Impact of Continuous Estroprogestin Treatment on Circulating Microparticle Levels in Deep Endometriosis Patients.

There has been increasing interest in the study of new pathogenic mechanisms in endometriosis (END), including the coagulation/fibrinolysis system and its link with inflammation and tissue remodeling. It has been suggested that END patients, especially with deep-infiltrating (DE) forms, could present a hypercoagulable state revealing higher levels of proinflammatory and procoagulant markers, such as total circulating microparticles (cMPs) and cMP-TF (tissue factor), released by cells in response to damage, activation, or apoptosis. However, no previous study has assessed the effect of END hormonal treatments on cMP and cMP-TF levels. Therefore, the aim of this study was to evaluate the impact of these treatments on cMP and cMP-TF levels in DE patients. Three groups were compared: DE patients receiving a continuous combined oral contraceptive regimen (CCOCR) (n = 41), DE patients without CCOCR (n = 45), and a control group (n = 43). cMP and cMP-TF levels were evaluated in platelet-free plasma. A significant decrease in the total cMP levels was found in the DE group with CCOCR versus the group without CCOCR, reflecting a higher chronic inflammatory status in DE patients that decreased with the treatment. cMP-TF levels were higher in DE patients receiving CCOCR versus those not receiving CCOCR, suggesting that treatments containing estrogens play a predominant role in suppressing the inhibitory pathway of TF.

Predictive value of the adjusted Global Anti-Phospholipid Syndrome Score on clinical recurrence in APS patients: a longitudinal study.

OBJECTIVE: To assess the effect of the average adjusted global APS score (aGAPSS) over time on recurrence of clinical manifestations in APS patients through a retrospective longitudinal study. MATERIAL AND METHODS: The study included 200 patients with APS. The aGAPSS was calculated for each patient at baseline and on a yearly basis for either up to 6 years (minimum 3 years) or just before the clinical event in patients who experienced clinical recurrence. The mean score per patient was computed. In patients under vitamin K antagonists (VKA) the percentage of time spent within the therapeutic range (TTR) was calculated. Cox regression analysis was performed to determine the cut-off value of the aGAPSS with the strongest association with clinical recurrence. RESULTS: Higher average aGAPSS values were found in patients who experienced clinical recurrence in comparison to patients who did not [8.81 (95% CI 7.53, 10.08) vs 6.38 (95% CI 5.64, 7.12), P = 0.001], patients with thrombotic recurrence compared with patients with obstetric recurrence [9.48 (95% CI 8.14, 10.82) vs 4.25 (95% CI 0.85, 7.65), P = 0.006] and patients with arterial thrombosis compared with patients with venous thrombosis [10.66 (S.D. 5.48) vs 6.63 (S.D. 4.42), P = 0.01]. aGAPSS values >13 points were associated with the highest risk of recurrence in multivariate analysis [HR = 3.25 (95% CI 1.93, 5.45), P < 0.0001]. TTR was not statistically different between patients who had thrombosis recurrence and patients who had not. CONCLUSIONS: Our data support the role of periodic (annual) monitoring of the aGAPSS score in predicting clinical recurrence in patients with APS.

Persistence of antiphospholipid antibodies over time and its association with recurrence of clinical manifestations: A longitudinal study from a single centre.

PURPOSE: To analyze the antiphospholipid antibody (aPL) persistence over time in patients with antiphospholipid syndrome (APS) and its association with clinical recurrence and to identify predictors of aPL persistence over time. PATIENTS AND METHODS: 200 patients with a diagnosis of APS and at least three follow-up aPL determinations were included. Persistent aPL profile was defined as the presence of lupus anticoagulant (LAC) and/or IgG/IgM anticardiolipin (aCL) and/or IgG/IgM anti-ß2 glycoprotein-I (aß2GPI) (> 99th percentile) antibodies in at least 66% of follow-up measurements. Multilevel mixed-effect generalized linear models with logit link were used. RESULTS: 112 (56%) patients maintained persistent aPL profiles over time, while 88 (44%) were transient. Median follow-up time was 172.5 months. Follow-up time did not affect the odds of aPL persistence in multivariate analysis (p = 1.00). Baseline triple aPL positivity [OR 78 (95%CI 16.9-359.7, p < 0.001)] and double aPL positivity [OR = 7.6 (95%CI 3.7-15.7, p < 0.001)] correlated with persistent aPLs over time, while isolated LAC [OR = 0.26 (95% CI 0.08-0.49, p = 0.002)] or isolated IgG/IgM aCL [OR = 0.20 (95% CI 0.11-0.59, p = 0.004)] positivity, were predictors of transient aPL profile. Patients with persistent aPLs had higher rate of clinical recurrence in comparison to patients with transient aPLs [OR = 2.48 (95%CI 1.34-4.58, p = 0.003)]. CONCLUSIONS: More than half of patients with baseline medium-high titer aPL positivity had persistent positive aPLs over time. Patients with persistent aPLs were more prone to present recurrence of clinical manifestations. Multiple aPL positivity increased the odds of a persistent aPL profile over time, while isolated LAC and aCL positivity decreased it.

