Venous Thromboembolism in Minimally Invasive Gynecologic Surgery: A Systematic Review

Venous thromboembolism (VTE) is the leading cause of preventable healthcare-related death after surgery. Although there is a large body of research on VTE in the general population as well as risk-assessment tools, evidence specific to the current practices in gynecologic surgery is more sparse. This review article seeks to discuss current literature on VTE in gynecologic surgery, with a focus on minimally invasive surgery. Evidence on risk factors for VTE in gynecologic surgery is evaluated as well as current recommendations use of thromboprophylaxis for prevention of VTE. Despite data showing that minimally invasive gynecologic surgery independently decreases risk of VTE compared with laparotomy, current clinical risk assessment tools and guidelines do not incorporate mode of surgery into recommendations for perioperative VTE prevention.     

PREVENTION AND TREATMENT OF VENOUS THROMBOEMBOLISM (VTE) IN OBSTETRICS

OBJECTIVE: to identify risk factors for venous thromboembolism (VTE) in the peripartum period and to provide guidelines for risk assessment and thromboprophylactic measures for VTE in pregnant women. Guidelines for diagnostic testing and for acute and long term treatment of VTE are also provided.OPTIONS: specific subgroups of pregnant women are defined and appropriate prophylactic measures are outlined. OUTCOMES: venous thromboembolism remains a major cause of morbidity and mortality in pregnancy and the postpartum period. Identification of risk and adequate prophylaxis can decrease the incidence of VTE.EVIDENCE: evidence was gathered using Medline (National Library of Medicine) to identify relevant studies and from bibliographies of articles thus identified.RECOMMENDATIONS: although evidence is lacking to date from Grade I studies (properly controlled randomized studies) in pregnant patients, there is good evidence to support the role of prophylaxis in reducing the incidence of VTE in patients identified to be at risk in the non-pregnant population (II B). Based on risk assessment more patients should be considered for thromboprophylaxis, including women with a past history of a VTE and a known thrombophilia on long-term anticoagulation, women with a past history of a VTE, women with a known thrombophilia who have never experienced a VTE and potentially considered in women at the time of Caesarean section (II B; III C). The occurrence of VTE is effectively reduced by the use of low dose unfractionated heparin. Experience with low molecular weight heparin and pregnancy is building, but is limited at present. Unfractionated heparin remains the standard for the treatment of VTE in pregnancy at the present time. Following initial heparinization for the treatment of VTE, patients should be continued on anticoagulation throughout pregnancy and for six to 12 weeks postpartum or a total of three months of anticoagulation (II A).     

Introduction: Obstetric venous thromboembolism

How to best reduce maternal risk from obstetric venous thromboembolism (VTE) is a relatively controversial topic. In comparison, for other leading causes of maternal mortality and severe morbidity such as obstetric hemorrhage and hypertension, there is general agreement on recommendations. While obstetric VTE poses a unique epidemiological and public health challenge, a number of recommendations related to care improvement and patient safety can be made. This edition of Seminars in Perinatology focuses on (i) overview of clinical research and epidemiology that can serve as a basis for informed decision making regarding VTE prophylaxis strategies, (ii) VTE prophylaxis implementation from a leadership perspective, (iii) future directions for research on obstetric VTE, and (iv) critical care management of obstetric VTE.     

The risk of venous thromboembolism associated with the use of tranexamic acid and other drugs used to treat menorrhagia: a case–control study using the General Practice Research Database

Objective  To assess whether use of tranexamic acid is associated with an increased risk of venous thromboembolism (VTE).
Design  Nested case–control study.
Setting  Database study using the General Practice Research Database for the years 1992–1998.
Population  Women aged 15–49 years with a diagnosis of menorrhagia.
Methods  Multivariate conditional logistic regression was used to estimate the risk for VTE associated with different drug treatments for menorrhagia, adjusting for confounders.
Main outcome measures  Adjusted odds ratios with 95% CI.
Results  A total of 134 cases of VTE and 552 matched controls were identified. Recent use of tranexamic acid was scarce, yielding an adjusted odds ratio for VTE of 3.20 (95% CI 0.65–15.78). The use of mefenamic acid (OR_adj 5.54 [95% CI 2.13–14.40]) or norethisterone (OR_adj 2.41 [95% CI 1.00–5.78]) was associated with an increased risk of VTE, as was a recent—in relation to menorrhagia—diagnosis of anaemia or a haemoglobin value <11.5 g/dl (OR_adj 2.23 [95% CI 1.02–4.86]).
Conclusions  We found that tranexamic acid was associated with an increased risk of VTE, although the risk estimate did not reach statistical significance. Increased risks of VTE associated with other treatments for menorrhagia were observed. The increased risk of VTE observed with a diagnosis of anaemia—a proxy for more severe menorrhagia—suggests that menorrhagia could be a prothrombotic condition. The observed association between VTE, tranexamic acid and other treatments for menorrhagia may thus partly be explained by confounding by indication. The possibility that menorrhagia is itself a risk factor for VTE merits further investigation.     

