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.