Apixaban Versus Vitamin K Antagonists in Patients With Antiphospholipid Syndrome: A Cohort Study.

ABSTRACT: Current guidelines recommend that direct anticoagulants should not be used in prevention of recurrent thrombosis in patients with antiphospholipid syndrome (APS). However, except for triple-positive APS and rivaroxaban use, little evidence supports such recommendation. In a real-life cohort study, we evaluated the risk of thromboembolism and bleeding in patients with APS on apixaban versus vitamin K antagonists (VKA). We enrolled 152 patients with APS (aged 44 years [interquartile range 36-56], 83% women), including 66 patients treated with apixaban 5 mg bid and 86 with warfarin (target international normalized ratio [INR] 2-3). During a median follow-up of 53 months, we recorded venous thromboembolism, ischemic stroke, or myocardial infarction, along with major bleeding. We observed 4 thrombotic events (6.1%, 3 venous thromboembolism and 1 ischemic stroke) in patients on apixaban and 12 events (14%, 9 venous thromboembolism, 2 ischemic strokes and 1 myocardial infarction) in VKA patients. Patients with APS on apixaban had similar risk of recurrent thromboembolism compared with those on warfarin (hazard ratio [HR] = 0.327, 95% confidence interval [CI]: 0.104-1.035). Thromboembolic events occurred less commonly in statin users (8% vs. 50%, P = 0.01) and more frequently in triple-positive APS (50% vs. 22.1%, P = 0.028) and in patients with higher D-dimer at baseline ( P = 0.023); the latter difference was present in the apixaban group ( P = 0.02). Patients on apixaban had similar risk of major bleeding compared with warfarin (HR = 0.54, 95% CI: 0.201-1.448). In real-life patients with APS, apixaban appears to be similar to VKA for the prevention of thromboembolism and risk of bleeding, which might suggest that some patients with APS could be treated with apixaban.

Nonvitamin K Antagonist Oral Anticoagulant in Patients With Venous Thromboembolism and Polycythemia Vera or Essential Thrombocythemia: A Cohort Study.

ABSTRACT: Thrombosis is the most common adverse event in patients with polycythemia vera (PV) and essential thrombocythemia (ET). Little is known about the use of nonvitamin K antagonist oral anticoagulants (NOACs) in patients with myeloproliferative neoplasms. We sought to evaluate the efficacy and safety of NOAC in a cohort of patients with PV and ET, who experienced venous thromboembolism (VTE). We enrolled 48 consecutive patients with PV (70.8%) and ET [median age 67.0 (interquartile range, 58.5-72.0) years], who experienced VTE. Patients received apixaban (39.6%), rivaroxaban (33.3%), or dabigatran (27.1%). During a median follow-up of 30 (interquartile range, 20.5-41.5) months, recurrent thrombotic events and bleeding were recorded. Four thrombotic events (3.3 per 100 patient-years) were reported. Three deep vein thrombosis episodes (2.5 per 100 patient-years) were experienced by 2 patients with PV, who received apixaban (5 mg bid) and dabigatran (150 mg bid), and 1 patient with ET, who received dabigatran (150 mg bid). One ischemic stroke occurred in a patient with PV on rivaroxaban (20 mg/d). There was 1 major bleeding (0.8 per 100 patient-years) in a patient with ET on dabigatran (150 mg bid) and 3 clinically relevant nonmajor bleeding (2.5 per 100 patient-years): 2 on rivaroxaban (20 mg/d) and 1 on apixaban (5 mg bid). We did not observe significant differences related to the type of NOAC. Three deaths (2.5 per 100 patient-years) unrelated to either VTE or bleeding were recorded. This study shows that NOACs may be effective and safe as secondary prevention of VTE in patients with myeloproliferative neoplasms.

Efficacy and Safety of Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial Fibrillation and Chronic Kidney Disease Stage G4: A Single-Center Experience.

