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					          The Role of Prophylactic
       Anticoagulation in the Surgical
                  Patient
        here is an ever-increasing awareness of the importance of the
 T      thrombotic process on patient outcomes after a variety of inter-
        ventions. Thrombosis is a complicated process that involves not
only the traditional clotting cascade but also the interaction of the
platelets, whose role in the progression of the clotting process is now
appreciated. We use the term prophylactic to include anticoagulant
therapy administered to prevent a thrombotic event before, during, or
after an intervention. Data will be offered to help the surgeon decide when
to use antithrombotic agents, when to discontinue them, and what the
relative advantages are of the drugs currently available. The shear number
of studies about the use of anticoagulants suggests that the evidence that
has been provided so far is inadequate to make evidence-based decisions
regarding their usage. Many of the studies are small and not powered to
identify small differences in effect. The technique of meta-analysis is
often used to circumvent this difficulty. Best evidence and recommenda-
tions from panels of experts are provided.

Evaluating the Evidence
Statistical Problems with Small Trials
  There are more than 50 clinical trials that just compare low molecular
weight heparin (LMWH) with unfractionated heparin (UFH), and there
are several meta-analyses. Meta-analyses are associated with publication
bias and oversimplification.1 In general, when meta-analyses are limited
to randomized, double-blinded clinical trials, the evidence is better than
that from observational studies but not equal to a randomized clinical trial
(RCT) with adequate power. Specific problems in the analysis of data
from the multitude of thromboprophylaxis trials are the variations in the
timing of drug administration and the variability in the duration of
treatment.

Curr Probl Surg 2003;40:81-130.
0011-3840/2003/$30.00 0 40/2/022222
doi:10.1067/msg.2003.022222

92                                                Curr Probl Surg, February 2003
TABLE 1. Evaluation of the evidence2
            Risk
Grade                              Method                          Recommendation
           benefit
1A      Clear          RCT with no limitations             Strong-No reservation
1B      Clear          RCT with flaws                       Strong-Most patients
1C      Clear          Overwhelming evidence from          Strong-Most patients
                         OS
1C      Clear          OS                                  Intermediate-More data may
                                                              change
2A      Unclear        RCT with important limitations      Intermediate-Best action may differ
2B      Unclear        RCT with inconsistent results       Weak-Alternative approaches better
2C      Unclear        OS                                  Very weak
RCT, Randomized clinical trial; OS, observational study.




Grading system for recommendations
  A strong recommendation (grade 1) occurs when experts believe that
benefits do or do not outweigh risks. If experts are less certain, they make
a weaker recommendation (grade 2). RCTs with consistent results provide
grade A recommendations; RCTs with inconsistent results or methods
flaws provide grade B recommendations. Observational studies provide
grade C results. When evidence from observational studies is overwhelm-
ingly compelling, a grade of C is given.2 Table 1 summarizes the
grading methods used throughout this monograph.
The Hypercoagulable State
The Syndromes
  Thrombosis of arteries and veins accounts for more than 2 million
deaths each year in the United States, and 50% of these events can be
attributed to a congenital or acquired coagulation or platelet abnormali-
ty.3,4
  Clinical suspicion should be high for a hypercoagulable state when a
patient experiences recurrent thromboses, there is a family history of
thrombosis, a history of spontaneous abortions, there is thrombosis in an
unusual site, a young person has a thrombotic disorder, and a patient has
a history of multiple exposures to heparin (Table 2). Patients with
hypercoagulable states have a 6-fold increased risk of failure when
arterial reconstructions are performed.5 Long-term anticoagulation re-
duces the risk for thrombosis.
  Activated Protein Resistance. Activated protein C (APC) resistance is
the most common risk factor for the development of venous thrombosis
and accounts for more than 50% of thromboses from inherited causes.6 In
Curr Probl Surg, February 2003                                                             93
TABLE 2. Clinical concerns that should initiate an evaluation of hypercoagulability7
Recurrent thromboses
Thrombus in unusual site
Young patient with thrombosis
Family history of thrombotic disorder
Premature or unexplained failure of vascular intervention
Multiple exposures to heparin
Spontaneous mid-term abortions




the normal state, APC is a naturally occurring anticoagulant that degrades
factors Va and VIIIa. Patients with functional APC-R do not demonstrate
in vitro evidence of anticoagulation in the presence of exogenous APC,
even with adequate levels of normal protein C. Most, but not all, of these
patients have an inborn error of metabolism that results in an abnormal
factor V (Leiden). In the setting of the factor V (Leiden) mutation, factor
Va is resistant to degradation, and the altered factor V remains a
procoagulant. Heterozygous individuals have a 7-fold increased risk for
DVT. Homozygous individuals have an 80-fold increased risk and will
likely have at least 1 thrombotic episode during their lifetime.7 APC-R is
also a factor in arterial occlusive disease in the younger patient population
and is a common finding in patients with failed arterial reconstructions.8
The diagnostic approach to this condition should begin with the func-
tional assay for APC-R that is far less costly than the polymerase chain
reaction that detects the factor V (Leiden). The prothrombin gene variant
(20210A) is another risk factor for venous and arterial thrombosis. Its
mechanism is unclear. Patients with these conditions require long-term
anticoagulation.9
  Antiphospholipid Syndrome. Patients with the antiphospholipid syn-
drome experience the development of antibodies against a variety of
protein-phospholipid complexes that result in a hypercoagulable state.
This diagnosis should be suspected in a patient with recurrent deep
venous thrombosis (DVT), with thrombotic complications after an arterial
reconstruction, arterial occlusions in unusual sites, recurrent mid preg-
nancy abortions, and/or thrombocytopenia. The diagnosis is confirmed by
assays for either the lupus anticoagulant or anticardiolipin antibodies.
Studies show that patients with antiphospholipid antibodies who undergo
arterial reconstruction have a higher incidence of disease progression that
those patients without the antibodies.10 The treatment includes warfarin
therapy for as long as antibodies persist. Pregnant women with this
syndrome should be treated with LMWH.
94                                                               Curr Probl Surg, February 2003
  Congenital Deficiency of Antithrombin III. Patients with congenital
deficiency of antithrombin III (AT III) are at increased risk for thrombo-
embolism. The prevalence of this genetic abnormality is 1:5000, and
thrombotic events usually occur in the second decade and are associated
with surgery, trauma, or pregnancy. The risk for DVT is 24% during the
period after operation.11 This is the only inherited disorder of coagulation
for which there is an Food and Drug Administration (FDA)–approved
replacement therapy. Commercially available antithrombin concentrates
have been available in the United States since 1990 (ATnativ; Kabi
Pharmacia, distributed by Baxter Healthcare Corp, Hyland Division,
Glendale, Calif). The goal of therapy is to increase the AT III levels to
more than 80% (protective levels) at all times during therapy. An initial
dose that is calculated to increase the AT III activity to 120% is
administered. The dose is calculated with the following formula: Units
required ([desired % AT III activity] [baseline % AT III activity])
   weight (kilograms)/1.2%.12 If AT III activity cannot be measured,
the formula can be used with the assumption that AT III activity is
50%, with a second dose administered 12 hours later that is 50% of the
initial dose. This regimen, in combination with prophylactic antico-
agulation, should provide protection against thromboembolism. AT III
treatment can be discontinued once warfarin therapy is at an appro-
priate level.
  Protein C and S Deficiencies. The proteins C and S are vitamin-K
dependent and may be decreased secondarily in patients with chronic
hepatic and renal failure. Protein C is activated by thrombin and becomes
a major anticoagulant and fibrinolytic agent. Protein S serves as a cofactor
to C and has no anticoagulant activity by itself. Deficiencies of protein C
usually cause venous thromboses at an early age. Patients with peripheral
arterial disease younger than 50 years of age have a 15% to 20%
incidence of protein C and S deficiencies.13 The treatment includes
anticoagulants and factor replacement with fresh frozen plasma during
times of risk. Life-long anticoagulation is indicated in patients with a
history of thrombosis.
  Hyperhomocystinemia. Elevated plasma homocystine levels are asso-
ciated with increased risks of arterial and venous thrombosis. Mild
hyperhomocystinemia occurs in 7% of the population.14 The coagulant
effect of homocystine relates to the product of its oxidation. Once
oxidized, potent free radicals form that cause endothelial damage and
activation of platelets and leukocytes. The treatment is folate in doses
sufficient to restore homocystine levels to normal.
Curr Probl Surg, February 2003                                           95
TABLE 3. Screening for hypercoagulability
A good history, including that of family
Tests during episode
  Platelet count
  Heparin-induced antiplatelet antibodies
  Lupus anticoagulant
  Anticardiolipin antibodies
  Homocystine level
  Functional activated protein C resistance
  Leiden mutation
  Prothrombin gene variant
Tests after anticoagulation has been stopped (at least 3 days after heparin is stopped)
  Proteins C and S
  Antithrombin III




