Danaparoid, a low molecular weight heparinoid consisting of a mixture of heparan, dermatan and chondroitin sulfates, has well established antithrombotic activity. The drug has a high antifactor Xa to antifactor IIa (thrombin) activity ratio, a low tendency to cause bleeding and minimal effects on the fibrinolytic system. Danaparoid has a low cross-reactivity rate with heparin-associated antiplatelet antibodies (0 to 20%; mean approximately 10%). This represents a significant advantage over low molecular weight heparins (LMWHs) as a potential replacement agent for unfractionated heparin (UFH) in patients with immune-mediated (type II) heparin-induced thrombocytopenia (HIT). In a worldwide compassionate-use programme involving a total of 667 patients with HIT to date, 93% of danaparoid treatment courses were considered to be successful. Thrombocytopenia resolved in 91% of episodes. In a multicentre randomised comparative trial of danaparoid and dextran in patients with HIT plus thrombosis (HITT), significantly more danaparoid than dextran recipients had resolution of thromboses, and an effective clinical response was achieved in significantly more danaparoid recipients. Results of a retrospective case-controlled study of danaparoid and ancrod in patients with HITT showed significantly fewer new or progressive thromboses with danaparoid. In the compassionate-use programme, danaparoid was associated with a mortality rate of 10.4% during treatment (up to 3.5 years) and 7.8% during the follow-up period (3 months). 14 of 114 deaths during the follow-up period were considered to be related to danaparoid therapy. A mortality rate of 23.5% was reported in patients accepted for but not treated with, danaparoid. Mortality rates with danaparoid, ancrod and dextran in the comparative studies were similar (7, 11 and 12%, respectively). Severe bleeding was reported in 3.1% of patients in the compassionate-use programme, persistent or recurrent thrombocytopenia in 2.6% and new thromboembolic events/extension of existing thrombosis in 1.7%. The incidence of bleeding was similar with danaparoid and dextran in a comparative trial. Although in vitro cross-reactivity does not always translate into clinical cross-reactivity, testing is currently recommended, when possible, before initiation of danaparoid therapy. Thus, danaparoid appears to be an effective and well tolerated replacement agent for UFH in many patients with HIT who require further anticoagulation. The drug has low cross-reactivity with HIT-associated antibodies. Further comparative trials are needed to confirm these promising findings.

BACKGROUND

Randomized clinical trials (RCTs) have usually supported using heparin prophylaxis against venous thromboembolism (VTE) in patients undergoing cranial neurosurgery. The tradeoff between benefit and bleeding risk, however, has not been adequately characterized.

OBJECTIVE

To conduct a systematic review and meta-analysis assessing the extent to which low-dose unfractionated heparin (LDUH) or low-molecular-weight heparin (LMWH) prophylaxis reduces the rate of VTE and increases the rate of intracerebral hemorrhage (ICH) and other bleeding in patients undergoing elective cranial neurosurgery.

METHODS

We selected RCTs that evaluated LDUH or LMWH prophylaxis of VTE in patients undergoing elective cranial neurosurgery. A meta-analysis assessing heparins vs no heparin (either with or without mechanical methods) was performed.

RESULTS

Eight RCTs were identified. Six RCTs involving 1170 patients evaluated LDUH or LMWH vs a control group. Five of 6 trials found a significant reduction in the risk of symptomatic and asymptomatic VTE with heparin prophylaxis. The pooled risk ratio was 0.58 (95% confidence interval, 0.45-0.75). ICH was more common in those receiving heparin, but not statistically significantly. For every 1000 patients who receive heparin prophylaxis, 91 VTE events will be prevented (approximately 35 of which are proximal deep vein thrombosis or pulmonary embolism and 9 to 18 of which are symptomatic), whereas 7 ICHs and 28 more minor bleeds will occur.

CONCLUSIONS

Heparin prophylaxis for patients undergoing elective cranial neurosurgery reduces the risk of VTE but may also increase bleeding risks with a ratio of serious or symptomatic VTE relative to serious bleeding that is only slightly favorable.

Nadroparin calcium is a low molecular weight heparin with a mean molecular weight of 4.5 kD. Compared with unfractionated heparin, nadroparin calcium has a greater ratio of anti-factor Xa/anti-factor IIa activity. Nadroparin calcium has a longer half-life and greater bioavailability than unfractionated heparin and can be administered by subcutaneous injection once daily for prophylaxis and twice daily for treatment. In clinical trials, nadroparin calcium has been shown to be at least as effective as unfractionated heparin in preventing deep venous thrombosis (DVT) after various surgical procedures including major orthopaedic and abdominal surgery, and in maintaining the patency of the extracorporeal circulation in adults and children undergoing haemodialysis. Nadroparin calcium is well tolerated, the most common adverse event associated with its use being the development of minor haematoma at the operative incision site. In postmarketing surveillance data to date, the incidence of major haemorrhage related to nadroparin calcium use has been very low (< 1%). Nadroparin calcium has also been associated with a very low incidence of thrombocytopenia (< 0.001%). Thus, nadroparin calcium is an effective alternative to unfractionated heparin in the prophylaxis or treatment of thromboembolic venous events, with the advantages of more convenient administration and a lower incidence of thrombocytopenia.

