The polyphenolic-polysaccharide preparation from Erigeron canadensis L. was isolated by multi-step process, characterized by chromatographic and spectroscopic methods, and was subjected to anion-exchange chromatography. The whole preparation demonstrated in vivo anticoagulant activity, and the effect was neutralized by protamine sulfate. It had also anti-platelet activity, limited to the cyclooxygenase pathway, induced by arachidonic acid. The plant preparation was fractionated to receive the fraction of the highest anticoagulant activity - 7-9IU/mg of heparin standard, expressed in aPTT. The influences of the plant preparation as well as its the most active fraction on thrombin and factor Xa inactivation by antithrombin, and on thrombin inhibition by heparin cofactor II, were compared. The both tested plant preparations inhibited thrombin as well as factor Xa amidolytic activities in the presence of antithrombin, but much higher concentrations were required to obtain the same effects like for unfractionated heparin. The mechanisms of anticoagulant activity in the case of the plant preparation are based on interactions with heparin cofactor II, to inactivate thrombin. Chromatographic and spectroscopic methods revealed its macromolecular polyanionic non-sulfated polyphenolic-polysaccharide conjugate, with carboxylic groups. The polysaccharide part constituted 32% of the total mass and was homogenous, with molecular mass 38kDa, containing mainly hexuronic acids, and much smaller amounts of glucose, arabinose, galactose, as well as some traces of mannose, xylose and rhamnose. Polyphenolic part, with molecular mass >12.5kDa, was rich in hydroxylic rests as well as in carboxylic groups, free and esterified. The polyphenolic-polysaccharide preparation from E. canadensis may become a new source of anticoagulant compound potentially useful in anticoagulant and anti-platelet therapy.

The anticoagulant effect of unfractionated heparin (UFH) is monitored using the activated partial thromboplastin time (APTT). An APTT of 1.5-2.5 times the control is usually taken as the therapeutic range and assumed to reflect an anti-activated factor X (anti-Xa) level of 0.35-0.7 u/ml. However, in some cases, despite administration of sufficient heparin to achieve a therapeutic anti-Xa assay level, the APTT remains sub-therapeutic. This 'apparent heparin resistance' is commonly due to high levels of factor VIII (FVIII). In these situations, the anti-Xa is usually preferred for monitoring in order to avoid, what might be, dangerously high levels of heparin. We hypothesized that at high FVIII levels, the heparin resistance encountered may be genuine rather than apparent and that higher doses of heparin may indeed be needed for an equivalent anticoagulant effect. The relationship between heparin level, APTT and anticoagulant effect at different FVIII concentrations was determined using thrombelastography and the thrombin generation assay. Thromboelastographic and thrombin generation parameters concurred with APTT, demonstrating a genuine heparin resistance in the presence of high FVIII levels. This suggests that APTT may be a more accurate measure of anticoagulant effect in vivo than anti-Xa.

BACKGROUND

Clinical trials have shown low-molecular weight heparin (LMWH) to be at least as safe and efficacious as unfractionated heparin (UFH) for preventing venous thromboembolism (VTE) in acutely-ill medical inpatients.

OBJECTIVE

To compare clinical and economic outcomes among acutely-ill medical inpatients receiving the LMWH enoxaparin versus UFH prophylaxis in clinical practice.

METHODS

Using a large, multi-hospital, US database, we identified persons aged>> or =40 years hospitalized for>> or =6 days for an acute medical condition (including circulatory disorders, respiratory disorders, infectious diseases, or neoplasms) from Q4 1999 to Q1 2002. From these patients, those who received thromboprophylaxis with either enoxaparin or UFH were identified. Surgical patients and those requiring or ineligible for anticoagulation were excluded. We compared the incidence of deep-vein thrombosis (DVT), pulmonary embolism (PE), and all VTE (i.e., DVT and/or PE). Secondary outcomes were occurrence of side-effects, length of hospital stay and total costs.

RESULTS

479 patients received enoxaparin prophylaxis and 2,837 received UFH. The incidence of VTE was 1.7% with enoxaparin prophylaxis versus 6.3% with UFH (RR = 0.26; p < 0.001). Occurrence of side effects, length of stay (10.00 days with enoxaparin vs. 10.26 days with UFH; p = 0.348) and total costs ($18,777 vs. $17,602; p = 0.463) were similar in the 2 groups.

CONCLUSIONS

We observed a 74% lower risk of VTE among patients receiving enoxaparin prophylaxis versus UFH prophylaxis. There was no significant difference in side effects or economic outcomes. These results provide evidence that the LMWH enoxaparin is more effective than UFH in reducing the risk of VTE in current clinical practice.

