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Deep Venous Thrombosis After Radical Pelvic Surgery

Authors:
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Deep Venous Thrombosis After
Radical Pelvic Surgery
Bedeir Ali-El-Dein
Mansoura University, Urology and Nephrology Center
Egypt
1. Introduction
Deep venous thrombosis or DVT is a blood clot formation in one or more of the deep veins.
The blood clot does not break down and therefore, it can become larger and occlude the
blood flow within the affected vein. The most frequent sites are the leg veins (femoral and
popliteal) and the deep pelvic veins. Rarely, the arm veins are affected (Paget-Schrötter
disease). Pulmonary embolism (PE) is the most dangerous complication of DVT. PE occurs
when the clot breaks into small pieces (emboli) and travel to the lung. The embolus may
travel to other vital organs and cause life-threatening complications such as stroke or heart
attack.
The etiology of thrombosis is exactly unknown, however, the Virchow’s triad of slow
circulation (stasis), increased blood coagulability and vessel wall intimal injury is the alleged
mechanism.
DVT and PE developing after trauma and pelvic surgery are of a major concern to surgeons
of all subspecialties. Therefore, proper assessment of the patient risk to develop DVT is of
paramount importance. The risk of DVT can be decreased significantly by adopting some
appropriate prophylactic procedures.
Although adopting anti-DVT prophylactic measures is not debatable, the use of these
measures has not yet been a universal issue, even in patients having no contraindications to
their use.
In this chapter, the term “radical pelvic surgeries” mean all types of major surgeries
performed to treat malignancies developing in the pelvis, such as radical cystectomy,
salvage cystectomy, radical prostatectomy, radical or pan-hysterectomy, radical surgery for
colo-rectal cancer and excision of a local tumor recurrence after primary radical surgery or
after definitive radiotherapy
2. Incidence
DVT constitutes a major health problem, especially among the elderly. In comparison with
previous era, the incidence of DVT remains the same among men and possibly increasing in
elderly females (Silverstein et al., 1998). On the other hand, the incidence of PE is decreasing
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over years (Silverstein et al., 1998). However, the incidence of DVT and PE may be
underestimated because of the missed diagnosis, absence of pertinent symptoms or the
absence of laws to permit routine autopsies in sudden post-operative mortalities in most
centers (Dalen & Alpert, 1975; Clagett, 1994). Furthermore, unexplained DVT may be the
first presentation in some malignancies, such as prostate, colorectal and bladder (Monreal &
Prandoni, 1999).
In a series of 2373 patients, the incidence of DVT was 0.87% after urologic surgeries for
prostate and bladder tumors, 2.8% in general surgery and 2% in gynecological surgeries
(Scarpa etal., 2007).
The incidence of DVT may be as low 2% after radical cystectomy (Ali-El-Dein et al., 2008;
Ghoneim et al., 2008), or as high as 40% following prolonged gynecological or obstetrical
surgery (Walsh et al., 1974; Clarke-Pearson et al., 1983). Patients undergoing large bowel
surgery also have a considerable risk of DVT and pulmonary embolism. The incidence of
DVT following radical cystectomy in our hospital is 2% to 2.6% and PE following DVT or
without prior DVT has long been a leading cause of post-operative death (Ali-El-Dein et al.,
2008; Ghoneim et al., 2008). In patients undergoing surgery or radiotherapy for treatment of
localized prostate cancer the incidence of DVT was 2% for pelvic lymphadenectomy alone
and 1.9% following prostatectomy, while fatal PE occurred in 2 patients (3.7%) after
prostatectomy (Bratt et al., 1994).
The incidence of DVT after gynecologic and obstetrical surgeries varies according to the
presence or absence of the known risk factors among patients and according to the methods
of diagnosis. It has been reported that this incidence is 14% after benign gynecological
surgeries (Walsh et al., 1974), while the rate has been higher (38%) for patients undergoing
surgery for gynecological tumors (Crandon & Knotts, 1983). In addition, among all causes of
death following gynecologic surgeries, PE has been a leading cause of postoperative
mortality in high risk women with gynecologic malignancy (Clarke-Pearson et al., 1983).
Following laparoscopic radical hysterectomy for cervical carcinoma the incidence of DVT
has been 3% (Chen et al., 2008).
In the study of yang et al. on 3645 patients undergoing surgery for colorectal cancer, 31
(0.85%) developed symptomatic venous thromboembolism or VTE (Yang et al., 2011).
