The ability of several low molecular weight (LMW) heparins and unfractionated heparin (UFH) to inhibit thrombin generation, and their anti-Xa and anti-IIa activities, were measured in the absence and presence of platelet factor 4 (PF4). The LMW heparins studied were 2-5 times less potent, on a weight basis, than UFH as inhibitors of thrombin generation in platelet-poor plasma; the inhibition of thrombin generation by LMW heparins correlated better with their anti-IIa activity (r = 0.98) than with their anti-Xa activity (r = 0.69). At low concentrations of PF4, the activity of LMW heparins in the thrombin generation test was neutralized less than that of UFH, but at higher PF4 concentrations all their activities could be neutralized except in anti-Xa assays. These observations support the hypothesis that anti-IIa activity is important for inhibition of thrombin generation by LMW heparins in vitro. However, when all the anti-IIa activity of LMW heparins was neutralized by PF4, considerable inhibitory activity remained in thrombin generation and anti-Xa assays, indicating that a portion of the anti-Xa activity of LMW heparins also contributes towards inhibition of thrombin generation.

166 patients aged 40-80 years were included in a controlled, randomized, double-blind study to determine the efficacy and safety of a single daily injection of a low molecular weight (LMW) heparin for prevention of deep-vein thrombosis compared to low dose conventional heparin. Patients received 1 x 1.500 aPTT units of a LMW heparin fraction (plus 2 x placebo injection) or 3 x 5.000 IU of an unfractionated heparin. During 10 days of treatment, patients underwent repeated clinical investigation, serial impedance plethysmography, and Doppler sonography for detection of thrombosis of the lower limbs. Combined application of these methods revealed evidence of thrombosis in 4.5% of patients on unfractionated heparin and 3.6% of patients on LMW heparin. Subcutaneous hematomas were significantly smaller in diameter upon treatment with LMW heparin (p less than 0.001). Antithrombin III levels were significantly higher at the end of the observation period in the LMW heparin group (p less than 0.005). Thrombocyte count, transaminases, creatinine, and haemoglobin did not change in either group. The results indicate that LMW heparin administered by a single s.c. dose daily may be as effective as low dose heparin in prevention of deep venous thrombosis in medical inpatients.

BACKGROUND

The bariatric surgical population is a particularly high risk population for VTE. It is unclear if standard (i.e. non-adjusted) thromboprophylaxis doses of low-molecular weight or unfractionated heparin provide adequate protection for obese patients undergoing bariatric surgery, or if higher doses are required. We sought to determine whether a weight based thromboprophylactic dosing regimen is safe and effective in the post-operative period for obese patients undergoing bariatric surgery.

METHODS

A systematic literature search strategy was conducted using MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and all EBM Reviews. Pooled proportions for the different outcomes were calculated.

RESULTS

A total of 6 studies (1 RCT, 4 cohort studies and one quasi experimental trial) containing 1,858 patients were include in the systematic review. Post bariatric surgery patients receiving weight-adjusted prophylactic doses of heparin products, had an in hospital rate of VTE of 0.54% (95% CI: 0.2 to 1.0%) compared to 2.0% (95% CI: 0.1 to 6.4%) for those that did not weight adjust doses. Rates of major bleeding were similar for both groups: 1.6% (95% CI: 0.6 to 3.0%) for patients receiving weight-adjusted dosing compared to 2.3% (95% CI: 1.1% to 3.9%) for those receiving standard doses of heparin products.

CONCLUSIONS

Adjusting the dose of heparin products for thromboprophylaxis post-bariatric surgery seems to be associated with a lower rate of in hospital VTE compared to a strategy of not adjusting the dose, although this did not reach statistical significance. This practice does not lead to an increase in adverse major bleeding events.

Venous thromboembolic disease (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE), is an underdiagnosed and underappreciated clinical problem in cancer patients that results in significant patient morbidity and mortality. Standard treatment practices, including the use of intravenous unfractionated heparin (UFH) for initial anticoagulation, the use of oral warfarin for chronic anticoagulation, and the prescription of only 3 to 6 months total therapy, may not be optimal in the setting of active cancer and ongoing anticancer therapy. Challenges of VTE management in cancer patients include heparin resistance because of excess circulating acute phase proteins, increased recurrence rates during warfarin therapy (target international normalized ratio 2 to 3), limited venous access to support therapeutic monitoring, and increased bleeding rates during anticoagulation. Bleeding during anticoagulation is of particular concern in patients with disease- or chemotherapy-related thrombocytopenia, central nervous system involvement with cancer, and recent surgical intervention. Low-molecular-weight heparins (LMWHs) have been shown to be equally effective and safe for initial anticoagulation compared with UFH and have gained popularity, especially in the setting of VTE in cancer. LMWHs have the advantage of less nonspecific protein binding, subcutaneous weight-based dosing without the need for monitoring in most cases, and less heparin-induced thrombocytopenia. Recent clinical trials have shown LMWHs are at least as effective as oral warfarin for long-term anticoagulation in cancer patients. Interest in LMWHs and several new classes of parenteral and oral anticoagulants extends beyond the primary and secondary prevention of VTE and includes antiangiogenesis, metastasis prevention, and survival prolongation.