Unfractionated heparin (UFH) is largely used as anti-thrombotic drug. While UFH has been shown to suppress lipopolysaccharide (LPS)-induced nuclear factor-κB (NF-κB) activation, intracellular upstream events that cause NF-κB down-regulation in response to UFH remain unclear. Thus, we investigated the involvement of phosphoinositide-3-OH kinase (PI3K)/Akt in the inhibition of LPS-activated NF-κB pathway by UFH in human pulmonary microvascular endothelial cells (HPMECs). Pretreatment with UFH (0.1-1U/ml) significantly inhibited LPS (10μg/ml)-stimulated interleukin (IL)-6 and IL-8 production in HPMECs. LPS activated Akt and NF-κB, whereas UFH suppresses LPS-induced Akt phosphorylation and NF-κB nuclear translocation, which were required for IL-6 and IL-8 gene transcription. Inhibition studies by using wortmannin abrogated NF-κB-mediated IL-6 and IL-8 expression, suggesting the requirement of PI3K/Akt pathway. Our data provided the first evidence that UFH might repress LPS-activated PI3K/Akt pathway, leading to inhibitory effect of NF-κB activation with diminished IL-6 and IL-8 expression in HPMECs.

BACKGROUND

We investigated the coagulation system in patients during extracorporeal membrane oxygenation (ECMO) initiated for respiratory failure and the influence of the ECMO circuit on coagulation tests; we compared different coagulation tests for monitoring unfractionated heparin (UH) therapy; we investigated whether or not coagulation parameters were predictive of bleeding during ECMO.

METHODS

Pilot study on twelve consecutive adult patients admitted at our general ICU for acute respiratory failure and placed on ECMO from November 2011 to October 2012. Coagulation tests were performed before ECMO start and daily, including day of circuit change and day of circuit removal. UH was monitored with activated partial thromboplastin time (APTT) ratio, at a therapeutic range of 1.5-2.0.

RESULTS

We observed no effect of ECMO circuit on coagulation parameters measured pre- and postlung, but platelet count decreased significantly over time (-82x10(3)/mmc, 95%CI 40-123). APTT showed a correlation with antifactor Xa activity, whereas other global coagulation tests such as activated clotting time, thromboelastography and endogenous thrombin potential did not. Major bleeding occurred in three patients but no difference in any coagulation parameter was observed between them and those who did not bleed.

CONCLUSIONS

This pilot study shows that ECMO initiated for respiratory support in adults does not change coagulation parameters. Over time a statistically significant reduction of platelet count was observed, possibly due to consumption within the circuit, consumption microangiopathy or the underlying patients' diseases. Although APTT was appropriate to monitor UH, major bleedings occurred and a lower therapeutic range may be advisable.

BACKGROUND

Cerebral venous sinus thrombosis (CVST) in children is associated with a high incidence of serious morbidity and mortality. The presenting features are variable. It can be diagnostically challenging and the optimal treatment is uncertain.

OBJECTIVE

To describe the features of a series of children with CVST treated in a single paediatric neurology centre and to discuss the role of local thrombolysis.

METHODS

Electronic databases were searched using diagnostic labels and International Classification of Diseases (ICD) codes to identify children aged 1 month to under 17 years with CVST. Their records were reviewed.

RESULTS

21 children were identified over a period of 8.25 years with a median age of 7.1 years. The presenting symptoms included headache (15 children), vomiting (14 children) and visual disturbance (eight children). Signs found included papilloedema (16 children), fever (six children) and sixth nerve palsy (six children). The most common underlying condition was middle ear infection (13 children). All cases received unfractionated heparin and four severe cases received local pharmacological thrombolysis. 48% of cases had an adverse outcome (death, chronic intracranial hypertension, residual hemiparesis or sixth nerve palsy).

CONCLUSIONS

CVST has non-specific presenting features and a high risk of significant morbidity. CVST is typically found in association with a predisposing condition. Although heparin is the mainstay of treatment, thrombolysis may reverse deterioration as seen in three cases in this series. However, there is insufficient evidence to recommend the routine use of thrombolysis at present.

Venous thromboembolic disease is a significant source of morbidity and mortality in hospitalized trauma patients. Multiple drugs and dosing regimens have been suggested for pharmacoprophylaxis. In this study, we compared efficacy, complications, and cost of unfractionated heparin administered subcutaneously three times a day with standard-dosed enoxaparin for prophylaxis of deep venous thrombosis (DVT) in adult trauma patients over 1 year. Patients admitted for greater than 72 hours who received pharmacoprophylaxis as part of a comprehensive DVT protocol were included. A change was made in the protocol from enoxaparin (30 mg twice a day or 40 mg per day) to heparin (5000 U three times a day) at midyear. Surveillance lower extremity venous ultrasound was performed according to established institutional guidelines. Data, including demographics, associated injuries, complications, and cost, were collected and analyzed. Four hundred seventy-six patients met inclusion criteria. Two hundred thirty-seven (49.8%) patients received enoxaparin and 239 (50.2%) received heparin. Proximal lower extremity DVTs were detected in 16 (6.75%) patients in the enoxaparin group and 17 (7.11%) in the heparin group (P = 0.999). Risk factors for DVT in these patients included spinal cord injury (P = 0.001) and closed head injury (P = 0.031). There was no difference between the incidence of pulmonary emboli and bleeding. There was an estimated yearly pharmacy cost savings of $135,606. In trauma patients, subcutaneous heparin dosed three times a day may be as effective as standard-dosed enoxaparin for prophylaxis of venous thromboembolism without increased complications. Heparin three times a day for venous thromboembolism prophylaxis was associated with significant pharmaceutical cost savings.