Screening
  Screening for patients suspected of having a hypercoagulable state
(Table 3) should be individualized. The best test is the patient’s personal
and family history. The platelet count should be determined in every
patient who receives heparin therapy. Certain conditions can be evaluated
at the time of the thrombosis; other conditions cannot be evaluated at the
time because the clotting process and/or anticoagulants may consume
certain factors. Heparin-induced antiplatelet antibodies, the lupus antico-
agulant, anticardiolipin antibodies, homocystine levels, the Leiden muta-
tion, and the prothrombin variant can be assessed during the thrombotic
episode. The remaining tests (protein C, S, antithrombin III) are measured
when the patient is no longer receiving anticoagulation therapy with
warfarin and the heparin has been stopped for at least 3 days. This time
delay allows for replenishment of clotting factors. Table 4 summarizes the
diagnosis and treatment of the common hypercoagulable states.
Prophylaxis of Venous Thromboembolism
Acceptance of the Concept
  The concept of prophylaxis has been accepted as valid by European
surgeons more readily than by North American surgeons. Bergqvist15
analyzed the results of 3 surveys that were conducted in Sweden and
found that the proportion of clinics that used some form of prophylaxis
increased from 81% in 1977 to 100% in 1988. A survey of 3500 Fellows
of the American College of Surgeons in 1993 that analyzed attitudes
towards the prevention of postoperative DVT found that 86% of North
American surgeons used some form of prophylaxis.16 Those surgeons did
96                                                          Curr Probl Surg, February 2003
TABLE 4. The common syndromes of hypercoagulability
         Syndrome                     Diagnosis                       Treatment
Antiphospholipid10             Lupus anticoagulant or      Warfarin or LMWH as long as
                                 anticardiolipin            antibodies persist
                                 antibodies
Antithrombin III deficiency11   AT III grade 80%            Antithrombin concentrate
                                                              (ATnativ, Kabi Pharmarcia) in
                                                              combination with heparin
Protein C and S                Protein C and S levels      Anticoagulation for life
  deficiency13                                                 combined with replacement of
                                                              factors during periods of risk
Activated protein-C            Measure functional APC-     Lifetime anticoagulation
  resistnace (APC-R)6–8        R and then PCR for factor
                                 V Leiden mutation
Hyperhomocystinemia14          Homocystine levels          Folate
Prothrombin gene variant9      Gene 202210A                Lifetime anticoagulation
Heparin-induced                Thrombocytopenia,           Remove all exposure to heparin,
  thrombocytopenia76–83          antibodies to platelets      aspirin; alternate
                                                              anticoagulant if thrombosis
                                                              diagnosed with Orgaran or
                                                              Refluden
LMWH, Low molecular weight heparin; ATIII, antithrombin III; PCR, polymerase chain reaction.




not rationalize the decision on the basis of the risk of complications, vis
a vis the risk of DVT. Prophylaxis is used in a higher proportion of
patients in teaching hospitals. The increased use of prophylaxis is due to
an increased awareness of the problem, improved mechanical devices,
and improved drug therapies. There is an increased usage of mechanical
devices, particularly intermittent pneumatic compression, in the United
States as compared with Europe. North American general surgeons are
particularly reluctant to use heparin as a method of prophylaxis on a
routine basis, reserving it for very high-risk patients in combination with
mechanical methods. A significant number of patients still receive aspirin
therapy for venous prophylaxis, despite the negative data and the lack of
endorsement from the National Institutes of Health.

Risk Factors
  Factors associated with higher risk for DVT after surgical procedures
are increased age, obesity, cancer, a history of DVT, recent surgical
procedures, and hypercoagulable states.17 The development of DVT in
pediatric patients is unusual, and prophylaxis is unnecessary unless 3 or
more of the mentioned risk factors are present.18 The second most
common cause of death in patients with cancer is thromboembolism.19
Curr Probl Surg, February 2003                                                           97
The highest risk occurs in patients with carcinoma of the pancreas, female
reproductive system, breast, colon, lung, and prostate.20 The risk for
embolic complications after DVT appears to be greatest in the first 5 days
after operation.

Etiologic Factors
  Most authorities agree that spontaneous DVT begins within the valve
cusp.21 One theory is that venous dilatation is responsible for local
hypoxic injury at the site of the early thrombus formation.22 Further
development of this hypothesis has focused on the role of vasoactive
mediators that are produced at the site of tissue injury, enter the
circulation, and have a vasodilatory effect on distant veins, which results
in endothelial damage.

Intermittent Pneumatic Compression
  A meta-analysis of all original articles from June 1966 to June 1996
evaluated the clinical effectiveness of intermittent pneumatic compres-
sion (IPC) devices in the prevention of DVT and pulmonary embolism
(PE) and compared these results to those with knee-high sleeves and
thigh-high sleeves.23 IPC devices reduced the relative risk of DVT by
62% when compared with placebo, by 47% when compared with
graduated compression stockings, and by 48% when compared with
low-dose heparin. IPC devices significantly reduced the risk of DVT
in high-risk patients, such as patients who undergo orthopedic and
general surgical procedures. When compared with warfarin in ortho-
pedic patients, IPC was better at preventing calf vein thrombosis, and
warfarin was better at preventing proximal DVT. IPC devices were not
protective against PE. IPC appears to have a beneficial effect beyond
the mechanical effect of compression on venous flow. There are 2
beneficial hematologic effects of IPC. First, IPC stimulates endoge-
nous fibrinolytic activity. The precise mechanism of this effect is not
clear, although tissue plasminogen activator is increased with IPC.24
The second hematologic effect of IPC is the stimulation of tissue
factor pathway inhibitor.25

Evidence-based Protocol
  Prevention of venous thromboembolism requires that every hospital
have a written policy and formal strategy (Table 5).26 Aspirin should
not be used as a sole prevention strategy (evidence grade 1A). General
surgical patients who are at low risk for DVT are those who are
younger than 40 years of age and undergoing minor procedures. They
98                                               Curr Probl Surg, February 2003
TABLE 5. Recommendations for venous prophylaxis15,17,23,26
              Surgical risk                                   Recommendation
Low: 40 yrs, minor procedure                       Early ambulation (grade 1C)
Moderate: minor procedures with                    Elastic stockings or IPC or low-dose UFH-
  thrombosis risk factors, age 40–60                 5000 IU subcutaneously q12h (grade
  yrs, major operation in patients 40                1A)
  yrs
High: 60 yrs, 40 yrs with major                    LMWH* or IPC (grade 1A)
  procedures and risk factors for
  thrombosis
Very high: 60 yrs with associated risk             LMWH* and IPC (grade 1A)
  factors for thrombosis
Total joint replacement32                          LMWH* or warfarin started before or
                                                     immediately after operation and
                                                     continued (grade 1A)
Very high with additional high risk for            IPC (grade 1C)
  bleeding23
*
 See Table 6.
IPC, Intermittent pneumatic compression; UFH, unfractionated heparin; LMWH, low molecular
weight heparin.




should have early ambulation as the sole recommended prophylaxis
(grade 1C). Minor surgical procedures in patients with additional risk
factors for thrombosis and every patient younger than 40 years of age
who undergoes major procedures and who have no additional risk
factors compose a moderate risk group. This group should have
low-dose UFH (5000 IU, subcutaneously, q12h), LMWH (Table 6),
elastic stockings (ES), or an IPC device (grade 1A). Higher risk
patients older than 60 years of age or patients older than 40 years of
age who undergo major procedures or with additional risk factors
should be treated with LMWH or intermittent compression (grade 1A).
Higher risk patients with an increased risk for bleeding should receive
mechanical prophylaxis with ES or IPC (grade 1C). Very high-risk
patients should receive heparin combined with ES or IPC (grade 1C).
Patients who undergo total hip replacement or total knee replacement
should have LMWH or adjusted-dose warfarin therapy started before
or immediately after the operation (grade 1A). These recommenda-
tions are suitable for all surgical specialties, with anticoagulants added
to mechanical devices as the risk of thrombosis increases. Duplex
scanning should be used liberally, particularly when anticoagulants are
not administered because of the risk of bleeding. All anticoagulants
should be used with caution in cases that involve either spinal or
epidural anesthesia (grade 1C ).
Curr Probl Surg, February 2003                                                           99
TABLE 6. Low molecular weight heparin preparations
       Drug                Dosage for prophylaxis               Dosage for treatment
Ardeparin (Normiflo)        50 anti-Xa IU/kg,              NA
                             subcutaneously
                             q12h
Dalteparin                 2500-5000 IU,                  200 IU/kg subcutaneously daily
  (Fragmin)                  subcutaneously daily
Enoxaparin                 30 mg, subcutaneously          1 mg/kg, subcutaneously q12h*
  (Lovenox)                  twice daily, or 40             or 1.5 mg/kg daily (inpatients
                             mg, subcutaneously             only)*
                             daily
Tinzaparin                 NA                             175 anti-factor Xa IU/kg daily*
  (Innohep)
NA, Not approved.
*
  Anti-factor Xa activity should be measured to guide dosing for patients who weigh more than
120 kg.




