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BACKGROUND: Venous thromboembolism (VTE), encompassing both deep vein thrombosis (DVT) and pulmonary embolism (PE), is a leading cause of morbidity and mortality worldwide. METHODS: GARFIELD-VTE is a prospective, non-interventional observational study of real-world treatment practices. We aimed to capture the 36-month clinical outcomes of 10,679 patients with objectively confirmed VTE enrolled between May 2014 and January 2017 from 415 sites in 28 countries. FINDINGS: A total of 6582 (61.6 %) patients had DVT alone, 4097 (38.4 %) had PE ± DVT. At baseline, 98.1 % of patients received anticoagulation (AC) with or without other modalities of therapy. The proportion of patients on AC therapy decreased over time: 87.6 % at 3 months, 73.0 % at 6 months, 54.2 % at 12 months and 42.0 % at 36 months. At 12-months follow-up, the incidences (95 % confidence interval [CI]) of all-cause mortality, recurrent VTE and major bleeding were 6.5 (7.0-8.1), 5.4 (4.9-5.9) and 2.7 (2.4-3.0) per 100 person-years, respectively. At 36-months, these decreased to 4.4 (4.2-4.7), 3.5 (3.2-2.7) and 1.4 (1.3-1.6) per 100 person-years, respectively. Over 36-months, the rate of all-cause mortality and major bleeds were highest in patients treated with parenteral therapy (PAR) versus oral anti-coagulants (OAC) and no OAC, and the rate of recurrent VTE was highest in patients on no OAC versus those on PAR and OAC. The most frequent cause of death after 36-month follow-up was cancer (n = 565, 48.6 %), followed by cardiac (n = 94, 8.1 %), and VTE (n = 38, 3.2 %). Most recurrent VTE events were DVT alone (n = 564, 63.3 %), with the remainder PE, (n = 236, 27.3 %), or PE in combination with DVT (n = 63, 7.3 %). INTERPRETATION: GARFIELD-VTE provides a global perspective of anticoagulation patterns and highlights the accumulation of events within the first 12 months after diagnosis. These findings may help identify treatment gaps for subsequent interventions to improve patient outcomes in this patient population. ispartof: THROMBOSIS RESEARCH vol:222 pages:31-39 ispartof: location:United States status: published

Diagnostic algorithms for deep vein thrombosis (DVT) include D-dimer for its high negative predictive value, thus reducing the need for imaging. Small thrombi may be associated with low D-dimer levels, increasing false negatives.To assess the sensitivity and thus the false negative rates of standard and age-adjusted D-dimer cut offs for isolated distal DVT (IDDVT) in outpatients.We enrolled consecutive outpatients with suspected DVT of the lower limbs referring to our vascular emergency department from 2009 to 2018. Patients underwent D-dimer testing (STA, Stago, cut-off: 500 μg/L), pretest clinical probability (PTP) evaluation and complete compression ultrasonography. Follow-up was 3 months.Among 3948 patients (M:1554-39%, median age 69), 486 proximal DVTs (12.3%) and 348 IDDVTs (8.8%) were diagnosed. Median D-dimer was higher in proximal than IDDVT (3960 vs 1400 μgr/L; p = 0.001). The false negative rate of the standard D-dimer cut-off was 2% (95%CI: 0.8-3.2%) for proximal DVT and 14.7% (95% CI: 11-81%) for IDDVT. The false negative rate of the age-adjusted cut-off was 4.9% (3-7%) for proximal DVT and 19.5% (95% CI: 15.4-24.7%) for IDDVT.Small calf thrombi are associated with low D-dimer levels, and age-adjusted D-dimer may be below the cut-off more frequently in subjects with IDDVT than standard cut-off D-dimer, although such D-dimer levels might exclude IDDVT that require treatment.

Coronavirus disease 2019 (COVID-19) has been shown to be strongly associated with increased risk for venous thromboembolism events (VTE) mainly in the inpatient but also in the outpatient setting. Pharmacologic thromboprophylaxis has been shown to offer significant benefits in terms of reducing not only VTE events but also mortality, especially in acutely ill patients with COVID-19. Although the main source of evidence is derived from observational studies with several limitations, thromboprophylaxis is currently recommended for all hospitalized patients with acceptable bleeding risk by all national and international guidelines. Recently, high quality data from randomized controlled trials (RCTs) further support the role of thromboprophylaxis and provide insights into the optimal thromboprophylaxis strategy. The aim of this statement is to systematically review all the available evidence derived from RCTs regarding thromboprophylaxis strategies in patients with COVID-19 in different settings (either inpatient or outpatient) and provide evidence-based guidance to practical questions in everyday clinical practice. Clinical questions accompanied by practical recommendations are provided based on data derived from 20 RCTs that were identified and included in the present study. Overall, the main conclusions are: (i) thromboprophylaxis should be administered in all hospitalized patients with COVID-19, (ii) an optimal dose of inpatient thromboprophylaxis is dependent upon the severity of COVID-19, (iii) thromboprophylaxis should be administered on an individualized basis in post-discharge patients with COVID-19 with high thrombotic risk, and (iv) thromboprophylaxis should not be routinely administered in outpatients. Changes regarding the dominant SARS-CoV-2 variants, the wide immunization status (increasing rates of vaccination and reinfections), and the availability of antiviral therapies and monoclonal antibodies might affect the characteristics of patients with COVID-19; thus, future studies will inform us about the thrombotic risk and the optimal therapeutic strategies for these patients.

