Marta Milan

The impact of residual thrombosis on the long-term outcome of patients with deep venous thrombosis treated with conventional anticoagulation.

The impact of residual vein thrombosis (RVT) on the long-term outcome of patients with deep vein thrombosis (DVT) is unknown. We assessed the incidence of recurrent venous thromboembolism (VTE), postthrombotic syndrome (PTS), arterial thrombotic events, and cancer in patients with DVT with and without RVT. For this purpose, we evaluated up to 3 years 869 consecutive patients with acute proximal DVT who had conventional anticoagulation. RVT, defined as ultrasound incompressibility of at least 4 mm in the common femoral and/or the popliteal vein after 3 months, was detected in 429 (49.4%) patients, and was more likely in males (adjusted odds ratio [OR], 1.82; 95% confidence interval [CI], 1.37-2.04), in patients with previous VTE (OR, 1.64; 95% CI, 1.06-2.54), and in those with extensive thrombosis (OR, 3.58; 95% CI, 2.19-5.86). During the 3-year follow-up, recurrent VTE developed in 84 (19.6%) patients with RVT and 43 (9.8%) patients without RVT (adjusted hazard ratio [HR], 2.03; 95% CI, 1.40-2.94); PTS in 225 (52.4%) and 118 (26.8%), respectively (HR, 2.34; 95% CI, 1.87-2.93); arterial thrombosis in 29 (6.7%) and 14 (3.2%), respectively (HR, 2.05; 95% CI, 1.08-3.88); and cancer in 21 (4.9%) and 8 (1.8%), respectively (HR, 3.09; 95% CI, 1.31-7.28). In conclusion, in patients treated with vitamin K antagonists for prevention of recurrent VTE, RVT doubles the risk of recurrent VTE, PTS, arterial thrombosis, and cancer. Males, patients with previous VTE, and those with extensive thrombosis are independent risk factors of RVT development. Studies addressing the impact of the novel direct anticoagulants on the development of RVT as well as the long-term complications of DVT are needed.

Post-thrombotic syndrome in patients treated with rivaroxaban or enoxaparin/vitamin K antagonists for acute deep-vein thrombosis A post-hoc analysis

Post-thrombotic syndrome (PTS) is a common complication of deep-vein thrombosis (DVT). Poor quality treatment with vitamin K antagonists (VKA) is a risk factor for PTS. We hypothesised that treatment with the direct oral anticoagulant (DOAC) rivaroxaban may lower PTS incidence as compared to enoxaparin/VKA, as DOACs have a more stable pharmacologic profile than VKA. We performed a post-hoc subgroup analysis of the Einstein DVT trial (n=3449). Kaplan-Meier survival analysis was performed to compare the cumulative incidence of PTS between the rivaroxaban and enoxaparin/VKA groups. Hazard ratios (HR) and 95 % confidence intervals (CI) were calculated using Cox proportional hazards models. We included 336 patients with a mean age of 58 ± 16 years and a median follow-up after index DVT of 57 months (interquartile range 48-64). Of these, 162 (48 %) had been treated with rivaroxaban and 174 (52 %) with enoxaparin/VKA. The cumulative PTS incidence at 60 months follow-up was 29 % in the rivaroxaban group and 40 % in the enoxaparin/VKA group. After adjusting for age, gender, body mass index, previous VTE, ipsilateral recurrent DVT, extent of DVT, idiopathic DVT, duration of anticoagulant treatment, compliance to assigned study medication, elastic compression stocking use and active malignancy, the HR of PTS development for rivaroxaban was 0.76 (95 % CI: 0.51-1.13). In conclusion, treatment of acute DVT with rivaroxaban was associated with a numerically lower but statistically non-significant risk of PTS compared to enoxaparin/VKA treatment. The potential effect on reducing PTS deserves evaluation in a large randomised trial.

