BACKGROUND

The clinical benefit of prophylaxis for venous thromboembolism (VTE) in laparoscopic bariatric surgery is unclear. Our objective was to assess the clinical burden of VTE after laparoscopic bariatric surgery.

METHODS

We performed a systematic review and meta-analysis. Studies were considered for the review if they reported on the methods used for antithrombotic prophylaxis and on the incidence of objectively confirmed VTE in patients who had undergone laparoscopic bariatric surgery.

RESULTS

Overall, 19 studies were included in the analysis. The weighted mean incidence (WMI) of pulmonary embolism was .5% (12 events in 3991 patients, 12 studies; 95% confidence interval [CI] .2-.9%; I(2) 38%) with unfractionated heparin (5000 UI twice or 3 times daily) or low-molecular-weight heparin (30 mg twice daily or 40 mg once daily). The WMI of major bleeding as originally reported in 7 of these studies was 3.6% (2741 patients; 95% CI .9-7.95; I(2) 94%). The WMI of screened VTE in 3 high-quality studies with different regimens of heparin prophylaxis was 2.0% (8 events in 458 patients; 95% CI .9-3.5%; I(2) 0%). The WMI of symptomatic VTE was .6% (4 studies; 7 events in 1328 patients; 95% CI .3-1.1%; I(2) 0%) and that of major bleeding was 2.0% (95% CI 1.0-3.4%; I(2) 55%), with weight-adjusted doses of heparin prophylaxis.

CONCLUSIONS

The rate of VTE after laparoscopic bariatric surgery seems to be relatively low with standard regimens for antithrombotic prophylaxis. The incidence of major bleeding seems to increase using weight-adjusted doses of heparin with no advantage in terms of VTE reduction.

BACKGROUND

Low molecular weight heparins have been shown to be effective and safe for prevention of venous thromboembolism. There is accumulating evidence that these new anticoagulants are also effective and safe for treatment of venous thromboembolism.

OBJECTIVE

The objective of this review was to determine the effect of fixed-dose, subcutaneous low molecular weight heparins compared with adjusted-dose, intravenous or subcutaneous, unfractionated heparin for initial treatment of acute deep venous thrombosis or pulmonary embolism.

METHODS

Trials were identified from the Cochrane Peripheral Vascular Diseases Group trials register and LILACS. The reviewers contacted colleagues and representatives of pharmaceutical companies for additional information about trials.

METHODS

Randomised trials comparing fixed-dose, subcutaneous low molecular weight heparin with adjusted-dose, intravenous or subcutaneous, unfractionated heparin in patients with venous thromboembolism.

METHODS

Two reviewers assessed trials for inclusion and quality, and extracted data independently.

RESULTS

Fourteen studies with a total of 4754 patients were included. By the end of follow up in ten trials, thrombotic complications occurred in 86 (4.3%) of the 1998 patients treated with low molecular weight heparin, compared with 113 (5.6%) of the 2021 patients treated with unfractionated heparin (odds ratio 0.76, 95% confidence interval 0.57 to 1.01). In eight trials a reduction in thrombus size was shown by 60% treated with low molecular weight heparin and 54% treated with unfractionated heparin (odds ratio 0.77, 95% confidence interval 0.61 to 0.97). At the end of the initial treatment period, in all 14 of the trials, major haemorrhages occurred in 30 (1.3%) of the 2353 patients treated with low molecular weight heparin, compared with 51 (2.1%) of the 2401 patients treated with unfractionated heparin (odds ratio 0.60, 95% confidence interval 0.39 to 0.93). By the end of follow up in 11 trials, 135 (6.4%) of the 2108 patients treated with low molecular weight heparin had died, compared with 172 (8.0%) of the 2137 patients treated with unfractionated heparin (odds ratio 0.78, 95% confidence interval 0.62 to 0.99). Five studies with a total of 1636 patients examined proximal (above the knee) thrombosis; 814 treated with low molecular weight heparin and 822 with unfractionated heparin. A sub-analysis of these trials showed statistically significant reductions favouring the action of low molecular weight heparin in three areas: thrombotic complications; major haemorrhages; and overall mortality. By the end of follow up 39 (4. 8%) patients treated with low molecular weight heparin had thrombotic complications, compared with 64 (7.8%) treated with unfractionated heparin (odds ratio 0.60, 95% confidence interval 0. 40 to 0.89). Major haemorrhages occurred in 8 (1.0%) treated with low molecular weight heparin, compared with 68 (8.3%) treated with unfractionated heparin (odds ratio 0.44, 95% confidence interval 0. 21 to 0.95). By the end of follow up, 44 (5.4%) treated with low molecular weight heparin had died, compared with 68 (8.3%) treated with unfractionated heparin (odds ratio 0.64, 95% confidence interval 0.43 to 0.93).

CONCLUSIONS

Low molecular weight heparin is at least as effective as unfractionated heparin in preventing recurrent venous thromboembolism, and significantly reduces the occurrence of major haemorrhage during initial treatment and overall mortality at the end of follow-up. It can be adopted safely as the standard therapy for deep venous thrombosis, and studies comparing individual low molecular weight heparins are merited.

