Clot time ratio (CTR) and treatment outcomes in Apixaban-treated atrial fibrillation patients.

There are clinical situations where information about the anticoagulant effects of Apixaban could be useful. Specialised methods for measuring Apixaban concentrations are not available at all medical laboratories while methods for measuring the functional effects of Apixaban, using clot time ratio (CTR), can be performed in most medical laboratories around the clock using well-established measurement procedures. The aim of this study was to investigate CTR in trough and peak samples during Apixaban treatment of atrial fibrillation and to correlate the findings to bleeds and thrombotic events. Three trough- and three peak samples from 61 patients (31 on Apixaban 5 mg twice daily and 30 on Apixaban 2.5 mg twice daily) were analysed with MRX PT DOAC. Patients were followed for 30 + /-15 months, and bleeds and thrombotic events were documented. The effect of Apixaban could be measured with MRX PT DOAC and there was a statistically significant difference between CTR in trough samples compared to peak samples (p < 0.001). A total of 21 patients suffered bleeds during follow-up; two patients suffered major bleeds, and 19 suffered minor bleeds. Patients with major bleeds had both mean peak- and mean trough CTR above the respective first to third quartile (Q1-Q3) range. Four patients suffered thromboembolic events. Generally, the peak CTRs were below or in the lower end of the peak Q1-Q3 for these patients. The new test MRX PT DOAC can be used to measure the effect of Apixaban during the treatment of atrial fibrillation. High mean peak- and mean trough CTR were seen in 2 patients with major bleeds, and low peak CTR was seen in 4 patients with thromboembolic events.

Clot time ratio (CTR) and relation to treatment outcome in patients with atrial fibrillation treated with Rivaroxaban.

BACKGROUND: There are situations where information about the anticoagulant effects of Rivaroxaban could be clinically useful. Methods for measuring Rivaroxaban concentrations are not available at all medical laboratories while the test MRX PT DOAC for measuring the functional effects of Rivaroxaban, in CTR (Clot Time Ratio), can be made available around the clock. The objectives of this study were to investigate CTR in trough and peak samples during Rivaroxaban treatment of atrial fibrillation and to correlate the findings to bleeding episodes. METHODS: 3 trough- and 3 peak samples from 60 patients (30 on 20 mg daily and 30 on 15 mg daily) were analyzed with PT DOAC. Patients were monitored for 20 months, and bleeding and thrombotic events were documented. Descriptive statistics were used to summarize the data and non-parametric t-test for comparison between groups. ROC curves for the prediction of DOAC plasma levels > 50 ng/mL as determined with LC-MS/MS and anti-FXa methods were computed. RESULTS: There was a significant difference between trough and peak CTR (median CTR 1.33 vs. 3.57, p < 0.001). 28 patients suffered bleeds. Patients on 20 mg Rivaroxaban with bleeds had higher mean peak CTR than patients without bleeds (CTR 4.11 vs. CTR 3.47, p = 0.040). There was no significant difference in mean CTR between patients on 15 mg Rivaroxaban with or without bleeds (CTR 3.81 vs. 3.21, p = 0.803), or when considering all patients (CTR 3.63 vs. 3.56, p = 0.445). Five out of seven patients on Rivaroxaban 20 with mean peak CTR above the dose specific first to third quartile range (Q1-Q3) suffered bleeds, while 7/16 patients with mean peak CTR within, and 1/7 patients with mean peak CTR below the Q1-Q3 suffered bleeds. The area under the ROC curve was > 0.98 at the upper limit of the PT DOAC reference interval and the negative predictive value of PT DOAC for the prediction of DOAC plasma levels > 50 ng/mL was > 0.96. CONCLUSIONS: The sample size was too low to draw any firm conclusions but is seems that MRX PT DOAC might be a useful laboratory test in situations where the effect of Rivaroxaban needs evaluation.

Acute effects of high intensity interval training versus moderate intensity continuous training on haemostasis in patients with coronary artery disease.

