1. © 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
6 VASCULAR SYSTEM 6 VENOUS THROMBOEMBOLISM — 1
6 VENOUS THROMBOEMBOLISM
John T. Owings, M.D., F.A.C.S.
Deep vein thrombosis (DVT) (deep thrombophlebitis) occurs in tionated heparin subcutaneously as prophylaxis against DVT fared
approximately 2.5 million people in the United States each year.1 no better than those treated with placebo.15 Subsequent work has
The incidence of DVT in surgical patients varies widely depend- shown that effective DVT prophylaxis can be achieved in this pop-
ing on the method of study: in eight series, the incidence of DVT ulation by using the LMWH enoxaparin.
verified by venography or autopsy ranged from 18% to 90% (aver-
COMPRESSION TECHNIQUES
age, 42%).2
Reviews suggest that pulmonary embolism (PE) occurs in Elastic stockings have long been used as prophylaxis for throm-
approximately 700,000 people in the United States each year, of boembolism. Most commercial stockings, however, do not fit ade-
whom about 200,000 will die as a result.3,4 In the absence of pro- quately or provide adequate compression and thus probably offer
phylaxis, fatal PE occurs in 4% to 7% of hip surgery patients and little or no benefit.4 Low-molecular-weight dextran, which lowers
in 0.1% to 0.8% of general surgery patients.3,5 In 40% to 60% of blood viscosity and inhibits platelet aggregation, may be helpful in
patients who die of PE, the diagnosis is not made clinically. PE may certain instances, but data showing greater efficacy as compared
be responsible for as many as 5% of postoperative deaths, and it with current techniques are lacking.12
may occur in as many as 25% of patients admitted to the hospi- Pneumatic devices that compress the venous plexuses of the
tal.6,7 Pulmonary infarction occurs in about 10% of PE patients.8 lower extremities are popular because they do not require antico-
Significant PE is believed, as a rule, to arise from thrombosis of agulation and thus are not associated with increased bleeding risk.
the deep veins of the thigh and the pelvis. Most studies of throm- Intermittent pneumatic compression is capable of intermittently
boembolism use DVT as a surrogate end point for PE. The only increasing venous flow velocities in the femoral and pelvic veins.16
major study of thromboembolism prophylaxis to date that suc- It has been argued that some of the benefit might derive from the
cessfully used death from PE as an end point required more than known tourniquet effect of enhancing fibrinolytic activity, attrib-
5,000 patients to reach statistical significance.9 Accordingly, the uted both to an increase in tissue plasminogen activator (t-PA) and
National Institutes of Health has concluded that using DVT as a to a decrease in plasminogen activator inhibitor (PAI). This argu-
surrogate for PE is a valid approach.10 ment seems to be valid for up to 24 hours of continuous use,17 but
The optimal treatment of thromboembolism is prevention, par- after that point, the effect is exhausted.16 Intermittent pneumatic
ticularly in persons at high risk [see Table 1].11,12 Risk factors for compression is a safe, albeit somewhat uncomfortable, method of
venous thromboembolism include increased age (≥ 30 years in preventing clots in patients immobilized for prolonged periods. It
some studies),13 major trauma (Injury Severity Score of 15 or is particularly useful in critical care units, where other forms of
greater or the presence of a pelvic or lower-extremity long bone prophylaxis are inapplicable or contraindicated.11
fracture), morbid obesity, major operation, prolonged immobility, Several different pneumatic compression devices have been
thrombophilia, and previous thromboembolism. developed. The first to gain widespread acceptance was the full-
length (calf and thigh) sequential compression stocking, which
proved effective in a number of settings, including trauma.18
Prophylaxis against Thromboembolism
In evaluating the effectiveness of the methods used to prevent
thromboembolic complications, it is important to consider the spe- Table 1—Risk Factors for the Development
cific population of patients studied. Within the surgical patient
population, there is one reasonable division: between (1) patients of Venous Thromboembolism
who have an ongoing pathologic process that affects coagulation Hypercoagulability
when first encountered and (2) elective patients for whom the sur- Congenital hypercoagulability
gical insult is the inciting risk factor. For the first group, the typi- Malignancy
cal patient is the polytrauma patient; for the second, the patient Oral contraceptives
undergoing elective hip or knee replacement. Polycythemia
The key distinction between these two groups lies in whether Thrombocytosis
prophylaxis can be given before the inciting insult. Several tech-
Venous stasis
niques for prophylaxis of thromboembolism that are effective when
Immobility
employed before the inciting event are completely ineffective if
Varicose veins
employed afterward. This point can be illustrated by comparing
Advanced age
elective colorectal surgery patients with trauma patients. In a 2001
Congestive heart failure
study, elective colorectal surgery patients who were given their first
Obesity
dose of unfractionated heparin before operation and then were
given additional doses of unfractionated heparin (5,000 units sub- Endothelial injury
cutaneously three times daily) after operation were as well protect- Trauma
ed against DVT as comparable patients receiving low-molecular- Recent surgery
weight heparin (LMWH) and were at lower risk for bleeding.14 In Severe infection
a 1996 study, however, trauma patients who were given unfrac-

2. © 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
6 VASCULAR SYSTEM 6 VENOUS THROMBOEMBOLISM — 2
Because some injured patients were unable to wear the device, var- heparin two or three times daily before, during, and after the oper-
ious modified compression devices were developed, including a ation substantially reduced thromboembolic complications with-
calf-only device and a foot pump designed to compress the plan- out increasing bleeding.5 This low-dose protocol has been criti-
tar venous plexus. Several studies have demonstrated that the var- cized as being insufficiently individualized for specific high-risk
ious compression devices are not all equally effective in preventing patients. Low-dose heparin acts by markedly augmenting the
thromboembolism. This is an important point because many of antithrombotic effect of antithrombin21; therefore, it may be inef-
the devices are marketed solely on the basis of compliance data fective if antithrombin levels are reduced, and higher doses may be
rather than efficacy data; those that are marketed without pub- more appropriate in such settings.
lished evidence of efficacy often use cost advantages to gain mar- Because of these pitfalls, an adjusted-dose technique was
ket share. devised in the mid-1980s.22 In this method, heparin is given
The effectiveness of pneumatic compression devices is based on (either subcutaneously or I.V.) in sufficient doses to elevate the
their ability to increase peak venous flow velocity in the large ves- activated partial thromboplastin time (aPTT) by 2 to 5 seconds,
sels of the thigh and the pelvis. Because some units create higher thereby compensating for depleted antithrombin levels in high-
peak flow velocities, it would be logical to assume that these units risk patients. This technique is superior to the low-dose method
would be more effective in reducing DVT. Support was lent to this for preventing venous thromboembolism,22 and for practical pur-
assumption by a 2000 study in which more than 300 patients poses, it should replace the latter as the standard prophylactic dos-
undergoing elective knee surgery were treated with different com- ing technique for unfractionated heparin.22,23
pression devices.19 Devices applying asymmetrical compression LMWH possesses the same antithrombin-potentiating penta-
(which results in higher peak venous flow velocity) were compared saccharide chain that unfractionated heparin does. Consequently,
with traditional compression devices, and calf-only devices were it is similarly ineffective if antithrombin levels are depleted. The
compared with calf-and-thigh devices. The two calf-and-thigh main advantage of LMWH over unfractionated heparin is that it
units studied proved superior to the calf-only unit, and the calf- has a more dependable half-life and bioavailability.Thus, it can be
and-thigh asymmetrical sequential compression device that gener- given without monitoring of drug effect or plasma heparin level.
ated higher peak flow velocities was superior to the traditional calf- Most of the clinical trials documenting the efficacy of LMWH
and-thigh device. Similar results were obtained in a 2004 study evaluated patients undergoing elective hip24,25 or knee operations.
