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The aging of the population in developed countries has been associated with a growing burden of degenerative joint disease and hip fracture, and this has contributed to a progressive increase in the utilisation of major hip and knee arthroplasty. In the absence of effective thromboprophylaxis, patients undergoing major orthopaedic surgery are at high risk of deep vein thrombosis, which may in turn lead to life-threatening complications such as pulmonary embolism, as well as long term sequelae including the post-thrombotic syndrome. However, increasing age is also associated with an increased risk of venous thromboembolism, and older orthopaedic patients are, therefore, at particularly high risk. Randomised trials have demonstrated that the risk of venous thromboembolism in these patients, as demonstrated by venography, can be reduced by more than 50% with the use of effective thromboprophylaxis. However, antithrombotic agents such as low molecular weight heparin and warfarin, which are widely used for the prevention of venous thromboembolism, are also associated with an increased risk of bleeding complications, and selection of the most appropriate strategy should, therefore, involve consideration of the potential risks as well as benefits of the currently available interventions.

The presence of an association between early subtherapeutic activated partial thromboplastin times (aPTTs) and recurrent venous thromboembolism (VTE) remains controversial. To determine the relation between early subtherapeutic aPTTs and recurrent VTE in patients who were treated with intravenous (i.v.) unfractionated heparin (UFH). We studied 961 patients with acute VTE who received i.v. UFH in 3 randomized trials that compared the use of i.v. UFH (loading dose: 5000 U i.v.; initial infusion, 1250-1280 U/h) with that of subcutaneous low-molecular-weight heparin. According to aPTT criteria, patients were classified as being in a subtherapeutic or a therapeutic state during the first 24 and 48 hours of treatment. All episodes of possible recurrent VTE were adjudicated by an independent committee that was unaware of the aPTTs. At 24 hours, in 886 patients who were eligible for the analysis, the rate of recurrent VTE in the subtherapeutic group was 6.7% (11/163) compared with 5.3% (38/723) in the therapeutic group. The odds ratio for recurrence in patients in the subtherapeutic vs the therapeutic group at 24 hours was 1.30 (95% confidence interval: 0.64-2.63; P = .46). At 48 hours, in 917 patients who were eligible for the analysis, the rate of recurrent VTE in the subtherapeutic group was 7.8% (5/64) compared with 5.7% (49/853) in the therapeutic group. The odds ratio for recurrence in patients in the subtherapeutic vs the therapeutic group at 48 hours was 1.32 (95% confidence interval: 0.51-3.44; P = .56). In patients with acute VTE who receive an i.v. bolus of 5000 U, followed by a starting dose of at least 1250 U/h of UFH, a subtherapeutic aPTT response during the first 48 hours of treatment is not associated with a large increase in the risk of recurrent VTE

Pulmonary embolism is the leading cause of maternal mortality in developed countries and accounts for 20% of pregnancy related deaths in the United States.1 2 The risk of pulmonary embolism and deep vein thrombosis, collectively known as venous thromboembolism, is increased during pregnancy and is further increased by the presence of inherited or acquired thrombophilias. We summarise the epidemiology and diagnosis of venous thromboembolism in pregnancy and discuss the anticoagulant management of women with inherited thrombophilia who are at risk of, or who develop, venous thromboembolism during pregnancy and the postpartum period. #### Scenario A 30 year old woman, a known heterozygote for the factor V Leiden mutation, presents at eight weeks' gestation in her first pregnancy wondering whether she should receive prophylactic anticoagulation to prevent recurrent venous thrombosis during pregnancy. Several years ago she developed a deep vein thrombosis of the left leg after an ankle fracture and prolonged immobilisation and was found to have the factor V Leiden mutation. The deep vein thrombosis was treated with anticoagulants for three months, and the woman has had no recurrent thromboembolic events since stopping warfarin. Her mother developed a deep vein thrombosis after surgery but did not undergo testing for thrombophilia. #### Methods We searched Medline and the Cochrane database of systematic reviews for studies evaluating the epidemiology, diagnosis, prevention, and treatment of venous thromboembolism during pregnancy and the postpartum period in women with inherited thrombophilia, using the key words “venous thrombosis”, “deep vein thrombosis”, “pulmonary embolism”, “pregnancy (complications)”, “thrombophilia”, and “anticoagulants.” Venous thromboembolism occurs in 10 per 100 000 women of childbearing age and affects 100 per 100 000 pregnancies.3 Inherited thrombophilia is present in 30%-50% of women with pregnancy associated venous thromboembolism,3w1 with factor V Leiden being the most frequently identified inherited thrombophilia in the white population (table 1⇓). #### Non-inherited conditions that increase the risk of venous thromboembolism in pregnancy ##### General conditionsw2

Along with compression ultrasonography of the legs, widely viewed as the preferred test for diagnosing deep venous thrombosis (DVT), D-dimer testing frequently is carried out because it is highly sensitive and a negative result may preclude the need for further testing. The latter test has, however, not been evaluated for diagnosing DVT in pregnancy because of its relatively low specificity. This study sought to determine the utility of the easily performed SimpliRED assay for diagnosing DVT in pregnant women. A prospective cohort study, conducted at university-affiliated Canadian hospitals, enrolled 149 consecutive pregnant women suspected of having DVT. They underwent compression ultrasonography on days 0, 3, and 7, and were followed up clinically after 3 months to determine the presence or absence of DVT. Whole blood samples were obtained at initial presentation for the SimpliRED assay. In this rapid test, blood is mixed with a conjugate of monoclonal antibody to D-dimer linked to a monoclonal antibody that binds to the red cell surface. High levels of D-dimer cause agglutination. DVT was diagnosed in 13 of the 149 participants (8.7%). All cases but one were diagnosed from initial compression ultrasonography. The SimpliRED assay was 100% sensitive and 60% specific, and had a negative predictive value of 100%. When stratifying the results of D-dimer testing by the presence or absence of patient risk factors, women having positive D-dimer test results in the first trimester of pregnancy had a high prevalence of DVT (62.5%) regardless of whether or not risk factors were present. Among pregnant women in whom DVT was not diagnosed, the assay was positive in no women in the first trimester, 24% of second-trimester pregnancies, and 51% of women in the third trimester. These findings indicate that the SimpliRED D-dimer assay is clinically useful in pregnant women suspected of having DVT. A negative result effectively excludes this diagnosis. The test appears to be useful for at least the first 2 trimesters of pregnancy.

The low specificity of ventilation-perfusion lung scanning complicates the management of patients with suspected pulmonary embolism.To determine the safety of a clinical model for patients with suspected pulmonary embolism.Prospective cohort study.Five tertiary care hospitals.1239 inpatients and outpatients with suspected pulmonary embolism.A clinical model categorized pretest probability of pulmonary embolism as low, moderate, or high, and ventilation-perfusion scanning and bilateral deep venous ultrasonography were done. Testing by serial ultrasonography, venography, or angiography depended on pretest probability and lung scans.Patients were considered positive for pulmonary embolism if they had an abnormal pulmonary angiogram, abnormal ultrasonogram or venogram, high-probability ventilation-perfusion scan plus moderate or high pretest probability, or venous thromboembolic event during the 3-month follow-up. All other patients were considered negative for pulmonary embolism. Rates of pulmonary embolism during follow-up in patients who had a normal lung scan and those with a non-high-probability scan and normal serial ultrasonogram were compared.Pretest probability was low in 734 patients (3.4% with pulmonary embolism), moderate in 403 (27.8% with pulmonary embolism), and high in 102 (78.4% with pulmonary embolism). Three of the 665 patients (0.5% [95% CI, 0.1% to 1.3%]) with low or moderate pretest probability and a non-high-probability scan who were considered negative for pulmonary embolism had pulmonary embolism or deep venous thrombosis during 90-day follow-up; this rate did not differ from that in patients with a normal scan (0.6% [CI, 0.1% to 1.8%]; P0.2).Management of patients with suspected pulmonary embolism on the basis of pretest probability and results of ventilation-perfusion scanning is safe.

