BACKGROUND

We compared the efficacy and safety of different dosages of a low-molecular-weight heparin, CY 216 D (Fraxiparine), in the treatment of submassive pulmonary embolism with unfractionated heparin in a prospective, randomized, dose-finding study.

RESULTS

The primary outcome was the evolution of pulmonary vascular obstruction. We enrolled 101 patients. Four patient groups were formed: standard heparin by continuous intravenous infusion (group 1) and Fraxiparine subcutaneously 400, 600, and 900 anti-Xa Institute Choay units/kg, respectively (groups 2, 3, and 4). Inclusions were stopped prematurely in groups 3 and 4 because of the incidence of major bleedings. At day 8, the improvement of the pulmonary vascular obstruction and the major bleedings were similar in groups 1 and 2.

CONCLUSIONS

The Fraxiparine dosage of 400 anti-Xa Institute Choay units/kg is as effective and safe as unfractionated heparin in the treatment of submassive pulmonary embolism.

Compared to other tRNAs all known histidine tRNAs have the unique feature of possessing an additional nucleotide at their 5' end. It is usually a guanosine residue but not in bacteriophage T5 tRNA which carries an additional uridine. The additional nucleotide is not encoded in eukaryotic histidine tRNA genes but is added in a post-transcriptional modification reaction (Cooley, L., Appel, B., and Söll, D. (1982) Proc. Natl. Acad. Sci. U. S. A. 79, 6475-6479) by histidine tRNA guanylyltransferase (tRNAHis guanylyltransferase). Here we report the purification of this enzyme from Saccharomyces cerevisiae and the determination of some of its physical properties. Six different steps including Polymin P precipitation, chromatography on DEAE-cellulose, phosphocellulose, heparin-agarose, ATP-agarose, and gel filtration on Superose 12 were employed for the purification of the guanylyltransferase from an S-100 extract. A Stokes radius of 46.5 +/- 0.5 A and a sedimentation coefficient (S20,w) of 7.8 +/- 0.2 were determined by gel filtration and rate zonal sedimentation, respectively. A relative molecular weight (Mr) of approximately 120,000 was calculated for the purified native enzyme. The Mr of the denatured protein is approximately 58,000 as demonstrated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. These results indicate a homodimeric (alpha 2) structure for the enzyme. Among all acceptor RNAs in unfractionated tRNA only tRNAHis is a substrate for the purified guanylyltransferase. The reaction requires ATP, a guanosine substrate, and a divalent metal ion. Treatment of guanylyltransferase with 5,5'-dithiobis(2-nitrobenzoic)-acid abolishes activity; this suggests the importance of sulfhydryl groups for enzymatic activity. The enzyme shows discrimination among different histidine tRNA species; tRNA from plant and prokaryotes are better substrates than mammalian and insect tRNAs.

BACKGROUND

Pregnancy increases the risk of mechanical heart valve (MHV) thrombosis. Warfarin is protective, but implies risks to the fetus. Unfractionated heparin (UFH) is less effective but does not harm the fetus. In general, anticoagulation is more stable and predictable with low molecular weight heparin (LMWH) than with UFH.

METHODS

Retrospective study of 12 pregnancies with MHV; 6 in aortic, 4 in mitral, and 2 in both positions, treated with therapeutic doses of subcutaneous LMWH twice daily throughout pregnancy. Doses were adjusted using anti-Xa monitoring. The frequency of thrombo-embolism with various anticoagulation regimes was calculated based on a literature review.

RESULTS

Median LMWH dose was 15500 IU/24 h, range 10000-20000 IU/24 h; median dose 257 IU/kg/24 h. Median peak LMWH in blood plasma ranged 0.54-0.92 anti-Xa U/mL. Thromboembolism developed in two women with aortic MHV despite LMWH levels in target range. One had systemic embolic episodes; in the other woman valve thrombosis was successfully thrombolysed. Both had initially received subtherapeutic doses. Thrombo-embolism was not observed in ten pregnancies treated as recommended. The pregnancies resulted in thirteen healthy babies; eight delivered by Cesarean section. Bleeding occurred in two women after Cesarean section due to preeclampsia.

CONCLUSIONS

Treatment with adjusted therapeutic doses of LMWH was successful in 10 of 12 pregnancies, and was not associated with fetal complications. Thromboembolism occurred in two pregnancies, possibly attributed to subtherapeutic doses of LMWH during the initial 3 weeks. Compared to UFH prophylaxis, therapeutic doses of LMWH appears to be more efficacious.

OBJECTIVE

We investigated the outcomes of switching to bivalirudin after initial administration of heparin in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention.