that compared knee-high compression devices.20 A few, however, addressed other patient populations (e.g., trauma
It is therefore important to recognize that although compliance patients).15 In these studies, the incidence of DVT in patients
is a critical component of compression devices, differences in effi- receiving unmonitored LMWH therapy was generally lower than
cacy must be taken into account. Given the absence of efficacy that in patients receiving placebo24 or low-dose heparin.15,25
data for many of the compression devices now in use, great cau- LMWH therapy and adjusted-dose heparin therapy were of
tion should be exercised in considering whether these products roughly equal efficacy.
should be adopted, regardless of anticipated cost savings. In the light of these data, it appears that LMWH can be recom-
mended over low-dose unfractionated heparin in elective, emer-
PROPHYLACTIC ANTICOAGULATION
gency, and trauma patients.Whether it is superior to adjusted-dose
A major study of thromboembolic prophylaxis in hip surgery unfractionated heparin therapy remains uncertain, though it is
patients found that subcutaneous administration of 5,000 units of clearly simpler to manage.Where compliance with monitoring and
Manifestations of superficial thrombophlebitis (e.g., pain, slight
swelling over vein, erythema, some edema in adjacent tissues)
are present. (A palpable subcutaneous cord is pathognomonic.)
One limb is at least several centimeters There has been no invasion in or The vein has been invaded, or there are
larger than the other near the vein systemic manifestations of infection
Assume associated DVT and treat Assume sterile thrombophlebitis; Assume septic thrombophlebitis; initiate therapy.
accordingly [see Figures 2, 4, 5, and 6]. initiate therapy. Do not immobilize Remove and culture I.V. catheter.
patient. Administer aspirin (1 tablet/day) If there are no systemic signs of infection, treat
or dipyridamole (50 mg q.i.d.). as for sterile thrombophlebitis.
If systemic signs are present, give antibiotics
(antistaphylococcal agents if skin organism is
responsible).
If patient is a drug addict or has a contaminated
wound, obtain Gram stain and culture and initiate
specific antibiotic therapy.
Phlebitis persists Phlebitis resolves Patient is in toxic state or does
Figure 1 Shown is an algorithm not respond to treatment
for the management of superficial Interrupt vein above area of thrombosis,
thrombophlebitis. or strip and remove vein. Consider ligation or drainage of
vein. Consider heparin therapy.

3. © 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
6 VASCULAR SYSTEM 6 VENOUS THROMBOEMBOLISM — 3
dose-adjusting protocols is an issue, unmonitored LMWH therapy cellulitis and streptococcal lymphangitis. For both conditions,
may well be preferable. there should be a proximal source (e.g., an open wound). If there
Fondaparinux, a synthetic form of the specific pentasaccharide is overt limb swelling in a patient who appears to have superficial
that interacts with antithrombin to potentiate its effect, has been phlebitis, DVT should be assumed and appropriate treatment [see
approved by the Food and Drug Administration. This agent is Deep Vein Thrombosis, below] initiated.
smaller than the LMWHs and seems to have the same advantages Superficial thrombophlebitis is largely benign but is often over-
over these substances that they have over unfractionated heparin— treated out of fear that infection may be contributing to phlebitis.
namely, increased bioavailability, longer half-life, and a more con- It is therefore important to differentiate between sterile and septic
sistent effect. As the molecular weight of the antithrombin poten- superficial thrombophlebitis.
tiator decreases, the antithrombotic effect focuses more sharply on
STERILE
inhibiting factor X (as opposed to factors II, IX, XII, etc.).
Before fondaparinux is uniformly adopted for thromboem- If there is no invasion in or near the superficial vein involved,
bolism prophylaxis, the supporting evidence should be carefully sterile thrombophlebitis can be assumed with minimal risk of mis-
considered. The initial findings are quite promising. In a prospec- diagnosis. It is best treated simply by giving aspirin (one tablet
tive, randomized trial that included approximately 1,700 hip frac- daily) or dipyridamole (50 mg four times daily).
ture patients, fondaparinux was superior to enoxaparin with re- If superficial phlebitis of the saphenous vein extends to the
spect to the incidence of venographically identified DVT26; how- saphenofemoral junction, interruption of the vein may be appro-
ever, the enoxaparin dosage (40 mg once daily) was lower than the priate. The choice of treatment is between interrupting the vein
dosage shown to be effective in trauma patients by previous inves- above the area of palpable thrombosis and stripping the vein. The
tigators (30 mg twice daily).15 No significant difference in bleeding second alternative carries a higher morbidity but can be effective
rates was observed. In another trial, which included approximate- when there are associated varicosities. Stripping of the channels
ly 700 patients undergoing elective knee surgery, fondaparinux, above and below the phlebitic process as well as the phlebitic area
2.5 mg once daily, proved superior to enoxaparin, 30 mg twice itself removes the risk of extension and subsequent recurrence.
daily.27 In this study, the bleeding rate was significantly higher with Several authors have explored medical management of patients
fondaparinux. with above-the-knee superficial thrombophlebitis, using an ap-
Ultimately, with regard to prophylactic anticoagulation, simple proach similar to that used for DVT. Therapeutic-dose heparin
logic applies. The more potent the anticoagulant used, the lower (unfractionated heparin or LMWH) is given initially, followed by
the risk of PE and the higher the risk of serious bleeding. It is there- long-term oral anticoagulation.The incidence of extension may be
fore appropriate to base one’s selection of an anticoagulant regi- higher than with surgical management, but the operative risks are
men on a careful weighing of the expected benefits against the avoided.30
anticipated bleeding risk.
SEPTIC
In some patients (e.g., those undergoing major gynecologic pro-
cedures), warfarin may be used instead of heparin.12,28 A low-dose If there are systemic manifestations of severe infection, septic
regimen (as little as 1 mg/day) may offer some prophylactic bene- thrombophlebitis is likely. In addition, the induration, tenderness,
fit.28 Warfarin anticoagulation must be started 3 or 4 days before and redness over and along the course of the vein are usually more
the surgical procedure. The international normalized ratio (INR) extensive than with sterile thrombophlebitis.
[see General Principles of Anticoagulation and Lytic Therapy, Septic thrombophlebitis associated with an I.V. catheter can be
below] should be kept below 3.0 to prevent excessive bleeding. detected by removing the device and culturing the tip. Antibiotics
Warfarin is not as easy to regulate as heparin is. In addition, the should be administered. In most cases, antistaphylococcal drugs
therapeutic effect takes several days to be realized and several more are appropriate. If the patient is a drug addict or phlebitis is asso-
days to wear off. Frequently, postoperative patients are unable to ciated with a contaminated wound, blood samples for culture and
resume a normal stable diet. Because warfarin interferes with the Gram staining should be obtained by aspirating the vein. Specific
clotting factors in the vitamin K pathway, dosage management in antibiotic therapy directed toward the organisms identified should
the immediate postoperative period is challenging. Because the risk then be instituted.
of intracranial bleeding is greater with warfarin than with heparin, If the patient is in a toxic state from presumed septic throm-
great care should be taken in using warfarin for immediate periop- bophlebitis in a subcutaneous vein or is not responding to treat-
erative prophylaxis. ment, it may be appropriate to ligate the vein, to drain it by cutting
down on the phlebitic process with the patient under local or gen-
PROPHYLACTIC VENA CAVAL INTERRUPTION
eral anesthesia and laying the vein open, or to combine ligation
Prophylactic vena caval interruption or filter placement provides with drainage. Moist compresses are then applied, the area is
prophylaxis only against PE, not against DVT, and thus is dis- immobilized, and antibiotics are administered. Heparin may occa-
cussed elsewhere [see Pulmonary Embolism, Minor, Vena Cava sionally be of value, particularly when the process appears to be
Filters, below].There is evidence that placement of a vena cava fil- extending into the deep venous system.
ter in fact increases the likelihood of DVT.29
Deep Vein Thrombosis
Superficial Thrombophlebitis DVT can involve either obstructive clots, which affect drainage
Characteristic clinical manifestations of superficial throm- of venous blood from an extremity, or nonobstructive clots, which
bophlebitis [see Figure 1] include pain and slight swelling of the are relatively asymptomatic. The latter may be more dangerous
extremity, with most of the edema over the course of the involved because such clots are not circumferentially attached to the vein
vein. Unless the patient is obese, a palpable, tender subcutaneous wall and thus are more likely to embolize. DVT may be divided
cord is usually found (a pathognomonic finding). Erythema may into three main forms: nonocclusive, occlusive, and phlegmasia
be present in the overlying skin.The differential diagnosis includes cerulea dolens (massive, limb-threatening DVT).