Immobility is a well-recognized risk factor for deep vein thrombosis (DVT) in surgical patients, whereas the level of DVT risk conferred by immobility is less defined in patients on medical wards. The aim of this study was to establish whether immobility and its duration are associated with the risk of DVT in acutely ill medical inpatients. We conducted a cohort study in acutely ill medical inpatients. Patients underwent whole leg ultrasound for suspected lower extremity DVT and were divided into two groups according to presence or absence of immobility, defined as total bed rest or sedentary without bathroom privileges. The endpoint was the detection of proximal DVT or isolated distal DVT (IDDVT). Among the 252 acutely ill medical inpatients with immobility (age 82.6 ± 10.3 years, female 63.9%), ultrasound showed 36 (14.3%) proximal DVTs and 39 (15.5%) IDDVTs, while there were 11 (4.4%) proximal DVTs and 26 (10.5%) IDDVTs among the 248 inpatients without immobility (age 73.6 ± 14.2 years, female 54.8%). The risk of proximal DVT was higher in immobile than in mobile patients (OR 3.59, 95% CI: 1.78–7.23, p = 0.0001), whereas the risk of IDDVT was similar between the two groups (OR 1.56, 95% CI: 0.92–2.66, p = 0.111). During the first 3 days of hospitalization, the frequency of all DVTs was similar in patients with and without immobility, but it was 0.26 ± 0.03 vs 0.18 ± 0.03, respectively, after 4 days. In conclusion, immobility for more than 3 days is a risk factor for proximal DVT in acutely ill medical inpatients. © The Author(s) 2021.

Cancer and COVID-19 are both well-established risk factors predisposing to thrombosis. Both disease entities are correlated with increased incidence of venous thrombotic events through multifaceted pathogenic mechanisms involving the interaction of cancer cells or SARS-CoV2 on the one hand and the coagulation system and endothelial cells on the other hand. Thromboprophylaxis is recommended for hospitalized patients with active cancer and high-risk outpatients with cancer receiving anticancer treatment. Universal thromboprophylaxis with a high prophylactic dose of low molecular weight heparins (LMWH) or therapeutic dose in select patients, is currentlyindicated for hospitalized patients with COVID-19. Also, prophylactic anticoagulation is recommended for outpatients with COVID-19 at high risk for thrombosis or disease worsening. However, whether there is an additive risk of thrombosis when a patient with cancer is infected with SARS-CoV2 remains unclear In the current review, we summarize and critically discuss the literature regarding the epidemiology of thrombotic events in patients with cancer and concomitant COVID-19, the thrombotic risk assessment, and the recommendations on thromboprophylaxis for this subgroup of patients. Current data do not support an additive thrombotic risk for patients with cancer and COVID-19. Of note, patients with cancer have less access to intensive care unit care, a setting associated with high thrombotic risk. Based on current evidence, patients with cancer and COVID-19 should be assessed with well-established risk assessment models for medically ill patients and receive thromboprophylaxis, preferentially with LMWH, according to existing recommendations. Prospective trials on well-characterized populations do not exist.

Occult cancer is detected in about 5% of patients with unprovoked venous thromboembolism (VTE) in the 12 months following VTE diagnosis. Current guidance suggests conducting a ‘limited’ cancer screening in these patients, consisting of medical history taking, physical examination, routine blood tests, chest X-ray, and age- and gender-specific testing, over full-body imaging. However, almost half of underlying cancers remain undetected with this approach. Blood-based liquid biopsies may provide an attractive addition or alternative to current cancer screening strategies, with a potentially higher detection rate while avoiding radiation or invasive testing. The PLATO-VTE study is an ongoing, investigator-initiated, multinational, prospective, observational cohort study comparing the sensitivity of novel biomarkers for detecting cancer with that of limited cancer screening in the setting of unprovoked VTE. Patients older than 40 years with a first episode of unprovoked VTE are eligible, while those with major and minor transient provoking risk factors for VTE are excluded. Patients undergo standard-of-care ‘limited’ cancer screening and are followed for 12 months for the occurrence of cancer. A blood sample for biomarker analysis is drawn within 10 days; a second sample is taken at 3 months to assess test result consistency over time. Three biomarkers are assessed: platelet mRNA, circulating tumor DNA, and plasma proteomics analysis. The sensitivity and predictive value of the biomarkers at baseline will be compared with those of limited screening. The results from the PLATO-VTE study may lead to reconsider current approaches for cancer screening in patients with unprovoked VTE.