The risk of venous thromboembolism (VTE) in pregnancy is 0.05-1.8%, six times greater than in the non-pregnant state, and pulmonary embolism remains the most common cause of maternal death. Maternal age, previous history of VTE, Caesarean section and the presence of thrombophilia, significantly increase the risk of VTE. Acquired or hereditary thrombophilia occur in almost two-thirds of women presenting with recurrent miscarriages, pre-eclampsia, intrauterine growth restriction, abruptio placentae, or stillbirth, which are associated with microvascular thrombosis in placental blood vessels. Women with VTE during pregnancy and especially those with thrombophilia require individualized management, based on the type of defect, the family history and the presence of additional risk factors. These factors are important in determining the dose and duration of antithrombotic therapy during pregnancy and the puerperium, and the thromboprophylactic strategy for future pregnancies. Oral anticoagulants are now seldom used during pregnancy because of their significant side effects. Low-molecular-weight heparins (LMWHs) are increasingly replacing unfractionated heparin in the prevention and treatment of VTE during pregnancy. LMWHs have also been shown to be effective in improving the outcome of pregnancy in women with previous obstetric complications.

BACKGROUND

Peripheral arterial disease (PAD) is frequently treated by balloon angioplasty. Restenosis/reocclusion of the dilated segments occurs often depending on length of occlusion, lower leg outflow, stage of disease and presence of cardiovascular risk factors. To prevent reocclusion, patients are treated with antithrombotic agents.

OBJECTIVE

To determine whether any antithrombotic drug is more effective in preventing reocclusion after peripheral endovascular treatment, compared to another antithrombotic drug, no treatment, placebo, or other vasoactive drugs.

METHODS

We searched the Cochrane Peripheral Vascular Diseases Group's trials register (last searched April 2004), the Cochrane Central Register of Controlled trials (CENTRAL Issue 2, 2004), MEDLINE and EMBASE (last searched June 2004).

METHODS

Randomised trials were categorised as A (double or single blinded) or B (not blinded). Participants included patients with symptomatic PAD treated by endovascular revascularisation of the pelvic or femoropopliteal arteries. Interventions were anticoagulant, antiplatelet or other vasoactive drug therapy compared with no treatment, placebo, or any other vasoactive drug. Clinical endpoints were re-obstruction, amputation, death, myocardial infarction, stroke and major bleeding.

METHODS

Details of the number of randomised patients, treatment, study design, study category, allocation concealment and patient characteristics were extracted. Analysis was based on intention-to-treat data. To examine the effects of binary outcomes such as amputation and major bleeding, odds ratios were computed using a fixed effect model. The 95% confidence intervals of the effect sizes were calculated.

RESULTS

A 60% reduction of recurrent obstruction was found with aspirin (ASA) 330 mg combined with dipyridamol (DIP) as compared to placebo at 12 months follow-up. At six months following endovascular treatment, a positive effect on patency was found with 50 to 100 mg ASA combined with DIP (n = 356). However, this was not significant. ASA/DIP tended towards showing a superior effect on patency after femoropopliteal angioplasty compared with VKA at three, six, and twelve months. Periinterventional treatment with LMWH in femoropopliteal obstructions resulted in significantly lower restenosis/reocclusion rates than with unfractionated heparin.

CONCLUSIONS

Aspirin 50 to 300 mg started prior to femoropopliteal endovascular treatment appears to be the most effective and is safe. Clopidogrel might be an alternative, but data are lacking. Abciximab might be a useful adjunctive for high risk patients with long segmental femoropopliteal interventions. Low molecular weight heparin seems to be more effective in preventing reocclusion or restenosis than unfractionated heparin.

Venous thromboembolism may be efficiently treated by one single daily administration of a high dose of low molecular weight heparin (LMWH). The present study investigates if the physiological deterioration of renal function associated with normal aging or the presence of an acute venous thromboembolism influences the pharmacodynamic pattern of the anti-factor Xa and anti-thrombin activities. Three groups of 12 subjects were investigated. The first 2 groups were composed of healthy volunteers differing by age (25 +/- 4 and 65 +/- 3 yrs) and creatinine clearance (114 +/- 15 and 62 +/- 6 ml x min(-1)). The third group was composed of patients hospitalized for deep vein thrombosis, having a mean age of 65 +/- 11 yrs and creatinine clearance of 76 +/- 8 ml x min(-1). Nadroparin was administered subcutaneously once daily at the dose of 180 anti-factor Xa IU.kg(-1) for 6 to 10 days. Serial sampling on day 1 and on the last day of administration (day n) allowed the pharmacodynamic parameters of the anti-factor Xa and anti-thrombin activities to be compared at the beginning and at the end of the treatment. The main findings were the following: (1) After repeated administration, a significant accumulation of the anti-factor Xa activity was observed in the healthy elderly and in the patients but not in the healthy young subjects (accumulation factor: 1.3). There was no evidence of accumulation of anti-thrombin activity; (2) There were significant correlations between the clearance of creatinine and the clearance of the anti-factor Xa activity but not with that of the anti-thrombin activity; (3) In the patients, the clearance of the anti-factor Xa and of the anti-thrombin activities were 1.4 and 2 times higher respectively than those calculated in the healthy elderly; (4) The mean ratio of the of anti-factor Xa and anti-thrombin clearances was close to 2 in the healthy subjects but equal to 5.4 in the patients. These results suggest that the mechanisms involved in the clearance of polysaccharide chains which support the anti-thrombin activity are different from those of the anti-factor Xa activity and that the enhanced binding properties of plasma proteins to unfractionated heparin reported in patients presenting an acute venous thromboembolism also exists for LMWH, predominantly for the anti-thrombin activity.