The objectives of the study were to determine whether the combination of a negative SimpliRED D-dimer assay and a low soluble fibrin result reliably excludes venous thromboembolism, and whether patients with proven venous thromboembolism and a normal SimpliRED D-dimer have evidence of impaired fibrinolysis. The study was a retrospective analysis of a cohort of 262 consecutive patients, 94 patients presenting with suspected deep venous thrombosis and 168 with suspected pulmonary embolism. Fifty-nine patients (22.5%) were classified as venous thromboembolism-positive, 27 with pulmonary embolism, and 32 with deep venous thrombosis. One hundred and fourteen patients (43.5%) had SimpliRED D-dimer and a soluble fibrin result of less than or equal to 2.0 microg/ml; the negative predictive value was 98.2% (95% confidence interval: 93.8-99.8%), and the likelihood ratio was 0.06. Eight patients with proven venous thromboembolism had a negative SimpliRED D-dimer; all had elevated ELISA D-dimer levels and six had elevated soluble fibrin levels. This suggests that patients with venous thromboembolism and a normal SimpliRED result do not have impaired fibrinolysis as a cause of their false-negative result. This study suggests that the combination of SimpliRED and soluble fibrin can be used to exclude venous thromboembolism in over 40% of patients who present with a clinical suspicion of deep venous thrombosis or pulmonary embolism and that the small group of patients with venous thromboembolism and a normal SimpliRED do not have impaired fibrinolysis.

Background Deep vein thrombosis is a common, important complication of major orthopedic surgery, particularly knee arthroplasty. Knee arthroscopy is performed more frequently and in younger patients than knee arthroplasty. However, the true risk of deep vein thrombosis in patients who undergo this procedure is unknown. Objective To determine the incidence of deep vein thrombosis after knee arthroscopy in a large cohort of patients. Methods Consecutive patients scheduled for knee arthroscopy were eligible for the study. Enrolled study patients received no thromboprophylaxis. They were discharged home the day of surgery and underwent unilateral contrast venography approximately 1 week after their operation. The primary outcome measure was the incidence of venous thromboembolism. Risk factors for deep vein thrombosis were evaluated. Results Among the 184 patients who had adequate venography, deep vein thrombosis was detected in 33 (17.9%; 95% confidence interval, 12.7%-24.3%). Of these, 9 were proximal (4.9%; 95% confidence interval, 2.3%-9.1%). No patient died and no patient presented with clinically suspected pulmonary embolism. Of 33 patients, only 20 (60.6%) with deep vein thrombosis had symptoms while 13 (39.4%) were asymptomatic. The risk of deep vein thrombosis was significantly higher among patients who had a tourniquet applied for more than 60 minutes. Conclusions The results of our study demonstrate that 17.9% of patients develop deep vein thrombosis after knee arthroscopy (most being either proximal or extensive). It is reasonable to perform a randomized trial to determine whether the incidence of deep vein thrombosis can be safely reduced in patients undergoing knee arthroscopy.

Thrombosis during pregnancy poses special problems. This review focuses on risk factors for the development of venous thromboembolism during pregnancy, diagnosis of deep vein thrombosis and pulmonary embolism during pregnancy, therapeutic recommendations for the treatment of acute thromboembolism during pregnancy, and thromboprophylaxis in the pregnant woman. Management of pregnant women with antiphospholipid antibodies is also reviewed.

(1997). Uterine vein thrombosis: an unusual variant of pelvic vein thrombophlebitis. Journal of Obstetrics and Gynaecology: Vol. 17, No. 1, pp. 106-107.

tients with acute venousthromboembolismconsistsof5to7daysofunfractionatedheparinorlow-molecular-weighthep-arin,overlappedwithandfollowedbylong-term oral anticoagulation with avitamin K antagonist such as warfa-rin. Heparins must be given parenter-ally, and their administration requiresconsiderable health care resources.Warfarinhasanunpredictabledosere-sponse,interactswithmanydrugs,andcanbeaffectedbychangesindiet;thus,continuedcoagulationmonitoringanddose adjustment are necessary.

Introduction The post thrombotic syndrome (PTS) is a chronic complication of deep venous thrombosis (DVT). It is not understood why up to 50% of DVT patients develop PTS despite optimal anticoagulation. In the Bio-SOX Study, we investigated whether markers of inflammation, one of the putative pathophysiologic processes leading to PTS, are of value in predicting the development of PTS in DVT patients. Objective To assess whether markers of inflammation measured at three time points after DVT diagnosis are predictors of risk of PTS. Methods The Bio-SOX is a sub-study of the SOX Trial, a multicenter, randomized controlled trial of elastic compression stockings for the prevention of PTS. Eight hundred and three patients with a first, symptomatic, proximal DVT were randomly allocated to receive active or placebo stockings to be worn daily, starting within 2 weeks of DVT diagnosis. During the SOX trial we prospectively collected blood samples from participants at baseline, one and six months. We measured plasma concentrations of C-reactive protein (CRP), interleukin (IL)-6, IL-10 and intercellular adhesion molecule (ICAM)-1 using validated established methods. Differences between median biomarker levels in PTS positive and negative patients (as defined by the Villalta scale applied over time starting at the 6 month visit) were assessed using the Wilcoxon rank-sum test. Multivariable logistic regression models were used to calculate crude and adjusted odds ratios (OR) of PTS by biomarker levels. Results Among study patients, 60.1% were male and mean age was 55.1 years. There were 334 cases of Villalta-defined PTS during follow up, with no significant difference in incidence between the active and placebo stockings groups. Median values of biomarkers between cases and noncases of PTS showed statistically significant differences in CRP and IL-6 at one and six months, ICAM-1 at all time points, and IL-10 at six months post DVT (Figure 1). Table 2 summarizes crude and adjusted ORs for PTS, using the median as a cut-off value. ICAM-1 was associated with PTS at all time points, IL-10 at six months, and CRP at 1 month post DVT, though this association was attenuated after adjustment. Conclusion The Bio-SOX Study is the first large scale prospective study we are aware of that evaluated the predictive role of biomarkers measured at baseline and relevant time points after acute DVT in the development of PTS. Findings suggest that inflammation plays an important role in PTS development. Among the studied biomarkers, ICAM-1 appeared to be most strongly associated with PTS development. ICAM-1 is an endothelial- and leukocyte-associated transmembrane protein important in stabilizing cell-cell interactions and facilitating leukocyte endothelial transmigration. Its expression and secretion by activated endothelial cells is induced by thrombin. Future therapeutic trials should be aimed at targeting this pathway. Disclosures: No relevant conflicts of interest to declare.

Background The post-thrombotic syndrome (PTS) is a frequent complication of deep venous thrombosis (DVT). Identifying predictors of PTS is important to counsel DVT patients on their expected prognosis and to identify patients who may benefit from closer monitoring or preventive strategies. Objective In a secondary analysis of the SOX Trial, we aimed to identify predictors of developing PTS during 2 years follow-up after a first episode of proximal DVT. Methods The study cohort consisted of participants in the SOX Trial, a multicenter (24 centres in Canada and U.S.) randomized placebo controlled trial of active elastic compression stockings vs. placebo stockings worn for 2 years after a first, symptomatic proximal DVT. PTS, the primary study endpoint, was diagnosed at or after the 6 month visit based on patient-reported pain and swelling of ≥ 1 month duration that were typical in character, i.e. worse at end of day or after prolonged sitting/standing and improved after rest/leg elevation (Ginsberg criteria). Cumulative incidences of PTS were compared in subgroups defined by sex, age category, body mass index (BMI) category, anatomic extent of index DVT, type of DVT (cancer-associated, secondary risk factor-associated, unprovoked) and 1-month Villalta score category (score 0-4: none; 5-9, mild; 10-14, moderate; >14, severe), using Cox regression. Losses to follow-up, withdrawals and deaths were censored as of last date of follow-up. Results are presented as cumulative incidence by 750 days follow-up and hazard ratios (HR) with 95% confidence intervals (CI). Results Among the 803 participants in the SOX Trial, 60% were male, mean age was 55.1 years, and 87% were out-patients. In analyses adjusted for intervention group (i.e. allocation to active vs. placebo stockings), iliac vein DVT (HR 2.26 [95% CI 1.12, 4.53]; reference category: popliteal DVT) and Villalta score category at 1 month after DVT (score 5-9, HR 2.74 [95% CI 1.62, 4.64]; score 10-14, HR 5.81[95% CI 2.99, 11.29]; score >14, HR 7.59 [95% CI 3.31, 17.44]; reference category: score Conclusions In a large prospective cohort of patients with proximal DVT who were participants in the SOX Trial, Villalta score category (which reflects severity of venous symptoms and signs) at 1 month after DVT was strongly predictive of development of PTS during 2 years follow-up. This confirms a similar finding that we first observed in the VETO cohort study (Kahn SR et. al., Annals Intern Med 2008). More extensive DVT was also associated with PTS. Patients with these risk factors may benefit from closer monitoring after proximal DVT, and in the case of iliac vein DVT, from more aggressive strategies to treat acute DVT. Disclosures: No relevant conflicts of interest to declare.