Venous Thromboembolism in Patients Receiving Neoadjuvant Chemotherapy for Advanced Ovarian Cancer and Impact on Survival

ObjectiveTo determine the incidence of venous thromboembolism (VTE) in patients with ovarian cancer receiving neoadjuvant chemotherapy (NACT), identify risk factors for VTE, and assess the effect of VTE on treatment trajectory and overall survival.MethodsThis is a retrospective cohort study of patients diagnosed with ovarian, fallopian tube, or primary peritoneal cancer treated with NACT between 2013 to 2016 in Alberta, Canada. The primary outcome was incidence of VTE during NACT. Secondary outcomes were risk factors for VTE and overall survival. Data related to patient demographics, cancer treatment, and incidence of VTE were collected. Statistical analyses included Kaplan-Meier estimates and univariate and multivariate Cox regression analysis.ResultsA total of 284 patients were included in this study. Average age at diagnosis was 63.8 years. The incidence of VTE during NACT was 13.3%. Patients with VTE were less likely to undergo interval debulking surgery (58.3%) than patients without VTE (78.6%). Kaplan-Meier estimates demonstrated a decrease in overall survival in patients who had VTE during NACT (15.0 mo; 95% CI 14.5–16.5) compared with patients who did not (26.8 mo; 95% CI 22.8–30.9) (P < 0.0001). Multivariate analysis identified albumin <35 g/L, BMI >30 kg/m², and non-serous histology as risk factors for VTE.ConclusionThe risk of VTE in this cohort was 13.3%, which was associated with decreased overall survival. These findings suggest that thromboprophylaxis may have a role in this patient population.     

Outcomes research on obstetric venous thromboembolism

Outcomes research on obstetric venous thromboembolism (VTE) involves a number of major challenges. While obstetric VTE, including deep vein thrombosis and pulmonary embolism, is relatively common on a population basis, diagnoses during pregnancy are relatively rare in comparison to high-risk scenarios such as orthopedic surgery. This review characterizes outcomes research on obstetric VTE with a focus on strengths, limitations, and appropriate inferences from existing research. It is divided into four sections. First, evidence regarding validity of diagnosis codes for VTE in administrative data is reviewed. Second, limitations of both clinical research and administrative-data study models are analyzed. Third, examples of high-quality obstetric VTE research from the literature and opportunities for improved research in the future are reviewed. Fourth, future directions for research are explored.     

妊娠相关静脉血栓栓塞症防治策略及中国实践

妊娠期和产褥期是静脉血栓栓塞症(VTE)明确的危险因素。妊娠相关VTE主要根据临床症状和体征、加压超声、肺通气/灌注扫描和CT肺动脉造影确诊。其防治首选低分子肝素,少数特殊患者使用普通肝素优于低分子肝素,溶栓治疗或放置下腔静脉滤器应严格把握指征。其中VTE的分娩期处理极具挑战性,需要产科、麻醉科、新生儿科以及血液科多科协作。近年来中国的VTE发生率有增高趋势,但缺乏实际的发病率数据以及有关VTE防治策略的研究,因此建立适合中国孕产妇的防治策略并采取多学科协作诊治的方式尤为重要。     