BACKGROUND

Unfractionated heparin (UFH) is frequently administered early in ST-segment elevation myocardial infarction. Whether the benefits of bivalirudin documented in the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial persist in patients previously administered UFH is unknown.

METHODS

We analyzed the outcomes of the 2,357 patients from HORIZONS-AMI treated with UFH before enrollment according to their subsequent randomization to bivalirudin (switch group, n = 1,178) or UFH plus a glycoprotein IIb/IIIa inhibitor (control group, n = 1,179).

RESULTS

At 30 days, major bleeding occurred in 7.6% of the switch group versus 12.3% of the control group (p = 0.0001). Switch patients had lower 30-day rates of cardiac mortality (1.6% vs. 2.9%, p = 0.04). At 2-year follow-up, switch patients experienced lower rates of major bleeding (8.4% vs. 13.0%, p = 0.0003), cardiac mortality (2.3% vs. 3.8%, p = 0.04), and reinfarction (4.0% vs. 7.1%, p = 0.0002). Two-year rates of definite/probable stent thrombosis were similar in switch and control patients (3.1% vs. 4.3%, p = 0.17).

CONCLUSIONS

In ST-segment elevation myocardial infarction patients who receive early treatment with UFH, switching to bivalirudin before primary percutaneous coronary intervention results in reduced rates of major bleeding and improved early and late cardiac survival.

BACKGROUND

Enoxaparin reduces ischemic events more effectively than unfractionated heparin (UFH) in patients treated conservatively for non-ST-segment elevation acute coronary syndrome. The SYNERGY trial compared these agents in high-risk patients undergoing early invasive treatment. Enoxaparin was noninferior to UFH for the 30-day primary end point of death/myocardial infarction (MI), but modestly increased bleeding.

RESULTS

This article compares the outcomes of the 4687 SYNERGY patients (47%) undergoing percutaneous coronary intervention, who were randomized to receive enoxaparin or UFH. Antithrombotic therapy was administered prerandomization in 78%. Crossover (usually in the catheterization laboratory) to the alternative antithrombotic occurred in 14.6% of enoxaparin patients and 2.9% of UFH-treated patients (P < .0001). Stenting was performed in 86.3%. Abrupt vessel closure occurred in 1.3% of enoxaparin patients and 1.7% of UFH-treated patients (P = .318). The rates of death/MI were similar at 30 days (13.1% with enoxaparin vs 14.2% with UFH, P = .289). GUSTO severe bleeding occurred with similar frequency in both groups (1.5% vs 1.6%, P = .688). TIMI major bleeding was more common with enoxaparin (3.7% vs 2.5% with UFH, P = .028). Transfusions were more frequent with enoxaparin than with UFH (6.8% vs 5.4%, P = .047). TIMI major bleeding increased with crossover from enoxaparin to UFH (from 3.7% to 7.8%) and from UFH to enoxaparin (from 2.5% to 8.6%). Statistical adjustment to model reasons for crossover did not affect the overall safety and efficacy outcomes.

CONCLUSIONS

In high-risk patients undergoing early percutaneous coronary intervention for acute coronary syndrome, enoxaparin avoids the need for monitoring and achieves similar effectiveness to UFH but is associated with more bleeding.

The most accepted therapy for DVT consists of anticoagulation with unfractionated heparin or low molecular weight heparin, followed by variable duration oral anticoagulation but thrombolytic therapy has been proposed in addition to standard anticoagulation. This paper reviews the literature on post thrombotic syndrome, the natural history of vein patency after therapy, and we perform a systematic review, using accepted standards for meta-analysis, to determine the outcomes when thrombolytic therapy is used to treat DVT. We demonstrate that thrombolytic therapy for DVT results in a significant increase in the risk of major hemorrhage and a significant increase in the rate of vein patency. However, although thrombolytic therapy is advantageous over anticoagulation as measured by early vein patency, a benefit in terms of a reduction in PTS risk, is unproven. Our review also shows that there is no evidence that there is a difference in efficacy between thrombolytic agents or that local therapy differs from systemic therapy. Finally, the potential role of catheter directed therapy is unknown since appropriate trials have not been performed but it is reasonable to use catheter directed therapy in patients with phlegmasia cerulea dolens. We conclude that more work is needed to define the role of thrombolytic therapy but it is too early to abandon this therapeutic modality.

BACKGROUND

Unfractionated heparin and the low molecular weight heparin, dalteparin, are used for prophylaxis against venous thromboembolism in patients undergoing craniotomy. These drugs were compared in a randomized, prospective pilot study comparing intermittent pneumatic compression devices plus dalteparin to intermittent pneumatic compression devices plus heparin.

