Antifibrinolytic Tranexamic Acid Research Articles

Postpartum Hemorrhage Management in 2012

Transfusion therapy in postpartum hemorrhage (PPH) traditionally has been modeled after precedents set in the Vietnam and Korean wars. However, data from recent military combat casualties suggest a different transfusion strategy. Transfusion of packed red blood cells, fresh frozen plasma, and platelets in a ratio of 1:1:1 improves dilutional coagulopathy and survival. Women who present with low fibrinogen at the time of diagnosis of PPH have poorer outcomes and might benefit from early fibrinogen replacement. The antifibrinolytic agent, tranexamic acid, decreases bleeding and progression to severe PPH, but its role in PPH management is evolving. Observational data suggest that the use of recombinant factor VIIa should be limited to bleeding that has not responded to an optimal transfusion strategy. Point-of-care testing using thromboelastography is helpful in guiding the selection of blood products to be transfused. Additionally, massive transfusion protocols can decrease the overall number of products transfused and improve outcomes.

Is it time for a new standard?

Is it time for a new standard?

Population pharmacokinetics of tranexamic acid in adults undergoing cardiac surgery with cardiopulmonary bypass

Interest in antifibrinolytic tranexamic acid (TA) has grown since the widespread removal of aprotinin, but its dosing during cardiac surgery is still debated. The objectives of this study were to investigate the population pharmacokinetics (PK) of TA given with either low- or high-dose continuous infusion schemes in adult cardiac surgery patients during cardiopulmonary bypass (CPB). Patients were randomized to receive either low-dose (10 mg kg(-1) followed by an infusion of 1 mg kg(-1) h(-1) throughout the operation, and 1 mg kg(-1) into the CPB) or high-dose (30 mg kg(-1), then 16 mg kg(-1) h(-1), and 2 mg kg(-1) into the CPB) TA. Serum TA concentrations were measured in 61 patients and the data were modelled using Monolix. TA concentrations were 28-55 µg ml(-1) in the low-dose group and 114-209 µg ml(-1) in the high-dose group throughout surgery. TA PK was best described by a two-compartment open model. The main covariate effect was bodyweight, whereas the CPB did not influence the PK. Assuming a bodyweight of 70 kg, the population estimates were 4.8 litre h(-1) for clearance, 6.6 litre for the volume of the central compartment, 32.2 litre h(-1) for the diffusional clearance, and the peripheral volume of distribution was 10.8 litre. The PK of TA was satisfactorily described by an open two-compartmental model, which was used to propose a dosing scheme suitable for obtaining and maintaining the desired plasma concentration in a stable and narrow range in cardiac surgery patients.