Venous thromboembolism (VTE) commonly occurs in patients with malignant disease. At the 1997 ISTH meeting, cancer and thrombosis was discussed in a state-of-the-art symposium. Since then, there have been many new developments on this topic. Tumors, through expression of tissue factor can activate coagulation. Furthermore, local peritumor activation of coagulation may have important effects on the biology of cancer. A randomized trial has been conducted which evaluated extensive screening to detect underlying malignancy vs. no screening in patients presenting with idiopathic VTE. No statistically significant difference was detected in cancer-related mortality between the two groups. A trial has evaluated extended prophylaxis in patients undergoing surgery for abdominal malignancy. There was a statistically significant reduction in venographically detected deep vein thrombosis in favor of 4 weeks of treatment. In contrast, there is clearly a need for more information on the use of thromboprophylaxis in medical cancer patients. Low molecular weight heparin (LMWH) has replaced unfractionated heparin as the first line treatment in the majority of patients with acute VTE. Many cancer patients with acute VTE can be treated safely at home with subcutaneous LMWH without admission to hospital. The results of a recent trial demonstrated that long-term low molecular weight heparin administered over a 6-month period substantially reduced the rate of recurrent VTE compared with oral anticoagulant therapy with no increase in bleeding. Finally, the first trial specifically designed to evaluate the anticancer effect of long-term LMWH in cancer patients has been conducted and will no doubt stimulate future research.

Vascular access site thrombosis is a major cause of morbidity in patients receiving hemodialysis. The role of hypercoagulable states in recurrent vascular access site thrombosis remains poorly understood. Data are limited regarding systemic anticoagulation to improve access graft patency, because of concern about hemorrhagic complications. We determined the prevalence of hypercoagulable states and clinical outcome (thrombotic and hemorrhagic) after initiation of antithrombotic therapy in a series of patients with recurrent vascular access site thrombosis. We evaluated 31 patients who had sustained 119 thrombotic events that resulted in vascular access graft failure during the year before evaluation. Sixty-eight percent of patients tested had elevated concentrations of antibody to anticardiolipin or topical bovine thrombin, and 18% of patients tested had heparin-induced antibodies. More than 90% of patients had elevated factor VIII concentration, 62% had elevated fibrinogen concentrations, and 42% had elevated C-reactive protein concentrations. Twenty-nine patients were given antithrombotic therapy: 13 with warfarin sodium, 12 with unfractionated heparin (UFH), and 11 with low molecular weight heparin (LMWH). Seven patients received more than one antithrombotic agent, sequentially. Nineteen patients have had no thrombotic events since beginning antithrombotic therapy (10 with warfarin, 3 with UFH, 6 with LMWH). Mean follow-up was 8.6 months (median, 7 months). Eight patients sustained 10 bleeding complications (5 with warfarin, 3 with UFH, and 2 with LMWH). In conclusion, hypercoagulable states are common in patients with recurrent vascular access site thrombosis. Antithrombotic therapy may increase vascular access graft patency, but is associated with significant risk for hemorrhage. Prospective studies are needed to evaluate the role and safety of antithrombotic agents in improving vascular access graft patency.

Binding polyanionic unfractionated heparin over the modified AN69 polyacrylonitrile membrane, the surface electronegativity of which has been neutralized by polyethyleneimine (AN69-ST), renders the membrane more hemocompatible. This property was tested in two groups of long-term hemodialysis patients. Results were rated as massive or partial clotting of a dialyzer at the end of the session. Group I patients were included in a prospective, cross-over study comparing standard dialysis with hemodialysis without systemic administration of unfractionated heparin (n = 12, 123 sessions). In all instances, priming was made with 2 I saline containing 5,000 IU/l heparin. Only patchy or partial clotting was observed in 11% and 39% of the sessions with standard and heparin-free administration, respectively. Group II patients were included in an open, observational pilot study testing the effects of the heparin-coated membrane, without systemic administration of heparin, in patients at high risk of bleeding (n = 68, 331 sessions). Massive clotting was observed in six sessions only (less than 2%) and normal or slightly patchy dialyzers were found in 88% of the sessions. It is concluded that the dialysis AN69 ST membrane, after adequate priming at bedside, can be used without systemic administration of heparin for hemodialysis in patients at high risk of bleeding.