The aim of this study was to assess the impact of baseline anemia on the outcomes of patients with ST elevation myocardial infarctions who underwent primary percutaneous coronary intervention in relation to contemporary adjunctive antithrombotic therapy and gender. In the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial, patients were randomized to bivalirudin alone or to unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor before primary percutaneous coronary intervention. Outcomes were assessed at 30 days and 1 year according to anemia and gender. Baseline anemia was present in 331 of 3,153 patients (10.5%). Patients with versus without baseline anemia had a more than twofold increase in major bleeding at 30 days (13.5% vs 6.7%, p <0.0001) and at 1 year (14.8% vs 7.2%, p <0.0001), an association that on multivariate analysis was independent of gender. Mortality was significantly higher in men with versus without baseline anemia (4.6% vs 1.8% at 30 days, p = 0.003; 8.9% vs 3.0% at 1 year, p <0.0001) but not in women (5.3% vs 3.6% at 30 days, p = 0.42; 7.5% vs 5.9% at 1 year, p = 0.54). On multivariate analysis, anemia independently predicted 1-year all-cause mortality in men but not in women. Bivalirudin compared with unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor resulted in twofold lower rates of all-cause and cardiac mortality and major bleeding in patients without but not in those with baseline anemia. In conclusion, baseline anemia was associated with increased major bleeding and death in patients with ST elevation myocardial infarctions who underwent primary PCI but was a stronger predictor of early and late mortality in men than in women. Paradoxically, in this post hoc analysis, the reductions in major bleeding and mortality in ST elevation myocardial infarction afforded by bivalirudin occurred primarily in patients without baseline anemia.

Forty-eight rats with biliary obstruction induced by double ligation and section of the common bile duct were randomly and blindly assigned to receive subcutaneous injection of either conventional heparin sodium (1000IU kg(-1)), three already marketed low molecular weight heparin (LMWH) preparations: nadroparin (1000 anti-Xa IU kg(-1)), tinzaparin (1000 anti-Xa IU kg(-1)), enoxaparin (180 anti-Xa IU kg(-1)) or saline. Drugs were administered once a day, starting 7 days after surgery and continued for 3 weeks. At the end of the treatment period, rats were killed and analyzed for blood biochemistry and liver pathology. Liver fibrosis was assessed by image analysis. Data indicated that treatment with nadroparin decreased plasma total bilirubin, serum alkaline phosphatase (ALP) and gamma glutamyltransferase (GGT) levels by 80.3, 70.7 and 42%, compared with bile duct ligated (BDL) control values. The reduction in plasma total protein observed in BDL controls was prevented by nadroparin. Enoxaparin-treated rats showed significant reduction in plasma total bilirubin and alanine aminotransferase levels by 32.5 and 38.4% versus BDL controls. Liver necrosis evaluated histologically was significantly reduced in the nadroparin- and enoxaparin-treated rats. Morphometric analysis showed significant reduction in fibrosis on nadroparin and enoxaparin treatment: area of fibrosis: 1.66 +/- 0.17% and 14.03 +/- 1.1% versus 18.94 +/- 2.4% (P<0.05); nadroparin and enoxaparin versus BDL control. By contrast, neither conventional heparin nor tinzaparin prevented the bile duct ligation-induced liver damage as indicated by increased plasma aminotransferases, ALP and GGT concentrations and the histological evidence of necrosis. Total serum bilirubin was increased by 27.5% in rats treated with conventional heparin, while ALP and GGT levels were 38.6 and 31.4% higher after tinzaparin treatment versus BDL controls. Significant increase in the area of fibrosis was observed after tinzaparin treatment compared to BDL control group. Results suggest a beneficial effect for nadroparin and enoxaparin in the therapy of patients with obstructive jaundice or cholestatic liver disorders. The present data from bile duct ligated rats suggest an antifibrotic effect for nadroparin and enoxaparin.

OBJECTIVE

The aim of this study was to understand the impact of attenuated plaque on distal embolization during stent implantation in patients with acute myocardial infarction (AMI).

BACKGROUND

Attenuated plaques identified by grayscale intravascular ultrasound (IVUS) might predict transient deterioration in coronary flow and/or no-reflow during percutaneous coronary intervention (PCI).

METHODS

We analyzed clinical, angiographic, and IVUS data from 364 patients (n = 364 infarct-related arteries) enrolled in the randomized HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial. No-reflow was final Thrombolysis In Myocardial Infarction (TIMI) flow grade ≤2 in the absence of mechanical obstruction. Attenuated plaque was hypoechoic or mixed atheroma with ultrasound attenuation without calcification. A mean attenuation score was created by measuring the angle of attenuation each 1 mm, scoring the angle as 1 to 4 (corresponding to <90°, 90° to 180°, 180° to 270°, or 270° to 360°, respectively), summing the scores, and normalizing for analysis length.

RESULTS

Overall, 284 (78.0%) patients had attenuated plaques; no-reflow occurred in 37 (10.2%). Patients with no-reflow had a higher mean attenuation score (median [interquartile range] 2.2 [0.0 to 2.8] vs. 1.3 [0.7 to 1.8], p < 0.001), lower baseline left ventricular ejection fraction (52.8% [43.2% to 61.5%] vs. 61.4% [52.2% to 68.1%], p = 0.002), and more baseline angiographic thrombus (89.2% vs. 74.1%, p = 0.043) with no differences in post-PCI stent expansion versus patients without no-reflow. Multivariate analysis indicated that mean attenuation score was the strongest predictor of no-reflow. The mean attenuation score that best predicted no-reflow was ≥2 points (90° to 180°, sensitivity of 81.5%, and specificity of 80.5%).