OBJECTIVE

Parenteral administration of low-molecular-weight heparins (LMWHs) and unfractionated heparin (UFH) resulted effective in improving the symptoms of experimental colitis in rat. Today, there is little information about their activity by intracolonic instillation. The scope of this study was to evaluate the ability of CB-01-05 (a LMWH with a mean molecular weight of about 5,700), compared to a series of other LMWHs and to UFH, directly instilled into the distal colon of the rat, to ameliorate dinitrobenzene (DNB)-induced experimental colitis.

METHODS

Adult male Wistar rats underwent colitis induction by intracolonic instillation of DNB. Starting 24 h after colitis induction, CB-01-05 (0.005-0.9 mg), other LMWHs (0.3-0.6 mg), and UFH (0.6 mg) were instilled, by rectal route, into the distal colon once a day for three consecutive days. On the day following the last administration, the animals were sacrificed and the distal colon was isolated, weighed, macroscopically examined, and processed for histology. Additional experiments in rat splenocytes, performed in order to elucidate the anti-inflammatory mechanisms of CB-01-05, were performed.

RESULTS

Among the tested items, only CB-01-05 at doses ranging from 0.2 to 0.9 mg was significantly effective in reducing colon weight increase and in improving both the mucosal damaged area and the histological score. The other LMWHs resulted far less effective, showing decreasing activity closely related with the decrease of their molecular weight, thus demonstrating their biological nonequivalence. CB-01-05 resulted also more active than UFH. CB-01-05 was shown to interfere with cytokines production by rat splenocytes, mainly inhibiting interferon (IFN)-gamma expression.

CONCLUSIONS

CB-01-05 instilled into the colon is well tolerated, has strong anti-inflammatory effect on DNB-induced colitis in rat, and is the most effective agent among other LMWHs and UFH. These results suggest that the anti-inflammatory activity of CB-01-05, together with its topical administration, could represent a new approach in the management of ulcerative colitis.

Low-molecular weight heparin (LMWH) is increasingly used in place of unfractionated heparin (UFH) in patients with unstable angina, and phase II clinical trials using fondaparinux for this indication are underway. Because unstable angina patients often require urgent percutaneous coronary interventions (PCI) or aortocoronary bypass surgery, a point-of-care test is needed to monitor the anticoagulant effect of these agents. The activated clotting time (ACT) and activated partial thromboplastin time (aPTT) are the tests most often used to monitor heparin. The purpose of this in vitro study was to determine whether the ACT or the aPTT can be used to monitor the anticoagulant effect of low-molecular weight heparin and fondaparinux. The ACT and aPTT were measured after heparin, enoxaparin or fondaparinux was added to the blood of healthy volunteers, in doses with equivalent inhibitory activity against activated factor X (factor Xa). To mimic the clinical scenario where an unstable angina patient, who has already received enoxaparin, is urgently taken for PCI or bypass surgery, the ACT was determined after heparin was added to blood containing clinically relevant doses of enoxaparin. We determined that enoxaparin produced significantly less prolongation of both the ACT and the aPTT than heparin, whereas fondaparinux had no effect on either of these tests. Addition of enoxaparin to heparin-containing plasma did not prolong the ACT beyond that produced by heparin alone. The ACT and aPTT therefore cannot be used to monitor low-molecular weight heparin or fondaparinux, highlighting the need for a point-of-care anti-factor Xa assay.

BACKGROUND

Bleeding associated with the use of unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) can be a serious complication of health-care management and should be the focus of quality improvement initiatives by institutions.

OBJECTIVE

To measure the incidence of bleeding with UFH and LMWH and evaluate associated risk factors.

METHODS

An observational cohort study was conducted at a secondary and tertiary care hospital in Canada. All adults receiving therapeutic doses of UFH or LMWH between April 2006 and March 2007, with the exception of cardiac surgery patients, were included. Bleeding episodes were classified per the GUSTO scale.

RESULTS

Of 3066 hospitalizations, the incidence of moderate or severe bleeding was 3.5%. Advanced age (OR 1.02, 95% CI 1.01 to 1.04; p < 0.001), female sex (OR 1.80, 95% CI 1.21 to 2.66; p = 0.003), UFH instead of LMWH (OR 4.72, 95% CI 2.17 to 10.30; p < 0.001), creatinine clearance (CrCl) (OR 0.89, 95% CI 0.84 to 0.95; p < 0.001, for a difference of 10 mL/min in CrCl), and supratherapeutic activated partial thromboplastin time (aPTT) (OR 3.88, 95% CI 2.25 to 6.69; p < 0.001 for >180 vs <90 seconds) were associated with a higher risk of bleeding in univariate analysis. In a multivariate model without aPTT, CrCl (OR 0.90, 95% CI 0.85 to 0.96; p < 0.001, for a difference of 10 mL/min in CrCl) and UFH (OR 2.35, 95% CI 1.11 to 4.98; p = 0.005) were significant predictors of bleeding. Among the bleeding episodes, 31% were in a postoperative context and 15% were following a puncture.