Background Acute deep venous thrombosis (DVT) is associated with leg pain and discomfort. Elastic compression stockings (ECS) have the potential to improve DVT-related leg pain by reducing the diameter of distended veins, increasing venous blood flow and reducing venous hypertension. To date, however, the effect of ECS on DVT-related leg pain has not been studied. In the SOX Trial, a randomized trial of active ECS vs. placebo ECS to prevent the post-thrombotic syndrome, we measured leg pain intensity at baseline and at several time-points during follow-up. Objective In a secondary, non-prespecified analysis of the SOX Trial, to determine whether active ECS, compared with placebo (sham) stockings, are effective to reduce leg pain associated with acute proximal DVT. Methods We did a multicenter (24 centres in Canada and U.S.) randomized placebo controlled trial of active ECS vs. placebo ECS after a first, symptomatic proximal DVT. Active ECS were knee length, 30-40 mm Hg (Class II) graduated ECS. Placebo ECS were manufactured to appear identical to active ECS but lacked therapeutic compression. Study stockings were worn on the DVT-affected leg daily and continued for up to 2 years. Exclusion criteria were >10 days since DVT diagnosis, not planned to be treated with anticoagulants, known peripheral arterial disease or limb phlegmasia, anticipated lifespan < 6 months, inability of patient or caregiver to apply ECS, thrombolysis to treat DVT, geographically inaccessible for follow-up visits or unable to give informed consent. Leg pain intensity was assessed on a 10-point Visual Analog Scale (0, no pain; 10, worst possible pain) via patient self-report at baseline, 14 days, 1 month and 60 days after randomization. We compared mean pain scores at each time point in the active ECS vs. placebo ECS groups using t-tests. We repeated this analysis, restricted to patients who reported daily stockings use at the 1 month visit (the first visit at which frequency of stocking use was assessed). We conducted pre-specified subgroup analyses by age, sex, and extent of DVT. Results are presented as mean difference (95% confidence interval [CI]) in pain intensity score between groups. All statistical tests were 2-sided and significance was set at P Results 410 patients were randomized to active ECS and 396 to placebo ECS. One and 2 patients, respectively, were found to be ineligible soon after randomization and excluded from the analysis. Mean time from DVT diagnosis to randomization was 4.7 days. Baseline characteristics were similar in the 2 groups (60% male, mean age 55.1 years, highest proximal extent of DVT was iliac or femoral vein in 70% and popliteal vein in 30%, 87% were out-patients). Pain scores diminished over time in both groups. There were no differences between groups in pain scores at any time-point (Table), and no evidence for subgroup interaction by age category, sex or anatomical extent of DVT (not shown). Conclusions In a large randomized placebo-controlled trial in patients with symptomatic proximal DVT, leg pain improved at each follow-up visit to a similar degree in patients randomized to active ECS and placebo ECS, and we did not find evidence for benefit of active ECS to reduce pain associated with acute proximal DVT. As our first follow-up assessment was 14 days after DVT, we were unable to evaluate if active ECS had a beneficial or detrimental effect on pain scores during the first 2 weeks after DVT. Disclosures: No relevant conflicts of interest to declare.

Patients with acute proximal deep-vein thrombosis are usually treated first in the hospital with intravenous standard (unfractionated) heparin. However, the longer plasma half-life, better bioavailability after subcutaneous administration, and more predictable anticoagulant response of low-molecular-weight heparins make them attractive for possible home use. We compared these two approaches.Patients with acute proximal deep-vein thrombosis were randomly assigned to receive either intravenous standard heparin in the hospital (253 patients) or low-molecular-weight heparin (1 mg of enoxaparin per kilogram of body weight subcutaneously twice daily) administered primarily at home (247 patients). The study design allowed outpatients taking low-molecular-weight heparin to go home immediately and hospitalized patients taking low-molecular-weight heparin to be discharged early. All the patients received warfarin starting on the second day.Thirteen of the 247 patients receiving low-molecular-weight heparin (5.3 percent) had recurrent thromboembolism, as compared with 17 of the 253 patients receiving standard heparin (6.7 percent; P=0.57; absolute difference, 1.4 percentage points; 95 percent confidence interval, -3.0 to 5.7). Five patients receiving low-molecular-weight heparin had major bleeding, as compared with three patients receiving standard heparin. After randomization, the patients who received low-molecular-weight heparin spent a mean of 1.1 days in the hospital, as compared with 6.5 days for the standard-heparin group; 120 patients in the low-molecular-weight- heparin group did not need to be hospitalized at all.Low-molecular-weight heparin can be used safely and effectively to treat patients with proximal deep-vein thrombosis at home.

Background The study objective was to determine the relative efficacy and safety of a low-molecular-weight heparinoid (Orgaran) compared with aspirin for the prevention of postoperative venous thromboembolism in patients undergoing surgery for fractured hips. A double-blind, randomized, controlled trial was used to study 251 consecutive eligible and consenting patients undergoing surgery for hip fracture in seven participating hospitals. Methods and Results Patients received either fixed-dose Orgaran by subcutaneous injection every 12 hours in a dose of 750 anti–Factor Xa units or aspirin 100 mg orally twice daily; both regimens were started 12 to 24 hours after surgery and continued for 14 days or until discharge, if sooner. All patients had postoperative 125 I-fibrinogen leg scanning and impedance plethysmography. If the results of one or both tests were positive, then venography was performed. Otherwise, venography was done at day 14, or sooner if the patient was ready for discharge. Pulmonary embolism in symptomatic patients was diagnosed on the basis of a high probability perfusion/ventilation lung scan, a positive angiogram, or a clinically significant embolism detected at autopsy. Evaluable venograms were obtained in 90 of the 125 patients randomly assigned to receive Orgaran and in 87 of the 126 patients assigned to receive aspirin. Venous thromboembolism was detected in 25 (27.8%) patients in the Orgaran group and in 39 (44.3%) patients in the aspirin group. Thus, there was a relative risk reduction of 37% with Orgaran ( P =.028; 95% confidence interval, 3.7% to 59.7%). Six (6.8%) of 88 patients in the Orgaran group and 12 (14.3%) of 84 patients in the aspirin group developed proximal deep vein thrombosis or pulmonary embolism, a relative risk reduction of 52% with Orgaran ( P =.137; 95% confidence interval, −30.7% to 84.6%). Hemorrhagic complications occurred in 2 (1.6%) patients given Orgaran and 8 (6.4%) patients given aspirin ( P =.10). There was one major bleed in the Orgaran group compared with four in the aspirin group. Conclusions This study demonstrates that Orgaran is significantly more efficacious than aspirin in preventing postoperative venous thromboembolism in patients undergoing surgery for fractured hips, with no evidence of any increase in hemorrhagic complications.

We studied whether TSH or phorbol myristate acetate (PMA) stimulates the hydrolysis of phospholipids, predominantly phosphatidylcholine, via phospholipase D (PLD) in FRTL-5 thyroid cells and whether this occurs as a consequence of protein kinase C (PKC) activation. FRTL-5 thyroid cells were labeled with [3H]myristate followed by incubation with 200 mM ethanol before the addition of agonist. PLD activity was assessed by the measurement of [3H]phosphatidylethanol from [3H]phospholipid (predominantly [3H]phosphatidylcholine). Compared to control values, bovine TSH (100 microU/ml) increased PLD activity by 480% and 600%, respectively, after 30 and 60 min of exposure. Studies with purified human and bovine TSH revealed similar results, indicating that this effect was due to TSH itself. PMA (100 nM) increased PLD activity at 10 min (630% of the control value), and this effect persisted up to 60 min (600% of the control value). To determine whether the effects of TSH on PLD occurred as a consequence of PKC activation, FRTL-5 thyroid cells were preincubated with the PKC inhibitor, chelerythrine (1 microM for 10 min), or were pretreated for 24 h with PMA (100 nM) to down-regulate PKC. PLD stimulation by TSH and PMA was largely abolished by such treatments. These studies indicate that in FRTL-5 thyroid cells, TSH and PMA are capable of stimulating PLD, and that PKC activation is responsible for this stimulation. The role of PLD activation could be to amplify and prolong the PKC signal by further production of diacylglycerol.

