Non-vitamin K antagonist oral anticoagulants in patients with severe inherited thrombophilia: a series of 33 patients.

: The aim of the study was to investigate whether treatment with non-vitamin K antagonist oral anticoagulants (NOACs) is effective and well tolerated in real-life patients following venous thromboembolism (VTE) associated with severe inherited thrombophilia. We evaluated 33 consecutive patients with severe inherited thrombophilia, defined as the presence of deficiencies in protein C, protein S, or anti-thrombin, homozygous factor V Leiden and prothrombin G20210A mutations, or combined defects. The patients were recruited from March 2010 to December 2015 and followed till July 2016. Rivaroxaban was used in 23 patients (70%), whereas dabigatran and apixaban were used in 4 patients each. During a median 21 (range 8-34) months' follow-up, three recurrent VTE episodes (9%) were observed. Deep vein thrombosis recurred after 6 months on rivaroxaban in a protein S-deficient 32-year-old woman who had heavy menstrual bleeding resulting in interruptions of therapy. A long journey preceded deep vein thrombosis recurrence after 12 months of rivaroxaban use in a 59-year-old obese man homozygous for prothrombin 20210A mutation. The third recurrent VTE following anticoagulation withdrawal prior to surgery and during hospitalization was observed in a 56-year-old woman with protein S deficiency and heterozygous factor V Leiden. The three patients continued use of NOACs, apixaban, dabigatran, and rivaroxaban, respectively. This largest real-life series of patients with severe thrombophilia receiving NOACs indicates that such patients could be safely and effectively treated with NOACs. Lower efficacy was observed in protein S deficiency. Recurrent VTE was mostly related with nonadherence, which highlights an important role of regular intake of NOACs in high-risk patients.

The use of direct oral anticoagulants in 56 patients with antiphospholipid syndrome.

INTRODUCTION: Antiphospholipid syndrome (APS) is a common acquired thrombophilia associated with a high thrombotic risk, in which vitamin K antagonists (VKA) represent the mainstay of therapy. Case series involving up to 35 patients with APS suggested limited efficacy and safety of direct oral anticoagulants (DOACs). MATERIAL AND METHODS: In the prospective case series we followed 56 consecutive patients with APS (44 women and 12 men, aged from 22 to 64years), including 33 (60%) associated with systemic lupus erythematosus (SLE) and 16 (28.6%) with triple APS who were treated with DOACs due to their preferences or unstable anticoagulation with VKA. DOACs were started at least 3months since the thromboembolic event in patients with D-dimer below 500ng/ml. RESULTS: Forty-nine (87.5%) patients were treated with rivaroxaban, 4 (7.3%) with dabigatran and 3 (5.4%) with apixaban. During follow-up of 2 to 43 (mean 22) months, 6 (10.7%, 5.8 per 100 patient-years) patients (4 women and 2 men, 4 with triple positive APS) experienced recurrent thrombosis, including deep vein thrombosis (n=4, including 2 episodes preceded by nonadherence), superficial vein thrombosis (n=1) and non-ST elevation myocardial infarction (n=1). The recurrence rate of VTE on DOACs was 5.8 per 100 patient-years. Two patients (3.6%) experienced severe bleeding. CONCLUSIONS: This case-series suggests that DOACs are safe in patients with APS. These findings need to be confirmed in larger studies.

Activated protein C resistance in patients following venous thromboembolism receiving rivaroxaban versus vitamin K antagonists: assessment using Russell viper venom time-based assay.

: Activated protein C resistance (APC-R) is assessed as part of thrombophilia screening, preferably in patients not taking oral anticoagulants. Rivaroxaban is known to alter some APC-R assays. To our knowledge, there have been no reports on the effect of rivaroxaban on the Russell viper venom time (RVVT)-based APC-R assay in real-life patients. In 168 consecutive outpatients suspected of having venous thromboembolism because of thrombophilia, APC-R was determined using the RVVT-based ProC Ac R assay (Siemens, Marburg, Germany). Patients receiving rivaroxaban or vitamin K antagonists were eligible. We measured rivaroxaban concentrations using the anti-Xa Biophen DiXal assay (Hyphen Biomed, Neuville-Sur-Oise, France) and factor V Leiden using the real-time PCR. APC-R was detected in 23 (28%) patients on rivaroxaban (n = 81) administrated 2-48 h since the blood draw, 15 (28%) patients on vitamin K antagonists (n = 54), and in four (12%) patients off anticoagulation (n = 33). Compared with nonanticoagulated patients, APC-R ratios were similar in patients on rivaroxaban, without any correlation with rivaroxaban concentrations (from 0 to 303 µg/l). None of the patients on rivaroxaban were found to have false-negative or false-positive APC-R ratios. Rivaroxaban concentrations up to 300 µg/l do not affect results of the ProC Ac R RVVT-based assay, which could be recommended in patients referred to a clinic for thrombophilia screening in whom the time since the last dose of rivaroxaban is uncertain.

Direct Oral Anticoagulants in Patients with Thrombophilia: Challenges in Diagnostic Evaluation and Treatment.