CONCLUSIONS

Our findings show that CrCl and aPTT values, as well as the type of heparin used, are significant predictors of bleeding in patients receiving UFH or LMWH and that dosages should be adjusted to patient weight. The reason for all supratherapeutic aPTT levels should be sought and corrective measures taken immediately.

OBJECTIVE

Patients with intracerebral hemorrhage (ICH) are at high risk for development of deep venous thrombosis. Current guidelines state that low-dose subcutaneous low molecular weight heparin or unfractionated heparin may be considered at 3 to 4 days from onset. However, insufficient data exist on hematoma volume in patients with ICH before and after pharmacological deep venous thrombosis prophylaxis, leaving physicians with uncertainty regarding the safety of this practice.

METHODS

We identified patients from our stroke registry (June 2003 to December 2007) who presented with ICH only or ICH+intraventricular hemorrhage and received either low molecular weight heparin subcutaneously or unfractionated heparin within 7 days of admission and had a repeat CT scan performed within 4 days of starting deep venous thrombosis prophylaxis. We calculated the change in hematoma volume from the admission and posttreatment CTs. Hematoma volume was calculated using the ABC/2 method and intraventricular hemorrhage volumes were calculated using a published method of hand drawn regions of interest.

RESULTS

We identified 73 patients with a mean age of 63 years and median National Institutes of Health Stroke Scale score 11.5. The mean baseline total hematoma volume was 25.8 mL±23.2 mL. There was an absolute change in hematoma volume from pre- and posttreatment CT of -4.3 mL±11.0 mL. Two patients developed hematoma growth. Repeat analysis of patients given pharmacological deep venous thrombosis prophylaxis within 2 or 4 days after ICH found no increase in hematoma size.

CONCLUSIONS

Pharmacological deep venous thrombosis prophylaxis given subcutaneously in patients with ICH and/or intraventricular hemorrhage in the subacute period is generally not associated with hematoma growth.

BACKGROUND

Unfractionated heparin (UFH) has been used clinically for 5 decades. Despite being a cornerstone of anticoagulation, UFH is limited by its unpredictable pharmacokinetic profile, which makes close laboratory monitoring necessary. The most common methods for monitoring UFH are the activated partial thromboplastin time (aPTT) and antifactor Xa heparin assay (anti-Xa HA), but both present challenges, and the optimal method to monitor UFH remains unclear.

OBJECTIVE

To compare the performance of the aPTT with the anti-Xa HA for efficiency and safety of monitoring intravenous UFH infusions.

METHODS

This was a single-center, retrospective, observational cohort study conducted in an 852-bed academic medical center.

RESULTS

One hundred patients receiving intravenous UFH for a variety of indications were enrolled in the study; 50 were assigned to each group. The mean (SD) time to achieve therapeutic anticoagulation was significantly less in the anti-Xa HA group compared with the aPTT group (28 [16] vs 48 [26] hours, p < 0.001). In addition, a greater percentage of anti-Xa HA patients compared to aPTT patients achieved therapeutic anticoagulation at 24 hours (OR 3.5; 95% CI 1.5 to 8.7) and 48 hours (OR 10.9; 95% CI 3.3 to 44.2). Patients in the anti-Xa HA group also had more test values within the therapeutic range (66% vs 42%, p < 0.0001). A significant difference was seen between the 2 groups in the number of aPTT or anti-Xa HA tests performed per 24 hours (p < 0.0001) and number of infusion rate changes per 24 hours (p < 0.01), both favoring the anti-Xa HA group.

CONCLUSIONS

Monitoring intravenous UFH infusions with the anti-Xa HA, compared to the aPTT, achieves therapeutic anticoagulation more rapidly, maintains the values within the goal range for a longer time, and requires fewer adjustments in dosage and repeated tests.

We have previously demonstrated that the nonspecific binding of unfractionated heparin (UFH) to plasma proteins has a marked modulating effect on its anticoagulant activity. Since some heparin-binding proteins are also acute-phase-reactant proteins, we explored the possibility that the induction of the acute-phase response can increase the plasma concentrations of heparin-binding proteins. The recovery of a fixed amount of UFH or low-molecular-weight heparin (LMWH) added in vitro to rat plasma samples obtained at various time intervals after the administration of intravenous endotoxin or subcutaneous turpentine was compared with that of saline-treated control animals. The anti-factor Xa activity was measured in the plasma samples before and after the addition of a chemically modified low-affinity heparin (LAH) to displace the proportion of the added heparin that is reversibly bound to plasma proteins. Our results show that at 6 hours post-endotoxin and at 24 hours post-turpentine treatment, virtually no anti-factor Xa activity could be measured in the plasma samples, while the expected levels were obtained for control plasma. After the addition of LAH to displace protein-bound UFH, essentially the same anti-factor Xa levels were measured in the plasma from all three treatment groups. These results indicate that induction of the acute-phase reaction can dramatically increase the levels of heparin-binding proteins in rat plasma. In addition, we compared the anti-factor Xa recovery of UFH with that of an LMWH from the plasma of endotoxin- and saline-treated rats and demonstrated that LMWH binds less to plasma proteins than UFH, even in plasma in which the levels of heparin-binding proteins are markedly elevated. The recovery of a fixed amount of UFH added in vitro to human plasma from septic patients was also reduced, but not to the same extent as seen in rat plasma. Removal of candidate heparin-binding and acute-phase proteins by immunodepletion indicated that vitronectin plays an important role in the nonspecific binding of UFH in patient plasma.