BACKGROUND

Complications following laparoscopic cholecystectomy are encountered infrequently due to increasing proficiency in laparoscopic surgery. The occurrence of portal venous thrombosis following laparoscopic cholecystectomy has not been previously described and forms the basis of this report.

METHODS

A healthy, 32-year-old, female on oral contraceptives underwent an uneventful laparoscopic cholecystectomy for symptomatic gallbladder disease. Sequential compression devices and mini-dose unfractionated heparin were used before the procedure. The patient was discharged home on the first postoperative day without complaints. She returned 1 week later with nausea, bloating, and diffuse abdominal pain.

RESULTS

Ultrasonography of the abdomen revealed thrombosis of the portal vein not seen in the preoperative ultrasound and the superior mesenteric vein. Computer tomography of the abdomen and pelvis on the same day confirmed this finding and showed a wedge-shaped infarction of the right lobe of the liver. The patient was anticoagulated with intravenous heparin. An extensive coagulation workup revealed elevation of the Immunoglobulin G anticardiolipin antibody. A percutaneous transhepatic portal vein thrombectomy was performed. A postprocedure duplex ultrasound of the abdomen demonstrated recannalization of the portal venous system with no flow voids. Anticoagulation therapy was continued, and the patient was discharged home with resolution of her ileus. She was maintained on a therapeutic dose of warfarin.

CONCLUSIONS

This case demonstrates an unusual complication of laparoscopic cholecystectomy. It may have resulted from the use of oral contraceptives, elevation of the Immunoglobulin G anticardiolipin antibody, unrecognized trauma, and was accentuated by the pneumoperitoneum generated for the performance of the laparoscopic cholecystectomy. Our case report provides insight and poses questions regarding necessary perioperative measures for thromboprophylaxis in young females on oral contraceptives undergoing elective laparoscopic abdominal surgery.

Enoxaparin, a low-molecular-weight heparin (LMWH), is widely used for the treatment and prophylaxis of thromboembolic disorders, such as deep vein thrombosis. Low-molecular-weight heparin products have smaller and more uniform molecular weights than unfractionated heparin, allowing them to exhibit a much greater affinity for factor Xa than factor IIa. Compared with traditional unfractionated heparin, LMWHs have proved to be equally efficacious and may be safer. The distinctive characteristics of LMWHs have resulted in decreased rates of bleeding and equivalent rates of thrombocytopenia compared with unfractionated heparin. This favorable safety profile has been identified in several studies and may have led clinicians to believe that LMWHs have lower frequencies of all common side effects. A 66-year-old woman developed increased hepatic transaminases during treatment with enoxaparin for a deep vein thrombosis; they returned to normal after enoxaparin discontinuation. A causal relationship between unfractionated heparin and asymptomatic, transient increases in hepatic transaminase levels has been documented; these increased levels also appear to be an underrecognized, adverse effect of LMWH therapy.

BACKGROUND

To estimate the three-month cumulative incidence of thromboembolism and bleeding among mechanical heart valve (MHV) patients receiving peri-procedural anticoagulation management, consecutive MHV patients referred to the Mayo Clinic Thrombophilia Center for peri-procedural anticoagulation management over the seven-year period, 1997-2003, were followed for three months for thromboembolism, bleeding and vital status.

METHODS

Warfarin was stopped 4-5 days prior to the procedure, and re-started after the procedure as soon as hemostasis was assured. The decision to provide bridging therapy with low molecular weight (LMWH) or unfractionated (UFH) heparin was individualized and based on the estimated risks of TE and bleeding.

RESULTS

556 MHV patients (372 aortic only, 136 mitral only, 48 with multiple valves) underwent 580 procedures. The three-month cumulative incidence of thromboembolism was 0.9% which included: cerebral ischemia (n=3), unstable angina (n=1), acute myocardial infarction (n=1). None were fatal. The cumulative incidence of major bleeding was 3.6% and fatal in 0.2%. The incidence of major bleeding events did not differ by postoperative anticoagulant strategy whether LMWH (3.7%), UFH (6.1%), or no heparin (2.4%) was used (p=0.26).