BACKGROUND

Binding of polycationic unfractionated heparin onto the modified AN69 polyacrylonitrile membrane, whose surface electronegativity has been neutralized by layering polyethyleneimine (AN69ST), produces stable coating. We investigated whether the heparin-coated membrane was suitable for regular haemodialysis with low heparin doses.

METHODS

Sheep were instrumented for extracorporeal circulation perfusing a dialyser equipped with either the AN69ST or the original AN69 membrane. Dialysis sessions were performed after priming the dialyser with heparinized saline. The session was conducted without systemic administration of heparin. In chronic haemodialysis patients, the AN69ST membrane was tested for safety, clotting and thrombin generation according to protocols of 4-h haemodialysis sessions with tapered heparin doses. The goal was to define optimal heparin requirements with the heparin-coated membrane in the setting of continuous or intermittent administration of heparin. Both unfractionated and low molecular weight heparin (LMWH) (enoxaparin) were tested.

RESULTS

In sheep, systemic heparin-free haemodialysis was conducted for 6 h without clotting using the heparin-coated dialyser. In the same conditions, massive clotting was observed within 90 min of dialysis with the native AN69 membrane. In man, through kinetic measurements of activated partial thromboplastin time (APTT), heparin anti-Xa concentration and thrombin-anti-thrombin complexes levels (TAT), significant dialyser clotting was avoided when APTT and anti-Xa concentration at 180 min of dialysis, were maintained at >40 s and >0.2 IU/ml, respectively. With the AN69ST heparin-coated membrane, thrombin generation was reduced then suppressed, as compared with the original AN69, primed in the same conditions. Safety of haemodialysis conducted with the AN69ST heparin-coated membrane and low doses of unfractionated heparin (50% reduction of the reference dose) was validated by a survey of 2590 sessions in 32 patients. Doses of LMWH were also safely reduced by 50%. In addition, haemodialysis without systemic administration of heparin was possible with minor risk of clotting.

CONCLUSIONS

During the rinsing phase, the ionic interactions between the new AN69ST polyacrylonitrile membrane and unfractionated heparin induce stable heparin coating. This allows a significant reduction of systemic anticoagulant requirements without increasing the risk of clotting, both in the experimental setting and in the chronic haemodialysis patients. Further studies are required to assess this advantage in patients with acute renal failure and at risk of bleeding and to reduce the metabolic consequences of long-term treatment with heparin.

Venous thromboembolism (VTE) prophylaxis is under-utilized in Asia because of the misconception that its incidence is lower in Asians as compared to the Caucasians. The available data on VTE in Asia is limited due to the lack of well-designed multicenter randomized controlled trials as well as non-standardized research designs, making data comparison difficult. Emerging data indicates that the VTE incidence is not low in Asia, and is comparable to that reported in the Western literature in some instances. There is also a trend towards increasing incidence of VTE, as demonstrated by a number of hospital-based studies in Asia. This could be attributed to lifestyle changes, ageing population, increasing awareness of VTE and wider availability of Duplex ultrasound. The risk of VTE in hospitalized patients remain the same in Asians and Caucasians, even though there may be factors that are inherent to patients in Asia that influence the slight variation in incidence. The utilization rate of VTE prophylaxis remains suboptimal in Asia. The Asian Venous Thrombosis Forum (AVTF) comprises participants from various countries such as China, Hong Kong, India, Indonesia, Korea, Malaysia, Philippines, Singapore, Taiwan, Thailand and experts from Australia and Europe. The forum evaluated the available data on VTE from the Asian region and formulated guidelines tailored to meet the needs of the region. We recommend that serious considerations are given to VTE prophylaxis especially in the at-risk group and a formal hospital policy be established to facilitate the implementation. On admission to the hospital, we recommend assessing the patients for both VTE and bleeding risk. We recommend mechanical prophylaxis for patients at increased risk of bleeding and utilizing it as an adjunctive measure in combination with pharmacological prophylaxis in patients with high risk of VTE. For patients undergoing general or gynecological surgery and with moderate risk for VTE, we recommend prophylaxis with one of the following: low dose unfractionated heparin (LDUH), low molecular weight heparin (LMWH), fondaparinux or intermittent pneumatic compression (IPC). For the same group of patients at high risk of VTE, we recommend pharmacological or combination of pharmacological and mechanical prophylaxis. For patients undergoing major orthopedic surgeries like total hip replacement, total knee replacement and proximal hip fracture surgery, we recommend using one of the following: LMWH, fondaparinux, rivaroxaban, apixaban, edoxaban, dabigatran, warfarin or aspirin with IPC. For patients admitted to the hospital with acute medical illness and has moderate risk of VTE, we recommend prophylaxis with LDUH, LMWH or Fondaparinux. For the same group at high risk of VTE, we recommend combination of pharmacological and mechanical prophylaxis.

