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Background: Peripheral arterial disease (PAD) was reported to increase the risk of new cardiovascular events in patients with acute coronary syndromes (ACS). However, most of the evidence comes from randomized clinical trials. We aimed to assess the impact of PAD on cardiovascular outcome and treatment decisions in ACS patients in a current real-life setting. Methods: START-ANTIPLATELET is a multicenter registry enrolling ACS patient. Baseline clinical characteristics and treatment at discharge were recorded and follow-up was repeated at 6-months and 1-year. PAD was defined as intermittent claudication and/or previous revascularization. Results: Among 1442 patients enrolled, 103 (7.1%) had PAD. PAD patients were older (71.8 ± 10.6vs66.2 ± 12.6 yrs., p < 0.0001), more frequently hypertensive (90.3vs68.6%, p< 0.0001), hypercholesterolemic (66vs52%, p= 0.037), diabetic (51.5vs24%, p= 0.0001), obese (28.2vs19.3%, p= 0.029) and with previous TIA (7.8vs2.8%, p= 0.005) or stroke (11.7vs3.1%, p< 0.0001). Clinical presentation and acute treatment were similar in non-PAD and PAD patients, but the latter were discharged significantly less frequently on dual antiplatelet therapy (DAPT) (68.9vs85%, p= 0.005). After a median follow-up time of 11.1 months, major cardio/cerebrovascular event-free survival [MACCE, including cardiovascular death, MI, TIA and stroke, target-vessel revascularization (TVR) and major arterial ischemic events] was significantly shorter (9.0vs11.2 months, p= 0.02; HR 3.2, 2.4–8.4) in PAD patients and net adverse cardiovascular events (NACE = MACCE plus major hemorrhages) were significantly more frequent (19.1%vs10.5%, p = 0.049). Conclusions: PAD identifies a subgroup of ACS patients at significantly increased cardiovascular risk, but these patients tend to be undertreated. Patients admitted for ACS should be screened for PAD and optimal medical therapy at discharge should be implemented.

Background Isolated distal deep vein thromboses (IDDVT) are frequently diagnosed; however, their natural history and real risk of complications are still uncertain. Though treatment is still not well standardized, international guidelines recommend no more than 3 months of anticoagulation therapy. We investigated how Italian clinicians treat IDDVT patients in their real life in our country. Methods Baseline characteristics and clinical history of the patients enrolled in the prospective, observational, multicenter START-Register for a first IDDVT or proximal DVT (PDVT) were analyzed. Results Overall, 412 IDDVT patients were significantly younger, with better renal function, and more frequent major transient risk factors, when compared with 1,173 PDVT patients. The anticoagulation duration was >180 days in 52.7% of IDDVT patients (70.7% in PDVT). During treatment, bleeding occurred in 5.6 and 2.8% patient-years in IDDVT and PDVT, respectively (p = 0082). Bleeding was more frequent in IDDVT than PDVT patients treated with warfarin (6.8 vs. 3.2 patient-years, p = 0.0228, respectively). Thrombotic complications occurred in 1.1 and 2.4% patient-years in IDDVT and PDVT patients, respectively. Analyzing together the two groups, 66.1% of bleeds and 86.1% thrombotic complications occurred after 90 days anticoagulation treatment. Conclusion The large majority of IDDVT patients received anticoagulation for more than 3 months. Most bleeding and thrombotic complications occurred after the first 90 days of anticoagulation therapy. These results indicate that an extended anticoagulation beyond 90 days in IDDVT patients is associated with increased risk of complications. Whether an extended treatment may lower recurrences after anticoagulation withdrawal should be assessed by specifically designed studies.

Background The protective effect of obesity on mortality in acute coronary syndromes (ACS) patients remains debated. We aimed at evaluating the impact of obesity on ischemic and bleeding events as possible explanations to the obesity paradox in ACS patients. Methods For the purpose of this sub-study, patients enrolled in the START-ANTIPLATELET registry were stratified according to Body Mass Index (BMI) into three groups: normal, BMI Results Patients were classified as follows: 410 (33.9%) normal, 538 (44.5%) overweight, 261 (21.6%) obese. Compared to the normal weight group, obese and overweight patients had a higher prevalence of cardiovascular risk factors, but were younger, with a better left ventricular ejection fraction (LVEF) and lower PRECISE-DAPT score. At one-year follow-up NACE was more frequently observed in normal than in overweight and obese patients (15.1%,8.6%,and9.6%, respectively; p=0.004), driven by a significantly higher rate of all-cause death (6.3%,2.6%, and 3.8%, respectively; p=0.008), while no significant differences were noted in terms of MI, stroke, and major bleeding. When correcting for confounding variables, BMI loses its power in independently predicting outcomes, failing to confirm the obesity paradox in a real-world ACS population. Conclusions Our study conflicts the obesity paradox in real-world ACS population, and suggest that the reduced mortality rate may be explained by a lower bleeding risk in obese patients allowing a more aggressive medical treatment, and by a better LVEF translating into a higher survival rate. Funding Acknowledgement Type of funding source: None