CONCLUSIONS

The three-month cumulative incidence of thromboembolism among MHV patients in whom anticoagulation is temporarily interrupted for an invasive procedure is low. Whereas bleeding exceeds thromboembolic complications, our current practice is to restart warfarin as soon as possible post-procedure. Post-procedural heparin use is reserved for patients with the highest thromboembolic risk (mitral MHV, multiple MHVs, MHV with prior stroke or atrial fibrillation) waiting at least 48 hours before initiating.

OBJECTIVE

To examine whether dalteparin, a low molecular weight heparin, prevents hepatic damage by inhibiting leukocyte activation, we analyzed its effect on ischemia/reperfusion (I/R) injury of rat liver in which activated leukocytes play a critical role.

METHODS

Prospective, randomized, controlled study.

METHODS

Research laboratory at a university medical center.

METHODS

Male Wistar rats weighing 220-280 g.

METHODS

Hepatic damage was evaluated by changes in serum transaminase concentrations after I/R. Coagulation abnormalities were evaluated by changes in serum concentrations of fragment E of fibrin and fibrinogen degradation products after I/R. Hepatic tissue blood flow was measured by laser-Doppler flow meter. Hepatic edema was evaluated by determination of the change in the wet/dry tissue weight ratio. Rats were intravenously injected with dalteparin or unfractionated heparin (300 units/kg) and subcutaneously injected with DX9056a, a selective inhibitor of activated factor X (3 mg/kg). To determine whether dalteparin inhibits leukocyte activation, we examined the effect of dalteparin on hepatic concentrations of interleukin-12, tumor necrosis factor-alpha, and hepatic myeloperoxidase activity after I/R in vivo. In addition, we examined increases in tumor necrosis factor-alpha production in rat monocytes and in intracellular calcium concentrations in neutrophils in vitro. We also examined the effect of dalteparin on endothelial production of prostacyclin using isolated rat hepatic sinusoidal cells in vitro.

RESULTS

Intravenous administration of dalteparin inhibited increases in serum levels of both transaminases and serum concentrations of fragment E of fibrin and fibrinogen degradation products in animals subjected to hepatic I/R. Hepatic tissue blood flow after reperfusion was increased by dalteparin. Dalteparin inhibited hepatic edema, increases in hepatic tissue levels of interleukin-12 and tumor necrosis factor-alpha, and accumulation of neutrophils in animals subjected to hepatic I/R. Neither DX9065a nor unfractionated heparin showed any therapeutic effects, despite potent inhibition of increases in serum levels of fragment E of fibrin and fibrinogen degradation products. Neither monocytic tumor necrosis factor-alpha production nor neutrophil activation was inhibited by dalteparin in vitro. Dalteparin enhanced the hepatic I/R-induced increases in hepatic tissue levels of 6-keto-prostaglandin (PG) F1alpha, a stable metabolite of prostacyclin, which is capable of inhibiting monocytic tumor necrosis factor-alpha production. Pretreatment with indomethacin completely reversed both of the therapeutic effects of dalteparin, whereas pretreatment with NS-398, a selective inhibitor of cyclooxygenase-2, did not. Dalteparin did not directly increase the endothelial production of prostacyclin in vitro.

CONCLUSIONS

Dalteparin might reduce I/R-induced liver injury in rats by attenuating inflammatory responses. These therapeutic effects might be independent of its anticoagulant activity but dependent on its capacity to enhance endothelial production of prostacyclin via cyclooxygenase-1 activation. Furthermore, the mechanism or mechanisms by which dalteparin promotes the endothelial production of prostacyclin in vivo might involve unknown factors other than endothelial cells.

Heparin-induced thrombocytopenia (HIT) occurs in 1% to 5% of patients treated with unfractionated high-molecular weight heparin and often results in limb- and/or life-threatening thrombotic complications. This disorder involves the formation of antibodies to a complex of Platelet Factor 4 (PF4) with the heparin. We believe that the pathogenesis of this disease begins with having an excess of platelet PF4 release. The freed PF4 is bound to platelet and other vascular membrane surfaces and has three critical roles in the initiation of HIT. (1) Infused heparin neutralizes a portion of excess surface PF4, directly enhancing local thrombosis. (2) The excess PF4 is mobilized into PF4/heparin complexes that stimulates HIT antibody production. (3) The remaining PF4 complexed to heparanoids and heparin on the vascular surfaces now bind to these HIT antibodies and through surface Fc gammaRII receptors leads to more platelet activation and removal, thrombus formation, and inflammation. These events, in turn, further stimulate PF4 release, perpetuating repetitive cycle that results in the clinical manifestations of this disorder.

OBJECTIVE

Unfractionated and low-molecular-weight heparin and low-dose aspirin are used for the prevention of pregnancy loss in pregnant women with thrombophilia. We investigated the effect of these drugs on in vitro models of human extravillous trophoblast motility and differentiation.

