Thrombosis and Haemostasis
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Published By Georg Thieme Verlag Kg

2567-689x, 0340-6245
Updated Saturday, 18 September 2021

Isabelle Mahé ◽  
Giancarlo Agnelli ◽  
Cihan Ay ◽  
Aristotle Bamias ◽  
Cecilia Becattini ◽  

Cancer-associated thrombosis (CAT) is associated with a high risk of recurrent venous thromboembolic events (VTE) that require extended anticoagulation in patients with active cancer, putting them at risk of bleeding.The aim of the API-CAT study (NCT03692065) is to assess whether a reduced-dose regimen of apixaban (2.5 mg twice daily [bid]) is non-inferior to a full-dose regimen of apixaban (5 mg bid) for the prevention of recurrent VTE in patients with active cancer who have completed ≥6 months of anticoagulant therapy for a documented index event of proximal deep-vein thrombosis and/or pulmonary embolism.APICAT is an international, randomized, parallel-group, double-blind, non-inferiority trial with blinded adjudication of outcome events. Consecutive patients are randomized to receive apixaban 2.5 mg or 5 mg bid for 12 months. The primary efficacy outcome is a composite of recurrent symptomatic or incidental VTE during the treatment period. The principal safety endpoint is clinically relevant bleeding, defined as a composite of major bleeding or non-major clinically relevant bleeding. Assuming a 12-month incidence of the primary outcome of 4% with apixaban and an upper limit of the 2-sided 95% confidence interval of the hazard ratio <2.0, 1722 patients will be randomized,assuming an up to 10% loss in total patient-years (β = 80%; α 1-sided = 0.025). This trialhas the potential to demonstrate that a regimen of extended treatment for patients with CAT beyond an initial 6 months, with a reduced apixaban dose,has an acceptable risk of recurrent VTE recurrence and decreases the risk of bleeding.

Behnood Bikdeli ◽  
Heather Hogan ◽  
Ruth Morrison ◽  
John Fanikos ◽  
Umberto Campia ◽  

Patients with acute venous thromboembolism (VTE) in the setting of transient provoking factors are typically treated with short-term anticoagulation. However, the risk of recurrence may be increased in the presence of enduring risk factors. In such patients, the optimal duration of treatment remains uncertain. HI-PRO is a single-center, double-blind randomized trial. Patients with deep vein thrombosis (DVT) or pulmonary embolism (PE) following a major provoking factor, including major surgery or major trauma, who completed at least 3 months of standard-dose therapeutic anticoagulation and have at least one enduring risk factor (such as obesity or heart failure), will be considered for inclusion. Patients will be randomized to apixaban 2.5 mg twice daily or placebo for 12 months. The primary efficacy outcome will be symptomatic recurrent VTE –a composite of DVT and/or PE at 12 months after randomization. Secondary efficacy outcomes include a composite of death due to cardiovascular causes, nonfatal myocardial infarction, stroke or systemic embolism, major adverse limb events, or coronary or peripheral ischemia requiring revascularization at 12 months, and individual components of these outcomes. The primary safety outcome is major bleeding according to the International Society on Thrombosis and Haemostasis definition. The study plans to enroll 600 patients (300 per arm) to have 80% power for detecting a 75% relative risk reduction in the primary outcome. Active recruitment began in March 2021. HI-PRO will provide clinically meaningful data on whether patients with provoked VTE and enduring risk factors have fewer adverse clinical outcomes if prescribed low-intensity extended duration anticoagulation.

Giancarlo Agnelli ◽  
Andrés Muñoz ◽  
Laura Franco ◽  
Isabelle Mahé ◽  
Benjamin Brenner ◽  

AbstractEfficacy and safety of anticoagulant treatment for venous thromboembolism (VTE) may vary in patients with different cancer sites. We evaluated the rates of VTE recurrence and major bleeding and the relative efficacy and safety of 6-month treatment with oral apixaban or subcutaneous dalteparin in patients with different cancer sites randomized in the Caravaggio study. Primary cancer was located at gastrointestinal sites in 375 patients (32.5%), lung in 200 (17.3%), breast in 155 (13.4%), genitourinary sites in 139 (12%), gynecological sites in 119 (10.3%), and was hematological in 85 patients (7.4%). Rates of VTE recurrence were 10.9% in patients with gynecological, 8.8% with gastrointestinal, 6.5% with genitourinary, and 5.5% with lung cancer with lower rates in the other sites of cancer. Rates of major bleeding were 7.2% in patients with genitourinary and 4.8% with gastrointestinal cancer, with lower rates in patients with other sites of cancer. The observed absolute risk difference in VTE recurrence in favor of apixaban was 11.9% in patients with gynecological, 5.5% with lung, 3.7% with genitourinary cancer, and 0.6% with gastrointestinal cancer. None of the risk differences was statistically significant. The rates of major bleeding in patients treated with apixaban or dalteparin was similar across patients with different cancer sites. In conclusion, recurrences appear to be more common in patients with gastrointestinal and gynecological cancer and major bleedings in patients with genitourinary and gastrointestinal cancer. Oral apixaban is a valid oral alternative to subcutaneous dalteparin for the treatment of a large spectrum of patients with cancer-associated VTE.