Many aspects of care such as management of hypercoagulable state in COVID-19 patients, especially those admitted to intensive care units is challenging in the rapidly evolving pandemic of novel coronavirus disease 2019 (COVID-19). We seek to systematically review the available evidence regarding the anticoagulation approach to prevent venous thromboembolism (VTE) among COVID-19 patients admitted to intensive care units. Electronic databases were searched for studies reporting venous thromboembolic events in patients admitted to the intensive care unit receiving any type of anticoagulation (prophylactic or therapeutic). The pooled prevalence (and 95% confidence interval [CI]) of VTE among patients receiving anticoagulant were calculated using the random-effects model. Subgroup pooled analyses were performed with studies reported prophylactic anticoagulation alone and with studies reported mixed prophylactic and therapeutic anticoagulation. We included twelve studies (8 Europe; 2 UK; 1 each from the US and China) in our systematic review and meta-analysis. All studies utilized LMWH or unfractionated heparin as their pharmacologic thromboprophylaxis, either prophylactic doses or therapeutic doses. Seven studies reported on the proportion of patients with the previous history of VTE (range 0-10%). The pooled prevalence of VTE among ICU patients receiving prophylactic or therapeutic anticoagulation across all studies was 31% (95% CI 20-43%). Subgroup pooled analysis limited to studies reported prophylactic anticoagulation alone and mixed (therapeutic and prophylactic anticoagulation) reported pooled prevalences of VTE of 38% (95% CI 10-70%) and 27% (95% CI 17-40%) respectively. With a high prevalence of thromboprophylaxis failure among COVID-19 patients admitted to intensive care units, individualised rather than protocolised VTE thromboprophylaxis would appear prudent at interim.

Keywords: Anticoagulation; COVID-19; Coronavirus 2019; Critically ill; Venous thromboembolism.

BACKGROUND

Excessive vascular permeability is a characteristic feature of ALI. We have previously demonstrated that UFH prevents LPS-induced disruption of endothelial barrier function in vitro. It was the objective of this study to determine whether UFH may attenuate endotoxin-induced lung vascular leak in mice and to further explore the possible underlying mechanisms.

METHODS

C57BL/6J mice were randomly divided into the control, LPS and LPS plus UFH groups. Sepsis was induced by intraperitoneal injection of LPS at a dose of 30 mg/kg. Mice in the LPS plus UFH group were intravenously received 8 units UFH (heparin sodium) diluted in 20 μl sterile saline at 0.5 h before the injection of LPS.

RESULTS

1) UFH pretreatment attenuated LPS-induced histopathological changes in Lung at 6 h; 2) Pretreatment of mice with UFH ameliorated LPS-induced lung edema and lung vascular leak at 6 h; 3) UFH pretreatment dramatically inhibited RhoA and ROCK activation in the lung tissues of LPS-treated mice (3 and 6 h). 4) UFH pretreatment significantly down-regulated ROCK1 gene expression, but did not affect the increased expression of ROCK2 mRNA in the lung tissues of LPS-treated mice at 3 or 6 h.

CONCLUSIONS

These data suggest that UFH may attenuate endotoxin-induced lung vascular leak by regulating RhoA/Rho kinase pathway.

BACKGROUND

Central venous catheter (CVC) placement increases the risk of thrombosis in people with cancer. Thrombosis often necessitates the removal of the CVC, resulting in treatment delays and thrombosis-related morbidity and mortality.

OBJECTIVE

To evaluate the relative efficacy and safety of anticoagulation for thromboprophylaxis in people with cancer with a CVC.

METHODS

We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 12, 2012), MEDLINE Ovid (January 1966 to February 2013), and EMBASE Ovid (1980 to February 2013). We handsearched conference proceedings, checked references of included studies, used the 'related citations' feature within PubMed, and searched clinicaltrials.gov for ongoing studies.

METHODS

Randomized controlled trials (RCTs) comparing the effects of any dose of unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), vitamin K antagonists (VKA), or fondaparinux with no intervention or placebo or comparing the effects of two different anticoagulants in people with cancer and a CVC.

METHODS

Teams of two review authors independently used a standardized form to extract data in duplicate. They resolved any disagreements by discussion. They extracted data on risk of bias, participants, interventions, and outcomes. Outcomes of interest included mortality, symptomatic deep venous thrombosis (DVT), asymptomatic DVT, major bleeding, minor bleeding, infection, and thrombocytopenia. Where possible, we conducted meta-analyses using the random-effects model.