Special Circumstances
  Critically Ill Patients. Acutely ill and/or critically ill patients are at
particular risk for venous thromboembolic complications and can not
afford the additional stress of thrombosis and PE. Two reports have
focused on the problem of venous thromboembolism in this group of
patients. In the first group, no patient received specific prophylaxis, and
all patients underwent venography to assess the incidence of DVT.27 In
the second group, patients were assigned randomly to receive either UFH
(5000 IU, subcutaneously q12h) or LMWH (enoxaparin 30 mg, subcu-
taneously q12h).28 The incidence of DVT was reduced by 30% in the
patients who received LMWH, as compared with the group who received
UFH. There were more major hemorrhages in the LMWH group. The
relative risk for hemorrhage with the use of LMWH has been studied in
trials that involved patients with serious medical illnesses. The FRAMI
(fragmin in acute myocardial infarction) study showed that a higher dose
grade was associated with increased efficacy, but a higher risk of
bleeding.29 The TIMI II (thrombolysis in myocardial infarction) study
demonstrated more bleeding complications when the higher of 2 doses of
LMWH was used.30 Some caution must be exercised before these results
are applied to critically injured patients. The latter tend to be younger than
patients with serious medical illness. Patients with traumatic injuries
should have prophylaxis with LMWH as soon as it is considered safe;
when this is contraindicated, ES or IPC should be used (grade 1C).
Screening with duplex ultrasound scans is indicated if prophylaxis is
suboptimal. If anticoagulation is contraindicated and DVT is diagnosed,
100                                                          Curr Probl Surg, February 2003
an inferior vena cava (IVC) filter should be inserted (grade 1C ).31 IVC
filters should not be used as primary prophylaxis (grade 1C).
   Colorectal Surgery. Colorectal surgery is associated with a higher risk
of thromboembolism than general surgical procedures. A review of the
literature by Wile-Jorgensen and colleagues32 identified 3 studies that
focused exclusively on colorectal procedures. These authors then suc-
cessfully contacted 16 other authors who included patients with colorectal
problems in their series. The ensuing analysis demonstrated that any type
of heparin is superior to no treatment or placebo in the prevention of
DVT, that LMWH and UFH were equally effective, and that the addition
of mechanical compression to any form of heparin is superior to heparin
alone.
   Patients with Cancer. The hypercoagulable tendencies of patients with
cancer and the increased risk for thromboembolism must be balanced
with increased risk of bleeding complications in patients undergoing
anticoagulation therapy.33 The risk of bleeding in patients with cancer
increases as the INR reaches supratherapeutic levels, and some investi-
gators suggest IVC filter placement as the primary means of prophylax-
is.34 Bergqvist and colleagues35 examined the optimal duration of therapy
for patients with cancer who undergo planned curative resections. Patients
(n      332) were assigned randomly to receive enoxaparin (40 mg,
subcutaneously daily) for 6 to 10 days, followed by either placebo or
enoxaparin for another 21 days. Bilateral venograms were performed
between days 25 and 31 in every patient. The primary efficacy end point
was DVT between days 25 and 31, and the primary safety end point was
bleeding during the 3-week period after randomization. The authors found
that the rates of DVT in the placebo group were significantly higher
(13.8% vs 5.5%; P .01), with no differences noted in bleeding or other
complications, and concluded that treatment should continue for 4 weeks
after planned curative operations for abdominal or pelvic cancer. These
data are comparable to those data that document the efficacy of prolonged
treatment with LMWH after orthopedic procedures36 and noncardiac
thoracic surgery37 and do not support the placement of IVC filters as the
primary means of prophylaxis. A meta-analysis of studies that compared
anticoagulation with IVC filters in patients with malignant disease
concluded that both treatments were equally effective but that filter
placement was less expensive and provided a greater gain in quality-
adjusted life expectancy, when anticoagulation monitoring was consid-
ered.38 Nonetheless, the preponderance of opinion favors a selective
approach to IVC filter placement, with anticoagulation used as primary
prophylaxis.
Curr Probl Surg, February 2003                                        101
  Peripheral Vascular Patients
  Infrainguinal Bypass. Leg swelling is a common occurrence after
infrainguinal bypass, but the incidence of DVT is not well documented.
Certainly the immobility, limb edema, and associated hypercoagulable
conditions would seem to put this patient population at risk. Passman and
colleagues39 prospectively evaluated 74 patients who had undergone
infrainguinal bypass grafting with bilateral venous duplex scanning
before the operation and then 1 week and 6 weeks after the operation.
These investigators found that the risk of DVT was low (2.8%) and that
routine prophylaxis was not indicated.
  Amputations. The association between DVT and patients who undergo
amputation has been investigated, with conflicting results. One of the
problems with most of the earlier studies is the method of diagnosis of the
DVT. Now that the accuracy of duplex scanning for DVT has been
validated, an accurate assessment of the relationship can be determined.
Yeager and colleagues40 used duplex scanning of both lower extremities
to evaluate prospectively 31 patients with above-knee amputations and 41
patients with below-knee amputations. The overall incidence of DVT was
11%. These investigators concluded that patients with a history of DVT
were at higher risk, that the DVT often occurred in the contralateral leg,
and that DVT may be present before the amputation. Their recommen-
dations include routine duplex scanning in any patient before amputation,
but DVT prophylaxis with anticoagulants is not routinely pursued.

Duration of Prophylaxis
  Hull and colleagues41 evaluated extended out-of-hospital LMWH pro-
phylaxis after elective hip arthroplasty. The authors reviewed data from
206 relevant studies and concluded that the evidence supported that the
extended use of LMWH as both effective and safe. The optimal duration
of anticoagulant therapy was not defined in these studies, and extended
therapy was associated with a risk of major bleeding that approached 3%
per year.42 Kearon and colleagues43 examined the optimal duration of
anticoagulant therapy after a first episode of DVT in a multicenter
randomized trial. These authors found that there is a high rate of
recurrence in those patients with idiopathic DVT when anticoagulation is
discontinued after 3 months of therapy. Patients who receive placebo had
a 27.4% incidence of recurrence as compared with an incidence of 1.3%
in patients who received warfarin therapy. The only patients at a higher
risk for a recurrence were those patients with the lupus anticoagulant.
Even the presence of factor V (Leiden) did not predict recurrence.
102                                              Curr Probl Surg, February 2003
Low Molecular Weight Heparin
Mechanism of Action
  LMWHs are at least as effective and safe as UFH and more convenient
to use. They can be used without laboratory monitoring, and there is a
more predictable relationship between dose and response. The anticoag-
ulant effects of the 2 types of heparin are different. The anticoagulant
effect of UFH is largely due to the inhibition of thrombin by the formation
of a 3-way complex of thrombin, antithrombin, and heparin. LMWH
(fractions and fragments of UFH) has less antithrombin activity, and the
anticoagulant effect is due to anti-factor Xa inhibition. The increased
bioavailability and plasma half-life enable once-per-day dosing as com-
pared with multiple injections for UFH. Dosing is based on body weight,
and monitoring is not necessary, except in patients with renal failure
because the excretion of drug is through the kidneys. Several experimen-
tal and clinical studies suggest that an improved cost/benefit ratio can be
expected with LMWH compared with UFH.
Comparisons to Unfractionated Heparin
  A recent meta-analysis was performed to (1) verify the clinical effect of
LMWH in the prevention of venous thromboembolism compared with
UFH, placebo, or no treatment; (2) to examine the effect of LMWH in a
subset of patients with cancer, and (3) to compare results with low and
high prophylactic dosages.44
  Prevention. Data from 59 RCTs and 48,624 patients qualified for use in
this analysis. Primary end point verification with objective tests (such as
duplex ultrasonography, fibrinogen uptake, impedance plethysmography,
or venography) were required. Patients who underwent orthopedic,
noncancer thoracic, or noncancer laparoscopic procedures were excluded
from the analysis. Secondary end points included bleeding and thrombo-
embolic complications.
  The incidences of venous thromboses, PE, and death for the no
treatment and placebo groups were 14.5%, 0.5%, and 0.9%, respectively.
These data put the patient who underwent general surgical procedures at
comparable risk for thromboembolic complications as patients with acute
myocardial infarction45 but at less risk than those patients who underwent
orthopedic procedures.46 The incidence of DVT was reduced by 72% in
the LMWH group (P .001). The incidence of PE was reduced by 71%
in the LMWH group (P           .018), and the overall mortality rate was
reduced by 46% (P         .09). Hemorrhage was more frequent in the
anticoagulated group (103% for major hemorrhage, 106% for total
Curr Probl Surg, February 2003                                         103
hemorrhage, 88% for wound hematoma, and 53% for transfusion require-
ments; P        .001 for all criteria). Wound hematomas occur more
frequently than major hemorrhage (10.3% vs 2.8%). When LMWH was
compared with UFH, LMWH was statistically superior for the prevention
of DVT, PE, all thromboembolism, major hemorrhage, total hemorrhage,
and wound hematoma. UFH was superior in reduced mortality rates and
transfusion requirements. When only the well-identified double-blind
series were analyzed the trends in favor of LMWH disappeared.
  Efficacy in Patients with Cancer. When the subset of patients with
cancer was analyzed, the efficacy and safety of LMWH relative to UFH
were similar to those in patients with nonmalignant disease. Low-dose
LMWH (3400 anti-Xa units or less) did not significantly reduce the
incidence of venous thromboembolism compared with UFH but did
reduce the incidence of hemorrhagic risk (P .005). High-dose LMWH
(greater than 3400 anti-Xa units) was more effective than UFH, particu-
larly in regard to the prevention of PE, but this benefit was counterbal-
anced by a significant increase in the risk of major hemorrhage. These
data are similar to those reported by Kakkar47 in general surgical patients.
Best evidence therefore suggests a close similarity between LMWH and
UFH with regard to both thromboembolic and hemorrhagic events, but
the ease of use of LMWH makes it preferable in contemporary practice.
  Dosing Information. Low-dose LMWH provides comparable efficacy
and increased safety over UFH; high-dose LMWH does not improve
efficacy, and safety is strongly decreased.48 Dosing information for
commercially available LMWHs is listed in Table 6.

