Prevention of venous thromboembolism in gynecologic surgeryDocument Transcript
Prevention of Venous Thromboembolism in the Gynecologic Surgery Patient
Daniel L. Clarke-Pearson, MD, FACS, FACOG
James M. Ingram Professor of Gynecologic Oncology
Duke University Medical Center
Durham, NC 27710
Deep venous thrombosis and pulmonary embolism, although largely preventable,
are significant complications in postoperative patients. The magnitude of this problem is
relevant to the gynecologist, because 40% of all deaths following gynecologic surgery are
directly attributed to pulmonary emboli (98). Pulmonary embolism is also the second
leading cause of death in women who undergo a legally induced abortion (99) and the
most frequent cause of postoperative death in patients with uterine (100) or cervical
The causal factors of venous thrombosis were first proposed by Virchow in 1858
and include the following: a hypercoagulable state, venous stasis, and vessel intima
injury. Two prospective studies have evaluated risk factors associated with the
postoperative occurrence of deep venous thrombosis in patients undergoing gynecology
surgery. In one study, the risk factors of 124 patients undergoing vaginal and abdominal
surgery for benign gynecologic disease were studied (102). Five factors were identified to
be associated with postoperative deep venous thrombosis included increasing age,
presence of varicose veins, being overweight, prolonged euglobulin lysis time, and
presence of serum fibrin-related antigen. In another prospective study, the risk factors
associated with venous thromboembolic complications were also assessed in 411 patients
undergoing major abdominal and pelvic surgery (103). Preoperative risk factors
identified in this study include advanced age; nonwhite race; increasing stage of
malignancy; history of deep venous thrombosis, lower extremity edema or venous stasis
changes; presence of varicose veins; being overweight; and a history of radiation therapy.
Intraoperative factors associated with postoperative deep venous thrombosis included
increased anesthesia time, increased blood loss, and the need for transfusion in the
operating room. Other recognized risk factors include patients with thrombophilias, the
use of estrogen, oral contraceptives, tamoxifen, pregnancy, obesity and prologned air
travel. It is important to recognize these risk factors in order to provided the appropriate
level of venous thrombosis prophylaxis.
During the past two decades, a number of prophylactic methods have undergone
clinical trials showing significant reduction in the incidence of deep venous thrombosis,
and a few studies have been completed that have demonstrated a reduction in fatal
pulmonary emboli. The ideal prophylactic method would be effective, free of significant
side effects, well accepted by the patient and nursing staff, widely applicable to most
patient groups, and inexpensive.
The use of small doses of subcutaneously administered heparin for the prevention
of deep venous thrombosis and pulmonary embolism is the most widely studied of all
prophylactic methods. More than 25 controlled trials have demonstrated that heparin
given subcutaneously 2 hours preoperatively and every 8–12 hours postoperatively is
effective in reducing the incidence of deep venous thrombosis. The value of low-dose
heparin in preventing fatal pulmonary emboli was established by a randomized,
controlled, multicenter international trial, which demonstrated a significant reduction in
fatal postoperative pulmonary emboli in general surgery patients receiving low-dose
heparin every 8 hours postoperatively (104). Trials of low-dose heparin in gynecologic
surgery patients are limited, and a clear consensus regarding the value of low-dose
heparin in all groups of patients has not been established, because of differences in
patient selection and length of follow-up. Three randomized controlled studies used the
same regimen of low-dose heparin administration: 5000 units subcutaneously 2 hours
preoperatively and every 12 hours for 7 days postoperatively. Two trials were conducted
in patients with benign gynecologic conditions (98%); all patients were older than 40
years of age, and follow-up was discontinued at the time of discharge from hospital (105,
106). One trial showed a 23% incidence of deep venous thrombosis in the control group,
as compared with a 6% incidence of deep venous thrombosis in the patients treated with
low-dose heparin (106). This difference was statistically significant (P,0.05). Although
this was a randomized trial, the control group contained a larger number of patients with
malignancy and, when the cancer patients were excluded from the trial analysis, there
was no significant value to the use of low-dose heparin in patients with benign
conditions. In the other study, the nontreated control group had a 29% incidence of deep
venous thrombosis compared with a 3.6% incidence in the group treated with low-dose
heparin (P,0.001) (105). A third trial evaluated a larger group of patients receiving
treatment in gynecologic oncology unit, only 16% of whom had benign gynecologic
conditions; follow-up included the first 6 weeks postoperatively (107). In this trial, there
was no difference in the incidence of thromboembolic complications between the control
group (12.4%) and the group treated with low-dose heparin (14.8%) (107).