Contraception-Related Venous Thromboembolism in a Pediatric Institution

Study ObjectiveTo define the thrombotic risk factors of young women presenting to a children's hospital with hormonal contraception-related venous thromboembolism (VTE). We hypothesized that the majority of patients would have additional risk factors for VTE.DesignClinical and laboratory data obtained retrospectively from electronic medical records concerning history of presentation, body mass index (BMI), medical and family history, medication profile, and relevant laboratory studies.SettingNationwide Children's Hospital in Columbus, Ohio, November 2008-May 2012.ParticipantsTwenty-six female patients, age 12-21 years, admitted for hormonal contraception-related VTE.ResultsFifty-seven VTE cases were reviewed, and 26 were identified as contraception-related VTE. 96% of patients had at least 1 additional risk factor for VTE, and 42% of patients had 2 or more additional risk factors. 50% patients had a BMI ≥25 kg/m². 35% of patients had a positive family history of VTE in a first or second-degree relative. 27% of patients were subsequently diagnosed with an inherited thrombophilia, 5 of whom had a positive family history.ConclusionIn a small population of adolescents presenting to a children's hospital with contraception-related VTE, the majority of patients had multiple risk factors for VTE. Obesity was the most common additional risk factor (50%) identified in our study population. More research is needed regarding the impact of obesity on contraception-related VTE in young women, and whether the presence of obesity should influence thrombophilia screening practices prior to prescribing contraception.     

Minimizing tumor burden by extensive cytoreductive surgery decreases postoperative venous thromboembolism in ovarian clear cell carcinoma

Purpose  

A venous thromboembolism (VTE) is prevalent in patients with ovarian clear cell carcinoma (OCCC). Tumor burden and extensive cytoreductive surgery are well-known risk factor for a VTE. The purpose of this study was to define the incidence of VTE after extensive cytoreductive surgery and to clarify the relationship between VTE and extensive cytoreductive surgery in patients with OCCC.     

D-dimer negative deep vein thrombosis in puerperium

Venous thrombo-embolism (VTE) is a major cause of morbidity and mortality during pregnancy. Most of the evidence being used in the management of this condition in pregnancy is extrapolated from the general population. One such intervention is the use of the D-dimer test for the diagnosis of thromboembolism in pregnancy. Although this test has been found to be useful in low-risk non-pregnant patients, its negative predictive value is limited in high-risk patients in the general population to be used as a reliable diagnostic tool. Considering pregnancy as a high-risk state for VTE, we have evaluated the role of D-dimer in diagnosing VTE in pregnancy and proposed a diagnostic algorithm for the management of VTE based on the current evidence available.     

Can we identify risk factors during pregnancy for thrombo-embolic events during the puerperium and later in life?

Objectives: To investigate parturients at risk to develop venous thrombo-embolic events (VTE) in the puerperium or later in life, during a follow-up of more than a decade and compare risk factors for VTE during the puerperium with VTE later in life.

Methods: A nested case–control study was conducted to profile parturients at risk for VTE and a secondary analysis to compare risk factors for VTE during or after puerperium. We used a cohort of 95?257 women who gave birth between the years 1988 and 1998.

Results: Independent risk factors to develop VTE were peripartum hysterectomy, stillbirth, cesarean delivery (CD), obesity, pregnancy-related hypertension, grandmultiparity and advanced maternal age. Women undergoing CD and those receiving blood transfusion were more likely to develop early versus late VTE (OR?=?2.0, 95% CI?=?1.15–3.5 and OR?=?11.0, 95% CI?=?2.25–55.5; respectively). Patients that encountered VTE during the puerperium had more pulmonary emboli and less deep vein thrombosis, compared with the late VTE group (p?Conclusions: Maternal age, grandmultiparity, pregnancy-related hypertension, CD, obesity, stillbirth and peripartum hysterectomy are independent risk factors for the development of VTE. CD and blood transfusion were predictive of early versus late VTE.     

妊娠合并复发性下肢静脉血栓伴家族性血栓病史一例并文献复习

分析吉林大学第二医院收治的1例妊娠合并复发性下肢静脉血栓伴家族性血栓病史病例的临床资料,并回顾分析既往相关文献及资料。妊娠妇女发生下肢静脉血栓栓塞症(VTE)风险是非妊娠妇女的5倍左右,既往下肢VTE史、家族性血栓病史均是VTE的高危因素。本例患者既往产褥期下肢静脉血栓溶栓治疗后再次复发,此次给予抗凝治疗后未出现不良后果。对于VTE高危型孕产妇,适当的抗凝治疗利大于弊,产褥期格外需要重视。如今剖宫产率的增加更提高了术后VTE发生的风险,因此产前的评估、产后的严密观察以及适当的抗凝治疗可以降低妊娠相关的复发性VTE发生率。     

Clinically significant venous thromboembolism after gynecologic surgery.

