Benilde Cosmi

Bleeding with anticoagulation therapy – Who is at risk, and how best to identify such patients

Anticoagulation with vitamin K antagonists (VKAs) has been shown to be effective in the prevention and treatment of thrombotic complications in various clinical settings, including atrial fibrillation (AF), venous thromboembolism (VTE), 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. The occurrence of bleeding during treatment is not only important for the treated subjects, but also for a correct and complete use of this therapy in all the subjects who have a clear clinical indication for anticoagulation. This review analyses the treatment- and person-associated risk factors for bleeding during VKAs and their combination in clinical prediction rules that have been proposed in the attempt to identify those patients at higher risk for bleeding. The clinical prediction rules may help physicians stratify patients into categories of risk and thus to evaluate their individual risk/benefit ratio of starting or prolonging an anticoagulant treatment.

Diagnosis and treatment of disseminated intravascular coagulation: Guidelines of the Italian Society for Haemostasis and Thrombosis (SISET)☆

BACKGROUNDnThe diagnosis and treatment of disseminated intravascular coagulation (DIC) remain extremely controversial.nnnPURPOSEnThe Italian Society for Thrombosis and Haemostasis commissioned a project to develop clinical practice guidelines for the diagnosis and treatment of DIC.nnnMETHODSnKey questions about the diagnosis and treatment of DIC were formulated by a multidisciplinary working group consisting of experts in clinical medicine and research. After a systematic review and discussion of the literature, recommendations were formulated and graded according to the supporting evidence. In the absence of evidence, evidence of low quality, or contradictory evidence, a formal consensus method was used to issue clinical recommendations.nnnRESULTS AND CONCLUSIONSnIn suspected DIC, we suggest the use of the diagnostic scores ISTH (grade C), JMHW (grade C) or JAAM (grade D) over stand alone tests. The cornerstone of the management of DIC remains the treatment of the underlying triggering disease. We do not suggest the use of antithrombin (grade D), dermatan sulphate (grade D), gabexate (grade D), recombinant factor VIIa (grade D), activated protein C (grade D), thrombomodulin (grade B). The use of unfractionated heparin or low-molecular-weight heparin is not suggested except for thromboembombolic prophylaxis in patients a high risk who do not have active bleeding (grade D). In patients with severe sepsis/septic shock and DIC we suggest the use of human recombinant activated protein C (grade D). In patients with DIC and active bleeding we suggest the use of transfusion therapy (platelets, plasma, cryoprecipitate) (grade D).

Prognostic significance of residual venous obstruction in patients with treated unprovoked deep vein thrombosis: a patient-level meta-analysis.

Residual venous obstruction (RVO) could improve the stratification of the risk of recurrence after unprovoked deep vein thrombosis (DVT), but results from clinical studies and study-level meta-analyses are conflicting. It was the objective of this analysis to determine if RVO is a valid predictor of recurrent venous thromboembolism (VTE) in patients with a first unprovoked DVT who had received at least three months of anticoagulant therapy. Individual patient data were obtained from the datasets of original studies, after a systematic search of electronic databases (Medline, Embase, Cochrane Library), supplemented by manual reviewing of the reference lists and contacting content experts. A multivariate, shared-frailty Cox model was used to calculate hazard ratios (HRs) for recurrent VTE, including, as covariates: RVO; age; sex; anticoagulation duration before RVO assessment; and anticoagulation continuation after RVO assessment. A total of 2,527 patients from 10 prospective studies were included. RVO was found in 1,380 patients (55.1%) after a median of six months from a first unprovoked DVT. Recurrent VTE occurred in 399 patients (15.8%) during a median follow-up of 23.3 months. After multivariate Cox analysis, RVO was independently associated with recurrent VTE (HR = 1.32, 95% confidence interval [CI]: 1.06-1.65). The association was stronger if RVO was detected early, i.e. at three months after DVT (HR = 2.17; 95% CI: 1.11-4.25), but non-significant if detected later, i.e. >6 months (HR = 1.19; 95% CI: 0.87-1.61). In conclusion, after a first unprovoked DVT, RVO is a weak overall predictor of recurrent VTE. The association is stronger if RVO is detected at an earlier time (3 months) after thrombosis.