The Use of Oral Anticoagulants49
The Initiation of Therapy
  Warfarin therapy should begin with a daily maintenance dose of 5 mg.
Lower initial doses should be considered in elderly patients, patients with
hepatic dysfunction or malnutrition, and patients at high risk for bleeding.
Warfarin should not be administered to pregnant patients during the first
and third trimester, to patients with alcoholism or drug abuse, and patients
with unsupervised dementia. A loading dose is not necessary and, in
certain situations, can be dangerous. Warfarin can be started simulta-
neously with heparin, unless an underlying hypercoagulable state is
suspected. In those situations, heparin anticoagulation should precede the
administration of warfarin. All dose adjustments should be based on the
international normalized ratio (INR) level. The appropriate INR targets
for a variety of conditions are listed in Table 7.
104                                               Curr Probl Surg, February 2003
TABLE 7. Recommended international normalized ratio (INR) levels116
                                        Target INR
        Indication                                                        Duration
                                         (range)
DVT prophylaxis                        2.5 (2.0-3.0)             4-6 Weeks after operation
DVT, episode 1                         2.5 (2.0-3.0)             3-6 Months
PE, treatment                          2.5 (2.0-3.0)             3-6 Months
Arterial embolus, AF                   2.5 (2.0-3.0)             Life
Arterial embolus, MI                   3.0 (2.5-3.5)             Variable
Bioprosthetic heart valves             2.5 (2.0-3.0)             3 Months after operation
Mechanical heart valves                3.0 (2.5-3.5)             Life
Prosthetic bypass grafts89             3.0-4.5                   Life of bypass graft
DVT, Deep venous thrombosis; PE, pulmonary embolism; AF, atrial fibrillation; MI, myocardial
infarction.




Indications and International Normalized Ratio
Recommendations
  Warfarin in adjusted doses to maintain the INR between 2.0 and 3.0 is
indicated for the following conditions: prophylaxis of DVT of high-risk
surgery, treatment of DVT, treatment of PE, prevention of arterial
embolism after acute myocardial infarction, in patients with atrial
fibrillation and tissue heart valves, and prevention of the propagation of
existing thrombus. The INR should be maintained in the range of 2.5 to
3.5 for patients with mechanical heart valves and for patients with
antiphospholipid syndrome. When warfarin is started with a dosage of 5
mg, the INR should reach the desired level in 4 to 5 days. If the INR on
day 2 of therapy exceeds 1.5, the dose of warfarin should be reduced. If
the INR is less than 1.5 on day 3, a higher maintenance dose will be
necessary. An INR between 1.5 and 2.0 suggests that the maintenance
dose will be 5 mg; an INR of more than 2.0 suggests that a lower dose will
be necessary.

The Treatment of Patients with Prolonged International
Normalized Ratio Levels
  The treatment of patients with excessive prolongation of the INR
depends on the level, whether the patient is bleeding, and whether the
patient is to undergo an invasive procedure. If the INR is less than 5.0 and
there is no bleeding or anticipated intervention, the warfarin should be
withheld until the INR is therapeutic. Patients with an INR of more than
5.0 but less than 9.0 who require rapid reversal before an intervention
should receive vitamin K1 (2-4 mg orally) and another 1 to 2 mg of
vitamin K1in 24 hours if the INR remains high. Warfarin can be resumed
Curr Probl Surg, February 2003                                                         105
when the INR is at target levels. Patients with an INR of more than 9.0
and no significant bleeding should receive vitamin K1 (3-5 mg orally)
with additional vitamin K1 after 24 hours, as necessary. For an INR of
more than 20 that is associated with serious bleeding, patients should
receive vitamin K1 10 mg by slow intravenous infusion that is supple-
mented with fresh frozen plasma (15 mL/kg) or prothrombin complex,
depending on the urgency.
  The risk of bleeding complications in patients who are treated with
long-term anticoagulants has been evaluated in numerous RCTs. A
meta-analysis of the trials that evaluated anticoagulation for atrial
fibrillation, recent myocardial infarction, and prosthetic heart valves by
Gullov and colleagues50 determined that the incidence of fatal and major
hemorrhage was reduced significantly by better control because of the
adoption of the INR. Regardless of the duration of therapy, patients who
receive warfarin anticoagulation therapy must be monitored closely.
Patients who are enrolled in the Veterans Affairs Stroke Prevention Trial
in nonrheumatic atrial fibrillation were monitored weekly for 12 weeks
and then monthly. Considerable dose adjusting was required, with only
28% of the patients in the desired range at 1 week and to 65% in the
desired range at week 12. Dosing adjustments were required in 40% of the
patients in the monthly surveillance period.51

Complications, Nonhemorrhagic
  The most serious nonhemorrhagic complication of warfarin therapy is
skin necrosis that occurs in patients with protein C and S deficiency. In
this condition, a hypercoagulable state occurs after 2 to 3 days of warfarin
therapy. This complication can be avoided if all patients are treated with
heparin for the first 4 days of warfarin therapy.

Efficacy in Patients with Coronary Artery Disease
  The value of aspirin in the secondary prevention of thrombotic
complications from coronary artery disease (CAD) has been established
firmly.52 There is emerging evidence that the simultaneous alteration in
platelet activity and fibrin formation may be more effective than either
strategy alone.53 The first Northwick Park Heart Study found an associ-
ation between the level of factor VII activity and CAD. Those patients in
whom CAD developed had elevated levels of factor VII (117%) as
compared with patients who were at low risk whose factor VII levels were
below normal (70%).54 This reduction in factor VII corresponds to raising
the INR to 1.5. This is less than the level necessary for efficacy in venous
thromboprophylaxis and likely to cause less major bleeding. A trial that
106                                               Curr Probl Surg, February 2003
evaluated low intensity oral anticoagulation with warfarin and low-dose
aspirin in the primary prevention of CAD was conducted in the United
Kingdom.55 A total of 5499 men who were at high risk for CAD were
assigned randomly into 4 groups: active warfarin and active aspirin
(group WA), active warfarin and placebo aspirin (group W), placebo
warfarin and active aspirin (group A), and placebo warfarin and placebo
aspirin (group P). Patients in the active aspirin groups received 75 mg
daily in a controlled release formulation. The warfarin dosage was
adjusted to maintain the INR at 1.5. The WA group experienced
significantly fewer ischemic cardiac events that the P group (8.7 vs 13.3
per 1000 person years; P       .006). Comparisons among the W and A
groups with the P group showed benefits (20% reduction in CAD events),
but these differences were not statistically significant. These data have
implications in high-risk patients who undergo operation, providing that
the benefits of cardiac protection exceed the risks of major hemorrhage.

Estrogen Therapy and Pregnancy56
Estrogen and Thrombosis
  Many women receive chronic estrogen therapy either as a contraceptive
or later in life as replacement therapy, although the latter practice is likely
to decrease with the new information from the Women’s Health Initiative
Trial.57 This study, which evaluated the use of estrogen and progestin in
healthy postmenopausal women, found that the overall health risks
exceeded the benefits of replacement therapy over an average period of
5.2 years. This trial will result undoubtedly in fewer women receiving
hormone therapy and less risk for thromboembolic problems that are
associated with surgical interventions. There is ample evidence that
indicates an increased risk for venous thromboembolism in women who
are receiving estrogen therapy, which ranges from 2 times to 11 times
normal.58 The addition of an inherited or acquired coagulation disorder
raises the risk of DVT 50-fold in a patient receiving estrogen therapy.59
The incidence of DVT is 5 times higher in pregnant patients than in
nonpregnant patients. Factors that may make pregnant women more
susceptible to the development of a DVT are varicose veins, iliac vein
compression, and stasis. In addition, levels of factors I, VII, VIII, IX, X,
XI, XII, and platelets are increased; antithrombin III and protein S are
decreased. These changes revert to baseline within 2 months of deliv-
ery.60 The Leiden mutation in the factor V gene predisposes patients to
thrombotic events and is relatively common in the obstetric population.
Curr Probl Surg, February 2003                                             107
The prothrombin gene variant (20210A), protein C and S deficiencies,
and anticardiolipin antibodies are also relatively common.61