Background: The long-term risk for recurrent venous thromboembolism (VTE) during extended anticoagulation for a first unprovoked VTE is uncertain. Objectives: To determine the incidence of recurrent VTE during extended anticoagulation of up to 5years in patients with a first unprovoked VTE. Methods: MEDLINE, EMBASE, and the Cochrane CENTRAL were searched to identify randomized trials and prospective cohort studies reporting recurrent VTE among patients with a first unprovoked VTE who were to receive anticoagulation for a minimum of six additional months after completing ≥3months of initial treatment. Unpublished data on number of recurrent VTE and person-years, obtained from authors of included studies, were used to calculate study-level incidence rate, and random-effects meta-analysis was used to pool results. Results: Twenty-six studies and 15603 patients were included in the analysis. During 11631 person-years of follow-up, the incidence of recurrent VTE and fatal pulmonary embolism per 100 person-years was 1.41 (95% CI, 1.03–1.84) and 0.09 (0.04–0.16), with 5-year cumulative incidences of 7.1% (3.0%–13.2%) and 1.2% (0.4%–4.6%), respectively. The incidence of recurrent VTE was 1.08 (95% CI, 0.77–1.44) with direct oral anticoagulants and 1.55 (1.01–2.20) with vitamin K antagonists. The case-fatality rate of recurrent VTE was 4.9% (95% CI, 2.2%–8.7%). Conclusions: In patients with a first unprovoked VTE, the long-term risk of recurrent VTE during extended anticoagulation is low but not negligible. Thus, clinicians and patients should be aware of this risk and take appropriate and timely action in case of suspicion of recurrent VTE. Estimates from this study can be used to advise patients on what to expect while receiving extended anticoagulation, and estimate the net clinical benefit of extended treatment to guide long-term management of unprovoked VTE. © 2021 International Society on Thrombosis and Haemostasis.

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: Few data are available on long-term atherothrombotic events after percutaneous transluminal angioplasty (PTA) for peripheral arterial disease (PAD). Restenosis after PTA may be a marker of a more aggressive atherothrombosis. Aim: To ascertain whether restenosis detected by duplex sonography (DUS) after PTA for iliac and femoro-popliteal disease is associated with a higher risk of cardiovascular events. Methods: We conducted a prospective cohort study of patients undergoing iliac or femoro-popliteal PTA for PAD. Patients were seen at one month, six months, one year and every year thereafter after PTA. At each visit, DUS was performed and accordingly restenosis was stratified into two categories (absent/present). The outcome was the composite of major adverse cardiovascular events (MACE). Results: Two hundred and fifty patients (aged 69 ± 11 years, male 59.2%) were enrolled. During a mean follow-up of 1207 ± 904 days, 102 (40.8%) patients developed restenosis. Restenosis was more frequent in patients with diabetes and critical limb ischaemia. MACEs (n = 76) were more frequent in the patients that developed restenosis vs. those that did not (40.2 vs. 23.6%, p =.005). Predictors of MACEs were diabetes (HR 2.02, 95%CI: 1.19–3.41, p =.009), presence of coronary heart disease at enrolment (HR 2.84, 95%CI: 1.78–4.53, p =.001) and restenosis (HR 1.87, 95%CI: 1.16–3.00, p =.010). Conclusion: Restenosis at DUS, diabetes, and coronary heart disease in patients who underwent iliac or femoro-popliteal PTA for PAD are associated with increased risk of arterial thrombotic event. Intervention trials are required to show the benefit of different therapeutic approaches in such patients at high risk of clinical deterioration.

Introduction: Co-administration of enoxaparin and a direct oral factor Xa inhibitor (xabans: apixaban, edoxaban, rivaroxaban) could give rise to the problem of overlapping the anti-Xa activity when measuring direct oral anticoagulant (DOAC) levels. We aimed to evaluate in vitro the degree of the interference of increasing enoxaparin concentrations on xaban plasma levels measured by different chromogenic anti-Xa assays with drug-specific calibrators and controls. Methods: Seven plasma samples were spiked with apixaban, edoxaban, or rivaroxaban at fixed concentration, and enoxaparin at increasing concentrations (0, 0.125, 0.250, 0.50, 1.0, 1.50, and 2.0IU/mL). The evaluated chromogenic assays were as follows: Biophen DiXaI and Biophen Heparin LRT (Hyphen BioMed), Berichrom Heparin and Innovance Heparin (Siemens), STA-Liquid Anti-Xa (Stago Diagnostics), Technochrom anti-Xa (Technoclone), and HemosIL Liquid Anti-Xa (Werfen). Results: The presence of enoxaparin caused increased DOAC levels, with over-estimation depending on the anti-Xa assay and on the heparin concentration in the sample. The smallest over-estimation was in the sample with enoxaparin 0.125IU/mL and the greatest in the sample with enoxaparin 2.0IU/mL (0%, 3.1%, and 7.4% vs 583.8%, 526.1%, and 415.2% for apixaban, edoxaban, and rivaroxaban, respectively). Biophen DiXaI showed lower interference compared to other methods (maximum over-estimation in the presence of enoxaparin 2.0IU/mL: 56.4% dosing rivaroxaban by Biophen DIXaI vs 583.8% dosing apixaban by Berichrom Heparin). Conclusion: The presence of enoxaparin interferes with xabans measurement by chromogenic anti-Xa assays causing falsely elevated DOAC levels, the over-estimation being dependent on the anti-Xa assay and on the heparin concentration in the sample.

