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Direct oral anticoagulants are associated with rates of major bleeding which are not negligible, albeit lower than those associated with vitamin K antagonists. No specific reversal agent for factor Xa (FXa) direct inhibitors is currently available for clinical use. A modified activated human FXa decoy protein, andexanet alfa, is being developed that binds FXa direct inhibitors in their active site, thus reversing their anticoagulant effect. The purpose of this article is to review the design, development and clinical trials of andexanet alfa. Andexanet alfa was shown to reverse FXa inhibitors anticoagulant activity both in thrombosis animal models, healthy volunteers and patients with acute major bleeding. Andexanet alfa has been studied in double-blind, placebo-controlled phase II and III studies. A preliminary report of the phase III study showed that an effective hemostasis was obtained after andexanet alfa infusion in the majority of the patients with acute major bleeding associated with FXa inhibitors. Additional studies are ongoing and andexanet alfa is expected to be launched in the market in the near future.

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 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.

Heparin-induced thrombocytopenia (HIT) has not been included as a possible cause of thrombocytopenia in Coronavirus Disease 2019 (COVID-19) patients. We report a case of HIT in a patient with COVID-19 treated with heparin. A 78-year-old man was admitted to our hospital for acute respiratory failure and acute renal failure due to SARS-CoV-2 infection; in intensive care unit, one 5000 IU heparin dose (day 0, platelet count 305,000/μL). On day 2, haemoglobin started to decrease and heparin was stopped. On day 10, platelet count was 153,000/μL and 5000 IU calcium heparin subcutaneously twice daily was started. The platelet further decreased, reaching 49,000/μL on day 17, and the patient was investigated for suspected HIT: an IgG specific chemiluminescence test for heparin-PF4 antibodies was positive and a femoral DVT was found at ultrasound. Argatroban was started, platelet count increased without any bleeding and thrombosis complication. Our experience shows that HIT may develop in heparin treated COVID-19 patients and should be included among the possible cause of thrombocytopenia in such patients.

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. 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). 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.

D-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. D-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. The 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. D-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.

Polycythemia Vera (PV) is a chronic, BCR::ABL1 -negative, myeloproliferative neoplasm characterized by increased hematocrit and platelet/leukocyte counts, as well as by a high risk of thrombosis and progression to myelofibrosis and acute leukemia. The initial discovery of the JAK2 V617F driver mutation, followed by a more in-depth knowledge of the mechanisms that regulate inflammation and iron homeostasis, significantly advanced our understanding of PV pathophysiology, paving the way for a shift from symptom-focused vs. biology-focused treatments. PV management is complex and should be individualized, considering age, comorbidities, clinical presentation, disease course, and patient preferences. As such, optimal care requires a dynamic approach involving coordinated collaboration among healthcare professionals, in order to reduce complications, and enhance patients’ quality of life and outcomes. This narrative review explores principles and benefits of integrated care for PV patients, illustrated through two representative clinical cases. We propose that a transdisciplinary approach be adopted throughout the diagnostic and therapeutic continuum for PV to optimize patient outcomes. The review also proposes a novel cytoreductive treatment algorithm in PV going beyond the conventional risk stratification based on patient’s age and history of thrombosis but rather focusing on patient’s characteristics and treatment needs. Finally, we examine ongoing clinical studies and the latest results and insights on PV therapies (including the JAK inhibitor ruxolitinib, the next-generation mono-pegylated type I interferon ropeginterferon alfa-2b, the iron metabolism modifiers and other experimental approaches) that could reshape the standard of care in PV.