We recently reported that the subcutaneous (s.c.) administration of a low-molecular-weight heparin (LMWH) fraction significantly inhibited de novo angiogenesis in the mesentery induced by the intraperitoneal (i.p.) injection of saline to adult rats compared with unfractionated heparin and high-molecular-weight heparin (HMWH) fractions. The present study assesses the effect on basic fibroblast growth factor (bFGF)-mediated de novo angiogenesis in the mesentery of the systemic administration of a LMWH fraction (2.6 kD) and a series of four HMWH fractions (about 20 kD) with varying degrees of polydispersity, charge density and anticoagulant activity. bFGF, a prototypic heparin-binding angiogenic growth factor, was injected i.p. at 220 pM on days 0-4. The heparins were given s.c. on days 0-13 or 0-14 at doses which were approximately within the range used clinically. Angiogenesis was assessed by microscopic morphometry and image analysis in groups of animals killed on days 14 and 15. Compared with the saline control, the LMWH and three of the HMWHs significantly inhibited angiogenesis in terms of microvascular length (MVL), a measure of microvascular density. Interestingly, the vascularized area (VA), a measure of microvascular spatial extension, and the total microvascular length (VA x MVL) were significantly lower in the LMWH-treated animals than in the animals treated with one of the HMWHs. The total microvascular length was, moreover, significantly reduced in the LMWH-treated animals compared with the combined data of all the HMWH-treated animals. No significant effects were related to the degree of charge density and anticoagulant activity of the heparins. In view of the putative significant angiogenic role of bFGF in human angiogenesis diseases, the present findings may have implications for the choice of anticoagulant treatment modality for patients suffering from cancer and other angiogenesis diseases.

Over the last 15 years, there has been a shift from unfractionated heparin to low-molecular-weight heparin or fondaparinux for many indications. Nonetheless, heparin continues to be used and it remains the drug of choice for selected indications and patients. This paper reviews when and how to use heparin and when low-molecular-weight heparin or fondaparinux may be a better choice. The paper also describes some of the new parenteral anticoagulants under development and provides perspective on how the introduction of rapid-acting oral thrombin or factor Xa inhibitors is likely to reduce or eliminate the need for bridging with parenteral anticoagulants.

Arterial thrombosis is typically platelet-rich. In this study, it is shown that heparin levels resulting in the usual activated partial thromboplastin time therapeutic range provide only a small anticoagulant effect in the presence of activated platelets. Thrombin inhibition is also negligible when heparin is added to platelet-rich plasma. Aspirin improves the anticoagulant effect of heparin in these circumstances, but the degree of anticoagulation is still considerably lower than that observed in platelet-poor plasma. A low molecular weight heparin (parnaparin) is more active in the presence of activated platelets (such as may occur in acute coronary syndromes) regardless of whether aspirin is used concomitantly.

There is increasing recognition that thrombotic complications may occur in patients with cirrhosis, and literature on antithrombotic treatment in these patients is rapidly emerging. Due to extensive haemostatic changes in patients with cirrhosis, careful monitoring of anticoagulant therapy may be required. Recent data suggest that plasma levels of low molecular weight heparin (LMWH) are substantially underestimated by the anti-activated factor X (anti-Xa) assay in patients with cirrhosis. We studied the in vitro recovery of antithrombin (AT)-dependent and -independent anticoagulant drugs in plasma from 26 patients with cirrhosis and 30 healthy controls and found substantially reduced anti-Xa levels when AT-dependent anticoagulant drugs were added to the plasma of patients with cirrhosis. LMWH (0·2 U/ml) had the poorest recovery in plasma from patients with cirrhosis (0·13 ± 0·06 U/ml, compared to 0·23 ± 0·03 U/ml in controls, P < 0·0001), followed by unfractionated heparin and fondaparinux. In contrast, the recovery of rivaroxaban and dabigatran was identical between patients and controls. These data suggest that the anti-Xa assay cannot be used to monitor AT-dependent anticoagulant drugs in patients with cirrhosis, as it substantially underestimates drug levels. The direct factor Xa and IIa inhibitors, however, may be monitored through the respective anti-Xa and anti-IIa assays in patients with cirrhosis.