4. © 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
6 VASCULAR SYSTEM 6 VENOUS THROMBOEMBOLISM — 4
NONOCCLUSIVE
often involves injection of dye not only at the foot or ankle level [see
Nonocclusive DVT is common in postoperative and trauma Figure 3] but also at the groin level for visualization of the iliac and
patients but all too often is not suspected until an embolic compli- femoral veins. This approach is uncomfortable and is associated
cation occurs.31 There may be absolutely no manifestations of clot with morbidity; in critically ill ICU patients, it may not be feasible.
on clinical examination, or there may be nonspecific swelling in an Accordingly, noninvasive evaluation techniques are favored.
extremity; rarely is there sufficient pain or tenderness to suggest The presence of intravascular clot can be confirmed by detect-
DVT. Consequently, it is essential to be aware of the major risk fac- ing D-dimer, a product formed when cross-linked fibrin is broken
tors [see Table 1]. down by the fibrinolytic system. Both qualitative and quantitative
When DVT develops in an outpatient, every effort should be assays are in current use. The various quantitative assays available
made to determine the cause [see Figure 2]. Apparent spontaneous have differing negative predictive values. The gold standard is the
onset is often the manifestation of an underlying malignancy or enzyme-linked immunosorbent assay (ELISA) method. Generally,
even a congenital clotting tendency that will necessitate lifelong 500 µg/L (in fibrin-equivalent units) or 250 µg/L (in standard
treatment [see Hypercoagulability States, below]. Conversely, when units) is an acceptable threshold for a positive result. The latex
risk factors for DVT are identified in a hospitalized patient, it can agglutination test, though inexpensive, has an unacceptably low
be assumed that the cause is acquired and that the clotting ten- sensitivity and is the one quantitative method that should not be
dency will be reversed upon recovery. used. Because some amount of physiologic intravascular clot (e.g.,
Before therapy is begun, the diagnosis should be verified. The at a wound site) is to be expected in many, if not most, patients at
differential diagnosis includes muscle contusion, plantar or gas- risk for DVT, a positive D-dimer assay is of little diagnostic value.
trocnemius muscle rupture, ruptured Baker’s cyst, popliteal artery D-dimer assay is therefore unsuitable for screening. In patients sus-
aneurysm, arthritis of the knee or the ankle, cellulitis, and myosi- pected of having DVT or PE, however, a negative D-dimer assay
tis.The gold standard for diagnosis of DVT is ascending venogra- can, for the most part, rule out DVT and, by extension, PE.32-34
phy. However, study of the entire lower-extremity venous system Various forms of plethysmography (e.g., impedance plethys-
mography) have been used to identify nonocclusive DVT.35,36
These techniques are accurate only when there is at least 50%
obstruction of the lumen of a deep vein.The presence of large col-
Nonocclusive DVT is suspected lateral vessels may result in a false-negative test result as well.
Doppler ultrasonography can be performed quickly and easily,
Patient may be asymptomatic, or there may be nonspecific though interpretation of the results requires considerable experi-
extremity swelling. PE is a common signal. Consider major ence. It has essentially the same drawbacks as plethysmography.35
risk factors, and attempt to determine cause. Real-time B-mode (duplex) ultrasonography can be valuable in
this setting.35,37,38 It can actually visualize thrombus within a vessel.
Inability to obliterate the vein with probe compression is addition-
Onset is apparently Patient has identifiable risk factors al evidence of thrombus. Often, experienced users can even differ-
spontaneous for DVT entiate between new and old thrombi on the basis of echogenicity.
Consider congenital Assume acquired clotting tendency. Duplex ultrasonography is quite sensitive and specific in patients
clotting tendency Proceed with workup. with suspected DVT, and its diagnostic qualities can be further
[see Figure 9]. enhanced by the addition of color flow imaging. It has in fact
become the noninvasive procedure of choice for assessment of clot
in the neck and the extremity vessels. Unfortunately, it is less spe-
cific proximal to the axilla and the inguinal ligament, where com-
Verify diagnosis pression of the vessels is difficult or impossible. Duplex ultra-
sonography is particularly valuable for detecting associated condi-
Perform D-dimer assay. tions that may confuse the diagnosis (e.g., muscle hematomas or a
Baker’s cyst).38
Ultimately, ascending venography is the most accurate method
of diagnosing DVT.39,40 If a good contrast study fails to demon-
D-dimer assay is negative D-dimer assay is positive strate the presence of clot, DVT is conclusively ruled out.
Once nonocclusive DVT is diagnosed, the treatment of choice
Follow patient clinically. Perform definitive diagnostic study is initial therapeutic-dose heparin therapy followed by warfarin
(e.g., duplex ultrasonography or
ascending venography). therapy. If the patient is responsible and reasonably well educated,
initial heparin anticoagulation can be done on an outpatient basis
with subcutaneous LMWH.41,42 If this approach is not appropri-
ate, inpatient therapeutic-dose I.V. heparin anticoagulation is em-
ployed. After 3 or 4 days, depending on the response, heparin is
Diagnostic study is Diagnostic study is positive
negative for DVT for DVT replaced with warfarin.
Give therapeutic-dose unfractionated OCCLUSIVE
Follow patient clinically.
heparin to aPTT of 60–90 sec
or Lower Extremity
LMWH (enoxaparin, 1 mg/kg, or
equivalent). Lower-extremity occlusive DVT [see Figure 4] is usually associ-
ated with swelling; however, if good collateral circulation or dupli-
Figure 2 Shown is an algorithm for the management of cate veins are present, especially in the thigh, only local inflamma-
nonocclusive DVT. tion may be apparent.Typical findings include pain and tenderness

5. © 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
6 VASCULAR SYSTEM 6 VENOUS THROMBOEMBOLISM — 5
Figure 3 Injection of dye into dorsal foot veins demonstrates occlusion of iliac veins with excellent pelvic collateral
circulation.
over the involved veins as well as swelling in the distal limb (which inadequate. Lytic therapy combined with heparin anticoagulation
may be minimal with the patient supine). The differential diagno- may be superior to heparin anticoagulation alone, leading to better
sis is essentially the same as for nonocclusive DVT. In addition, clearance of clot from the valves with improved function and less
lower-extremity DVT can be associated with PE: free-floating clot risk of postphlebitic syndrome.43
may occur in conjunction with occlusive clot.