METHODS

Chorion from term placentas was digested and extravillous trophoblast isolated. Extravillous trophoblast formed giant multinuclear cells that were counted after 24, 36, and 48 hours of culture. This model was then used to investigate the effect of unfractionated, low-molecular-weight heparin and aspirin on in vitro extravillous trophoblast differentiation at both therapeutic and supratherapeutic doses. In addition, the effect of unfractionated and low-molecular-weight heparin on hepatocyte growth factor-stimulated SGHPL-4 cell (extravillous trophoblast cell line) motility was determined by time-lapse microscopy.

RESULTS

At therapeutic doses unfractionated heparin promoted extravillous trophoblast differentiation. However, low-molecular-weight heparin inhibited giant multinuclear cells formation. At supratherapeutic doses, both low-molecular-weight and unfractionated heparin promoted extravillous trophoblast differentiation. Low-dose aspirin had minimal effects on the extravillous trophoblast differentiation. Both unfractionated and low-molecular-weight heparin inhibited hepatocyte growth factor-stimulated extravillous trophoblast motility at supratherapeutic doses. At a therapeutic dose of 0.25 IU/mL, only unfractionated heparin inhibited hepatocyte growth factor-stimulated motility, whereas low-molecular-weight heparin had no effect.

CONCLUSIONS

Our data suggest that unfractionated and low-molecular-weight heparin have differing effects on trophoblast differentiation and motility at therapeutic doses. This finding may be one of many factors that contribute to the clinical scenario.

Thromboembolism, including both venous and arterial events, occurs commonly amongst patients with cancer. The occurrence of thromboembolism has significant consequences for cancer patients, including direct and indirect associations with mortality, morbidity, requirement for long-term anticoagulant therapy and consumption of healthcare resources. Recent studies have resulted in a better understanding of clinical risk factors and biomarkers of cancer-associated thrombosis, and a risk assessment model incorporating both has now been validated in multiple settings. Thromboprophylaxis with either unfractionated heparin or low-molecular-weight heparins (LMWHs) has been shown to be safe and effective in high-risk settings such as hospitalization for medical illness and the postsurgical period. Emerging new data from randomized studies have focused on outpatient prophylaxis, suggesting potential benefits in this setting as well. Treatment of cancer-associated thrombosis requires long-term anticoagulation with LMWH. Results from ongoing and planned trials of novel anticoagulants in the cancer setting are awaited.

The endothelial protein C receptor (EPCR) facilitates protein C activation and plays a protective role in the response to Escherichia coli-mediated sepsis in primates. Previously, a soluble form of EPCR (sEPCR) in human plasma was characterized, and several studies indicated that generation of sEPCR is regulated by inflammatory mediators, including thrombin-mediated up-regulation of surface metalloproteolytic activity in vitro. This study addressed the question of whether plasma sEPCR levels reflect changes in thrombin generation in patients undergoing anticoagulant treatment. The sEPCR levels in patients treated with coumarin-type oral anticoagulants were significantly lower than those in healthy asymptomatic adult volunteers (105.3 +/- 70.8 ng/mL [n = 55] versus 165.8 +/- 115.8 ng/mL [n = 200]; P <.0001). A similar decline in plasma sEPCR levels was found in patients treated with unfractionated heparin. In healthy volunteers, sEPCR levels declined to about 100 ng/mL within 3 days after initiation of an 8-day period of warfarin administration and increased within 2 days after its cessation. Plasma sEPCR levels returned to pretreatment values within 1 week, and the changes in plasma sEPCR levels mirrored changes in values for international normalized ratios. A similar decline in sEPCR levels with time was observed in 7 patients beginning treatment with warfarin for a thrombotic disorder. Prothrombin fragment 1 + 2 levels also decreased in volunteers and patients given warfarin. These results show that plasma sEPCR levels decline in response to treatment with anticoagulants whose mechanism of action is known to decrease in vivo thrombin production.