OBJECTIVE

To assess the use of low molecular weight heparin for the treatment of venous thromboembolism in pregnancy.

METHODS

A prospective observational study.

METHODS

The maternity units in two university teaching hospitals and one district general teaching hospital.

METHODS

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 s.c., twice daily, based on early pregnancy weight.

METHODS

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.

OBJECTIVE

Evaluation of the effectiveness and safety of the low molecular weight heparin (LMWH) tinzaparin versus unfractionated heparin (UFH) followed by acenocoumarol in proximal deep venous thrombosis (DVT).

METHODS

Prospective, randomized clinical trial.

METHODS

Consecutive patients (n=108) with acute leg DVT, confirmed by duplex, were randomized to either tinzaparin alone or UFH and acenocoumarol for 6 months. Patients were evaluated ultrasonographically at entry, 1, 3, 6 and 12 months. Thrombus regression, reflux distribution and the incidence of complications were studied. A cost-analysis, comparing the two treatments, was performed.

RESULTS

The overall incidence of major events (mortality, DVT recurrence, pulmonary embolism, major bleeding, heparin-induced thrombocytopenia) was significantly different (p=0.035) in favor of tinzaparin (7 versus 17 events). The ultrasonographic clot volume score (an index of recanalization) decreased significantly in both treatment groups. However, tinzaparin produced significantly more extended overall recanalization from 3 months onwards (p<0.02). Thrombus regression was equivalent or in favor of tinzaparin in the different DVT subgroups and venous segments, but the statistical significance varied. Reflux showed non-significant differences overall or in subgroups. A cost-analysis resulted in favor of LMWH.

CONCLUSIONS

A fixed daily dose of tinzaparin for 6 months was at least as effective and safe as UFH and acenocoumarol. Regarding major events and recanalization, there was a significant benefit in favor of tinzaparin. Long-term DVT treatment with tinzaparin could represent an alternative to conventional treatment.

BACKGROUND

Venous thromboembolism (VTE), although rare, is a major cause of maternal mortality and morbidity, and methods of prophylaxis are therefore often used for women considered to be at risk. This may include women who have given birth by caesarean section, those with a personal or family history of VTE and women with inherited or acquired thrombophilias (conditions that predispose people to thrombosis). Many methods of prophylaxis carry risks of adverse effects, and as the risk of VTE is often low, it is possible that the benefits of thromboprophylaxis may be outweighed by harms. Guidelines for clinical practice have been based on expert opinion rather than high-quality evidence from randomised trials.

OBJECTIVE

To assess the effects of thromboprophylaxis in women who are pregnant or have recently given birth and are at increased risk of VTE on the incidence of VTE and adverse effects of treatment.

METHODS

We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (27 November 2013).

METHODS

Randomised trials comparing one method of thromboprophylaxis with placebo or no treatment, and randomised trials comparing two (or more) methods of thromboprophylaxis.

METHODS

At least two review authors assessed trial eligibility and quality and extracted the data.