If both legs are swollen, the proximal extent of the thrombus is Upper Extremity
likely in the vena cava. If one entire leg is swollen, the proximal For all practical purposes, upper-extremity DVT [see Figure 5]
extent must be in the iliac veins. If the swelling is limited to the involves only the axillary, the subclavian, or the innominate vein (or
lower leg below the knee, the thrombus is probably in the superfi- a combination thereof). Involvement of the superior vena cava is
cial femoral vein. If the only manifestations are minimal swelling rare, mainly occurring in chronic conditions (e.g., long-term venous
and calf tenderness, the thrombus is probably limited to the sural catheterization). Arm thrombophlebitis is characterized by pain and
vein, the gastrocnemius vein, or both. swelling with tenderness over the involved vein. Often, it is relative-
If the patient has a history of DVT, is hospitalized, and is at risk ly asymptomatic: because of the excellent collateral circulation in
for recurrence, heparin therapy may be started before test results the arm, thrombosis must be extensive to produce marked swelling.
are available (provided that there is no contraindication to antico- Spontaneous onset of axillary or subclavian vein thrombosis can
agulation). If the patient is an outpatient, is hospitalized but lacks occur in association with thoracic compression syndromes (effort
risk factors for DVT, or has a contraindication to anticoagulation, thrombosis) or as a complication of so-called Saturday night palsy,
a D-dimer assay should be performed. If the assay is negative, an in which an alcoholic sleeps with the axilla compressed by the arm
alternative diagnosis should be sought. If it is positive, the diag- of a chair. If a potential mechanical cause is not apparent, other
nostic workup of DVT should proceed. If diagnostic studies yield possible causes must be explored. The onset of swelling, tender-
equivocal results and venography is difficult or impossible, treat- ness, or fever in a patient with a central venous catheter is an indi-
ment should proceed as if the diagnosis had been confirmed. cation for removal of the catheter. If there is no bacteremia or fever,
The treatment of choice is immobilization in bed, elevation of if there has been a catheter in the vein, and if the problem devel-
the limb (with or without elastic compression), and therapeutic- oped spontaneously, sterile thrombophlebitis may be assumed.
dose heparin (unfractionated heparin or LMWH), followed by 3 In these cases, once the catheter is removed, anticoagulation is
to 6 months of warfarin therapy. If the episode is mild, recovery is unnecessary.44
usually prompt. If pain and swelling do not respond promptly to Subclinical nonocclusive clot is probably of little significance
anticoagulation, either the diagnosis is wrong or anticoagulation is because documented PE from the upper extremity is quite rare.

6. © 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
6 VASCULAR SYSTEM 6 VENOUS THROMBOEMBOLISM — 6
Noninvasive tests [see Nonocclusive, above] typically yield positive
Signs of lower-extremity occlusive DVT or PE are present results when the upper extremity is involved.39 Moreover, distal
vein catheterization is easy, and phlebography is relatively uncom-
Determine whether condition is immediately threatening to plicated.These techniques should be used whenever the diagnosis
life or limb.
is in doubt.
The morbidity of occlusive upper-extremity DVT can be sub-
stantial. Thus, if the patient presents with massive swelling of the
Condition is immediately Condition is not immediately upper limb, therapeutic-dose heparin anticoagulation should be
life- or limb-threatening life- or limb-threatening initiated immediately, and consideration should be given to lytic
therapy.43 If phlebography shows compression of arm veins at the
Treat as for phlegmasia Perform D-dimer assay.
cerulea dolens [see Figure 5].
thoracic inlet after lytic therapy or spontaneous recovery from the
thrombotic process, resection of rib 1 may be indicated, particu-
larly if positional morbidity is present.45,46
Septic DVT is more common in the upper extremity than in the
D-dimer assay is negative D-dimer assay is positive lower, primarily because upper-extremity veins are more frequent-
ly catheterized and more often used for injection of illicit drugs. If
Follow patient clinically. Perform definitive diagnostic study phlebitis occurs in a catheterized vein with fever and sepsis, the
to confirm DVT or PE. catheter should be removed immediately, the tip cultured, and
DVT: duplex ultrasonography or Gram staining done on any clot present. Broad-spectrum antibi-
ascending venography.
otics should be administered until more specific antibiotic therapy
PE: pulmonary angiography.
can be instituted. Heparin anticoagulation is the primary treat-
ment unless contraindicated.
Ligation and drainage are not as practical for deep veins as for
Diagnostic study is Diagnostic study is positive
superficial veins, but either may be indicated on rare occasions if
negative for DVT or PE for DVT of PE the process does not respond to conventional therapy within 3 or
4 days and marked swelling and fever persist. Drainage is done on
Follow patient clinically. Give therapeutic-dose unfractionated the most accessible portion of the phlebitic process. For ligation,
heparin to aPTT of 60–90 sec
or the proximal end of the process should be identified via surgery or
LMWH (enoxaparin, 1 mg/kg, or phlebography and the vein then ligated proximally.
equivalent).
MASSIVE (PHLEGMASIA CERULEA DOLENS)
Follow with 3–6 mo of warfarin therapy.
Phlegmasia cerulea dolens [see Figure 6] is most apt to occur in
Figure 4 Shown is an algorithm for the management of lower-
dehydrated, cachectic patients and is usually superimposed on
extremity occlusive DVT. another critical illness. It can involve either the upper or the lower
extremity but more commonly affects the lower. In the lower
Signs of upper-extremity occlusive DVT are present
(some patients are relatively asymptomatic)
Look for signs of septic state.
Patient has no signs of Patient has signs of systemic infection
systemic infection
Assume septic DVT.
Perform D-dimer assay. Remove any foreign body; obtain culture and Gram
stain as appropriate.
Give broad-spectrum antibiotics; give more specific agent
once organism is identified.
Perform definitive diagnostic study (duplex
D-dimer assay is negative D-dimer assay is positive
ultrasonography or ascending venography).
Follow patient clinically. Perform definitive diagnostic
study (duplex ultrasonography
or ascending venography).
Diagnostic study is Diagnostic study is positive
negative for DVT for DVT
Figure 5 Shown is an algorithm for the management of upper- Give therapeutic-dose heparin.
Treat systemic infection.
extremity occlusive DVT. If phlebitis persists, consider
ligation or drainage of vein.

7. © 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
6 VASCULAR SYSTEM 6 VENOUS THROMBOEMBOLISM — 7
and cardiac irritability (with frequent premature beats or tachy-
Signs of phlegmasia cerulea dolens are present arrhythmias).54-56 These changes may resolve in moments, and the
patient may then appear perfectly normal. In these circumstances,
Limb is massively swollen, bluish, and mottled distally. Gangrene is
noted. Acute fluid loss and hypovolemic shock are common. the embolus probably either is small or is composed of relatively
fresh clot that produces only transient obstruction when it enters
the pulmonary vascular tree.
Treat phlegmasia cerulea dolens
It was long believed that after operation, hospitalization, or
injury, the earliest PE might occur was 4 to 7 days after the insult.
Replace fluids with isotonic saline, and elevate limb. Start therapeutic- A 1997 study of previously healthy trauma patients, however,
dose heparin, and arrange for lytic therapy. found that approximately 25% of the PE episodes occurred in the
first 4 days after injury.57 Accordingly, the presence of clinical signs
and symptoms consistent with PE in a patient with risk factors
calls for appropriate workup, regardless of how soon after the insult
Phlegmasia resolves Phlegmasia persists they appear.