Exercise training is associated with an acute net increase in coagulation, which may increase the risk of atherothrombosis in coronary artery disease (CAD) patients. We sought to compare the acute haemostatic effects of a bout of moderate-intensity continuous (MICT) and high-intensity interval training (HIIT) in patients with CAD. Patients after a recent myocardial infarction were randomized into a HIIT or MICT session of exercise training on a stationary bike. Blood was sampled at baseline, after the exercise bout and after a one-hour resting period. We measured overall haemostatic potential (OHP), overall coagulation potential (OCP), fibrinogen, D-dimer and von Willebrand factor (vWF) and calculated overall fibrinolytic potential (OFP). Linear mixed models for repeated measures were constructed to assess the treatment effect. A total of 117 patients were included. OCP, OHP, fibrinogen, D-dimer and vWF significantly increased after exercise and returned to baseline after a one-hour rest, OFP decreased after exercise and returned to baseline levels after a one-hour rest. Linear mixed models showed a significant difference between HIIT and MICT in fibrinogen (p 0.043) and D-dimer (p 0.042). Our study has shown that an exercise bout is associated with a transient procoagulant state in patients with CAD, with similar exercise-induced haemostatic changes for HIIT and MICT.

Prognostic Factors for Restenosis of Superficial Femoral Artery after Endovascular Treatment.

High incidence of superficial femoral artery (SFA) restenosis after percutaneous transluminal angioplasty (PTA) poses a persistent challenge in peripheral arterial disease (PAD) treatment. We studied how the patients' and lesions' characteristics, thrombin generation, overall haemostatic potential (OHP), and single nucleotide polymorphisms (SNPs) of the NR4A2 and PECAM1 genes affected the likelihood of restenosis. In total, 206 consecutive PAD patients with limiting intermittent claudication due to SFA stenosis who were treated with balloon angioplasty with bailout stenting when necessary were included. Patients' clinical status and patency of the treated arterial segment on ultrasound examination were assessed 1, 6, and 12 months after the procedure. Restenosis occurred in 45% of patients, with less than 20% of all patients experiencing symptoms. In the multivariate analysis, predictors of restenosis proved to be poor infrapopliteal runoff, higher lesion complexity, absence of treated arterial hypertension, delayed lag phase in thrombin generation, and higher contribution of plasma extracellular vesicles to thrombin concentration. Poor infrapopliteal runoff increased the risk of restenosis in the first 6 months, but not later. The negative effect of poor infrapopliteal runoff on SFA patency opens questions about the potential benefits of simultaneous revascularisation of below-knee arteries along with SFA revascularisation.

Comparison of antithrombin activity assays in detection of patients with heparin binding site antithrombin deficiency: systematic review and meta-analysis.

Antithrombin (AT) deficiency increases the risk for venous thromboembolism, therefore, a highly sensitive assay to identify this condition is crucial. The aim of this paper was to perform a meta-analysis comparing AT activities measured by different AT activity assays in patients with heparin binding site AT deficiency. In addition, the diagnostic sensitivity of selected assays was compared depending on the available data. An extensive literature search was performed considering results with publication date up to July 10, 2021. Seven relevant English-language observational studies, comparing AT activity measured by different AT activity assays in Caucasian Europeans with either the AT Budapest III or AT Padua I mutation were included in meta-analyses. There was no significant difference in AT activity between Labexpert and Innovance in patients with AT Budapest III (P = 0.567) and AT Padua I (P = 0.265), while AT activity determined by HemosIL was significantly higher compared to Innovance for both mutations (AT Budapest III: P < 0.001; AT Padua I: P < 0.001). These results are in line with the results of comparison of diagnostic sensitivity. In patients with AT Budapest III, the AT activity was also higher when measured with Berichrom compared to Innovance (P = 0.002), however, the results of comparison of diagnostic sensitivity across studies were variable. No significant difference (P = 0.117) in AT activity as well as diagnostic sensitivity was observed between Sta-Stachrom and Innovance. The results of our study suggest that Innovance, Labexpert and Sta-Stachrom are the most sensitive activity assays for detection of AT Budapest III and AT Padua I, whereas HemosIL showed considerably lower sensitivity for these two variants. As revealed in our study, the diagnostic sensitivity of AT activity assays to type II heparin binding site AT deficiency is different, and in some assays mutation dependent.