Background Patients with atrial fibrillation (AF) experience a high mortality rate despite optimal antithrombotic treatment. Characteristics of AF patients at higher mortality risk have been barely described so far and no risk score has been specifically developed at this aim. Furthermore, a clinical approach based on risk scores present some limits such as to not consider some important risk factors for mortality, and many available scores have poor predictive value. Cluster analysis may play a role in overcoming limitations of risk scores, especially in the case of overlapping risk factors. Purpose To identify of clinical phenotypes by using an unbiased statistical approach, such as the cluster analysis. Methods Cluster analysis was used to identify clinical phenotypes of AF patients associated with all-cause mortality in 5,171 AF patients from the START registry. Clinical variables used for the analysis were age, sex, diabetes, previous cerebrovascular events, previous cardiovascular events, heart failure, peripheral artery disease, use of non-vitamin K oral anticoagulants, cancer, pulmonary disease, smoking habit, previous major bleeding. The risk of all-cause mortality in each cluster was analyzed. Results We identified 4 clusters (Figure 1). Cluster 1 was composed by youngest patients, with obesity and paroxysmal AF; Cluster 2 by patients with low cardiovascular risk factors and high proportion of cancer; Cluster 3 by men with diabetes and coronary and peripheral artery disease, a high proportion of thrombocytopenia, and a high use of aspirin, proton pump inhibitors, and statins; Cluster 4 included the oldest patients, mainly women, with previous cerebrovascular disease, persistent/ permanent AF, heart failure, kidney disease and anemia. In this cluster there was the highest use of digoxin and NOACs. During 9856,84 patient/years of observation, 386 deaths (3.92%/year) occurred. Mortality rates significantly increased across clusters: 0.42%/year (cluster 1, reference group), 2.12%/year (cluster 2, adjusted hazard ratio [aHR] 3.306, 95% confidence interval [CI] 1.204–9.077, p=0.020), 4.41%/year (cluster 3, aHR 6.702, 95% CI 2.433–18.461, p Conclusions We identified different clinical phenotypes of AF patients by cluster analysis which were specifically associated with mortality. This approach may help identify patients at higher risk of mortality. Figure 1 Funding Acknowledgement Type of funding source: None

An international, multi-centre trial was carried out to test the haemorheological effects of ketanserin, a serotonin antagonist, after treatment of intermittent claudicants for 1 year. Ha ...

Essentials The risk of bleeding influences the duration of anticoagulation (AC) after venous thromboembolism. We assessed the ACCP bleeding risk score in an inception-cohort of patients receiving AC. 53% were categorized at high-risk, but their bleeding rate was low during long-term AC. ACCP score had low predictive value for bleeding. Summary Background The American College of Chest Physicians (ACCP) guideline proposes a score to decide on extended anticoagulation after an unprovoked venous thromboembolism (VTE). Methods We investigated the ACCP score to predict bleeding risk in an inception cohort of 2263 patients on long-term anticoagulation (1522 treated with vitamin K antagonists [VKAs] and the remaining with direct oral anticoagulants [DOACs]) belonging to the Italian START2 Register. Results More than half the patients were categorized as high risk; nevertheless, a higher proportion received anticoagulation for > 1 year compared with those in the low-risk category. For 3130 years (median 12 [interquartile range 6, 24] months), 48 bleeding outcomes occurred (1.53%/year) in the cohort (1.7%/year and 0.95%/year in high- and low-risk categories, respectively). The c-statistic of the ACCP score was 0.55 (0.48-0.63), 0.50 (0.42-0.58) and 0.56 (0.48-0.64) in low-, moderate- and high-risk categories, respectively. The bleeding incidence was higher during the first 90 days of treatment (3.0%/year) than afterwards (1.2%/year; relative risk (RR), 2.5 [1.3-4.7]), and similar among the three categories. The bleeding rate was not different during the initial 3 months of treatment in patients receiving VKAs or DOACs; it was, however, lower in the latter patients in the subsequent period (0.5%/year vs. 1.4%/year, respectively). Conclusion The bleeding rate during extended treatment was rather low in our patients. ACCP score had insufficiently predictive value for bleeding and cannot be used to guide decisions on extended treatment. New prediction tools for bleeding risk during anticoagulant treatments (including DOACs) are required.

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Venous thromboembolism (including deep vein thrombosis and pulmonary embolism) and atrial fibrillation are common conditions in Western countries. The mainstay of treatment and prevention for these diseases is fast-acting anticoagulant drugs such as heparins and vitamin K antagonists. The use of these drugs is, however, complex and demanding for both patients and physicians. Recently, new antithrombotic drugs that act directly by inhibiting activated coagulation factors such as factor X or thrombin have been developed and investigated in phase III clinical trials. The aim of this article is to review: (i) the need to develop new drugs; (ii) their efficacy/safety as demonstrated in clinical trials; (iii) the need for laboratory monitoring and (iv) the direction towards the use of these new drugs in the real-life clinical situation.