In a subsequent trial (108), two more intense heparin regimens were evaluated in
high-risk gynecologic oncology patients. Heparin was given either in a regimen of 5000
units subcutaneously 2 hours preoperatively and every 8 hours postoperatively or 5000
units subcutaneously every 8 hours preoperatively (a minimum of three preoperative
doses) and every 8 hours postoperatively. Both of these prophylaxis regimens were
effective in significantly reducing the incidence of postoperative deep venous thrombosis
in patients with gynecologic cancers.
Although low-dose heparin is considered to have no measurable effect on
coagulation, most large series have noted an increase in the bleeding complication rate,
especially a higher incidence of wound hematoma. Up to 10–15% of otherwise healthy
patients develop a transiently prolonged activated partial thromboplastin time (APTT)
after 5000 units of heparin is given subcutaneously (109). Retrospective studies have
suggested that low-dose heparin contributed to an increased occurrence of lymphocysts
(110, 111), although a prospective study only demonstrated an increase in retroperitoneal
lymph drainage volume in patients treated with low-dose heparin but no increase in the
incidence of lymphocysts (109). Although relatively rare, thrombocytopenia is associated
with low-dose heparin use and has been found in 6% of patients after gynecologic
surgery (109). If patients remain on low dose heparin for greater than 4 days it would be
reasonable to check a platelet count to assesss the possiblity of the occurrence of heparin
Low Molecular Weight Heparins
Low molecular weight heparins (LMWH) are fragments of unfractionated heparin
which vary in size from 4,500 to 6,500 daltons. When compared to unfractionated
heparin, LMWH have more anti-Xa and less anti-thrombin activity, leading to less effect
on partial thromboplastin time. Decreased platelet inhibition and microvascular bleeding
has been noted with LMWH, which may also lead to fewer bleeding complications (112).
An increased half-life of 4 hours (in both intravenous and subcutaneous administrations)
leads to increased bioavailability when compared to unfractionated heparin. The increase
in half-life of LMWH’s allows the convenience of once a day dosing.
Several commercially available LMWH preparations are internationally available
but only two (i.e. enoxaparin and dalteparin) have been approved by the FDA for DVT
prophylaxis in the United States.
Four randomized controlled trials have compared LMWH to unfractionated heparin in
patients undergoing gynecologic surgery. In all studies, there was a similar incidence of
DVT. Bleeding complications (113-115) were also similar between the unfractionated
heparin and LMWH groups. In a trial evaluating LMWH (dalteparin) in a gynecologic
cancer population the LMWH was associated with less bleeding complications than
would have been expected. The rate of thromboembolism was approximately 2% in this
collective group of 521 operative patients, with DVT diagnosed in 7 patients receiving
unfractionated heparin and 3 patients receiving LMWH prophylaxis. A recent meta-
analysis of general surgery and gynecological surgery patients from 32 trials likewise
indicated that daily LMWH administration is as effective as unfractionated heparin in
DVT prophylaxis without any difference in hemorrhagic complications (116). Caution
should be maintained in interpretation of assimilated data involving LMWH since
different anti-Xa activities are associated with the different preparations (117). In a
comparison of prophylactic methods of DVT treatment, LMWH has been suggested by
some investigators to be more cost effective than unfractionated heparin due to the
convenience of once daily dosing (118, 119).
Stasis in the veins of the legs has been clearly demonstrated while the patient is
undergoing surgery and continues postoperatively for varying lengths of time. Stasis
occurring in the capacitance veins of the calf during surgery, plus the hypercoagulable
state induced by surgery, are the prime factors contributing to the development of acute
postoperative deep venous thrombosis. Prospective studies of the natural history of
postoperative venous thrombosis have shown that the calf veins are the predominant site
of thrombi and that most thrombi develop within 24 hours of surgery (120). Reduction of
venous stasis in the perioperative period by various methods has been less extensively
investigated than pharmacologic methods such as low-dose heparin. However,
mechanical prophylactic methods may play an important role in the prevention of
postoperative deep vein thrombosis.
Although probably of only modest benefit, reduction of stasis by short
preoperative hospital stays and early postoperative ambulation should be encouraged for
all patients. Elevation of the foot of the bed, raising the calf above heart level, allows
gravity to drain the calf veins and should further reduce stasis. More active forms of
mechanical prophylaxis include elastic gradient compression stockings and external
pneumatic leg compression.