Thigh-length versus below-knee compression elastic stockings for prevention of the postthrombotic syndrome in patients with proximal-venous thrombosis: a randomized trial

Although below-knee compression elastic stockings (CES) are effective for the prevention of the postthrombotic syndrome (PTS), a substantial number of patients with deep venous thrombosis still develop PTS. In the present open-label, randomized clinical trial, we compared thigh-length with below-knee CES for the prevention of PTS. A total of 267 patients with the first episode of proximal deep venous thrombosis were randomized to wear either thigh-length or below-knee CES for 2 years. After 3, 6, 12, 18, 24, and 36 months, they were assessed for PTS manifestations according to the Villalta scale. PTS developed in 44 (32.6%) of the 135 patients randomized to thigh-length CES and in 47 (35.6%) of the 132 allocated to below-knee CES, for an adjusted hazard ratio of 0.93 (95% confidence interval, 0.62-1.41). Severe PTS developed in 3 patients in each group. CES-related side effects developed in 55 (40.7%) of the 135 patients allocated to thigh-length CES and in 36 (27.3%) of those randomized to the below-knee group (P = .017), and led to premature discontinuation of their use in 29 (21.5%) and 18 (13.6%) patients, respectively. We conclude that thigh-length CES do not offer a better protection against PTS than below-knee CES and are less well tolerated.

The predictive ability of bleeding risk stratification models in very old patients on vitamin K antagonist treatment for venous thromboembolism: results of the prospective collaborative EPICA study

The optimal duration of anticoagulant treatment after venous thromboembolism (VTE) should be evaluated in relation to bleeding risk. This assessment is particularly difficult with elderly patients, because of their increased risk of both recurrences and hemorrhages. Bleeding risk stratification models have been proposed, but their predictive ability in very elderly patients is unknown. We aimed to assess six bleeding stratification models in this setting, by using information available in our dataset.

D-dimer use for deep venous thrombosis exclusion in elderly patients: a comparative analysis of three different approaches to establish cut-off values for an assay with results expressed in D-dimer units

The use of adapted cut‐off values in the elderly, combined with clinical probability (PTP), increases the proportion of patients in whom venous thromboembolism (VTE) can be safely excluded, compared with the conventional cut‐off value of 500 μg/L fibrinogen equivalent units (FEU). We evaluated the clinical performance of three different approaches to establish cut‐off values for a D‐dimer assay whose results are expressed in D‐dimer units (D‐DU).

Risk factors for recurrent events in subjects with superficial vein thrombosis in the randomized clinical trial SteFlux (Superficial Thromboembolism Fluxum)

BACKGROUND/AIMSnTo evaluate risk factors for recurrent events in patients enrolled in the SteFlux (Superficial Thromboembolism Fluxum) clinical trial which compared different doses and duration of low molecular weight heparin (parnaparin) for superficial vein thrombosis (SVT).nnnMATERIALS AND METHODSnOutpatients with acute SVT of at least 4 cm in length of the internal or external saphenous veins or their collaterals were randomized in a double blind fashion to receive either parnaparin 8500 UI aXa od for ten days followed by placebo for 20 days or 8500 UI aXa od for ten days followed by 6400 UI aXa od for 20 days or 4250 UI aXa od for 30 days. Outcomes were the composite of symptomatic and asymptomatic deep vein thrombosis, pulmonary embolism and SVT recurrence or extension in the first 30+/-3 days with a 60+/-3 day follow-up.nnnRESULTSn98 outcomes (14.7%) were recorded during 93 days among 664 patients (M/F: 246/418, mean age 65). After correction for treatment, outcomes during 33 days were associated with previous venous thromboembolism (VTE) and/or SVT and/or family history of VTE (odds ratio-OR: 2.5; 95% confidence interval - CI: 1.4-4.8; p=0.003). After stopping LMWH treatment, only the absence of varicose veins (OR: 2.5; 95% CI 1.3-5.0; p=0.004) and previous VTE and/or SVT and/or family history of VTE (OR: 1.9; 95% CI:1.0-3.7; p=0.048) were significantly associated with outcomes.nnnCONCLUSIONSnSVT patients with these factors may deserve a higher intensity and/or longer anticoagulant treatment.