The differential diagnosis includes acute respiratory distress syn-
Consider thrombectomy. drome (ARDS), aspiration, atelectasis, heart failure, pneumonia,
and systemic infection. If the diagnosis is not obvious but the risk
Figure 6 Shown is an algorithm for the management of massive of PE is substantial and there is no contraindication to anticoagu-
DVT (phlegmasia cerulea dolens). lation, heparin therapy (therapeutic-dose unfractionated heparin or
LMWH) may be instituted while diagnostic tests are being select-
ed and performed.
extremity, there is usually simultaneous thrombosis of the iliac, If PE is unlikely, the risk from anticoagulation is high, or other
femoral, common femoral, and superficial femoral veins.The limb serious diagnostic possibilities cannot be ruled out, specific studies
is massively swollen, bluish, and mottled. Eventually, it becomes (e.g., intravascular coagulation, spiral computed tomography, or
nonviable as arterial flow stops because of arterial spasm associat- pulmonary angiography) should be ordered before anticoagulation.
ed with venous outflow obstruction.The problem is compounded In a stable patient with suspected PE, a blood D-dimer level
by acute massive fluid loss into the limb, which can result in hypo- should be obtained. If the result is negative, PE can be excluded
volemic shock. and further diagnostic studies canceled. As with DVT, a positive
Treatment involves rapid and aggressive fluid replacement, ele-
vation of the limb, and aggressive heparin anticoagulation or
catheter-directed lytic therapy.47,48 If the patient does not respond, Table 2—Clinical Features of Pulmonary
thrombectomy may be considered, provided that the associated
Embolism: Differential Diagnosis
disease does not carry a fatal prognosis.49 The procedure is best
done transfemorally with a limited incision so that anticoagulation
Clinical Feature Other Conditions Associated with Feature
can be continued postoperatively. If anticoagulation cannot be
continued, thrombophlebitis will recur immediately. Aspiration
Atelectasis
Pneumonia
Pulmonary Embolism Dyspnea
Pneumothorax
It is widely agreed that PE is grossly underdiagnosed.3,4,50,51 Pulmonary edema
Most episodes (up to 90%) are unsuspected,52,53 and only a minor- Systemic infection
ity (10% to 25%) of fatal episodes are diagnosed before death. Clin-
ical manifestations include dyspnea, hemoptysis, pleurisy, heart Cardiac tamponade
failure, and cardiovascular collapse; however, each of these is also Intracardiac injury
Heart failure
associated with other conditions [see Table 2]. Risk factors for PE are Myocardial contusion
similar to those for DVT [see Table 1]. Myocardial infarction
PE should be distinguished from pulmonary infarction. Of the Bronchial injury
approximately 10% of all pulmonary emboli that are recognized Pulmonary contusion
clinically, only 10% are associated with pulmonary infarction.8 Hemoptysis
Tracheal erosion
Because the lung has excellent collateral circulation, obstruction of Unsuspected neoplasm
the larger pulmonary arteries rarely leads to death of lung tissue.
When pulmonary infarction does occur, the diagnosis is usually Chest wall injury
obvious; hemoptysis, pleuritic chest pain, and a wedge-shaped Pneumonia
Pleurisy
density on chest x-ray are the classic manifestations. In most PE Pneumothorax
patients (i.e., those without pulmonary infarction), these findings Subphrenic inflammation
are absent, and the chest x-ray may even be normal. Air embolism
For the purposes of clinical diagnosis and treatment, PE is best Cardiac tamponade
classified as minor (or suspected), moderate, or catastrophic [see Hypovolemia
Figure 7]. Cardiovascular
Myocardial infarction
collapse
MINOR Severe hypoxemia
Systemic infection
Manifestations of minor PE [see Figure 7a] may include tran- Tension pneumothorax
sient tachypnea (with perhaps a slight change in blood gas values)

8. © 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
6 VASCULAR SYSTEM 6 VENOUS THROMBOEMBOLISM — 8
b
a Signs of minor PE (transient
Signs of moderate PE (transient hypotension,
tachypnea, slight change in blood
tachycardia or other arrhythmias, tachypnea,
gases, premature beats,
↓ PO2 and PCO2, apprehension, symptoms
tachyarrhythmia) are present
and signs of pulmonary infarction) are present
Perform D-dimer assay.
Patient is judged to be at PE is unlikely, or
substantial risk anticoagulation seems risky
If there is no contraindication to Perform D-dimer assay. D-dimer assay is negative D-dimer assay is positive
anticoagulation, give therapeutic-
dose heparin while diagnostic tests Seek alternative explanation Assess risk of anticoagulation and
are selected. (Alternatively, assume for signs. likelihood of PE.
diagnosis and continue treatment
as long as risk is present.)
PE is likely PE is unlikely, or
D-dimer assay is negative D-dimer assay is positive anticoagulation seems risky
Give therapeutic-dose
No treatment is indicated, except Confirm results with pulmonary heparin.
Attempt to make specific
for prophylaxis in high-risk patients. angiography. Consider lytic therapy diagnosis via pulmonary
Initiate (or continue) therapeutic- for acute episodes. angiography.
dose heparin.
Figure 7 Shown are algorithms for the management of (a) minor,
(b) moderate, and (c) catastrophic PE.
Diagnosis is not confirmed Diagnosis is confirmed
D-dimer assay does not confirm DVT or PE.The negative predic- If patient is at risk for embolism If anticoagulation is not
tive value of the assay for DVT and PE is between 90% and 100% and anticoagulation is not contraindicated, give
when an appropriate assay with an appropriate cutoff value is contraindicated, give therapeutic-dose heparin.
used.31-33 If a patient is experiencing a life-threatening respiratory prophylactic-dose heparin. If it is, consider vena caval
event consistent with PE, the D-dimer assay should be skipped, interruption.
therapy instituted, and formal diagnostic studies performed.
Noninvasive evaluation of the legs may establish the presence of
DVT necessitating anticoagulation. This circuitous way of estab- c
lishing the diagnosis of PE has severe limitations. When noninva- Signs of catastrophic PE (cardiac arrest, circulatory collapse,
sive assessment aimed at detecting clot in the major leg veins is bradyarrhythmia, severe hypotension, left heart failure)
done before documented PE, it yields positive results in only 33% are present
to 45% of cases.58 Venography is more sensitive than duplex ultra-
Give 100% O2 by ET tube. Give cardiotonic agents and massive
sonography. When it is used to diagnose venous thrombosis, as doses of heparin. Consider Trendelenburg’s procedure or
many as 30% to 40% of patients with PE are found not to have clot cardiopulmonary bypass.
in the major veins of the leg or the abdomen. If the duplex scan or
venogram is positive for DVT and there are no contraindications,
anticoagulation may be begun. If, on the other hand, a patient is Provide further treatment as needed
suspected of having PE but is sent for a duplex scan in place of a
pulmonary arteriogram, and the duplex scan is negative, workup If patient survives emergency treatment and improves, continue
therapeutic-dose heparin and consider lytic therapy or a caval filter.
must continue. It is unacceptable in such cases to assume that the
negative result excludes PE.
The initial enthusiasm for the use of lung scans to diagnose or
screen for PE has diminished.59,60 Current thinking about the use from CT scanning for PE were quite promising.61
of scans for this purpose may be summarized as follows. If a scan In the past few years, CT has undergone rapid increases in
is read as high probability, there is roughly an 85% chance that the sophistication. Specifically, as CT technology has moved from sin-
diagnosis is correct. If a scan is read as normal, there is roughly a gle-detector to multiple-detector (light-speed) scanners, the sensi-
5% chance that the patient had PE. If a scan is read as low or inter- tivity achievable with this modality has skyrocketed. As a result,
mediate probability (the most likely scenario), the likelihood that the negative predictive value of CT in this setting—that is, the
the diagnosis is correct is little better than random chance. degree to which a negative CT pulmonary angiogram can be relied
As a result of the dramatic improvements in CT imaging, many on to rule out PE—has risen dramatically.62 For most institutions,
proposed replacing pulmonary angiography with CT. There were the result of this technologic improvement is that CT angiography
several good arguments for this proposal. First, CT scanning is is now the primary radiologic diagnostic study for excluding PE. It
less invasive than pulmonary angiography. Second, it does not has been argued that CT angiography cannot yet replace pul-
require the immediate presence of a radiologist. Third, it is less monary angiography altogether, because thrombolytic therapy (if
costly at most institutions. Finally, CT scanning is usually more required) may be provided during pulmonary angiography, where-
easily obtained than pulmonary angiography. The initial results as it typically cannot be provided during CT angiography. This

9. © 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
6 VASCULAR SYSTEM 6 VENOUS THROMBOEMBOLISM — 9
MODERATE
argument probably applies only to the sickest PE patients, who are
the ones most likely to benefit from thrombolytic therapy and least Manifestations of moderate PE [see Figure 7b] include transient
likely to be able to tolerate a second load of dye (as when pul- hypotension, tachycardia or other cardiac dysrhythmias, tachypnea
monary angiography is done for treatment purposes after CT with a significant fall in arterial oxygen and carbon dioxide ten-
angiography). sion, apprehension, and symptoms or signs of pulmonary infarc-
For critically ill patients, who tolerate diagnostic testing poorly, tion54,56; there may be signs of right heart failure as well. Electro-
pulmonary angiography is a more appropriate initial study [see cardiography is rarely helpful in the differential diagnosis. Acute
Figure 8].3,50,63 If the angiogram is obtained immediately after the right axis deviation, new incomplete right bundle branch block,
clinical episode, particularly if the patient is still symptomatic, a and changes in S1, Q3, or T3 are thought to characterize this disor-
negative result rules out PE. However, if the patient improves or der but are found in only a small percentage of patients with
recovers before angiography, the angiogram may be falsely nega- proven PE.