Insulin resistance, lipids and body composition in patients with coronary artery disease after combined aerobic training and resistance training: a randomised, controlled trial.

BACKGROUND: The effect of resistance training (RT) in cardiac rehabilitation (CR) on insulin resistance remains elusive. We examined whether the addition of high-load (HL) or low loads (LL) RT has any effect on the levels of insulin resistance and lipids versus aerobic training (AT) alone in patients with coronary artery disease (CAD). METHODS: Seventy-nine CAD patients were randomised to HL-RT [70-80% of one repetition maximum (1-RM)] and AT, LL-RT (35-40% of 1-RM) and AT or AT (50-80% of maximal power output), and 59 patients [75% males, 15% diabetics, age: 61 (8) years, left ventricular ejection fraction: 53 (9) %] completed the study. Plasma levels of glucose, insulin, blood lipids [total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL)] cholesterol and body composition were measured at baseline and post-training (36 training sessions). RESULTS: Training intervention had only time effect on lean mass (p = 0.002), total and LDL cholesterol levels (both p < 0.001), and no effects on levels of glucose and insulin resistance (homeostatic assessment 2-insulin resistance). Total and LDL cholesterols levels decreased following AT [mean difference (95% confidence interval); total cholesterol: - 0.4 mmol/l (- 0.7 mmol/l, - 0.1 mmol/l), p = 0.013; LDL: - 0.4 mmol/l (- 0.7 mmol/l, - 0.1 mmol/l), p = 0.006] and HL-RT [total cholesterol: - 0.5 mmol/l (- 0.8 mmol/l, - 0.2 mmol/l), p = 0.002; LDL: - 0.5 mol/l (- 0.7 mmol/l, - 0.2 mmol/l), p = 0.002]. No associations were observed between post-training change in body composition and post-training change in blood biomarkers. CONCLUSIONS: RT when combined with AT had no additional effect beyond AT alone on fasting glucose metabolism, blood lipids and body composition in patients with CAD. Trial registration number NCT04638764.

HFpEF and Atrial Fibrillation: The Enigmatic Interplay of Dysmetabolism, Biomarkers, and Vascular Endothelial Dysfunction.

Background: Heart failure with preserved ejection fraction (HFpEF) has a complex pathophysiology that encompasses systemic proinflammatory state and dysregulated levels of cardiometabolic and oxidative stress biomarkers. The prevalence of both HFpEF and atrial fibrillation (AF) is continuously rising, especially in the elderly. The aim of our study was to explore if there were any differences in biomarker levels and vascular function in the elderly patients with HFpEF with and without AF and to assess interconnections between clinically relevant biomarkers and cardiac and vascular function. Methods: This was a cross-sectional study of patients ≥ 65 years with HFpEF who were divided into 2 groups based on the presence or absence of AF. We have sonographically assessed echocardiographic parameters of left ventricular systolic and diastolic function and the peripheral vascular function parameters, namely, pulse wave velocity (PWV) and flow-mediated dilation (FMD). NT-proBNP, irisin, leptin, adiponectin, insulin-like growth factor 1 (IGF-1), and malondialdehyde (MDA) blood levels were determined. Results: Fifty-two patients (mean age 80 ± 7 years, 67% females) were included. Patients with HFpEF and AF had significantly lower levels of irisin (median 4.75 vs. 13.5 ng/mL, p = 0.007), leptin (median 9.5 vs. 15.0 ng/L, p = 0.023), and MDA (median 293 vs. 450 ng/mL, p = 0.017) and significantly higher values of NT-proBNP (median 2365 vs. 529 ng/L, p < 0.001) but not vascular function parameters, as compared to HFpEF patients without AF. MDA was significantly correlated with diastolic function (r = 0.395, p = 0.007) and FMD (r = 0.394, p = 0.011), while adiponectin was inversely associated with FMD (r = -0.325, p = 0.038) and left ventricular ejection fraction (r = -0.319, p = 0.029). Conclusions: Our results have demonstrated that patients with HFpEF and AF have significantly lower leptin, irisin, and MDA levels compared to patients with HFpEF but without AF. These results offer new insights into the complexity of vascular function and cardiometabolic and oxidative stress biomarkers in the context of HFpEF, AF, and aging.