Inherited and acquired thrombophilic alterations in patients with superficial vein thrombosis of lower limbs

Inherited and acquired thrombophilic alterations in patients with superficial vein thrombosis of lower limbs -

The influence of factor V Leiden and G20210A prothrombin mutation on the presence of residual vein obstruction after idiopathic deep-vein thrombosis of the lower limbs

It was our aim to assess whether factor V Leiden (FVL) and G20210A prothrombin (FII) mutation are associated with the presence of residual vein obstruction (RVO) after a standard course of anticoagulation for a first episode of idiopathic proximal deep-vein thrombosis (DVT) of the lower limbs, with or without symptomatic pulmonary embolism (PE). Patients were enrolled in two prospective multicentre studies: PROLONG and PROLONG II. RVO was detected by compression ultrasonography according to the method of Prandoni on the day of anticoagulation withdrawal. Patients were also screened for FVL and FII mutation. The presence of FVL and/or FII mutation was determined in 872/963 (90.5%) patients, in 753 of whom RVO was assessed. FVL was significantly less frequent among subjects with isolated PE (7/176:4%) than among patients with either DVT and PE (15/133:11.3%; p=0.0018) or isolated DVT (89/563:15.8%; p<0.0001), confirming the FVL paradox. The rate of FII mutation was similar among patients with isolated PE (11/176:6.2%) and patients with either DVT and PE (12/133:9%) or isolated DVT (52/563:9.2%). FVL and FII mutation were not significantly associated with RVO at the multivariate analysis in all patients, although data suggest that FVL and FII mutation may have a differential effect on RVO in the subgroups of patients with DVT and DVT plus PE patients. Male sex and isolated DVT were significantly associated with RVO in all patients. In conclusion, male sex and isolated DVT are associated with RVO, while FVL and FII mutations are not significantly associated with RVO in this study.

The influence of VKORC1 3730 G > A polymorphism on warfarin dose: reply

Dear Sirs, Skov et al. object that the effect of the variant allele rs7294 which is associated with higher warfarin requirements is not relevant in our dosing algorithm, its effect being significant at the univariate but not at the multivariate analysis. Skov et al. also show that there is not a complete linkage disequilibrium but a significant correlation between rs 7294 and the variant allele rs 9934438 which is associated with warfarin sensitivity, based on the data of their study [1]. The frequency of the variant allele rs 7294 was 9.6% in their study vs 7.3% in our derivation group and 10% in the validation group. The partial linkage disequilibrium between the rs 7294 and the rs 9934438 is also consistent with data previously published by Wadelius et al [2]. In the algorithm recently elaborated by Pavani et al. [3], various parameters were included in the multiple linear regression model, and they concluded that the incorporation of VKORC1*3 (rs 7294) and VKORC1*4 (6009 C/T) could help in a precise prediction of therapeutic warfarin dose. Moreover, in a recent meta-analysis [4], Jorgensen et al. showed that for the Caucasian ethnic group, the pooled effect estimate of the VKORC SNP rs 7294 on warfarin dosing was nonsignificant for heterozygotes versus wild-types, but was statistically significant for mutant-types versus wild-types. In our study [5], we chose to employ a simultaneous multivariate regression as our analysis was exploratory and hypothesis generating. The loss of significance of the effect of rs 7294 at the multivariate analysis could be due to our limited sample size, as acknowledged in our discussion, and larger studies are required to confirm our algorithm.