RESULTS

Of 9559 identified citations, we included 12 RCTs (17 publications) reporting follow-up data on 2823 participants. Two of the RCTs included children. Of the 10 RCTs including 2564 adults, one compared prophylactic dose heparin with low-dose VKA. Three RCTs compared VKA with no VKA and four RCTs compared heparin with no heparin. Two additional trials had three separate arms comparing heparin, VKA, and no intervention. Prophylactic-dose heparin, compared with no heparin, was associated with a statistically significant reduction in symptomatic DVT (risk ratio (RR) 0.48; 95% confidence interval (CI) 0.27 to 0.86; moderate-quality evidence). However, results did not confirm or exclude a beneficial or detrimental effect of heparin on mortality (RR 0.82; 95% CI 0.53 to 1.26; moderate-quality evidence), major bleeding (RR 0.49; 95% CI 0.03 to 7.84; low-quality evidence), infection (RR 1.00; 95% CI 0.54 to 1.85; moderate-quality evidence); thrombocytopenia (RR 1.03; 95% CI 0.80 to 1.33; moderate-quality evidence), or minor bleeding (RR 1.35; 95% CI: 0.62 to 2.92). Low-dose VKAs, compared with no VKAs, were associated with a statistically significant reduction in asymptomatic DVT (RR 0.43; 95% CI 0.30 to 0.62). Results did not confirm or exclude a beneficial or detrimental effect of VKAs on mortality (RR 1.04; 95% CI 0.89 to 1.22; low-quality evidence), symptomatic DVT (RR 0.51; 95% CI 0.21 to 1.22; low-quality evidence), major bleeding (RR 7.60; 95% CI 0.94 to 61.49; very-low-quality evidence), or minor bleeding (RR 3.14; 95% CI 0.14 to 71.51). The use of heparin, compared with VKA was associated with a statistically significant increase in thrombocytopenia (RR 3.73; 95% CI 2.26 to 6.16; low-quality evidence) and asymptomatic DVT (RR 1.74; 95% CI 1.20 to 2.52). However, results did not show or exclude a beneficial or detrimental effect on any of the other outcomes of interest (very-low-quality evidence).

CONCLUSIONS

Compared with no anticoagulation, we found a statistically significant reduction of symptomatic DVT with heparin and asymptomatic DVT with VKA. Heparin was associated with a higher risk of thrombocytopenia and asymptomatic DVT when compared with VKA. However, the findings did not rule out other clinically important benefits and harms. People with cancer with CVCs considering anticoagulation should balance the possible benefit of reduced thromboembolic complications with the possible harms and burden of anticoagulants.

Venous thromboembolism (VTE), manifesting as either deep vein thrombosis or pulmonary embolism, is common worldwide including in Japan. The number of patients clinically diagnosed with VTE is increasing with the majority of cases occurring out-of-hospital and of milder severity. Cancer is the largest risk factor for VTE and VTE in cancer patients confers an increased 1-year mortality rate. However, the majority of VTE cases are considered "idiopathic" or "unprovoked." The limited efficacies of unfractionated heparin and warfarin have stimulated the development of new anticoagulant therapies. Recently, parenteral and oral administration of the Xa inhibitors fondaparinux and edoxaban, respectively, was approved in Japan. These agents have the potential to provide safer and more efficacious treatment options for VTE. Although further randomized studies are required to validate the utility of these agents, they are expected to substantially improve quality of life in VTE patients. This review summarizes the current status of VTE management in Japan focusing on current epidemiology and recent advances in anticoagulant therapy.

Arterial and venous thromboembolism are leading causes of morbidity and mortality around the world. For almost 70 years, heparins (unfractionated heparin and low molecular weight heparins) and vitamin K antagonists have been the leading therapeutic medical options for the treatment and prevention of thromboembolic disorders. Nevertheless, the many limitations of these traditional anticoagulants have fuelled the search for novel agents over the past 15 years, and a new class of oral anticoagulants that specifically target activated factor X and thrombin has been developed and is now commercially available. In this narrative review, the evolution of anticoagulant therapy is summarised, with a focus on newer oral anticoagulants.

Low molecular weight heparin (LMWH), unfractionated heparin (UFH) and warfarin were compared with respect to efficacy and safety in the prevention of thrombo-embolism in general surgery. Meta-analysis (MA) with a priori definition of the MA protocol was used to combine the results from randomised trials with patients who underwent general surgery and deep-vein thrombosis (DVT) prophylaxis with LMWH, UFH or warfarin. Forty-four studies were identified for assessment and 33 were included, however, none for warfarin. For efficacy (DVT and pulmonary embolism) and major bleeding, no significant difference between the LMWH- and UFH-treated groups was demonstrated. The relative risk of minor bleedings for LMWH versus UFH was 0.75 (0.64-0.88; 95% confidence interval) and is significant (p < 0.05). Within the limitations of the MA, LMWH and UFH did not differ significantly in terms of prevention of thrombo-embolism, but LMWH had a significantly better safety profile. On this basis, LMWH may be preferable to UFH in the prevention of thrombo-embolism in general surgery.