CONCLUSIONS

Attenuated plaque was present in three-quarters of patients with AMI. The amount of attenuated plaque strongly correlated with no-reflow; the larger the attenuated plaque, the greater the likelihood of no-reflow. (Dual Arm Factorial Randomized Trial in Patients w/ST Segment Elevation AMI to Compare the Results of Using Anticoagulation With Either Unfractionated Heparin + Routine GP IIb/IIIa Inhibition or Bivalirudin + Bail-out GP IIb/IIIa Inhibition; and Primary Angioplasty with stent implantation with Either a Slow Rate-release Paclitaxel-eluting Stent [TAXUS™] or Uncoated Bare Metal Stent [EXPRESS2™]; NCT00433966).

BACKGROUND

The purpose of this study was to stratify plastic surgery patients into venous thromboembolism risk categories; identify patients at highest risk for venous thromboembolism; and quantify rates of postoperative all-cause mortality, venous thromboembolism, and hematoma/bleeding on different forms of thromboprophylaxis. Furthermore, this study aimed to determine the compliance and average duration of outpatient chemoprophylaxis.

METHODS

A retrospective cohort study was carried out on a single plastic surgeon's experience. Venous thromboembolism risk stratification identified patients at highest risk. Records were reviewed for regimen of thromboprophylaxis and for occurrences of all-cause mortality, venous thromboembolism, and hematoma/bleeding. Outpatient compliance and duration of low-molecular-weight heparin chemoprophylaxis was also documented.

RESULTS

During the study time period, 173 operations involved 120 patients at highest risk for venous thromboembolism. Among highest risk patients, one (0.8 percent) suffered a pulmonary embolism, eight (6.7 percent) experienced a deep vein thrombosis, and 15 (12.5 percent) endured a hematoma/bleed. Thirteen of 14 outpatients (92.9 percent) were compliant with low-molecular-weight heparin and remained on chemoprophylaxis for an average of 7.4 days.

CONCLUSIONS

Mechanical prophylaxis plus subcutaneous heparin (unfractionated or low-molecular-weight heparin) conferred a statistically significant reduction in the rate of venous thromboembolism without a significant increase in bleeding versus mechanical prophylaxis alone. Subgroup analysis of patients placed on mechanical prophylaxis plus low-molecular-weight heparin revealed similar statistically significant findings. Outpatients placed on low-molecular-weight heparin chemoprophylaxis demonstrated excellent compliance and comfort with self-administration. Therefore, the use of mechanical prophylaxis supplemented with low-molecular-weight heparin is strongly recommended as the first-line regimen for thromboprophylaxis in plastic surgery patients at highest risk for venous thromboembolism.

After parenteral injection, heparin is removed from the blood via two mechanisms, saturable and non-saturable. The saturable mechanism represents clearance by the reticuloendothelial system and endothelial cells, to which heparin binds with a high affinity. The non-saturable mechanism is represented by renal excretion. The contribution of the two mechanisms to the clearance of heparin varies according to the dose delivered and the molecular weight of the heparin preparation. At low doses, unfractionated heparin (UH) is removed mainly via the saturable mechanism, while at higher doses the contribution of the non-saturable mechanism to its clearance becomes pre-eminent. This model accounts for the major pharmacokinetic properties of UH. After bolus intravenous injection of low doses, UH disappears from the blood exponentially with a dose-dependent half-life; at higher doses, UH disappears with a concave-convex pattern. Under continuous intravenous infusion there is a non-linear relationship between the dose of UH injected and the steady-state plasma concentration. After subcutaneous injection, the bioavailability of the anti-factor Xa activity increases with the dose delivered and tends toward 100% at high doses. In contrast, low molecular weight heparins (LMWH) are mainly removed by non-saturable renal excretion. This explains the dose independence of the pharmacokinetic parameters of LMWH, the excellent bioavailability of the subcutaneous route at any dose, and the prolongation of LMWH half-life in cases of chronic renal insufficiency. However, the model does not explain the large interindividual variability of the pharmacokinetic parameters of both UH and LMWH.

BACKGROUND

Epidemiology and clinical management of acute venous thromboembolism (VTE) are not readily available in Japan.

RESULTS

The Japan VTE Treatment Registry (JAVA) is a multicenter cohort study of consecutive patients with an objectively confirmed, symptomatic acute pulmonary embolism (PE), symptomatic acute deep vein thrombosis (DVT), or asymptomatic acute proximal DVT. Of the 1,076 patients enrolled with acute VTE, 68.7% presented with an isolated DVT; 17.0% had PE alone; and 14.4% had both. VTE management was characterized by a high rate of inferior vena cava filter insertion (40.6%), frequent thrombolysis (21.1%), and sub-therapeutic unfractionated heparin-based anticoagulation, followed by warfarin prescription, mostly targeting an international normalized ratio of 2.0 (range, 1.5-2.5). During a mean observation period of 252.5 days, 29 recurrent cases of VTE were documented, yielding an incidence rate of 3.9 per 100 patient-years. A total of 123 patients died during the study period, corresponding to a rate of 16.6 deaths per 100 patient-years. The incidence of major bleeding was 3.2% per patient-year, including 2 fatal hemorrhages and 7 intracranial hemorrhages.