METHODS

One hundred patients undergoing craniotomy were randomly allocated to receive perioperative prophylaxis with subcutaneous (SC heparin, 5000 units every 12 hours, or dalteparin, 2,500 units once a day, begun at induction of anesthesia and continued for 7 days or until the patient was ambulating. Entry criteria were age over 18 years, no deep vein thrombosis (DVT) preoperatively as judged by lower limb duplex ultrasound and no clinical evidence of pulmonary embolism preoperatively. Patients with hypersensitivity to heparin, penetrating head injury or who refused informed consent were excluded. Patients underwent a duplex study 1 week after surgery and 1 month clinical follow-up. All patients were treated with lower limb intermittent pneumatic compression devices.

RESULTS

There were no differences between groups in age, gender, and risk factors for venous thromboembolism. There were no differences between groups in intraoperative blood loss, transfusion requirements or postoperative platelet counts. Two patients receiving dalteparin developed DVT (one symptomatic and one asymptomatic). No patient treated with heparin developed DVT and no patient in either group developed pulmonary embolism. There were two hemorrhages that did not require repeat craniotomy in patients receiving dalteparin and one that did require surgical evacuation in a patient treated with heparin. Drug was stopped in two patients treated with dalteparin because of thrombocytopenia. None of these differences were statistically significant.

CONCLUSIONS

There was no significant difference in postoperative hemorrhage, venous thromboembolism or thrombocytopenia between heparin and dalteparin. The results suggest that, given the small sample size of this trial, both drugs appear to be safe and the incidence of venous thromboembolism by postoperative screening duplex ultrasound appears to be low when these agents are used in combination with intermittent pneumatic compression devices.

We recently designed a group of novel exosite-2-directed sulfated, small, allosteric inhibitors of thrombin. To develop more potent inhibitors, monosulfated benzofuran tri- and tetrameric homologues of the parent designed dimers were synthesized in seven to eight steps and found to exhibit a wide range of potencies. Among these, trimer 9a was found to be nearly 10-fold more potent than the first generation molecules. Michaelis-Menten studies indicated an allosteric mechanism of inhibition. Competitive studies using a hirudin peptide (exosite 1 ligand) and unfractionated heparin, heparin octasaccharide, and γ'-fibrinogen peptide (exosite 2 ligands) demonstrated exosite 2 recognition in a manner different from that of the parent dimers. Alanine scanning mutagenesis of 12 Arg/Lys residues of exosite 2 revealed a defect in 9a potency for Arg233Ala thrombin only confirming the major difference in site of recognition between the two structurally related sulfated benzofurans. The results suggest that multiple avenues are available within exosite 2 for inducing thrombin inhibition.

Venous thromboembolism (VTE) in pregnancy and the postpartum is an important cause of maternal morbidity and mortality; yet, there are few robust data from clinical trials to inform an approach to diagnosis and management. Failure to investigate symptoms suggestive of pulmonary embolism (PE) is a consistent finding in maternal death enquiries, and clinical symptoms should not be relied on to exclude or diagnose VTE. In this consensus statement, we present our recommendations for the diagnosis and management of acute deep venous thrombosis (DVT) and PE. All women with suspected DVT in pregnancy should be investigated with whole leg compression ultrasonography. If the scan is negative and significant clinical suspicion remains, then further imaging for iliofemoral DVT maybe required. Imaging should be undertaken in all women with suspected PE, as the fetal radiation exposure with both ventilation/perfusion scans and CT pulmonary angiography is within safe limits. Low-molecular-weight heparin (LMWH) is the preferred therapy for acute VTE that occur during pregnancy. In observational cohort studies, using once-daily regimens appears adequate, in particular with the LMWH tinzaparin; however, pharmacokinetic data support twice-daily therapy with other LMWH and is recommended, at least initially, for PE or iliofemoral DVT in pregnancy. Treatment should continue for a minimum duration of six months, and until at least six weeks postpartum. Induction of labour or planned caesarean section maybe required to allow an appropriate transition to unfractionated heparin to avoid delivery in women in therapeutic doses of anticoagulation.

Unfractionated heparin has historically been used as the anticoagulant of choice in the management of a number of thrombotic diseases. Recognition of the limitations of heparin has led to the development of a newer class of anticoagulants, the direct thrombin inhibitors. Argatroban is a synthetic small molecule that selectively inhibits thrombin at its active site. In preclinical studies, argatroban has been shown to be more effective than heparin in preventing arterial thrombosis and in promoting vessel patency in conjunction with thrombolysis in a number of animal models. In clinical trials, argatroban has been shown to be as effective as heparin in the management of ST-segment elevation myocardial infarction in conjunction with thrombolysis. It has been shown to be an effective anticoagulant in patients undergoing percutaneous coronary interventions. In patients with heparin-induced thrombocytopenia and heparin-induced thrombocytopenia complicated by thrombosis, argatroban significantly decreases the risk of thrombotic events. Small studies have demonstrated a potential role for its use in ischemic stroke and hemodialysis. Additional studies are warranted to confirm argatroban's efficacy in a wide variety of clinical settings.