Venous thromboembolic disease, including deep venous thrombosis (DVT) and pulmonary embolism (PE), is an under-diagnosed and under-appreciated medical problem that results in significant patient morbidity and mortality. Inadequate venous thromboprophylaxis in surgical as well as medically ill patients results in DVT and PE that negatively impact patient outcomes and increase health-care costs. A high index of clinical suspicion combined with an evidence-based use of diagnostic tests helps identify patients with acute thrombosis. Failure to accurately and promptly diagnose and treat DVT and PE can result in excess morbidity and mortality due to postthrombotic syndrome, pulmonary hypertension, and recurrent thrombosis. Conversely, unnecessary anticoagulation provides risk in the absence of any tangible benefit. The immediate commencement of parenteral anticoagulant therapy with intravenous unfractionated heparin or a subcutaneous low molecular weight heparin (LMWH) upon presentation with DVT or PE (often even before objective diagnosis confirmation) is necessary to minimize propagation, embolization, and recurrence rates. We favor weight-based LMWH therapy in most of our patients with DVT because of the ability to treat exclusively or primarily in the outpatient setting. We still admit patients with PE for a minimum duration of 2 days for close observation. Subsequent conversion to oral anticoagulation with warfarin (target INR of 2.0 to 3.0 in most patients) should include an overlap with parenteral therapy of at least 4 to 5 days and until a stable target INR has been achieved. A minimum of 3 to 6 months of anticoagulation is recommended following a first episode of idiopathic DVT and any PE. A shorter course of therapy may be sufficient following a situational (eg, after surgery and postpartum) or calf DVT. Long-term, and at times lifelong, therapy should be considered in patients with thrombosis in the setting of a persistent acquired or inherited hypercoagulable state. Thrombolytic therapy probably should be reserved for young patients with iliofemoral DVT, any patient with a threatened limb due to impending venous limb gangrene, and those with PE who have objective evidence of cardiopulmonary compromise. Unfavorable risk-to-benefit and cost-to-benefit ratios make more extensive use of thrombolytics undesirable. The prevention of the postthrombotic syndrome with fitted, graduated compression garments and age- and gender-appropriate cancer screening are indicated in all patients with DVT in an attempt to minimize morbidity and mortality. Hypercoagulable state testing is indicated when the results of individual tests will significantly impact the choice of anticoagulant, intensity of therapy, therapeutic monitoring, family screening, family planning, prognosis determination, and most of all, duration of therapy.

BACKGROUND

The management of patients presenting to hospital emergency departments with suspected deep vein thrombosis (DVT) is problematic because urgent diagnostic imaging capability is sometimes unavailable. Experienced physicians using clinical skills alone can classify patients with suspected DVT into low-, moderate-, and high-probability categories.

OBJECTIVE

To determine the accuracy of an explicit clinical model for the diagnosis of DVT when applied by emergency department physicians and to assess the safety and feasibility of a management strategy based on the clinical pretest probability for patients presenting to the emergency department with suspected DVT outside of regular hospital staff work hours.

METHODS

A prospective cohort study was performed in the emergency departments of 2 tertiary care institutions involving 344 patients with suspected DVT. Patient conditions were evaluated by an emergency department physician who determined the pretest probability for DVT to be low, moderate, or high using an explicit clinical model. Patients for whom DVT was considered a low pretest probability were discharged from the emergency department and returned the following day for venous compression ultrasound imaging of the affected leg. Patients for whom DVT was considered a moderate pre-test probability received a single, weight-adjusted dose of subcutaneous unfractionated heparin sodium (between 12 500 and 20 000 U), were discharged from the emergency department, and returned the next morning to undergo ultrasonography. Patients for whom DVT was considered a high pretest probability were admitted to the hospital, administered intravenous unfractionated heparin, and ultrasonography was arranged within 24 hours. Patients with positive ultrasonographic findings were diagnosed with DVT, except for those with low pretest probability for whom confirmatory venography was performed. Patients with DVT excluded in the initial evaluation period did not receive anticoagulant therapy. All patients were followed up for 90 days to monitor development of thromboembolic or bleeding complications.

RESULTS

Twenty-four (49.0% [95% confidence interval (CI), 34.5%-63.6%]) of 49 patients in the high-probability category, 15 (14.3% [95% CI, 8.3%-22.4%]) of 105 in the moderate-, and 6 (3.2% [95% CI, 1.2%-6.7%]) of 190 in the low-probability category were confirmed to have DVT. Overall, 45 (13.1%) of 344 patients were confirmed to have DVT. No patient developed pulmonary embolism or major bleeding complications within 48 hours of initial evaluation in the emergency department. Of the 301 patients who had DVT excluded during the initial evaluation period, only 2 (0.7% [95% CI, 0.1%-2.3%]) developed venous thromboembolic complications (calf vein thromboses in both) in the 3-month follow-up period.

CONCLUSIONS

Using an explicit clinical model, emergency department physicians can accurately classify patients with suspected DVT into high-, moderate-, and low-probability groups. A management plan based on probability for DVT that avoids the need for urgent diagnostic imaging is safe and feasible in the emergency department setting.

OBJECTIVE

To survey physicians' anticoagulation preferences in patients with chronic atrial fibrillation who are undergoing elective surgery.

METHODS

A survey was performed that asked physicians to provide pre- and postoperative anticoagulation preferences for two clinical scenarios of patients with chronic atrial fibrillation (high stroke risk, low stroke risk) undergoing elective surgery. In addition to the interruption of warfarin therapy, perioperative anticoagulation options were as follows: a) in-hospital full dose intravenous heparin; b) outpatient full dose subcutaneous unfractionated heparin or low molecular weight heparin (LMWH); c) low dose unfractionated heparin or LMWH (postoperative only); d) nothing other than stopping warfarin preoperatively and restarting it postoperatively; or e) another anticoagulant strategy.