Atrial fibrillation (AF) is associated with increased stroke and bleeding risk in patients with chronic kidney disease (CKD). Little is known about the real-life use of non-vitamin K antagonist oral anticoagulants (NOACs) in CKD stage G4. In a retrospective cohort study, we enrolled 182 consecutive AF patients with CKD stage G4 including 90 (49%) subjects on NOAC, ie, 61 on apixaban 2.5 mg bid and 29 on rivaroxaban 15 mg qd, and 92 (51%) subjects on warfarin. Thromboembolic and bleeding events were recorded during a mean follow-up of 26.3 months. There were no differences in demographic, clinical, and laboratory variables at baseline between the 2 treatment groups. During follow-up, arterial thromboembolic events occurred in 11 (12.22%) subjects on NOAC and 7 (7.61%) on warfarin, (hazard ratio [HR] 1.70; 95% CI, 0.65-4.42), with similar risk of ischemic stroke (9 [10%] vs. 7 [7.61%], P = 0.56, respectively). Major bleedings or clinically relevant nonmajor bleeding occurred in 14 (15.56%) on NOAC and 13 (14.13%) on warfarin, (HR 1.12; 95% CI, 0.53-2.39), with similar risk of gastrointestinal bleeding (HR 0.70; 95% CI, 0.20-2.47). We observed no difference in all-cause mortality related to the type of anticoagulants, but it tended to be lower in the apixaban group compared with rivaroxaban group (14.7% vs. 31%, P = 0.07), without any differences in thromboembolic and bleeding events. The study suggests that AF patients with CKD stage G4 receiving reduced-dose NOAC or warfarin have similar risk of thromboembolism and bleeding in everyday practice of a tertiary anticoagulation center.

Unfavourably altered plasma clot properties in patients with primary Raynaud's phenomenon: association with venous thromboembolism.

Associations of Raynaud's phenomenon (RP) with venous thromboembolism (VTE) are unclear. We investigated the occurrence of RP together with prothrombotic state markers and fibrin clot properties in VTE patients. In this prospective cohort study we enrolled 360 patients free of known autoimmune disease. D-dimer, von Willebrand factor (vWF), plasma clot permeability (Ks), clot lysis time (CLT) along with fibrinolysis activators and inhibitors were determined at least 3 months since the VTE event. The presence/absence of RP was diagnosed at least 6 months before VTE. Primary RP occurred in 57 subjects (17%) with a 3.6-fold higher prevalence among women. Patients with RP had 11% higher fibrinogen, 16% higher vWF, 5% lower Ks, and 10% longer CLT (all p < 0.05). Females with RP (21%) had 6.6% lower Ks, 11.2% longer CLT, and 18.5% higher vWF (all p < 0.05) compared with men. CLT was predicted by PAI-1 and vWF levels. Regression analysis showed that RP was a predictor of prolonged CLT in the whole patient group (OR 3.46, 95% CI 1.92-6.24) and in women following VTE (OR 2.75, 95% CI 1.31-5.78). Primary RP patients tend to form denser plasma fibrin clots displaying impaired lysability and increased endothelial damage. RP might be a novel risk factor for VTE, especially in women.

Direct oral anticoagulants in the treatment of cerebral venous sinus thrombosis: a single institution's experience.

AIM OF THE STUDY: Oral anticoagulants, preferentially vitamin K antagonists (VKA), are recommended for 3-12 months in patients with cerebral venous sinus thrombosis (CVST). We present a series of patients with CVST treated with direct oral anticoagulants (DOAC). MATERIALS AND METHODS: We prospectively recruited 36 patients with CVST (aged 40.3 ± 9.2 years, 58.3% female) treated with DOAC based on the physician's or patient's preferences. Functional outcome was assessed with modified Rankin Scale. Recanalisation was assessed on imaging at 3-6 months post the event. Patients were followed for a median of 30 [interquartile range (IQR) 25-37] months. RESULTS: After use of heparin (median: 6 days; IQR 5-8.75), patients received dabigatran (150 mg bid, n = 16 or 110 mg bid, n = 2), rivaroxaban (20 mg qd, n = 10) or apixaban (5 mg bid, n = 8) for a median of 8.5 months (IQR 6.25-12). Complete or partial recanalisation was observed in 34 cases (94.4%). Three patients (8.3%) experienced major bleeding: menorrhagia on rivaroxaban (n = 2) and gastrointestinal bleeding on dabigatran (n = 1). A favourable functional outcome was observed in 24 (66.7%) patients, without any fatality. CSVT recurred in two patients (5.6%) and two venous thromboses developed in two other patients with inherited thrombophilia after anticoagulation withdrawal. CONCLUSIONS AND CLINICAL IMPLICATIONS: DOACs could be an alternative to VKA in CVST patients.

Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial Fibrillation and Thrombocytopenia.