Is antivitamin K reversal required in patients with cirrhosis undergoing liver transplantation?

BACKGROUND: Antivitamin K agent (AVK) reversal in patients with cirrhosis awaiting liver transplantation (LT) is not defined in guidelines. We investigated the effect of reversion with prothrombin complex concentrate (PCC) on intraoperative transfusion, bleeding, and safety in LT patients on AVK. STUDY DESIGN AND METHODS: In 511 patients undergoing LT, we identified 25 patients treated with AVK (AVK group) and 13 patients with incidental portal vein thrombosis (PVT) without AVK (incidental PVT group). Fifty patients who underwent LT without PVT or AVK matched by age, model for end stage of liver disease (MELD), body mass index (BMI), and cirrhosis etiology were selected as the control group. RESULTS: There were no significant differences between the three groups in intraoperative blood loss, transfusion, and postoperative bleeding. In the AVK group, there were no differences between patients who received PCC and those who did not in intraoperative blood loss, red blood cells, fibrinogen, and platelet transfusion, or postoperative bleeding. PCC use had no effect on RBC transfusion in patients who had international normalized ratio or clotting time above versus below median values of the two parameters at baseline (2.3 and 103 s, respectively). No thrombotic events were detected in patients who received PCC. DISCUSSION: These data suggest that systematic administration of PCC to revert AVK prior to LT should be reconsidered.

Procoagulant microparticles are associated with arterial disease in patients with systemic lupus erythematosus.

Microparticles (MPs) have been associated with inflammatory and thrombotic disease. High levels of MPs have been identified in patients with systemic lupus erythematosus (SLE) and associated with cardiovascular disease. We analyzed the procoagulant activity of MPs and its correlation with arteriosclerosis and arterial thrombosis in SLE patients. Eighty-seven patients with SLE were included: 22 (25.3%) with associated antiphospholipid syndrome (APS), 32 (36.8%) without antiphospholipid antibodies (aPL) and 33 (37.9%) with aPL but without APS. Subclinical arteriosclerosis, defined as the presence and number of plaques, was evaluated by ultrasonography of carotid arteries. Thrombotic events were confirmed by objective methods. The procoagulant activity of MPs was determined by a functional assay with annexin V. Subclinical arteriosclerosis was found in 19 (21.8%) patients. Thirteen episodes of arterial thrombosis and eight of venous thrombosis were recorded. The procoagulant activity of MPs was greater in patients with arterial thrombosis (17.28 ± 8.29 nM vs 12.96 ± 7.90 nM, p < 0.05). In patients without arterial thrombosis, greater procoagulant activity of MPs was identified in patients with multiple (≥ 2) carotid plaques (17.26 ± 10.63 nM vs 12.78 ± 7.15 nM, p = 0.04). In the multivariate analysis, the procoagulant activity of MPs was independently associated with multiple (≥ 2) carotid plaques and arterial thrombosis [OR = 1.094 (95%CI 1.010-1.185), p = 0.027 and OR = 1.101 (95%CI 1.025-1.182), p = 0.008; respectively]. In conclusion, the procoagulant activity of MPs is associated with arteriosclerosis burden and arterial thrombosis in patients with SLE.

Study of the analytical performance at different concentrations of hematological parameters using Spanish EQAS data.