RESULTS

In the high stroke risk scenario, the proportions of respondents preferring anticoagulation options a, b, d and e in the preoperative period were 24%, 20%, 54% and 2%, respectively; the proportions preferring options a, b, c, d and e in the postoperative period were 35%, 13%, 15%, 35% and 1%, respectively. In the low stroke risk scenario, the proportions of respondents preferring options a, b, d and e in the preoperative period were 7%, 10%, 80% and 3%, respectively; the proportions preferring options a, b, c, d and e in the postoperative period were 11%, 9%, 10%, 68% and 2%, respectively.

CONCLUSIONS

In patients with chronic atrial fibrillation who underwent elective surgery, perioperative anticoagulant management preferences varied widely in patients at high risk for stroke, but were more uniform and less aggressive in patients at low risk for stroke.

Anticoagulation in hospitalized patients is frequently associated with medication errors. To determine the extent and severity of this problem, we reviewed consecutively reported, anticoagulation-related medication errors over a 3-year period. We identified 130 medication errors. There were 1.67 medication errors for every 1,000 patients treated with anticoagulants. These were most often associated with unfractionated heparin (66.2%), followed by warfarin (21.5%), low-molecular-weight heparin (9.2%), argatroban (1.5%), and lepirudin (1.5%). There were no deaths attributed to any anticoagulant medication errors, but 6.2% of patients required medical intervention and 1.5% needed prolonged hospitalization. Medication errors frequently occur with anticoagulant therapy in hospitalized patients.

BACKGROUND

Cancer patients undergoing major abdominal or pelvic surgery are at considerable risk of venous thromboembolism (VTE). The genesis of thromboses in malignancy is complicated, and reflects the interaction and derangement of multiple molecular pathways. Furthermore, the nature and location of the cancer, as well as the type surgery involved, are thought to affect the level of VTE risk. These considerations may therefore affect treatment decisions.

METHODS

We performed multiple Medline searches with terms including but not limited to VTE, cancer, surgery, abdominal, colorectal, unfractionated heparin (UFH), and low-molecular-weight heparin (LMWH) to identify reviews, meta-analyses, nonrandomized and randomized controlled trials, and clinical guidelines relating to management of VTE in patients with abdominal cancer.

RESULTS

VTE incidence in patients with malignancy varied according to cancer type, location, stage of progression, and the use of catheters and/or chemotherapy. Thromboprophylaxis with UFH or LMWH reduces the risk of developing VTE in these patients. However, LMWHs have a favorable risk-benefit profile over UFH and extending the duration prophylaxis may improve outcomes.

CONCLUSIONS

A number of recommendations can be made for the prevention of VTE in patients undergoing abdominal or pelvic surgery for cancer: (1) risk-stratify all patients according to defined evidence-based guidelines; (2) for most abdominal surgical oncology patients at risk, use of both an anticoagulant and mechanical means are indicated and beneficial; and (3) consider extended-duration prophylaxis (up to 28 days) in those patients with major abdominal/pelvic operations and impaired mobility, preferably with LMWH.

OBJECTIVE

We sought to evaluate the safety and efficacy of recombinant nematode anticoagulant protein c2 (rNAPc2) in patients with non-ST-segment elevation acute coronary syndrome (nSTE-ACS).

BACKGROUND

Recombinant NAPc2 is a potent inhibitor of the tissue factor/factor VIIa complex that has the potential to reduce ischemic complications mediated by thrombin generation.

METHODS

A total of 203 patients were randomized 4:1 to double-blinded intravenous rNAPc2 or placebo every 48 h for a total of 1 to 3 doses in 8 ascending panels (1.5 to 10 microg/kg). All patients received aspirin, unfractionated heparin (UFH), or enoxaparin and early catheterization; clopidogrel and glycoprotein IIb/IIIa blockers were encouraged. Two subsequent open-label panels evaluated 10 mug/kg rNAPc2 with half-dose UFH (n = 26) and no UFH (n = 26). The primary end point was the rate of major plus minor bleeding. Pharmacokinetics, pharmacodynamics, continuous electrocardiography, and clinical events were assessed.

RESULTS

Recombinant NAPc2 did not significantly increase major plus minor bleeding (3.7% vs. 2.5%; p = NS) despite increasing the international normalized ratio in a dose-related fashion (trend p < or = 0.0001). Higher-dose rNAPc2 >> or =7.5 microg/kg) suppressed prothrombin fragment F1.2 generation compared with placebo and reduced ischemia by >50% compared to placebo and lower-dose rNAPc2. Thrombotic bailout requiring open-label anticoagulant occurred in 5 of 26 patients treated without UFH, but none in the half-dose UFH group (19% vs. 0%; p = 0.051).