Autologous 3D Tissue-Engineered Bone Marrow For Drug Screening In MM Patients

IntroductionMultiple myeloma (MM) is the second most prevalent hematological malignancy, and it remains incurable with a median survival of 3 to 5 years. Despite the introduction of several novel drugs, only 60% of the patients respond to therapy, and more than 75% of patients relapse after 5 years. The interaction of MM cells with extracellular matrix (ECM) and stromal cells in the bone marrow (BM) milieu was shown to play a crucial role in MM progression and drug resistance. Therefore, an appropriate model that demonstrates the complex interactions between MM cells and their environment and predicts the response to treatment of MM patients is warranted. The goal of this study is to produce an in vitro model of BM microenvironment in MM, which will mimic the BM in the patient and have closest prediction of cell-behavior in vivo. MethodsScaffolds for the 3D tissue-engineered BM (3DBM) were prepared by crosslinking BM supernatants from MM patients with calcium chloride in the presence of the antifibrinolytic tranexamic acid. The concentration of the different components for scaffold formation and physico-chemical properties of the scaffold were optimized. Then, we incorporated cellular components (MM cell lines and stromal cell lines) and ECM components (fibronectin) to 3DBM scaffold. We tested the effect of different MM cell densities, fibronectin concentration, and presence of different densities of stromal cells in the scaffold on the proliferation of MM cells, which was analyzed by flow cytometry. After optimization of the cellular and ECM components, we tested the sensitivity of MM cells to chemotherapeutic agents used in MM, including melphalan, bortezomib and carfilzomib, in 3DBM scaffolds with and without the presence of stromal cells. We assessed the sensitivity of MM cells to the drugs in the 3DBM scaffolds compared with the sensitivity in two-dimensional (2D) classic in vitro tissue culture system, with or without the presence of stromal cells. ResultsWe optimized the conditions for the production of a 3DBM from BM supernatants from MM patients. We found that calcium concentration was a critical factor for the formation of the 3DBM scaffold; and 1mg/ml calcium chloride was the optimal concentration for fastest and most stable scaffold formation. Moreover, we found that the presence of an antifibrinolytic agent was essential for the stabilization of the scaffold, and 4mg/ml of tranexamic acid was sufficient to stabilize the scaffold.We optimized the conditions for seeding of the cellular components and found that MM cells proliferated in the 3DBM scaffolds better than in regular 2D tissue culture plates, in which the expansion rate over 3 days was about 5-folds in the 3DBM, compared to about 2.4-folds in 2D classic in vitro tissue culture system. In addition, we optimized the co-culture condition of MM cells with stromal cells and found that the ratio of MM/stroma of 3/1 generated the highest proliferation of MM cells in the 3DBM scaffolds. Similarly, the addition of ECM components (fibronectin) increased the proliferation of MM in the 3DBM by about 30%.In addition, we tested the effect of the 3DBM scaffold on drug resistance of MM cells. In a 2D classic in vitro tissue culture system approximately about 40-50% of the MM cells were killed using the different chemotherapies, the culture of MM cells in 3DBM decreased the sensitivity of MM cells to treatment, and addition of stromal cells to the co-culture decreased the sensitivity of MM cells to treatment in both 3D and 2D. We found that the co-culture of MM cells with stromal cells in the 3DBM treatment and using the same concentrations of the different chemotherapies killed only 5-15% of the MM cells. ConclusionsWe produced and characterized a 3D scaffold made from supernatant of BM aspirates from MM patients. This 3DBM is all made from patient material (autologous), no synthetic scaffolds were used, and it could represent the closest in vitro model to the BM in MM. The 3DBM induced drug resistance in MM cells, especially when it contained stromal cells. The autologous 3DBM seems to be closer to the real BM microenvironment, therefore, a better drug screening method than 2D classic in vitro tissue culture systems. Disclosures:No relevant conflicts of interest to declare.

Efficacy of Tranexamic Acid and Aminocaproic Acid on Bleeding in Spine Surgery: A Meta-Analysis

Spine surgery may be associated with substantial blood loss necessitating transfusions. Blood loss-associated morbidity can be due to direct risks, such as hypotension and organ damage, or as result of blood transfusions. The antifibrinolytics tranexamic acid (TXA) and epsilon aminocaproic acid (EACA) are lysine analogues which inhibit activation of plasminogen and have been shown to reduce surgical blood loss.

Association of Cryoprecipitate and Tranexamic Acid With Improved Survival Following Wartime Injury

To quantify the impact of fibrinogen-containing cryoprecipitate in addition to the antifibrinolytic tranexamic acid on survival in combat injured. Retrospective observational study comparing the mortality of 4 groups: tranexamic acid only, cryoprecipitate only, tranexamic acid and cryoprecipitate, and neither tranexamic acid nor cryoprecipitate. To balance comparisons, propensity scores were developed and added as covariates to logistic regression models predicting mortality. A Role 3 Combat Surgical Hospital in southern Afghanistan. A total of 1332 patients were identified from prospectively collected U.K. and U.S. trauma registries who required 1 U or more of packed red blood cells and composed the following groups: tranexamic acid (n = 148), cryoprecipitate (n = 168), tranexamic acid/cryoprecipitate (n = 258), and no tranexamic acid/cryoprecipitate (n = 758). In-hospital mortality. Injury severity scores were highest in the cryoprecipitate (mean [SD], 28.3 [15.7]) and tranexamic acid/cryoprecipitate (mean [SD], 26 [14.9]) groups compared with the tranexamic acid (mean [SD], 23.0 [19.2]) and no tranexamic acid/cryoprecipitate (mean [SD], 21.2 [18.5]) (P < .001) groups. Despite greater Injury Severity Scores and packed red blood cell requirements, mortality was lowest in the tranexamic acid/cryoprecipitate (11.6%) and tranexamic acid (18.2%) groups compared with the cryoprecipitate (21.4%) and no tranexamic acid/cryoprecipitate (23.6%) groups. Tranexamic acid and cryoprecipitate were independently associated with a similarly reduced mortality (odds ratio, 0.61; 95% CI, 0.42-0.89; P = .01 and odds ratio, 0.61; 95% CI, 0.40-0.94; P = .02, respectively). The combined tranexamic acid and cryoprecipitate effect vs. neither in a synergy model had an odds ratio of 0.34 (95% CI, 0.20-0.58; P < .001), reflecting nonsignificant interaction (P = .21). Cryoprecipitate may independently add to the survival benefit of tranexamic acid in the seriously injured requiring transfusion. Additional study is necessary to define the role of fibrinogen in resuscitation from hemorrhagic shock.