RESULTS

Nineteen trials, at an overall moderate risk of bias, met the inclusion criteria for the review. Only 16 trials, involving 2592 women, assessing a range of methods of thromboprophylaxis, contributed data to the review. Six trials compared methods of antenatal prophylaxis: heparin versus no treatment/placebo (two trials), and low molecular weight heparin (LMWH) versus unfractionated heparin (UFH) (four trials). Nine trials assessed prophylaxis after caesarean section: four compared heparin with placebo; three compared LMWH with UFH; one compared hydroxyethyl starch (HES) with UFH; and one compared five-day versus 10-day LMWH. One study examined prophylaxis with UFH in the postnatal period (including following vaginal births).For antenatal prophylaxis, none of the included trials reported on maternal mortality, and no differences were detected for the other primary outcomes of symptomatic thromboembolic events, symptomatic pulmonary embolism (PE) and symptomatic deep venous thrombosis (DVT) when LMWH or UFH was compared with no treatment/placebo or when LMWH was compared with UFH. The risk ratios (RR) for symptomatic thromboembolic events were: antenatal LMWH/UFH versus no heparin, RR 0.33; 95% confidence interval (CI) 0.04 to 2.99 (two trials, 56 women); and antenatal LMWH versus UFH, RR 0.47; 95% CI 0.09 to 2.49 (four trials, 404 women). No differences were shown when antenatal LMWH or UFH was compared with no treatment/placebo for any secondary outcomes. Antenatal LMWH was associated with fewer adverse effects sufficient to stop treatment (RR 0.07; 95% CI 0.01 to 0.54; two trials, 226 women), and fewer fetal losses (RR 0.47; 95% CI 0.23 to 0.95; three trials, 343 women) when compared with UFH. In two trials, antenatal LMWH compared with UFH was associated with fewer bleeding episodes (defined in one trial of 121 women as bruises>> 1 inch (RR 0.18, 95% CI 0.09 to 0.36); and in one trial of 105 women as injection site haematomas of ≥ 2 cm, bleeding during delivery or other bleeding (RR 0.28; 95% CI 0.15 to 0.53)), however in a further trial of 117 women no difference between groups was shown for bleeding at delivery. The results for these secondary outcomes should be interpreted with caution, being derived from small trials that were not of high methodological quality.For post-caesarean/postnatal prophylaxis, only one trial comparing five-day versus 10-day LMWH after caesarean section reported on maternal mortality, observing no deaths. No differences were seen across any of the comparisons for the other primary outcomes (symptomatic thromboembolic events, symptomatic PE and symptomatic DVT). The RRs for symptomatic thromboembolic events were: post-caesarean LMWH/UFH versus no heparin, RR 1.30; 95% CI 0.39 to 4.27 (four trials, 840 women); post-caesarean LMWH versus UFH, RR 0.33; 95% CI 0.01 to 7.99 (three trials, 217 women); post-caesarean five-day versus 10-day LMWH, RR 0.36; 95% CI 0.01 to 8.78 (one trial, 646 women); postnatal UFH versus no heparin, RR 0.16; 95% CI 0.02 to 1.36 (one trial, 210 women). For prophylaxis after caesarean section, in one trial (of 580 women), women receiving UFH and physiotherapy were more likely to have bleeding complications ('complications hémorragiques') than women receiving physiotherapy alone (RR 5.03; 95% CI 2.49 to 10.18). In two additional trials, that compared LMWH with placebo, no difference between groups in bleeding episodes (major bleeding; major bruising; bleeding/bruising reported at discharge) were detected. No other differences in secondary outcomes were shown when LMWH was compared with UFH post-caesarean, nor when post-caesarean HES was compared with UFH, post-caesarean five-day LMWH was compared with 10-day LMWH, or when UFH was compared to no heparin postnatally.

CONCLUSIONS

There is insufficient evidence on which to base recommendations for thromboprophylaxis during pregnancy and the early postnatal period, with the small number of differences detected in this review being largely derived from trials that were not of high methodological quality. Large scale, high-quality randomised trials of currently used interventions are warranted.

OBJECTIVE

This study sought to assess the safety and the efficacy of bivalirudin compared with unfractionated heparin (UFH) alone in the subset of patients at increased risk of bleeding undergoing transfemoral elective percutaneous coronary intervention (PCI).

BACKGROUND

Bivalirudin, a synthetic direct thrombin inhibitor, determines a significant decrease of in-hospital bleeding following PCI.

METHODS

This is a single-center, investigator-initiated, randomized, double-blind, controlled trial. Consecutive biomarker-negative patients at increased bleeding risk undergoing PCI through the femoral approach were randomized to UFH (UFH group; n = 419) or bivalirudin (bivalirudin group; n = 418). The primary endpoint was the rate of in-hospital major bleeding.

RESULTS

The primary endpoint occurred in 11 patients (2.6%) in the UFH group versus 14 patients (3.3%) in the bivalirudin group (odds ratio: 0.78; 95% confidence interval: 0.35 to 1.72; p = 0.54). Distribution of access-site and non-access-site bleeding was 18% and 82% in the UFH group versus 50% and 50% in the bivalirudin group (p = 0.10).

CONCLUSIONS

The results of this randomized study, carried out at a single institution, suggest that there is no difference in major bleeding rate between bivalirudin and UFH in increased-risk patients undergoing transfemoral PCI. (Novel Approaches in Preventing and Limiting Events III Trial: Bivalirudin in High-Risk Bleeding Patients [NAPLES III]; NCT01465503).

OBJECTIVE

The objectives of this study are to determine the incidence of symptomatic venous thromboembolism (VTE) in neurosurgery intensive care unit (NSICU) patients with spontaneous or traumatic intracranial hemorrhage and to identify the common VTE risk factors by injury type.

METHODS

This retrospective, single-center cohort study included adult patients admitted to the NSICU between January 2001 and July 2004 with a primary diagnosis of subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), or traumatic brain injury (TBI). Patients and VTE events were identified using ICD-9 codes. All patients received low-dose unfractionated heparin or enoxaparin and intermittent pneumatic compression device. Descriptive statistics were used to describe patient characteristics.