Objectives Few data are available on thrombophilic risk factors and clinical outcome in patients undergoing percutaneous transluminal angioplasty (PTA) for peripheral arterial disease (PAD). We investigated the role of homocysteine, fibrinogen, Factor VIII (FVIII), lupus anticoagulant (LAC) and FII G20210A, and FV R506Q (FV Leiden) mutations as prognostic factors in 230 patients who underwent PTA for PAD (Fontaine’s stages: IIb through IV; aged 69 ± 1 years). Design and methods A prospective study. Major adverse cardiovascular events (MACE) were the composite ‘end’ point. Results During the follow-up (24.3 ± 1.5 months), 96 (41.7%) patients reached the ‘end’ point. According to Cox regression analysis, diabetes and critical limb ischaemia were predictors of MACE, whereas each single thrombophilic alteration was not. Thrombophilic alterations were more frequent in patients that reached the ‘end’ point, and the patients with two alterations (hazard ratio (HR) 2.55 confidence interval (CI): 1.20–5.46, p = 0.015) and those with three or more alterations (HR 2.91 CI: 1.31–6.45, p = 0.009) had an increased risk for MACE versus those without alterations. Thrombophilic alterations were not associated with limb loss during the follow-up. Conclusion The presence of multiple thrombophilic alterations in patients who underwent PTA for PAD is associated with increased risk of arterial thrombotic events.

SummaryAnticoagulant treatments are given to prevent and/or treat thrombotic complications in many clinical conditions, including atrial fibrillation (the most frequent indication for anticoagulant treatment), venous thromboembolism, acute coronary syndromes and after invasive cardiac procedures. Anticoagulation with vitamin K antagonists (VKAs) is currently almost the unique kind of therapy for chronic anticoagulation. It is highly effective in the prevention or treatment of thrombotic events but it is associated with a non negligible risk of bleeding, that is the most important complication of this therapy and a major concern for both physicians and patients. The risk of bleeding and the difficulties for the patients and health care providers associated with the necessary correct management of this treatment are limiting factors for a more widespread prescription of the treatment, leaving without an effective therapy a significant proportion of patients who would have a clear clinical indication for chronic anticoagulation. This review analyses the treatment- and person-associated risk factors for bleeding during VKAs and the tools that have been proposed to assess the individual risk of bleeding. New oral anticoagulant drugs seem to overcome at least some of the limitations of VKAs. Potentially, they can allow a less demanding and more stable anticoagulant treatment, with less side-effects allowing that more patients can receive an appropriate anticoagulant treatment. Based on the so far available phase III clinical studies, it is possible to assume that also these new drugs are associated with a risk of bleeding, that is probably related to the intensity of treatment.

SummaryAnticoagulation with vitamin K antagonists (VKAs) is effective in the prevention and treatment of thrombotic complications in many clinical conditions, including atrial fibrillation (that represents today the most frequent indication for anticoagulant treatment), venous thromboembolism, acute coronary syndromes and after invasive cardiac procedures. Bleeding is the most important complication of VKAs and a major concern for both physicians and patients, limiting a more widespread prescription of the treatment. As a result, a non negligible proportion of all the subjects who would have a clear clinical indication for anticoagulation do not receive an effective treatment.This review analyses the treatment- and person-associated risk factors for bleeding during VKAs. New oral anticoagulant drugs seems to overcome at least some of the limitations of VKAs. Potentially, they can allow a less demanding and more stable anticoagulant treatment, with less side-effects allowing that more patients can receive an appropriate anticoagulant treatment. Based on the so far available phase III clinical studies, it is possible to assume that these new drugs are associated with a risk of bleeding, that is probably related to the intensity of treatment.

Evaluation of the risk of recurrent venous thromboembolism (VTE) is required to determine the optimal duration of secondary prophylaxis. Application of global assays reflecting the pro- versus anti-coagulant balance in vivo would be desirable. We aimed at investigating the relationship between recurrent VTE and the Protac-induced coagulation inhibition (PICI) assay, which is based on tissue factor-induced thrombin generation measured by a chromogenic substrate. One-hundred-ninety patients were followed-up after a first episode of unprovoked, objectively documented VTE for 2.7 years after stopping treatment with vitamin K antagonists (VKA). PICI was measured 1 month after stopping treatment as the percentage of the OD values recorded without or with Protac. The lower the PICI%, the greater the pro- versus anti-coagulant imbalance. The study outcome was objectively-documented symptomatic recurrent VTE. Patients with PICI% ≤ 74% had crude hazard-ratios (HR) (95% CI) for recurrent VTE of 2.86 (1.01–8.12) as compared to those with PICI% > 87%. After adjustment for age, gender, type of index event, VKA duration and normal/abnormal D-Dimer, HR (95% CI) were substantially unchanged [2.91 (1.01–8.38)]. The corresponding values after further adjustment for the above variables plus the absence/presence of the most frequent thrombophilic alterations were 3.38 (1.16–9.84). These HR values compare favorably with those obtained in a previous study investigating the thrombin generation test performed in the presence of thrombomodulin. In conclusion, the measurement of PICI helps to identify patients at higher risk of VTE recurrence. Advantages of PICI over thrombin generation tests are easy performance in general clinical laboratories, easy standardization and no special equipment.