Optimal duration of anticoagulation Provoked versus unprovoked VTE and role of adjunctive thrombophilia and imaging tests

Once anticoagulation is stopped, the risk of recurrent venous thromboembolism (VTE) over years after a first episode is consistently around 30%. This risk is higher in patients with unprovoked than in those with (transient) provoked VTE, and among the latter in patients with medical than in those with surgical risk factors. Baseline parameters that have been found to be related to the risk of recurrent VTE are the proximal location of deep-vein thrombosis, obesity, old age, male sex and non-0 blood group, whereas the role of inherited thrombophilia is controversial. The persistence of residual vein thrombosis at ultrasound assessment has consistently been shown to increase the risk, as do persistently high values of D-dimer and the early development of the post-thrombotic syndrome. Although the latest international guidelines suggest indefinite anticoagulation for most patients with the first episode of unprovoked VTE, strategies that incorporate the assessment of residual vein thrombosis and D-dimer have the potential to identify subjects in whom anticoagulation can be safely discontinued. Moreover, new opportunities are offered by a few emerging anti-Xa and anti-IIa oral compounds, which are likely to induce fewer haemorrhagic complications than vitamin K antagonists while preserving the same effectiveness; and by low-dose aspirin, which has the potential to prevent the occurrence of both venous and arterial thrombotic events.

ABO blood groups and the risk of venous thrombosis in patients with inherited thrombophilia.

BACKGROUND Although having a non-O blood type is now regarded as a risk factor for venous thromboembolism, the strength of this association is poorly defined, as is its interaction with inherited thrombophilia. MATERIALS AND METHODS The prevalence of non-O blood group and inherited thrombophilia (deficiencies of natural anticoagulants, factor V Leiden and prothrombin G20210A mutation) was assessed in a series of 712 consecutive patients with proximal deep vein thrombosis of the lower limbs who were referred to our Institution between 2004 and 2010, and in 712 age- and gender-matched healthy volunteers. Odds ratios (OR) of deep vein thrombosis and their 95% confidence intervals (CI) were computed for non-O group and thrombophilia, both separately and in combination. RESULTS A non-O blood group was present in 492 cases and 358 controls (OR 2.21; 95% CI, 1.78 to 2.75). A thrombophilic abnormality was present in 237 cases and 105 controls (OR 2.82; 2.18 to 3.66). The combination of non-O group and thrombophilia was present in 152 cases and 51 controls (OR 7.06; 4.85 to 10.28). DISCUSSION Having a non-O blood group is associated with an increased risk of proximal deep vein thrombosis of the lower limbs with or without pulmonary embolism. The addition of inherited thrombophilia increases the thrombotic risk conferred by non-O group alone by almost 3-fold.

The risk of recurrent thromboembolic disorders in patients with unprovoked venous thromboembolism: New scenarios and opportunities

The risk of recurrent thromboembolic disorders in the 10-year period following an episode of unprovoked venous thromboembolism (VTE) ranges between 30 and 50%, the rate being higher in patients with primary deep venous thrombosis (DVT) than in those with primary pulmonary embolism (PE). The clinical presentation with primary PE increases by more than three times the risk of a new PE episode over that with isolated DVT. Baseline parameters that increase this risk are the proximal location of DVT, obesity, old age and male sex, whereas the role of thrombophilia is controversial. An increasing role is played by post-baseline parameters such as the ultrasound assessment of residual vein thrombosis and the determination of D-dimer. While the latest international guidelines suggest indefinite anticoagulation for most patients with the first episode of unprovoked VTE, new scenarios are being offered by the identification of risk stratification models and by strategies that have the potential to help identify patients in whom anticoagulation can be safely discontinued, such as those that incorporate the assessment of D-dimer and residual vein thrombosis. New opportunities are being offered by low-dose aspirin, which has recently been reported to decrease by more than 30% the risk of recurrent events without increasing the bleeding risk; and especially by a few emerging anti-Xa and anti-IIa oral compounds, which are likely to induce fewer haemorrhagic complications than vitamin K antagonists while preserving at least the same effectiveness, do not require laboratory monitoring, and can be used immediately after the thrombotic episode.