3. Pathogenesis and risk factors
The traditional Virchow’s triad of hypercoagulability, Stasis of the venous stream and vessel
wall (endothelial) trauma is still the basis of description of the pathophysiology of DVT.
One or more of these three factors may explain DVT in patients with radical pelvic
surgeries. The risk factors and the underlying pathogenetic mechanisms of DVT are shown
in table (1).
A major factor is immobilization (prolonged bed rest), which can impair venous drainage
from the lower limb with subsequent venous stasis (Clark & Cotton, 1968).
The other reasons that can induce venous stasis as well as other risk factors for DVT/PE are
enlisted in table (1).
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175
Stasis: -Immobilization.
-Pelvic masses.
- A gravid uterus
- Surgically induced hematomas.
- lymphocysts also can lead to venous stasis
Vessel wall injury: -Surgical trauma.
-Intravascular catheters.
-Malignant involvement of the vessels of the
tumor.
Thrombophilia
-Factor V Leiden mutation.
-Prothrombin gene mutation.
-G20210A.
-Antithrombin deficiency
-Factors I, V, VIII, IX, X, and XI.
-The presence of activated intermediate
coagulation products such as thrombin-
antithrombin III complexes .
-Abnormalities of the platelets .
-Tissue factor and cancer procoagulant
-Factors that influence vascular endothelial
permeability such as vascular endothelial growth
factor.
-Protein C deficiency
-Protein S deficiency
General factors:
-Obesity
-Prior history of DVT
-Hormonal therapy, -Chemotherapy, or
radiotherapy for cancer
-Old age
-Oral contraceptive pills or hormonal replacement
therapy
-Pregnancy and the postpartum period
-Burns
-Sepsis
-Systemic lupus erythematosus
-Polycythemia rubra vera
-Thrombocytosis
-Erythropoiesis-stimulating agents
-Dysfibrinogenemias and disorders of
plasminogen activation
-Intravenous (IV) drug abuse
-Acute medical illness
-Inflammatory bowel disease
-Myeloproliferative disorders
-Paroxysmal nocturnal hemoglobinuria
-Nephrotic syndrome
-Positive family history of DVT/PE
-Smoking
Table 1. Risk factors in DVT following radical pelvic surgeries
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Endothelial injury of the vessel wall may be induced by surgical dissection in various
radical pelvic surgeries (e.g. radical cystectomy) or from infiltration of the vessel wall by the
tumor. In addition, catheters placed distally or proximally in the venous system are among
the risk factors (Evans et al., 2010). However, in this situation, the risk of DVT/PE is
determined by multiple factors including catheter size (Evans et al., 2010), degree of vein
trauma during catheter insertion and dwell and hypercoagulability of the patient’ blood.
Hypercoagulability or thrombophilia or prothrombotic state is a blood coagulation disorder
with a subsequent increase in the incidence of thrombosis (Heit, 2007). There are multiple
genetic and acquired risk factors that influence thrombophilia. The presence of these
inherited risk factors alone usually does not cause thrombosis unless an additional risk
factor is present (Heit, 2007; Kyrle et al., 2010).
Antithrombin deficiency, which is the first major form of thrombophilia, was identified in
1965, while the most common defects, such as factor V Leiden mutation and prothrombin
gene mutation G20210A were described in the 1990s (Dahlbäck, 2008; Rosendaal & Reitsma,
2009). The risk of developing DVT/PE increases significantly if one of these abnormalities is
present in patients undergoing radical pelvic surgery.
There are various possibilities, which can induce a hypercoagulable state during major
radical pelvic surgeries. These possibilities include decreased fibrinolytic activity associated
with surgery (Egan et al., 1974), increased level of coagulation factors I, V, VIII, IX, X, and
XI, the presence of activated intermediate coagulation products such as thrombin-
antithrombin III complexes and abnormalities of the platelets (Piccioli et al., 1996). In
addition, the malignant cells may secrete a substance promoting coagulation, such as tissue
factor and cancer procoagulant or factors that influence vascular endothelial permeability
such as vascular endothelial growth factor and subsequently stimulate fibrin deposition
(Goad & Gralnick, 1996).
In the prospective study of Duke University Medical Center 411 patients undergoing major
abdominal and pelvic gynecologic surgery were evaluated for DVT and the related possible
risk factors (Clarke-Pearson et al., 1987). In this study, the important factors, which
maintained statistical significance in stepwise logistic regression model were age, edema of
the ankle, type of surgery, nonwhite race, presence of varicose veins, history of radiation
preoperatively, past DVT and duration of surgery.
