Antithrombotic treatment of retinal vein occlusion: a position statement from the Italian Society on Thrombosis and Haemostasis (SISET).

Retinal vein occlusion (RVO) represents a common cause of visual impairment and blindness. RVO may be associated with both local (e.g., hyperopia, glaucoma) and systemic (e.g., hypertension, diabetes, smoking, obesity, and dyslipidaemia) risk factors. The association with thrombophilia remains controversial. Data on the use of antithrombotic therapy for RVO are poor and inconsistent with most of the information being derived from observational studies. Here we provide a position statement from the Italian Society on Thrombosis and Haemostasis (SISET) to guide the clinical and therapeutic management of patients with RVO based on the available evidence and expert opinion.

Risk of intracranial bleeding in patients with primary brain cancer receiving therapeutic anticoagulation for venous thromboembolism: A meta-analysis.

INTRODUCTION: Venous thromboembolism (VTE) is common in glioma patients. Also, spontaneous intracerebral hemorrhage (ICH) is frequently observed in subjects with primary brain tumors. Thus, the management of anticoagulant therapy for VTE is challenging and controversial in these patients. We performed a meta-analysis to clarify the risk of ICH in glioma patients treated with anticoagulant therapy for VTE compared to glioma patients without VTE. MATERIALS AND METHODS: A systematic search of the literature was conducted using PubMed, Scopus, and EMBASE databases between January 1980 and January 2019 without language restrictions. Summary statistics for ICH were obtained by calculating the odds ratio (OR) using a random effects model, and heterogeneity across studies was estimated by the I2 statistic. The Newcastle-Ottawa Scale was used to evaluate the quality of studies. RESULTS: A total of 368 studies were initially identified. Of these, 346 were excluded after title review. The remaining 22 studies were reviewed in detail. According to the PICO criteria, 15 studies were excluded. Finally, 7 studies were included in the meta-analysis. The OR for ICH in glioma patients receiving therapeutic anticoagulation for VTE versus those who did not receive anticoagulation was 3.66 (95% confidence interval [CI], 1.84-7.29; I2  = 31%). CONCLUSIONS: This meta-analysis demonstrates that anticoagulation for VTE increases the risk of ICH in subjects with malignant brain tumors. Future studies are warranted to fully understand the best medical treatment of VTE in glioma patients.

Upper extremity deep vein thrombosis treated with direct oral anticoagulants: a multi-center real world experience.

Upper-extremity deep vein thrombosis (UEDVT) accounts for about 5-10% of all cases of deep vein thrombosis (DVT). It is often associated with cancer and/or presence of a central venous catheter (CVC), but it may also occur in the absence of these favoring conditions. The safety and efficacy of using direct oral anticoagulants (DOACs) in subjects with UEDVT has not been systematically evaluated and the only data available in the literature derive from anecdotal evidence, analysis of registries, and small single-centre studies. In addition, a specific analysis of UEDVT not associated with cancer and/or CVC has never been made. In this study, we specifically focused on patients with no cancer and without a CVC who were diagnosed with a first episode of UEDVT and were treated with a DOAC. We studied 61 patients, treated in six Italian centres between January 2014 and December 2018. Treatment lasted at least 3 months in all patients. In terms of efficacy, no recurrence of thrombosis or pulmonary embolism were recorded, while Doppler ultrasonography, performed after at least three months of treatment, documented in all cases either partial or complete recanalization of obstructed veins. In terms of safety, no cases of major bleedings were recorded. This is the only series available in the literature of patients treated with DOACs for UEDVT not associated with cancer and/or CVC. This small multicenter real world experience supports the concept that DOACs might be safe and effective for treating UEDTV. Further studies are required to better understand the role of DOACs in these patients.

Aspirin Plus Clopidogrel vs Aspirin Alone for Preventing Cardiovascular Events Among Patients at High Risk for Cardiovascular Events.

Clinical Question: Among patients at high risk for or with established cardiovascular disease (ie, history of peripheral artery disease, stroke, or coronary artery disease without a coronary stent), is the addition of clopidogrel to aspirin associated with lower risk of mortality and cardiovascular events compared with aspirin alone? Bottom Line: Clopidogrel plus aspirin is associated with a reduced risk for myocardial infarction and ischemic stroke and an increased risk for major bleeding compared with aspirin alone among patients at high risk for or with an established cardiovascular disease but without a coronary stent. However, combined therapy is not associated with lower mortality.

Initial and Long-Term Treatment of Pulmonary Embolism: Current Approach and Future Perspectives.

