Thromboembolism Prophylaxis in Gynecologic Surgery

Updated: Mar 13, 2016
  • Author: Howard A Shaw, MD, MBA; Chief Editor: Kris Strohbehn, MD  more...
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Overview

Overview

Venous thromboembolism (VTE) is a leading cause of disability and death in postoperative hospitalized gynecologic patients. Pulmonary embolism (PE) remains the most common preventable cause of hospital death and is responsible for approximately 150,000-200,000 deaths per year in the United States. [1] In general, VTE occurs in the form of a deep venous thrombosis (DVT) or PE.

Other chronic conditions may result from acute conditions such as postthrombotic syndrome, venous insufficiency, and pulmonary hypertension. This article provides practical background and evidence-based recommendations for clinical practice.

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Epidemiology

Approximately two million patients in the United States are diagnosed with deep venous thrombosis (DVT) each year. Of these patients, nearly 60,000 die and one third develop pulmonary embolism (PE). [2] Overall, PE has a case-fatality rate of approximately 12%, with lower rates in younger patients and higher rates in patients with cancer. [3, 4] First-time–diagnosed venous thromboembolism (VTE) has an incidence of 1-2 per 1,000 individuals per year. [4, 5] Patients at bedrest are 9 times more likely to develop VTE than the general population. [6] The odds ratio of increased VTE risk in hospitalized and surgical patients is 11.1 and 5.9, respectively. [6]

Without thromboprophylaxis, patients who undergo major gynecologic surgery have a prevalence of DVT in the range of 15%-40%. [7] Asymptomatic DVT is also highly associated with the development of significant PE. [8] Because most PE-associated fatalities occur within 30 minutes of onset, leaving a very narrow window for medical intervention, clinicians must identify those at high risk for VTE and administer effective thromboprophylaxis to minimize the occurrence of this potentially preventable cause of death.

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Definitions of Risk

Traditionally, gynecologic surgical patients have been classified preoperatively into 1 of 4 risk categories; low, medium, high, and highest risk. [9] This classification is used to determine the most appropriate thromboprophylaxis regimen for specific patients. Based on the procedure type and duration, age, and presence of additional risk factors, a risk of venous thromboembolism (VTE) is determined.

Table 1. Traditional Risk Classification for Gynecologic Surgery* (Open Table in a new window)

Risk level Definition
Low Surgery lasting < 30 minutes in patients < 40 years with no additional risk factors
Moderate Surgery lasting < 30 minutes in patients with additional risk factors; surgery lasting < 30 minutes in patients aged 40-60 years with no additional risk factors; major surgery in patients < 40 years with no additional risk factors
High Surgery lasting < 30 minutes in patients >60 years or with additional risk factors; major surgery in patients >40 years or with additional risk factors
Highest Major surgery in patients >60 years plus prior VTE, cancer, or molecular hypercoagulable state
*Modified from ACOG Practice Bulletin No. 84: Prevention of deep vein thrombosis and pulmonary embolism. Obstet Gynecol. Aug 2007;110(2 Pt 1):429-40. [PMID: 17666620]. [9]

In May 2012, the American College of Chest Physicians (ACCP), [10, 11] in their published evidence-based clinical practice guidelines, described several methods for stratifying the risk of VTE in nonorthopedic surgical patients. This classification is broken down into the risk percentage among patients who would have no VTE prophylaxis: very low (< 0.5%), low (approximately 1.5%), moderate (approximately 3%), and high risk (approximately 6%).

In addition, two methods are described to develop an overall risk score, the Rogers Score and the Caprini Score (see Tables 2 and 3). [1, 11] These scores can then be used to place patients in an ACCP risk class (see Table 4).