It has been found that the risk factors for distal DVT are different from those of proximal
DVT. In the national (France) multicenter prospective OPTIMEV study, out of 6141 patients
with symptoms suggestive of DVT, diagnosis was objectively confirmed in only 1643 and
isolated distal DVT was more common than proximal one (Galanaud et al., 2009). In this
study, acute or transient risk factors, such as recent surgery, recent plaster immobilization
and recent travel, were more frequently discovered in distal DVT. On the other hand, in
proximal DVT chronic risk factors such as active cancer, congestive heart failure or
respiratory insufficiency and age above 75 years were more frequent.
Active cancer and related chemotherapy can increase the incidence of DVT by multiple
mechanisms. In chronic lymphocytic leukemia patients, studies showed a link between
lenalidomide associated DVTs and inflammation, upregulation of TNFα and endothelial cell
dysfunction (Aue etal., 2011).
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177
4. Diagnosis of DVT/PE
The majority of cases of DVT/PE have one or more risk factor. Many cases of DVT/PE are
asymptomatic. Suspected pulmonary embolism is a medical emergency and can be fatal. In
symptomatic DVT cases, the patient may present with lower limb pain, unilateral leg swelling,
redness and sometimes prominent superficial veins. A tender calf, especially with dorsiflexion
(Homan’s sign) and rarely a palpable venous cord are among the possible physical signs.
However, the presence of these manifestations is nonspecific, because in more than 50% of the
cases presenting with these symptoms, DVT is absent (Dainty et al., 2004). Therefore, diagnosis
of DVT based on symptoms only is problematic and proper hospital assessment and further
diagnostic tools are needed for accurate diagnosis. Similarly, most of the symptoms and signs
of PE are nonspecific and simulate post-surgery pulmonary complications. However,
physicians should maintain a high degree of suspicion if the patient is complaining of pleuritic
chest pain, hemoptysis, dyspnea, tachycardia and tachypnea.
4.1 Laboratory testing
The use of a simple prediction tool, together with the laboratory tests of D-dimers and
arterial blood gases (ABG) in cases of suspected PE are useful tools to exclude or prove DVT
(Crisan et al., 2011). D-dimers are fibrinogen degradation products which are generally
present at higher concentrations than normal in the blood of people with DVT.
4.2 Imaging in DVT
Imaging for DVT includes B-mode duplex Doppler ultrasound, impedance
plethysmography, contrast venography, and magnetic resonance venography (MRV).
Doppler ultrasound is currently the most common technique for the diagnosis of
symptomatic DVT. B-mode ultrasonography allows a bi-dimensional image of the vessels of
the lower extremity and when compression techniques are used, a sensitivity of up to 90%
and a specificity of 96% to 100% can be achieved in the detection of DVT (Cronan et al., 1987;
O'Leary et al., 1988).
In duplex ultrasonography B-mode is combined with Doppler flow, therefore, providing
information about flow velocity. When color Doppler flow is used with compression B-
mode ultrasonography (color duplex ultrasonography), additional data on the direction of
flow is gained (Cronan et al., 1987; O'Leary et al., 1988).
Impedance plethysmography is a noninvasive diagnostic test that has a good accuracy in the
detection of proximal DVT, when the results are analyzed in combination with positive
clinical data (Kearon et al., 1998). However, false positive results may be obtained with this
test and if the results of this test are non-diagnostic or not coping with the clinical data,
venography should be performed (Kearon et al., 1998).
Contrast venography is still the gold standard for the diagnosis of DVT and is used by
investigators as a reference standard for testing the new noninvasive diagnostic DVT
measures (Tapson et al., 1999).
The technique is done as classically described (Rabinov & Paulin, 1972). A misdiagnosis is
expected if all the deep veins from the leg up to the vena cava are not seen. When there is a
persistent filling defect in the lumen of 2 or more veins, the diagnosis of DVT is confirmed
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(Rabinov & Paulin, 1972). Currently, contrast venography is rarely indicated nowadays and
has been replaced by the noninvasive measures. It is sometimes performed to confirm the
diagnosis of a clinically suspected DVT. However, if noninvasive imaging is normal or
inconclusive and still DVT is clinically suspected, venography is done to confirm the
diagnosis. In the cases of clinical suspicion of DVT, a negative contrast venography rules out
the need for anticoagulant treatment (Hull et al., 1981). The test has certain limitations and
complications.
Magnetic resonance venography (MRV) is an accurate noninvasive venographic technique for
the detection of DVT. It has a sensitivity and specificity comparable to contrast venography
(Carpenter et al., 1993). Furthermore, it can detect thrombi places not seen by the conventional
venography, such as pelvic, ovarian veins or vena cava. Two major limitations for MRV are
present, namely, the expensive cost and prolonged time necessary (Carpenter et al., 1993).