Inflammatory and Prothrombotic Biomarkers, DNA Polymorphisms, MicroRNAs and Personalized Medicine for Patients with Peripheral Arterial Disease.

Classical risk factors play a major role in the initiation and development of atherosclerosis. However, the estimation of risk for cardiovascular events based only on risk factors is often insufficient. Efforts have been made to identify biomarkers that indicate ongoing atherosclerosis. Among important circulating biomarkers associated with peripheral arterial disease (PAD) are inflammatory markers which are determined by the expression of different genes and epigenetic processes. Among these proinflammatory molecules, interleukin-6, C-reactive protein, several adhesion molecules, CD40 ligand, osteoprotegerin and others are associated with the presence and progression of PAD. Additionally, several circulating prothrombotic markers have a predictive value in PAD. Genetic polymorphisms significantly, albeit moderately, affect risk factors for PAD via altered lipoprotein metabolism, diabetes, arterial hypertension, smoking, inflammation and thrombosis. However, most of the risk variants for PAD are located in noncoding regions of the genome and their influence on gene expression remains to be explored. MicroRNAs (miRNAs) are single-stranded, noncoding RNAs that modulate gene expression at the post-transcriptional level. Patterns of miRNA expression, to some extent, vary in different atherosclerotic cardiovascular diseases. miRNAs appear to be useful in the detection of PAD and the prediction of progression and revascularization outcomes. In conclusion, taking into account one's predisposition to PAD, i.e., DNA polymorphisms and miRNAs, together with circulating inflammatory and coagulation markers, holds promise for more accurate prediction models and personalized therapeutic options.

The Correlation between the Triglyceride-Glucose Index and Coagulation Markers in Patients with Recent Acute Myocardial Infarction.

Background: Metabolic abnormalities and hypercoagulability seem to have an important predictive role in patients with coronary artery disease (CAD). The triglyceride-glucose (TyG) index has emerged as a good marker for metabolic syndrome with predictive value for cardiovascular events. Overall haemostatic potential (OHP) is a reliable global haemostatic essay to identify hypercoagulability in CAD patients. The aim of our study was therefore to evaluate a possible correlation between the TyG index and haemostatic derangements in patients with CAD. Methods: Consecutive patients referred for the first follow-up visit after acute myocardial infarction between December 1, 2018, and March 31, 2020, and did not meet exclusion criteria were included. We determined OHP, overall coagulation potential (OCP), overall fibrinolytic potential (OFP), fibrinogen, D-dimer, and von Willebrand factor from peripheral blood samples. The TyG index was calculated with the previously described and validated formula. Linear regression models were constructed for the multivariate analysis. Results: A total of 117 patients (mean age 56 ± 10 years, 20% women) were included. A correlation was found between TyG index and OCP (r = 0.229, p = 0.026), TyG index and OHP (r = 0.202, p = 0.050), and TyG index and fibrinogen (r = 0.271, p = 0.005). In the multivariate model which accounted for sex, age, and BMI, the correlation between TyG index and OCP (R 2 0.108; ANOVA for regression p = 0.035; beta 2.08 [0.79-4.01], p = 0.042) and between TyG index and fibrinogen (R 2 0.11; ANOVA for regression p = 0.015; beta 0.35 [0.08-0.62], p = 0.012) emerged as statistically significant. Conclusion: The TyG index, a marker of metabolic syndrome, has a strong correlation with a hypercoagulability state in CAD, as determined by the OCP and higher fibrinogen levels. Our findings suggest that metabolic syndrome may be an important driver of atherothrombotic risk in patients with CAD.

Association between Lipoprotein Subfractions, Hemostatic Potentials, and Coronary Atherosclerosis.