RESULTS

The overall incidence of symptomatic VTE was 3.8% (n = 1195). The incidence of VTE was 6.7% in SAH patients (n = 179), 2.9% in ICH patients (n = 516), and 3.8% in TBI patients (n = 500). The most commonly identified risk factors in the three groups were: greater than 40 years of age, immobility due to paresis or restrictions for mechanical ventilation, presumed infection, and presence of indwelling central venous catheter. There was no objective evidence of intracranial bleeding associated with pharmacologic VTE prophylaxis in VTE patients.

CONCLUSIONS

This is the first study to determine symptomatic VTE incidence and to identify common risk factors by injury type in nontumor patients who are not routinely screened with venous duplex ultrasonography but receiving early IPC and LDUH. Further studies are needed to determine the overall incident of symptomatic and nonsymptomatic VTE and independent risk factors for VTE events in NSICU patients.

Mesenchymal stem cells (MSCs) have emerged as a potent therapeutic tool for the treatment of a number of pathologies, including immune pathologies. However, unwelcome effects of MSCs on blood coagulation have been reported, motivating us to explore the thrombotic properties of human MSCs from the umbilical cord. We revealed strong procoagulant effects of MSCs on human blood and platelet-free plasma using rotational thromboelastometry and thrombodynamic tests. A similar potentiation of clotting was demonstrated for MSC-derived extracellular vesicles (EVs). To offer approaches to avoid unwanted effects, we studied the impact of a heparin supplement on MSC procoagulative properties. However, MSCs still retained procoagulant activity toward blood from children receiving a therapeutic dose of unfractionated heparin. An analysis of the mechanisms responsible for the procoagulant effect of MSCs/EVs revealed the presence of tissue factor and other proteins involved in coagulation-associated pathways. Also, we found that some MSCs and EVs were positive for annexin V, which implies the presence of phosphatidylserine on their surfaces, which can potentiate clot formation. Thus, we revealed procoagulant activity of MSCs/EVs associated with the presence of phosphatidylserine and tissue factor, which requires further analysis to avoid adverse effects of MSC therapy in patients with a risk of thrombosis.

BACKGROUND

The constituents of vascular endothelial glycocalyx, such as syndecan-1 and heparan sulphate (HS), can be detected in the plasma of patients and animals with septic shock. However, the dynamics of glycocalyx degradation and its association with inflammation remains largely unknown. In this study, we investigated the association between the biomarkers of acute endothelial glycocalyx degradation and inflammatory factors. We also evaluated the effect of unfractionated heparin (UFH) on glycocalyx shedding in a canine septic shock model.

METHODS

Twenty adult beagle dogs were randomly allocated to one of the following four groups (n = 5): (1) a sham group; (2) a shock group [3.5 × 10(8) colony-forming unit (cfu) Escherichia coli (E. coli)/kg]; (3) a basic therapy group (sensitive antibiotics and 0.9% saline, 10 ml/kg/h); and (4) a heparin group (40 units/kg/h UFH plus basic therapy). After the onset of septic shock, systemic haemodynamic indices were measured. Endothelial glycocalyx degradation markers (i.e., syndecan-1, HS) and inflammatory factors [i.e., interleukin 6 (IL-6), tumour necrosis factor (TNF)-α], platelet count and activated partial thromboplastin time were measured at various time points.

RESULTS

A lethal dose of E. coli induced a progressive septic shock model. We observed increased syndecan-1 and HS levels, which correlated with IL-6 and TNF-α in the septic shock model. The glycocalyx shedding was reduced by UFH, which might be regulated by the inhibition of inflammatory factors.

CONCLUSIONS

A therapeutic dose of UFH can protect glycocalyx from shedding by inhibiting inflammation. Additional studies with larger sample sizes are needed to confirm our conclusions.

There is growing concern about the development of antibacterial resistance with the use of antibiotics in catheter lock solutions. The use of an antibiotic that is not usually used to treat other serious infections may be an alternative that may reduce the clinical impact should resistance develop. We conducted a randomized controlled trial to compare a solution of minocycline and EDTA with the conventional unfractionated heparin for the prevention of catheter-related bacteremia in hemodialysis patients during a period of 90 d. The study included 204 incident catheters (27.8% tunneled); 14 catheters were excluded because of early dysfunction and 3 because of protocol violations. We observed catheter-related bacteremia in 19 patients in the heparin group (4.3 per 1000 catheter-days) and in 5 patients in the minocycline-EDTA group (1.1 per 1000 catheter-days; P = 0.005). We did not detect a significant difference in the rate of catheter removal for dysfunction. Catheter-related bacteremia-free survival was significantly higher in the minocycline-EDTA group than in the heparin group (P = 0.005). In conclusion, a minocycline-EDTA catheter lock solution is effective in the prevention of catheter-related bacteremia in hemodialysis patients.