Venous thromboembolism (VTE) remains a significant cause of morbidity and mortality in hospitalized patients with acute medical illness. The high prevalence of VTE in this patient population, its clinically silent nature, and associated morbidity and mortality indicate that prophylactic therapy is appropriate in those determined to be at increased risk. Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) have been shown to reduce the incidence of VTE and are the primary therapies used for prophylaxis in these patients. Although both UFH and LMWH have received grade 1A recommendations for the prevention of VTE in at-risk medical patients in the 2004 American College of Chest Physicians consensus conference statements, LMWH has advantages over UFH in its once-daily dosing scheme, reduced incidence of major and minor bleeding events, and reduced incidence of heparin-induced thrombocytopenia. Fondaparinux is a novel antithrombotic agent characterized by specificity for factor Xa and a lack of platelet interaction. A recent clinical trial in hospitalized patients with acute medical illness found that fondaparinux significantly reduced the incidence of both VTE and fatal pulmonary embolism compared with placebo, without increased major bleeding. Despite the availability of effective thromboprophylactic therapies, VTE prophylaxis continues to be underutilized in hospitalized medical patients.

Since the early nineties it has been shown that low molecular weight heparin (LMWH) has significant advantages over unfractionated heparin and oral anticoagulants for both the treatment and the prevention of thrombosis, not only in adults, but also in children. The present review was based on an 'EMBASE', 'Medline' and 'PubMed' search including literature published in any language since 1980 on LMWH in neonates, infants and children. It included paediatric pharmacokinetic studies, the use of LMWH in children with venous thrombosis, LMWH administration in paediatric patients with ischaemic stroke, and its use in order to prevent symptomatic thromboembolism in children at risk. An increasing rate of off-label use of LMWH in children has been reported, showing that LMWHs offer important benefits to children with symptomatic thromboembolic events and poor venous access. Two well-conducted pharmacokinetic studies in this age group showed that neonates and younger infants require higher LMWH doses than older children to achieve the targeted anti-Xa levels, due to an increased extra vascular clearance. Recurrent symptomatic thromboses under LMWH occur in approximately 4% of children treated for venous thrombosis, and in 7% of children treated for stroke; major bleed was documented in 3% of children with therapeutic target LMWH anti-Xa levels, whereas minor bleeding was reported in approximately 23% of children receiving either therapeutic or prophylactic doses, respectively. Further randomized controlled trials are recommended to evaluate the optimum duration and application for different LMWH indications in children.

BACKGROUND

As reported by major clinical series in the literature, about 2% of patients receiving unfractionated heparin (UFH) develop immune-mediated (type II) heparin-induced thrombocytopenia (HIT) that may be complicated in 30-75% of cases by a paradoxical thrombotic syndrome (HITTS), either arterial or venous. HITTS carries relevant rates of mortality and morbidity, amongst which cerebral and/or myocardial infarction and limb amputations. It is unclear as yet why some patients suffer from isolated thrombocytopenia (HIT), whilst others have HITTS. The aim of the present study was to look for clinical and laboratory features related to the occurrence of HITTS.

METHODS

We retrospectively analysed the clinical records of 56 patients with proven HIT, as diagnosed on clinical grounds and by in vitro demonstration of immunoglobulin (IgG)/IgM against the PF4/heparin complex. Thirty-four patients (61%) had HITTS (19 venous thrombosis, seven arterial thrombosis, five arterial and venous thrombosis, two skin necrosis, one diffuse intravascular coagulation), whereas 22 had uncomplicated HIT. Amongst HITTS patients, two had limb amputation, five had recurrent thrombosis and seven died. Amongst HIT patients three died from causes unrelated to HIT.

RESULTS

No significant difference in sex, age, previous exposure to heparin, UFH route of administration or dose, duration of therapy, time of onset of thrombocytopenia and platelet count recovery, nor antiheparin/PF4 antibodies subtype (IgG or IgM) was detected when comparing HIT and HITTS. In contrast, in the HITTS group a higher prevalence of orthopaedic surgery (15 of 34 vs. 2/22; P=0.01), a significantly lower platelet count nadir (43 +/- 32 vs. 75 +/- 63 x 109/L; P=0.01) and a significantly higher titre of antiheparin/PF4 antibodies, expressed as optical density of enzyme-linked immunosorbent assay (ELISA); (1989 +/- 1024 vs. 1277 +/- 858; P=0.009), were observed in comparison with the HIT group. Amongst HITTS patients, the prevalence of venous thrombosis was significantly higher in orthopaedic patients and in those being treated for venous thromboembolism (18/24 vs. 1/9 patients, chi2 8.4, P=0.004), whilst arterial thrombosis (ART) occurred more often in heparin treatment for arterial disease (3/4 vs. 4/29 patients, chi2 4.6, P=0.03).

CONCLUSIONS

Orthopaedic surgery, the severity of thrombocytopenia and high antiheparin/PF4 antibodies titre are adverse prognostic or concurrent factors in the development of HITTS.

BACKGROUND

Obese patients are at increased risk of acute coronary syndromes (ACS). We evaluated the prevalence of obesity in a large ACS population, as well as the relationship between body mass index (BMI) and the use of cardiac medications and procedures, clinical outcomes, and treatment effects between enoxaparin and unfractionated heparin (UFH).

METHODS

Using the database of the SYNERGY trial, we identified 9978 patients in 12 countries who were randomly assigned to receive enoxaparin or UFH. Patient weight at baseline and 30-day follow-up was recorded. BMI information was available on 9837 patients. BMI was analyzed in clinically meaningful categories (<20, 20-25, 30-35,>> or =35 kg/m(2)) and as a continuous variable.

