Sofia Barbar

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.

Risk factors, antithrombotic treatment and outcome in retinal vein occlusion: an age-related prospective cohort study

Antithrombotic treatment for retinal vein occlusion (RVO) is controversial, although RVO has been surmised as a predictor of a subsequent vascular event. We aimed to evaluate risk factors, the effects of antithrombotic therapy and the occurrence of subsequent vascular events in patients with a first episode of RVO, according to age of RVO onset.

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.

The Risk of Cancer Progression in Women With Gynecological Malignancies and Thrombophilic Polymorphisms: A Pilot Case-Control Study

Cancer produces a hypercoagulable state, which might lead to thrombosis, and on contrary, unprovoked venous thromboembolism might be the manifestation of an occult cancer. In this pilot case-control study, we assessed the risk of gynecological malignant diseases related to the presence of the factor V Leiden and prothrombin G20210A polymorphisms. Fifty-two women underwent an operation for gynecological malignancy and were enrolled in the study. Women who underwent an operation for gynecological nonmalignant disease in the same days of cases were considered as controls. The presence of factor V Leiden and prothrombin G20210A was assessed in case and control groups. In all, 7 out of 52 cases were carriers of the 2 polymorphisms compared with 20 out of 198 controls (odds ratio = 1.3; 95% confidence interval, 0.6-3.0). The results were also similar when the risk was considered separately for the site of cancer. As for advanced and metastatic malignancies, the odds ratios were 2.3 (95% confidence interval, 0.9-6.0) and 3.3 (95% confidence interval, 1.0-11), respectively, compared to noncancer patients. When these 2 groups were compared to nonadvanced cancer group, the odds ratios for carriers of polymorphisms were 2.7 (95%confidence interval, 0.7-11.0) and 3.9 (95%confidence interval, 0.8-18.6) for advanced cancer and metastatic malignancies, respectively. Women with factor V Leiden or prothrombin G20210A polymorphisms who developed gynecological malignancy might present with a higher stage of cancer at the time of surgery. Larger case-control studies in similar cohort of patients are needed to confirm these findings.

Scoring Systems for Estimating Risk of Venous Thromboembolism in Hospitalized Medical Patients

Abstract Deep vein thrombosis and pulmonary embolism are associated with considerable morbidity and mortality in hospitalized patients, accounting for up to 10% of hospitalization‐related deaths in both surgical and medical patients. Pharmacologic thromboprophylaxis has been demonstrated to be effective, safe, and cost‐effective in preventing hospital‐acquired venous thromboembolism (VTE) among medical inpatients, and clinician awareness of thrombotic risk promotes prescription of thromboprophylaxis. Guidelines recommend stratification of thrombotic risk for all patients and, unless contraindicated, administration of VTE prophylaxis. Based on several recognized predisposing and exposing risk factors for VTE, several scoring systems have been published in the past 15 years. Borrowing models developed in the surgical setting, recognized risk factors for VTE complications in medical inpatients have been combined in different weighted scores and derived and validated in heterogeneous medical populations. Although the perfect score, balancing thrombotic and hemorrhagic risk, has probably not yet been built, the adoption of an easy‐to‐use risk assessment model has the potential to support physicians in properly stratifying VTE risk in medical inpatients, tailoring thromboprophylaxis prescription.

Physicians’ compliance with the Padua Prediction Score for preventing venous thromboembolism among hospitalized medical patients