Pulmonary embolism is associated with variable risk of early mortality, ranging from less than 1% to more than 15%. Risk stratification, based on clinical variables and signs of right ventricular dysfunction, is crucial to decide the best management and treatment strategy. Home therapy may be an option for low-risk patients, whereas patients at intermediate risk need to be hospitalized and some of them, at intermediate high risk, may require more intensive monitoring to early detect signs of haemodynamic decompensation. The initial treatment is based on anticoagulants with rapid onset of action, either parenteral (heparin/fondaparinux) or oral (direct oral anticoagulants, DOACs). Thereafter, DOACs (or, if contraindicated, vitamin K antagonists) needs to be continued for at least 3 months. Beyond this period, an individual re-evaluation of the risk-to-benefit ratio of anticoagulation should be performed, based on several factors, including the type of index event, age, sex, D-dimer and residual venous obstruction. Possibly safer strategies can be offered to higher risk patients requiring extended duration of treatment, including the DOACs apixaban and rivaroxaban at reduced dose.

Long-term recurrence of venous thromboembolism after short-term treatment of symptomatic isolated distal deep vein thrombosis: A cohort study.

Isolated distal deep vein thrombosis (IDDVT) is a common clinical manifestation of venous thromboembolism (VTE). However, there are only scant and heterogeneous data available on the long-term risk of recurrent VTE after IDDVT, and the optimal therapeutic management remains uncertain. We carried out a retrospective cohort study of consecutive patients diagnosed with symptomatic IDDVT between 2004 and 2011, according to a predefined short-term treatment protocol (low molecular weight heparin (LMWH) for 4-6 weeks). The primary outcome was the occurrence of recurrent VTE. A total of 321 patients were enrolled. IDDVT was associated with a transient risk factor or cancer in 165 (51.4%) and 56 (17.4%) patients, respectively. LMWH was administered for 4-6 weeks to 280 patients (87.2%), who were included in the primary analysis. Overall, during a mean follow-up of 42.3 months, 42 patients (15%) developed recurrent VTE, which occurred as proximal DVT or PE in 21 cases. The recurrence rate of VTE per 100 patient-years was 3.5 in patients with transient risk factors, 7.2 in patients with unprovoked IDDVT, and 5.9 in patients with cancer ( p=0.018). At multivariable analysis, unprovoked IDDVT and previous VTE were significantly associated with recurrent VTE (HR 2.16, 95% CI 1.12-4.16 and HR 1.97, 95% CI 1.01-3.86, respectively). In conclusion, the long-term risk of recurrent VTE after IDDVT treated for 4-6 weeks is not negligible, in particular in patients with unprovoked IDDVT or cancer. Further studies are needed to clarify whether a longer, but definite treatment duration effectively prevents these recurrences.

Treating patients with cancer and acute venous thromboembolism.

INTRODUCTION: Cancer and venous thromboembolism (VTE) are closely related, with a high risk of VTE associated with cancer and a strong impact of VTE on cancer prognosis. The management and treatment of cancer-associated VTE are particularly challenging and, in many cases, are not guided by a high level of evidence. AREAS COVERED: In this review, we present the best therapeutic approach to acute deep vein thrombosis (DVT) and pulmonary embolism (PE) and to some controversial issues, such as home treatment, optimal duration of anticoagulation, management of VTE recurrence during anticoagulant treatment, and of unsuspected PE. Then, the available evidence on other cancer-related VTE manifestations is presented, such as catheter-related thrombosis and splanchnic vein thrombosis. EXPERT OPINION: While solid evidence exists on the advantage of low molecular weight heparin (LMWH) over vitamin K antagonists (VKAs) during the first 3 to 6 months after acute DVT and/or PE, several issues have not been sufficiently investigated yet. These include the role of LMWH beyond the first 3 to 6 months, whether it is still more effective than VKA and if its intensity could be safely reduced, the strategies to identifying accurate predictors of VTE recurrence and the role of direct oral anticoagulants.

Epidemiology and pathophysiology of venous thromboembolism: similarities with atherothrombosis and the role of inflammation.

Venous thromboembolism (VTE) is a multifactorial disease. Major provoking factors (e. g. surgery, cancer, major trauma, and immobilisation) are identified in 50-60 % of patients, while the remaining cases are classified as unprovoked. However, minor predisposing conditions may be detectable in these patients, possibly concurring to the pathophysiology of the disease, especially when co-existing. In recent years, the role of chronic inflammatory disorders, infectious diseases and traditional cardiovascular risk factors has been extensively investigated. Inflammation, with its underlying prothrombotic state, could be the potential link between these risk factors, as well as the explanation for the reported association between arterial and venous thromboembolic events.

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.

Patient selection for thromboprophylaxis in medical inpatients.