BACKGROUND The long-term risk for major bleeding in patients receiving extended (beyond the initial 3 to 6 months) anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain. PURPOSE To determine the incidence of major bleeding during extended anticoagulation of up to 5 years among patients with a first unprovoked VTE, overall, and in clinically important subgroups. DATA SOURCES MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to 23 July 2021. STUDY SELECTION Randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding among patients with a first unprovoked VTE who were to receive oral anticoagulation for a minimum of 6 additional months after completing at least 3 months of initial anticoagulant treatment. DATA EXTRACTION Two reviewers independently abstracted data and assessed study quality. Unpublished data required for analyses were obtained from authors of included studies. DATA SYNTHESIS Among the 14 RCTs and 13 cohort studies included in the analysis, 9982 patients received a vitamin K antagonist (VKA) and 7220 received a direct oral anticoagulant (DOAC). The incidence of major bleeding per 100 person-years was 1.74 events (95% CI, 1.34 to 2.20 events) with VKAs and 1.12 events (CI, 0.72 to 1.62 events) with DOACs. The 5-year cumulative incidence of major bleeding with VKAs was 6.3% (CI, 3.6% to 10.0%). Among patients receiving either a VKA or a DOAC, the incidence of major bleeding was statistically significantly higher among those who were older than 65 years or had creatinine clearance less than 50 mL/min, a history of bleeding, concomitant use of antiplatelet therapy, or a hemoglobin level less than 100 g/L. The case-fatality rate of major bleeding was 8.3% (CI, 5.1% to 12.2%) with VKAs and 9.7% (CI, 3.2% to 19.2%) with DOACs. LIMITATION Data were insufficient to estimate incidence of major bleeding beyond 1 year of extended anticoagulation with DOACs. CONCLUSION In patients with a first unprovoked VTE, the long-term risks and consequences of anticoagulant-related major bleeding are considerable. This information will help inform patient prognosis and guide decision making about treatment duration for unprovoked VTE. PRIMARY FUNDING SOURCE Canadian Institutes of Health Research. (PROSPERO: CRD42019128597).

Introduction: Cancer-associated thrombosis (CAT) refers to the most common thromboembolic complication of cancer which is venous thromboembolism (VTE). CAT primary prophylaxis, treatment, and secondary prevention are challenging for the complexity of cancer patients, who exhibit hypercoagulability with concomitant-heightened bleeding risk. Areas covered: In this review, the author examines the role of low molecular weight heparins (LMWH), which have been the standard of care for CAT treatment for many years. Direct oral anticoagulants (DOACS) have practical advantages over subcutaneous LMWH, especially for long-term therapy. The author then discusses the results of two RCTs which separately compared the direct oral factor Xa inhibitors, apixaban or rivaroxaban, with placebo for CAT prophylaxis in ambulatory high-risk cancer patients and found that DOACS reduced VTE but increased bleeding. Finally, the author discusses four RCTS separately comparing an oral direct factor Xa inhibitor (edoxaban, rivaroxaban, or apixaban) with LMWH for CAT treatment. DOACS showed non-inferior efficacy, although rivaroxaban and edoxaban showed higher bleeding rates, especially in gastrointestinal cancers. Expert opinion: DOACS have a convenient route of administration and do not require laboratory monitoring, although choice of anticoagulants for CAT depends on factors such as tumor type, bleeding risk, concomitant drugs, and comorbidities.

The impact of the COVID-19 pandemic has been dramatic worldwide, with China, Italy, and now US at its epicenter. Researchers and clinicians are studying and testing different approaches in the attempt to prevent the infection and minimize its severity. Major efforts are focused on optimizing mechanical ventilation, antiviral, and supportive treatment; however, the role of heparin and low molecular weight (LMW) heparin in this setting has been largely overlooked. This review summarizes the available evidence about the role of heparan sulfate as a key entry mechanism for SARS-CoV-2; the efficacy of heparin and LMW heparin in counteracting its entry into the cell, the recent experimental findings obtained in in vitro studies using the LMW heparin enoxaparin Inhixa®, the role of heparin and LMW heparin in modulating the cytokine storm, and the evidence for the use of LMW heparin in the prevention and treatment of the thromboembolic complications of COVID-19. The available evidence suggests that LMW heparin appears as a promising tool in the treatment of COVID-19. Whether its systematic use is associated with a reduction in complications and ultimately mortality of these patients is being tested in several studies starting worldwide.

