Comparison of low molecular weight heparin vs. unfractionated heparin in gynecological surgery. II: Reduced dose of low molecular weight heparin.

In a double blind, randomized trial the hemorrhagic complications of a reduced dose of low molecular weight heparin (LMWH) (Fragmin, KabiPharmacia) were compared to those of the conventional dose of unfractionated heparin (UH). 2500 anti-XaU of LMWH was given once daily and UH in a dose of 5000 anti-XaU twice daily. During a one year period 141 patients undergoing gynecological surgery were included in this study. The patients were examined clinically for hematomas and for deep venous thrombosis (DVT) on the third and fifth day. Venography was performed when DVT was suspected. No patients developed clinical DVT. One woman in the LMWH group had pulmonary embolism 3 days after the prophylaxis was stopped. Two women in the LMWH group died, one from a stroke on day 2, one from cancer on day 39. There was no significant difference in serious bleeding complications between the two regimens, 20% in the LMWH group and 14% in the UH group. Even with the reduced dose of LMWH the mean plasma concentration of heparin in the LMWH group was higher (mean 0.14 anti-XaU/ml) than in the UH group (0.029 anti-XaU/ml) 3 hours after injection on the 2nd postoperative day. A reduced dose of LMWH (2500 anti XaU once daily) does not cause more bleeding complications than the conventional heparin regimen to prevent thrombosis, as was the case in our previous study with 5000 anti XaU of LMWH once daily.     

Prevention of venous thromboembolic events after gynecologic surgery

Venous thromboembolic events (deep vein thrombosis [DVT] and pulmonary embolism) are serious preventable complications associated with gynecologic surgery. Preoperative risk assessment of the individual patient will provide insight into the level of risk and the potential benefits of prophylaxis. Common risks include a history of venous thromboembolism, age, major surgery, cancer, use of oral contraceptives or hormone therapy, and obesity. Based on the presence of risk factors, the patient should be categorized into one of four risk groups and appropriate thromboprophylaxis prescribed. Randomized clinical trials in gynecologic surgery and general surgery have established the significant value of thromboprophylaxis. For moderate- and high-risk patients undergoing surgery for benign gynecologic conditions, low-dose unfractionated heparin, low molecular weight (LMW) heparins, intermittent pneumatic leg compression, and graded compression stockings all have demonstrated benefit. If using low-dose unfractionated heparin in high-risk patients, the heparin should be administered 5,000 units every 8 hours. Because DVT often begins in the perioperative period, it is important to initiate low-dose unfractionated heparin or administer the first LMW heparin dose either 2 hours preoperatively or 6 hours after the surgical procedure. Low molecular weight heparin has the advantage of being administered once daily but is more expensive than low-dose unfractionated heparin. In addition, LMW heparin has not been shown to be more effective and has similar risk of bleeding complications when compared with low-dose unfractionated heparin. In the very high-risk patient, a combination of two prophylactic methods may be advisable and continuing LMW heparin for 28 days postoperatively appears to be of added benefit.     

Comparison of low molecular weight heparin vs. unfractionated heparin in gynecological surgery

In a double-blind, randomized trial, the antithrombotic effect and haemorrhagic complications of low molecular weight heparin (LMWH) (Heparin fragment 2165, KabiVitrum) and unfractionated heparin (UH) were compared. LMWH (5000 anti-XaU) was injected every 24 h, UH (5000 IU) every 12 h; both drugs by subcutaneous injection. During 1984-85, 215 patients were examined clinically and by plethysmography. Venography was performed whenever DVT was suspected. None of the patients proved to have DVT. Bleeding complications were found in 54% of the cases. The LMWH group had a statistically significant predominance of bleeding complications as reflected by wound haematomas (p = 0.02) and the number of blood transfusions (p = 0.02). The heparin concentration was higher in the LMWH group (mean 0.13 IU/ml) than in the UH group (mean 0.13 IU/ml) measured 2 h after the injection. In the doses administered, LMWH and UH seem effective in the prevention of thrombosis. The increased bleeding tendency in the LMWH group probably was a consequence of the to high dosage.     