Intermittent claudication is the main clinical feature of chronic symptomatic atherothrombotic disease of the lower limbs (peripheral arterial disease [PAD]). The natural history of these patients includes a relatively limited risk for deterioration toward acute or chronic critical limb ischaemia and amputation. Patients with PAD have a high cardiovascular mortality rate, however, which is related to acute myocardial infarction and stroke (fourfold to sixfold increase in l0-year risk for these conditions). In fact, PAD is often associated with multifocal atherothrombotic arterial involvement. The presence of diffuse atherothrombotic lesions in PAD patients significantly increases their cardiovascular risk burden. Conversely, in the general population as well as in coronary patients the presence of PAD is an independent risk factor for increased mortality. Evidence of plaque instability may occur simultaneously at different locations. Finally, increased intima-media thickness at the common carotid and femoral arteries can be associated with overt disease at other arterial regions.

Deep vein thrombosis (DVT) has an annual incidence of 0.2% in the urban population. First episodes of calf vein thrombosis (CVT) and proximal DVT are frequently elicited by risk factors, including varicose veins, cancer, pregnancy/postpartum, oral contraceptives below the age of 50 years, immobility or surgery. Leg pain and tenderness in the calf and popliteal fossa on physical examination may result from other conditions than DVT labeled as alternative diagnosis (AD) Congenital venous thrombophilia is present in every third first DVT, increased FVIII in every fourth first DVT, and FV Leiden/FII mutation in 40% of women on oral anticonceptive pill before reaching the menopause. Routine thrombophilia testing for FV Leiden/prothrombin mutation and FVIII as main risk factor for venous thrombosis is recommended. Primary superficial venous thrombosis (SVT) and DVT patients with a autosomal dominant family history of DVT are candidates for thrombophilia testing for congenital AT, PC and PS deficiency. The requirement for a safe diagnostic strategy of CVT and DVT should be based on an objective post-test incidence of venous thromboembolism (VTE) of less than 0.1% with a negative predictive value for exclusion of DVT of 99.9% during 3 months follow-up. Modification of the Wells score by elimination of the "minus 2 points" for AD is mandatory and will improve the diagnostic accuracy of CVT/DVT suspicion in the primary care setting and outpatient ward. The sequential use of complete DUS, ELISA D-dimer testing and modified clinical Wells' score assessment is safe and effective for the exclusion and diagnosis of CVT, DVT and AD. About 10% to 20% of patients with DVT develop overt post-thrombotic syndrome (PTS) at one year post-DVT, and both PTS and DVT recurrences further increase to about 30% during long-term follow-up. Objective risk stratification of PTS complications using DUS for recanalization and reflux and D-dimer testing will become an integral part in routine clinical practice to assess the optimal duration of wearing medical elastic stockings and anticoagulation for the prevention DVT recurrence as the best option to reduce the incidence and costs of suffering from irreversible PTS.

ATIII is decreased in sepsis and/or shock and its baseline value correlates with mortality. The efficacy of ATIII therapy on mortality was assessed in a selected group of patients admitted to the intensive care unit (ICU) in a double-blind, randomized, multicenter study.120 patients admitted to the ICU with an ATIII concentration70% were randomized to receive ATIII (total dose 24000 units) or placebo treatment for 5 days; 56 patients had septic shock.ATIII concentrations in the treated group remained constant throughout the treatment period (range 97-102%). The Kaplan-Meier analysis showed no difference in overall survival between the two groups: 50 and 46% for ATIII and placebo, respectively. Septic shock and hemodynamic support were unbalanced in the two groups at admission. Therefore the Cox analysis was carried out after adjusting for these two variables. Treatment with ATIII decreases the risk of death with an odds ratio (OR) of 0.56. Of the covariates analyzed, septic shock and the baseline multiple organ failure score were negatively associated with survival and plasma activity level was positively associated with survival with an OR of 0.97 for each 1% increase in the ATIII plasma concentration at baseline.The results of ATIII treatment in this population of patients suggests that replacement therapy reduces mortality in the subgroup of septic shock patients only.

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Introduction Idiopathic venous thromboembolism (VTE) is associated with the risk of cancer but the risk factors for cancer development in such patients are still uncertain. Aim To assess risk factors for the development of cancer after a standard course of anticoagulation in patients with first episode of idiopathic VTE. Materials and Methods Subjects were enrolled in the three large prospective multicentre studies: PROLONG (NEJM 2006) PROLONG II (Blood 2010) and DULCIS (Blood 2014). Women whose index event was hormone related were excluded from the analysis. The development of cancer was recorded during a 2-year follow-up. Results 1,805 patients were enrolled (M/F: 510/453), mean age: 62, median: 67; range:18-87 years). Cancer developed in 55 patients (3% ; 1.7% pt-years) of whom 15 (2.0%; 1.1 % pt-years) had PE with or without DVT and 40 (3.8%; 2.1% pt-years) had DVT without PE (p = 0.03). The development of cancer was associated with DVT without PE (HR:1.8; 95% CI: 1.1-3.3) and age > 65 (HR: 2.5; 95%: 1.3-4.9). Among patients with DVT, with or without PE, the development of cancer was associated with the presence of residual vein obstruction > 4 mm (RVO) at compression ultrasound (HR: 1.8, 95% CI: 1.1-3.3) and age > 65 (HR: 2.8; 95% CI: 1.3-6.2). Conclusions Age > 65 years, DVT without PE and the presence of RVO are significantly associated with the risk of developing cancer after a first episode of idiopathic VTE over a two-year follow-up.