BACKGROUND

Anticoagulation may improve survival in patients with cancer through an antitumor effect in addition to the perceived antithrombotic effect.

OBJECTIVE

To evaluate the efficacy and safety of parenteral anticoagulants in patients with cancer with no therapeutic or prophylactic indication for anticoagulation.

METHODS

A comprehensive search included (1) an electronic search (February 2010) of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL) Issue 1, 2010, MEDLINE, EMBASE and ISI the Web of Science; (2) handsearch of conference proceedings; (3) checking of references of included studies; and (4) use of the 'related citation' feature in PubMed.

METHODS

Randomized controlled trials (RCTs) assessing the benefits and harms of parenteral anticoagulation in patients with cancer but no therapeutic or prophylactic indication for anticoagulation.

METHODS

Using a standardized form we extracted in duplicate data on methodological quality, participants, interventions and outcomes of interest including all-cause mortality, symptomatic thromboembolism, major bleeding, minor bleeding and quality of life (QoL).

RESULTS

Of 8187 identified citations, nine RCTs enrolling 2857 patients fulfilled the inclusion criteria. In all included RCTs the intervention consisted of heparin (either unfractionated heparin or low molecular weight heparin). Overall, the effect of heparin therapy on mortality was not statistically significant at 12 months (risk ratio (RR) 0.93; 95% CI 0.85 to 1.02) but it was statistically significant at 24 months (RR 0.92; 95% CI 0.88 to 0.97). Heparin therapy was associated with a statistically and clinically important reduction in venous thromboembolism (RR 0.55; 95% CI 0.37 to 0.82). There were no statistically significant effects on major bleeding (RR 1.30; 95% CI 0.59 to 2.88), minor bleeding (RR 1.05; 95% 0.75 to 1.46) or QoL. The quality of evidence was high for symptomatic venous thromboembolism, moderate for mortality, major bleeding and minor bleeding, and low for QoL.

CONCLUSIONS

Heparin was associated with a significant reduction of death at 24 months but not 12 months. It was also associated with a reduction in venous thromboembolism but based on the RCTs in this review it had no significant effect on major bleeding, minor bleeding or QoL. Future research should further investigate the survival benefit of different types of anticoagulants in patients with different types and stages of cancer. The decision for a patient with cancer to start heparin therapy for survival benefit should balance the benefits and downsides and integrate the patient's values and preferences.

BACKGROUND

Selecting initial anticoagulant dose by patient weight for acute pulmonary embolism and deep vein thrombosis has clinical credibility; however, uncertainty remains regarding how to dose obese patients with newer anticoagulants because outcome data are sparse.

OBJECTIVE

To use the Matisse trials' comparison of sc fondaparinux once daily with control heparin therapies (intravenous unfractionated heparin for pulmonary embolism, sc enoxaparin 1 mg/kg b.i.d. for deep vein thrombosis) for initial treatment in order to compare primary outcomes (venous thromboembolism recurrence and major bleeding) in obese patients.

METHODS

Primary outcomes were compared in subsets composed of patients weighing < or = and>> 100 kg and with body mass index (BMI) < 30 and>> or = 30 kg/m(2). Medians and ranges for weight and BMI were compared for patients suffering either recurrence or major bleeding.

RESULTS

Twenty-two thousand and one patients received fondaparinux and 2217 received enoxaparin or unfractionated heparin. Four hundred and ninety-six patients (11%) weighed>> 100 kg and 1216 (28%) had a BMI>> or = 30. Treatment groups had similar characteristics. The upper limit in subject weight for recurrence was 166 kg (BMI 58), and for major bleeding 120 kg (BMI 39). The incidences of recurrence and major bleeding were similar for each patient subset of weight and BMI for both fondaparinux and heparin treatment groups. Among patients with a primary outcome, median weights and BMIs were also similar.

CONCLUSIONS

The current recommended doses of fondaparinux and heparins for the treatment of venous thromboembolism appear to provide similar protection against recurrence and major bleeding to one another and to obese and non-obese patients.