AIMS: Thrombocytopenia was one of the exclusion criteria in randomized trials in which non-vitamin K antagonist oral anticoagulants (NOACs) were tested. The safety of NOACs in patients with atrial fibrillation (AF) and thrombocytopenia remains unclear. METHODS: We studied 62 patients with AF aged from 53 to 85 (mean 70.5) years with platelet count from 50 to 100 × 109/L who were treated with rivaroxaban 15 mg once daily (33.9%), dabigatran 110 mg twice daily (bid) (54.8%), or apixaban 2.5 mg bid (11.3%). Age- and sex-matched AF patients with normal platelet count and similar CHA2DS2-VASc scores who were treated with the recommended doses of NOACs served as a reference group. RESULTS: Patients were followed for a mean of 55 months (range, 23-64 months). In the thrombocytopenia group bleeding risk was higher (mean HAS-BLED score 2.0, vs. 1.0, P < 0.0001). During follow-up in thrombocytopenic and normocytopenic patients, we observed similar rates of major bleeding (1.8%/year vs. 2.7%/year, P = 0.49), clinically relevant nonmajor bleeding (CRNMB) (1.5%/year vs. 1.1%/year, P = 0.74), ischemic stroke and transient ischemic attacks (1.8%/year vs. 1.5%/year, P = 0.8), and death (1.06%/year vs. 1.11%/year, P = 0.96). The risk of bleeding and stroke was unaffected by the type of the NOAC used in both groups. Major bleedings and clinically relevant nonmajor bleeding in thrombocytopenic patients on NOACs were predicted only by age (hazard ratio 1.1, 95% confidence interval 1.0-1.3, P = 0.04). CONCLUSIONS: Our findings indicate that in AF patients with mild thrombocytopenia, anticoagulation with NOAC at reduced doses seems to be safe and effective.

Anti-DFS antibodies occur more commonly in patients following unprovoked venous thromboembolism.

Introduction: It has been reported in a small group of patients that a significant percentage of patients with anti-DFS (dense fine speckled) antibodies has a history of idiopathic arterial or venous thrombosis and/or obstetric complications. To our knowledge there have been no larger studies regarding the prevalence of anti-DFS antibodies in provoked and unprovoked venous thromboembolism (VTE). Aim of the study: We investigated how common anti-DFS70 antibodies occur in patients following VTE and which factors affect their occurrence in this disease. Material and Methods: We screened 287 consecutive adult patients, aged below 60 years, with documented VTE treated for at least 3 months, and 129 age-matched healthy controls. Patients with cancer, severe comorbidities, documented autoimmune diseases, including antiphospholipid syndrome were ineligible. The anti- -DFS70 antibodies were determined based on immunofluorescence on Hep-2 cells. The specific immunofluorescence pattern, characterized by dense fine speckles distributed the nucleus, observed at serum dilution equal to or greater than 1:100, was considered as positive and was confirmed using the semiquantitative ELISA-DFS that provided results as a ratio (RU/ml) with a cut-off of 1. Results: There was no difference in the prevalence of anti-DFS70 antibodies in the VTE and control patients (n=12, 4.18% vs. n=6, 4.65%, p=0.68). Anti-DFS antibodies represented 9.16% of all positive ANA patterns (n=131) in VTE patients, which was a much lower proportion compared with 26.1% of all 23 positive ANA patterns in healthy subjects (p=0.031). The presence of anti-DFS antibodies did not correlate with demographic or clinical variables including time since last VTE event, type of anticoagulation and its quality. The prevalence of anti-DFS70 antibodies was higher in patients with ANA titer ≥1:320 compared to those with the titer < 1:320 (75% vs. 37%, p=0.01). Of importance, higher prevalence of anti-DFS antibodies was observed in patients with unprovoked VTE compared to those with provoked VTE (75% vs. 25%, p=0.01). Among the VTE patients with heritable thrombophilia, i.e. factor V Leiden or prothrombin G20210A mutations, 25.8% of subjects (n=8) had anti-DFS antibodies. Moreover, anti-DFS titer was associated with serum alpha and gamma globulin levels (r=0.47, p=0.027; and r=0.39, p=0.045, respectively), but not with inflammatory markers or D-dimer in VTE patients. Conclusions: Anti-DFS antibodies are present in <5% of VTE patients and are associated with unprovoked VTE including that related to heritable thrombophilia. It might suggest that these antibodies are involved in the pathogenesis of idiopathic VTE.

Direct oral anticoagulants in patients with severe inherited thrombophilia: a single-center cohort study.