RESULTS

Thirty-two percent of patients were obese (BMI> or =30), with a greater proportion of patients with obesity from North America (36%) compared with other regions. Enoxaparin was dosed as 1 mg/kg regardless of body weight without maximum. The first dose of enoxaparin was underdosed in 15% of patients assigned enoxaparin, and obese patients were more likely to be underdosed than non-obese patients. Obese patients were younger, less often white, had more diabetes, hypertension, hyperlipidemia, family history of coronary artery disease, and congestive heart failure but fewer strokes, less peripheral vascular disease, and less often smoked. After adjustment, increased BMI was not an independent predictor of bleeding outcomes or 30-day death/myocardial infarction (MI), but increased BMI was predictive of lower 1-year mortality in the subgroup of patients with BMI at baseline below approximately 30 kg/m(2). No statistical interaction term was observed between obesity and randomized therapy for the outcomes of death/MI at 30 days and 6 months; death at 30 days, 6 months, and 1 year; and GUSTO or TIMI bleeding.

CONCLUSIONS

Nearly one third of patients in SYNERGY were obese. Despite multiple comorbidities, obese patients had better unadjusted short- and long-term outcomes. After adjustment, higher BMI was not an independent predictor of in-hospital bleeding events or 30-day death/MI, but increased BMI was an independent predictor of 1-year mortality in patients with lower BMI but not in heavier patients. No interaction between the randomized treatment and obesity for efficacy and safety outcomes was observed across the range of BMI in this dataset. Standard dosing of enoxaparin should be used in patients without extreme obesity due to limited outcome data in these patients.

The antithrombotic activity of a fucosylated chondroitin sulfate extracted from the body wall of a sea cucumber was assessed using a stasis thrombosis model in rats. Intravenous administration of the polysaccharide reduced thrombosis in a dose-dependent manner. We also compared the antithrombotic action of the sea cucumber chondroitin sulfate with that of standard mammalian glycosaminoglycans, mainly heparin and dermatan sulfate. Intravascular injection of fucosylated chondroitin sulfate at the dose totally preventing thrombus formation produced a much more intense modification of the plasma anticoagulant activity than antithrombotic doses of unfractionated heparin, low-molecular-weight heparin and mammalian dermatan sulfate. Thus, it is possible that the mechanism of antithrombotic action of these polysaccharides are different. For fucosylated chondroitin sulfate, it depends mostly on modifications of the plasma anticoagulant activity, but it may involve additional effects in the case of mammalian glycosaminoglycans, perhaps modifications induced in the cells of the vessel wall. The anticoagulant and possibly the antithrombotic actions of fucosylated chondroitin sulfate are mostly dependent on heparin cofactor II activity, and both are markedly reduced with the decrease of the chain size of the polymer. Overall, the sulfated polysaccharide from the invertebrate revealed an unequivocal effect in preventing experimental venous thrombosis, is a useful tool to investigate the antithrombotic action in mammals and may offer an alternative for future development of a new therapeutic agent.

Introduction: Endovascular therapy has been shown to be an effective and safe treatment for tandem occlusion. The endovascular therapeutic strategies for tandem occlusions strokes have not been adequately evaluated and the best approach is still controversial. The TITAN (Thrombectomy in TANdem occlusions) registry was a result of a collaborative effort to identify the best therapeutic approach for acute ischemic stroke due to tandem lesion. In this review, we aim to summarize the main findings of the TITAN study and discuss the challenges of treatment for tandem occlusion in the era of endovascular thrombectomy. Methods: A review of the data from the multicenter international observational and non-randomized TITAN registry was performed. The TITAN registry included acute ischemic stroke patients with tandem lesions (proximal intracranial occlusion and cervical carotid artery occlusion or stenosis>90%) who were treated with thrombectomy with or without carotid artery stenting. Results: Prior intravenous thrombolysis and emergent cervical carotid stenting were associated with higher reperfusion (mTICI 2b-3 and mTICI 3) rates at the end of the intervention. Poor outcome did not occur more frequently after stenting than after conservative treatment of the cervical carotid lesion. Emergent carotid stenting with antithrombotic agents and intracranial thrombectomy yielded higher reperfusion rate and good outcome (90 day mRS 0-2) compared to other strategies (carotid artery stenting and thrombectomy without antithrombotic, angioplasty and thrombectomy, or thrombectomy alone). Pretreatment intravenous thrombolysis was not associated with increased risk of hemorrhagic complications. Likewise, periprocedural unfractionated heparin did not modify the efficacy and safety results. Etiology of carotid artery lesion (atherosclerosis vs. dissection) did not emerge as predictor of outcome or recanalization. Conclusion: Emergent stenting of the cervical carotid lesion with antithrombotic agents in conjunction to thrombectomy appears to be the best treatment strategy for acute ischemic strokes with tandem lesions. These findings will be further investigated in the ongoing randomized controlled TITAN trial.