Immune-mediated heparin-induced thrombocytopenia (HIT) is a rare but severe adverse effect of heparin therapy. Only few data are available on clinical presentation, diagnosis and management of HIT in children. Records of all patients sent to our laboratory between 1995 and November 2003 were reviewed. To identify literature reports a Medline search was performed, the reference lists of those publications were screened and the abstracts of meetings on thrombosis and hemostasis between 2000 and 2003 were assessed. We identified 12 new HIT patients between 13 months and 18 years of age from our laboratory and 71 reports on HIT in children in the literature. For the assessment of frequency of HIT all studies enrolling>> 100 patients were analyzed. HIT is rare in children. In pediatric patients, there seem to be two risk groups: newborns and infants under 4 years of age undergoing cardiac surgery (incidence approximately 1-2%), and teenagers treated with heparin for thrombosis. For confirmation of HIT in children, antigen assays are most important. There are conflicting data on the optimal cut-off, with one randomized, double-blind trial indicating that the cut-off established in adults is appropriate. There are no systematic studies on alternative anticoagulants in children affected by HIT. Most data are available for lepirudin and danaparoid. Substitution of unfractionated heparin by low-molecular-weight heparins for regular anticoagulation may reduce the incidence of HIT.

BACKGROUND

Heparin administration is usually limited to intravenous or subcutaneous injection. Oral delivery of heparin is an alternative to this and has been in great demand for treating patients who are at a high risk of deep vein thrombosis or pulmonary embolism. In this study, new heparin derivatives were synthesized to enhance the oral absorption of heparin in the gastrointestinal tract. Methods and Results- By using heparin of 3000 Da [LMWH(3 kDa)], heparin of 6000 Da [LMWH(6 kDa)], and unfractionated heparin (UFH), we synthesized 3 kinds of conjugates of heparin and deoxycholic acid (DOCA): LMWH(3 kDa)-DOCA, LMWH(6 kDa)-DOCA, and UFH-DOCA. After oral administration of 100 mg/kg of heparin-DOCA, the maximum activated partial thromboplastin times of the LMWH(3 kDa)-DOCA, LMWH(6 kDa)-DOCA, and UFH-DOCA were 31.0+/-6.0, 87.8+/-11.1, and 51.0+/-8.7 seconds, respectively. The peak plasma concentrations of LMWH(3 kDa)-DOCA, LMWH(6 kDa)-DOCA, and UFH-DOCA were 0.06+/-0.02, 0.76+/-0.15, and 0.41+/-0.13 IU/mL, respectively. The bioavailability of LMWH(6 kDa)-DOCA at the 20-mg/kg dosage was calculated to be 7.8%.

CONCLUSIONS

LMWH(6 kDa)-DOCA was found to have a high anticoagulant effect when administered orally and could be used as a new oral anticoagulant agent. Furthermore, the present work proposed a new method for oral delivery of macromolecules and polysaccharide drugs.

The objective of the this study was to examine the effects of fondaparinux, a synthetic anticoagulant substance similar to heparin, on osteoblasts compared with previously used heparins. Its effects have been shown in clinical trials to be highly effective in thromboembolism prophylaxis. Unfractionated heparin (UFH), dalteparin, enoxaparin and fondaparinux were added to osteoblast cultures in the therapeutic range and two decimal powers above and below it in each case. The results showed that the mitochondrial activity and protein synthesis of osteoblasts treated with fondaparinux were significantly higher than in the other groups. Similar effects could be demonstrated for the matrix collagen type II content and calcification. In contrast enoxaparin, dalteparin and UFH lead to a significant decrease of matrix collagen type II content and calcification in concentrations equal or higher than the therapeutic one. No inhibitory in-vitro effects of fondaparinux on human osteoblasts could be demonstrated within the concentration range investigated (0.01-100 microg/ml). We conclude that fondaparinux can be used to avoid the heparin-related negative influence on osteoblast-dependent fracture healing and endoprosthetic implant integration.

The therapeutic armamentarium of parenteral anticoagulants available to clinicians is mainly composed by unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), fondaparinux, recombinant hirudins (i.e. bivalirudin, desirudin, lepirudin) and argatroban. These drugs are effective and safe for prevention and/or treatment of thromboembolic diseases but they have some drawbacks. Among other inconveniences, UFH requires regular anticoagulant monitoring as a result of variability in the anticoagulant response and there is a risk of serious heparin-induced thrombocytopaenia (HIT). LMWH, fondaparinux and recombinant hirudins are mainly cleared through the kidneys and their use in patients with severe renal insufficiency may be problematic. LMWH is only partially neutralized by protamine while fondaparinux and recombinant hirudins have no specific antidote. Novel anticoagulants in development for parenteral administration include new indirect activated factor Xa (FXa) inhibitors (idrabiotaparinux, ultra-low-molecular-weight heparins [semuloparin, RO-14], new LMWH [M118]), direct FXa inhibitors (otamixaban), direct FIIa inhibitors (flovagatran sodium, pegmusirudin, NU172, HD1-22), direct FXIa inhibitors (BMS-262084, antisense oligonucleotides targeting FXIa, clavatadine), direct FIXa inhibitors (RB-006), FVIIIa inhibitors (TB-402), FVIIa/tissue factor inhibitors (tifacogin, NAPc2, PCI-27483, BMS-593214), FVa inhibitors (drotrecogin alpha activated, ART-123) and dual thrombin/FXa inhibitors (EP217609, tanogitran). These new compounds have the potential to complement established parenteral anticoagulants. In the present review, we discuss the pharmacology of new parenteral anticoagulants, the results of clinical studies, the newly planned or ongoing clinical trials with these compounds, and their potential advantages and drawbacks over existing therapies.