Direct oral anticoagulants (DOACs) or non-vitamin K oral anticoagulants (NOACs) are increasingly used in the prevention of recurrent venous thromboembolism (VTE), including that associated with thrombophilia. The efficacy of DOACs in thrombophilic patients, especially those with severe trombophilia or triple positive antiphospholipid syndrome (APS) with arterial thromboembolic events, remains controversial. Most case reports and case series indicate that DOACs are an attractive therapeutic option in the vast majority of these patients at high risk of recurrent VTE with more concerns raised in high-risk APS patients and these deficient in protein S (PS). Adherence to DOACs is of paramount importance in these patients. In this review we presented available data on the management of patients with thrombophilia using rivaroxaban, dabigatran or apixaban at standard doses. Moreover, we also demonstrated the overall effects of DOACs on coagulation tests, particularly those determined during thrombophilia screening such as lupus anticoagulant, antithrombin, protein C, PS, activated protein C ratio. Despite the paucity of data from randomized studies, the current evidence supports the use of DOACs in thrombophilia, especially those who prefer such treatment or have unstable anticoagulation with vitamin K antagonists or unacceptable adverse events while using these drugs.

False-positive lupus anticoagulant in patients receiving rivaroxaban: 24 h since the last dose are needed to exclude antiphospholipid syndrome.

Rivaroxaban, a direct factor Xa inhibitor, affects laboratory clotting tests. We report here 10 venous thromboembolism patients with false-positive lupus anticoagulant during rivaroxaban therapy. Two dilute Russell Viper Venom time (dRVVT)-based integrated assays, HemosIL dRVVT Screen/HemosIL dRVVT Confirm (Instrumentation Laboratory, LA1/LA2 (Siemens, Germany) and LA1/LA2 (Siemens, Marburg, Germany), showed that the patients were lupus anticoagulant-positive. Antiphospholipid antibodies were negative except for one patient. Screening activated partial thromboplastin time-based assay PTT lupus anticoagulant was lupus anticoagulant-positive, whereas the confirmatory Staclot lupus anticoagulant (both Diagnostica Stago, France) was lupus anticoagulant-negative. Re-examination after discontinuation of rivaroxaban (>24 h) ruled out the presence of lupus anticoagulant. Our data indicate that to reliably evaluate lupus anticoagulant in patients on rivaroxaban, blood should be drawn 24 h after the last dose.

Acquired factor V inhibitor in a woman following aortic aneurysm surgery.

A 67-year-old woman with nephrotic syndrome as a complication of membranous glomerulonephritis associated with chronic active hepatitis B virus infection developed factor V inhibitor following emergency aortic aneurysm surgery followed by massive blood transfusions and haemodialysis. On the second postoperative day, prothrombin time and activated partial thromboplastin time increased and were unresponsive to fresh frozen plasma. Epistaxis and urethral bleeding were observed, followed by mucosal mouth bleeding. A very low factor V activity less than 5% was found and a factor V inhibitor was detected at 7.76 Bethesda Units. Treatment with corticosteroids was successful. In this patient, several conditions known to predispose to the generation of factor V inhibitor occurred simultaneously. Four months later, factor V inhibitor (225 Bethesda Units) recurred and the patient died of intracerebral haemorrhage.

Nonstenotic bicuspid aortic valve is associated with elevated plasma asymmetric dimethylarginine.

BACKGROUND: Recently, it has been reported that nonstenotic bicuspid aortic valve (BAV) with dilated proximal aorta is linked with increased matrix metalloproteinase-2 (MMP-2) and endothelial dysfunction. OBJECTIVE: We wondered whether asymmetric dimethylarginine (ADMA), a nitric oxide synthase inhibitor, might be altered and associated with MMP-2 in BAV patients. We assessed the relation between ADMA levels and aortic diameters and hypothesized that elevated ADMA might be an independent predictor of progressive aortic dilatation in BAV patients. METHODS: We studied 20 patients with nonstenotic BAV (17 men and 3 women, median age 27, range 24-33 years). Twenty age-matched patients with tricuspid aortic valves served as controls. Plasma levels of ADMA, symmetric dimethylarginine (SDMA), L-arginine, serum MMP-2, MMP-9, and plasma total homocysteine (tHcy), together with parameters of aortic elasticity, were measured. RESULTS: ADMA and MMP-2 levels were higher in the BAV group compared with controls (medians, 0.55 vs. 0.43 µmol/l, P < 0.001 and 1.25 vs. 1.00 µmol/l, P < 0.001, respectively). The BAV patients also had higher SDMA and tHcy levels than controls (0.39 vs. 0.35 µmol/l, P < 0.001 and 11.5 vs. 9.7 µmol/l, P = 0.006). ADMA levels in BAV patients correlated with aortic annulus (r = 0.4, P = 0.043), peak aortic velocity (r = 0.6, P = 0.001), aortic distensibility (r = 0.6, P = 0.004), aortic stiffness index (r = 0.7, P < 0.001), and aortic strain (r = 0.7, P < 0.001) as well as with MMP-2 (r = 0.6, P = 0.002) and tHcy (r = 0.4, P = 0.042). CONCLUSIONS: This study is the first to show that circulating ADMA together with MMP-2 is a marker of proximal ascending aortic dilatation and impaired aortic elastic properties in nonstenotic BAV patients. It might be speculated that plasma ADMA could be helpful in identifying BAV patients at a higher risk of aortic aneurysm.