Summary. Background: Little information is available on the long-term clinical outcome of cerebral vein thrombosis (CVT). Objectives and methods: In an international, retrospective cohort study, we assessed the long-term rates of mortality, residual disability and recurrent venous thromboembolism (VTE) in a cohort of patients with a first CVT episode. Results: Seven hundred and six patients (73.7% females) with CVT were included. Patients were followed for a total of 3171 patient-years. Median follow-up was 40 months (range 6, 297 months). At the end of follow-up, 20 patients had died (2.8%). The outcome was generally good: 89.1% of patients had a complete recovery (modified Rankin Score [mRS] 0–1) and 3.8% had a partial recovery and were independent (mRS 2). Eighty-four per cent of patients were treated with oral anticoagulants and the mean treatment duration was 12 months. CVT recurred in 31 patients (4.4%), and 46 patients (6.5%) had a VTE in a different site, for an overall incidence of recurrence of 23.6 events per 1000 patient-years (95% confidence Interval [CI] 17.8, 28.7) and of 35.1 events/1000 patient-years (95% CI, 27.7, 44.4) after anticoagulant therapy withdrawal. A previous VTE was the only significant predictor of recurrence at multivariate analysis (hazard ratio [HR] 2.70; 95% CI 1.25, 5.83). Conclusions: The long-term risk of mortality and recurrent VTE appears to be low in patients who survived the acute phase of CVT. A previous VTE history independently predicts recurrent events.

Venous thromboembolism (including deep vein thrombosis and pulmonary embolism) and atrial fibrillation are common conditions in Western countries. The mainstay of treatment and prevention for these diseases is fast-acting anticoagulant drugs such as heparins and vitamin K antagonists. The use of these drugs is, however, complex and demanding for both patients and physicians. Recently, new antithrombotic drugs that act directly by inhibiting activated coagulation factors such as factor X or thrombin have been developed and investigated in phase III clinical trials. The aim of this article is to review: (i) the need to develop new drugs; (ii) their efficacy/safety as demonstrated in clinical trials; (iii) the need for laboratory monitoring and (iv) the direction towards the use of these new drugs in the real-life clinical situation.

SummaryThe occurrence of a “rebound hypercoagulable state” in patients after discontinuation of oral anticoagulants is still a matter of debate and no definite recommendation can be made on the best procedure for anticoagulant withdrawal. The present study investigated the changes in the levels of markers of activated blood coagulation in 32 patients (pts) in whom warfarin treatment (for venous thromboembolic disease) was randomly withdrawn abruptly (n = 17, group A) or gradually (n = 15, group B: ⅔ of initial dose the 1st week, ⅓ the 2nd weeks and nothing from the 3rd week on). Blood was sampled at baseline, once a week for the first three weeks and after 2 months. At the 1st week group A had significantly higher F1+2 and TAT values (p

SummaryAcute venous thromboembolism (VTE) is treated with parenteral administration of heparin or derivatives, in conjunction with oral vitamin K antagonists (VKAs) to reach and maintain INR values between 2.0 and 3.0 for at least 3 months; the duration of a further period of treatment for secondary prevention of recurrences is still matter of debate. If bleeding occurs during treatment the decision will be based on: a) type of bleeding (major or minor), and b) thrombotic risk if anticoagulation is withheld (characteristics of patients and time elapsed from the index VTE). In case of major bleeding anticoagulation should be stopped and reversed. A first but insufficient measure is i.v. vitamin K administration. Fresh frozen plasma is widely used; however, large volumes are needed (at least 15 mL/kg body weight) with risk for fluid overload. Prothrombin complex concentrate infusion, with 3 or (better) the 4 pro-coagulant factors, is a more efficient (fast and safe) measure. In patients at high thrombotic risk (first month or other conditions) and absolute contraindication for anticoagulation a caval filter is recommended, to avoid as much as possible lifethreatening pulmonary embolism.

Summary. Aim: To determine if the mode of presentation of venous thromboembolism (VTE), as deep vein thrombosis (DVT) or pulmonary embolism (PE), predicts the likelihood and type of recurrence. Methods: We carried out a patient-level meta-analysis of seven prospective studies in patients with a first VTE who were followed after anticoagulation was stopped. We used Kaplan-Meier analysis to determine the cumulative incidence of recurrent VTE according to mode of presentation, and multivariable Cox regression to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for mode of and extent of DVT as potential risk factors for recurrence. Results: The 5-year cumulative rate of recurrent VTE in 2554 patients was 22.6%. In 869 (36.1%) patients with PE, the 5-year rate of any recurrence (DVT or PE) was 22.0%, and recurrence as PE was 10.6%. In 1365 patients with proximal DVT, the 5year recurrence rate was 26.4%, and recurrence with PE was 3.6%. The risk of recurrence as PE was 3.1-fold greater in patients presenting with symptomatic PE than in patients with proximal DVT (HR, 3.1; 95% CI, 1.9–5.1). Patients with proximal DVT had a 4.8-fold higher cumulative recurrence rate than those with distal DVT (HR, 4.8; 95% CI, 2.1–11.0). Conclusion: Whilst DVT and PE are manifestations of the same disease, the phenotypic expression is predetermined. Patients presenting with PE are three times more likely to suffer recurrence as PE than patients presenting with DVT. Patients presenting with calf DVT are at low risk of recurrence and at low risk of recurrence as PE.