CONCLUSIONS

VTE management in Japan is characterized by a highly aggressive strategy in the acute phase, in contrast to protocols that use low-level anticoagulation. The VTE recurrence rates in Japan and Western countries are similar, but mortality is higher in Japan, with significant variability depending on patient and management characteristics.

BACKGROUND

Heparin-induced thrombocytopenia (HIT) is caused by platelet-activating antibodies that recognize platelet factor 4 (PF4)/heparin complexes. The frequency of HIT is highly variable in different clinical settings, and is more frequent with unfractionated heparin (UFH) than with low-molecular-weight heparin (LMWH), despite the in vitro observation that HIT antibodies activate platelets similarly well with LMWH as with UFH. An important difference between UFH, LMWH, and fondaparinux is their widely differing plasma concentrations. We aimed to provide a model that included anticoagulant concentrations and PF4 availability as risk factors influencing the anti-PF4/heparin immune response.

METHODS

By photon correlation spectroscopy we determined the concentrations at which UFH, LMWH, and fondaparinux form complexes optimally with PF4. Plasma concentrations of UFH and LMWH were calculated based on ex vivo pharmacokinetic data, with information on fondaparinux and PF4 concentrations taken from the literature.

CONCLUSIONS

The main features of our model are: optimal complex formation occurs at prophylactic-dose UFH and high PF4 levels, whereas therapeutic-dose LMWH concentrations are too high for optimal complex formation; in contrast, concentrations of fondaparinux are usually below the optimal stoichiometric range. Thus, immunization should occur more often in situations with major rather than minor platelet activation, and--for a given degree of platelet activation (PF4 availability)--as: prophylactic-dose UFH>therapeutic-dose UFH>prophylactic-dose LMWH, fondaparinux>therapeutic-dose LMWH. Our model provides a framework for explaining empirical observations that LMWH induces less anti-PF4/heparin antibodies than does UFH, and that anti-PF4/heparin antibodies are more often found in patients undergoing major surgery than in medical patients.

Coronavirus disease 2019 (COVID-19), the clinical syndrome associated with infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has impacted nearly every country in the world. Despite an unprecedented focus of scientific investigation, there is a paucity of evidence-based pharmacotherapies against this disease. Because of this lack of data-driven treatment strategies, broad variations in practice patterns have emerged. Observed hypercoagulability in patients with COVID-19 has created debate within the critical care community on the therapeutic utility of heparin. We seek to provide an overview of the data supporting the therapeutic use of heparin, both unfractionated and low molecular weight, as an anticoagulant for the treatment of SARS-CoV-2 infection. Additionally, we review preclinical evidence establishing biological plausibility for heparin and synthetic heparin-like drugs as therapies for COVID-19 through antiviral and anti-inflammatory effects. Finally, we discuss known adverse effects and theoretical off-target effects that may temper enthusiasm for the adoption of heparin as a therapy in COVID-19 without confirmatory prospective randomized controlled trials. Despite previous failures of anticoagulants in critical illness, plausibility of heparin for COVID-19 is sufficiently robust to justify urgent randomized controlled trials to determine the safety and effectiveness of this therapy.

Keywords: COVID-19; heparin; venous thromboembolism.

Unfractionated heparin is frequently used in tertiary pediatric centers for the prophylaxis and treatment of thromboembolic disease. Recent evidence suggests that the clinical outcomes of unfractionated heparin therapy in children are poor, as determined by target-range achievement and adverse-event rates. These reports of poor outcomes may be related to an age-dependent mechanism of action of unfractionated heparin. Furthermore, several published studies have indicated that unfractionated heparin-monitoring assays currently in clinical use have significant limitations that likely affect the safety and efficacy of anticoagulant management. This review summarizes the growing body of evidence suggesting that pediatric-specific recommendations for unfractionated heparin therapy management are required to improve clinical outcomes related to this commonly prescribed medication.

The optimal approach to early postoperative anticoagulation after mechanical valve implantation remains controversial. This review article examines the pathogenesis of thrombus formation and the different strategies for early postoperative anticoagulation. The most commonly reported anticoagulation regimens had the after estimates of early postoperative thromboembolism and hemorrhage: oral anticoagulation alone (0.9%, 3.3%); oral anticoagulation with intravenous unfractionated heparin (1.1%, 7.2%); and oral anticoagulation with low molecular weight heparin (0.6%, 4.8%). Although intravenous heparin may be associated with a higher incidence of hemorrhage, a randomized trial is needed to provide the best evidence regarding early postoperative anticoagulation after mechanical valve implantation. Nearly four decades have passed since the first mechanical prosthetic valves were implanted. Frequent thromboembolic complications with the first mechanical valves led to recommendations of universal anticoagulation for these patients. Since then, several design changes and modifications have been made to improve the longevity, hemodynamics, and thrombogenicity of newer generation mechanical valves. With improved blood flow, less stasis, and less thrombogenic materials, lower rates of thromboembolism have been reported. Despite these advances however, thromboembolism and anticoagulant-related bleeding continue to account for 75% of all complications after mechanical valve replacement. Occurring most commonly within six months after implantation, these complications can adversely affect mortality and quality of life. Furthermore, the threat of their occurrence creates a psychological burden for each patient with a mechanical valve. The need for life-long anticoagulation in patients with mechanical valves is not in dispute, and the perioperative management of anticoagulation during non-cardiac surgery has been reviewed extensively. However, the approach to early postoperative anticoagulation after mechanical valve implantation is still a matter of debate. The optimal intensity and timing of anticoagulation to prevent early thromboembolism after valve replacement surgery without postoperative bleeding complications is unknown. Hence, many anticoagulation protocols have been proposed, but a lack of consensus remains. The objectives of this study were (1) to reexamine the pathogenesis of thrombus formation and the need for anticoagulation; (2) to critically review the literature on early postoperative anticoagulation strategies; and (3) provide an estimate of the incidence of bleeding and thromboembolism for each approach to early postoperative anticoagulation.