Assessment of left ventricle function in patients with symptomatic and asymptomatic aortic stenosis by 2-dimensional speckle-tracking imaging.

BACKGROUND: Global longitudinal peak strain (GLPS) quantifies left ventricle (LV) long-axis contractility. Early detection of LV systolic dysfunction is pivotal in diagnosis and treatment of patients with aortic stenosis (AS). This study was performed to assess LV longitudinal systolic function by GLPS derived from 2-dimensional speckle tracking imaging (2D-STI) in AS patients in comparison to standard echocardiographic parameters. MATERIAL/METHODS: Laboratory tests, standard echocardiography, tissue Doppler imaging (TDI) and 2D-STI examinations with GLPS calculation were performed in 49 consecutive patients with moderate to severe AS with LV ejection fraction ≥50% and 18 controls. RESULTS: While LVEF do not differentiate AS patients from controls, GLPS was significantly decreased in the AS group (-15.30 ± 3.25% vs. -19.60 ± 2.46% in controls, p<0.001). GLPS was significantly reduced in symptomatic AS patients as compared to the asymptomatic AS group [-15.5 (11.8-16.8) vs. -17.5 (14.7-18.9)%, p=0.02]. CONCLUSIONS: In aortic stenosis patients, despite normal left ventricle ejection fraction, long-axis left ventricular function is impaired, which manifests in global longitudinal peak strain reduction. GLPS reveals that LV function impairment is more pronounced in symptomatic as compared to asymptomatic AS patients. Further studies are needed to determine the prognostic significance of early LV function impairment in aortic stenosis patients showed by GLPS.

High tea and vegetable consumption is associated with low ADMA generation in older healthy subjects.

Asymmetric dimethylarginine (ADMA) has been recognized as a marker of cardiovascular risk. We sought to investigate whether consumption of tea, coffee, fruit or vegetables is associated with ADMA. In 148 consecutive apparently healthy subjects (104 men and 44 women aged 40 to 70), daily tea, coffee, fruit and vegetable consumption was ascertained by questionnaire. Plasma ADMA, symmetric dimethylarginine (SDMA), and l-arginine levels were measured by high-performance liquid chromatography. Median tea and coffee consumption was 2 cups/d, while vegetable and fruit intake was 152 (120-179)g/d and 120 (108-134)g/d, respectively. Median plasma ADMA, SDMA and arginine were 0.47 (0.43-0.53)µmol/L, 0.59 (0.54-0.66)µmol/L and 86 (68-101)µmol/L, respectively. ADMA correlated inversely with tea (r = -0.70, P < .0001) and vegetable consumption (r = -0.50, P < .0001) even after adjustment for age, sex, body mass index, smoking status, and potential dietary and biochemical parameters. No association between ADMA and fruit consumption was found. ADMA correlated positively with coffee intake (r = 0.37, P < .0001), although these associations were less potent after adjustment for dietary factors. Higher tea and vegetable intake is associated with lower plasma ADMA levels in healthy middle-aged subjects.

A history of early stent thrombosis is associated with prolonged clot lysis time.

It has been demonstrated that formation of compact plasma fibrin clots resistant to plasmin-mediated lysis characterises patients following in-stent thrombosis (IST). The relationship between defective fibrinolysis, reflected as prolonged clot lysis time (CLT) and IST is unclear. We sought to investigate whether patients with acute and subacute IST have impaired fibrinolytic capacity. We studied 41 definite IST patients, including 15 with acute and 26 with subacute IST experienced 2-73 months prior to enrollment, versus 41 controls matched for demographics, cardiovascular risk factors, concomitant treatment and angiographic/stent parameters. CLT, reflecting lysis of a tissue factor-induced plasma clot by exogenous tissue plasminogen activator, together with plasminogen activator inhibitor-1 (PAI-1) antigen and activity, thrombin-activatable fibrinolysis inhibitor (TAFI) antigen and activity, thrombomodulin (TM), plasminogen and α2-antiplasmin (α2AP) were measured. There were no inter-group differences in angiographic parameters, indication to the first PCI, culprit vessel or a type of stent. Patients with IST had 11% longer CLT (p=0.005) and 13% higher PAI-1 antigen (p=0.04) compared to controls. There were positive correlations in both groups between CLT and PAI-1 antigen and TAFI activity (all p<0.001). Multiple regression analysis showed that CLT (odds ratio [OR]=1.04 per 1 minute, 95% CI 1.01-1.08, p=0.02) and platelet count (OR=1.01 per 1,000/µl, 95% CI 1.00-1.02, p=0.034) were independent predictors of IST (R(2)=0.28, p<0.05). Concluding, impaired fibrinolytic potential, that is in part determined by plasma PAI-1 antigen and TAFI activity, characterises patients with a history of acute and subacute IST, which might help identify patients at higher risk of IST.