Summary. Background: A number of variables have been evaluated for risk stratification in patients with acute pulmonary embolism (PE). Whereas increased D-dimer levels have been associated with mortality at 3 months, its role in predicting short-term outcome (the period of time during which any therapeutic decision has to be taken) remains unclear. Methods: RIETE is an ongoing, prospective registry of consecutive patients with acute venous thromboembolism. We assessed the prognostic value of D-dimer levels at baseline, measured with an automated latex agglutination test (IL Test D-dimer � ), on the 15-day outcome in patients with acute PE. Overall mortality, fatal PE and major bleeding rates were compared by quartile. Results: As of February 2008, 1707 patients with acute PE underwent D-dimer testing. Of these, 72 patients (4.2%) died during the first 15 days, 11 (0.6%) had recurrent PE, and 29 (1.7%) had major bleeding. Overall mortality increased with increasing D-dimer levels, from 2.7% in the first quartile (< 1050 ng mL )1 ) to 7.0% in the fourth quartile (‡ 4200 ng mL )1 ). The rates of fatal PE and major bleeding also increased. On multivariate analysis, patients with D-dimer levels in the fourth quartile had an increased risk for overall death (odds ratio, 1.8; 95% CI, 1.1–3.2), fatal PE (odds ratio, 2.0; 95% CI, 1.0–3.8) or major bleeding (odds ratio, 3.2; 95% CI, 1.5–7.0). Conclusions: PE patients with D-dimer levels in the fourth quartile had an increased incidence of overall death, fatal PE and major bleeding within 15 days both before and after multivariate adjustment.

Objective This study aims to assess the predictive value of residual venous obstruction (RVO) for recurrent venous thrombo-embolism (VTE) in a study using D-dimer to predict outcome. Design This is a multicentre randomised open-label study. Methods Patients with a first episode of idiopathic VTE were enrolled on the day of anticoagulation discontinuation when RVO was determined by compression ultrasonography in those with proximal deep vein thrombosis (DVT) of the lower limbs. D-dimer was measured after 1 month. Patients with normal D-dimer did not resume anticoagulation while patients with abnormal D-dimer were randomised to resume anticoagulation or not. The primary outcome measure was recurrent VTE over an 18-month follow-up. Results A total of 490 DVT patients were analysed (after excluding 19 for different reasons and 118 for isolated pulmonary embolism (PE)). Recurrent DVT occurred in 19% (19/99) of patients with abnormal D-dimer who did not resume anticoagulation and 10% (31/310) in subjects with normal D-dimer (adjusted hazard ratio: 2.1; p = 0.02). Recurrences were similar in subjects either with (11%, 17/151) or without RVO (13%, 32/246). Recurrent DVT rates were also similar for normal D-dimer, with or without RVO, and for abnormal D-dimer, with or without RVO. Conclusions Elevated D-dimer at 1 month after anticoagulation withdrawal is a risk factor for recurrence, while RVO at the time of anticoagulation withdrawal is not.

The optimal treatment of isolated distal deep vein thrombosis (ID-DVT) is still controversial. A complete anticoagulation as soon as the diagnosis is made is recommended by some authors. Alternatively, other authors suggest to perform serial ultrasonography assessments to detect the possible extension of DVT towards proximal veins. Only in this case the treatment should be initiated. Furthermore, the optimal duration of treatment is far from established. The Treatment of Isolated Calf Thrombosis (TICT) study was set up to assess the efficacy and safety of a particular treatment regimen of ID-DVT based on low molecular weight heparins (LMWH).The drug treatment consisted of a twice-daily subcutaneous administration of a full dose of weight-adjusted LMWH for one week, followed by a half dose of LMWH administered once-daily for another three weeks. At the end of the four-week period of treatment, a colour-coded Doppler ultrasonography (CCDU) assessment was scheduled and after three months a follow-up visit was performed. If a patient was unable to attend the visit, he was contacted by a phone-call to assess if any adverse events occurred. The study enrolled 192 outpatients with ID-DVT confirmed by CCDU. Twenty-one out of 192 patients (10.9%) were excluded for violation of protocol. Thus 171 (39.9% men, mean age of 60.45 years ) were eligible and were included in the study. Sixty-one patients (36.6%) presented an unprovoked ID-DVT.Events during the period of treatment (4 weeks). Ten out of 171 patients (5.8%) had complications: five patients showed an extension proximal to the knee (2.9%) all with an unprovoked ID-DVT; two showed an extension of thrombus within the distal veins. Three patients (1.7%) suffered from minor bleeding; there was no major bleeding. Further events during three months of observation occurred. Five patients had thrombus recurrences: four patients showed a proximal DVT (3 with a previous unprovoked ID-DVT, 1 with a previous ID-DVT secondary to a traumatic leg fracture, with persistent difficulty of deambulation); one, with a previous secondary thrombosis, showed a ID-DVT.In our study only 2.9% of patients with ID-DVT showed a progression of thrombosis to proximal deep veins; the majority of thrombus progression, during the treatment period, was observed in patients with unprovoked ID-DVT. Our results support the usefulness of a prolonged treatment in unprovoked ID-DVT.