tive, implying that the clot was minimal or was disposed of by nat- If the diagnosis is probable and there are no likely alternatives,
ural lytic processes. Thus, a negative angiogram in such a patient heparin therapy should be initiated. Lytic therapy is of debatable
does not unequivocally rule out PE.64 The pulmonary angiogram utility in these patients: compared with standard heparin therapy,
does, however, establish the degree of patency of the pulmonary it appears not to reduce mortality or pulmonary dysfunction sig-
vasculature, which affects prognosis. nificantly, yet it carries a higher risk of bleeding.3,66 Moreover, lytic
PE can occur even immediately after injury in previously healthy therapy is often contraindicated because of recent surgery, injury,
persons.57 These early emboli are generated from fresh clot and or vascular punctures.
thus are more easily fragmented and broken down.They are much If there is a relative contraindication to anticoagulation (e.g., an
more likely to be found in the periphery.65 For these reasons, CT acute surgical wound, a previous bleeding episode, or an allergic
is less sensitive in detecting them.65 Accordingly, patients with sus- reaction to heparin) or alternative diagnoses are likely, specific
pected PE shortly after injury or operation should undergo pul- diagnosis is required, ideally via pulmonary angiography. Periph-
monary arteriography. eral noninvasive venous studies may be helpful because if they
If all diagnostic tests for PE yield negative results, therapeutic show significant venous obstruction, the likelihood of PE increas-
anticoagulation is not indicated; however, if risk factors are pres- es and the need for therapy is documented. Ventilation-perfusion
ent, prophylaxis is indicated. If test results are suggestive or in- scanning, again, is valuable only if strongly positive.
dicative of PE, therapeutic heparin anticoagulation should be If there is no contraindication to heparin therapy and the diag-
continued. nosis is strongly suspected but not confirmed, therapeutic-dose
heparin anticoagulation should be started.67,68 Treatment is con-
tinued if the diagnosis is verified and stopped if the diagnosis is
excluded.69-72
Vena Caval Filters
Vena caval interruption has often been recommended for pa-
tients with documented PE despite apparently adequate systemic
anticoagulation, but many authorities now advocate vena caval fil-
ter placement even in patients who do not have documented
thromboembolism but are at high risk and in whom anticoagula-
tion is contraindicated.73-75 Supporting data come largely from
studies with historical controls. In the one prospective, random-
ized, controlled trial involving patients with thromboembolic dis-
ease, there was no reduction in mortality at any time, nor was there
even a reduction in PE at 2 years; however, there was an increased
incidence in DVT over that period.29 These findings suggest that
vena cava filters should be reserved for patients with documented
DVT, a contraindication to anticoagulation, and a high risk of sub-
sequent PE.
In 2005, an 8-year follow-up analysis of the patients enrolled
in the aforementioned prospective, randomized trial29 was pub-
lished.76 Over the 8-year period, the incidence of PE was lower in
the group that received inferior vena cava filters than in the group
that did not; however, there was an increased rate of recurrent
DVT in the filter group. Overall, there was no significant difference
in mortality between the two groups. The authors reiterated their
recommendation that vena cava filters be used with restraint.
If vena caval interruption is considered necessary, it should be
done percutaneously via either the jugular or the femoral route. If
it is done by the latter route, phlebography (from the insertion site
through the vena cava) should be performed first to document the
absence of clot along the planned route. A number of different
vena caval filters are currently on the market. Each is slightly dif-
Figure 8 Pulmonary angiogram shows unequivocal filling defects ferent from the others, but none has demonstrated clear superior-
in multiple arteries. ity in preventing PE or reducing caval thrombosis. Surgeons

10. © 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
6 VASCULAR SYSTEM 6 VENOUS THROMBOEMBOLISM — 10
should be aware of the advantages and disadvantages of the types thrombin stores are depleted, progressively higher heparin doses
available at their institutions. will be required to achieve the same degree of anticoagulation.
Removable filters are now widely available. Several have been Unfractionated heparin therapy is also frequently referred to as
approved by the FDA and are in clinical use. Because these devices conventional anticoagulation.78-80 Before therapy is begun, a clot-
were approved comparatively recently, data on long-term efficacy ting battery should be performed, consisting of the aPTT, the
and complication rates are not yet available. INR, the platelet count, and levels of fibrinogen, antithrombin, and
One of the most critical questions that remains unanswered is, D-dimer. High fibrinogen levels and platelet counts are seen in
what will be the long-term consequences when the damage caused patients with chronic clotting syndromes,81 probably representing
by the venotomy required for filter removal is superimposed on the overcompensation for increased utilization. Elevated D-dimer lev-
endothelial damage caused by the filter? This question should be els suggest intravascular clotting with activation of the fibrinolytic
kept in mind, as should the reservations expressed by the authors system.
of the only prospective, randomized trial of inferior vena caval fil- In the average patient, therapeutic-dose heparin anticoagulation
ters published to date.29,76 Still, it appears that removable vena begins with administration of 5,000 to 10,000 units, followed by
caval filters are likely to have a role to play in this setting. They continuous I.V. infusion at a rate sufficient to double or triple the
should be considered in patients who are at extremely high risk for aPTT—typically, 1,000 to 2,000 units/hr. When dosages higher
PE, who have an absolute contraindication to anticoagulation for a than 2,000 units/hr are required, antithrombin depletion is highly
finite period, and in whom anticoagulation can be instituted upon probable.
removal of the filter. Tight control of the aPTT change as a result of heparin thera-
py is not as important as monitoring for evidence of bleeding and
CATASTROPHIC
platelet depletion. Clinical evidence of bleeding is not necessarily a
Catastrophic PE [see Figure 7c] is most apt to be superimposed contraindication to anticoagulation. Minimal amounts of blood
on a critical illness or a major operation.The peak incidence is 7 to may be lost in the urine or through the GI tract; if the patient has
10 days after the procedure or the onset of clinical illness, though a clearly identifiable need for anticoagulation, such minor blood
emboli may occur at any time.54 The reason for this apparent delay loss should be accepted. Only when transfusion is indicated to
is that for the clot to remain intact after embolization to the pul- maintain the hematocrit should discontinuance of heparin be con-
monary vasculature, it must mature in the vascular system, a sidered. At that point, if the risks of bleeding seem to outweigh the
process that takes several days. Fresh clot breaks up readily and benefits of anticoagulation, heparin infusion can be stopped or
dissipates promptly, whereas older clot is resistant to lysis. The reduced to prophylactic levels. It is important to watch for falls in
manifestation of early embolization of fresh clot to the pulmonary the hematocrit indicative of significant bleeding. The most com-
vasculature is ARDS. Embolization of older clot can produce acute mon sites for hemorrhagic complications are surgical wounds and
pulmonary obstruction and acute right heart failure, making radi- the retroperitoneum. Retroperitoneal bleeding is generally asymp-
ologic diagnosis of PE relatively easy.54 Occlusion of large portions tomatic until the patient progresses to hemorrhagic hypovolemic
of the vasculature is associated with hemodynamic catastrophe. shock.