Background Heparin administration in COVID-19 patients is recommended by expert consensus, although evidence about dosage, duration and efficacy are limited. We aim to investigate the association between different dosages of low molecular weight heparin (LMWH) and mortality among COVID-19 hospitalized patients. Methods and results Retrospective study of 450 laboratory-confirmed COVID-19 patients admitted to Sant'Orsola Bologna Hospital from March 01 to April 10, 2020. Clinical, laboratory and treatment data were collected and analyzed. The in-hospital mortality between COVID-19 patients treated with standard prophylactic LMWH dosage vs. intermediate LMWH dosage was compared. Out of 450 patients, 361 received standard deep vein thrombosis (DVT) prophylaxis enoxaparin treatment (40-60mg daily) and 89 patients received intermediate enoxaparin dosage (40-60 mg twice daily) for 7 days. No significant differences in the main demographic characteristics and laboratory testings at admission were observed in the two heparin regimen subgroups, except for older age and prevalence of hypertension in the group treated with "standard" prophylaxis LMWH dosage. The intermediate LMWH administration was associated with a lower in-hospital all-cause mortality compared to the "standard" prophylactic LMWH dosage (18.8% vs. 5.8%, p = 0.02). This difference remained significant after adjustment with the propensity score for variables that differed significantly between the dosage groups (OR= 0.260, 95% CI 0.089-0.758, p=0.014). Conclusions Intermediate LMWH dosage seems to be associated with lower incidence of mortality compared to standard DVT prophylaxys in hospitalized COVID-19 patients. Our study paves the way to further pathophysiological investigations and controlled studies of anticoagulation therapy in Covid-19 disease.

Unfractionated heparin (UFH) is the most commonly used anticoagulant during cardiac surgery. UFH can be easily monitored and its effect rapidly reversed by a low cost agent, protamine. However heparin use can be complicated by a rare and potentially fatal adverse immunological reaction namely heparin-induced thrombocytopenia (HIT). In HIT, heparin binds to platelet factor 4 (PF4), which is released by activated platelets. As a result, an immunological response can ensue with the development of IgG antibodies against heparin/PF4 complexes. The IgG/heparin/PF4 immune complexes activate platelets with intravascular platelet consumption resulting in thrombocytopenia and increased thrombin production with paradoxical, potentially life-threatening, thrombotic complications instead of bleeding. HIT diagnosis is based on the combination of pre-test clinical probability and the detection of platelet activating antibodies against heparin/PF4 complexes with immunological and functional assays. When HIT is confirmed, any form of heparin should be stopped and non-heparin alternative anticoagulants should be started. Only argatroban and danaparoid are currently licensed for HIT. Cardiac surgery should be delayed in patients with acute or sub-acute HIT until anti-heparin/PF4 antibodies are detectable. In case of urgent cardiac surgery or procedures, bivalirudin is an option, although no reversal agents are available. Other options are pre-operative therapeutic plasmapheresis or use of anti-platelet agents such as tirofiban, epoprostenol with UFH, albeit with increased risk of bleeding.

Heparin-induced thrombocytopenia (HIT) is an immune adverse reaction to heparin that is associated with life-threatening thrombotic complications. More rarely, HIT may begin after stopping of heparin or after flushes of heparin (autoimmune HIT). Fondaparinux has been proposed as a candidate treatment for HIT, but there are few data on its use in autoimmune HIT. An 86-year-old man with a history of diabetes mellitus, arterial hypertension, and hypercholesterolemia was admitted to our hospital for carotid endarterectomy. During surgery, only one heparin dose of 5,000 U was used. Platelet count started to decrease on the 11th day after surgery. Since the patient was not receiving heparin treatment/prophylaxis, HIT was not suspected. On day 19, platelet count was 61 × 103/μL, and the patient was investigated for a diagnosis of HIT. Immunoglobulin (Ig)-G-specific enzyme-linked immunosorbent assay (ELISA) was positive and HIT was confirmed by a platelet aggregation test; fondaparinux 5 mg once a day was started. During fondaparinux treatment, platelet count did not increase and a lower leg deep vein thrombosis occurred. Fondaparinux was stopped and rivaroxaban 15 mg twice a day was started. Platelet count returned to base line after 10 days from fondaparinux withdrawal. There was no thrombotic event or bleeding complication during rivaroxaban treatment. Anecdotal evidence suggests risk of failure of fondaparinux treatment for autoimmune HIT and supports the use of rivaroxaban for treatment of HIT, justifying larger studies.