Inherited thrombophilia: treatment during pregnancy

OBJECTIVE: Inherited thrombophilia is associated with thromboembolic events and/or poor obstetric outcome. We evaluated the pregnancy outcome in women with inherited thrombophilia treated with low-molecular-weight heparin (LMWH). METHODS: 38 thrombophilic women with a history of thromboembolic events and/or poor obstetric outcome were treated during their 39 consecutive pregnancies with LMWH from pregnancy verification until 4-6 weeks in puerperium. A fixed dose of enoxaparin 4,000 IU/day (except 1 case who required nadroparin 0.3 ml/day) was administered in most cases, adopting a higher dose (6,000 IU/day to 6,000 IU twice a day) in those with previous thromboembolic events. RESULTS: In the treated women, all had a good obstetric outcome, whereas in the previous untreated pregnancies (n = 78), the rate of fetal loss (early and late) was 76.9%, only 12 live infants survived (66.6%). Moreover, birth weight resulted significantly higher in live infants born to treated pregnancies in comparison to that of previous untreated pregnancies (p = 0.009). No maternal thrombosis or major bleeding complications were recorded. CONCLUSIONS: The treatment with LMWH improved pregnancy outcome resulting effective and safe in thrombophilic women with a history of thromboembolic events and/or poor obstetric outcome.     

Assessment of the effectiveness of using low molecular weight heparin in the prophylaxis of venous thrombo-embolic diseases in obstetrics

OBJECTIVES: Assessment of the effectiveness of using low molecular weight heparin in the prophylaxis of venous thrombo-embolic diseases in pregnant women, parturients and puerperants. MATERIAL AND METHODS: 14,106 female patients were retrospectively analysed in the period between 1990-1999. The patients were divided into 4 groups: I--142 pregnant patients with crural varices, II--10 pregnant patients who had suffered from deep venous thrombosis, III--5 patients with implanted artificial cardiac valves, IV--13,949 patients without any risk factors. In the patients in groups I-III low molecular weight heparin was used prophylactically. RESULTS: In the studied groups no cases of pulmonary embolism were observed. Superficial venous thrombosis occurred in 10 women (3 in group I and 7 in group IV). Deep venous thrombosis occurred in 5 patients (2 in group I and 3 in group IV). In patients who received low molecular weight heparin over a long period of time, no excessive bleeding during delivery was observed. Other complications in the form of osteoporosis and thrombocytopenia were also not observed. CONCLUSIONS: 1. Administering of low molecular weight heparin during pregnancy, labour and puerperium has no influence on the increase of maternal et fetal complications. 2. Administering of low molecular weight heparin in pregnant women, in labour and in puerperium with increase risk of thrombo-embolic disease allows to avoid pulmonary arteries embolism. 3. Pregnant women and women in puerperium with increased risk of venous thrombo-embolic disease should be under control of experienced obstetrician in cooperation with vascular surgeon and hematologist.     

Low molecular weight heparin for the treatment of venous thromboembolism in pregnancy: a case series

Objectives To assess the use of low molecular weight heparin for the treatment of venous thromboembolism in pregnancy.
Design A prospective observational study.
Setting The maternity units in two university teaching hospitals and one district general teaching hospital.
Population Thirty-six consecutive women presenting with objectively diagnosed venous thromboembolism during pregnancy and the immediate puerperium.
Methods Treatment with the low molecular weight heparin enoxaparin, approximately 1 mg/kg sc, twice daily, based on early pregnancy weight.
Main outcome measures Peak anti-Xa activity (three hours post-injection), alterations in treatment, side effects and the use of regional anaesthesia.
Results In 33 women, the initial dose of enoxaparin provided satisfactory peak anti-Xa activity (median 0.8 u/mL, range 0.44–1.0 u/mL) and was continued. Three women required dose reduction since peak anti-Xa activities were above the therapeutic range (1.2, 1.2 and 1.1 u/mL). No woman developed thrombocytopaenia, haemorrhagic complication or further thromboembolic episode. Two women developed allergic skin reactions on enoxaparin and were changed to tinzaparin. Fifteen women had regional anaesthesia for delivery, with a reduced dose of enoxaparin (40 mg once daily), all without complication.
Conclusions Enoxaparin is a safe and effective treatment for venous thromboembolism during pregnancy and confers a major advantage over unfractionated heparin through its simplified regimen of administration.     