Scintigraphy has been described as a diagnostic tool for DVT (Knight, 1993). However, the
data of its clinical efficacy compared to the standard methods are still lacking.
4.3 Imaging in PE
The diagnosis of PE may be made by a variety of imaging techniques, including chest X-ray,
ventilation-perfusion scan, computed tomography (CT) of the chest vessels and pulmonary
angiography.
On clinical suspicion of PE, the initial evaluation is made using chest X-ray,
Electrocardiography (ECG) and ABG. Further evaluation is made by ventilation-perfusion
scan, CT of the chest vessels (Gulsun Akpinar & Goodman, 2008).
Currently, CT venography combined with pulmonary CT angiography for the detection of
PE is increasingly used to confirm the diagnosis of suspected PE and the results have been
extremely promising (Krishan et al., 2011).
5. Prophylaxis of DVT/PE
The incidence of DVT and subsequent PE can be decreased by adopting certain prophylactic
mechanical and/ or pharmacologic measures, which have been proved to be safe and
effective in most types of major surgeries (Martino et al., 2007; Geerts et al., 2008).
Mechanical methods act by reducing stasis of venous blood and may stimulate endogenous
fibrinolysis, while pharmacologic agents act by clot prevention through the various steps of
the clotting cascade (Martino et al., 2007; Geerts et al., 2008).
5.1 Mechanical measures
Mechanical prophylaxis is usually simple to conduct and relatively less costy. It may be
achieved through the use of graduated compression stockings, anti-embolism stocking,
electrical stimulation of the leg muscles, intermittent external pneumatic calf compression
and/ or the use of specific tables (Martino et al., 2007; Geerts et al., 2008; Miller, 2011).
5.2 Pharmacologic measures
These measures are very effective in most surgeries and therefore, should be made a routine
practice (Agnelli, 2004). Low-dose unfractionated heparin or low-molecular-weight heparin
Deep Venous Thrombosis After Radical Pelvic Surgery
179
(LMWH) are the drugs of choice in patients undergoing radical pelvic operations in the
fileds of general, vascular, major urologic and gynecologic surgeries (Agnelli, 2004). In
urologic patients judged as low-risk, early postoperative mobilization is the only measure
needed. On the other hand, higher-risk patients should receive vitamin K antagonists,
LMWH and/ or fondaparinux (Agnelli, 2004).
Some investigators recommended a double prophylaxis of mechanical measures as well as
pharmacologic measures using pre- and post-operative anticoagulation, usually in the form
of LMWH (Whitworthet al., 2011). They found that the use of preoperative anticoagulation
seems to significantly decrease the risk of DVT in high-risk patients undergoing major
gynecologic surgeries. In addition, there was no significant change in the rates of
complications secondary to this protocol.
5.3 Dual prophylaxis
DVT may develop while the patient is on prophylaxis, therefore, the idea of dual
prophylaxis (mechanical and pharmacologic) has emerged (Dainty et al., 2004; Whitworthet
al., 2011).
This combination has been evaluated in patients undergoing colorectal operations. A
combination of low-dose unfractionated heparin and graduated compression stockings has
been found to be 4-fold more effective than low-dose unfractionated heparin alone in
DVT/PE prophylaxis (Wille-Jorgensen et al., 2003). Similarly, this dual prophylaxis has been
found to be cost-effective in high-risk patients undergoing surgeries for gynecologic tumors
(Dainty et al., 2004).
5.4 Duration of prophylaxis during radical pelvic surgeries
Following radical pelvic surgery, mechanical prophylaxis may be started before the
operation, while pharmacologic prophylaxis is usually started after the operation and
continued daily for 5–10 days or until the patient was fully mobile (Geerts et al., 2008;
unpublished data by the author).
6. Treatment of DVT/PE
The goals of treatment of patients with DVT and PE are to prevent local growth of the
thrombus, prevent the thrombus from breaking down into small pieces (emboli) and
traveling to other places, prevent complications of DVT, prevent recurrence of the thrombus
and in some clinical situations accelerate fibrinolysis (Hirsh & Hoak, 1996).