PK-driven prophylaxis versus standard prophylaxis: When a tailored treatment may be a real and achievable cost-saving approach in children with severe hemophilia A

BACKGROUND Prophylaxis is the gold standard for the treatment of children with severe hemophilia. In the last years a new approach to prophylaxis based on annual bleeding rate (ABR), pharmacokinetics (PK) and lifestyle of each patient has begun to be adopted in hemophilia treatment. AIM Aim of our observational retrospective study was to evaluate whether in a group of children with severe hemophilia A (HA) a tailored approach may be used to replace standard therapy, reducing costs. METHODS PK evaluation was carried out in six hemophiliac children followed at our Hemophilia Center, and already receiving recombinant factor VIII (rFVIII) on prophylaxis, using a computing program (MyPKfit®). Bayesian curve was created for each child and tailored prophylaxis was estimated considering a trough level of 1%. RESULTS The weekly frequency of infusions was reduced in one patient, while it was slightly increased in three children. As to the remaining children, only the dosage was changed. Scheduled follow-up revealed a complete adherence to treatment, a reduction of bleeds using PK-regimen and a general improvement in the quality of life. The comparison between the direct and indirect costs of treatment during standard and PK-driven prophylaxis showed a total saving of € 54,797.40 (-10.67%) in case of tailored prophylaxis. CONCLUSION A therapeutic approach based on PK and clinical characteristics of each patient may change standard treatment. Based on our results, tailored prophylaxis could be an effective option for children with HA reducing costs.

An international survey on isolated subsegmental pulmonary embolism.

The large and growing number of radiological examinations performed for several thoracic diseases with multidetector-row CT (MDCT) scanners are leading to a marked increase in newly diagnosed isolated (i.e. without a concomitant diagnosis of deep venous thrombosis) subsegmental PE (I-SSPE), often incidentally identified. A diagnosis of SSPE may account for up to 12% of positive CT scans performed for suspected PE, whereas the proportion of incidental PE in patients undergoing chest CT varies from 1.5% to over 4% [1–3]. Whether MDCT findings of SSPE show true emboli or something else (artifacts?in situ thrombosis?) is still an unresolved issue and studies directly comparing the findings of the most recent MDCT scanners with those of pulmonary angiography are lacking. However, a number of indirect criteria could help radiologists to exclude false positive diagnoses (e.g. lack of concomitant atelectasis, pleural effusion or interstitial disease). The prognostic value of these findings is still undefined, especially in asymptomatic patients, and evenmore so it is unclear whether affected patients should be treated, with which drugs, at what dosage and how long. As the achievement of high-quality randomized clinical trials on I-SSPE is likely to be unrealistic, we decided to explore this topic through an inquiry on the current perception of the problem among physicians practicing in several European countries.We submitted a questionnaire to attendees of medical conferences and members of both Italian thrombosis research program networks and of the Registro Informatizado de Pacientes con Enfermedad Tromboembolica (RIETE), an international registry on venous thromboembolism (VTE) collecting data from 14 countries. The questionnaire was a list of multiple-choice questions with additional freely fillable lines of text if more detailed comments were needed, without any presentation of clinical cases and inquiring whether an I-SSPE requires treatment, which factors should influence the clinical decisions, which drugs should be used, at what dosage and how long, whether the identification of I-SSPE should prompt the search for a thrombophilic defect and/or an underlying malignancy. The definition adopted of ISPPE was that of a diagnosis, by MDCT scanning and confirmed by the radiologist, of a single ormultiple pulmonary sub-segmental emboli not associated with the concomitant presence of both segmental emboli and thrombosis in the peripheral venous circulation, identified primarily but not exclusively by an ultrasound examination. The survey focused on the symptomatic or asymptomatic clinical presentations of I-SPPE episodes and the incidental nature of some episodes could have been considered by physicians among the factors that influenced their clinical decisions. The survey was conducted either on-line, on a dedicated internet portal of our Department or manually on paper forms; several invitations to complete the on-line questionnaire were sent out via e-mail and paper copies of the questionnaire were distributed among attendees of major scientific