BACKGROUND

Heparanase is an endo-β-D-glucuronidase dominantly involved in tumor metastasis and angiogenesis. Recently, we demonstrated that heparanase is involved in the regulation of the hemostatic system. Our hypothesis was that heparanase is directly involved in activation of the coagulation cascade.

METHODS

Activated factor X and thrombin were studied using chromogenic assays, immunoblotting and thromboelastography. Heparanase levels were measured by enzyme-linked immunosorbent assay. A potential direct interaction between tissue factor and heparanase was studied by co-immunoprecipitation and far-western assays.

RESULTS

Interestingly, addition of heparanase to tissue factor and activated factor VII resulted in a 3- to 4-fold increase in activation of the coagulation cascade as shown by increased activated factor X and thrombin production. Culture medium of human embryonic kidney 293 cells over-expressing heparanase and its derivatives increased activated factor X levels in a non-enzymatic manner. When heparanase was added to pooled normal plasma, a 7- to 8-fold increase in activated factor X level was observed. Subsequently, we searched for clinical data supporting this newly identified role of heparanase. Plasma samples from 35 patients with acute leukemia at presentation and 20 healthy donors were studied for heparanase and activated factor X levels. A strong positive correlation was found between plasma heparanase and activated factor X levels (r=0.735, P=0.001). Unfractionated heparin and an inhibitor of activated factor X abolished the effect of heparanase, while tissue factor pathway inhibitor and tissue factor pathway inhibitor-2 only attenuated the procoagulant effect. Using co-immunoprecipitation and far-western analyses it was shown that heparanase interacts directly with tissue factor.

CONCLUSIONS

Overall, our results support the notion that heparanase is a potential modulator of blood hemostasis, and suggest a novel mechanism by which heparanase increases the generation of activated factor X in the presence of tissue factor and activated factor VII.

During the last decade, new anticoagulant drugs with anti-factor-Xa properties have been described (1, 2). Among them is fondaparinux that has been licensed recently. It is a pentasaccharide mimicking the site where heparin binds to antithrombin III (1). This new drug has produced very promising clinical results in the prophylaxis of venous thrombosis after orthopedic surgery (3). Here we report two different clinical situations in which fondaparinux has yielded a successful outcome: first, a patient with repeated cutaneus reaction to several different low molecular weight heparins (LMWH), and second, a patient with severe heparin-induced thrombocytopenia (HIT). We decided to use fondaparinux in both cases since it is commercially available in Spain and mostly because the absence of in vitro cross-reaction with heparins, as discussed later.

Background and purpose: Currently there are no licensed vaccines and limited antivirals for the treatment of COVID-19. Heparin (delivered systemically) is currently used to treat anticoagulant anomalies in COVID-19 patients. In addition, in the UK, Brazil and Australia, nebulised unfractionated heparin (UFH) is being trialled in COVID-19 patients as a potential treatment. A systematic comparison of the potential antiviral effect of various heparin preparations on live wild-type SARS-CoV-2, in vitro, is needed.

Experimental approach: Seven different heparin preparations including UFH and low molecular weight heparins (LMWH) of porcine or bovine origin were screened for antiviral activity against live SARS-CoV-2 (Australia/VIC01/2020) using a plaque inhibition assay with Vero E6 cells. Interaction of heparin with spike protein RBD was studied using differential scanning fluorimetry, and the inhibition of RBD binding to human ACE2 protein using ELISA assays was examined.

Key results: All the UFH preparations had potent antiviral effects, with IC₅₀ values ranging between 25-41 μg ml^-1 whereas LMWHs were less inhibitory by ~150-fold (IC₅₀ range 3.4 - 7.8 mg ml^-1 ). Mechanistically we observed that heparin binds and destabilizes the RBD protein, and furthermore we show heparin directly inhibits the binding of RBD to the human ACE2 protein receptor.

Conclusions and implications: This comparison of clinically relevant heparins shows UFH has significantly stronger SARS-CoV-2 antiviral activity compared to LMWHs. UFH acts to directly inhibit binding of spike protein to the human ACE2 protein receptor. Overall the data strongly support further clinical investigation of UFH as a potential treatment for patients with COVID-19.

Keywords: COVID-19; LMWH; SARS-CoV-2; UFH; heparin; nebulised.