Introduction: To measure direct factor Xa inhibitor (apixaban, edoxaban, rivaroxaban) concentrations, dedicated chromogenic anti-Xa assays are recommended as suitable methods to provide rapid drug quantification. Moreover, the high-performance liquid chromatography with ultraviolet detection (HPLC-UV) is reported as a reliable quantitative technique. We investigated seven anti-Xa assays and an HPLC-UV method for measurement of apixaban and rivaroxaban levels in patients enrolled in the START-Register. Methods: A total of 127 apixaban and 124 rivaroxaban samples were tested by HPLC-UV and the following anti-Xa assays: Biophen DiXaI and Heparin LRT (Hyphen BioMed), Berichrom and Innovance Heparin (Siemens), STA-Liquid Anti-Xa (Stago Diagnostics), Technochrom anti-Xa (Technoclone), and HemosIL Liquid Anti-Xa (Werfen). Each method was performed in one of the participating laboratories: Bologna, Cremona, Florence, and Padua. Results: Our data confirmed the overestimation of apixaban and rivaroxaban levels by the antithrombin-supplemented anti-Xa method (Berichrom). Performances and reproducibility of the six anti-Xa assays not supplemented with antithrombin and the HPLC-UV method were good, with limits of quantification from 8-39ng/mL (apixaban) and 15-33ng/mL (rivaroxaban). The six chromogenic methods showed good concordances with the quantitative HPLC-UV [bias: −26.9-22.3ng/mL (apixaban), −11.3-18.7ng/mL (rivaroxaban)]. Higher bias and wider range between limits of agreement were observed at higher concentrations [200ng/mL: bias −42.2-36.8ng/mL (apixaban) and −20.1-68.9ng/mL (rivaroxaban)]. Conclusion: Overall, the anti-Xa assays not supplemented with antithrombin and the HPLC-UV method proved to be suitable for apixaban and rivaroxaban quantification.

The post-thrombotic syndrome (PTS) is a long-term complication of deep vein thrombosis (DVT) of the lower limbs occurring in 40–50% of patients (1). Impaired thrombus resolution with persistent obstruction is involved in the pathogenesis of PTS, similarly to chronic thromboembolic pulmonary hypertension (CTEPH), which however develops only in a small minority of subjects after pulmonary embolism (PE)(2). Both PTS and CTEPH are associated with substantial morbidity and high healthcare expenses (2). PTS epidemiology reflects that of venous thromboembolism (VTE), which is estimated to affect 104–183 subjects per 100,000 person-years among Caucasians (3, 4), encompassing PE and DVT, with an incidence ranging from 29 to 78 and 45 to 117, per 100,000 person-years, respectively (5, 6). PTS can occur in severe forms in 10% and with the development of leg ulcers in 1–3% of patients (1). Leg ulcers …

The post-thrombotic syndrome (PTS) is a long-term complication of deep vein thrombosis (DVT) of the lower limbs occurring in 40–50% of patients (1). Impaired thrombus resolution with persistent obstruction is involved in the pathogenesis of PTS, similarly to chronic thromboembolic pulmonary hypertension (CTEPH), which however develops only in a small minority of subjects after pulmonary embolism (PE) (2).

© 2018 European Federation of Internal Medicine Despite recent advances in the treatment of Deep Vein Thrombosis (DVT) provided by Direct Oral Anticoagulants (DOAC), a substantial proportion of lower limb DVT patients will develop some degree of post-thrombotic syndrome (PTS) within 2 years. Systemic thrombolysis, although effective in reducing the risk of PTS and leg ulceration, is associated with a high risk of major bleeding, making it unsuitable for the vast majority of patients. A local approach, aimed at delivering the fibrinolytic drug directly into, or near to, the thrombus surface, is attractive because of the possibility of lowering of the administered drug dose, thus reducing the bleeding risks. However, even after the recent publication of the ATTRACT trial, only weak evidence is available about the efficacy and safety of Catheter Directed Thrombolysis (CDT), either alone (pharmacological technique) or in combination with additional endovascular approaches (pharmacomechanical technique, PMT) including percutaneous mechanical thrombectomy, angioplasty with or without stenting and ultrasound-assisted CDT. The present review is aimed at providing the physicians with a comprehensive evaluation of the current evidence about this relevant topic, in order to build a reliable conceptual framework for a more appropriate use of this resource.