This collaborative study, organized by the Hemostasis Subcommittee of C.I.S.M.E.L., evaluated the accuracy, precision, and comparability of the following six widely used fibrinogen assays: total clottable fibrinogen (Blombäck and Blombäck), clotting time (Von Clauss), turbidimetry (Ellis and Stransky), Chromotime System, prothrombin time (PT)-derived, and radial immunodiffusion (RID). The same frozen samples, with normal and high contents of fibrinogen, were examined in four laboratories. The methods were calibrated with an internal standard whose fibrinogen content was determined gravimetrically. Both the Von Clauss and the RID methods were reliable, accurate, and precise, if adequate calibration was used. The PT-derived method was highly reproducible, but had some problems with accuracy. We demonstrate that an adequate calibration procedure is indispensable for reliable fibrinogen measurements whatever method is used. Because neither the calibration procedures proposed by the manufacturers nor the use of lyophilized commercial plasmas is adequate for this purpose, we urge that an international standard for fibrinogen measurement be promptly established.

The assessment of the risk of recurrent venous thromboembolism (VTE) is important to determine the optimal duration of secondary prophylaxis. The risk can be estimated by measuring individual parameters reflecting hypercoagulability. Because of the large numbers of such putative parameters, the assessment in individual patients is complex. Application of global assays reflecting the pro-/anti-coagulant balance in vivo would be desirable.To investigate the relationship between recurrent VTE and thrombin generation (TG).Two hundred and fifty-four patients were followed-up after a first episode of unprovoked, objectively documented VTE for a period of 2.7 years after discontinuation of treatment with vitamin K antagonists. TG was measured 1 month after discontinuation of treatment as endogenous thrombin potential (ETP), peak thrombin and lag-time in the presence or absence of thrombomodulin. The study outcome was objectively documented symptomatic recurrent VTE.Patients with ETP or peak (measured in the presence of thrombomodulin) of960 nm(*)min or193 nm had hazard ratios (HR) (95% CI) for recurrent VTE of 3.41 (1.34-8.68) or 4.57 (1.70-12.2) as compared with those with an ETP563 nm(*)min or peak115 nm. Patients with lag-time14.5 min had HR of 3.19 (1.29-7.89) as compared with those with lag-time20.8 min. HR for ETP, peak or lag-time measured in the absence of thrombomodulin were smaller than those measured in the presence of thrombomodulin.The measurement of TG helps to identify patients at higher risk of VTE recurrence. The increased risk may be better appreciated if the test is performed in the presence of thrombomodulin.

Two diagnostic imaging strategies for suspected deep venous thrombosis (DVT) in symptomatic patients are currently used: a serial compression ultrasound examination of proximal veins, or a single complete ultrasound investigation of proximal and distal veins. These strategies lead to different results since only the latter allows diagnosis of isolated calf DVT (ICDVT).We analyzed the approach of Italian centers in looking for ICDVT using the observational MASTER registry which prospectively collected information on patients with acute symptomatic venous thromboembolism.ICDVT was diagnosed in 170 of the 1772 patients with leg DVT (9.6%). The rate of diagnosed ICDVT vs total DVT differed between centers from 0% to 24%. Patients with ICDVT were younger (P0.0001); diagnosis was more frequently delayed (P0.0001), temporary risk factors were more frequent, cancer was less frequent (P0.001), and pulmonary embolism (PE) was more frequent at presentation (P0.05). More ICDVT patients received LMWH only, not followed by oral anticoagulation (P0.001).The diagnostic strategy for suspected leg DVT differs greatly among Italian centers. A relatively high rate of PE was recorded in patients with ICDVT for reasons which are open to debate. Prospective, well designed studies on the clinical risks and the need for diagnosing ICDVT, and the advantages/disadvantages of the two diagnostic procedures are urgently needed.

TheG20210A prothrombin mutation, associated with elevated prothrombin levels, is a risk factor for venous thromboembolism (VTE) and displays a strong interaction with oral contraceptives (OC). Nodata are available onVTE risk ofOCuse in women with high prothrombin levels, either associated or not with themutation. The aim of this study was to evaluate the risk of VTE in OC users with high prothrombin levels, either including or excluding carriers of the prothrombin mutation. Prothrombin levels were measured by a chromogenic assay in 152 women who suffered from VTE in reproductive age and in 296 healthy women. Subjects carrying thrombophilic alterations other than the G20210A prothrombin mutation were excluded. Prothrombin levels were stratified into quartiles. The OR of subjects in the upper quartile were 3.10[95%confidence interval (CI)1.73-5.55] and2.07(95%CI1.11-3.85)in all women and in those not carrying the prothrombin mutation, respectively. Among the 152 patients, 88 had experienced VTE during OC; in the control group we considered as OC users the women who had used OC for at least 6 months in the 2 years before presentation but had stopped the treatment at least 3 months before the time of blood sampling (n=127).For the interaction betweenOCand prothrombin levels only the two extreme strata of prothrombin were considered. Women with the lowest prothrombin levels and who did not use OC were used as reference category. The VTE risk of using OC in subjects with prothrombin levels in the upper quartile was increased5.4-fold (95%CI2.38-12.3) and3.5-fold (95%CI1.48-8.22) in all women and in those not carrying the prothrombin mutation, respectively. We conclude that elevated prothrombin levels, even in women without the G20210A prothrombin mutation, are associated with an increased risk for venous thromboembolism and that oral contraceptive use potentiates such association. © 2003 International Society on Thrombosis and Haemostasis.