Table 2. Rogers Score for VTE Risk Assessment* (Open Table in a new window)

Risk Factor Risk Score Points
Operation type  
Respiratory and hemic 9
Cardiovascular 7
Aneurysm 4
Mouth, palate 4
Stomach, intestines 4
Integument 3
Hernia 2
ASA physical status classification  
3, 4, or 5 2
2 1
Female sex 1
RVU  
>17 3
10-17 2
2 points for each condition 2
Disseminated cancer  
Chemotherapy for malignancy within 30 days of surgery 2
Preoperative serum sodium level >145 mmol/L 2
Transfusion >4 units of packed RBCs in 72 hours before surgery 2
Ventilator-dependent 2
1 point for each condition  
Wound class (clean/contaminated) 1
Preoperative hematocrit level ≤38% 1
Preoperative bilirubin level >1 mg/dL 1
Dyspnea 1
Albumin level < 3.5 mg/dL 1
Emergency 1
0 points for each condition  
ASA physical status class 1 0
Work RVU < 10 0
Male sex 0
*Modified from Rogers SO Jr, Kilaru RK, Hosokawa P, Henderson WG, Zinner MJ, Khuri SF. Multivariable predictors of postoperative venous thromboembolic events after general and vascular surgery: results from the patient safety in surgery study. J Am Coll Surg. Jun 2007;204(6):1211-21. [PMID: 17544079].



Abbreviations: ASA, American Society of Anesthesiologists; WVU, Work Relative Value Unit



Table 3: Caprini Risk Assessment Model* (Open Table in a new window)

1 Point 2 Points 3 Points 5 Points
Age 41-60 years Age 61-74 years Age ≥75 years Stroke (1 month)
Minor surgery Arthroscopic surgery History of VTE Elective arthroplasty
BMI >25 kg/m2 Major open surgery (>45 minutes) Family history of VTE Hip, pelvis, or leg fracture
Swollen legs Laparoscopic surgery (>45 minutes) Factor V Leiden Acute spinal cord injury (< 1 month)
Varicose veins Malignancy Prothrombin 20210A  
Pregnancy or postpartum Confined to bed (>72 hours) Lupus anticoagulant  
History of unexplained or recurrent spontaneous abortion Immobilizing plaster cast Anticardiolipin antibodies  
Oral contraceptives or hormone replacement use Central venous access Elevated serum homocysteine  
Sepsis (< 1 month)   Heparin-induced thrombocytopenia  
Serious lung disease, including pneumonia (< 1 month)   Other congenital or acquired thrombophilia  
Abnormal pulmonary function      
Acute myocardial infarction      
Congestive heart failure      
History of inflammatory bowel disease      
Medical patient at bedrest      
*Modified from Bahl V, Hu HM, Henke PK, Wakefield TW, Campbell DA Jr, Caprini JA. A validation study of a retrospective venous thromboembolism risk scoring method. Ann Surg. Feb 2010;251(2):344-50. [PMID: 19779324].

Table 4. VTE Risk Scores and Categories for General Surgical Patients [12] * (Open Table in a new window)

VTE Risk Category Rogers Score Caprini Score Baseline Risk of VTE Without Prophylaxis, %
Very low < 7 0 < 0.5
Low 7-10 1-2 1.5
Moderate >10 3-4 3
High N/A ≥5 6
*Modified from Kahn SR, Lim W, Dunn AS, Cushman M, Dentali F, Akl EA, et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. Feb 2012;141(2 Suppl):e195S-226S. [PMID: 22315261].
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Inherited and Acquired Hypercoagulable Disorders

Multiple inherited risk factors influence coagulability but do not usually result in venous thromboembolism (VTE) in the absence of a contributing medical event, such as pregnancy, surgery, or exogenous hormone ingestion. [13] The most prevalent genetic mutations found in patients with VTE are factor V Leiden mutation and prothrombin gene mutation G20210A. Patients with either of these conditions during pregnancy or major surgery are at an increased risk of perioperative VTE.

Factor V Leiden mutation is the most common inherited thrombophilia, affecting 5% of whites. [14, 15] One in 5 patients diagnosed with VTE and 50% of those with thrombophilia are found to have this mutation. Whites are almost the exclusive carrier of the prothrombin G20210A mutation, and it is found in only 6% of patients with VTE. Factor V Leiden causes activated protein C resistance, while the prothrombin G20210A mutation causes an abnormally elevated prothrombin level, resulting in a 3-fold higher VTE rate. [16] Either mutation can be diagnosed via DNA analysis, while factor V Leiden may also be found via an abnormal activated protein C resistance assay result.