The recent position paper of the European Society of Cardiology (ESC) on cardiovascular toxicity of cancer treatments has attracted considerable interest by healthcare professionals, since it is the first concrete help in the difficult task of monitoring and approaching cardiovascular side effects of anticancer treatments. The ESC expert opinion was not intended as a clinical practice guideline; however, it reports major cardiovascular complications grouped into nine categories, addressing current clinical strategies for prevention and mitigation. In this point of view, we discuss key challenges emerging from critical appraisal of the ESC position paper: (1) the wide spectrum of cardiovascular toxicities associated with oncological drugs, focusing on targeted agents, (2) managing strategies in patients with cardiac implantable devices, (3) the underappreciated (but emerging) immune-related cardiovascular toxicities of checkpoint inhibitors, which may also result in severe heart failure and fulminant myocarditis, (4) the evolving role of anticoagulation in oncology, and the evidence supporting (or not) the use of direct-acting oral anticoagulants in cancer-associated thrombosis.

Deep vein thrombosis (DVT) is an important cause of morbidity and mortality in hospitalized patients. The Wells score for DVT pretest probability (PTP) was validated in outpatients, but its utility for inpatients is unclear. The aim of this study was to establish the prevalence of inpatient proximal and distal DVT and the Wells score performance in inpatients. A single-center cross-sectional study was conducted in a university hospital. During 183days, all inpatients with suspected lower-extremity DVT were evaluated with the Wells score and whole-leg ultrasound. Among 634 inpatients (age 77.5 ± 13.8 years, males 39.3%), 507 (80.0%) were from medical wards and 127 (20.0%) from surgical wards. During the study period, there were 11,662 hospital admissions in the surgical/medical services. Whole-leg ultrasound detected 128 DVTs (20.2%); 51 (39.8%) were proximal and 77 (60.1%) were isolated distal DVTs. Estimated DVT prevalence in hospital setting was 1.09% (95% CI 0.93–1.31), and isolated distal DVT prevalence was 0.66% (95% CI 0.53–0.82). DVT frequency in low-, moderate-, and high-PTP groups was 9.8%, 24.3%, and 41.5%, respectively (p = 0.001). The area under the receiver operating characteristic curve for the Wells score was 0.67 ± 0.03 for all DVTs and 0.75 ± 0.04 for only proximal DVTs. A high PTP had a sensitivity of 24% (95% CI 14–37%) and a specificity of 93% (95% CI 91–95%) for proximal DVT diagnosis. In hospitalized patients, isolated distal DVT has a higher incidence than expected, and the Wells score accuracy for proximal DVT is similar to that found in outpatients.

BackgroundD-dimer levels measured during and after vitamin K antagonist withdrawal may be used in clinical practice to assess the individual risk of recurrent venous thromboembolism. Currently, direct oral anticoagulants (DOACs) are frequently used in venous thromboembolism treatment; however, their pharmacokinetics and pharmacodynamics characteristics are completely different than vitamin K antagonists. The present study aimed at comparing the results of D-dimer levels during and after anticoagulation withdrawal in patients with venous thromboembolism treated with DOACs or warfarin.Material and methodsD-dimer levels were measured in 527 patients ("cases") during DOACs treatment (T0) and after 15 (T15), 30 (T30), 60 (T60) and 90 (T90) days after their discontinuation and in 527 patients ("controls") enrolled in the DULCIS study (all treated with warfarin), matched for sex, age (+/-3 y), type of D-dimer assay and site of venous thromboembolism. Both cases and controls received anticoagulant treatment after a first venous thromboembolism event that was unprovoked or associated with weak risk factors.ResultsThe rate of positive D-dimer results was significantly higher in cases than in controls at T0 (10.8% vs 5.1%, p = 0.002) and at T30 (18.8% vs 11.8%, p = 0.019), as well as at the other time-points, though not statistically significant.ConclusionD-dimer levels during and after stopping an anticoagulant treatment for a venous thromboembolism episode differ between patients treated with a DOAC than in those treated with warfarin. Specifically designed prospective studies are warranted to reassess the use of D-dimer as predictor of the risk of recurrent venous thromboembolism in patients treated with DOACs.

Background Thrombocytopenia is associated with increased mortality in the general population, but few data exist in patients with atrial fibrillation ( AF ) taking oral anticoagulants. We investigated factor determinants of thrombocytopenia in a large cohort of patients affected by AF and its association with total mortality. Methods and Results Multicenter prospective cohort study, including 5215 patients with AF from the START (Survey on Anticoagulated Patients Register) registry, 3877 (74.3%) and 1338 (25.7%) on vitamin K or non–vitamin K antagonist oral anticoagulants, respectively. Thrombocytopenia was defined by a platelet count 9 /L. Determinants of thrombocytopenia were investigated, and all‐cause mortality was the primary survival end point of the study. Thrombocytopenia was present in 592 patients (11.4%). At multivariable logistic regression analysis, chronic kidney disease (odds ratio [ OR], 1.257; P =0.030), active cancer ( OR, 2.065; P =0.001), liver cirrhosis ( OR, 7.635; P OR, 1.234; P =0.046) were positively associated with thrombocytopenia, whereas female sex ( OR, 0.387; P OR, 0.787; P =0.032) were negatively associated. During a median follow‐up of 19.2 months (9942 patient‐years), 391 deaths occurred (rate, 3.93%/year). Mortality rate increased from 3.8%/year to 9.9%/year in patients with normal platelet count and in those with moderate‐severe thrombocytopenia, respectively (log‐rank test, P =0.009). The association between moderate‐severe thrombocytopenia and mortality persisted after adjustment for CHA 2 DS 2 VAS c score (hazard ratio, 2.431; 95% CI, 1.254–4.713; P =0.009), but not in the fully adjusted multivariable Cox regression analysis model. Conclusions Thrombocytopenia is common in patients with AF . Despite an increased incidence of mortality, thrombocytopenia was not associated with mortality at multivariable analysis. Thrombocytopenia may reflect the presence of comorbidities associated with poor survival in AF .