BACKGROUND

Low-molecular-weight heparins are frequently used to treat venous thromboembolism, but optimal dosing regimens and clinical outcomes need further definition.

METHODS

In this multicenter, open-label study with blinded adjudication of end points, we randomly assigned patients with acute deep-vein thrombosis to one of three treatment regimens: intravenous administration of unfractionated heparin; subcutaneous administration of a low-molecular-weight heparin, reviparin, twice a day for one week; or subcutaneous administration of reviparin once a day for four weeks. The primary end point was evidence of regression of the thrombus on venography on day 21; secondary end points were recurrent venous thromboembolism, major bleeding within 90 days after enrollment, and death.

RESULTS

Of the patients receiving unfractionated heparin, 40.2 percent (129 of 321) had thrombus regression, as compared with 53.4 percent (175 of 328) of patients receiving reviparin twice daily and 53.5 percent (167 of 312) of the patients receiving reviparin once daily. With regard to thrombus regression, reviparin administered twice daily was significantly more effective than unfractionated heparin (relative likelihood of thrombus regression, 1.28; 97.5 percent confidence interval, 1.08 to 1.52), as was reviparin administered once daily (relative likelihood, 1.29; 97.5 percent confidence interval, 1.08 to 1.53). Mortality and the frequency of episodes of major bleeding were similar in the three groups.

CONCLUSIONS

In acute deep-vein thrombosis, reviparin regimens are more effective than unfractionated heparin in reducing the size of the thrombus. Reviparin is also more effective than unfractionated heparin for the prevention of recurrent thromboembolism and equally safe.

The history of the traditional anticoagulants is marked by both perseverance and serendipity. The anticoagulant effect of heparin was discovered by McLean in 1915, while he was searching for a procoagulant in dog liver. Link identified dicumarol from spoiled sweet clover hay in 1939 as the causal agent of the sweet clover disease, a hemorrhagic disorder in cattle. Hirudin extracts from the medicinal leech were first used for parenteral anticoagulation in the clinic in 1909, but their use was limited due to adverse effects and difficulties in achieving highly purified extracts. Heparins and coumarins (i.e.: warfarin, phenprocoumon, acenocoumarol) have been the mainstay of anticoagulant therapy for more than 60 years. Over the past decades, the drug discovery paradigm has shifted toward rational design following a target-based approach, in which specific proteins, or "targets", are chosen on current understandings of pathophysiology, small molecules that inhibit the target's activity may be identified by high-throughput screening and, in selected cases, these new molecules can be developed further as drugs. Despite the application of rational design, serendipity has still played a significant role in some of the new discoveries. This review will focus on the discovery of the main anticoagulant drugs in current clinical use, like unfractionated heparin, low-molecular-weight heparins, fondaparinux, coumarins (i.e.: warfarin, acenocoumarol, phenprocoumon), parenteral direct thrombin inhibitors (DTIs) (i.e.: argatroban, recombinant hirudins, bivalirudin), oral DTIs (i.e.: dabigatran) and oral direct factor Xa inhibitors (i.e.: rivaroxaban, apixaban).

BACKGROUND

The aim of this study was to assess the effect of thrombolysis versus heparin treatment on echocardiographic parameters and clinical outcome, during hospitalization and within the first 180 days after admission, in patients with first episode of submassive pulmonary embolism (SPE) and right ventricle dysfunction (RVD).

METHODS

Consecutive patients (age, 18-75 years) with a first episode of SPE, symptoms onset since no more than 6 hours, normal blood pressure (>100 mm Hg), echocardiographic evidence of RVD and positive lung spiral computed tomography were double-blind randomized: 1 group received 100 mg of alteplase (10-mg bolus, followed by a 90-mg intravenous infusion over a period of 2 hours), while the other group received matching placebo. In addition to alteplase or placebo, both groups received an unfractionated heparin treatment. Echocardiogram was performed at admission, at 24, 48 and 72 hours, at discharge and at 3 and at 6 months after randomization.

RESULTS

Seventy-two patients were included into the study; 37 were assigned to thrombolysis and 35 to placebo. Both groups were well matched with regard to features and clinical presentation. Thrombolysis group showed a significant early improvement of RV function compared with heparin group, and this improvement was observed also during the follow-up (180 days). The same group also showed significant reduction in clinical events during the hospitalization and follow-up.

CONCLUSIONS

Our data suggest that, in hemodynamically stable patients with SPE, thrombolysis shows an earliest reduction of RVD and a more favorable trend in clinical outcome, so, it could merit consideration in SPE.

BACKGROUND

The purpose of this study was to describe our experience in the conservative management of large rectus sheath hematoma (RSH) in patients undergoing anticoagulation therapy.