Venous Prophylaxis during Pregnancy
  Heparin does not cross the placental barrier and has become the gold
standard anticoagulant during pregnancy. Patients who receive long-term
warfarin anticoagulation therapy should be counseled about the risks of
pregnancy. If pregnancy is elected, patients can be switched to adjusted-
dose UFH or LMWH. Pregnant patients with mechanical heart valves
present an added challenge because they require therapeutic anticoagu-
lation that can be achieved in several ways throughout the pregnancy.
Adjusted-dose UFH can be used throughout the pregnancy. Alternatively,
heparin can be used until week 13; warfarin can be used until the middle
of the third trimester, and then heparin can be restarted until delivery.
  Pregnant patients who are at moderate risk are those patients with a
previous DVT that was associated with a transient risk factor and no
current risk factors (such as morbid obesity or strict bed rest). Duplex
surveillance and postpartum anticoagulants are indicated in this group
(grade 1C). Patients with a history of an unexplained DVT but who are
not receiving long-term anticoagulation therapy should have duplex
surveillance, low-dose UFH (5000 IU, subcutaneously q12h), or prophy-
lactic LMWH (Table 6) in addition to postpartum anticoagulants (grade
1C ). Patients who are at very high risk for recurrent thromboembolism
should be treated with intravenous UFH to maintain the activated partial
thromboplastin time (APTT) within the therapeutic range (grade 1C). If
LMWH is chosen in place of UFH, the dosing should be adjusted
according to body weight. Heparin therapy must be discontinued 4 to 6
hours before delivery. Women with more than 3 miscarriages and women
with a history of preeclampsia or abruption and antiphospholipid antibody
should receive prophylactic LMWH (grade 1A). Anticoagulation should
be continued for 6 weeks or 3 to 6 months if a diagnosis of venous
thromboembolism is verified. Warfarin can be used in the postpartum
period, initially overlapped with LMWH or UFH until the INR is more
than 2.0.

Platelet Antagonists
Physiologic Features
 The role of antiplatelet agents has been investigated in arterial throm-
bosis and embolism, occlusive and hemorrhagic strokes, angina and
myocardial infarctions, venous thromboprophylaxis and PE, and resteno-
108                                             Curr Probl Surg, February 2003
ses and occlusions after arterial reconstructions. It is now evident that the
platelet plays a role of varying significance in all of these areas. Platelets
are derived from the bone marrow megakaryocytes and have a life span
of 10 days. The intact endothelium is nonreactive to the platelet, but in the
setting of an interruption of a blood vessel or certain immune complexes,
the platelet becomes activated. When this occurs, the platelet changes
shape from a disc to a spiny sphere, and the surface membrane develops
the capacity to catalyze interactions between activated coagulation
proteins. The platelet thus interacts with the coagulation cascade in the
early stages of thrombus formation to form thrombin that generates the
fibrin that is necessary to stabilize the hemostatic plug.
Mechanisms of Blocking Platelet Function
and Aggregation
  There are 5 avenues for blocking platelet function and aggregation: (1)
blocking cyclooxygenase and thromboxane A2 production, (2) blocking
thromboxane synthase, (3) blocking the thromboxane A2-receptor, (4)
inhibiting exposure of Gp IIb/IIIa receptor sites, or (5) directly blocking
these receptors. The final common pathway by which all platelet agonists
ultimately effect platelet aggregation is the transformation of the Gp
IIb/IIIa receptor site on the platelet membrane.
Aspirin
  Mechanism of Action. Aspirin, the most commonly used anti-platelet
agent, irreversibly inhibits the formation of thromboxane A2 and rein-
forces the effects of other platelet antagonists.62 Aspirin doses between 75
and 162.5 mg are effective for all indicated uses (Table 8). Regular
aspirin is absorbed in the stomach with peak plasma levels, which occur
in 30 minutes. Enteric coated aspirin is absorbed more slowly with
evidence of antiplatelet activity in 3 to 4 hours after administration. The
antiplatelet effect lasts for the life of the platelet.
  Indications for Use. Aspirin as a primary preventive measure for CAD
is not recommended for patients younger than 50 years of age with no
other risk factors (grade 2B). Aspirin is recommended for patients older
than 50 years of age with a major risk factor for CAD such as cigarette
smoking, hypertension, diabetes mellitus, elevated serum cholesterol, and
family history (Grade men 2A, grade women 2C). Aspirin is also
recommended for patients with noncardiac transient ischemic attack
(TIA) but in this situation is more effective when combined with
dipyridamole (grade 1A). Aspirin should be administered to patients
before and after carotid endarterectomy (CE; grade 1A) and femoral
Curr Probl Surg, February 2003                                           109
TABLE 8. Recommendations for the use of aspirin52,62– 65,117
                     Indication                                Strength of recommendation
Primary prevention of CAD in patients 50 yrs of           Not indicated (grade 2B)
  age without risk factors
Primary prevention of CAD with risk factors55             Indicated in men (grade 2A)
                                                          Indicated in women (grade 2C)
TIA, noncardiac                                           Indicated, but more effective with
                                                            dipyridamole (grade 1A)
Before and after operation for patients who               Indicated (grade 1A)
  undergo carotid endarterectomy70,71
Patients with angina pectoris and/or myocardial           Indicated (grade 1A)
  infarction
Patients with atrial fibrillation                          Not indicated (grade 1A)
Patients with prosthetic arterial bypass grafts87–89      Indicated - started pre-op (grade
                                                            1A); combine with warfarin for
                                                            high-risk grafts (grade 1A)
Patients with saphenous vein grafts85                     Indicated (grade 1C )
Venous thromboprophylaxis46                               Not indicated (grade 1A)
CAD, Coronary artery disease; TIA, transient ischemic attack.



popliteal bypass grafts (grade 1C for saphenous vein, grade 1A for
prosthetic). Any patient with the clinical impression of an acute myocar-
dial infarction or angina pectoris should receive aspirin, which should be
continued indefinitely (grade 1A). Aspirin should not be administered
concurrently with warfarin, except for patients with very high risk for
thromboembolism or failure of either drug alone (grade 2C). Patients with
atrial fibrillation are better treated with warfarin, and aspirin does not add
therapeutic benefit. The use of aspirin with warfarin is indicated in certain
situations such as arterial embolization from mechanical heart valves and
atrial fibrillation despite adequate anticoagulation. When administered
together, the risk of bleeding is increased significantly.63 The bleeding
risk can be lowered by the use of low doses of both aspirin and warfarin
(INR, 1.5-2.0), but this may not be effective in these difficult to treat
patients. Although aspirin reduces the incidence of vascular occlusions by
25%, most arterial thrombotic events still occur in patients who take
aspirin.64
  Side Effects. The most common side effects of aspirin are gastrointes-
tinal and range from mild erosions to frank ulceration of the gastric
mucosa. The most alarming side effect, however, is the small, but real,
incidence of intracranial hemorrhage in healthy men who receive aspirin
for prophylaxis against heart attack and stroke.65 When aspirin is used as
secondary prophylaxis (ie, in higher-risk patients), the risk of intracranial
bleeding is superceded because of the relatively greater benefit of aspirin
in this setting.
110                                                             Curr Probl Surg, February 2003
Adenosine Diphosphate Receptor Antagonists
  A group of antiplatelet agents that act as specific adenosine diphosphate
receptor antagonists has been approved. The 2 drugs that are available
currently are ticlopidine hydrochloride (Ticlid) and clopidogrel bisulfate
(Plavix). Ticlid is indicated for patients who have had a stroke or TIA and
are unable to take aspirin. The effect of Ticlid reaches 50% of maximum
after 4 days of treatment. Problems with neutropenia (1.6%) and agran-
ulocytosis (0.8%) require regular monitoring and have limited its usage.
Plavix is indicated in patients at high risk for myocardial infarction and/or
stroke and has fewer serious side effects. Its effect is rapid, achieving
platelet inhibition within 2 hours of dosing. The most common side effect
is rash (0.3%). This agent can also be used when aspirin cannot be used
and in cases of aspirin failure. The clopidogrel versus aspirin in patients
at risk of ischemic events (CAPRIE) trial that involved 19,000 patients
showed that clopidogrel was superior to aspirin in reducing arterial
thrombotic events and was safer with fewer hemorrhages.66
  A study that examined whether the combination of aspirin and clopi-
dogrel increased the risk of bleeding was performed in response to the
increasing use of combination therapy in contemporary practice.67 The
hematologic end point in this trial was the measurement of bleeding
times, which were elevated after combination therapy. This does not
correlate necessarily with surgical bleeding but raises some concerns,
because combination therapy will be used increasingly as the results of
the clopidogrel in unstable angina to prevent recurrent events trial
(CURE) study are made available. This trial showed a significant benefit
for patients with acute coronary syndromes who were receiving combined
therapy.68