Background External quality assessment programs are one of the currently available tools to evaluate the analytical performance of clinical laboratories, where the measurement error (ME) obtained can be compared with quality specifications to evaluate possible deviations. The objective of this work was to analyze the ME behavior over the analytical range to assess the need to establish concentration-dependent specifications. Methods A total of 389,000 results from 585 laboratories and 2628 analyzers were collected from the Spanish external quality assessment schemes (EQAS) in hematology during the years 2015-2016. The parameters evaluated included white blood cells, red blood cells, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelets, prothrombin time, activated partial thromboplastin time, neutrophils, lymphocytes, monocytes, eosinophils, basophils, reticulocytes, hemoglobin A2, antithrombin, factor VIII, protein C and von Willebrand factor. The 90th percentile of ME was calculated for every concentration evaluated of each parameter. Results We found a significant variation in the analytical performance of leukocytes, platelets, neutrophils, lymphocytes, monocytes, eosinophils, basophils, prothrombin time, reticulocytes, hemoglobin A2, antithrombin and protein C. Furthermore, this ME variation may not allow complying with the same biological variability requirements within the whole analytical range studied. Conclusions Our work shows the importance of implementing concentration-dependent specifications which can help laboratories to use proper criteria for quality specifications selection and for a better external quality control results evaluation.

Host-Derived Molecules as Novel Chagas Disease Biomarkers: Hypercoagulability Markers in Plasma.

The most severe clinical symptomatology of Chagas disease affects ~30% of those chronically infected with the Trypanosoma cruzi parasite. The pathogenic mechanisms that lead to life-threatening heart and gut tissue disruptions occur "silently" for a longtime in a majority of cases. As a result, despite there are several serological and molecular methods available to diagnose the infection in its acute and chronic stages, diagnosis is often achieved only after the onset of clinical symptoms in the chronic phase of the disease. Furthermore, although there are two drugs to treat it, the assessment of their performance is impractical with current parasite-derived diagnostics, and therapeutic efficacy cannot be acknowledged in a timely manner.In this chapter we present two procedures to measure host-derived molecules as surrogates of therapeutic response against chronic T. cruzi infection. Their outputs relate to the generation and activity of thrombin, a major component of the blood coagulation cascade. This is due to the fact that a hypercoagulability state has been described to occur in chronic Chagas disease patients and revert after treatment with benznidazole.

Circulating Neutrophil Extracellular Traps Are Elevated in Patients With Deep Infiltrating Endometriosis.

Neutrophil extracellular traps (NETs) have been described to be related to the pathogenesis of inflammatory and autoimmune conditions. Endometriosis is currently considered a chronic inflammatory condition. Therefore, we performed a preliminary case-control study to compare the circulating plasma NET levels in patients with surgically confirmed endometriosis (E group, n = 82) and those of patients without surgical findings of endometriosis (C group, n = 35). Venous blood samples were obtained at the time of surgery. Circulating plasma NET levels were assessed as histone-DNA complexes (ie, nucleosomes) by a quantitative sandwich enzyme-linked immunosorbent assay. The results were expressed in arbitrary units. Circulating plasma NET levels were significantly higher in the E group compared with the C group (median [25th; 75th percentiles]): E group: 0.734 [0.484; 1.363]; C group: 0.541 [0.411; 0.653]; P = .005). The subanalysis of E group patients with deep infiltrating endometriosis (DIE group) or without DIE (non-DIE group) showed that plasma NET levels were higher in the DIE group ( P = .02). No differences were observed in NET levels among patients with and without severe pelvic pain or in patients with and without infertility, regardless of the presence of endometriotic lesions. Therefore, our study shows significantly higher NET levels in patients with endometriosis, which seem to be attributed to increased levels in the subgroup of patients with DIE, suggesting that the presence of elevated circulating plasma NET levels may reflect an inflammatory status in this gynecological condition. Further research is warranted to confirm our findings and to assess the exact role of NETs in the pathophysiological mechanisms of endometriosis.

The H1 haplotype of the endothelial protein C receptor protects against arterial thrombosis in patients with antiphospholipid syndrome.