Acutely ill medical patients may be at increased risk of venous thromboembolism, both during hospitalization and after discharge. International guidelines recommend thromboprophylaxis for high-risk medical patients with low bleeding risk for a maximum of 14 days. There are two approaches to identify the high-risk patient: adhering to the inclusion criteria used in randomized clinical trials or using risk assessment models. With both approaches, about 40% of medical inpatients should result at increased risk of venous thrombosis. However, in the real world, medical inpatients are more fragile than patients enrolled in clinical trials, and thus also require a careful assessment of the individual bleeding risk. The complex balance between risks and benefits of thromboprophylaxis has become particularly relevant in studies assessing extended prophylaxis beyond hospitalization in this setting. In the present review, we will summarize the most recent evidence on this topic.

Certoparin for the treatment and prevention of thrombosis: pharmacological profile and results from clinical studies.

INTRODUCTION: Several low-molecular-weight heparins are available for the prevention and treatment of venous thromboembolism and arterial thrombosis. Certoparin has been extensively tested in different clinical settings for about 20 years. AREAS COVERED: The authors provide a drug evaluation based on literature searches performed through Medline. Specifically, the authors review studies on the pharmacological characteristics of certoparin and the clinical trial and post-marketing studies in the field of venous thromboembolism. Furthermore, the authors also review the available smaller studies performed in clinical settings for indications such as stroke, atrial fibrillation, and hemodialysis. EXPERT OPINION: Certoparin has proved to be effective and safe therapy for preventing venous thromboembolism in different surgical and medical settings. With regards to DVT treatment, certoparin shows the peculiar feature of being used at a fixed, weight-independent dose (subcutaneous 8000 IU twice daily). Unfortunately, certoparin has no specific data from clinical trials on treatment of pulmonary embolism. Furthermore, certoparin has not been specifically tested in unusual site thrombosis. Certoparin represents a valid option for venous thromboembolism prevention and DVT treatment. Further studies are also required to provide data on the use of certoparin to treat acute pulmonary embolisms and to further substantiate results on atrial fibrillation and bridging therapy.

Novel oral anticoagulants for the prevention of venous thromboembolism in surgical patients.

Pharmacologic prophylaxis with low-dose unfractionated heparin, low molecular weight heparin or fondaparinux has clearly demonstrated to reduce the rate of thromboembolic events in surgical patients. In the last decade, several novel oral anticoagulants have been tested in surgical patients, but only in the setting of major orthopedic surgery. Based on the results of the studies, dabigatran, rivaroxaban and apixaban have been approved by the European Medicines Agency for the prevention of venous thromboembolism after elective hip or knee replacement surgery. The novel anticoagulants represent an appealing alternative to current prophylaxis strategies that are mostly based on subcutaneous injection of low molecular weight heparin and have also been recommended by recently updated guidelines. Their role in other settings, such as hip fracture surgery, or in non-orthopedic surgery, may deserve future evaluation.

The short- and long-term risk of venous thromboembolism in patients with acute spinal cord injury: a prospective cohort study.

Venous thromboembolism (VTE) is a frequent complication in the acute setting after spinal cord injury (SCI). Less is known about the long-term risk of VTE in these patients. It was the aim of this study to prospectively evaluate the short- and long-term risk of VTE in a cohort of patients after acute SCI and during rehabilitation and post-rehabilitation follow-up period. From January 2003 to November 2007 all consecutive adult patients admitted to a Spinal Rehabilitation Unit (RU) after surgical treatment in three Neurosurgical Units for SCI, were enrolled. After an accurate evaluation of their neurosurgical medical records the patients were prospectively evaluated for VTE occurrence. Ninety-four patients (80 males; mean age 40.3 years, SD 15.9) were recruited. All the patients received thromboprophylaxis with low-molecular-weight heparin combined with compressive stockings during hospitalization (median duration 7 months, IQR 4.5-8.8). Over a median follow-up period of 36.3 months (IQR 4.4-48) after SCI, VTE was diagnosed in 22 patients (23.4%) The majority of VTE events were recorded during the first three months of follow-up (34.4 VTE events/100 patient-years in the first 3 months and 0.3 VTE events/100 patient-years thereafter); age over 45 years (HR 8.4, 95% CI 3-23.5), previous VTE (HR 6.0, 95% CI 1.6-23.3) and paraplegia (HR 4.7, 95% CI 1.6-13.7) were independently associated with the occurrence of VTE. In conclusion, the risk of VTE in patients suffering from SCI is high despite the use of thromboprophylaxis, in particular in some patients categories. However, this risk appears to be limited to the first 3 months after the index event.

Clinical approach to splanchnic vein thrombosis: risk factors and treatment.