Antithrombin-III (AT-III), protein C, and protein S are uncommon causes of VTE but should be considered in patients who test negative for factor V Leiden and prothrombin mutation but report multiple thrombotic events in their family history. Since AT-III, protein C, and protein S inhibit coagulation, heterozygote carriers have a 10-fold increased risk of VTE, and homozygotes have severe thrombotic events soon after birth. [17] Any of these 3 disorders can be diagnosed via serum assays, but results are unreliable during an acute thrombotic event and during anticoagulation therapy.

Genetic or acquired elevated homocysteine levels have been linked to VTE. Homozygous carriers of the methylenetetrahydrofolate reductase variant 677T have slightly elevated homocysteine levels and a slightly increase risk of thrombosis and arteriosclerosis. [18] Dietary deficiencies of folate, vitamin B6, and vitamin B12 result in acquired hyperhomocysteinemia. [13] It is unknown whether homocysteine itself is a risk factor or simply a marker, and it is unclear whether lowering homocysteine levels would decrease VTE risk. [19]

Antiphospholipid syndrome is an acquired thrombophilia associated with both arterial and venous thrombosis. Fifty percent of patients with systemic lupus erythematosus (SLE) test positive for antiphospholipid antibodies. Testing for lupus includes serum assays for both lupus anticoagulant and anticardiolipin antibodies. Lupus anticoagulant is the more significant test since it reveals b2-glycoprotein-1 antibodies, which correlate highly with thromboembolic complications and morbidity during pregnancy. [20] Clinicians should consider testing in patients with VTE, SLE, recurrent pregnancy loss, early and/or severe preeclampsia, and/or thrombocytopenia. [21]

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Venous Thromboembolism Prophylaxis in Gynecologic Surgery

Graded compression stockings or elastic stockings, intermittent pneumatic compression (IPC) devices, low-dose unfractionated heparin (LDUH), low molecular weight heparin (LMWH), fondaparinux, aspirin, inferior vena cava (IVC) filters, and surveillance with venous compression ultrasonography (VCU) have all been used to prevent venous thromboembolism (VTE). The incidence of VTE in gynecologic oncology patients has been reported to be 1%-6.5%. [22, 23, 24]

In high-risk patients, a combined regimen of medical and mechanical prophylaxis may improve clinical efficacy, although there is limited evidence in gynecologic patients. Extrapolation from the general surgery literature suggests a significant benefit from a combined regimen. [25, 26]

Some investigators question the benefits of routine use of VTE prophylaxis in patients who undergo minimally invasive surgery for gynecologic malignancies. [27] In a study that included 419 women who underwent such surgery (at least a simple/radical total laparoscopic hysterectomy or pelvic lymph node dissection), the rate of VTE was 0.57% within 30 postoperative days in the 352 patients (84%) who did not receive any VTE prophylaxis. Of the 62 women who received VTE prophylaxis, no VTEs occurred in the same postoperative time period. [27]

The American College of Obstetricians and Gynecologists (ACOG) recommends that, until more evidence is accumulated, patients undergoing laparoscopic surgery should be stratified by risk category and should receive prophylaxis similar to that provided to patients undergoing laparotomy. [9] Among members of the Society of Gynecologic Oncology, the preferred method of VTE prevention during laparoscopic surgery for high-risk patients was combination prophylaxis. [28]

In general, optimal prophylaxis for gynecologic surgery considers the risk of VTE and bleeding complications, as well as the wishes of the individual patient. [29]

Grading the evidence

ACOG grades the quality of evidence in the literature according to the method outlined by the U.S. Preventive Services Task Force, as follows:

  • I: Evidence obtained from at least one properly designed randomized controlled trial
  • II-1: Evidence obtained from well-designed controlled trials without randomization
  • II-2: Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group
  • II-3: Evidence obtained from multiple time series with or without the intervention; dramatic results in uncontrolled experiments could also be regarded as this type of evidence
  • III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

Then, based on the highest level of evidence found in the data, recommendations are provided and graded by ACOG according to the following categories:

  • level A: Recommendations are based on good and consistent scientific evidence
  • level B: Recommendations are based on limited or inconsistent scientific evidence
  • level C: Recommendations are based primarily on consensus and expert opinion

For the 2012 ACCP guidelines for the prevention of VTE in nonorthopedic surgical patients, the group used the grades of the Recommendations, Assessment, Development, and Evaluation system to assess the quality of evidence and describe the strength of recommendations (see Table 5). [30, 31, 32]

Table 5. Strength of the Recommendations Grading System [12] * (Open Table in a new window)

Grade of Recommendation Benefit vs Risk and Burdens Methodologic Strength of Supporting Evidence Implications
Strong recommendation, high-quality evidence (1A) Benefits clearly outweigh risk and burdens or vice versa. Consistent evidence from randomized controlled trials without important limitations or exceptionally strong evidence from observational studies. Recommendation can apply to most patients in most circumstances. Further research is very unlikely to change our confidence in the estimate of effect.
 
Strong recommendation, moderate-quality evidence (1B) Benefits clearly outweigh risk and burdens or vice versa. Evidence from randomized controlled trials with important limitations (inconsistent results, methodologic flaws, indirect or imprecise) or very strong evidence from observational studies. Recommendation can apply to most patients in most circumstances. Higher-quality research may well have an important impact on our confidence in the estimate of effect and may change the estimate.
 
Strong recommendation, low- or very-low-quality evidence (1C) Benefits clearly outweigh risk and burdens or vice versa. Evidence for at least one critical outcome from observational studies, case series, or randomized controlled trials, with serious flaws or indirect evidence. Recommendation can apply to most patients in many circumstances. Higher-quality research is likely to have an important impact on our confidence in the estimate of effect and may well change the estimate.
 
Weak recommendation, high-quality evidence (2A) Benefits closely balanced with risks and burden. Consistent evidence from randomized controlled trials without important limitations or exceptionally strong evidence from observational studies. The best action may differ depending on circumstances or patient or societal values. Further research is very unlikely to change our confidence in the estimate of effect.
 
Weak recommendation, moderate-quality evidence (2B) Benefits closely balanced with risks and burden. Evidence from randomized controlled trials with important limitations (inconsistent results, methodologic flaws, indirect or imprecise) or very strong evidence from observational studies. Best action may differ depending on circumstances or patient or societal values. Higher-quality research may well have an important impact on our confidence in the estimate of effect and may change the estimate.
 
Weak recommendation, low- or very-low-quality evidence (2C) Uncertainty in the estimates of benefits, risks, and burden; benefits, risk, and burden may be closely balanced. Evidence for at least one critical outcome from observational studies, case series, or randomized controlled trials, with serious flaws or indirect evidence. Other alternatives may be equally reasonable. Higher-quality research is likely to have an important impact on our confidence in the estimate of effect and may well change the estimate.
*Modified from Kahn SR, Lim W, Dunn AS, Cushman M, Dentali F, Akl EA, et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. Feb 2012;141(2 Suppl):e195S-226S. [PMID: 22315261].
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Specific Prophylaxis Strategies

A wide variety of venous thromboembolism (VTE) prophylactic measures have been shown to reduce deep venous thrombosis (DVT) formation. However, the real desire for VTE prophylaxis is to prevent fatal PE in gynecologic surgery patients. Since pulmonary embolism (PE) is relatively rare, most studies in the literature have not been sufficiently powered to show a reduction in mortality as a result of VTE prophylaxis. Without hard data, it still seems reasonable to assume that the prevention of VTE will reduce the incidence of PE in gynecologic surgery patients.

The currently available methods include both mechanical and pharmacologic interventions. Mechanical methods promote circulation and reduce venous stasis. Pharmacologic methods prevent clot formation by effects at different points on the clotting cascade. The individual methods and the evidence for using each are discussed below.

Graduated compression stockings (elastic stockings)

Graduated compression stockings have the advantage of being simple and relatively low cost. Postoperative DVT usually develops within 24 hours after surgery. Graduated compression stockings prevent pooling of blood in the calf veins.