DVT is treated by immediate institution of anticoagulant therapy. Treatment is given as
either unfractionated heparin or low molecular weight heparins, followed by few weeks to 6
months of oral anticoagulant therapy (Clarke-Pearson & Abaid, 2008). However, life-long
anticoagulation has been recommended in some patients with active cancers after partial
improvement or failure of treatment, because they remain at very high risk to recurrent DVT
(Clarke-Pearson & Abaid, 2008).Low concentrations of heparin can inhibit the early stages of
blood coagulation. However, higher concentrations are needed to inhibit the much higher
concentrations of thrombin that are formed if the DVT process is not modulated (Hirsh &
Hoak, 1996).
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When unfractionated heparin is used, we usually start by a bolus injection followed by
continuos infusion and the dose is then adjusted to maintain the level of activated partial
thromboplastin time (APTT) at 1.5–2.5 times the control value (Clarke-Pearson & Abaid,
2008). Oral anticoagulation (warfarin) should be started on the first day of the heparin
infusion aiming to achieve an international normalized ratio (INR) of 2.0-3.0. IV heparin
may be discontinued in 5 days if an adequate INR level has been established (Clarke-
Pearson & Abaid, 2008). Studies have demonstrated that some of the new anticoagulants,
such as hirudin and its fragments, are effective inhibitors of clot-bound thrombin and
therefore, they may provide a better efficacy than heparin in neutralizing the procoagulant
effects of the fibrin-bound thrombin (Weitz et al., 1990).
Low molecular weight heparins such as enoxaparin and dalteparin have been proved to be
as effective and safe as unfactionated heparin in the treatment and recurrence prophylaxis of
DVT/PE (Quinlan et al., 2004). They have the advantage of the possibility to be given in the
outpatient setting (Clarke-Pearson & Abaid, 2008).
Fibrinolysis can be performed by one of the fibrinolytic enzymes, such as streptokinase,
urokinase and TPA, all of them can increase the dissolution rate of the thromus or embolus
(Hirsh & Hoak, 1996). They are not routinely recommended in the treatment of DVT/PE,
because of their cost and the high risk of bleeding (Hirsh & Hoak, 1996). Thrombolytic
therapy is indicated in all patients with massive pulmonary embolism and in some selected
cases of proximal DVT or with severe obstruction (Hirsh & Hoak, 1996). Thrombolytic
therapy has the advantage of preserving the pulmonary microcirculation after PE and
decreasing the possibility of post-thrombotic syndrome (PTS) following DVT (Linn et al.,
1988). Intrapulmonary artery infusion of urokinase in extensive PE has been found to be safe
and effective in treatment of patients with and without contraindication to the use of
systemic thrombolytic therapy (McCotter et al., 1999). With the recommended dose,
thrombolytic therapy produces significant and rapid resolution of pulmonary emboli with a
low morbidity and mortality rate. However, in lower extremity DVT, therapeutic
thrombolysis is still controversial.
In PE immediate anticoagulant therapy is given and respiratory support is maintained. In
addition, pulmonary artery catheterization with the administration of thrombolytic agents
has been tried as previously mentioned (McCotter et al., 1999).
Surgical intervention of the thrombus or embolus is rarely indicated. However, surgical
extirpation of the thrombus (venous thrombectomy), of the embolus (pulmonary
embolectomy) and endovascular therapies to treat DVT have been reported with promising
results (Lindow et al., 2010; Jenkins, 2011).
Long-term results after transfemoral venous thrombectomy for iliofemoral DVT has shown
that the technique is safe and effective and can prevent the development of severe post-
thrombotic syndrome in the long term (Lindow et al., 2010).
Inferior vena cava filters have been introduced to prevent PE in patients in whom
anticoagulation therapy is contraindicated, has failed or has been associated with
complications and in patients with extensive free-floating thrombi or residual thrombi
following massive PE (Chung et al., 2008; Kalva et al., 2008).
Deep Venous Thrombosis After Radical Pelvic Surgery
181
7. Conclusion
Deep venous thrombosis and pulmonary embolism are among the major post-operative
complications that develop after radical pelvic surgeries. Pulmonary embolism is one of the
leading causes of post-operative mortality in these patients. Most of the cases are
asymptomatic and in the majority of patients dying from pulmonary embolism the
embolism is diagnosed at autopsy. Treatment is essentially prophylactic and the primary
treatment objectives are to prevent PE, decrease morbidity and to prevent the risk of
developing the post-thrombotic syndrome (PTS). High-risk patients may be subject for dual
mechanical and pharmacologic prophylaxis with good results. Anticoagulation provides the
main stay of treatment. Thrombolytic therapy is currently used for massive pulmonary
embolism and some selected cases of deep venous thrombosis. Surgical (thrombectomy or
embolectomy) or endovascular techniques have been tried with promising results.
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