Background: Dyslipidemias are associated with atherosclerotic plaque formation and a prothrombotic state, thus increasing the risk of both atherosclerotic vascular disease and atherothrombotic adverse events. We sought to explore the association between lipoprotein subfractions, overall hemostasis, and coronary calcifications in individuals at intermediate cardiovascular risk. Methods: Consecutive statin-naive individuals at intermediate cardiovascular risk referred for coronary artery calcium score (CACS) scanning were included. CACS was assessed using a 128-slice dual-source CT scanner. Traditional lipid profile, high-density lipoprotein (HDL) subfractions 2 and 3, and small dense low-density lipoproteins (sdLDL) were measured with commercially available assays. Overall hemostatic (OHP) and coagulation potentials (OCP) were measured spectrophotometrically, using fibrin aggregation curves after exposure to thrombin and recombinant tissue-type plasminogen activator, respectively. Overall fibrinolytic potential (OFP) was calculated as a difference between the two areas under curves. Results: We included 160 patients (median age 63 (interquartile range (IQR), 56-71 years, 52% women, and median CACS 8, IQR 0-173 Agatston units). HDL3 levels-but not sdLDL or hemostatic potentials-were significantly associated with CACS zero, even after adjusting for age, sex, arterial hypertension, dyslipidemia, diabetes, and smoking history (OR 0.980 (0.962-0.999), p = 0.034). HDL3 was also significantly associated with OCP (r = -0.232, p adjusted for age and sex 0.037). Conclusions: In patients at intermediate cardiovascular risk, HDL3 is associated with both subclinical atherosclerosis and overall coagulation. Our findings are in line with studies reporting on an inverse relationship between HDL3 and atherosclerosis and provide one possible mechanistic explanation for the association between novel lipid biomarkers and coagulation derangements.

Biological Variation in Rotational Thromboelastometry in Patients with Atrial Fibrillation Receiving Rivaroxaban.

Rotational thromboelastometry (ROTEM) is a viscoelastic hemostasis test used primarily in the management of bleeding after trauma or in cardiac surgery. To allow safe and valid clinical interpretation of test results, objective specifications for analytical performance are needed, which are generally based on biological variation within (CVI) and between (CVG) individuals. The aim of this study was to evaluate biological variation in ROTEM in patients receiving rivaroxaban. Sixty patients with atrial fibrillation on stable rivaroxaban therapy were included, from whom blood was collected on six occasions: three times at trough and three at peak rivaroxaban concentrations. ROTEM® Extem and LowTF were measured as well as rivaroxaban concentration, PT, APTT, and anti-Xa. Within- (CVI) and between-subject (CVG) biological estimates were calculated. Knowledge of these biological variation components will help to establish the appropriate objective analytical performance specifications for ROTEM analysis.

Apixaban concentration variability and relation to clinical outcomes in real-life patients with atrial fibrillation.

In some clinical situations, measurements of anticoagulant effect of apixaban may be needed. We investigated the inter- and intra-individual apixaban variability in patients with atrial fibrillation and correlated these results with clinical outcome. We included 62 patients receiving either 5 mg (A5, n = 32) or 2.5 mg (A2.5, n = 30) apixaban twice-daily. We collected three trough and three peak blood samples 6-8 weeks apart. Apixaban concentration was measured by liquid chromatography-tandem mass-spectrometry (LC-MS/MS) and by anti-Xa. Patients on A2.5 were older, had lower creatinine clearance, higher CHA2DS2VASc (4.7 ± 1.0 vs. 3.4 ± 1.7) and lower trough (85 ± 39 vs. 117 ± 53 ng/mL) and peak (170 ± 56 vs. 256 ± 91 ng/mL) apixaban concentrations than patients on A5 (all p < 0.01). In patients on A5, LC-MS/MS showed a significant difference between through levels and between peak levels (p < 0.01). During apixaban treatment, 21 patients suffered bleeding (2 major). There was no association between bleeding and apixaban concentrations or variability. Four patients who suffered thromboembolic event had lower peak apixaban concentrations than patients without it (159 ± 13 vs. 238 ± 88 ng/mL, p = 0.05). We concluded, that there was a significant intra- and inter-individual variability in apixaban trough and peak concentrations. Neither variability nor apixaban concentrations were associated with clinical outcomes.