Shoshana Revel-Vilk ◽  
Mira Naamad ◽  
Dafna Frydman ◽  
Michael R. Freund ◽  
Tama Dinur ◽  

Patients with Gaucher disease (GD) are at increased risk of bleeding and have varying degrees of thrombocytopenia, making the analysis of platelet function difficult. This study aimed to provide a clinically relevant quantitative assessment of platelet function and determine its relationship with bleeding and GD-related data. Methods: Unstimulated and stimulated platelet function was measured by whole blood flow cytometry of platelet surface activated αIIbβ3 integrin (detected with monoclonal antibody PAC1), P-selectin (CD62P), and lysosomal-associated membrane protein (LAMP3/CD63) in 149 GD patients. Results: GD patients had a higher level of unstimulated CD63 expression than healthy subjects, which was mildly correlated with glucosylsphingosine (lyso-Gb1) levels (r 0.17, p-value 0.042). Splenectomized GD patients had a higher level of unstimulated αIIbβ3 integrin and P-selectin expression. Reduced platelet reactivity (-2 SD of reference range) was found in 79 (53%, 95% CI 44%-61%) patients, of whom 10 (6.7%, 95% CI 3.3%-12%) had more severe platelet dysfunction. In a multivariate model, only lyso-Gb1 levels were associated with the more severe platelet dysfunction. Fifty-four (49%) of 128 adult patients who completed the bleeding tendency questionnaire reported positive bleeding history. In a multivariate logistic model, older age (OR (95% CI), 1.05 (1.01-1.1)) and low P-selectin reactivity (OR (95% CI), 2.03 (1.25-3.35)) were associated with more than one bleeding manifestation. Conclusion: Flow cytometry enables the study of platelet function in thrombocytopenic GD patients. A platelet degranulation defect, but not αIIbβ3 integrin activation defect, is associated with clinical bleeding. In vivo increased CD63 expression may be related to GD-related inflammation.

Jan Astermark ◽  
Cihan Ay ◽  
Manuela Carvalho ◽  
Roseline D'Oiron ◽  
Philippe De Moerloose ◽  

Introduction: A second peak of inhibitors has been reported in patients with severe haemophilia A (HA) aged >50 years in the UK.1 The reason for this suggested breakdown of tolerance in the ageing population is unclear, as is the potential impact of regular exposure to the deficient factor by prophylaxis at higher age. No data on haemophilia B (HB) has ever been reported. Aim: The ADVANCE Working Group investigated the incidence of late-onset inhibitors and the use of prophylaxis in patients with HA and HB aged ≥40 years. Methods: A retrospective, observational, cohort, survey-based study of all patients aged ≥40 years with HA or HB treated at an ADVANCE HTC. Results: Information on 3,095 people aged ≥40 years with HA or HB was collected. Of the 2,562 patients with severe HA, the majority (73% across all age groups) received prophylaxis. In patients with severe HA, the inhibitor incidence per 1,000 treatment years was 2.37 (age 40–49), 1.25 (age 50–59) and 1.45 (age 60+). Overall, the inhibitor incidence was greatest in those with moderate HA (5.77 (age 40–49), 6.59 (age 50–59) and 4.69 (age 60+) and the majority of inhibitor cases were preceded by a potential immune system challenge. No inhibitors in patients with haemophilia B were reported. Conclusion: Our data do not identify a second peak of inhibitor development in older patients with haemophilia. Prophylaxis may be beneficial in older patients with severe, and possibly moderate HA, to retain a tolerant state at higher age.