SummaryStudy objective. To determine whether levels of thrombin-antithrombin III (TAT) in plasma, taken two weeks pre-operatively, predict the development of deep vein thrombosis (DVT) in patients undergoing major hip or knee surgery.Design. Prospective cohort.Setting. Tertiary-care referral centre, university-affiliated hospital.Patients. Ninety eight consecutive patients undergoing elective hip or knee surgery.Intervention. All eligible consenting patients were seen in a preoperative clinic two weeks prior to surgery and had blood taken for measurement of plasma TAT level. After surgery, they received a combination of unfractionated heparin 5000 Units 12-hourly subcutaneously, and antiembolism stockings (TEDS), as prophylaxis against DVT. Contrast venography was performed prior to discharge, and according to the results, patients were classified as having proximal (popliteal and/or more proximal) DVT (n = 12), calf DVT (n = 7) or no DVT (n = 79).Measurements and Results. The mean TAT level was significantly higher in patients who developed DVT (5.7 μg/l) than in those who did not (4.1 μg/l), p = 0.035. Using cut-points of 3.5 and 5.5 μg/l for the TAT level, patients could be categorized as high, intermediate, and low risk for the development of DVT. The proportion of patients with TAT levels of ≥3.5μg/l who developed calf or proximal DVT was significantly higher than the proportion of patients with TAT levels of 5.5 μg/l who developed proximal DVT was significantly higher than the proportion of patients with TAT levels of ≤5.5 μg/l who developed proximal DVT (p = 0.03).Conclusions. This study demonstrates that pre-operative TAT levels correlate with the risk of developing DVT after major orthopedic surgery. Further studies are needed to determine the reason(s) for this observation and whether rational recommendations about prophylaxis and screening for DVT can be made based on the results of a pre-operative TAT level.

The clinical diagnosis of deep-vein thrombosis is generally thought to be unreliable. From experience, we hypothesised that this widely held view might be incorrect. We developed a clinical model and prospectively tested its ability in three tertiary care centres to stratify symptomatic outpatients with suspected deep-vein thrombosis into groups with high, moderate, or low probability groups of deep-vein thrombosis. We evaluated our clinical model in combination with venous ultrasonography to determine the potential for an improved and simplified diagnostic approach in patients with suspected deep-vein thrombosis. All patients were clinically assessed to determine the probability for deep-vein thrombosis before they had ultrasonography and venography. All tests were performed and interpreted by independent observers. In 529 patients, the clinical model predicted prevalence of deep-vein thrombosis in the three categories: 85% in the high pretest probability category, 33% in the moderate, and 5% in the low category. There was no statistical difference in the performance of the model in the three centres. The model demonstrated excellent interobserver reliability (Kappa = 0.85). There were important differences with ultrasonography between the high and low pretest probability groups for both positive predictive values (100% (95% CI, 94-100%) vs (63% [35-85%], respectively). Thus, use of the clinical model combined with ultrasonography would decrease the number of false positive and negative diagnosis if venography were done when the ultrasound result and pretest probability were discordant. The diagnostic process could be simplified by excluding those patients with low pretest probability and normal ultrasound results from serial testing.

Background The clinical utility of using a novel whole blood assay for D-dimer (SimpliRED), alone or in combination with impedance plethysmography (IPG), was investigated in a two-center, prospective cohort study of 214 consecutive patients with clinically suspected deep vein thrombosis (DVT). Methods and Results All patients underwent the SimpliRED D-dimer assay, contrast venography, and IPG. According to the results of venography, 43 patients had proximal DVT (popliteal and/or more proximal veins), 10 had isolated calf DVT, and 161 had DVT ruled out. The D-dimer had a sensitivity of 93% for proximal DVT and of 70% for calf DVT, an overall specificity of 77%, and a negative predictive value of 98% for proximal DVT. The sensitivity and specificity of IPG for proximal DVT were 67% and 96%, respectively. When analyzed in combination with the IPG results, it was determined that (1) the combination of a negative D-dimer and a normal IPG had a negative predictive value of 97% for all DVT and of 99% for proximal DVT and occurred in 58% of patients (likelihood ratio, 0.1) and (2) the combination of a positive D-dimer and an abnormal IPG had a positive predictive value of 93% for any DVT and of 90% for proximal DVT and occurred in 14% of patients (likelihood ratio, 42.6). When the D-dimer and IPG results were discordant, it was not possible to exclude or diagnose DVT reliably; discordant results occurred in 28% of patients. Conclusions The SimpliRED D-dimer assay, which can be performed and interpreted at the bedside within 5 minutes, has great potential in patients with clinically suspected DVT, especially for ruling out DVT, and is complementary to IPG. The assay should be evaluated in large clinical management studies.

In order to determine whether there is a relationship between acquired free protein S deficiency and increased thrombin generation, we performed a cross-sectional study of patients with systemic lupus erythematosus (SLE). Plasma samples were assayed for free protein S and were correlated to levels of prothrombin fragments (F1 + 2); an elevated level of F1 + 2 was used as a surrogate marker for a prothrombotic state. Assays for anticardiolipin antibodies (ACA) and lupus anticoagulant (LA) were performed on two separate blood samples taken at least 3 months apart in order to detect the presence of antiphospholipid antibodies. Of the 36 subjects, 9 had reduced free protein S levels compared to 0 of 21 controls (P = 0.01) and the mean free protein S level was significantly lower in the SLE population than in controls (0.30 +/- 0.08 U/mL versus 0.43 +/- 0.10 U/mL, P0.001). Of the 24 subjects with antiphospholipid antibodies, 9 had reduced free protein S levels, compared to 0 of 12 subjects without antiphospholipid antibodies (P = .01). The mean F1 + 2 level was significantly higher in study subjects with reduced free protein S levels than in those with normal free protein S levels (1.22 +/- 0.50 nmol/L versus 0.78 +/- 0.27 nmol/L, P = 0.05). This study confirms an association between antiphospholipid antibodies and reduced free protein S levels and demonstrates that patients with SLE and acquired free protein S deficiency generate more thrombin than patients with SLE and normal free protein S levels. Further studies are needed to determine whether the thrombotic diathesis associated with the presence of antiphospholipid antibodies is directly caused by the concomitant presence of acquired free protein S deficiency.