CONCLUSIONS

In patients with nSTE-ACS managed with standard antithrombotics and an early invasive approach, additional proximal inhibition of the coagulation cascade with rNAPc2 was well tolerated. rNAPc2 doses>> or =7.5 microg/kg suppressed F1.2 and reduced ischemia, though some heparin may be necessary to avoid procedure-related thrombus formation. (Anticoagulation With rNAPc2 to Eliminate MACE/TIMI 32; http://www.clinicaltrial.gov/ct/show/NCT00116012?order=1; NCT00116012).

Patients treated with a vitamin K antagonist may require interruption of their anticoagulation prior to an invasive procedure or surgery, and as a result, may be placed at a higher risk for thromboembolic events during this time. Either low-molecular-weight heparin (LMWH) or unfractionated heparin is frequently used to bridge the gap in anticoagulation treatment because of their relatively rapid onset and offset of action compared to warfarin. Despite the lack of randomized trials supporting the efficacy of this bridging therapy, guidelines have been developed to assist providers with this common clinical challenge. Key issues in bridging therapy include identifying patients who can safely undergo an invasive procedure while continuing their vitamin K antagonist, identifying those who will likely gain the most benefit from bridging anticoagulation, and determining the optimal dose and timing of parenteral anticoagulants in the perioperative period.

The purpose of the present communication is to evaluate the importance of blood flow and surface reactivity for measurement of antithrombotic drug activity or efficacy in selected model systems of thrombus formation. Such information is essential for proper evaluation of antithrombotic drug profiles. The continuous development of flow-dependent thrombosis models for in vitro (anticoagulated blood) and ex vivo (native blood) studies and their application in in vivo animal models from the early 1970s and onwards are briefly considered. Central to this process was the development of various types of perfusion chambers in which a thrombogenic surface is exposed to flowing blood. Such perfusion chambers have been inserted into arteriovenous (AV) shunts in baboon, pig, dog, and rabbit. These approaches have allowed reproducible testing of traditional and novel experimental antithrombotic drugs, and studies on novel drug strategies under well-defined shear conditions and surface reactivity. Shear-dependent antithrombotic efficacy in these models is observed with anticoagulants such as unfractionated heparin, low-molecular weight heparins, or selective inhibitors of thrombin, Factor Xa, or Factor VIIa. However, the degree of shear dependency depends on the nature of the thrombogenic surface, e.g., the inhibition is more pronounced on a tissue factor (TF)-rich surface than on a collagen-rich surface, particularly at venous or low arterial shear. Platelet antagonists such as the COX-1 inhibitor aspirin, inhibitors of thromboxane A2 (TxA2) synthetase, the TxA2 platelet receptor, and of von Willebrand factor (vWf) are shear dependent also, being more efficient at high arterial shear. In contrast, the platelet ADP antagonist clopidogrel, or antagonists to the active platelet membrane glycoprotein IIb-IIIa complex (GPIIb-IIIa) are shear independent. At extremely high arterial shear, which activates platelets and elicit aggregates of circulating platelets, aspirin looses its antithrombotic effect, whereas ADP and GPIIb-IIIa antagonists still interrupt thrombus formation. In general, results obtained with these models mimic and predict antithrombotic efficacy in man when comparison is possible. Information on antithrombotic efficacy in flow devices with various thrombogenic surfaces is now sufficiently available to suggest recommendations for experimental conditions, particularly with regard to blood flow and reactive surfaces.

Recent studies suggest that anticoagulant drugs and cimetidine therapy in malignancy may improve cancer survival and inhibit the metastatic process. In this study we investigated and compared the effects of anticoagulant drugs (unfractionated heparin, warfarin, acetylsalicylic acid, low-molecular-weight heparins--nandroparinum, enoxaparinum, dalteparinum and reviparinum), cimetidine and combination of cimetidine with anticoagulants on adhesion of highly invasive breast cancer cells lines - BT 549 and MDA-MB-231 (MDA 231)--in vitro. High antiadhesion effect was observed with cimetidine, warfarin and acetylsalicylic acid. Low-molecular-weight heparins had a small antiadhesion effect in independent use. In combination with cimetidine, a potential effect of cimetidine on the antiadhesion was observed. The antiadhesion effect was dependent on the type of the cancer cell line. Different effects between cell lines BT 549 and MDA 231 were observed. The strongest antiadhesion effect was obtained using the combination of cimetidine with acetylsalicylic acid. In the majority of applications of the drugs and their combinations, a proportional antiadhesion effect was dependent on the concentration and time. We suppose that anticoagulant drugs might have higher antimetastatic effect in combination with cimetidine. The choice of anticoagulants can decrease the adhesion, decrease tumor angiogenesis and cause the shortening of blood clotting time. Cimetidine can decrease the adhesion of cancer cells and increase the activity of NK cells. Indeed, according to our results, application of cimetidine and anticoagulant drugs intensifies the antiadhesion effect together with other antimetastatic effects.