Background: Careful assessment of bleeding history is the first step in the evaluation of patients with mild/moderate bleeding disorders, and the use of a bleeding assessment tool (BAT) is strongly encouraged. Although a few studies have assessed the utility of the ISTH-BAT in patients with inherited platelet function disorders (IPFD) none of them was sufficiently large to draw conclusions and/or included appropriate control groups. Objectives: The aim of the present study was to test the utility of the ISTH-BAT in a large cohort of patients with a well-defined diagnosis of inherited platelets disorder in comparison with two parallel cohorts, one of patients with type-1 von Willebrand disease (VWD-1) and one of healthy controls (HC). Patients/Methods: We enrolled 1098 subjects, 482 of whom had inherited platelet disorders (196 IPFD and 286 inherited platelet number disorders [IT]) from 17 countries. Results: IPFD patients had significantly higher bleeding score (BS; median 9) than VWD-1 patients (median 5), a higher number of hemorrhagic symptoms (4 versus 3), and higher percentage of patients with clinically relevant symptoms (score > 2). The ISTH-BAT showed excellent discrimination power between IPFD and HC (0.9

Background Parenteral anticoagulants and vitamin K antagonists (VKAs) have constituted the cornerstone of venous thromboembolism (VTE) treatment. Meanwhile, direct oral anticoagulants (DOACs) provide physicians with an alternative. The Global Anticoagulant Registry in the FIELD (GARFIELD)-VTE observes real-world treatment practices. Objectives Describe initial anticoagulation (AC) treatment patterns in VTE patients who received parenteral AC, VKAs, and/or DOACs within ±30 days of diagnosis. Methods VTE patients were categorized into parenteral AC only, parenteral AC with transition to VKA, VKA only, parenteral AC with transition to DOAC, and DOAC only. Results A total of 9647 patients were initiated on AC treatment alone. 4781 (49.6%) patients received DOACs ± parenteral ACs; 3187 (33.0%), VKA ± parenteral ACs; and 1679 (17.4%) parenteral ACs alone. Rivaroxaban was the most frequently used DOAC (79.4%). DOACs were more frequently used in North America/Australia (58.1%), Europe (52.2%), and Asia (47.6%) than in Latin America (29.7%) and the Middle East/South Africa (32.5%). In patients with suspected VTE, most received parenteral AC monotherapy (67.7%). Patients with deep vein thrombosis were more likely to receive DOACs alone than those with pulmonary embolism with or without deep vein thrombosis (36.2% vs 25.9%). Active cancer patients received parenteral AC alone (58.9%), with 25.5% receiving DOAC ± parenteral AC and 12.8% parenteral AC and VKA. A total of 46.5% of pregnant patients received parenteral AC monotherapy, 34.0% were treated with VKA ± parenteral AC, and 19.5% received a DOAC (± parenteral AC). Conclusion AC treatment patterns vary by patient population, geographic region and site of VTE. Guidelines for AC therapy are not always adhered to.

ntroduction: Idiopathic or unprovoked venous thromboembolism is an event occurring in the absence of any apparent provoking or triggering environmental risk factors, such as surgery, trauma, and immobilization. Areas covered: Unprovoked VTE can be associated with occult cancer, but only limited, and not extensive cancer screening, may be warranted, as the rate of occult cancer is low in such patients. Routine thrombophilia testing is not currently recommended as it does not influence the management of the disease. The duration of anticoagulation for unprovoked VTE after the first three months is still debated as the disease tends to recur regardless of treatment duration. Expert commentary: Prognostic scores incorporating patient related risk factors, such as age and sex, and global markers of hypercoagulability, such as D-dimer, have been proposed for identifying high risk patients who are candidates for extended anticoagulation beyond three months. Direct oral anticoagulants, aspirin and sulodexide could be alternative to vitamin K antagonists (VKA) for long term treatment in such patients. The most up to date guidelines suggest DOACs over VKA for non-cancer VTE in the first three months and also long-term in subjects at low or moderate risk of bleeding, albeit with grade 2B strength of recommendation.