Abstract 393 Background: The post-thrombotic syndrome (PTS) is a burdensome, costly complication of deep venous thrombosis (DVT). Investigating strategies to prevent PTS is important, as treatments for PTS are limited. To date, randomized trials of elastic compression stockings (ECS) to prevent PTS were small, single-center, none used a placebo control and results are conflicting. Objective: To determine whether ECS, compared with inactive (placebo) stockings, are effective to prevent PTS in patients with proximal DVT. Methods: We conducted a multicenter (24 centres, Canada and U.S.) randomized placebo controlled trial of active ECS (A-ECS) vs. placebo ECS (P-ECS) to prevent PTS after a first, symptomatic proximal DVT. A-ECS were knee length 30–40 mm Hg (Class II) graduated ECS. P-ECS were manufactured to look identical to A-ECS but lacked therapeutic compression. Stockings were mailed directly to patients and worn on the DVT-affected leg daily for up to 2 years. Patients did not wear their stockings at study follow-up visits (1, 6, 12, 18 and 24 months) to maintain study personnel blinding. The primary study outcome, PTS, was diagnosed at or after the 6 month visit using the Ginsberg measure (leg pain and swelling of 3 1 month duration and typical in character: worse end of day or after prolonged sitting/standing and improved after rest/leg elevation). All PTS diagnoses were confirmed by the local study physicians. Secondary outcomes were incidence and severity of PTS using the Villalta scale, venous ulcers, VTE recurrence and death from VTE. A sample size of 800 patients was targeted based on a hypothesized cumulative incidence of the primary outcome of 30% in P-ECS vs. 20% in A-ECS, 2-tailed a of 0.05 and 80% power, and anticipated 25% rate of death/withdrawal/lost-to-follow-up. Using a modified intent to treat approach, we performed a time-to-event analysis using a Cox proportional hazards model adjusted for center to calculate hazard ratios (HR) and 95% confidence intervals (CI) to compare rates of the primary outcome in A-ECS vs. P-ECS. A similar time-to-event analysis was performed for Villalta PTS (Villalta score ≥ 5 at or after the 6 month visit). Results: From 2004–2010, 398 patients were randomized to A-ECS and 408 to P-ECS. 3 patients found to be ineligible soon after randomization were excluded from the analysis. Median time from DVT diagnosis to randomization was 4 days. Baseline features were similar in the 2 groups; overall, 60% were male, mean age was 55 years, and most proximal extent of DVT was iliac or femoral vein in 70% and popliteal vein in 30% of patients. The cumulative incidence of PTS (primary outcome) by 750 days was 14.8% in A-ECS vs. 12.3% in P-ECS ( Figure ) (HRadj 1.17; 95% CI 0.75–1.81; p=0.49). The cumulative incidence of Villalta PTS (secondary outcome) was 52.1% in A-ECS vs. 52.2% in P-ECS (HRadj 0.96; 95% CI 0.78–1.19; p=0.69). Additional outcomes were also similar in the two intervention groups ( Table ). Rates of loss to follow-up (5.5% vs. 5.4%) and withdrawal (8.3% vs. 9.1%) were similar in A-ECS and P-ECS. Overall, ∼70% of patients in both groups continued the intervention throughout study follow-up, and of these, >80% of patients in both groups reported use for ≥ 3 days per week. Conclusions: In a large randomized placebo-controlled trial, ECS did not prevent the occurrence of PTS after a first proximal DVT and did not influence the severity of PTS or rate of recurrent VTE. The reported benefits of ECS to prevent PTS in some prior studies could be due, at least in part, to bias from open-label design. Whether ECS may be of benefit to manage symptoms of established PTS should be evaluated in future studies. Active ECS (n = 397) Placebo ECS (n = 406) Villalta severity category * None (score 181 (51.9%) 182 (50.8%) Mild (5-9) 114 (32.6%) 116 (32.4%) Moderate (10-14) 30 (8.6%) 37 (10.3%) Severe (>14 or ulcer) 24 (6.9%) 23 (6.4%) Ipsilateral leg ulcer 16 ulcers in 16 patients 17 ulcers in 16 patients Recurrent VTE 45 events in 33 patients 44 events in 38 patients Recurrent ipsilateral DVT 18 events in 16 patients 17 events in 17 patients Death 36 (9.0%) 36 (9.1%) Death due to PE 0 0 Serious adverse event due to ECS 0 0 Adverse event due to ECS # 7 8 * Highest Villalta score at or after 6-month visit. Missing for 48 patients in each group; # leg rash or itching. Download : Download high-res image (26KB) Download : Download full-size image Disclosures: Kahn: NIH: Research Funding; Canadian Institutes for Health Research: Research Funding; Sigvaris: Research Funding.

Objective: To compare the potency, reversibility, and perioperative bleeding risk of Hepalean with those of PPC heparin. Conclusions: PPC heparin use was associated with greater heparin and protamine dose requirements than Hepalean. These findings indicate that heparin preparations are not interchangeable and suggest that a direct comparison of the potency with the brand in use is needed if a change is made to ensure that the agents exert similar anticoagulant effects in vivo. Methods: Because in vitro testing failed to detect differences in the potency or protamine reversibility of the 2 heparin preparations, we conducted a parallel group, single-center, double-blind, randomized, controlled trial to compare the anticoagulant effects of Hepalean to those of PPC heparin in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass. Results: From June 1, 2011, to June 30, 2011, we randomly assigned 11 patients to receive PPC heparin and 10 to receive Hepalean. Despite similar initial doses of heparin, the median initial activated clotting time was numerically lower in the PPC heparin group than in the Hepalean group (median, 516.0 seconds; interquartile range, 481.0-633.0; vs median, 584.0 seconds, interquartile range, 520.0-629.0; P = .418). Those given PPC heparin required a greater total heparin dose (median, 46,000.0 U; interquartile range, 39,500.0-60,000.0 vs median, 34,500.0 U; interquartile range, 32,250.0-37,000.0; P = .011) and a greater dose of heparin per kilogram than those given Hepalean (median, 572.9 U/kg; interquartile range, 443.0-659.7 vs median, 401.1 U/kg; interquartile range, 400.0-419.4; P = .003). The key secondary results included an increased median total protamine dose (median, 600.0 mg; interquartile range, 550.0-700.0; vs median, 500.0 mg; interquartile range, 425.0-542.5; P = .026) and a trend toward increased chest tube output within 24 hours (median, 830.0 mL; interquartile range, 425.0-1135.0; vs median, 702.5 mL; interquartile range, 550.0-742.5; P = .324). Refereed/Peer-reviewed

The aims of this paper are to discuss the: (1) pharmacology of low-molecular-weight heparins (LMWHs) emphasizing their synthesis, mechanism of action, and comparison with the parent compound, unfractionated heparin (UFH); and (2) recent controversial approval by the Food and Drug Administration (FDA) of a generic enoxaparin. Enoxaparin is one of several LMWHs that are currently available worldwide for clinical use. LMWHs are derived by chemi- cal or enzymatic depolymerization of the "parent" molecule, UFH. Both UFH and LMWHs exert their primary antithrombotic effect by binding to and catalyzing the naturally-occurring anticoagulant, antithrombin. LMWHs are more effective at inhibiting factor Xa than factor IIa (thrombin). They also produce less heparin-induced thrombocytopenia and osteoporosis than UFH and are at least as effective and safe as UFH for each approved indication. They are safe and effective when given subcutaneously once or twice daily, without the need for anticoagulant monitoring, and are suitable for out-of-hospital treatment. The FDA first approved enoxaparin (Lovenox ®

Summary1. Study objective: To determine whether single injections of Hirulog, a direct thrombin inhibitor, can inhibit thrombin generation in patients with calf vein thrombosis and, if so, if the inhibition is sustained.2. Design: Phase II open label cohort study.3. Setting: Tertiary-care referral centres, university affiliated hospitals.4. Patients: 10 patients with venographically-demonstrated calf vein thrombosis.5. Intervention: Patients received a single injection of Hirulog, either 1.0 mg/kg subcutaneously or 0.6 mg/kg as a 15 min intravenous infusion. Prothrombin fragment (F1+2) levels, as an index of thrombin generation, were measured before as well as 6 h post- and 24 h post-Hirulog administration. Patients were followed with non-invasive tests to detect thrombus extension into the proximal veins.6. Results: There was a significant reduction in the levels of F1+2 with both regimens, 6 h after Hirulog. The Fl+2 levels 24 h post-Hirulog showed a significant increase relative to the 6 h post-Hirulog results. One patient developed thrombus extension into the popliteal vein and was treated with conventional anticoagulants.7. Conclusion: The single injections of Hirulog used in the study produced incomplete and temporary suppression of F1+2. Complete and permanent inhibition of thrombin generation with Hirulog in patients with calf vein thrombosis may require higher doses, multiple subcutaneous injections and/or prolonged intravenous infusion.