Pneumatic compression versus low molecular weight heparin in gynecologic oncology surgery: a randomized trial.

OBJECTIVE: To compare the efficacy and treatment-related complications of low molecular weight heparin and external pneumatic compression in the prevention of venous thromboembolism of postoperative gynecologic oncology patients. METHODS: A total of 211 patients over age 40 years, undergoing a major operative procedure for gynecologic malignancy, were randomized to receive perioperative thromboembolism prophylaxis with either low molecular weight heparin (n = 105) or external pneumatic compression (n = 106). Demographic data and clinical outcome were recorded for each patient. All patients underwent bilateral Doppler ultrasound of the lower extremities on postoperative days 3-5 to evaluate for the presence of occult deep vein thrombosis. A follow-up interview 30 days after surgery sought to detect patients who developed deep vein thrombosis or pulmonary embolism after hospital discharge. RESULTS: Venous thrombosis was diagnosed in two patients receiving low molecular weight heparin and in one patient receiving external pneumatic compression. The frequency of bleeding complications, measured by the number of required perioperative transfusions, and estimated intraoperative blood loss was similar between the two groups. CONCLUSION: Low molecular weight heparin and external pneumatic compression are similarly effective in the postoperative prophylaxis of thromboembolism. The use of low molecular weight heparin is not associated with an increased risk of bleeding complications when compared with external pneumatic compression. We believe that both modalities are reasonable choices for prophylaxis in this high-risk group of patients.     

Comparison of enoxaparin, a low-molecular-weight heparin, and unfractionated heparin, with or without dihydroergotamine, in abdominal hysterectomy.

The effects of administration of low-molecular-weight heparin (enoxaparin 20 mg) once a day, of unfractionated heparin (5000 IU twice a day, and of unfractionated heparin (2500 IU) plus dihydroergotamine (0.5 mg) twice a day were assessed in 100 patients undergoing abdominal hysterectomy. The test medications were given subcutaneously 2 hours before operation and for 3 days thereafter. There were no thromboembolic complications. Intraoperative blood loss, wound haematomas and blood loss via drains during four days after operation were similar in the three groups. None of the 37 patients receiving enoxaparin experienced major postoperative bleeding. Six out of 31 patients receiving unfractionated heparin without dihydroergotamine and two out of 32 patients receiving dihydroergotamine in addition experienced major bleeding necessitating re-operation and/or blood transfusion, (P < 0.05). Enoxaparin caused less major bleeding than unfractionated heparin with or without dihydroergotamine in patients undergoing hysterectomy.     

低分子肝素在产科常见疾病中的应用

低分子肝素（LMWH）在达到有效的抗凝血作用的同时,可以减少肝素所致的出血等不良反应,在临床上具有一定的应用价值。目前LMWH广泛应用于产科临床,其不仅能预防妊娠期和产褥期深静脉血栓形成（DVT）,还能预防、治疗易栓症引起的子痫前期（PE）、胎儿生长受限（FGR）等产科常见并发症。对妊娠期及产褥期DVT的危险因素进行评估后,可考虑使用LMWH。研究发现,LMWH也能改善非易栓症孕妇的不良妊娠结局,降低高危人群（有胎盘早剥、早发型PE病史的孕妇）患早发型PE、重度PE、FGR及晚期流产的风险,延长妊娠时间,提高新生儿存活率和出生体质量。现综述近年来LMWH应用于产科DVT、PE和FGR的相关研究进展。     

Prevention of postpartum venous thrombosis with low doses of heparin

Postpartum superficial and deep venous thrombosis were found in 22.3 % and 5.3 % of women with varicose veins who delivered vaginally, or by cesarean section. The preventive use of low doses of heparin (5,000 U every 12 h injected subcutaneously) in 116 parturients with varicose veins reduced significantly the incidence of postpartum venous thrombosis. None of the 26 women with previous thrombosis who received preventive treatment, developed such an event.     