Typically, the clinical onset of catastrophic PE comes when a As a rule, the therapeutic dose of LMWH is twice the prophy-
patient, having just been mobilized, performs a vigorous Valsalva lactic dose.The various LMWHs currently on the market all have
maneuver in the course of his or her first postoperative bowel slightly different activities and half-lives. Enoxaparin may be taken
movement. The great abdominal veins distend, and any clot pres- as prototypical. The accepted prophylactic dose for enoxaparin is
ent tends to be stripped loose. If a large clot embolizes, immediate 30 mg twice daily, and the therapeutic dose is 60 mg (or 1 mg/kg)
collapse and cardiac arrest may result; in some cases, brady- twice daily.
arrhythmia or severe hypotension precedes the actual arrest. A major benefit of using LMWHs to treat DVT and PE is that
Immediate emergency treatment comprises intubation and admin- therapeutic doses can be given subcutaneously.41,42 As a result,
istration of 100% oxygen, heparin anticoagulation, and, if cardiac patients may be treated as outpatients both in the acute phase of
arrest occurs, cardiopulmonary resuscitation. A Swan-Ganz cath- the disease and in the subacute phase, during the transition to oral
eter should be inserted as soon as possible so that the effects of anticoagulants. This approach requires that patients be clinically
therapy can be monitored. Cardiotonic agents (e.g., dopamine, 2.0 stable and able to follow dosing instructions. Because there are no
to 5.0 µg/min, or dobutamine, 2.5 to 10.0 µg/kg/min) should be validated methods of monitoring LMWH therapy, an initial assess-
administered to strengthen myocardial function. If sudden arrest ment of antithrombin activity is appropriate. If this is low, unfrac-
occurs in circumstances that permit emergency thoracotomy, tionated heparin therapy in conjunction with aPTT monitoring is
Trendelenburg’s procedure can be performed; however, it is rarely probably preferable.
indicated and even more rarely successful. If the patient survives
initial emergency treatment and improves, high-dose heparin ther- High Dose
apy should be continued and lytic therapy considered.71,77 High-dose heparin therapy is reserved for patients who are
dying of PE or are at risk for immediate limb loss from phlegma-
sia cerulea dolens. Such therapy consists of administering a large
General Principles of Anticoagulation and Lytic Therapy enough dose of heparin to elevate the aPTT off the scale.The max-
imum aPTT that can be measured by our laboratory is 150 sec-
HEPARIN ANTICOAGULATION
onds; high-dose heparin treatment should therefore yield an aPTT
higher than this value. Theoretically, given that a fully anticoagu-
Therapeutic Dose lated patient should not form clot at all, the aPTT should be infi-
Heparin therapy may be instituted with either unfractionated nite.This method of treatment may be used in patients with imme-
heparin or LMWH. In either case, the key is to give enough heparin diately life-threatening PE or phlegmasia cerulea dolens when the
soon enough to have a beneficial effect. Both types of heparin exert more conventional technique, catheter-directed thrombolytic ther-
their effect by potentiating antithrombin; thus, if a patient’s anti- apy, is unavailable.

11. © 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
6 VASCULAR SYSTEM 6 VENOUS THROMBOEMBOLISM — 11
In most patients, high-dose therapy begins with a 20,000 unit anticoagulant must be used. The most widely accepted agent for
I.V. bolus, followed by infusion of 5,000 units/hr I.V.82-86 The end this purpose is lepirudin (a direct thrombin inhibitor).92 Other
point of therapy is clinical evidence of improvement. In patients direct thrombin inhibitors (e.g., argatroban) and heparinoids (e.g.,
being treated for PE, pulmonary function should improve. danaproid) have also been successfully used to provide anticoagu-
Because complete anticoagulation is the essential principle of lation in patients with HIT. None of the LMWHs are acceptable
high-dose heparin therapy, there is no need to be concerned about in this setting, and at present, the FDA does not allow use of the
an upper limit for the dosage: if the patient cannot clot, doubling pentasaccharide in severe HIT.
or even tripling the dosage should not increase the risk of bleed- Unlike warfarin, heparin does not cross the placenta and has not
ing. Moreover, because the incidence of bleeding is very low in the been associated with fetal malformations; thus, it is preferred for
first 2 or 3 days of therapy, regardless of the dosage,85,86 high ini- thrombotic complications of pregnancy. Heparin can be adminis-
tial dosages do not carry an unacceptable bleeding risk. After tered subcutaneously in an outpatient setting for 3 to 6 months.
heparin has been observed to have an effect and a prolonged Long-term administration can lead to osteoporosis and sponta-
aPTT documented, the high dosage should be continued for at neous vertebral fractures.93
least 24 hours, then decreased by 500 to 1,000 units/hr over the Very rarely, heparin therapy can lead to adrenal hemorrhage
next 24 hours. If the clinical effect is maintained and improvement and consequent adrenal insufficiency.79 If acute adrenal insuffi-
continues, the dosage can be decreased by another 500 to 1,000 ciency is suspected, anticoagulant therapy should be discontinued
units/hr over the following 24 hours. In theory, once all clotting and high-dose steroid therapy (preferably with hydrocortisone)
stops, natural antithrombin levels should recover, allowing lower initiated.Treatment should not await laboratory confirmation. CT
dosages of heparin to be effective. After 3 or 4 days of therapy, the scanning may be useful. Heparin may suppress aldosterone syn-
dosage may be reduced to more conventional levels [see Thera- thesis, especially with prolonged use.79
peutic Dose, above].
If the initial improvement is lost, the dosage should be restored Reversal of Heparin Effect
to its previous high level and maintained there for several days The anticoagulant effect of heparin disappears within hours
before any attempt is made to reduce it again. The platelet count after discontinuance. If the effect must be reversed quickly, the
and the hematocrit should be carefully monitored, the latter at patient should receive protamine sulfate I.V. This agent binds the
least four times a day. Heparin should be discontinued or the heparin and prevents it from activating antithrombin. Protamine
dosage reduced only when the risks of bleeding and transfusion sulfate should be given in the smallest dosages that still evoke the
exceed the benefits of anticoagulation. In a monitored environ- desired result—typically, about 1 mg for every 100 units of heparin
ment, patients very rarely die of hemorrhage; rather, they die of the remaining in the patient. It should be administered slowly over 5
consequences of clotting. to 10 minutes; rapid infusion can cause shortness of breath, flush-
ing, bradycardia, hypotension, or anaphylaxis. On rare occasions,
Complications patients previously sensitized to protamine may experience mas-
The most devastating hemorrhagic risk of heparin therapy— sive platelet aggregation, as manifested by catastrophic arterial
fortunately, a rare one—is intracranial bleeding. The risk of major thrombosis. Patients particularly likely to manifest this adverse
hemorrhage ranges from 4% to 9% and is directly affected by how reaction include diabetics and persons with fish allergies. Prota-
tightly the INR is controlled.87 The risk is greatest in elderly mine has little or no capacity for reversing either LMWH or fonda-
patients, particularly women,79 but it is still small in comparison parinux. Research aimed at developing specific protamines to
with the obvious risks posed by the clotting episode. Nevertheless, inactivate the LMWHs is now being carried out, but at present, no
the existence of this risk makes it appropriate to use high-dose such agents are available in the United States.
heparin primarily in life-threatening conditions.