INTRODUCTION: Genetic variants in the endothelial protein C receptor gene (PROCR) may contribute to the thrombosis risk by regulating levels of the soluble form of this protein (sEPCR). We evaluated whether PROCR polymorphisms and sEPCR levels play a role in the thrombotic manifestations of antiphospholipid syndrome. MATERIALS AND METHODS: One hundred and seventy-five patients (62 with primary antiphospholipid syndrome, 30 with antiphospholipid syndrome associated with systemic lupus erythematosus, 40 with systemic lupus erythematosus without antiphospholipid antibodies and 43 with systemic lupus erythematosus and antiphospholipid antibodies) and 66 healthy controls were included. PROCR H1 and H3 haplotypes were determined by genotyping 7014G/C and 1651C/G tag-polymorphisms, respectively. sEPCR levels were determined by enzyme-linked immunosorbent assay. RESULTS: PROCR haplotype distribution was similar among groups of patients and controls. PROCR H1 and H3 haplotypes were less prevalent in antiphospholipid syndrome patients with arterial thrombosis than those without arterial thrombosis, but statistical significance was only reached for the H1 haplotype (58.0% vs. 85.7%, p = 0.003; odds ratio: 0.23 [95% CI 0.08-0.65]). No relationship between the PROCR H1 and H3 haplotypes and venous thrombosis was found. sEPCR levels were higher in H3 than in H1 carriers (175.5 [95% CI 60.9-290.1] ng/ml vs. 69.1 [95% CI 61.5-76.9] ng/ml, p < 0.01). No relationship of sEPCR with arterial or venous thrombosis was found. CONCLUSION: The PROCR H1 haplotype was less frequently found in APS patients with arterial thrombosis, suggesting a protective effect of PROCR H1 against arterial thrombosis in these patients. No relationship between sEPCR and thrombosis was found.

Enzyme-linked immunosorbent assays for therapeutic drug monitoring coumarin oral anticoagulants in plasma.

The development of high-throughput immunochemical assays to assist on precision medicine for patients treated with coumarin oral anticoagulants (OA) is reported. The assays are able to quantitate Warfarin (W) and/or Acenocoumarol (ACL) directly in plasma samples without any previous sample pretreatment. The detectabilities (W, 3.52 ±â€¯2.25 nM and ACL, 1.56 ±â€¯0.64 nM) and the working ranges achieved (W, 1.19 ±â€¯0.73 to 12.05 ±â€¯2.99 nM and ACL 0.63 ±â€¯0.20 to 10.19 ±â€¯6.69 nM) are within the therapeutic levels usually found in patients treated with these drugs. The assays are specific with only cross-recognition of 4'-NH2-ACL on the ACL ELISA, which is one of the main metabolites of this drug. Moreover, accuracy studies performed with blind spiked samples show very good correlation between the spiked and the measured concentrations. Finally, a small clinical pilot study has been performed analyzing 96 plasma samples from treated and untreated patients, showing that the assay is able to quantitate ACL. The results obtained allow envisaging the possibility to use these assays for pharmacokinetic studies, dosage assessment or therapeutic drug monitoring.

Tromboc@t Working Group recommendations for management in patients receiving direct oral anticoagulants. / Recomendaciones del Grupo Catalán de Trombosis (Tromboc@t Working Group) para el tratamiento de los pacientes que reciben anticoagulantes orales directos.

BACKGROUND AND OBJECTIVES: In recent years, direct oral anticoagulants (DOACs) have become an alternative to vitamin K antagonists (VKA) for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) as well as for prevention and treatment of deep venous thrombosis. Pivotal trials have demonstrated non-inferiority and potential superiority compared to warfarin, which increases the options of anticoagulant treatment. In our setting, the Anticoagulant Treatment Units (ATUs) and Primary Care Centres (PCCs) play an important role in the education, follow-up, adherence control and management in special situations of anticoagulated patients. These considerations have motivated us to elaborate the present consensus document that aims to establish clear recommendations that incorporate the findings of scientific research into clinical practice to improve the quality of care in the field of anticoagulation. MATERIAL AND METHODS: A group of experts from the Catalan Thrombosis Group (TROMBOC@T) reviewed all published literature from 2009 to 2016, in order to provide recommendations based on clinical evidence. RESULTS: As a result of the project, a set of practical recommendations have been established that will facilitate treatment, education, follow-up and management in special situations of anticoagulated patients with ACODs. CONCLUSIONS: Progressive increase in the use of DOACs calls for measures to establish and homogenise clinical management guidelines for patients anticoagulated with DOACs in ATUs and PCCs.

Venous Thrombotic Events After Liver Transplantation.