Deep venous thrombosis associated with large leiomyomata uteri. A case report

BACKGROUND: The association of deep venous thrombosis (DVT) with uterine leiomyomata has been reported only rarely in the English-language literature. These concomitant findings occurred in a woman with no other known risk factors for development of DVT. CASE: A 49-year-old, Caucasian woman, gravida 3, para 3, with a past medical history significant for large uterine leiomyomata, menorrhagia and anemia, presented with acute edema of the left lower extremity. Doppler studies revealed compression of the left iliofemoral vein with associated thrombosis. No risk factors for DVT were identified. Intravenous heparin was initiated, with eventual preoperative placement of an inferior vena cava Greenfield filter. A total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed without complications. CONCLUSION: Large uterine leiomyomata are a potential cause of lower extremity venous stasis and resulting thrombosis and can be treated with hysterectomy.     

Prophylactic and therapeutic enoxaparin during pregnancy: indications, outcomes and monitoring

OBJECTIVES: To evaluate the efficacy and safety of prophylactic and therapeutic enoxaparin in pregnancy. STUDY DESIGN: Three-year prospective audit. SETTING: Tertiary level obstetric hospital. POPULATION: Fifty-two women who received subcutaneous enoxaparin, either a prophylactic dose (40 mg daily) in 26 pregnancies or therapeutic dose (1 mg/kg twice daily) in 32 pregnancies. MATERIALS AND METHODS: Pregnant women treated with enoxaparin were prospectively entered into a register. Data were retrieved by case note review. MAIN OUTCOME MEASURES: Pregnancy outcomes, treatment complications and anti-Xa levels. RESULTS: In the prophylactic group there were no fetal losses, thromboembolic events or complications related to enoxaparin. In the therapeutic group there were four first trimester miscarriages, a termination and 27 live births. Therapeutic enoxaparin prevented further thromboembolism without complications. One woman was treated with intermediate dose enoxaparin when she presented at 5 weeks' gestation on warfarin and 7 weeks after a venous thromboembolism. She developed a recurrent pulmonary embolus 3 weeks later and was subsequently treated with therapeutic enoxaparin. In the therapeutic group the enoxaparin dose/kg correlated poorly with anti-Xa levels, and dose adjustments were made. Therapeutic mean (SD) trough and peak anti-Xa levels were 0.33 U/mL (0.14) and 0.86 U/mL (0.24) in the first trimester and 0.48 U/mL (0.19) and 0.84 U/mL (0.23) in the third trimester. CONCLUSIONS: In the present series, prophylactic and therapeutic enoxaparin treatment during pregnancy was effective and safe. Studies are required to determine the optimal duration of treatment with therapeutic enoxaparin following venous thromboembolism in pregnancy and the clinical relevance of anti-Xa monitoring.     

Incidence,clinical characteristics,and timing of objectively diagnosed venous thromboembolism during pregnancy

Objective: To determine the incidence, timing, and associated clinical characteristics of objectively diagnosed pregnancy-associated venous thromboembolism (VTE).Methods: A retrospective review of VTE cases occurring between 1978 and 1996 was performed. Cases of deep venous thrombosis (DVT) and pulmonary embolism (PE) were identified by ICD-9 discharge diagnosis code and review of antepartum and coagulation laboratory databases. Study inclusion criteria required the objective diagnosis of VTE with either Doppler ultrasound, impedance plethysmography, pulmonary angiography, ventilation-perfusion scanning, or CT/MRI.Results: Among 268,525 deliveries there were 165 (0.06%) episodes of VTE (1/1627 births). There were 127 cases of DVT and 38 cases of PE. Only 14% (23/165) had a prior history of DVT or PE. Most DVTs occurred in the left leg (104/127, 81.9%). Nearly three quarters of the DVTs (95/127, 74.8%) occurred in the antepartum period. Among the antepartum DVT cases, half were detected prior to 15 weeks of gestation (47/95, 49.5%), with only 28 cases occurring after 20 weeks (P < .0001). The majority of the PEs occurred in the postpartum period (23/38, 60.5%). There were only 3 maternal deaths due to PE, all associated with cesarean section. Only 1 patient developed PE while on heparin therapy for DVT while 11 others had complications attributable to heparin use.Conclusion: Most pregnancy-related VTE occurs in the antepartum period. The risk of deep venous thrombosis appears to begin early in pregnancy, even before the second trimester. The highest risk period for pulmonary embolism is after cesarean delivery. Maternal complications of heparin anticoagulation during pregnancy are rare.     