BACKGROUND

Deep venous thrombosis with subsequent pulmonary embolism or post-thrombotic syndrome is a feared complication in the intensive care unit. Therefore, routine prophylactic anticoagulation is widely recommended. Aside from unfractionated heparin, low molecular weight heparins, such as certoparin, have become increasingly used for prophylactic anticoagulation in critically ill patients. In this prospective study, we evaluated the potency of 3,000 IU certoparin administered once daily to reach antithrombotic antifactor Xa (aFXa) levels of 0.1 to 0.3 IU/ml in 62 critically ill patients.

METHODS

AFXa levels were determined 4, 12 and 24 h after injection of certoparin. Prothrombin time, activated partial thromboplastin time, antithrombin, fibrinogen, hemoglobin, platelet count, serum urea and creatinine concentrations were documented before and 12 and 24 h after injection of certoparin.

RESULTS

Four hours after certoparin injection (n = 32), 28% of patients were within the antithrombotic aFXa range. After 12 and 24 h, 6% achieved antithrombotic aFXa levels. Because of a severe pulmonary embolism in one study patient, an interim analysis was performed, and the dosage of certoparin was increased to 3,000 IU twice daily. This regime attained recommended antithrombotic aFXa levels in 47%, 27%, 40% and 30% of patients at 4, 12, 16 and 24 h, respectively, after twice daily certoparin injection (n = 30). Antithrombin and fibrinogen concentrations slightly increased during the observation period. Low antithrombin concentrations before certoparin were independently correlated with underdosing of certoparin. Patients with aFXa levels <0.1 IU/ml 4 h after certoparin injection required vasopressors more often and had lower serum concentrations of creatinine and urea than patients with antithrombotic aFXa levels.

CONCLUSIONS

Standard dosages of certoparin of 3,000 IU given once or twice daily are ineffective for attaining the recommended aFXa levels of 0.1 to 0.3 IU/ml in critically ill patients. Low antithrombin levels before certoparin administration were independently associated with low aFXa levels. Renal function and vasopressor therapy may further influence the effectiveness of certoparin in ensuring adequate antithrombotic prophylaxis.

BACKGROUND

Unfractionated heparin is a strongly anionic anticoagulant used extensively in medicine to prevent blood clotting. In the case of an emergency bleeding in response to heparin, the protamine sulfate is administered. Despite its extensive clinical use, protamine may produce life-threatening side effects such as systemic hypotension, catastrophic pulmonary vasoconstriction or allergic reactions. Recent studies have demonstrated new organ-specific complications of the heparin reversal with protamine.

METHODS

Past and present knowledge of the mechanisms responsible for the toxicity of protamine and the most promising potential replacements of protamine in the different phases of development.

CONCLUSIONS

Despite of the low therapeutic index, protamine is the only registered antidote of heparins. The toxicology of protamine depends on a complex interaction of the high molecular weight, a cationic peptide with the surfaces of the vasculature and blood cells. The mechanisms involve membrane receptors and ion channels targeted by different vasoactive compounds, such as nitric oxide, bradykinin or histamine. Unacceptable side effects of protamine have led to a search for new alternatives: UHRA, LMWP, and Dex40-GTMAC3 are in the preclinical stage; the two other agents (andexanet alfa and PER977) are already in the advanced clinical phases.

UNASSIGNED

To review maternal and foetal outcomes in women with mechanical heart valves (MHVs) treated with vitamin-K antagonists (VKAs), first-trimester heparin followed by VKAs (sequential treatment), low molecular weight heparin (LMWH) and unfractionated heparin (UFH) during pregnancy, in order to inform practice.

UNASSIGNED

Medline, Embase and Central were searched from inception until February 2016. Two reviewers independently screened 1786 titles, reviewed 110 full-texts and extracted data and assessed risk-of-bias from 46 articles. Pooled incidence (95% confidence intervals) was calculated for maternal and foetal outcomes. Included studies had a moderate or high risk-of-bias. With VKAs, sequential treatment and LMWH, maternal mortality occurred in 0.9% (0.4-1.4), 2.0% (0.8-3.1) and 2.9% (0.2-5.7), thromboembolic complications in 2.7% (1.4-4.0), 5.8% (3.8-7.7) and 8.7% (3.9-13.4), livebirths in 64.5% (48.8-80.2), 79.9% (74.3-85.6) and 92.0% (86.1-98.0) and anticoagulant-related foetal/neonatal adverse events (embryopathy or foetopathy) in 2.0% (0.3-3.7), 1.4% (0.3-2.5) and 0%, respectively. When UFH is used throughout pregnancy, 11.2% (2.8-19.6) suffered thromboembolic complications. Foetal loss and adverse events occurred with first-trimester warfarin doses ≤ 5 mg/day, although there were more livebirths [83.6% (75.8-91.4) vs. 43.9% (32.8-55.0)] and fewer foetal anomalies [2.3% (0.7-4.0) vs. 12.4% (3.3-21.6)] with lower doses than with warfarin>> 5 mg/day.

UNASSIGNED

VKAs are associated with fewest maternal complications but also with fewest livebirths. Sequential treatment does not eliminate anticoagulant-related foetal/neonatal adverse events. LMWH is associated with the highest number of livebirths. The safety of UFH throughout pregnancy and first-trimester warfarin ≤ 5 mg/day remains unconfirmed.