Hospitalization for acute medical illnesses confers an 8-fold increased risk of venous thromboembolic (VTE) disorders that persists for up to 3 months and is even higher after discharge than during in-hospital stay [1]. However, in spite of strong evidence in favor of thromboprophylaxis [2–4], several observation studies from various countries found that less than 50% of admitted medical patients at risk receive prophylaxis against VTE [5–8]. We have recently identified and validated a suitable and effective risk assessment model, the Padua Prediction Score (PPS), for optimal stratification of the thrombotic risk in hospitalized medical patients [9]. Its implementation in the Departments of Internal Medicine has recently been suggested by the latest ACCP consensus guidelines [10]. For the purpose of that investigation, attending physicians were not informed about the thrombotic risk of their patients and, as a result, less than 40% managed their patients correctly [9]. In an attempt to assess whether awareness of the thrombotic risk – as assessed with the PPS – has the potential to increase the rate of appropriate thromboprophylaxis in high-risk medical patients, we performed a second prospective investigation within the same framework as the first. On this occasion, we alerted the attending physicians to the thrombotic risk of their patients by tracing a well visible red line on the clinical chart of those who were at high risk. In addition, for further confirmation that the adoption of the PPS has the potential to improve patients’ outcome, we registered the thrombotic and hemorrhagic events occurring up to 90 days after recruitment in the high-risk patients. Any decisions concerning use and timing of prophylaxis were left to the discretion of the attending physicians. The investigation was approved by the Ethical Board of the University Hospital of Padua. Out of 1600 consecutive patients admitted to the Second Division of Internal Medicine of the University Hospital of Padua (Italy) between January 2010 and December 2011, 797 were excluded due to indications for anticoagulant treatment (740), contraindications for pharmacological prophylaxis (40), failure to give informed consent (10) or difficulties in obtaining follow-up information (8). Accordingly, 803 patients were recruited, of whom 296 (39.6%) were at high risk and 507 at low risk of VTE based on the PPS. Table 1 shows the main clinical features of the high-risk patients. Consistent with the previous investigation [8], prescriptions were regarded as adequate if enoxaparin 4000 U, dalteparin 5000 U or fondaparinux 2.5 mg were administered once a day within 48 h of hospital admission and for at least 80% of the hospital stay. Of the 296 high-risk patients, 262 (88.5%) received adequate pharmacological prophylaxis during hospitalization, this proportion being more than twice as high as that (186/469, 39.6%; P < 0.00001) recorded in the previous study [8]. The remaining 34 (11.5%) were either not treated or received inadequate prophylaxis. The median duration of prophylaxis during hospital stay was 12 days (interquartile range, 3–15). Thromboprophylaxis was continued after discharge in 50 patients (19.1%) for variable periods (ranging from 1 to 5 weeks). Thromboprophylaxis was also administered in 15 (2.9%) low-risk patients. Patients developing a clinical suspicion of DVT and/or PE were diagnosed by means of pre-test clinical probability and D-dimer [11,12]. Those with low pre-test probability and negative D-dimer were regarded as free from complications. For all other combinations, objective tests were performed in order to confirm or exclude the clinical suspicion (compression ultrasonography of the whole deep vein system in the case of suspected DVT; spiral CT or V/Q scanning of the lungs in the case of suspected PE) with the use of widely accepted diagnostic criteria. In the event of death, the diagnosis of PE was accepted if it was Correspondence: Paolo Prandoni, Department of Cardiothoracic and Vascular Sciences, Clinica Medica 2, University of Padua, Via Giustiniani 2, 35128 – Padua, Italy. Tel.: +39 49 8212656; fax: +39 49 8218731. E-mail: paoloprandoni@tin.it

High dose of human plasma-derived FVIII-VWF as first-line therapy in patients affected by acquired haemophilia A and concomitant cardiovascular disease: four case reports and a literature review

Haemostatic control is the first priority in acquired haemophilia A (AHA) and recent consensus recommendations suggest using bypassing agents (BAs) (recombinant activated FVII (rFVIIa) and activated prothrombin complex concentrate) as first-line treatment of bleeds. FVIII concentrates, both plasma-derived and recombinant, may be used with low inhibitor titre, minor haemorrhagic episodes and when bypassing drugs are not available [1]. The use of BAs may be associated with thrombotic complications, especially in the elderly with cardiovascular comorbidity, and should be carried out cautiously, as a literature review reported that 7% of patients treated with rFVIIa experienced thrombotic events [2]. Efficacy of FVIII concentrates in AHA has been reported since the early 1990s. Yet the published reports are retrospective, include few patients and deal with heterogeneous populations (see Table 1). Two main protocols have been recorded in the literature [3,4], but FVIII is often used at a much lower dosage. For instance, the data provided by the EACH2 Registry [5] reporting that the efficacy of FVIII treatment is lower than using BAs would show median doses inferior to those recommended in the literature (initial mean dose 50 U kg , total mean dose for patient 20 000 U, period-treatment range 4–6 days). This letter reports on the experience of our Centre in the use of high-dose human plasma-derived FVIII-VWF (HP-FVIII-VWF) concentrates in four patients affected by AHA and concomitant cardiovascular disease treated with a standardized protocol and include a review of the literature on the usage of HP-FVIII in the treatment of AHA.