Biocompatibility Parameters with Standard and Increased Dose of Citrate in Hemodialysis-A Randomized Trial.

BACKGROUND: The dose of citrate needed in regional citrate anticoagulation (RCA) to achieve optimal biocompatibility is unknown. We performed a randomized trial comparing two doses (ACTRN12613001340729). METHODS: In 30 patients a single hemodialysis with either standard (2.7 mmol/L) or increased dose of citrate (4 mmol/L) was performed. C5a-desArg, myeloperoxidase (MPO), thrombin-antithrombin complex (TAT), and platelet factor 4 (PF4) were measured and the inner surface of the dialyzer fibers was evaluated with scanning electron microscopy (SEM). RESULTS: A good separation of anticoagulation effect was achieved (post-filter ionized calcium 0.20 vs. 0.31 mmol/L, p < 0.05). There was no effect of citrate dose on any of the biocompatibility parameters; transient and parallel increase in PF4 after 30 min and parallel increase in TAT after 4 h were observed. There were no visually detected clotting problems within the circuit and no significant hypocalcemia in either group. SEM clotting score was excellent and comparable in both groups (p = 0.59). CONCLUSIONS: Given the excellent results in both groups, absence of between group differences and inability of the increased dose of citrate to completely blunt the small residual increase in PF4 and TAT, we conclude that the standard dose of citrate seems sufficient in RCA for chronic hemodialysis.

The in vitro addition of idarucizumab to plasma samples from patients increases thrombin generation.

Dabigatran interferes with many coagulation tests. To overcome this obstacle the use of idarucizumab as an in vitro antidote to dabigatran has been proposed. The aim of this study was to test the effect of idarucizumab as an in vitro antidote to dabigatran in ex vivo plasma samples from routine clinical patients examined by a thrombin generation assay (TGA). From 44 patients with atrial fibrillation five blood samples were collected. Thrombin generation was measured in all samples before and after the addition of idarucizumab. When idarucizumab was added to baseline plasma (no dabigatran), it caused a significantly shorter Lag Time and Time to Peak Thrombin, and a higher Peak Thrombin and Endogenous Thrombin Potential (ETP) of TGA. Similar results were obtained when idarucizumab was added to dabigatran-containing plasma, with TGA parameters comparable to baseline + idarucizumab plasma, but not to baseline plasma. In summary, our study showed that in vitro addition of idarucizumab to plasma samples from patients increases thrombin generation. The use of idarucizumab to neutralize dabigatran in patient plasma samples as well as the clinical relevance of in vitro increased thrombin generation induced by idarucizumab needs further investigation.

Hemodynamic and Hemostatic Response to Blood Flow Restriction Resistance Exercise in Coronary Artery Disease: A Pilot Randomized Controlled Trial.

BACKGROUND: Blood flow-restricted resistance training (BFR-RT) has been proven to be safe and efficacious in healthy older adults, but not in cardiovascular disease. OBJECTIVE: The aim of this study was to investigate the acute and training induced effects of BFR-RT on hemostatic and hemodynamic responses in patients with coronary artery disease (CAD). METHODS: Stable patients with CAD were randomized to 8 weeks of BFR-RT (30%-40% 1-repetition maximum unilateral knee extension) combined with aerobic training or aerobic training alone (control group). At baseline and after 4 and 8 weeks, blood samples were taken before and after BFR exercise, whereas hemodynamic parameters were monitored throughout the exercise. RESULTS: Twenty-four patients (12 per group; mean age, 60 ± 2 years; mostly male [75%]) completed the study. The BFR-RT significantly improved systolic blood pressure (-10 mm Hg; P = .020) and tended to lower diastolic blood pressure (-2 mm Hg; P = .066). In contrast, no posttraining alterations were observed in N-terminal prohormone B-type natriuretic hormone, fibrinogen, and D-dimer values. During BFR exercise, all hemodynamic variables significantly increased after the first and second set, whereas blood pressure immediately lowered after the cuff was released in the third set. Last, significant interaction was only observed for repetitions × intensity (P < .001; partial η2 = 0.908) of diastolic blood pressure at higher exercise intensity (40% 1-repetition maximum). CONCLUSIONS: The BFR-RT was proven to be safe, with favorable hemodynamic and hemostatic responses in patients with CAD, and can be recommended as an additional exercise modality in cardiac rehabilitation.Trial Registration:ClinicalTrial.gov Identifier: NCT03087292.