METHODS

This is a retrospective study of the medical histories of 12 cases of RSH (11 female, one male; mean age = 67.6 years). Seven patients were taking oral anticoagulants, three were taking intravenous unfractionated heparin, and two were taking subcutaneous low-molecular-weight heparin. Six patients had a history of coughing fits. Ultrasound examination and computed tomography (CT) was performed in all cases.

RESULTS

Clinically, the majority of patients presented acute abdominal pain, infraumbilical masses, and anemic syndrome. Ultrasonography demonstrated nine of the 12 cases of RSH, and CT showed the hematoma in all 12 cases. Type II (five cases) and type III (seven cases) indicate moderate and severe hematomas, respectively. Excessive anticoagulation was observed in eight cases, and coagulation within correct ranges was seen in the remaining four cases. In five patients the normalization of coagulation was achieved by administering vitamin K1 and fresh frozen plasma. All cases of type III hematoma required blood transfusion. Conservative treatment was effective in all cases.

CONCLUSIONS

RSH must be suspected in women of advanced age undergoing treatment with anticoagulants who present the clinical triad of acute abdominal pain, infraumbilical mass, and anemic syndrome. CT is the examination of choice for the diagnosis of RSH. Early diagnosis of RSH permits conservative management, even in the case of large hematomas with hemodynamic repercussions and avoids unnecessary surgical intervention.

Vascular endothelial growth factor (VEGF), a potent and specific activator of endothelial cells, is expressed as multiple homodimeric forms resulting from alternative RNA splicing. VEGF121 does not bind heparin while the other three isoforms do, and it has been documented that the binding of VEGF165 to its receptor is dependent upon cell surface heparin sulfate proteoglycans. Little is known about the biochemical mechanism that allows for heparin regulation of growth factor binding. For example, it is not clear whether heparin interactions with growth factor or with cell surface receptors or both are essential for VEGF binding to its receptor. In this manuscript we provide results which are consistent with the hypothesis that an interaction between heparin and a site on the KDR receptor subtype is essential for VEGF165 binding. First, we demonstrate that expression of KDR into a CHO cell line deficient in heparan sulfate biosynthesis does not allow VEGF165 binding unless heparin is exogenously added during the binding assay. Secondly, we show that a ten amino acid synthetic peptide, corresponding to a sequence from the extracellular domain of the KDR, both inhibits VEGF165 binding to the receptor and also binds heparin with high avidity. Third, affinity purification of heparin molecules on a KDR-derived peptide affinity column, together with capillary electrophoresis and polyacrylamide electrophoresis analysis, was used to show that the KDR-derived peptide interacts with a specific subset of polysaccharide chains contained in the unfractionated heparin. Taken together, these results are consistent with the hypothesis that interactions between cell surface heparan sulfate proteoglycans and the VEGF receptor contribute to allowing maximal VEGF binding.

Recent studies suggest that low molecular weight heparin (LMW heparin) therapy in malignancy may improve cancer survival following surgical resection. We studied prospectively whether cancer mortality during follow-up in women with previously untreated breast, and pelvic cancer is reduced in those who randomly received LMW heparin (Certoparin) compared to patients given unfractionated heparin (UF heparin) for thrombosis prophylaxis during primary surgery. In a prospective, randomized, double-blind clinical trial, 160 patients received Certoparin and 164 UF heparin until post-operatively day 7. Survival estimations are based on the outcome data from a subset of 140 LMW heparin - and 147 UF heparin recipients. Long-term survival in the Certoparin group compared to the UF heparin group was significantly improved after 650 days (P=0. 0066) but not thereafter when analysis was performed on all cancer cell types combined. In the probability estimates survival benefit within this time was restricted to patients with pelvic cancer but was not observed in breast cancer. However, in breast cancer patients who received LMW heparin the impact of classical tumor prognostic markers was statistically significant after 1,050 days but not after 650 days. Thus, breast cancer patients with unfavorable prognosis seem to benefit in terms of survival advantage from LMW heparin within the 650 days after surgery. These results suggest that improvement in cancer survival can be achieved after even a short course of treatment with LMWH (compared to UFH) given for DVT prophylaxis in the post-operative period. An effect of UFH on disease outcome is not excluded. Further definitive trials of LMWH vs. placebo for cancer outcome (rather then DVT) using doses and schedules that may be more optimal are indicated.

OBJECTIVE

The delay between the availability of clinical evidence and its application to the care of patients with acute coronary syndrome (ACS) in the Kingdom of Saudi Arabia remains undefined. The Saudi Project for Assessment of Coronary Events (SPACE) registry provides a comprehensive view of the current diagnostic and treatment strategies for patients with ACS; thus, the registry may be used to identify opportunities to improve the care of these patients.

METHODS

Eight hospitals in different regions of Saudi Arabia were involved in the pilot phase of the registry, from December 2005 to July 2006. The study patients included individuals with ST segment elevation myocardial infarction (STEMI), non-STEMI and unstable angina.

RESULTS

A total of 435 patients (77% men and 80% Saudis) with a mean age of 57.1 years were enrolled. Medical history included previously diagnosed ischemic heart disease (32%), percutaneous coronary intervention (12%), diabetes mellitus (53%), hypertension (48%), current smoking (39%), hyperlipidemia (31%) and family history of premature coronary artery disease (11%). The median door-to-needle time for fibrinolytic therapy received by patients with STEMIs was 90 min. Inhospital medications included acetylsalicylic acid (98%), clopidogrel (73%), angiotensin- converting enzyme inhibitors (74%), beta-blockers (73%), statins (88%), unfractionated heparin (80%), low-molecular weight heparin (22%) and glycoprotein IIb/IIIa inhibitors (9%). The inhospital mortality rate was 5%.