A recent Cochrane review reported a 65% reduction in DVT formation with the use graduated compression stockings when compared to no prophylaxis. [33]

The drawbacks of graduated compression stockings include improper fitting, in which the stockings may act as a tourniquet, causing an increase in venous stasis. Because of this, knee-length stockings are recommended. [9] In addition, the use of graduated compression stockings has been associated with an increased risk of skin complications, including ulcers, blisters, and necrosis. [12]

Intermittent pneumatic compression devices

IPC devices diminish blood stasis by repetitively compressing the calf with a removable pneumatic wrap.

Several meta-analyses have assessed the effectiveness of IPC versus no prophylaxis in perioperative patients. These analyses report that IPC reduced the risk of both asymptomatic and distal DVT by 60%. Proximal DVT risk was diminished by 50%. [34] Many studies to date have too few a number of patients to properly assess IPC effectiveness in PE prevention or mortality.

After major gynecologic surgery, IPC devices reduce DVT formation as effectively as LMWH and low-dose heparin. [23, 24, 35] Adherence to ideal IPC use is often suboptimal, but, when used properly, they may increase systemic fibrinolysis, [36, 37] although this was not confirmed in data from a large series analysis. [38, 39] IPC should be worn continuously on the calf until a perioperative patient is fully ambulatory and ready for hospital discharge. [7] One study of intraoperative use of IPC in gynecologic oncology surgical patients showed a 3-fold reduction in VTE. [40]

Low-dose unfractionated heparin

One of the most extensively studied thromboprophylaxis methods is low doses (10,000-15,000 units/d) of subcutaneously administered unfractionated heparin. LDUH is not only proven effective in VTE prevention, but it also a low cost to administer.

Many studies show that effective DVT prevention is best achieved when LDUH is administered 2 hours prior to surgery and continued every 8-12 hours postoperatively. [7] Benign gynecologic surgery patients benefit from LDUH administered preoperatively and again at 12-hour intervals postoperatively. [7] Gynecologic oncology surgical patients require a different approach of 5,000 units of heparin 2 hours preoperatively, repeated every 8 hours postoperatively in order to effectively prevent VTE. [41]

A published meta-analysis reported that LDUH was associated with an 18% reduction in the odds of death from any cause, a 47% reduction in the odds of fatal PE, and a 41% reduction in the odds of nonfatal PE, along with a 57% increase in the odds of nonfatal major bleeding. [12] Other studies have not shown an increase of intraoperative blood loss with LDUH use but have noted an increase in postoperative wound hematoma formation. [41, 42] When administering LDUH for more than 4 days, patients should be monitored for heparin-induced thrombocytopenia, which is reported in approximately 6% of patients. [41]

Low molecular weight heparin

Since original studies dating back to 1985, [43] LMWH has been proven an effective thromboprophylaxis. When compared to LDUH, LMWH has once-daily dosing, a greater bioavailability and longer half-life, and, thus, a more predictable form of pharmacokinetics. [44] Studies show that LMWH and LDUH have similar efficacy rates in VTE prevention. [44] Similar risk reduction to intermittent IPC use was also seen when LMWH was administered preoperative and daily postoperatively. [24] In patients undergoing gynecologic oncology surgery, recent prospective trials showed a 2% incidence of VTE when LMWH prophylaxis was administered preoperatively and postoperatively. [45]

Original reports proposed that LMWH yielded a decreased incidence of perioperative bleeding and wound hematoma formation owing to its lower antithrombin activity and increased levels of antifactor Xa. Although more expensive than LDUH, LMWH is rarely associated with heparin-induced thrombocytopenia; thus, screening is not recommend with extended use. [9] However, a recent meta-analysis has shown that LMWH may actually double the risk of major perioperative bleeding and wound hematoma formation. [12] These findings were confirmed in another recent study by the British National Collaborating Centre for Acute Care, which studied GI, gynecologic, urological, and thoracic surgery. [12]

Major risk factors for VTE usually dictate LMWH therapy duration. Noted risk factors include prior VTE, cancer diagnosis, age older than 60 years, extended surgical time, and bedrest. [45] Forty percent of patients with cancer who develop VTE do so more than 3 weeks postoperatively. [45] Four weeks of LMWH administration postoperatively, versus only 1 week of therapy, reduced VTE risk by 60%, with no increase in bleeding or thrombocytopenia. [46]