ORAL ANTICOAGULATION
A more common complication of full heparin anticoagulation is
retroperitoneal bleeding. This problem is accentuated in elderly Warfarin is the prototypical oral anticoagulant; the agents in this
patients. Because aging is associated with loss of connective tis- class have much the same effects, differing primarily with respect
sue elasticity, bleeding into retroperitoneal connective tissue that to potency and duration of action.79,80 Warfarin is also available in
would normally be insignificant can become life-threatening. an I.V. form; however, in view of its mechanism of action, caution
Usually, this is not a serious problem if the hematocrit is followed, should be exercised when it is given parenterally.
heparin dosing adjusted, and lost blood replaced. When the per-
ceived risk of bleeding outweighs the thrombotic risk, heparin Dosage
should be discontinued. Historically, warfarin dosage has been regulated by monitoring
Two forms of acute heparin-induced thrombocytopenia (HIT) the prothrombin time (PT), with a PT 1.5 to 2.5 times normal (11
have been reported.88-91 Mild HIT occurs in 2% to 5% of patients or 12 seconds) generally considered to represent the optimal level.
2 to 15 days after the initiation of therapy.The platelet count usu- In response to the wide variations in PT reported by different lab-
ally remains at about 100,000/mm3, and treatment can be contin- oratories, the World Health Organization (WHO) has recom-
ued without undue risk of bleeding or thrombosis. Severe HIT is mended substituting the INR for the PT ratio so that all laborato-
much less frequent. It usually occurs about 7 to 14 days after the ry assessments will be comparable.94 An INR of 2.0 to 3.0 corre-
initiation of heparin therapy and is reversible once the drug is dis- sponds to a PT that is 1.3 to 1.5 times normal (moderate dose);
continued. It is not dependent on the heparin dose given. Clinical an INR of 3.0 to 4.5 corresponds to a PT that is 1.5 to 2.0 times
manifestations include a substantial (at least 50%) drop in the normal (high dose). Lower INRs are recommended for all but
platelet count followed by a thrombotic episode (frequently both extremely high-risk patients (e.g., those with mechanical heart
arterial and venous). An ELISA directed at the platelet factor valves) [see Table 3].94
4–heparin complex is generally accepted for laboratory confirma- Initially, the daily dose of warfarin required to increase the INR
tion of the diagnosis. Treatment consists of discontinuance of to between 2.0 and 3.0 is estimated and administered.The INR is
heparin. If the patient still requires anticoagulation, a different then checked every morning. If it suddenly overshoots the target

12. © 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
6 VASCULAR SYSTEM 6 VENOUS THROMBOEMBOLISM — 12
elimination of the intestinal flora by antimicrobial agents, may have
Table 3—Recommendations for Use of similar effects. For these reasons, warfarin should be used with
Varying Dosages of Warfarin great caution in patients who are receiving antibiotics or who can-
not tolerate a regular diet.
The dosage of warfarin is regulated by monitoring the INR. A less There are some serious interactions that increase the risk of
intense therapeutic range (INR = 2.0 to 3.0, corresponding to a PT bleeding without altering the INR. These include inhibition of
1.3 to 1.5 times normal with a WHO-designated thromboplastin) is
appropriate for the following applications: platelet function by drugs such as aspirin and gastritis or gastric
ulceration induced by anti-inflammatory drugs. Obviously, when
1. The prevention of venous thromboembolism in high-risk patients.
placing a patient on more than one anticoagulant simultaneously,
2. The treatment of venous thrombosis and PE after an initial
course of heparin. great care must be taken.
3. The prevention of systemic embolism (a) in patients with tissue Complications
heart valves, (b) in selected patients with atrial fibrillation, (c) in
patients with acute anterior wall myocardial infarction, and (d) in Bleeding is the major complication of oral anticoagulation.Tight
patients with valvular heart disease.
control of warfarin therapy is essential for minimizing this compli-
A more intense therapeutic range (INR = 3.0 to 4.5, corresponding cation.87 Bleeding is rare when the INR is kept below 3.0. When
to a PT 1.5 to 2.0 times normal with a WHO-designated
thromboplastin) is appropriate for patients with mechanical bleeding does occur, a preexisting lesion is likely. If the bleeding is
prosthetic valves and patients with recurrent systemic embolism. minor, the warfarin dosage should be adjusted; if it is major, the
INR—international normalized ratio—PT—prothrombin time—WHO—World Health
drug may have to be discontinued.The risk of intracerebral or sub-
Organization dural hematoma is greater with warfarin than with heparin, partic-
ularly in patients older than 50 years. If there is any sign of hem-
orrhage, the next anticoagulant dose should be withheld and the
range, the warfarin dosage is reduced. If the INR has not reached INR measured. For continued or serious bleeding, 5 to 10 mg of
or surpassed 1.5 after the third dose, the dosage is increased. The vitamin K1 oxide (phytonadione) I.V. is effective. Several hours
maintenance dosage averages about 5 mg/day but may range from may pass before hemostasis improves significantly, and 24 hours or
1 to 10 mg/day. longer may be needed for maximal effect. If immediate restoration
While the maintenance dosage is being determined, the INR of hemostatic competence is necessary, levels of vitamin K–depen-
should be checked daily. Once the patient stabilizes, the INR can dent coagulation factors can be raised by giving fresh frozen plas-
be checked less often: twice weekly for the first few weeks, once ma, 10 to 20 ml/kg body weight, or prothrombin complex con-
weekly for the next several months, and once monthly thereafter if centrate.96
the patient is stable. The patient should be cautioned about drug Administration of warfarin during pregnancy can cause birth
interactions. If the dosages of other medications are changed, the defects and abortion and therefore is contraindicated. Warfarin-
impact on the INR should be investigated and the warfarin dosage induced skin necrosis is a rare complication of oral anticoagulant
adjusted as appropriate. therapy.90 This syndrome, characterized by the appearance of skin
lesions shortly after initiation of treatment, may be the result of a
Duration
There is no general agreement on how long oral anticoagulant
therapy should be continued after a thromboembolic event. Table 4—Factors Influencing
Current data suggest that the duration of therapy should be based
Response to Warfarin
on the level of underlying risk rather than on the severity of the
event. For patients with a limited risk period (e.g., a young patient
with a femur fracture and no other risk factors), an 8- to 12-week Factors Leading to Factors Leading to
Increased Response Decreased Response
course is as efficacious as a longer course.95 For patients with a life-
long risk (e.g., a patient with a congenital hypercoagulability syn- Drugs Drugs
drome or cancer), a therapeutic dosage for 3 to 6 months, followed Allopurinol Barbiturates
by a low dosage for the remainder of the patient’s life, is indicat- Amiodarone Cholestyramine
ed.87 Lengthening the duration of full anticoagulant therapy in Aspirin Diuretics
patients with long-term risk factors appears only to delay the recur- Cephalosporins Ethanol (chronic use)
rence of thromboembolism, not to prevent it. Cimetidine Phenytoin
Clofibrate Rifampin
Drug Interactions
Disulfiram Vitamin K
Response to warfarin is affected not only by various bodily fac- Ethanol (acute intoxication) Foods
tors but also by drug interactions [see Table 4]. Such interactions are Heparin Green leafy vegetables
most dangerous when drugs administered in parallel are taken Metronidazole
Bodily factors
intermittently.79,80 Increased metabolic clearance of the drug can Sulfinpyrazone
Hereditary resistance
result from administration of barbiturates, rifampin, or phenytoin; Trimethoprim-sulfamethoxazole
Hypometabolic states
long-term use of alcohol; ingestion of large amounts of vitamin K; Bodily factors Pregnancy
and rich foods. Elevated levels of coagulation factors during preg- Age Uremia
nancy also decrease warfarin’s effectiveness. Congestive heart failure
Decreased metabolism or displacement from protein-binding Dietary inadequacy
sites caused by phenylbutazone, sulfinpyrazone, metronidazole, Hypermetabolic states
disulfiram, allopurinol, cimetidine, amiodarone, or acute intake of Intestinal flora loss
ethanol can elevate the INR and increase the risk of hemorrhage. Liver disease
Relative vitamin K deficiency, resulting from inadequate diet or the