We investigated the safety and efficacy of direct oral anticoagulants (DOACs) in patients with venous thromboembolism (VTE) associated with severe inherited thrombophilia. In this single-center cohort study, we enrolled 56 consecutive VTE patients with severe inherited thrombophilia, defined as the presence of antithrombin (n = 18), protein C (n = 12) and protein S (n = 12) deficiencies, homozygous Factor V Leiden (n = 3) and prothrombin G20210AA (n = 4) mutations, or combined defects (n = 7). During a median follow-up of 44.5 (IQR 30-52.5) months, rivaroxaban was used in 30 (53.6%), apixabanin 14 (25%), and dabigatran in 12 (21.4%) subjects. Recurrent nonfatal VTE was observed in 5 (8.9%) patients (2.4 per 100 patient-years), treated with rivaroxaban (n = 4) and apixaban (n = 1). Major bleeding and clinically relevant non-major bleeding (CRNMB) occurred in 2 (3.5%) and 4 (7%) subjects, respectively (0.96 per 100 patient-years and 1.92 per 100 patient-years, respectively), including 4 patients on rivaroxaban. The event-free survival analysis showed that the use of rivaroxaban was associated with increased risk of recurrent VTE or bleeding, compared with apixaban or dabigatran (HR 2.76, 95% CI 1.26-3.92, p = 0.039). In conclusion, the results of our cohort study indicate that full-dose dabigatran or apixaban are effective and safe in patients with severe inherited thrombophilia.

Chronic Kidney Disease and Its Impact on a Prothrombotic State in Patients with Atrial Fibrillation.

It is unclear whether chronic kidney disease (CKD) increases thromboembolism in atrial fibrillation (AF). We conducted a retrospective cross-sectional analysis of 502 non-anticoagulated AF patients (median age, 66 (60-73) years, median CHA2DS2-VASc score, 3.0 (2.0-4.0)) with an estimated glomerular filtration rate (eGFR) ≥ 15 mL/min/1.73 m2. Endogenous thrombin potential (ETP), clot permeability (Ks), and clot lysis time (CLT), among others, were determined. Patients with stage 4 CKD (n = 87; 17.3%) had higher ETP and prolonged CLT compared with those with stage 3 CKD. In patients with stages 3 to 4 CKD (n = 180; 35.9%) N-terminal pro-B-type natriuretic peptide predicted low Ks (the lowest quartile, odds ratio [OR] per 100 pg/mL: 1.03, 95% confidence interval [CI]: 1.01-1.06) and prolonged CLT (the top quartile, OR per 100 pg/mL: 1.05, 95% CI: 1.02-1.08), but not high ETP. In the whole cohort, after adjustment for CHA2DS2-VASc score, stage 4 CKD, but not stage 3 CKD, predicted high ETP (OR: 9.06; 95% CI: 4.44-18.46) and prolonged CLT (OR: 3.58; 95% CI: 1.76-7.28), but not low Ks. compared to the reference eGFR category. This study is the first to demonstrate the prothrombotic and antifibrinolytic alterations in AF patients with stage 4 CKD, but not stage 3 CKD irrespective of clinical stroke risk factors.

Altered Plasma Clot Properties and Trauma-Related Venous Thromboembolism despite Thromboprophylaxis.

BACKGROUND: Prothrombotic clot phenotype may characterize patients developing deep vein thrombosis (DVT) despite pharmacological thromboprophylaxis. We studied the role of fibrin clot properties and its potential determinants in individuals who experienced DVT after lower limb injury. METHODS: In a case-control study, we assessed 50 patients who developed DVT despite prophylactic use of low-molecular-weight heparins (the failed thromboprophylaxis group) after a lower limb injury, and three age- and sex-matched control groups, 50 patients each: (1) patients with trauma-related DVT without prior thromboprophylaxis; (2) individuals with unprovoked DVT; (3) patients without history of DVT (the no-DVT controls). Fibrin clot properties, along with thrombin concentration and α2-antiplasmin, were assessed following 3 months of anticoagulation in all DVT patients. RESULTS: Compared with the no-DVT controls, the failed thromboprophylaxis group exhibited denser fibrin networks (12.8% lower clot permeability [Ks], p = 0.0008) and impaired fibrinolysis (46.2% longer clot lysis time [CLT], p = 0.0001 and 8% lower rate of D-dimer release from clots, p = 0.0008). In the unprovoked DVT, similar Ks and 14.9% shorter CLT (p = 0.02) were reported compared with the failed thromboprophylaxis group. The failed thromboprophylaxis patients had higher odds of having elevated peak thrombin generation (>241.5 nM, 90th percentile in the no-DVT controls; odds ratio [OR]: 3.62; 95% confidence interval [CI], 1.86-7.06; p = 0.002), and higher odds of having elevated α2-antiplasmin (>115.05%; OR: 3.38; 95% CI, 1.64-6.98; p = 0.001). CONCLUSION: Patients who experienced DVT despite thromboprophylaxis following lower limb trauma display a strongly prothrombotic fibrin clot phenotype, including increased clot density and hypofibrinolysis associated with higher plasma α2-antiplasmin.