OBJECTIVE: To review the incidence and outcome of clinically significant venous thromboembolism (VTE) following gynecologic surgery in a population receiving provider-specified prophylaxis. STUDY DESIGN: A computerized patient database was used to identify all patients diagnosed with VTE following gynecologic surgery from 1992 to 1997. Medical records were retrospectively reviewed. Clinically significant postoperative VTE was defined as pulmonary embolism or deep venous thrombosis, suggested by symptoms and physical findings, with subsequent confirmation by appropriate imaging study. Patients having VTE at the time of preoperative hospital admission and patients diagnosed with VTE after postoperative day 30 were excluded. RESULTS: Fifty-three patients developed postoperative VTE after > 30,000 gynecologic surgical procedures (incidence, < 1 event per 500 procedures). Forty-eight (91%) patients received some form of prophylaxis. Patients with benign disease, surgical anesthesia less than three hours and no history of prior VTE or factor V Leiden deficiency rarely developed postoperative VTE (incidence, < 1 event in 4,000 procedures). Thirteen (25%) patients had complications from anticoagulation therapy requiring prolonged hospital stay or readmission. CONCLUSION: Clinically significant VTE following gynecologic surgery is rare in the absence of malignancy, prolonged surgical anesthesia or hypercoagulation factors. Complications from anticoagulation therapy are common among gynecologic patients undergoing treatment for VTE.     

A Review of Hormonal Contraception and Venous Thromboembolism in Adolescents

BackgroundThe number of adolescents who are prescribed hormonal contraception (HC) for contraceptive and noncontraceptive indications is increasing. Approximately 1 of 4 female adolescents will use some form of HC by age 19 years. Venous thromboembolism (VTE) is a rare, but life-threatening complication associated with HC use. Although adolescents aged 15 to 19 years have the lowest absolute HC-associated VTE risk, they still account for 5.9% of HC-associated VTE. The absolute HC-associated VTE risk for those younger than 15 years of age is not well described.ObjectiveThe objectives of this report are to describe the current literature regarding HC-associated VTE in adolescents, to review the coagulation cascade and in vivo coagulation, to highlight differences between the adolescent and adult coagulation profiles, to discuss coagulation profile changes related to HC use, and to identify knowledge deficits for future study.ConclusionThe mechanisms and confounding variables that lead to HC-associated VTE in all adolescents are not well understood because many large HC studies exclude female adolescents younger than 18 years of age. Because of the paucity of data in this age group, observational studies and randomized controlled trials of VTE risk in adolescents on varying forms of HC are needed. Studies should include female adolescents across the entire adolescent age span (12-21 years) to better understand HC-associated VTE risk in this population.     

我国妇产科静脉血栓栓塞症发生率研究现状

我国妇科术后静脉血栓栓塞症（VTE）发生率为0.02%～2.26%,孕产妇围产期VTE发生率为0.056%～0.188%。但由于研究方法的缺陷,VTE发生率可能被低估。建议开展大规模、多中心、前瞻性流行病学调查,健全和完善各地孕产妇保健系统,以准确估计VTE发生率,为其治疗和预防提供可靠依据。     