Study objective To determine whether measurement of D-dimer, using an enzyme-linked immunosorbent assay (ELISA) with a cutoff of 300 ng/ml, and a latex agglutination assay with a cutoff of 500 ng/ml, is clinically useful in patients with suspected pulmonary embolism (PE). Design Prospective cohort. Setting Tertiary care referral center, university-affiliated hospital. Patients Two hundred twenty-one consecutive patients with clinically suspected PE. Intervention All patients had blood drawn to measure levels of D-dimer and underwent ventilation/perfusion (V/Q) lung scanning and bilateral impedance plethysmography (IPG); pulmonary angiography was performed in nine patients. Patients were classified as follows: (1) PE-positive; positive pulmonary angiography or high probability V/Q scan or non-high-probability V/Q scan and either abnormal IPG (either at presentation or on serial testing and confirmed by contrast venography) or symptomatic thromboembolic event within 3 months of presentation; or (2) PE-negative; normal V/Q scan or normal pulmonary angiography or non-high-probability V/Q scan and either normal serial IPG or abnormal IPG with normal venography and absence of symptomatic venous thromboembolism within 3 months of followup. Forty-three patients were classified as PE positive and 178 patients were classified as PE negative. Measurements and results The sensitivities, specificities, positive predictive values, and negative predictive values of the ELISA and latex agglutination assay were calculated for all patients and for the subgroup of patients with non-high-probability V/Q scans. The ELISA D-dimer, using a cutoff of 300 ng/ml, showed a sensitivity and negative predictive value of 100 percent in all patients and patients with non-high-probability V/Q scans, but the corresponding specificities were only 26 percent and 13 percent, respectively. The latex agglutination assay for D-dimer using a cutoff of 500 ng/ml showed the following: sensitivities of 84 percent in all patients and 90 percent in patients with non-high-probability scans, negative predictive values of 93 percent in all patients, and 98 percent in patients with non-high-probability scans and specificities of 56 percent in all patients and 55 percent in patients with non-high-probability scans. Conclusions This study demonstrates that an ELISA D-dimer result of less than 300 ng/ml excludes PE but occurs in a small proportion of patients with clinically suspected PE. The latex agglutination assay, using a cutoff of 500 ng/ml, has potential clinical utility in excluding PE in the subgroup of patients with clinically suspected PE and non-high-probability V/Q scans. However, the 95 percent confidence interval on the observed sensitivity of the latex agglutination assay in patients with non-high-probability V/Q scans is wide. Therefore, these promising results should be confirmed in a large clinical trial before the latex agglutination assay is used to make management decisions.

To compare two methods of determining a therapeutic range of activated partial thromboplastin time (aPTT) results.Cohort studies.Referral teaching hospital.Inpatients who received unfractionated heparin intravenously for venous thromboembolic disease.A therapeutic range determined by aPTT ratios of 1.5 to 2.5 times the control value as compared with a therapeutic range determined by protamine titration heparin levels of 0.2 to 0.4 U/mL.For all aPTT reagents studied, a ratio of 1.5 times the control value is much less than a minimum protamine titration heparin level of 0.2 U/mL. Various manufacturers' aPTT reagents and reagent lots from the same manufacturer show considerable variation in response to heparin and therefore have different therapeutic ranges.A different dose of heparin would be required to produce an aPTT ratio of 1.5 times the control value, depending on the reagent used. Establishing a therapeutic range for aPTT results using protamine titration heparin levels of 0.2 to 0.4 U/mL as a reference standard is practical and compensates for the variable response of aPTT reagents to heparin.

Abstract 566 Background and objectives: Deep venous thrombosis (DVT) is a common and serious vascular condition that is frequently complicated by the chronic post-thrombotic syndrome. Costs of DVT may occur over a long period and may be medical and non-medical in nature. During a Canadian multicenter cohort study of the long-term outcomes after DVT (The Venous Thrombosis Outcomes [VETO] Study), we prospectively quantified resource use and costs related to DVT during two years after DVT diagnosis, and identified clinical determinants of costs. Methods: The study population consisted of 355 consecutive patients diagnosed with objectively confirmed acute DVT at one of 7 participating hospitals in the province of Quebec, Canada. Using a societal perspective, we tracked total medical resource use (hospitalizations, physician visits, other health professional visits, medications, ambulance services, stockings, assistive devices) and non-medical resource use (loss of productivity, home care, transportation) incurred by DVT during the 2 years after diagnosis. Data sources included weekly patient-completed cost diaries, nurse-completed case report forms (baseline, 1, 4, 8, 12, 24 months and at any DVT-related clinical event) and the Quebec provincial administrative healthcare database (“RAMQ”). Resources for each patient were valued using individual patient level information obtained from RAMQ and patient diaries. Statistics Canada data, provincial health professionals associations and local suppliers were used to estimate resource costs if individual information was not available. The value of lost productivity was estimated using a friction-cost approach. Multivariate regression modeling for predictors of medical costs during 2 years included baseline demographic and clinical characteristics as well as the development of post-thrombotic syndrome (PTS) during study follow-up. Results: At study entry, mean age was 56.5 years, 50.1% were male, 2/3 were out-patients and 58.0% had proximal DVT. The mean duration of heparin and warfarin treatment was 7.6 days (SD 6.0) and 21.6 weeks (SD 10.0), respectively. During 2 years follow-up, the rate of DVT-related hospitalization was 3.5 per 100 patient-years (95% CI 2.2, 4.9). Patients reported, on average, 15.0 (SD 14.5) physician visits and 0.7 (SD 1.2) non-physician visits. Patients required 12.7 (SD 9.2) transportations, 38.6 (SD 138.0) hours of assistance and missed 12.1 (SD 39.8) workdays. The average per-patient total cost over 2 years was Can$4109 (95% CI $3658, $4561) with 63.7% of costs attributable to non-medical resource use. The two largest medical cost components were hospitalizations (Can$502; 95% CI $261, $744) and physician visits (Can$356; 95% CI $320, $392). More than two-thirds of all resource consumption occurred during the first 4 months after diagnosis. In multivariate analysis focusing on determinants of medical costs, concomitant pulmonary embolism (p = 0.002), idiopathic DVT (p= 0.003), and development of post-thrombotic syndrome during follow-up (p= 0.002) were independently associated with increased costs. Conclusion: The economic burden of DVT over the two years following initial diagnosis is substantial with almost two-thirds of costs attributable to non-medical resource use. Concomitant pulmonary embolism, idiopathic DVT, and development of PTS are important predictors of medical costs after DVT. Better adherence to thromboprophylaxis strategies and use of measures to prevent occurrence of PTS have the potential to diminish costs and resource utilization related to DVT. Disclosures: No relevant conflicts of interest to declare.

Abstract 5116 Background: D-dimer assays are currently used as a one-size-fits-all diagnostic test for DVT where the same cutpoint is used to define a positive result for all patients. This approach ignores the relationship between the diagnostic properties of the assay and the pretest probability of the disease. Objective: We conducted a randomized, allocation concealed, controlled, assessor-blinded trial to compare the safety and efficiency of two diagnostic strategies for D-dimer testing for first acute DVT of the lower limb: Selective use of D-dimer testing, using different D-dimer cutpoint levels according to clinical pretest probability (C-PTP) and the traditional Uniform approach. Method: 1723 consecutive eligible inpatients and outpatients at 5 clinical centres (4 in Ontario, 1 in Montreal) had their C-PTP assessed using the Wells' Score and were randomized to either: Uniform D-dimer testing, in which all patients had a D-dimer test and a level of Results: The incidence of VTE during 3 months of follow-up in patients who were not diagnosed with DVT at initial presentation was 1.1% (9/811) with Uniform testing, and 1.1% (9/814) with Selective testing (difference 0.004%, 95% CI:-1.122, 1.111). The incidence of VTE during 3 months of follow-up in patients in the Low C-PTP Select arm (D-dimer cutpoint 1.0 μ g FEU/mL) was 0% (0/356), and in the Low C-PTP Uniform arm (D-dimer cutpoint 0.5 μ g FEU/mL), it was 0.3% (1/336). Conclusion: This is the first randomized controlled clinical trial to show that Selective use of D-dimer testing, with a higher D-dimer cutpoint in patients with Low C-PTP, is safe and potentially more efficient than current practice. Funded by the Heart & Stroke Foundation of Ontario. Disclosures: Linkins: Trinity Biotech: in-kind donation of D-dimer kits; BioMerieux: in-kind donation of D-dimer kits; Stago Diagnostica: in-kind donation of D-dimer kits. Bates:bioMerieux: in-kind donation of D-dimer kits; Trinity Biotech: Consultancy, in-kind donation of D-dimer kits. Kearon:BioMerieux: in-kind donation of D-dimer kits; Trinity Biotech: in-kind donation of D-dimer kits; Stago Diagnostica: in-kind donation of D-dimer kits.