Key summary points Aim To assess whether preoperative DOAC activity measurement enables surgery within 48 h amongst hip fracture patients at a similar prevalence compared with patients receiving other antithrombotics and patients receiving no antithrombotics. Findings Preoperative DOAC drug measurement significantly delayed the time to surgery, whereas DOACs were associated with greater perioperative blood loss, even amongst patients with low presurgical drug levels and regardless of the type of anaesthesia. Message In patients with hip fracture who are receiving DOACs, a protocol for expedited surgery can be applied in which DOACs are stopped before surgery for at least 48 h for factor Xa inhibitors and according to renal function and up to 96 h after the last dose of dabigatran. In this protocol, no drug-level testing is performed. Introduction The use of direct oral anticoagulants (DOACs) may delay surgery in older hip fracture patients. Aim To assess whether preoperative DOAC activity measurement enables surgery within 48 h in hip fracture patients at a similar prevalence compared to patients receiving other antithrombotics or no antithrombotics. Methods A retrospective observational cohort study of hip fracture patients older than 65 years admitted to three Orthogeriatrics units in Italy from 2015 to 2022 was conducted. At admission, demographical and comorbid conditions were recorded, and antithrombotics were stopped. Patients on vitamin K antagonists (VKAs) underwent international normalized ratio (INR) assessments and received vitamin K to achieve an INR below 1.5. Patients receiving DOACs who were enrolled before 2018 underwent daily drug testing, and surgery was performed only after DOAC levels were near or below trough levels. Hours from hospital admission to surgery, perioperative total blood loss, major bleeding and mortality at 90 days were recorded. Results Amongst the 747 patients (median age 85 years; M/F: 192/555), the prevalence of surgery within 48 h was significantly lower amongst patients receiving DOACs (47%) than amongst patients receiving antiplatelet agents (77%) and patients receiving no antithrombotic agents (73%). Preoperative DOAC measurements significantly delayed the time to surgery (median 51 vs. 42 h: P  < 0.05). The major bleeding and mortality rates at 90 days did not differ based on the type of antithrombotics used. The degree of perioperative blood loss was greater in patients receiving DOACs, regardless of drug measurement, than in patients taking other antithrombotics. Conclusions DOAC measurement may delay hip fracture surgery, as even low presurgical levels of DOACs are associated with greater perioperative blood loss.

Background: Hospital-acquired deep vein thrombosis (DVT) is an important cause of morbidity and mortality. Objectives: The purpose of this study was to evaluate the prevalence of proximal lower limb DVT and isolated distal DVT (IDDVT) and their relationship to the Padua Prediction Score (PPS) in acutely ill, hospitalized patients. Methods: In a single-center cross-sectional study, all inpatients from medical departments with suspected lower-extremity DVT were evaluated with whole-leg ultrasonography during 183 days from 2016 to 2017. Results: Among the 505 inpatients (age 78.0 ± 13.3, females 59.2%) from medical departments, 204 (40.2%) had PPS ≥ 4, but only 54.4% of them underwent pharmacological thrombo-prophylaxis. Whole-leg ultrasonography detected 47 proximal DVTs (9.3%) and 65 IDDVTs (12.8%). Proximal DVT prevalence was higher in patients with high PPS vs. those with low PPS (12.7% vs. 7.0% p = 0.029, respectively), whereas IDDVT prevalence was similar in patients with high and low PPS (14.7% vs. 11.6% p = 0.311, respectively). The area under the receiver operating curve (AUC) for the PPS was 0.62 ± 0.03 for all DVTs, 0.64 ± 0.04 for proximal DVTs, and 0.58 ± 0.04 for IDDVTs. Conclusions: In hospitalized patients, IDDVT had similar prevalence regardless of PPS risk stratification. Adherence to thrombo-prophylaxis in patients was still far from optimal.

In patients presenting non-high clinical pretest probability (PTP), a negative d-dimer can exclude venous thromboembolism without imaging tests. However, each d-dimer assay should be validated in prospective studies. We evaluated an automated d-dimer immunoassay using the Sclavo Auto d-dimer (Sclavo Diagnostics Int, Sovicille, Italy) provided by Dasit Diagnostica (Cornaredo, Milan, Italy). Three hundred two consecutive outpatients suspected of leg deep vein thrombosis (DVT) with non-high PTP were included. The Sclavo Auto d-dimer assay was evaluated on 2 analyzers (Sysmex CA-7000 and Sysmex CS-2100; Sysmex Corporation, Kobe, Japan, provided by Dasit). The cutoff value (200 ng/mL) was established a priori. Prevalence of DVT was 11.9%. Since no false-negative patients were detected, the sensitivity and negative predictive values (NPVs) were 100% (sensitivity = CA-7000: 100% [95% confidence interval, CI: 93.3-100], CS-2100: 100% [95% CI: 93.3-100]; NPV = CA-7000: 100% [95% CI: 97.9-100], CS-2100: 100% [95% CI: 98.0-100]). Specificity was 65.4% (95% CI: 59.4-71.1) and 69.2% (95% CI: 63.3-74.7) for CA-7000 and CS-2100, respectively. Specificity increased when a higher cutoff value (234 ng/mL) was used for patients aged ≥60 years without compromising the safety. Assay reproducibility was satisfactory at concentrations near the cutoff value (total coefficient of variations <10%). In conclusion, the Sclavo Auto d-dimer assay was accurate when used for DVT diagnostic workup in outpatients with non-high PTP. Based on its high sensitivity and NPV, it can be used as a stand-alone test in outpatients with non-high PTP. Given its high specificity, the number of patients in whom further imaging techniques can be avoided increased, improving the yield of the test.