剖宫产术后深静脉血栓形成的临床研究

目的:探讨剖宫产术后DVT的诊治及预防。方法:回顾分析2002年8月至2005年12月我科收治的剖宫产术后并发下肢DVT的患者47例,分析其临床特点及诊断治疗的方法,并结合文献复习讨论预防措施。结果:既往有血栓病史、经产妇、肥胖是剖宫产术后DVT的危险因素,主要临床症状为患肢粗肿、疼痛,部分患者有呼吸系统的非特异性症状,DVT的辅助诊断首选血浆D-二聚体检测结合静脉彩色多普勒超声显像。采用全身或局部抗凝、溶栓等药物或手术取栓治疗,部分患者放置可回收性IVCF预防致死性PE,均取得较好的近期疗效。结论:对于存在DVT危险因素的孕产妇,剖宫产手术前后应采取积极预防措施。LMWH是常用的和安全的抗凝药物,能有效预防和治疗DVT。     

Effect of heparin on activated partial thromboplastin time in patients undergoing gynecologic or obstetric surgery

The exaggerated prolongation of the activated partial thromboplastin time (APTT) by heparin prophylaxis for postoperative thromboembolism may cause bleeding complications. We examined the effects of various doses of unfractionated heparin on the APTT in patients who underwent a gynecologic or obstetric operation. A total of 68 patients who underwent a gynecologic operation (n = 47) or a cesarean section (n = 21) with risk factors for thromboembolism received a continuous intravenous infusion of unfractionated heparin (110-285 IU/kg/day) after surgery until the patient was mobilized the next day. A group of 61 postoperative patients who did not receive heparin served as controls. The APTT was measured in these 129 patients preoperatively and on postoperative day 1. A clinical deep vein thrombosis occurred in only 1 patient, who was in the control group. No bleeding complications occurred in any patient. The percent change in the APTT was significantly correlated with the dose of heparin administered (p < 0.001). Compared with the control group, the mean APTT was not prolonged in the patients who received heparin at 110-149 IU/kg/day. It was prolonged significantly in the patients who received heparin at greater than 150 IU/kg/day. An exaggerated prolongation of the APTT, defined as an APTT greater than 150% of the preoperative value, was found in 0 of 32 patients in the 110-149 IU/kg/day group, 1 of 28 patients (3.6%) in the 150-199 IU/kg/day group and 2 of 8 patients (25%) in the 200-285 IU/kg/day group. The continuous postoperative administration of intravenous heparin at less than 200 IU/kg/day does not result in an exaggerated prolongation of the APTT.     

Thromboembolic risk in pregnant women with SARS-CoV-2 infection – A systematic review

The infection by SARS-CoV-2 is associated with a thromboembolic complications risk theoretically increased. Pregnancy, isolated, is considered a pro-thrombotic state.This systematic review has the main goal to evaluate the thromboembolic risk in pregnant women with COVID-19 disease, namely for pulmonary embolism (PE) and deep vein thrombosis (DVT). The secondary goal is the evaluation of the need for thromboprophylaxis in these cases.Three databases - PubMed, Scopus and Web of Science – were searched on October 2021, using the following Mesh terms and keywords: “(covid-19 OR SARS-CoV-2 OR Covid) AND (pregnancy) AND (coagulopathy OR blood coagulation disorders OR thrombotic complications OR thromboembolic risk OR venous thromboembolism OR venous thrombosis)”. Information about thrombotic complications in pregnancy and thromboprophylaxis was collected, by two independent reviewers.In total, 12 articles were analyzed, corresponding to 18205 pregnant women with SARS- CoV-2 infection. A total of 85 cases of thromboembolic events were diagnosed (0.46%, 95% CI 0.37–0.58%), of which only 17 reported the use of thromboprophylaxis (20.00%, 95% CI 12.10–30.08%). There were 3 deaths due to thromboembolic complications (3.53%, 95% CI 0.73–9.97%).In conclusion, in pregnant women, the SARS-CoV-2 infection increases the risk of thromboembolic complications. However, the risk is not greater than in the general population. It is recommended thromboprophylaxis with low molecular weight heparin for hospitalized pregnant women, and in groups with moderate to high thromboembolic risk at home self-isolation.     