Re-Evaluation of the Role of Antifibrinolytic Therapy with Lysine Analogs in Liver Transplantation in The Post-Aprotinin Era

Purpose of review: Hemorrhage, blood and blood product transfusions and the need for surgical re-exploration for bleeding can have a detrimental effect on patient outcome during liver surgery. Following the suspension of aprotinin from the market only the antifibrinolytics tranexamic acid (TA) and epsilon-aminocaproic acid (EACA) are left as pharmacological options to reduce hemostatic activation and associated bleeding complications. Considering the apparent usefulnes of aprotinin in liver surgery and transplantation, its loss has left a void within the armamentarium of drugs available to reduce blood loss. The need for large independent safety studies has become evident. The current review focuses on the drugs that are available, the safety and efficacy data that supports their use and the indications warranting further trails. Recent findings: Both TA and EACA are effective in reducing blood loss and transfusion requirements in liver surgery. Analysis of data is complicated as the dosing regimens, especially for tranexamic acid, varies enormously and the agents are highly overdosed in most relevant trials. New data indicates that in a dose-dependent fashion, TA is associated with an increase in adverse events with transient renal failure highlighted as a particular problem. It appears that all the anti-fibrinolytics have side effects that may impact on morbidity and mortality and it may be that aprotinin is no worse. The use of these agents needs to be balanced against benefit especially in the management of high risk cases.

Most Effective Regimen of Tranexamic Acid in Knee Arthroplasty: A Prospective Randomized Controlled Study in 240 Patients

The antifibrinolytic tranexamic acid reduces surgical blood loss, but studies have not identified an optimal regimen. We studied different dosages, timings, and modes of administration to identify the most effective regimen of tranexamic acid in achieving maximum reduction of blood loss in TKA. We prospectively studied five regimens (four intravenous, one local; 40 patients each) with a control group (no tranexamic acid). The four intravenous (10-mg/kg dose) regimens included (1) intraoperative dose (IO) given before tourniquet deflation, (2) additional preoperative dose (POIO), (3) additional postoperative dose (IOPO), and (4) all three doses (POIOPO). The fifth regimen was a single local application (LA). Two independent parameters of drain loss and total blood loss, calculated by the hemoglobin balance method, were evaluated statistically. Both parameters were reduced in all five regimens as against the control. A significant reduction in drain loss was seen in the POIO, IOPO, and POIOPO groups whereas total blood loss was significantly reduced in the POIO, POIOPO, and LA groups. The POIOPO group had the least drain loss (303 mL) and least total blood loss (688 mL). The IO group had the greatest drain loss and the IOPO group the greatest total blood loss. Single-dose tranexamic acid did not give effective results. The two-dose regimen of POIO was the least amount necessary for effective results. When compared against the control, this regimen produced reduction of drain loss and total blood loss, whereas the IOPO regimen did not. The three-dose regimen of POIOPO produced maximum effective reduction of drain loss and total blood loss.

Safety and Effectiveness of two treatment regimes with tranexamic acid to minimize inflammatory response in elective cardiopulmonary bypass patients: a randomized double-blind, dose-dependent, phase IV clinical trial