Aspirin and recurrent venous thromboembolism in patients with symptomatic atherosclerosis: retrospective cohort study

thesis by platelets: historical and new perspectives. J Thromb Haemost 2009; 7: 241–6. 11 Massberg S, Konrad I, Schurzinger K, Lorenz M, Schneider S, Zohlnhoefer D, Hoppe K, Schiemann M, Kennerknecht E, Sauer S, Schulz C, Kerstan S, Rudelius M, Seidl S, Sorge F, Langer H, Peluso M, Goyal P, Vestweber D, Emambokus NR, et al. Platelets secrete stromal cell-derived factor 1{alpha} and recruit bone marrow-derived progenitor cells to arterial thrombi in vivo. J ExpMed 2006; 203: 1221– 33. 12 Stellos K, Langer H, Daub K, Schoenberger T, Gauss A, Geisler T, Bigalke B, Mueller I, Schumm M, Schaefer I, Seizer P, Kraemer BF, Siegel-Axel D, May AE, Lindemann S, Gawaz M. Platelet-derived stromal cell-derived factor-1 regulates adhesion and promotes differentiation of human CD34+ cells to endothelial progenitor cells. Circulation 2008; 117: 206–15.

Further evidence in support of the association between venous thrombosis and atherosclerosis: a case-control study.

INTRODUCTION Whether there is an association between venous thromboembolism (VTE) and atherosclerosis is still controversial. AIMS In a case-control study conducted on subjects older than 50, we assessed the prevalence of symptomatic or subclinical atherosclerosis in a group of unselected patients with unprovoked VTE, and compared it with that of patients with secondary VTE and of matched control individuals free from VTE disorders. METHODS Cases and controls were enquired about the presence of previous symptomatic manifestations of atherosclerosis. Those with a negative history underwent the ultrasound assessment of carotid arteries following a standardized procedure. An intima-media thickness higher than 0.9 mm or the detection of at least one carotid plaque was regarded as a subclinical manifestation of atherosclerosis. After adjusting for age, gender and risk factors for atherosclerosis, we calculated the odds ratio (OR) for symptomatic or subclinical atherosclerosis in patients with unprovoked VTE as compared to those with secondary VTE and controls. RESULTS We recruited 100 patients with unprovoked VTE, 100 with secondary VTE and 100 control individuals. In patients with unprovoked VTE, the adjusted OR for symptomatic or subclinical atherosclerosis was 5.1 (95% CI, 2.0 to 13.1) in comparison to patients with secondary VTE, and 14.5 (95% CI, 5.8 to 36.3) in comparison to controls. The prevalence of atherosclerosis was higher in patients with secondary VTE than in controls (OR, 3.1; 95% CI, 1.6 to 6.1). CONCLUSION The results of this study confirm the presence of a strong association between venous thrombosis and atherosclerosis.

An association between residual vein thrombosis and subclinical atherosclerosis: Cross-sectional study

BACKGROUND The association between venous and arterial thrombotic disorders is still unclear. We assessed the association between residual vein thrombosis (RVT) and subclinical atherosclerosis in a cohort of patients with unprovoked (or associated with weak risk factors) proximal deep-vein thrombosis (DVT). METHODS In a multicenter cross-sectional study, consecutive patients over 40years free from atherosclerotic disorders received the ultrasound assessment of the leg vein system and that of carotid arteries approximately three months after an episode of proximal DVT. In each center the evaluation was done by two independent assessors. The presence of RVT was defined as the incompressibility of at least 4mm in either the popliteal or the common femoral vein, and that of subclinical atherosclerosis as the presence of increased (>0.9mm) intima-media tickness (IMT) and/or carotid plaques. RESULTS Out of 252 patients (mean age, 67; males, 53%; unprovoked, 77%), the presence of RVT was found in 139 (55.2%). An increased IMT was shown in 76 (54.7%) patients with and in 35 (31.0%) without RVT (p<0.001). At least one carotid plaque was found in 80 (57.6%) patients with and in 36 (31.9%) without RVT (p<0.001). After adjusting for the baseline characteristics, the odds ratio of subclinical atherosclerosis (increased IMT and/or carotid plaques) was 2.8 (95% CI, 1.6 to 4.7). CONCLUSION The ultrasound detection of RVT after an episode of proximal DVT that is either unprovoked or triggered by weak risk factors is associated with a higher prevalence of subclinical atherosclerosis. These findings may have implications for patient prognosis.