Oral Contraceptive Use and the Cardiovascular Health of Canadian Women

Objectives: to review the published literature on the association between oral contraceptive (OC) use and cardiovascular disease, in particular venous thromboembolism (VTE) and acute myocardial infarction (AMI). To determine if there is an increased risk for VTE due to the use of the new progestins. To use the results of the analysis to construct a Canadian model.Methods: meta-regression was used to analyze adjusted relative risks from 18 studies for VTE and from 15 studies for AMI. The resulting risks were applied to the Canadian population of OC users, to calculate event and mortality rates for both, second and third generation progestin use.Results: the relative risk of VTE with the use of OCs consisting of low dose ethinyl estradiol (EE) with new progestins was 7.7 and with other progestins was 3.5, compared with non-use. The relative risk of AMI with new progestins was 1.2 and with other progestins was 2.9. In the Canadian model, there were 25 VTE and two AMI events annually/100,000 women for users of OCs with new progestins, and 11 VTE and four AMI events for users of OCs with other progestins, compared to three VTE and two AMI events for similar non-users. The exclusive use of OCs with new progestins potentially would decrease by seven the annual number of OC-attributable cardiovascular deaths in Canada.Conclusions: the published results appear to exaggerate both the VTE risk and the AMI benefit associated with the new progestins, because of bias including differences in the duration of use. Oral contraceptives should be avoided by women with other risk factors for cardiovascular disease; however, the typical OC user should not avoid or choose an OC based on the extremely small shifts in the cardiovascular risks between VTE and AMI.     

常用实验室指标与产后静脉血栓栓塞症相关性研究

目的分析产后发生静脉血栓栓塞症(venous thromboembolism,VTE)的临床流行病学特征及常用实验室检验指标与产后VTE的相关性,探讨其对VTE发生风险的预测价值。方法选择2015年1月1日至2019年12月31日在华中科技大学同济医学院附属协和医院分娩且发生产后VTE的孕妇为研究对象,以年龄和孕周匹配对照,回顾性研究产后VTE发生的流行病学特点及实验室数据。结果5年总体妊娠相关VTE发病率为0.376%,其中孕期VTE发病率为0.121%,产后VTE发病率为0.255%。产后新发VTE主要发生在分娩后2~4d,以远端下肢静脉血栓形成为主要临床类型。产后较低的血红蛋白与白蛋白比值、D二聚体差值升高与产后VTE的发生相关,产后血红蛋白/白蛋白比值每降低1,发生VTE风险增减3.61倍(P=0.008)。产前产后D二聚体的差值每增加1mg/L,发生VTE风险增加1.31倍(P=0.013),差异有统计学意义。结论产后血红蛋白和血清白蛋白比值降低、D二聚体的差值增加与VTE有密切相关性,可能作为VTE新的预测指标。     

Incidence and risk factors for postoperative venous thromboembolism in patients with ovarian cancer: Systematic review and meta-analysis

BackgroundVenous Thromboembolism (VTE) is a leading cause of morbidity and mortality in patients with ovarian malignancy. There is no meta-analysis available on this topic so far. The aim of our study was to quantitatively synthesize the data from studies with respect to the incidence and risk factors for postoperative VTE among cases with epithelial ovarian cancer (EOC).MethodsPubMed, Web of Science, and Embase were searched for papers containing the key words “venous thromboembolism”, “postoperative”, “postoperation”, “ovarian neoplasm”, “ovary neoplasm”, “ovarian cancer”, “ovary cancer”, and “cancer of ovary”. Studies selection, data extraction, quality assessment of eligible studies were performed independently by our different reviewers. Meta-analyses were conducted to determine postoperative VTE incidence and risk factors in women with EOC. Sensitivity analysis were used to verify the robustness of the results of meta-analyses if necessary.ResultsIn total, 19 studies were included in this meta-analysis. The pooled incidence for postoperative symptomatic VTE was 3% (95% CI, 0.03–0.04) and for postoperative symptomatic as well as asymptomatic VTE was 8% (95% CI, 0.07–0.09). The presence of history of VTE (OR, 2.37), advanced-stages (OR, 2.35), high complexity of surgery (OR, 2.20), clear cell carcinoma of ovary (OR, 2.53) and residual disease>1 cm (OR, 2.57) significantly increase the likelihood of having postoperative VTE. Other risk factors for postoperative VTE in EOC patients were BMI>30 (OR, 1.58), per 10-years increase in age (OR, 1.22), ASA score>2 (OR, 1.45), ascites (OR, 2.07), the diameter of residual disease is between 0 cm to 1 cm (OR, 2.06) and smoking history (OR, 1.54).ConclusionsThis study revealed that VTE, especially subclinical VTE, is a prevalent complication in postoperative patients with EOC. History of VTE, advanced FIGO stages, high complexity of surgery, obesity, older age, ascites, higher ASA score, smoking history and suboptimal debulking are associated with this increased incidence of postoperative VTE among patients with EOC.PROSPERO registration number: CRD42020209662.