BackgroundIn cardiopulmonary bypass (CPB) patients, fibrinolysis may enhance postoperative inflammatory response. We aimed to determine whether an additional postoperative dose of antifibrinolytic tranexamic acid (TA) reduced CPB-mediated inflammatory response (IR).MethodsWe performed a randomized, double-blind, dose-dependent, parallel-groups study of elective CPB patients receiving TA. Patients were randomly assigned to either the single-dose group (40 mg/Kg TA before CPB and placebo after CPB) or the double-dose group (40 mg/Kg TA before and after CPB).Results160 patients were included, 80 in each group. The incident rate of IR was significantly lower in the double-dose-group TA2 (7.5% vs. 18.8% in the single-dose group TA1; P = 0.030). After adjusting for hypertension, total protamine dose and temperature after CPB, TA2 showed a lower risk of IR compared with TA1 [OR: 0.29 (95% CI: 0.10-0.83), (P = 0.013)]. Relative risk for IR was 2.5 for TA1 (95% CI: 1.02 to 6.12). The double-dose group had significantly lower chest tube bleeding at 24 hours [671 (95% CI 549-793 vs. 826 (95% CI 704-949) mL; P = 0.01 corrected-P significant] and lower D-dimer levels at 24 hours [489 (95% CI 437-540) vs. 621(95% CI: 563-679) ng/mL; P = 0.01 corrected-P significant]. TA2 required lower levels of norepinephrine at 24 h [0.06 (95% CI: 0.03-0.09) vs. 0.20(95 CI: 0.05-0.35) after adjusting for dobutamine [F = 6.6; P = 0.014 corrected-P significant].We found a significant direct relationship between IL-6 and temperature (rho = 0.26; P < 0.01), D-dimer (rho = 0.24; P < 0.01), norepinephrine (rho = 0.33; P < 0.01), troponin I (rho = 0.37; P < 0.01), Creatine-Kinase (rho = 0.37; P < 0.01), Creatine Kinase-MB (rho = 0.33; P < 0.01) and lactic acid (rho = 0.46; P < 0.01) at ICU arrival. Two patients (1.3%) had seizure, 3 patients (1.9%) had stroke, 14 (8.8%) had acute kidney failure, 7 (4.4%) needed dialysis, 3 (1.9%) suffered myocardial infarction and 9 (5.6%) patients died. We found no significant differences between groups regarding these events.ConclusionsProlonged inhibition of fibrinolysis, using an additional postoperative dose of tranexamic acid reduces inflammatory response and postoperative bleeding (but not transfusion requirements) in CPB patients. A question which remains unanswered is whether the dose used was ideal in terms of safety, but not in terms of effectiveness.Current Controlled Trials numberISRCTN: ISRCTN84413719

373 Risk factors associated with recurrent seizures following cardiac surgery

373 Risk factors associated with recurrent seizures following cardiac surgery

Postpartale Eklampsie und fulminantes HELLP-Syndrom

Postpartum onset of eclampsia and HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome is a rare but life-threatening complication for both mother and fetus. A case of a 38-year-old parturient (gravida 2, para 1) who was asymptomatic prior to delivery is reported. Emergency caesarean section had to be performed due to sudden onset of fetal bradycardia as a result of partial placental separation. The perioperative course was characterized by new onset hypertension, nausea and restlessness; within 2 h the patient suffered a generalized seizure which was treated with magnesium sulfate and hydralazine. Despite management in accordance with current guidelines, the condition deteriorated with hypotension, anemia and renal failure. On further examination hematomas in the abdominal cavity and walls were identified and laboratory tests confirmed HELLP syndrome with severe coagulopathy. Explorative laparotomy revealed diffuse bleeding without a significant isolated source or postpartum uterine hemorrhage. Retrospectively, the anemia could be ascribed to severe hemolysis and diffuse bleeding from coagulopathy. The patient required packed red cells, platelets, fresh frozen plasma and prothrombin complex. After admission to the intensive care unit persistent diffuse bleeding mainly caused by hyperfibrinolysis and renal failure occurred, which required blood transfusion, antifibrinolytic (tranexamic acid) and renal replacement therapy (continuous veno-venous hemodiafiltration with citrate) for 6 days. The patient recovered without any sequelae and was discharged 26 days later. Placental separation with new onset peripartum hypertension is to be interpreted as a precursor of severe gestosis and associated complications, especially disseminated intravascular coagulation (DIC), acute renal failure and pleural effusion. A differentiation between a rapid drop in hemoglobin concentration secondary to hemolysis in postpartum HELLP syndrome rather than postpartum hemorrhage can be challenging. In addition, HELLP syndrome can lead to rapidly developing, fulminant hyperfibrinolysis in the context of DIC. Keys to successful management of postpartum gestosis and associated complications are early detection and perception of clinical and laboratory warning signs, a multidisciplinary approach with rapid and consistent targeted symptomatic therapy to save the mother and fetus.