Gp IIb/IIIa Inhibitors
  Antiplatelet agents directed against the final common pathway, the
fibrinogen receptor on the platelet membrane, are extremely potent and
are used with a greater risk of bleeding complications. Abciximab
(ReoPro) is a monoclonal antibody directed against the Gp IIb/IIIa
receptor sites. This and several other agents in various stages of
development have the net effect of reducing the amount of platelet
membrane available to form thrombus. Abciximab blocks the platelet
aggregation seen in patients with heparin-induced thrombocytopenia
(HIT) but is not a sufficient anticoagulant as a sole agent in this condition.
ReoPro can be used with heparin and aspirin to decrease cardiac ischemic
Curr Probl Surg, February 2003                                           111
TABLE 9. Antiplatelet agents (non-aspirin)
            Drug                     Indication for use                 Action/timing
Abciximab (ReoPro)74,75          Used with heparin and          Group IIb/IIIa inhibitor
                                   aspirin to reduce            Onset of action within
                                   complications after            minutes, half-life 24–48
                                   PTCA and unstable              hours
                                   angina
Clopidogrel (Plavix)66–68        Reduce atherosclerotic         ADP receptor antagonist
                                   events (MI, stroke,          Onset of action within 24
                                   vascular death) in high-       hours - duration 5 days after
                                   risk patients                  stopping
Dipyridamole (Persantine)63      Additive effect with aspirin   Inhibits phosphodiesterase
                                   in patients with TIA
Eptifibatide (Integrelin)         Acute coronary syndrome        Group IIb/IIIa antagonist
                                   with heparin and aspirin     Has a reversible effect when
                                      PTCA                        drug is discontinued and
                                                                  action is very brief
Ticlopidine (Ticlid)94           CVA prophylaxis in             ADP receptor antagonist
                                   patients who cannot          Onset of action within 4 days
                                   take aspirin                 Duration 2 weeks after
                                                                  stopping
PTCA, Percutaneous transluminal coronary angioplasty; MI myocardial infarction; ADP,
adenosine diphosphate; TIA, transient ischemic attack; CVA, cerebrovascular accident.




complications before and after percutaneous coronary interventions.
Table 9 lists the indications for use of the nonaspirin antiplatelet agents.
  CE is the most frequently performed vascular procedure in the United
States. In the last decade, there has been a large increase in case volume
after confirmation of the efficacy of CE by the North American Symp-
tomatic Carotid Endarterectomy Trial and ACAS trials. Despite the
efficacy of CE over medical treatment for extracranial cerebral vascular
disease, the risk of an ipsilateral perioperative stroke after CE remains at
2% to 7%.69,70 There are 2 main types of operation-related stroke. The
intraoperative stroke, apparent on recovery from anesthesia, is attribut-
able directly to intraoperative ischemia or embolization. The postopera-
tive stroke that occurs sometime after an uneventful recovery from
operation is due to vessel occlusion or embolization from the thrombo-
genic endarterectomized surface. Evidence suggests that platelets adhere
to the exposed surface collagen within minutes of restoring flow.71
Microparticulate embolization can be detected by transcranial Doppler
ultrasound with good correlation between the detection of 25 or more
emboli in the middle cerebral artery distribution during any 10-minute
period after operation and an increased occurrence of TIA and/or stroke.72
Infusion of dextran 40 has been shown to decrease the rate of emboliza-
112                                                             Curr Probl Surg, February 2003
tion of microparticulate debris,73 but no data are available on the role of
Gp IIb/IIIa antagonists in this setting.
  Recent success in decreasing thrombotic events in both percutaneous
coronary interventions and acute myocardial infarction with platelet Gp
IIb/IIIa antagonists has stimulated interest in furthering the applications
of these drugs. A recent RCT that used abciximab in acute ischemic
stroke documented safety when it was administered up to 24 hours after
stroke onset, with a trend toward improvement in functional outcomes.74
Abciximab has also been used in conjunction with heparin and aspirin in
carotid artery percutaneous angioplasty and stenting and is thought
potentially to reduce recurrent stenoses.75 Unfortunately, the use of
platelet Gp IIb/IIIa inhibitors with open surgical procedures has not been
studied because of concerns of bleeding.

Heparin-induced Thrombocytopenia
Diagnosis
  Occasionally patients who require anticoagulation during a surgical
procedure will have a history of HIT. This immune disorder occurs in 2%
to 4% of patients who receive heparin therapy, and these patients have a
2.6-fold increase in the incidence of perioperative thromboses.76 Patients
with heparin-associated antiplatelet antibodies that are exposed to heparin
may have platelet aggregation and thrombosis. When the diagnosis is
suspected (falling platelet count, resistance to heparin anticoagulation,
unexplained thrombosis), all sources of heparin must be discontinued; the
plasma should be tested for antiplatelet antibodies, and platelet function
should be blocked with aspirin.

Treatment Options
  When rapid anticoagulation is required, there are 3 classes of drugs that
can be used: (1) LMWH, (2) heparinoids, or (3) thrombin inhibitors.
Although there are reports of the successful use of LMWH, there is a
significant risk of cross-reactivity, and the use of these drugs should be
avoided in this situation, unless studies reveal no cross-reactivity with the
patient’s antibodies. The likelihood of cross-reactivity approaches 33%
against enoxaparin (Lovenox) and dalteparin (Fragmin). The heparinoid,
danaproid (Orgaran), is approved for patients with HIT who require
anticoagulation therapy during a surgical procedure. Orgaran is purified
from porcine intestinal mucosa and has been used as the sole anticoag-
ulant for hemodialysis, cardiopulmonary bypass, and DVT.77–79 Cross-
reactivity is approximately 10%, and patients with HIT who receive
Curr Probl Surg, February 2003                                           113
Orgaran therapy should undergo platelet reactivity testing.80 Some
caution must be used when Orgaran is used as an anticoagulant during a
surgical procedure because the incidence of bleeding after cardiopulmo-
nary bypass has been reported to be 23%.81 The high incidence of
bleeding is due to the long anticoagulant effect (plasma anti-factor Xa
activity is 25 hours) and the absence of a reversing agent. Protamine
sulfate reverses the antithrombin effect, but not the anti-factor Xa activity.
The intraoperative treatment is further complicated because the activated
clotting time and the activated partial thromboplastin time have no value
in the determination of the anticoagulant effect. The only reliable
intraoperative monitoring assay for Orgaran effect is the anti-factor Xa
assay that is measured every 20 minutes.82 Intraoperative dosing should
be titrated, and only the amount required should be administered. An
anti-factor Xa grade of more than 1.0 U/mL is necessary to prevent clots
in the filters of the cardiopulmonary bypass machine, but levels of more
than 1.50 U/mL have been associated with excessive postoperative
bleeding.
  Lepirudin (Refludan) a recombinant hirudin, has also been used in
patients with HIT. A prospective multicenter trial that involved 82
patients with HIT was conducted to evaluate Refludan.83 There were 51
patients with thrombosis, 5 patients with thrombosis who received
thrombolysis therapy, 18 patients without thrombosis, and 8 patients with
thrombosis during cardiopulmonary bypass. Outcomes were compared
with a historic group of 120 patients. The incidences of death, amputation,
and new thromboembolic events were reduced significantly in the patients
who were treated with Refludan; bleeding complications were similar in
both groups. The drug has a half-life of 1.3 hours in patients with normal
renal function and is associated with a rapid recovery of platelet counts
and prolongation of the activated partial thromboplastin time. These are
major advantages when compared with Orgaran. Patients with HIT who
require prolonged anticoagulation therapy should be converted to warfa-
rin therapy as soon as possible.

Antithrombotic Therapy in Peripheral Arterial
Occlusive Disease
Arterial Embolism
  Systemic heparin followed by oral anticoagulation is indicated in
patients with atrial fibrillation or post–myocardial infarction and
arterial embolization (grade 1C). The purpose of anticoagulation in
114                                                Curr Probl Surg, February 2003
TABLE 10. Antithrombotic treatment in peripheral arterial disease   85–90


               Indication                                                   Recommendation
Arterial embolism                                               Antiplatelet - No
                                                                Warfarin - Yes
Aortofemoral bypass                                             Antiplatelet - No
                                                                Warfarin - No
Carotid endarterectomy                                          Antiplatelet - Yes
                                                                Warfarin - No
Prosthetic femoropopliteal bypass                               Antiplatelet - Yes
                                                                Warfarin - No
Saphenous vein femoropopliteal bypass                           Antiplatelet - Yes
                                                                Warfarin - No
Infrageniculate bypass                                          Antiplatelet - Yes
                                                                Warfarin - Yes, with INR of
                                                                  3.0– 4.5
INR, Internaitonal normalized ratio.