BACKGROUND

Thromboelastography/metry (TEG®; Haemoscope, Niles, IL/ROTEM®; Tem International GmbH, Munich, Germany) is increasingly used to guide transfusion therapy. This study investigated the diagnostic performance and therapeutic consequence of using kaolin-activated whole blood compared with a panel of specific TEM®-reagents to distinguish: dilutional coagulopathy, thrombocytopenia, hyperfibrinolysis, and heparinization.

METHODS

Blood was drawn from 11 healthy volunteers. Dilutional coagulopathy was generated by 50% dilution with hydroxyethyl starch 130/0.4 whereas thrombocytopenia (mean platelet count 20 ×10⁹/l) was induced using a validated model. Hyperfibrinolysis and heparin contamination were generated by tissue plasminogen activator 2 nM and unfractionated heparin 0.1U/ml, respectively. Coagulation tests were run on ROTEM® delta.

RESULTS

Kaolin-activated whole blood showed no differences between dilutional coagulopathy and thrombocytopenia (mean clotting time 450 s vs. 516 s, α-angle 47.1° vs. 41.5°, maximum clot firmness 35.0 mm vs. 34.2 mm, all P values ≥0.14). Hyperfibrinolysis specifically disclosed an increased maximum lysis (median: 100%, all P values less than 0.001), and heparin induced a distinctly prolonged clotting time (2283 s, all P values less than 0.02). The coagulopathies were readily distinguishable using a panel of TEM-reagents. In particular, dilutional coagulopathy was separated from thrombocytopenia using FIBTEM (maximum clot firmness 1.9 mm vs. 11.2 mm, P < 0.001). The run time of analysis to achieve diagnostic data was shorter applying a panel of TEM-reagents. A transfusion algorithm based on kaolin suggested platelets in case of dilutional coagulopathy, whereas an algorithm applying TEM-reagents suggested fibrinogen.

CONCLUSIONS

Monoanalysis with kaolin was unable to distinguish coagulopathies caused by dilution from that of thrombocytopenia. Algorithms based on the use of kaolin may lead to unnecessary transfusion with platelets, whereas the application of TEM-reagents may result in goal-directed fibrinogen substitution.

BACKGROUND

The aim of the current study was to perform two separate meta-analyses of available studies comparing low-molecular-weight heparins (LMWHs) vs. unfractionated heparin (UFH) in ST-elevation myocardial infarction (STEMI) patients treated (i) with primary percutaneous coronary intervention (pPCI) or (ii) with PCI after thrombolysis.

METHODS

All-cause mortality was the pre-specified primary endpoint and major bleeding complications were recorded as the secondary endpoints. Relative risk (RR) with a 95% confidence interval (CI) and absolute risk reduction (ARR) were chosen as the effect measure.

RESULTS

Ten studies comprising 16,286 patients were included. The median follow-up was 2 months for the primary endpoint. Among LMWHs, enoxaparin was the compound most frequently used. In the pPCI group, LMWHs were associated with a reduction in mortality [RR (95% CI) = 0.51 (0.41-0.64), P < 0.001, ARR = 3%] and major bleeding [RR (95% CI) = 0.68 (0.49-0.94), P = 0.02, ARR = 2.0%] as compared with UFH. Conversely, no clear evidence of benefits with LWMHs was observed in the PCI group after thrombolysis. Meta-regression showed that patients with a higher baseline risk had greater benefits from LMWHs (r = 0.72, P = 0.02).

CONCLUSIONS

LMWHs were associated with greater efficacy and safety than UFH in STEMI patients treated with pPCI, with a significant relationship between risk profile and clinical benefits. Based on this meta-analysis, LMWHs may be considered as a preferred anticoagulant among STEMI patients undergoing pPCI.

BACKGROUND

Deep venous thrombosis (DVT) is much less common in the upper than in the lower extremity. Furthermore, there is limited information on risk factors for and the prognosis of upper extremity (UE)DVT in the general population.