Idarucizumab for dabigatran reversal in daily clinical practice: A case series.

BACKGROUND: Real-life experience with idarucizumab, which reverses the anticoagulant effect of dabigatran, is currently limited. OBJECTIVE: To evaluate efficacy and safety of the clinical use of idarucizumab after its availability in Slovenia. METHODS: We analysed consecutive cases treated with idarucizumab in Slovenia from January to October 2016. The decision to reverse dabigatran with idarucizumab was made by the treating clinicians, as was the assessment of clinical outcomes and blood sampling/monitoring (activated partial thromboplastin time, thrombin time and diluted thrombin time) before and after use. RESULTS: Idarucizumab was used in 17 cases. One patient was treated with the antidote twice with an interval of 2 months between treatments. The indications for idarucizumab use were: emergency surgery (4/17), severe bleeding (11/17; seven with intracranial bleeding) and ischaemic stroke (2/17). During surgery, no excessive bleeding was reported. Five patients died due to cardiogenic, haemorrhagic or septic shock, intracranial bleeding or multiple organ failure. Among cases with laboratory data available, baseline coagulation tests were prolonged in 12/13 cases with bleeding or emergency surgery. After idarucizumab administration, normal coagulation parameters were confirmed in 10/11. However, re-occurrence of dabigatran effect was noted later in four patients with creatinine clearance less than 30 ml min, and one patient with persistent bleeding required retreatment with idarucizumab. CONCLUSION: Our first experiences with idarucizumab use in daily-care settings support a rapid and efficient decrease in the anticoagulant effect of dabigatran in emergency situations. Late re-occurrence of dabigatran effect was noted in a subset of patients with severe renal failure.

Progression of coronary calcium burden and carotid stiffness in patients with essential thrombocythemia associated with JAK2 V617F mutation.

BACKGROUND AND AIMS: Patients with myeloproliferative neoplasms often succumb to cardiovascular events, but little is known on the early stages of their vascular disease. We studied how patients with JAK2 V617F positive essential thrombocythemia (ET) without overt atherosclerotic disease differed from control subjects in the progression of carotid artery stiffness and preclinical atherosclerosis. METHODS: Thirty-six patients with JAK2 V617F positive ET and 38 age-, gender- and Framingham coronary heart disease (CHD) -matched control subjects were examined twice within 4 years. Clinical and laboratory testing, echo-tracking ultrasound of carotid arteries, coronary calcium measurement and digital plethysmography were performed (ClinTrials.gov NCT03828422). RESULTS: Coronary calcium correlated with the Framingham CHD risk score at the first examination in the control group (rs = 0.410), but not among the ET patients (rs = 0.116). Both groups progressed in coronary calcium, but the outliers were more prominent among ET patients. Carotid artery stiffness increased with time in the ET patients much more than in the control group: the increase in ß-index 1.95 (SD 2.18) vs. 0.22 (SD 1.99), p < 0.001, and the increase in carotid pulse wave velocity 0.72 (SD 0.92) vs. 0.08 (SD 0.72) m/s, p = 0.001. There was no correlation between carotid stiffness and Framingham CHD risk in either group. Digital endothelial function did not change. CONCLUSION: Carotid artery stiffness progressed faster in patients with JAK2 V617F positive ET than in control subjects. Coronary calcium correlated with the Framingham CHD risk only in control subjects. This indicates that JAK2 V617F positive ET acted as a non-classical risk factor for vascular disease.