Re-evaluation of the role of antifibrinolytic therapy with lysine analogs during cardiac surgery in the post aprotinin era

Hemorrhage, transfusions and the need for re-exploration can have a detrimental effect on patient outcome in cardiac surgery. With the suspension of aprotinin from the market, only the antifibrinolytics tranexamic acid and epsilon-aminocaproic acid (EACA) are left as pharmacological options to reduce hemostatic activation and associated bleeding complications. In light of the aprotinin story, the need for large independent safety studies has become evident. The current review will focus on the question of how far the quality of available data allows for judging these agents with regard to safety and efficacy, as well as whether or not new trails are warranted. Both, tranexamic acid and EACA are effective in reducing blood loss and transfusion requirements in cardiac surgery. Analysis of data is complicated as the dosing scheme, especially for tranexamic acid, varies extremely and the agents are highly overdosed in most relevant trials. Newer data indicates that in a dose-dependent fashion, tranexamic acid is associated with an increase of adverse events, particularly the observation of seizures. In these studies, however, tranexamic acid has also been highly overdosed. The lysine analogs are unspecific enzyme inhibitors. Therefore, it is conceivable that an overdosing might reveal severe clinical side-effects beyond the inhibition of plasmin. Further studies re-evaluating the drug safety of tranexamic acid and EACA using the recommended and approved doses are necessary.

Novel, oral tranexamic acid improves the general quality of life (SF-36v2™ health survey measures) in women with menorrhagia

OBJECTIVE: To assess the effect of a novel, oral formulation of the antifibrinolytic tranexamic acid (TA, Lysteda™) on general quality of life of women with heavy menstrual bleeding (HMB, menorrhagia).

The in vitro cross-effects of inhibitors of renin-angiotensin and fibrinolytic systems on the key enzymes of these systems

The effects of hypotensive agents (captopril, enalaprilate, and lisinopril) on the activities of components of the fibrinolytic system (FS) and the effects of antifibrinolytic agents (6-aminohexanoic acid (6-AHA) and tranexamic acid (t-AMCHA)) on the activities of angiotensin converting enzyme (ACE) were studied in vitro. Enalaprilate did not affect the FS activity. Captopril considerably inhibited the amidase activities of urokinase (u-PA), plasminogen tissue activator (t-PA), and plasmin ([I]50 (2.0-2.6) +/- 0.1 mM), and the activation of Glu-plasminogen affected by t-PA and u-PA ([I]50 (1.50-1.80) +/- 0.06 mM), which may be due to the presence of a mercapto group in the inhibitor molecule. Lisinopril did not affect the amidase activities of FS enzymes, but stimulated Glu-plasminogen and u-PA activation and inhibited activation of t-PA-fibrin-bound Glu-plasminogen ([I]50 (12.0 +/- 0.5) mM). Presumably, these effects can be explained by the presence in lisinopril of a Lys side residue, whose binding to lysine-binding Glu-plasminogen centers resulted, on the one hand, in the transformation of its closed conformation to a semi-open one and, on the other hand, in its desorption from fibrin. Unspecific inhibition of the activity of ACE, a key enzyme of the renin-angiotensin system, in the presence of 6-AHA and t-AMCHA ([I]50 10.0 +/- 0.5 and 7.5 +/- 0.4 mM, respectively) was found. A decrease in the ACE activity along with the growth of the fibrin monomer concentration was revealed. The data demonstrate that, along with endogenous mediated interactions, relations based on the direct interactions of exogenous inhibitors of one system affecting the activities of components of another system can take place.

Excessive hemorrhage after dental extractions using low-molecular-weight heparin (Lovenox) anticoagulation therapy