Elastic Stockings In a survey of general surgeons in the U.S., gradient elastic stockings
were second only to low-dose heparin as the prophylactic method of choice in high-risk
and moderate high-risk surgical patients (121). The simplicity of elastic stockings and the
absence of significant side effects are probably the two most important reasons that they
are often included in routine postoperative care. Controlled studies of graduated pressure
stockings are limited but do suggest modest benefit when they are carefully fitted (122).
Poorly fitted stockings may be hazardous to some patients who develop a tourniquet
effect at the knee or midthigh (99). Variations in human anatomy do not allow perfect fit
of all patients to available stocking sizes.
External Pneumatic Compression The largest body of literature dealing with the
reduction of postoperative venous stasis deals with intermittent external compression of
the leg by pneumatically inflated sleeves placed around the calf or leg during
intraoperative and postoperative periods. Various pneumatic compression devices and leg
sleeve designs are available, and the current literature has not demonstrated superiority of
one system over another. Single-chambered calf compression devices have been studied
most extensively in gynecologic surgery and appear to significantly reduce the incidence
of deep venous thrombosis on a level similar to that of low-dose heparin. In addition to
increasing venous flow and pulsatile emptying of the calf veins, external pneumatic
compression also appears to augment endogenous fibrinolysis, which may result in lysis
of very early thrombi before they become clinically significant (123).
The duration of postoperative external pneumatic compression has differed in
various trials. External pneumatic compression may be effective only when used in the
operating room or in the operating room and for the first 24 hours postoperatively (124,
125), although they should remain in use in patients who are not ambulatory.
External pneumatic compression used in patients undergoing major surgery
for gynecologic malignancy has been found to reduce the incidence of postoperative
venous thromboembolic complications by nearly threefold (126). Calf compression
was applied intraoperatively and for the first 5 postoperative days. In a subsequent trial of
similar patients that was designed to evaluate whether external pneumatic compression
might achieve similar benefits when used only intraoperatively and for the first 24 hours
postoperatively, there was no reduction of deep venous thrombosis when compared with
the control group (127). Patients with gynecologic malignancies may remain at risk
because of stasis and hypercoagulable states for a longer period than general surgical
patients and therefore appear to benefit from longer use of external pneumatic
External pneumatic leg compression has no significant side effects or risks,
although patient tolerance has been cited as a drawback to its use. However, we have had
only five patients of nearly 900 treated with external pneumatic compression request
removal because of discomfort. The equipment is easily managed by the nursing staff,
and although the initial capital outlay for external pneumatic compressors may seem
large, the cost per patient is slightly less than that of low-dose heparin given for 7 days
We have investigated the risk factors associated with the failure of external
compression to prevent DVT in a retrospective analysis of 1862 consecutive gynecologic
surgery patients who received postoperative intermittent pneumatic compression at Duke
University between 1992-1997. A history of prior DVT, diagnosis of cancer and age >60
years were factors independently associated with the development of DVT despite IPC
prophylaxis (p<0.05). Patients having two or more of these factors had a 16 fold
increased risk of postoperative DVT despite prophylaxis (p<0.05) (129). In these
extremely high risk- patients, combined methods of prophylaxis ought to be considered.
Combination therapy using heparin and compression stockings has been utilized
in other high risk surgical patients in an attempt to diminish both the hypercoaguability
and venous stasis that can be found in postoperative patients at high risk for
thromboembolism. The prophylactic use of LDH has been compared to LDH combined
with graduated compression stockings (GCS) in DVT prophylaxis among general surgery
patients. Willie-Jorgensen and associates (130), in an investigation involving 245
patients undergoing acute extensive abdominal operations, demonstrated that the rate of
postoperative DVT was significantly lower among 79 patients receiving a combination
regimen of GCS and LDH (i.e. 5000 units SQ 1 hour preoperatively and q12 hours
postoperatively) than patients receiving only the LDH regimen (P=0.013). A statistically
significant improvement (P<0.05) in postoperative DVT was similarly noted by the same
investigators in the evaluation of 176 patients undergoing elective abdominal surgery
(131). A meta-analysis of 6 studies involving 898 general surgery patients has shown
that combination therapy with LDH and GCS provides significantly better DVT
prophylaxis postoperatively than either single modality (Odds ratio 0.40; 95% CI
0.27-0.59) (132). Recently, a multicenter prospective randomized clinical trial
demonstrated that combination prophylaxis consisting of GSC and LMWH was more
effective in DVT prevention than GCS alone (Relative risk 0.52; 95 percent confidence
interval, 0.17 to 0.95, p=0.04) (133). “Combination” prophylaxis might be considered in
the highest risk gynecologic oncology patients, although the efficacy, risks, and costs
have not been studied.
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