this setting is both to prevent further embolic episodes and to
minimize proximal and distal propagation of thrombus (Table 10).84
Vascular Grafts
  Data do not support the use of prophylactic anticoagulation for vascular
reconstructions of high-flow, low-resistance arteries, such as aortofemoral
bypass grafts (grade 1C). Antiplatelet therapy has been shown to reduce the
risk of arterial graft failure in the femoropopliteal segment (grade 1A).85 A
meta-analysis of 5 RCTs that compared antiplatelet therapy with placebo
shows that 12 patients need treatment for 1 to 3 years to prevent 1 graft
occlusion. Antiplatelet therapy is more effective in the prevention of
occlusion of prosthetic grafts compared with vein grafts. Many investigators
believe that oral anticoagulation improves the patency rates after infraingui-
nal reconstruction, but the evidence that supports this belief is weak. The only
RCT that compared oral anticoagulation with placebo showed that 6 patients
required treatment to prevent 1 occlusion and 7 patients required treatment to
prevent 1 amputation.86 The effect of a combination of antiplatelet and oral
anticoagulants on graft occlusion and other vascular complications was
reviewed in a meta-analysis by Tangelder and colleagues.87 Outcomes
measures were occlusion of bypass grafts, the occurrence of stroke and/or
myocardial infarction, and death. The results confirmed the efficacy of
antiplatelet and anticoagulant therapy in prolonging graft patency without
any secondary benefit in other variables.
  Veteran Affairs Cooperative Study no. 362 examined the benefits of
long-term warfarin therapy in patients with lower extremity arterial bypass
grafts.88 The results show that the addition of warfarin does not add
Curr Probl Surg, February 2003                                                                115
protection beyond that provided by aspirin, the exception being
prosthetic above-knee prosthetic bypasses. Conflicting evidence was
presented by the investigators in the Dutch Oral Anticoagulant or
Aspirin study who found that, when the INR is targeted at 3.0 to 4.5,
warfarin provides added benefit to aspirin.89 Both trials determined,
however, that aspirin treatment provided the major benefit in terms of
graft patency. The explanation for the different effects of warfarin in
these 2 prospective trials probably had something to do with the INR
targets. In the Veterans Affairs study, the INR range that was selected
was 1.4 to 2.8, considerably lower than the bypass oral anticoagulants
or aspirin trial. The Veterans Affairs study also excluded high-risk
patients for thrombosis who were included in the bypass oral antico-
agulants or aspirin study. In another evaluation of warfarin therapy,
Sarac and colleagues90 found that the combination of drugs improved
patency rates in high-risk venous bypass grafts from 56% in patients
who received aspirin therapy alone, as compared with 77% in patients
on the combination over a 3-year period of follow-up. Most of these
studies point out that the long-term administration of warfarin in-
creases the risk of lethal intracranial hemorrhage.
  Jackson and colleagues91 examined the effects of warfarin anticoagulation
on the ischemic sequalae of graft occlusion. These investigators found that
the ischemic consequences of polytetrafluoroethylene (PTFE) bypass failure
were more severe than after vein graft failure. Warfarin lessened the ischemic
impact of PTFE grafts without an effect in patients with failed vein grafts but
did not lower the incidence of severe ischemia in failed PTFE to the level
seen with failed vein grafts.
  McMillen and colleagues92 evaluated the use of LMWH in the
perioperative period after 69 infrageniculate bypass grafts with PTFE.
LMWH was compared with UFH. This was a nonrandomized observa-
tional study that used UFH between April 1993 and October 1994 and
LMWH between October 1994 and January 1996. Coagulation studies
and the mean number of postoperative days were significantly lower in
the LMWH group, but there were no significant differences in graft
thrombosis or mortality rates.

Antithrombotic Treatment after Catheter-based
Arterial Interventions
The Role of Warfarin
  The rapid advances in balloon and stent technology for the treatment of
arterial and venous lesions have been abetted by the use of a variety of
116                                                 Curr Probl Surg, February 2003
anticoagulants. Warfarin was the first agent used after a canine experi-
ment by Palmaz and colleagues93 that showed decreased platelet deposi-
tion on intravascular stents in the group treated with a combination of
heparin, aspirin, dipyridamole, and dextran compared with the groups
treated with heparin alone or heparin with aspirin. Somehow, the authors
concluded that warfarin should be added to patients as a “safety net.” As
a result, the early stent trials and the FDA incorporated warfarin into their
guidelines. In 1991 the focus changed away from warfarin in an attempt
to reduce bleeding complications, shorten hospital stays, and improve
outcomes towards aspirin and ticlopidine.94 Data were collected largely in
registries; a large meta-analysis of 2295 patients revealed a statistically
significant and clinically meaningful improvement in results after coro-
nary stenting in patients who received ticlopidine therapy. Because the
comparisons were uncontrolled, the transition from warfarin to ticlopidine
was slow in the United States, as reflected in a consensus document from
the American College of Cardiology in 1996 that still recommended
warfarin anticoagulation for high-risk stent deployments.95

The Role of Anti-Platelet Agents
  The recommendation for warfarin, however, passed because data from
several randomized, placebo-controlled trials unequivocally showed the
superiority of ticlopidine over warfarin, as measured by the mortality rate
at 6 weeks, myocardial infarction, and the need for repeat revasculariza-
tion.96 At this time, clopidogrel has become the agent of choice in
combination with aspirin.97 The final chapter has not been written,
however, because new evidence that was presented in the enoxaparin and
ticlopidine after elective stenting trial suggests that LMWH (enoxaparin)
may be the optimal anticoagulant after coronary artery stenting.98

Recommendations
  The best available evidence suggests that the following protocol is
appropriate for patients who undergo percutaneous arterial interventions.
All patients should be pretreated with 80 to 325 mg of aspirin (grade 1A).
Plavix (300 mg loading dose followed by 75 mg/day) should be
administered to those patients who cannot tolerate aspirin (grade 1A).
Plavix can be added to aspirin for those patients who undergo stent
placement, but the supporting data are not as strong (grade 2A). Gp
IIb/IIIa inhibitors should be administered to reduce the incidence of
ischemic complications after percutaneous transluminal coronary angio-
plasty (grade 1A). There are no data to support the use of the Gp IIb/IIIa
inhibitors during noncardiac interventions. One of the concerns about the
Curr Probl Surg, February 2003                                           117
TABLE 11. Indications for perioperative anticoagulation49
                                                                        Strength of
                      Indication
                                                                     recommendation
Arterial embolism atrial fibrillation                                        1C
Mitral valve prolapse with documented embolization                          1A
Mobile aortic atheroma 4 mm by TEE                                          2C
Unexplained pulmonary embolism in patient with                              1C
   patent foramen ovale
Bileaflet mechanical aortic valve, tilting disk valve                        2A
   in mitral position, caged ball or disk valve53
Recent DVT44                                                                1A
Hypercoagulable state58                                                     1A
TEE, Transesophageal echocardiogram; DVT, deep venous thrombosis.




aggressive combination of Gp IIb/IIIa inhibitors and the obligatory
periprocedural use of heparin is the incidence of access site complica-
tions, which can be reduced by the reduction of the heparin dose to 50 to
70 IU/kg when Gp IIb/IIIa agents are used and the removal of the access
sheath when the activated clotting time falls below 150 seconds (grade
1A).
Operation in the Patient Who Undergoes
Anticoagulation Therapy
Which Patients Require Perioperative Anticoagulation
Therapy?
  Surgeons are often presented with a patient who is receiving anticoag-
ulation therapy who requires an intervention, and the surgeon must decide
whether the anticoagulant can be discontinued safely for the immediate
perioperative period. Indications and guidelines for perioperative antico-
agulation are listed in Tables 11 and 12. If there is a low risk of
thromboembolism, as in patients who are undergoing anticoagulation
therapy for chronic atrial fibrillation or for a history of DVT, the
anticoagulation may be discontinued 3 to 4 days before the procedure,
which allows the INR to return to near-normal values. Warfarin therapy
can then be resumed in these patients when oral intake is started. In
patients with atrial fibrillation, the risk of postoperative thromboembolism
is increased from 4.5% to 17.6% when 2 or more of the following factors
are present: a TIA or stroke or other thromboembolic events within the
past several months, hypertension, or recent congestive heart failure.99
These patients should receive short-term low-dose heparin (5000 IU
UFH, subcutaneously) during the procedure and shortly thereafter, and
118                                                         Curr Probl Surg, February 2003
TABLE 12. Operating on a patient who has received anticoagulation therapy
            History/risk                                Recommendation
Low risk (eg, history of DVT,        Discontinue anticoagulants 4–5 days before operation
  chronic atrial fibrillation)          and let INR return to normal; resume warfarin after
                                       operation
Moderate risk (eg, atrial fibrillationLow-dose UFH (5000 IU subcutaneously q12h) during
  with recent history of embolic       and shortly thereafter the procedure until warfarin is
  event, congestive heart failure)     resumed; LMWH is also a good choice here
High risk (eg, mechanical heart      Full anticoagulation with UFH
  valve)
Endovascular intervention in patient Reduce heparin dose to 50–70 mg/kg and remove
  receiving Gp IIb/IIIa inhibitor or   access sheath when ACT 150 seconds
  Plavix therapy
Open procedure in patient receiving Be prepared to use Tisseel for topical hemostasis
  antiplatelet agents, particularly
  Plavix
DVT, Deep venous thrombosis; INR, international normalized ratio; UFH, unfractionated
heparin; LMWH, low molecular weight heparin; ACT, activated clotting time.