CONCLUSIONS

The first nationwide registry of patients with ACS in the Kingdom of Saudi Arabia is presented. In contrast to registries from developed countries, our cohort is characterized by a younger age at presentation and a much higher prevalence of diabetes mellitus. Most patients with STEMIs did not receive fibrinolytic therapy within the time recommended in the American College of Cardiology/American Heart Association guidelines. The results of the present pilot study show potential targets for improvement in care.

In this study the hypothesis was assessed whether heparin-associated thrombocytopenia (HAT) may be caused by an antibody dependent on polysulfated oligosaccharide epitopes, present not only on heparin but also on different polysulfated substances such as dextran sulfate and pentosan polysulfate. We found that the major factor for eliciting platelet activation with sera of HAT type II patients is neither the structure nor the AT III binding capacity of an oligosaccharide, but rather its grade of sulfation. This was shown by in vitro crossreactivity studies with 40 sera of HAT type II patients using unfractionated heparins, LMW heparins (Fragmin, Fraxiparin), enoxaparin, LMW heparinoid (Org 10172 and its subfractions), de-N-sulfated heparin, dermatan sulfate, dextran sulfate, pentosan polysulfate and dextran. Platelet activation was measured by the heparin induced platelet activation (HIPA) assay and the serotonin release assay (SRA). The platelet activating factor was isolated with the IgG fraction, but did not bind to heparin and dextran sulfate fixed to a solid phase. By isoimmune fixation electrophoresis a monoclonal gammopathy was ruled out in the three sera assessed. The in vivo effect of different LMW heparins and the heparinoid Org 10172 was observed in 10 patients with HAT type II. In a prospective study, a compatible heparin-like anticoagulant was selected for 10 HAT patients for whom further parenteral anticoagulation was required. The only substance that showed no crossreactivity in vitro was the LMW heparinoid Org 10172, which differs from heparin and LMW heparins by its low-grade sulfation. Upon treatment with the heparinoid, all 10 patients had a good clinical outcome, even if they had previously developed thromboembolic complications under LMW heparin administration.(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND

Since hypercoagulability might result in recurrent miscarriage, anticoagulant agents could potentially increase the chance of live birth in subsequent pregnancies in women with unexplained recurrent miscarriage, with or without inherited thrombophilia.

OBJECTIVE

To evaluate the efficacy and safety of anticoagulant agents, such as aspirin and heparin, in women with a history of at least two unexplained miscarriages with or without inherited thrombophilia.

METHODS

We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (1 October 2013) and scanned bibliographies of all located articles for any unidentified articles.

METHODS

Randomised and quasi-randomised controlled trials that assessed the effect of anticoagulant treatment on live birth in women with a history of at least two unexplained miscarriages with or without inherited thrombophilia were eligible. Interventions included aspirin, unfractionated heparin (UFH), and low molecular weight heparin (LMWH) for the prevention of miscarriage. One treatment could be compared with another or with no-treatment (or placebo).

METHODS

Two review authors (PJ and SK) assessed the studies for inclusion in the review and extracted the data. If necessary they contacted study authors for more information. We double checked the data.

RESULTS

Nine studies, including data of 1228 women, were included in the review evaluating the effect of either LMWH (enoxaparin or nadroparin in varying doses) or aspirin or a combination of both, on the chance of live birth in women with recurrent miscarriage, with or without inherited thrombophilia. Studies were heterogeneous with regard to study design and treatment regimen and three studies were considered to be at high risk of bias. Two of these three studies at high risk of bias showed a benefit of one treatment over the other, but in sensitivity analyses (in which studies at high risk of bias were excluded) anticoagulants did not have a beneficial effect on live birth, regardless of which anticoagulant was evaluated (risk ratio (RR) for live birth in women who received aspirin compared to placebo 0.94, (95% confidence interval (CI) 0.80 to 1.11, n = 256), in women who received LMWH compared to aspirin RR 1.08 (95% CI 0.93 to 1.26, n = 239), and in women who received LMWH and aspirin compared to no-treatment RR 1.01 (95% CI 0.87 to 1.16) n = 322).Obstetric complications such as preterm delivery, pre-eclampsia, intrauterine growth restriction and congenital malformations were not significantly affected by any treatment regimen. In included studies, aspirin did not increase the risk of bleeding, but treatment with LWMH and aspirin increased the risk of bleeding significantly in one study. Local skin reactions (pain, itching, swelling) to injection of LMWH were reported in almost 40% of patients in the same study.

CONCLUSIONS

There is a limited number of studies on the efficacy and safety of aspirin and heparin in women with a history of at least two unexplained miscarriages with or without inherited thrombophilia. Of the nine reviewed studies quality varied, different treatments were studied and of the studies at low risk of bias only one was placebo-controlled. No beneficial effect of anticoagulants in studies at low risk of bias was found. Therefore, this review does not support the use of anticoagulants in women with unexplained recurrent miscarriage. The effect of anticoagulants in women with unexplained recurrent miscarriage and inherited thrombophilia needs to be assessed in further randomised controlled trials; at present there is no evidence of a beneficial effect.