OBJECTIVE

To estimate incidence, risk factors, and prognosis in UEDVT.

METHODS

Among a total of 1203 patients with venous thromboembolism (VTE) diagnosed during 1998-2006 in the prospective population-based Malmö thrombophilia study, 63 (5%, 33 men [52%, age 54+/-17years], and 30 women [48%, age 55+/-22years]) had UEDVT and were evaluated concerning risk factors, treatment, recurrent VTE, and mortality.

RESULTS

At diagnosis, 19(30%) patients had known malignancy and 6(10%) had VTE heredity. Among female UEDVT patients 4(13%) used hormone therapy, 1(3%) was pregnant, while none was in the postpartum period. Of all 63 UEDVT patients, 12(19%) were heterozygous, and 3(5%) homozygous for the Factor V Leiden (FVL)-mutation. Two (3%) patients were heterozygous for the prothrombin mutation, and 1 patient (1.6%) showed both heterozygous FVL-mutation and lupus anticoagulant antibodies. Phlebography had been used for diagnosis in 48(76%), ultrasonography in 16(25%), and computer tomography (CT) in 9(14%) patients. Twenty-two patients (35%) were treated in hospital, and the remaining 41(65%) as out-patients. Sixty-two (98%) was treated with low molecular weight heparin (LMH), 60(95%) with oral anticoagulants (OAC), 3(5%) with unfractionated heparin, and 3(5%) with thrombolysis. VTE recurrence rate during median 62 (range 31-117) month of follow-up was 8/63(13%). Fifteen (24%) UEDVT patients died during follow-up; 9(47%) of the 19 patients with known malignancy at diagnosis and 6(14%) of the other patients. Yearly incidence of UEDVT was 3.6/100.000 (95% confidence interval [CI], 3.3 - 4.03).

CONCLUSIONS

Malignancies and the FVL mutation were common among patients with UEDVT. Mortality during follow-up vas high.

BACKGROUND

Most ischaemic strokes are caused by a blood clot blocking an artery in the brain. Clot prevention with anticoagulants might improve outcomes if bleeding risks are low. This is an update of a Cochrane review first published in 1995, with recent updates in 2004 and 2008.

OBJECTIVE

To assess the effectiveness and safety of early anticoagulation (within the first 14 days of onset) in people with acute presumed or confirmed ischaemic stroke.

METHODS

We searched the Cochrane Stroke Group Trials Register (June 2014), the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Database of Systematic Reviews (CDSR), the Database of Reviews of Effects (DARE) and the Health Technology Assessment Database (HTA) (The Cochrane Library 2014 Issue 6), MEDLINE (2008 to June 2014) and EMBASE (2008 to June 2014). In addition, we searched ongoing trials registries and reference lists of relevant papers. For previous versions of this review, we searched the register of the Antithrombotic Trialists' (ATT) Collaboration, consulted MedStrategy (1995), and contacted relevant drug companies.

METHODS

Randomised trials comparing early anticoagulant therapy (started within two weeks of stroke onset) with control in people with acute presumed or confirmed ischaemic stroke.

METHODS

Two review authors independently selected trials for inclusion, assessed trial quality, and extracted the data.

RESULTS

We included 24 trials involving 23,748 participants. The quality of the trials varied considerably. The anticoagulants tested were standard unfractionated heparin, low-molecular-weight heparins, heparinoids, oral anticoagulants, and thrombin inhibitors. Over 90% of the evidence relates to the effects of anticoagulant therapy initiated within the first 48 hours of onset. Based on 11 trials (22,776 participants) there was no evidence that anticoagulant therapy started within the first 14 days of stroke onset reduced the odds of death from all causes (odds ratio (OR) 1.05; 95% confidence interval (CI) 0.98 to 1.12) at the end of follow-up. Similarly, based on eight trials (22,125 participants), there was no evidence that early anticoagulation reduced the odds of being dead or dependent at the end of follow-up (OR 0.99; 95% CI 0.93 to 1.04). Although early anticoagulant therapy was associated with fewer recurrent ischaemic strokes (OR 0.76; 95% CI 0.65 to 0.88), it was also associated with an increase in symptomatic intracranial haemorrhages (OR 2.55; 95% CI 1.95 to 3.33). Similarly, early anticoagulation reduced the frequency of symptomatic pulmonary emboli (OR 0.60; 95% CI 0.44 to 0.81), but this benefit was offset by an increase in extracranial haemorrhages (OR 2.99; 95% CI 2.24 to 3.99).