Combination prophylaxis

The combined use of compression stockings and either LDUH or LMWH has been analyzed in the general surgery literature. A Cochrane review of 19 studies revealed that LDUH in conjunction with graduated compression stockings was 4 times more effective in VTE prevention than LDUH alone. [46] A study of neurosurgical patients also showed a significant VTE reduction with combined LMWH and graduated compression stockings compared with compression stockings alone. [46]

In a cost-benefit analysis of prophylaxis for postoperative VTE in patients with gynecologic malignancies, Japanese investigators suggested a strategy that combined unfractionated heparin three times daily combined with graduated compression stockings and intermittent pneumatic compression; close monitoring of oxygen saturation; and perioperative bilateral circumference measurements of the thighs and calves. [47]

There are no randomized trial data in the gynecology literature to prove the benefits of combining mechanical and pharmacologic therapies in VTE prophylaxis. However, if gynecologic patients fall into high-risk VTE categories (ie, >40 years, cancer diagnosis, prior VTE), a dual prophylactic approach may be warranted to reduce both hypercoagulability and venous stasis. [40] Combined therapy is recommended by the Ninth American College of Chest Physicians Consensus Conference for patients at high risk for VTE. [12] A decision analysis in high-risk gynecologic oncology patients found that combined IPC devices and LMWH use is cost-effective. [25]

Other considerations

The ACOG recommends prophylaxis for women undergoing surgery who have deficiencies of protein C, protein S, or AT-III and for heterozygous carriers of factor V Leiden or prothrombin gene mutation G20210A without a personal history of thrombosis. [9] These patients, by definition, would fall into the “highest risk” category for perioperative VTE.

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Recommendations

Based on current ACOG and ACCP evidence-based guidelines, below are recommendations for venous thromboembolism (VTE) prophylaxis in gynecologic surgical patients.

Patients at very low risk for venous thromboembolism (< 0.5%) (ACOG low risk)

Early ambulation (grade 1B)

Patients at low risk for venous thromboembolism (approximately 1.5%) (ACOG moderate risk)

IPC (grade 2C) placed before the initiation of surgery and continued until the patient is fully ambulatory

Patients at moderate risk for venous thromboembolism (approximately 3%) (ACOG high risk and level A evidence) but not at high risk for bleeding complications LMWH (grade 2B) or dalteparin 2,500 antifactor-Xa units or enoxaparin 40 mg administered subcutaneously 12 hours before surgery and once a day postoperatively until discharge

LDUH (grade 2B) or unfractionated heparin (5,000 units) administered subcutaneously 2 hours before surgery and every 12 hours after surgery until discharge

IPC (grade 2C) placed before the initiation of surgery and continued until the patient is fully ambulatory

Patients at moderate risk for venous thromboembolism (approximately 3%) (ACOG high risk) and at high risk for bleeding complications

IPC (grade 2C) placed before the initiation of surgery and continued until the patient is fully ambulatory

Patients at high risk for venous thromboembolism (approximately 6%) (ACOG high risk and level A evidence) but not at high risk for bleeding complications

LMWH (grade 2B) or dalteparin 2,500 antifactor-Xa units or enoxaparin 40 mg administered subcutaneously 12 hours before surgery and once a day postoperatively until dischargeLDUH (grade 2B) or unfractionated heparin (5,000 units) administered subcutaneously 2 hours before surgery and every 12 hours after surgery until discharge

PLUS

IPC (grade 2C) placed before the initiation of surgery and continued until the patient is fully ambulatory

Patients at high risk for venous thromboembolism (approximately 6%) (ACOG highest risk) undergoing cancer surgery but not at high risk for bleeding complications

LMWH extended for a duration of 4 weeks (grade 1B)

Patients at high risk for venous thromboembolism (approximately 6%) (ACOG highest risk) and at high risk for bleeding complications

IPC (grade 2C) placed before the initiation of surgery and continued until the patient is fully ambulatory

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