Patients with mechanical prosthetic valves and patients with atrial fibrillation are at increased risk for thromboembolism. The thromboembolism risk for anticoagulated patients with mitral mechanical heart valves is 1.5% to 4.6% per year,1 and the risk is 1.0% to 1.7% per year2 for patients with atrial fibrillation. If the patient is not anticoagulated, the thromboembolism risk is 23% per year for patients with aortic mechanical heart valves1 and 1.0% to 8.1% per year for patients with atrial fibrillation.2,3 The most common drug used for anticoagulation in these patients is warfarin sodium (Coumadin; Bristol-Myers Squibb, Princeton, NJ), which requires continuous management and laboratory evaluation.4 Minor surgical procedures, such as uncomplicated dental extractions, are commonly managed on an outpatient basis. Typically, the warfarin sodium is discontinued for 3 to 5 days before surgery and restarted 1 to 2 days after the dental extractions. In some cases, clinicians prefer to maintain the warfarin sodium and keep the patient’s international normalized ratio (INR) in the range of 3.0 to 4.05-7 and occasionally use the topical antifibrinolytic tranexamic acid.5,8 Some clinicians prefer to discontinue the warfarin sodium before surgery until the INR normalizes while maintaining anticoagulation with low–molecular-weight heparin (LMWH).9-11 The LMWH is sometimes discontinued before surgery and restarted 12 hours after surgery.12 The warfarin sodium is restarted the day after surgery, and when the INR has reached acceptable levels the LMWH is discontinued. This report describes excessive hemorrhage after dental extractions using LMWH anticoagulation therapy. The bleeding was stopped after discontinuing the anticoagulant. Report of a Case

Current treatment of dysfunctional uterine bleeding

Objectives: We performed a review of the treatment modalities for dysfunctional uterine bleeding. Methods: Dysfunctional uterine bleeding can be treated medically or surgically. Medical treatment consists of anti-fibrinolytic tranexamic acid, non-steroidal anti-inflammatory drugs, the combined contraception pill, progestogen, danazol, or analogues of gonadotrophin releasing hormone. The levonorgestrel releasing intra uterine device is developed for contraception, but is also effective in the treatment of dysfunctional uterine bleeding. Surgical treatment includes endometrial ablation of the first and second-generation, and hysterectomy. This review contains current available evidence on the effectiveness of these therapies. Results: Antifibrinolytic tranexamic acid is the most effective medical therapy to treat dysfunctional uterine bleeding. In general medical therapy is not as effective as endometrial resection in terms of patient satisfaction and health related quality of life. The levonorgestrel releasing intra uterine device is an effective treatment for dysfunctional uterine bleeding. No difference in quality of life was observed in patients treated with a levonorgestrel releasing intra uterine device as compared to hysterectomy. Ablation techniques of the first generation are effective and safe when used by trained surgeons, but have a learning curve. Ablation techniques of the second generation are effective, but long-term follow-up data are not available. Similarly, there are no large randomised controlled trials comparing the levonorgestrel releasing intra uterine device to first and second-generation ablation techniques. Hysterectomy, the traditional standard of care, has a relatively high complication rate, but it generates a high satisfaction rate and good health related quality of life scores. Conclusion: Since none of the treatments for dysfunctional bleeding is superior to one of the others, and since all treatments have their advantages and disadvantages, counselling of patients with dysfunctional bleeding should incorporate medical approach, levonorgestrel releasing IUD, endometrial ablation and hysterectomy.

The use of tranexamic acid (AMCA) in IUDs as an anti-bleeding agent.

ABSTRACTMenstrual blood loss was evaluated in 200 women receiving a U‐coil intrauterine contraceptive device loaded with the antifibrinolytic, tranexamic acid (AMCA). The IUDs were inserted in patients at Ain Shams University, Cairo, Egypt, in May 1974; the women were followed up for 6 months. The AMCA‐loaded U‐coil has a core containing 38 mg of crystalline tranexamic acid loaded with a silastic tube 52 mm in length with an inside–outside diameter of 1.57–2.41 mm. The daily release rate of tranexamic acid was determined to be 4.3 μg with an initial high release of 29.0 μg. This group of women was compared to a similar group previously fitted with a copper loaded U‐coil. There were no pregnancies reported in either group, and expulsions were minimal. The 6‐month removal rates for the tranexamic acid U‐coil group was 1.1 per 100 acceptors. The corresponding figure for the copper comparison group was 9.9 per 100 acceptors. Reports of heavy menstrual bleeding were more prevalent at the one‐ and 3‐month follow‐ups for the copper U‐coil acceptors than for those using the AMCA loaded U‐coil. There were no apparent differences at the 6‐month follow‐up. The demonstrated capacity of tranexamic acid to reduce menstrual blood loss based on perceptual reports suggests that this agent can be valuable in increasing the acceptability and safety of intrauterine devices.