Gregory YH Lip ◽  
George Ntaios

No Abstract

Yunnan Zhang ◽  
Yi Zhang ◽  
Xiujin Shi ◽  
Baidi Lin ◽  
Jialun Han ◽  

Abstract Objective This article compares the clinical outcomes of clopidogrel and ticagrelor in patients with acute coronary syndrome (ACS) without cytochrome P450 (CYP)2C19 loss-of-function (LOF) alleles and investigates whether clopidogrel could be an alternative P2Y12 inhibitor without increasing the risk of ischemic events. Methods Patients were divided into the clopidogrel-treated group and the ticagrelor-treated group. Inverse probability of treatment weighting (IPTW) calculated by propensity scores was used to adjust confounding covariates. The primary outcome was major adverse cardiovascular or cerebrovascular events (MACCEs) within 12 months. The secondary outcomes were MACCEs plus unstable angina, and clinically significant bleeding events. Results Finally, 2,199 patients were included. Of them, 1,606 were treated with clopidogrel, and 593 were treated with ticagrelor. The mean age of the original cohort was 59.92 ± 9.81 years. During the 12-month follow-up period, MACCEs occurred in 89 patients (4.0%). No significant differences were observed in MACCEs (IPTW-adjusted hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.65–1.18), MACCEs plus unstable angina (IPTW-adjusted HR, 1.20; 95% CI, 0.91–1.59), or clinically significant bleeding events (IPTW-adjusted HR, 0.81; 95% CI, 0.53–1.23) between the clopidogrel- and ticagrelor-treated groups. Conclusion In patients with ACS without CYP2C19 LOF alleles, clopidogrel was not associated with a higher risk of MACCEs when compared with ticagrelor. The main findings of this study support use of clopidogrel in CYP2C19 LOF noncarriers as an alternative P2Y12 inhibitor, which may reduce medical expenses and adverse reactions caused by more potent P2Y12 inhibitors in these patients.

Gro Grimnes ◽  
Soerajja Bhoelan ◽  
Kristian Hindberg ◽  
Mark Davids ◽  
Max Nieuwdorp ◽  

Abstract Rationale Inflammation is present in several conditions associated with risk of venous thromboembolism. The gut microbiome might be a source of systemic inflammation and activation of coagulation, by translocation of lipopolysaccharides from gram-negative bacteria to the systemic circulation. Objective To investigate whether a vancomycin-induced shift of the gut microbiome in a gram-negative direction influences systemic inflammation and plasma factor (F) VIII procoagulant activity (FVIII:C). Methods and Results We performed a randomized controlled trial including 43 healthy volunteers aged 19 to 37 years. Twenty-one were randomized to 7 days of oral vancomycin intake and 22 served as controls. Feces and blood were sampled at baseline, the day after the end of intervention, and 3 weeks after intervention. Gut microbiome composition was assessed by amplicon sequencing. FVIII:C was measured using an activated partial thromboplastin time-based assay, cytokines were measured using multiplex technology, complement activation was measured using the enzyme-linked immunosorbent assay, and high-sensitivity C-reactive protein (CRP) was measured by an immunoturbidimetric assay. Vancomycin intake reduced gut microbiome diversity and increased the abundance of gram-negative bacteria. Change in FVIII:C in the intervention group was +4 IU/dL versus −6 IU/dL (p = 0.01) in the control group. A similar change was observed for log-transformed CRP (+0.21 mg/dL vs. −0.25 mg/dL, p = 0.04). The cytokines and complement activation markers remained similar in the two groups. Conclusion The found slight increases in FVIII:C and CRP levels might support the hypothesis that a vancomycin-induced gram-negative shift in the gut microbiome could induce increased systemic inflammation and thereby a procoagulant state.

Weiqi Li ◽  
Yongjie Ma ◽  
Chunmei Zhang ◽  
Binlin Chen ◽  
Xiandan Zhang ◽  

AbstractPlatelet granule secretion plays a key role in atherothrombosis. Curcumin, a natural polyphenol compound derived from turmeric, exerts multiple biological activities. The current study sought to investigate the efficacy of tetrahydrocurcumin (THC, the major active metabolite of curcumin) on platelet granule secretion in vitro and thrombus formation in vivo. We found that THC significantly attenuated agonist-induced granule secretion in human gel-filtered platelets in vitro, including CD62P and CD63 expression and platelet factor 4, CCL5, and adenosine triphosphate release. These inhibitory effects of THC were partially mediated by the attenuation of cytosolic phospholipase A2 (cPLA2) phosphorylation, leading to a decrease in thromboxane A2 (TxA2) generation. Moreover, the MAPK (Erk1/2, JNK1/2, and p38 MAPK) signaling pathways were downregulated by THC treatment, resulting in reduced cPLA2 activation, TxA2 generation, and granule secretion. Additionally, THC and curcumin attenuated murine thrombus growth in a FeCl3-induced mesenteric arteriole thrombosis model in C57BL/6J mice without prolonging the tail bleeding time. THC exerted more potent inhibitory effects on thrombosis formation than curcumin. Through blocking cyclooxygenase-1 activity and thus inhibiting platelet TxA2 synthesis and granule secretion with aspirin, we found that THC did not further decrease the inhibitory effects of aspirin on thrombosis formation. Thus, through inhibiting MAPKs/cPLA2 signaling, and attenuating platelet TxA2 generation, granule secretion, and thrombus formation, THC may be a potent cardioprotective agent.

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