Cost-effectiveness of deep venous thrombosis prophylaxis in gynecologic oncology surgery

OBJECTIVE: To estimate the cost-effectiveness of preventive strategies for deep vein thrombosis (DVT) in patients undergoing surgery for gynecologic cancer. METHODS: A model was constructed to estimate the costs and outcomes associated with the use of external pneumatic compression, unfractionated heparin, and low molecular weight heparin in women with cervical, endometrial, and ovarian cancer. We estimated cost per DVT prevented, per fatal pulmonary embolus (PE) prevented, and per life-year saved. Probability estimates for various outcomes and efficacies were obtained from the literature, using data specific for gynecologic patients when available. RESULTS: Cost-effectiveness estimates ranged from $27 per life-year saved for a 55-year-old endometrial cancer patient to $5132 per life-year saved for a 65-year-old with ovarian cancer. Although low molecular weight heparin and unfractionated heparin were cost-effective compared with no prophylaxis, each was less effective than external pneumatic compression in the base case. The results of the analysis were sensitive to assumptions about the relative risk of DVT, the life expectancy of the patient, the costs of future treatment, and the relative effectiveness of the different strategies: If unfractionated heparin or low molecular weight heparin is at least 2-3% more effective than external pneumatic compression, then the incremental cost per life-year of either would be less than $50,000 compared with external pneumatic compression. CONCLUSION: Prophylaxis of DVT is cost-effective in terms of life-years gained even for patients with relatively short life expectancies, such as ovarian cancer patients. External pneumatic compression appears to be the most cost-effective strategy under our baseline assumptions, but further studies in gynecologic cancer are needed to validate our conclusions.     

Thromboembolic diseases in pregnancy

In pregnancy, thromboembolic complications are six times more frequent than in nonpregnant women. Maternal age, idiopathic or secondary thrombosis in the patients history, the mode of delivery, bed rest and / or obesity as well as the thrombophilic defects are considerable factors for an increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE). Compared to unfractionated heparins (UFHs) prophylactic treatment relies mainly on low molecular weight heparins (LMWHs) which safety is now well established in pregnant women. In view of their multiple side effects oral anticoagulants such as cumarine or aspirin are contraindicated or of subordinate importance. The procedures to exclude DVT follow the usual diagnostic algorithms considering maximum radiation protection in case of further apparative diagnostics. Although there are reported good experiences with LMWHs in the treatment of DVT, UFHs are still the preferred drugs in this clinical condition. Insufficient heparin treatment or impending postthrombotic complications may be reasons for additional therapies like thrombolysis or operative thrombectomy.     

Administration of low molecular weight heparin within two hours before caesarean section increases the risk of wound haematoma

A retrospective analysis of the relation between time interval from prophylactic administration of low molecular weight heparin (LMWH) to delivery and the occurrence of wound haematoma was performed in all women, who had a caesarean section in 1998. After administration of LMWH within 2 hours of surgery, the percentage of women with a wound haematoma was significantly larger (12% vs 3%). Multivariate regression analysis, including other risk factors for wound haematoma, indicated administration of LMWH within 2 hours prior to delivery as the only statistically significant factor, which influenced the development of wound haematoma (odds ratio = 5.3,  95% CI = 1.2–22.8  ).     

Prevention of postoperative thromboembolism by dextran 70 or low-dose heparin

The efficacy of intravenous infusion of dextran 70 or subcutaneous administration of low-dose heparin in preventing postoperative thromboembolic complications has been investigated in a prospective randomized trial. During part 1 of the study, 232 patients over the age of 40 years who were undergoing major gynecologic surgery underwent a complete test protocol. The 125I fibrinogen uptake test (FUT) was used for the diagnosis of deep vein thrombosis (DVT) in 117 patients in the dextran and 115 patients in the heparin group. Heparin was significantly more effective than dextran for reducing DVT (P less than .001). During part 2 of the study no FUT was done but the incidence of clinical and fatal pulmonary embolism (PE) and the number of complications were studied. Of 444 patients (parts 1 and 2) 1 fatal and 2 nonfatal pulmonary emboli were diagnosed. All the emboli occurred in the dextran group. The benefit: hazard ratio appeared to favor heparin for the prophylaxis of DVT.