Splanchnic vein thrombosis (SVT) is an unusual manifestation of venous thromboembolism which involves one or more abdominal veins (portal, splenic, mesenteric and supra-hepatic veins). SVT may be associated with different underlying disorders, either local (abdominal cancer, liver cirrhosis, intra-abdominal inflammation or surgery) or systemic (hormonal treatment, thrombophilic conditions). In the last decades, myeloproliferative neoplasm (MPN) emerged as the leading systemic cause of SVT. JAK2 mutation, even in the absence of known MPN, showed a strong association with the development of SVT, and SVT was suggested to be the first clinical manifestation of MPN. Recently, an association between SVT, in particular supra-hepatic vein thrombosis, and paroxysmal nocturnal hemoglobinuria has also been reported. SVT occurs with heterogeneous clinical presentations, ranging from incidentally detected events to extensive thrombosis associated with overt gastrointestinal bleeding, thus representing a clinical challenge for treatment decisions. In the absence of major contraindications, anticoagulant therapy is generally recommended for all patients presenting with acute symptomatic SVT, but there is no consensus about the use of anticoagulant drugs in chronic or incidentally detected SVT. High quality evidence on the acute and long-term management is substantially lacking and the risk to benefit-ratio of anticoagulant therapy in SVT still needs to be better assessed.

Management of bleeding in patients receiving conventional or new anticoagulants: a practical and case-based approach.

Anticoagulant drugs are highly effective for the prevention and treatment of venous and arterial thromboembolism. However, their use is also associated with an increased risk for bleeding, with an associated ∼10% case-fatality rate. Appropriate strategies for the management and reversal of anticoagulant-associated bleeding are clinically important and, ideally, should be standardized. These include general resuscitation, and diagnosis and local treatment of the bleeding source, and one or more of the following interventions: transfusion of red cells; transfusion of clotting factor replacements; and administration of anticoagulant antidotes and other prohaemostatic agents. Reversal strategies for the 'conventional' anticoagulants are based largely on clinical evidence, whereas evidence to guide the management of bleeding associated with 'new' anticoagulants is emerging. This review provides an evidence-based, but practical, patient-focused approach for the management of bleeding associated with the old and new anticoagulants.

Splanchnic vein thrombosis: new risk factors and management.

Splanchnic vein thrombosis (SVT) is a rather heterogeneous disease which involve one or more abdominal veins draining from different organs, including small and large bowel, liver, spleen and pancreas, and it may be associated with a wide spectrum of underlying disorders, either local or systemic. The role of new risk factors for SVT, including the JAK2 V617F mutation and the paroxysmal nocturnal hemoglobinuria clone, has been highlighted in recent years. The clinical presentations of SVT are variable and, not uncommonly, may include the concomitant presence of extensive thrombosis and gastrointestinal bleeding, thus representing a clinical challenge for treatment decisions. High quality evidence on the acute and long-term management is substantially lacking, thus requiring further research on SVT.

Unusual site thrombosis.

Venous thromboses in unusual sites are rare and heterogenous manifestations of venous thromboembolism (VTE). These uncommon diseases are each characterized by peculiar pathophysiological and clinical features, mainly reflecting the different characteristics of the organs of origin. Moreover, the relative frequency and importance of risk factors associated with their development may be different compared to those of the classical manifestations of VTE, such as deep vein thrombosis of the lower limbs or pulmonary embolism. The need for anticoagulant therapy for unusual site thrombosis (UST) is generally accepted. However, several questions remain unanswered: what is the best therapeutic agent, is it safe, and for how long should it be used? These questions persist mainly due to the low level of available evidence given the rarity of these diseases. The short- and long-term prognoses, and in particular the risk of recurrence and mortality, are quite heterogenous among the different manifestations of UST and even within each of them, depending mainly on the predisposing causes.

Oral rivaroxaban after symptomatic venous thromboembolism: the continued treatment study (EINSTEIN-extension study).

Over recent years, research on anticoagulant drugs has been guided by the requirement for convenient administration and a wide therapeutic window to allow fixed dosing without the need for coagulation monitoring. Rivaroxaban is the first of a new class of anticoagulant drugs, the direct, selective inhibitors of Factor Xa. The EINSTEIN-extension study compared rivaroxaban with placebo in patients who completed their standard treatment course after venous thromboembolism (VTE), in whom there was equipoise with respect to the need for continued anticoagulation. After 6-12 months of treatment, rivaroxaban significantly reduced the risk of recurrent VTE at the cost of a moderate increase in bleeding complications. Overall, these results suggest that rivaroxaban can be a valid alternative to warfarin for patients requiring long-term secondary prevention of VTE. However, additional data are needed for special populations including the elderly, patients with cancer, renally impaired patients and morbidly obese patients, all of whom were scarcely represented in this trial.