Objective To compare the relative safety and efficacy of a low-molecular-weight heparinoid (ORG 10172) with unfractionated heparin in the prevention of deep vein thrombosis in patients with acute ischemic stroke. Design Double-blind randomized trial. Setting Seven Canadian university-affiliated hospitals. Participants Eighty-seven patients with acute ischemic stroke resulting in lower-limb paresis. Intervention Patients received either low-molecular-weight heparinoid, 750 anti-factor Xa units twice daily, or unfractionated heparin, 5000 units subcutaneously twice daily. Treatment was continued for 14 days or until hospital discharge if sooner. Measurements Deep vein thrombosis was diagnosed using 125I-labeled fibrinogen leg scanning and impedance plethysmography. Venography was indicated if either test was positive. Overt hemorrhage, major or minor, was assessed clinically. Results Venous thrombosis occurred in four patients (9%) given low-molecular-weight heparinoid and in 13 patients (31%) given heparin (relative risk reduction, 71%; 95% CI, 16% to 93%. The corresponding rates for proximal vein thrombosis were 4% and 12%, respectively (relative risk reduction, 63%; P greater than 0.2). The incidence of hemorrhage was 2% in both groups. Conclusion Low-molecular-weight heparinoid, given in a fixed dose of 750 anti-factor Xa units subcutaneously twice daily, is more effective than subcutaneous low-dose heparin for the prevention of deep vein thrombosis in patients with acute ischemic stroke.

Sir—John Eikelboom and colleagues (June 3, p 1936) conclude from their meta-analysis that low-molecular-weight heparins offer no clinical benefits over unfractionated heparin in acute coronary syndromes. However, this conclusion runs contrary to the findings of two major randomised controlled trials included in the meta-analysis, Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events Study Group (ESSENCE) and Thrombolysis in Myocardial Infarction 11B Trial (TIMI 11B), which showed a significant reduction in acute cardiac events with enoxaparin compared with unfractionated heparin. The choice of endpoints—death and myocardial infarction—was intended to keep differences in outcome definitions from different studies to a minimum. But recurrent angina and need for revascularisation are important in assessing the long-term effect of therapy. Comparison of triple and double endpoints from ESSENCE at 48 h to 43 days also invalidates Eikelboom and colleagues’ contention that the anxiolytic agents with fewer side-effects than conventional benzodiazepine anxiolytics. Flaws in the methods of drug trials have led to a regrettable stop in the development in BRPAs.

To compare the sensitivity, specificity, and predictive values of compression ultrasonography (US) in postoperative orthopedic patients with those of (a) impedance plethysmography in postoperative patients and (b) compression US in symptomatic outpatients, the authors performed an investigator-blinded cohort study. One hundred thirty-four consecutive inpatients who had undergone elective knee-replacement surgery or surgery for a fractured hip and 65 consecutive outpatients with clinically suspected venous thrombosis who had undergone venography were evaluated. Compression US allowed detection of 11 of 21 (52.4%) proximal-vein thrombi but was insensitive to calf-vein thrombi in the orthopedic patients. Compression US had a significantly greater specificity and positive predictive value than impedance plethysmography for all thrombi in orthopedic patients; compression US also had greater sensitivity. The sensitivity of compression US for proximal-vein thrombi was significantly higher (92.1%) in symptomatic outpatients than in orthopedic patients. The authors conclude that compression US has significant advantages over impedance plethysmography in the detection of proximal-vein thrombi in patients who have undergone hip- or knee-replacement surgery.

Despite its affinity for fibrin, tissue plasminogen activator (t-PA) administration causes systemic fibrinogenolysis. To investigate the mechanism, t-PA was incubated with plasma in the presence or absence of a fibrin clot, and the extent of fibrinogenolysis was determined by measuring B beta 1-42. In the presence of fibrin, there is a 21-fold increase in B beta 1-42 levels. The potentiation of fibrinogenolysis in the presence of fibrin is mediated by soluble fibrin degradation products because (a) the extent of t-PA induced fibrinogenolysis and clot lysis are directly related, (b) once clot lysis has been initiated, fibrinogenolysis continues even after the clot is removed, and (c) lysates of cross-linked fibrin clots potentiate t-PA-mediated fibrinogenolysis. Fibrin degradation products stimulate fibrinogenolysis by binding t-PA and plasminogen because approximately 70% of the labeled material in the clot lysates binds to both t-PA- and plasminogen-Sepharose, and only the bound fractions have potentiating activity. The binding site for t-PA and plasminogen is on the E domain because characterization of the potentiating fragments using gel filtration followed by PAGE and immunoblotting indicates that the major species is (DD)E complex, whereas minor components include high-molecular weight derivatives containing the (DD)E complex and fragment E. In contrast, D-dimer is the predominant species found in the fractions that do not bind to the adsorbants, and it has no potentiating activity. Thus, soluble products of t-PA-induced lysis of cross-linked fibrin potentiate t-PA-mediated fibrinogenolysis by providing a surface for t-PA and plasminogen binding thereby promoting plasmin generation. The occurrence of this phenomenon after therapeutic thrombolysis may explain the limited clot selectivity of t-PA.

Despite evidence that effective regimens are available for the prevention of venous thrombosis in fractured hip patients, many centers do not use prophylaxis. In order to evaluate the efficacy and safety of heparin and graduated compression stockings, we conducted a cohort study of 55 consecutive fractures hip patients treated postoperatively with heparin, 5,000 U every 12 h, and graduated compression stockings. The rates of venous thromboembolism and bleeding were compared with an historical cohort from Hamilton. Before discharge, 51 patients underwent bilateral venography. Deep venous thrombosis (DVT) occurred in 10 of the 51 patients (incidence of 20%); three had proximal DVT (incidence of proximal DVT was 6%). DVT was seen in 29 of the 63 control patients (incidence 46%); 19 had proximal DVT (incidence of proximal DVT was 30%). The differences in the rates of DVT and proximal DVT are statistically significant (p less than 0.01). Bleeding occurred in one patient in the treatment group (incidence 2%) and five patients in the control group (incidence 8%). This study confirms that therapy with heparin and graduated compression stockings is effective, inexpensive, and convenient for the prevention of venous thrombosis in fractured hip patients and is associated with a low bleeding risk.

The reason some patients with deep venous thrombosis (DVT) develop the postthrombotic syndrome is not well understood.To determine the frequency, time course, and predictors of the postthrombotic syndrome after acute DVT.Prospective, multicenter cohort study.8 Canadian hospital centers.387 outpatients and inpatients who received an objective diagnosis of acute symptomatic DVT were recruited from 2001 to 2004.Standardized assessments for the postthrombotic syndrome using the Villalta scale at 1, 4, 8, 12, and 24 months after enrollment. Mean postthrombotic score and severity category at each interval was calculated. Predictors of postthrombotic score profiles over time since diagnosis of DVT were identified by using linear mixed modeling.At all study intervals, about 30% of patients had mild (score, 5 to 9), 10% had moderate (score, 10 to 14), and 3% had severe (score14 or ulcer) postthrombotic syndrome. Greater postthrombotic severity category at the 1-month visit strongly predicted higher mean postthrombotic scores throughout 24 months of follow-up (1.97, 5.03, and 7.00 increase in Villalta score for mild, moderate, and severe 1-month severity categories, respectively, vs. none; P0.001). Additional predictors of higher scores over time were venous thrombosis of the common femoral or iliac vein (2.23 increase in score vs. distal [calf] venous thrombosis; P0.001), higher body mass index (0.14 increase in score per kg/m(2); P0.001), previous ipsilateral venous thrombosis (1.78 increase in score; P = 0.001), older age (0.30 increase in score per 10-year age increase; P = 0.011), and female sex (0.79 increase in score; P = 0.020).Decisions to prescribe compression stockings were left to treating physicians rather than by protocol. Because international normalized ratio data were unavailable, the relationship between anticoagulation quality and Villalta scores could not be assessed.The postthrombotic syndrome occurs frequently after DVT. Patients with extensive DVT and those with more severe postthrombotic manifestations 1 month after DVT have poorer long-term outcomes.

Heparin and the vitamin K antagonists are effective for the prevention and treatment of both venous and arterial thromboembolism. The major side effect of both groups of anticoagulants is bleeding and the purpose of this review is to review the hemorrhagic effects of heparin and oral anticoagulants. The mechanisms of bleeding for both groups of anticoagulants will first be discussed, and then the incidence of bleeding in the major clinical situations for which these drugs are indicated will be discussed. Some of the clinical and laboratory features that have been associated with bleeding over the last few years will be discussed and then, briefly, the management of patients who bleed while being treated with anticoagulants will be discussed. For the purposes of this review, bleeding that is intracranial, retroperitoneal, intraocular or bleeding that causes death, hospitalization or transfusion will be classified as major. All other clinically overt bleeding will be classified as minor.