A prospective cohort study on patients treated with anticoagulants for cerebral vein thrombosis

Cerebral vein thrombosis (CVT) is a potentially fatal disorder for which treatment guidelines are scanty. To assess the short‐ and long‐term benefit of anticoagulant therapy, we performed a prospective cohort study on CVT patients.

Incidence of arterial embolism in patients on treatment with old and new anticoagulants for venous thromboembolism.

The separate nature of venous and arterial thrombotic disorders has recently been challenged. Patients with venous thromboembolism (VTE) have an increased risk of subsequent symptomatic arterial cardiovascular events, the risk being higher in those with unexplained episodes. Among the implications of this association, there is the potential for old and new antithrombotic drugs to impact on the development of both venous and arterial cardiovascular events. According to the results of recent studies, aspirin in low doses, when administered for the long-term management of patients with unprovoked VTE, reduces by approximately 35% the risk of recurrent VTE while offering a considerable protection against the development of arterial cardiovascular events. By contrast, there is no room to expect a reduction in the risk of subsequent arterial cardiovascular events in patients treated with vitamin K antagonists (VKA) in comparison to patients in whom VKAs are discontinued. According to the results from recent randomized clinical trials, the likelihood of arterial cardiovascular events in patients on the novel direct factor Xa inhibitors is unlikely to differ from that of patients receiving conventional anticoagulation. As dabigatran has been associated with a slight increase in the risk of myocardial infarction over warfarin, its use should be discouraged in patients with coronary heart disease. The long-term use of low-dose apixaban beyond the first months in patients with unprovoked VTE may decrease the long-term risk of arterial, as well as venous, thrombotic events.

The value of inhibitors of factor Xa for the treatment of pulmonary embolism

The introduction of factor Xa inhibitors advocated the initiation of clinical trials that addressed the value of anticoagulation in patients with hemodynamically stable primary pulmonary embolism (PE). In the Matisse trial in patients with PE, fondaparinux administered at therapeutic doses followed by vitamin K antagonists (VKA) has shown a comparable efficacy and safety profile to that seen with intravenous adjusted-dose unfractionated heparin/VKA. A long-acting derivative of fondaparinux, idraparinux, failed to achieve similar results. On the other hand, the Cassiopea study revealed that once weekly injections of idrabiotaparinux, a slightly modified form of idraparinux, have similar efficacy and better safety profile compared to VKAs in the long-term treatment of patients with PE. However, the inconvenient parenteral administration of both fondaparinux and idrabiotaparinux limits their routine clinical use. The availability of antithrombotic compounds that can be administered orally in fixed dose, owing to their predictable pharmacokinetics and pharmacodynamics, and have a lower potential for drug and food interactions has opened new horizons for the treatment of patients with PE. The Einstein PE, Amplify and Hokusai studies, conducted with rivaroxaban, apixaban and edoxaban, respectively, showed that for the treatment of PE they possess a more favorable benefit-to-risk profile than the conventional antithrombotic drugs. In addition, rivaroxaban and apixaban make it possible to treat uncomplicated PE patients from the beginning, without the need for the parenteral administration of heparins or fondaparinux, and edoxaban allows the treatment of fragile patients with lower doses. All of them cover a wide spectrum of clinical presentations, including PE patients at intermediate risk.