the thrombus is
being extracted from the iliocaval system. Digital subtraction venography
should be performed to ascertain completeness of the thrombectomy.
Infrainguinal extraction of the thrombus is aided by the intraoperative
placement of an Esmarch bandage from foot to thigh. Thrombectomy balloon
catheters (3F and 4F) are passed through the femoral veins and, possibly, the
posterior tibial veins as well.
Thrombolytic agents may be administered intraoperatively through the
posterior tibial veins. t-PA is the most commonly used agent and may be
administered intraoperatively.
After the thrombectomy is performed, an arteriovenous fistula should be
constructed, connecting the proximal greater saphenous vein or one of its larger
tributaries to the superficial femoral artery in an end-to-side fashion.
Completion venography should be performed to exclude the presence of
residual thrombus or proximal venous stenosis. If one is present, balloon
angioplasty with or without stent placement may be necessary.
When percutaneous endovascular therapy is performed as a single
treatment modality, and many centers are now reporting this as a first-line
therapy, the popliteal veins are usually accessed with duplex ultrasonography
as an aid. Prone positioning is rarely necessary. If extensive thrombus is
present, access via the posterior tibial vein is usually successful. A 6-F sheath
is usually adequate. An infusion wire is passed through the thrombus just to its
proximal extent, often into the vena cava. Infusion is usually performed in the
most proximal segment first, usually in the iliac veins.
A common protocol is to infuse tPA (1 mg/hr) through the infusion wire
as well as through the sheath for 24 hours, then to change the sheath perfusion
to lower dose heparin after 24 hours. The infusion is then performed in the
superficial femoral and popliteal vein segments. Clinical improvement is often
noted with clearing of the profunda venous segment. Performance of
simultaneous percutaneous mechanical thrombectomy is controversial and may
not give better results than postprocedure balloon dilation.
Postoperative Details
Intravenous heparin is administered throughout the postoperative period
to prolong the aPTT (2-2.5 times the reference range for aPTT). This is
continued until the patient is adequately anticoagulated with warfarin or one of
the coumarin derivatives (international normalized ratio [INR] range of 2.0-
3.0). The optimal duration of oral anticoagulation is not established.
A sequential compression device is also placed, or, at a minimum, an ace
bandage is placed for control of edema. Once the edema is at its minimum, the
patient may be fitted for a thigh-length compression stocking. Ambulation is
encouraged, if the patient is able.
Complications
The incidence of postphlebitic syndrome may be as high as 94% among
survivors. Pulmonary embolism is common, and prophylactic placement of an
inferior vena cava filter is recommended in most cases. Thrombectomy in
patients with phlegmasia cerulea dolens (PCD) is associated with a high rate of
rethrombosis. Amputation and death are common.
Outcome and Prognosis
Despite all of the therapeutic modalities described above, phlegmasia
cerulea dolens (PCD) and venous gangrene still remain life-threatening and
limb-threatening conditions with overall mortality rates of 20-40%. Pulmonary
embolism (PE) is responsible for 30% of the deaths reported from PCD.
Overall, amputation rates of 12-50% have been reported among survivors. The
postphlebitic sequelae are apparent in 60-94% of survivors. Strict adherence to
the use of long-term compression stockings helps to control chronic edema.
Future and Controversies
Phlegmasia alba dolens, phlegmasia cerulea dolens (PCD), and venous
gangrene still remain a challenge to the vascular surgeon. Treatment modalities
continue to evolve. Endovascular management may offer hope of successful
and more effective management, with less morbidity, than traditional surgery.
The role of mechanical thrombectomy, compared with thrombolysis, is unclear.
Small numbers of patients and lack of randomized trials preclude clear
recommendations.
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