Excerpt To the Editor:The article by White and colleagues (1) addresses the clinical utility of duplex ultrasound for the diagnosis of venous thrombosis. Duplex ultrasound appears to be sensitive a...

The high frequency of residual radiologic abnormalities after initial deep vein thrombosis (DVT) makes management of patients with suspected recurrence difficult. D-dimer (DD) and serial compression ultrasonography (CUS) of the proximal veins have a high sensitivity and negative predictive value (NPV) in suspected first DVT. We hypothesized that it would be safe to withhold anticoagulation in patients with suspected recurrence who had a negative sensitive DD or negative serial CUS when DD testing was positive. In a multicentre prospective cohort study, patients underwent DD testing with an immunoturbidometric assay (MDA DD). If the DD was negative (

D-Dimer testing is often used with compression ultrasonography for the diagnosis of deep venous thrombosis (DVT) in nonpregnant patients. The D-dimer test is highly sensitive, and a negative result can obviate the need for further testing for DVT. This test has not been studied for DVT diagnosis in pregnancy because its specificity was deemed too poor.To determine the sensitivity and specificity and assess the utility of the SimpliRED assay (Agen Biomedical, Brisbane, Australia) for the diagnosis of DVT in pregnant women.Prospective cohort study.5 tertiary university-affiliated Canadian hospitals providing care to obstetric patients.149 consecutive pregnant women with suspected DVT who presented to 1 of the participating centers over 5 years.Participating women were tested with compression leg ultrasonography (single or serially on days 0, 3, and 7) and received 3 months' clinical follow-up for the presence or absence of DVT. Whole blood was tested with the SimpliRED assay at initial presentation, and results were correlated with ultrasonography and clinical findings for the presence or absence of DVT.The sensitivity, specificity, and negative predictive value of the SimpliRED assay were calculated, along with the prevalence of false-positive SimpliRED assay results (with 95% CIs).The prevalence of DVT in the cohort was 8.7% (95% CI, 5.2% to 14.4%). The sensitivity of the SimpliRED assay was 100% (CI, 77% to 100% [13 of 13 patients]), the specificity was 60% (CI, 52% to 68% [81 of 135]), and the negative predictive value was 100% (CI, 95% to 100% [81 of 81]). The SimpliRED assay was positive in 0% (CI, 0% to 60%), 24% (CI, 14% to 37%), and 51% (CI, 40% to 61%) of women in the first, second, and third trimesters, respectively, among pregnant patients in whom DVT was not diagnosed.The prevalence of DVT in the cohort was low, resulting in wide CIs. The clinician's previous impression was used to determine pretest probability in the absence of a validated clinical prediction rule for pregnant women.The SimpliRED assay may be useful in pregnancy because a normal result excludes DVT and occurs frequently enough to be clinically helpful.

Background Post thrombotic syndrome (PTS) is a burdensome and costly complication of deep venous thrombosis (DVT) that develops in 20–40% of patients within 1–2 years after symptomatic DVT. Affected patients have chronic leg pain and swelling and may develop ulcers. Venous valve disruption from the thrombus itself or thrombus-associated mediators of inflammation is considered to be a key initiating event for the development of venous hypertension that often underlies PTS. As existing treatments for PTS are extremely limited, strategies that focus on preventing the development of PTS in patients with DVT are more likely to be effective and cost-effective in reducing its burden. Elastic compression stockings (ECS) could be helpful in preventing PTS; however, data on their effectiveness are scarce and conflicting. Methods/Design The SOX Trial is a randomized, allocation concealed, double-blind multicenter clinical trial. The objective of the study is to evaluate ECS to prevent PTS. A total of 800 patients with proximal DVT will be randomized to one of 2 treatment groups: ECS or placebo (inactive) stockings worn on the DVT-affected leg daily for 2 years. The primary outcome is the incidence of PTS during follow-up. Secondary outcomes are severity of PTS, venous thromboembolism (VTE) recurrence, death from VTE, quality of life and cost-effectiveness. Outcomes will be evaluated during 6 clinic visits and 2 telephone follow ups. At baseline, 1 and 6 months, blood samples will be obtained to evaluate the role of inflammatory mediators and genetic markers of thrombophilia in the development of PTS (Bio-SOX substudy). Discussion The SOX Trial will be the largest study and the first with a placebo control to evaluate the effectiveness of ECS to prevent PTS. It is designed to provide definitive data on the effects of ECS on the occurrence and severity of PTS, as well as DVT recurrence, cost-effectiveness and quality of life. This study will also prospectively evaluate the predictive role of biomarkers that are reflective of putative underlying pathophysiological mechanisms in the development of clinical PTS. As such, our results will impact directly on the care of patients with DVT. Trial Registration NCT00143598 and ISRCTN71334751

Longer duration of treatment does not reduce risk of recurrence unless continued indefinitely

BACKGROUND: As clinical assessment of pretest probability (PTP) is now considered the first step in the diagnostic evaluation of DVT it is important to know if the clinical features of DVT are the same in men and women. OBJECTIVES: We sought to answer the following questions: 1) Is the prevalence of DVT the same in men and women who are referred for diagnostic testing? 2) Are the clinical features of DVT the same in men and women? 3) Does the Wells’ clinical prediction model for first DVT perform similarly in men and women? METHODS: We performed a retrospective analysis of individual patient data from three studies that evaluated diagnostic testing in outpatients with a suspected first episode of DVT. Associations were assessed using univariable and multivariable analyses. RESULTS: A total of 1838 patients were eligible for final analyses, of whom 1132 (62%) were women and 706 (38%) were men. DVT was objectively diagnosed in 208 patients (11%). QUESTION 1: The prevalence of DVT was higher in men (14%) than in women (9%) (p=0.001). In a multivariable analysis that included eleven other clinical variables male gender was independently associated with a higher prevalence of DVT (OR 1.5, 95% CI 1.1–2.1). QUESTION 2: Of the confirmed episodes of DVT, “swelling of the entire leg” was observed more often in women (41%) than in men (16%) (p3cm” (OR 8.2 vs. 2.9; p 60 yrs” (OR 1.8 vs. 0.9; p=0.02) and “bedridden for greater than 3 days” (OR 3.7 vs. 1.4; p=0.05). CONCLUSIONS: Among outpatients referred with a suspected first episode of DVT, the prevalence of DVT is higher in men than in women but DVT is more extensive in women. Entire leg swelling is a more common and important sign of DVT in women than in men and the Wells prediction rule behaves differently in men than in women.

Severe post-thrombotic syndrome (PTS) is responsible for considerable disability, reduced quality of life and increased health care costs. Current therapies are limited and often ineffective. Methods: We performed a two-center, randomized, cross-over controlled trial to evaluate Venowave™, a novel lower-limb venous return assist device, for the treatment of severe PTS. Eligible subjects were allocated to receive, in randomized order, Venowave™ for 8 weeks and control-device for 8 weeks. Participants were crossed-over after a 4-week (wash-out) period. The primary outcome measure was a clinical success, defined as; 1) reported benefit from the device with; 2) moderate (or greater) improvement in symptoms of PTS; and 3) willingness to continue using the device long-term. Secondary outcome measures included venous disease-specific quality of life (QOL) (measured by VEINES-QOL questionnaire; higher scores indicate better QOL) and PTS severity (measured by the Villalta PTS scale; higher scores indicate more severe PTS). The study was registered with ClinicalTrials.gov (NCT00182208). Results: Thirty-two patients were enrolled. Of these, 26 (80%) were also using graduated compression stockings. Twenty-six participants completed both trial periods. The primary outcome measure occurred in 10 participants receiving Venowave and 4 participants receiving the control-device (P=0.1). Two participants reported a clinical success with both devices. Mean Villalta scale score at the end of treatment period was significantly lower for Venowave™ (12.2; SD 6.3) compared to control (15.0; SD 6.1). (P=0.004) Mean VEINES-QOL score at the end of treatment period was significantly greater for Venowave™ (52.5; SD 5.8) compared to control (50.2; SD 6.2). (P=0.004) Conclusions: Venowave ™ is a very promising new therapy for patients with severe PTS, which may be used alone or in combination with graduated compression stockings. In our study population of patients with severe PTS, refractory to standard therapies, almost one-third of patients reported clinical improvement with Venowave™.