CONCLUSIONS

Since the last version of the review, no new relevant studies have been published and so there is no additional information to change the conclusions. Early anticoagulant therapy is not associated with net short- or long-term benefit in people with acute ischaemic stroke. Treatment with anticoagulants reduced recurrent stroke, deep vein thrombosis and pulmonary embolism, but increased bleeding risk. The data do not support the routine use of any of the currently available anticoagulants in acute ischaemic stroke.

BACKGROUND

Pharmacologic thromboprophylaxis reduces the risk for venous thromboembolism after total hip replacement (THR) or total knee replacement (TKR). New oral anticoagulants (NOACs), including direct thrombin inhibitors and factor Xa inhibitors, are emerging options for thromboprophylaxis after these procedures.

OBJECTIVE

To compare the benefits and risks of NOACs versus standard thromboprophylaxis for adults having THR or TKR.

METHODS

MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews from January 2009 through March 2013.

METHODS

English-language systematic reviews.

METHODS

Two independent reviewers abstracted data and rated study quality and strength of evidence.

RESULTS

Six good-quality systematic reviews compared NOACs with low-molecular-weight heparin (LMWH) for thromboprophylaxis after THR or TKR. Risk for symptomatic deep venous thrombosis, but not risk for death or nonfatal pulmonary embolism, was reduced with factor Xa inhibitors compared with LMWH (4 fewer events per 1000 patients). Conversely, the risk for major bleeding increased (2 more events per 1000 patients). Outcomes of dabigatran did not significantly differ from those of LMWH. Indirect evaluation of NOACs by common comparison with LMWH showed nonsignificantly reduced risks for venous thromboembolism with rivaroxaban compared with dabigatran (risk ratio [RR], 0.68 [95% CI, 0.21 to 2.23]) and apixaban (RR, 0.59 [CI, 0.26 to 1.33]) but increased major bleeding. New oral anticoagulants have not been compared with warfarin, aspirin, or unfractionated heparin.

CONCLUSIONS

Head-to-head comparisons among NOACs were not available. Efficacy is uncertain in routine clinical practice.

CONCLUSIONS

New oral anticoagulants are effective for thromboprophylaxis after THR and TKR. Their clinical benefits over LMWH are marginal and offset by increased risk for major bleeding.

BACKGROUND

U.S. Department of Veterans Affairs.

Venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism, is a common and potentially preventable cause of morbidity and mortality. Unfractionated heparin, low-molecular-weight heparin, and warfarin have been the cornerstone of VTE prevention and treatment but are being replaced by recently approved non-vitamin K antagonist oral anticoagulants (NOACs): dabigatran, rivaroxaban, apixaban, and edoxaban. The NOACs are at least as effective and as safe as heparins and warfarin for VTE prevention and treatment and are more convenient because they have a low propensity for food and drug interactions and are given in fixed doses without routine coagulation monitoring. The remaining limitations of currently available NOACs include their dependence on renal and hepatic function for clearance, and the lack of an approved antidote. Betrixaban is a new NOAC with distinct pharmacological characteristics: minimal renal clearance, minimal hepatic metabolism, and long half-life. It has undergone successful Phase II studies in orthopedic thromboprophylaxis, and in stroke prevention in atrial fibrillation. Currently, it is being evaluated in a Phase III trial of extended thromboprophylaxis in medical patients (APEX study). In this article, we describe the development of betrixaban, review its pharmacological profile, discuss the results of clinical trials, and examine its potential for VTE prevention and treatment.

BACKGROUND

The hemostatic system of children changes with age and differs significantly from the hemostatic system of adults. Age-specific reference values are therefore required for most hemostatic variables. Thromboelastography (TEG) is a point-of-care coagulation test that may provide superior evaluation and management of coagulopathies after cardiac surgery, when large-dose unfractionated heparin is administered for cardiopulmonary bypass. In this study, we established reference values for kaolin-activated TEG in healthy children, to facilitate accurate interpretation of pediatric TEG results.

METHODS

Kaolin-activated TEG was performed on 100 healthy children undergoing elective day surgery and 25 healthy adult volunteers. The following TEG variables were recorded: reaction time, coagulation time, alpha angle, maximum amplitude, percentage lysis 30 min after maximum amplitude was reached, and the coagulation index. Differences between age-groups were evaluated using analysis of variance.

RESULTS

Age-specific reference values for kaolin-activated TEG in healthy children between 1 mo and 16 yr of age are presented. No significant differences between children and adults were observed.

CONCLUSIONS

TEG results, from a particular clinical setting, must be compared to age-specific, as well as analyzer- and activator-specific, reference values to allow for correct interpretation of the results. Reference values provided here will be of use in acute clinical situations where a practical monitor of hemostasis is required.