Low molecular weight heparins (LMWH) have become the reference drugs for the prevention and treatment of venous thromboembolism. Among the newer antithrombotic agents, the pentasaccharide is the most advanced and promising alternative of low molecular weight heparins. The pentasaccharide is a synthetic and specific inhibitor of activated coagulation factor X (factor Xa). The pentasaccharide is identical to the active sequence of heparin which is present in about a third of commercially available heparin mixtures. The pentasaccharide binds specifically to antithrombin III (ATIII) thus potentiating its inhibitory activity on factor Xa. As a result, thrombin generation and the formation of fibrin and thus of thrombi is inhibited. After a large phase II dose finding clinical trial, four large clinical trials with pentasaccharide in the prevention of venous thromboembolism in hip or knee surgery have been conducted in Europe and North America. The results of these trials show that pentasaccharide prevents venous thromboembolism to a larger extent than enoxaparine with an overall risk reduction of 50% and no significant increase in bleeding. Among newer antithrombotic drugs, an oral, direct thrombin inhibitor, ximelagatran, has been developed and evaluated in the prophylaxis of venous thromboembolism in hip or knee surgery in comparison with enoxaparine with promising RESULTS. Oral direct thrombin inhibitors have the advantage of predictable dose response with the possibility of oral administration without laboratory monitoring.

Summary. A protein S gene polymorphism, detectable by restriction analysis of amplified exonic sequences, was investigated in a family with members affected by protein S deficiency, deep vein thrombosis and ictus. The clinical laboratory findings as well as RFLP analysis were consistent with the presence of a type WP III protein S deficiency clearly marked by a polymorphic allele, thus enabling us to determine the carrier status in several subjects. The RFLP analysis, extended to platelet mRNA after reverse transcription and amplification, demonstrated that the mRNA produced by the putative defective gene was present in a subject affected by thrombosis.

We carried out a prospective, randomized trial to test whether a computer-based decision support system to initiate and maintain oral anticoagulant (OA) treatment can improve the laboratory quality of therapy.Two separate sets of patients on oral anticoagulants, in five Italian anticoagulant clinics, were studied: 335 patients in the first three months of treatment (stabilization phase), 916 patients (775 patient-years) beyond the third month of treatment (maintenance phase). Patients were randomized to a computerized system, which included algorithms able to suggest OA dosing and to schedule appointments (computer-aided dosing) or to an arm in which OA were prescribed by the same teams of expert physicians without such algorithms (control group). Primary outcomes were: A) the percentage of patients reaching a stable state of anticoagulation during each of the first three months of treatment; B) the percentage of time individuals spent within the aimed therapeutic range (maintenance phase).Patients in the computer-aided dosing group achieved a stable state significantly faster (p0.01) and they spent more time within the therapeutic range during maintenance (p0.001) than controls. The favorable effect of computer-aided dosing was mainly due to a reduction of the time spent below the therapeutic range and was associated with an increase of mean INR value, of anticoagulant drug dosage, and with a reduction of the number of appointments per patient (all changes significant: p0.001).The computer decision-aided support improves the laboratory quality of anticoagulant treatment, both during long-term maintenance and in the early, highly unstable phase of treatment, and it also significantly reduces the number of scheduled laboratory controls.

Self-testing and self-monitoring with portable prothrombin time (PT) monitors has been shown to be feasible and safe. However the ability of patients on chronic oral anticoagulant therapy (OAT) to self-adjust their dose without specific training has never been properly evaluated. The aims of this study were to evaluate: 1) the ability of patients on chronic OAT to self-adjust their dose without specific training; 2) the integration of a portable PT monitor (Coagucheck, Roche Diagnostics, Germany) for home use into routine patient care in anticoagulation clinics.A nested case-control study was conducted in four centers of the Italian Federation of Anticoagulation Clinics (FCSA). Patients (n=78) on stable OAT for at least 6 months (cases: 47 men, 31 women, age range: 18-75 years) were enrolled on a volunteer basis after passing an Abbreviated Mental Test and providing informed consent. After three instruction sessions on the use of Coaguchek, subjects performed the PT test at home, communicated the INR results to the Center and suggested the dose adjustment and date for next control as they thought appropriate. However, they were requested to follow the prescription made by the Center. Controls (78 subjects) matched by age (+/- 5 years), sex and therapeutic range with the cases, were selected from among those who attended the anticoagulation clinics and managed by usual care.When compared with the dose prescribed by the Clinic, the dose suggested by warfarin and acenocoumarol users was equal to or within +/- 6% of the mean weekly dose in 80% and 82% of suggestions, respectively. Time spent in the therapeutic range during the study was the same (80%) for cases and controls.Selected patients on chronic anticoagulant therapy can acquire a satisfactory ability for self-adjustment of OAT dose without specific training.