warfarin therapy can be resumed after the operation. LMWH is a good
choice here, except for patients with mechanical heart valves who require
full anticoagulation with UFH. Both warfarin and heparin pose an
increased risk for bleeding complications.100 When patients who take
warfarin therapy need dental work and there is a risk of oral hemorrhage,
the patient can be given a mouthwash with epsilon aminocaproic acid, and
the anticoagulant therapy can be continued (grade 2B). There are several
studies that demonstrate the safety of operating in patients who receive
warfarin therapy.101,102
Is LMWH a Better Intraoperative Anticoagulant?
  Although most surgeons continue to use UFH in the operating room, it
is well recognized that there is considerable variability between individ-
uals to fixed dosages. After an intravenous dose, the disappearance curve
of UFH follows nonlinear kinetics and has an initial disappearance phase
followed by a convex curve.103 There are data to suggest that LMWH has
significant advantages in terms of predictable levels of anticoagulant
activity. The pharmacokinetics of intravenously administered UFH and
LMWH during aortofemoral bypass grafting were analyzed and com-
pared.104 The anticoagulant effect, as measured by anti-factor Xa activity,
was more sustained in the LMWH group, and the interindividual variation
of anti-factor Xa activity in the LMWH group was smaller. When using
LMWH, the surgeon must recognize that the anticoagulant effect does not
correlate with the APTT but rather with the anti-factor Xa activity and
Curr Probl Surg, February 2003                                                           119
that the latter effect is not reversed with protamine. The ability to monitor
anti-factor Xa activity is essential if one wishes to use LMWH in the
operative setting because concentrations that exceed 0.4 anti-factor Xa
produce a critically enhanced risk of hemorrhage.105
  The anticoagulant effect of heparin is reversed by protamine, but many
studies have concluded that the coagulation status does not need to return
to baseline normal to insure hemostasis.106 In a study that evaluated the
need for protamine after vascular reconstructions, Dorman and col-
leagues107 found that routine use was not necessary and that the incidence
of wound hematomas and reoperations was not increased in the group of
patients who did not receive protamine therapy. Protamine itself can
result in a number of adverse effects, particularly in patients with diabetes
mellitus who receive protamine-insulin injections.

Heparin versus Warfarin: Is One Safer?
  An experiment to evaluate the bleeding tendencies of various strategies
of periprocedural anticoagulation was performed by Caliendo and col-
leagues.108 White rabbits were divided into 3 groups: rabbits in group I
received warfarin to raise the INR to 2.5 to 3.5, rabbits in group II
received heparin to raise the partial thromboplastin time to 1.5 to 2.0
times control, and rabbits in group III received no anticoagulation. Group
I animals then had warfarin discontinued until the INR was 2.0 to 2.5, and
group II animals had heparin discontinued 6 hours before the proposed
surgical procedure and the prothrombin time returned to baseline. All
animals underwent laparotomy and a controlled 1-cm full-thickness
laceration of the right lobe of the liver that was then repaired. The extent
of bleeding and the time to hemostasis was measured in each animal.
Group I animals were restarted on warfarin on the evening of the
procedure. Group II animals had a continuous intravenous heparin
infusion that was started 6 hours after operation. All animals were killed
24 hours after the operation. The heparin-treated animals had significantly
more blood loss than the other 2 groups. There were no differences
between the control and warfarin-treated animals.
  The results of this animal study prompted these investigators to evaluate
the same regimens in 40 patients who were undergoing anticoagulation
therapy with mechanical heart valves, atrial fibrillation, an active DVT, a
hypercoagulable state, or a previous peripheral bypass. Operations were
performed in 29 patients (60%) who received warfarin therapy. The other
patients were either converted from warfarin to heparin therapy or
underwent anticoagulation primarily with heparin. There were thrombotic
complications that were related to the cessation of warfarin therapy in 5
120                                               Curr Probl Surg, February 2003
of 15 patients. Four of the 5 thromboses occurred in patients who were not
converted to heparin therapy because of a perceived low risk of
thromboembolic events. Four of these 5 patients required operation for
the complication. There were 12 patients with bleeding complications, 5
of whom required reoperation. Bleeding was more common in the
patients who received heparin therapy (8/20, 40%) as compared with
patients who received warfarin therapy (4/30, 13%). Bleeding in the
warfarin group correlated with the INR. If the INR was less than 3, 2 of
24 patients had bleeding complications, whereas an INR of more than 3
was associated with bleeding in 2 of 4 patients. Bleeding complications
were also correlated with the age of the patient. No patient younger than
62 years of age had a bleeding problem, whereas 12 of the 34 patients
who were older than 62 years of age had bleeding problems, regardless of
the type of anticoagulation therapy. These data suggest that it may not be
necessary to stop warfarin in the perioperative period for a variety of
operations, provided that the INR is less than 3, whereas periprocedural
heparin is associated with bleeding complications. Caution must be used,
however, in older patients because age appears to be an independent
variable that is associated with bleeding complications.
Topical Agents
  Topical hemostatic agents are useful particularly in patients who receive
anticoagulation therapy and who undergo operative procedures. Oxidized
cellulose, purified gelatin, and bovine collagen serve as templates on
which thrombus forms and require the formation of fibrin from circulating
blood. More recently fibrin sealants that are prepared from thrombin and
fibrinogen have been approved for clinical use and have been useful in
vascular procedures109 and splenic trauma.110 Tisseel VH (Baxter Health-
care Corporation, Deerfield, IL) is a 2-component fibrin sealant that
contains thrombin, calcium chloride, and aprotinin (fibrinolysis inhibitor
solution). The reconstituted components are mixed and applied topically.
The thrombin transforms the fibrinogen in the solution into fibrin, and the
aprotinin prevents early degradation of the fibrin. When Tisseel was
compared with historic controls in patients who undergo laparotomy for
blunt or penetrating injuries to the spleen and/or liver, patients who were
treated with Tisseel had significantly fewer splenectomies and hepatec-
tomies (1/45 vs 33/56; P .001).111

New Anticoagulants
Agents that are focused on the inhibition of thrombin (such as hirudin and
argatroban) have been approved for use in patients with HIT. Several
Curr Probl Surg, February 2003                                         121
other agents are currently in trials that target other factors in the clotting
cascade. These include agents that target clotting enzymes that are higher
in the pathways (such as factor Xa, factor IXa, and the factor VIIa/tissue
factor complex).112

Direct Thrombin Inhibitors
  Fondaparinux is a new class of antithrombotic agent that binds
selectively to antithrombin, which causes it to inhibit factor X. This agent
was found to be more effective than enoxaparin in a prospective
randomized trial that was conducted in 64 centers after elective knee
surgery. A total of 1049 patients were assigned randomly to receive either
enoxaparin (Lovenox) 30 mg twice daily or 2.5 mg of fondaparinox
(Arixtra). Treatment was continued for 5 to 9 days, and primary efficacy
(DVT) was assessed between days 5 and 11. The study demonstrated that
fondaparinox was more effective than enoxaparin in the prevention of
DVT after major elective knee surgery, although major bleeding compli-
cations were more frequent.113

Hirudin
  Hirudin is a polypeptide found in the saliva of leeches that inhibits
thrombin and prevents the conversion of fibrinogen to fibrin, activation of
factors V, VIII, and XIII, and thrombin-induced platelet activation. Direct
thrombin inhibitors are active against both circulating and thrombus-
bound thrombi, unlike heparin that is active only against the former.
Several recombinant analogs are available. In a multicenter trial that
compared the efficacy of desirudin (Revasc, CGP 39393, 15 mg,
subcutaneously twice daily) with UFH (5000 IU, subcutaneously three
times daily) in patients who underwent total hip arthroplasty, the former
was found to be superior in the prevention of proximal DVT by 79%
without any increase in bleeding complications.114 Anticoagulant therapy
was continued for 8 to 11 days. During a 6-week period of follow-up,
there were documented pulmonary emboli in 4 patients, each of whom
received heparin therapy. The anticoagulant effects of argatroban have
also been compared with UFH. Both produced dose-related anticoagulant
effects (increased activated clotting time, APTT). Argatroban had a 4-fold
shorter dissipation (half-life, 18 to 41 minutes vs 23 to 134 minutes for
UFH).115

Ancrod
 Ancrod is a thrombin-like enzyme that is found in the venom of the
Malayan pit viper. The anticoagulant effect of ancrod is the result of a
122                                                Curr Probl Surg, February 2003
decrease in the fibrinogen levels, the production of fibrin monomers, and
the subsequent stimulation of tissue plasminogen activator. The level of
fibrinogen must be closely monitored, however, lest bleeding complica-
tions occur.
Oral Heparin
  Oral heparins, for many reasons, are the ideal long-term anticoagulant.
Several delivery systems have been evaluated and are in various stages of
the FDA approval process. Baughman and colleagues116 report the results
of a RCT in humans using sodium N-[8(-2-hydroxybenzoyl)amino]
caprylate and LMWH. Measurements of the anticoagulant effect included
APTT, tissue factor pathway inhibitor, and factors I, Ia, and Xa 1 hour
after dosing in normal volunteers. Heparin that was administered orally
with sodium N-[8(-2-hydroxybenzoyl)amino] caprylate produced signif-
icant elevations of all the clotting parameters and was well tolerated.

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