Thromboprophylaxis is not well defined after liver transplantation (LT). The aim of this study was to evaluate the incidence of splanchnic vein thrombosis (SVT) and nonsplanchnic vein thrombosis (NSVT) after LT. Liver transplantations performed between 2009 and 2013 in our institution were reviewed. Demographic, intraoperative, and postoperative data were recorded. Low-molecular-weight heparin was only administered postoperatively if intraoperative thrombectomy was performed or in patients preoperatively anticoagulated. Of a total of 328 patients, 72% were male with a median age of 56 years, score of model for end-stage liver disease 18 (11-23), and 88% had liver cirrhosis. The incidence of postoperative venous thrombotic events was 4.6%: 8 (2.4%) patients had SVT and 7 (2.1%) patients had NSVT. After logistic regression analysis, intraoperative thrombectomy and Child A classification emerged as risk factors for SVT (odds ratio [OR]: 77, 95% confidence interval [95% CI]: 14-421) and NSVT (OR: 20, 95% CI: 3-170), respectively. The incidence of SVT in patients who undergo intraoperative thrombectomy was 33%, whereas the incidence of NSVT in patients grouped as Child A was 7.5%. Our results suggest that thromboprophylaxis should be considered after LT in patients with cirrhosis grouped as Child A and in patients who undergo intraoperative thrombectomy.

The anticoagulant rivaroxaban lowers portal hypertension in cirrhotic rats mainly by deactivating hepatic stellate cells.

In cirrhosis, increased intrahepatic vascular resistance (IHVR) is the primary factor for portal hypertension (PH) development. Hepatic stellate cells (HSCs) play a major role increasing IHVR because, when activated, they are contractile and promote fibrogenesis. Protease-activated receptors (PARs) can activate HSCs through thrombin and factor Xa, which are known PAR agonists, and cause microthrombosis in liver microcirculation. This study investigates the effects of the oral anticoagulant, rivaroxaban (RVXB), a direct antifactor Xa, on HSC phenotype, liver fibrosis (LF), liver microthrombosis, and PH in cirrhotic rats. Hepatic and systemic hemodynamic, nitric oxide (NO) bioavailability, LF, HSC activation, and microthrombosis were evaluated in CCl4 and thioacetamide-cirrhotic rats treated with RVXB (20 mg/kg/day) or its vehicle for 2 weeks. RVXB significantly decreased portal pressure (PP) in both models of cirrhosis without changes in portal blood flow, suggesting a reduction in IHVR. RVXB reduced oxidative stress, improved NO bioavailability, and ameliorated endothelial dysfunction. Rivaroxaban deactivated HSC, with decreased alpha-smooth muscle actin and mRNA expression of other HSC activation markers. Despite this marked improvement in HSC phenotype, no significant changes in LF were identified. RVXB markedly reduced fibrin deposition, suggesting reduced intrahepatic microthrombosis. CONCLUSION: RVXB decreases PP in two rat models of cirrhosis. This effect is mostly associated with decreased IHVR, enhanced NO bioavailability, HSC deactivation, and reduced intrahepatic microthrombosis. Our findings suggest that RVXB deserves further evaluation as a potential treatment for cirrhotic PH. (Hepatology 2017;65:2031-2044).

Differential inhibitory action of apixaban on platelet and fibrin components of forming thrombi: Studies with circulating blood and in a platelet-based model of thrombin generation.

INTRODUCTION: Mechanisms of action of direct oral anticoagulants (DOAC) suggest a potential therapeutic use in the prevention of thrombotic complications in arterial territories. However, effects of DOACs on platelet activation and aggregation have not been explored in detail. We have investigated the effects of apixaban on platelet and fibrin components of thrombus formation under static and flow conditions. METHODS: We assessed the effects of apixaban (10, 40 and 160 ng/mL) on: 1) platelet deposition and fibrin formation onto a thrombogenic surface, with blood circulating at arterial shear-rates; 2) viscoelastic properties of forming clots, and 3) thrombin generation in a cell-model of coagulation primed by platelets. RESULTS: In studies with flowing blood, only the highest concentration of apixaban, equivalent to the therapeutic Cmax, was capable to significantly reduce thrombus formation, fibrin association and platelet-aggregate formation. Apixaban significantly prolonged thromboelastometry parameters, but did not affect clot firmness. Interestingly, results in a platelet-based model of thrombin generation under more static conditions, revealed a dose dependent persistent inhibitory action by apixaban, with concentrations 4 to 16 times below the therapeutic Cmax significantly prolonging kinetic parameters and reducing the total amount of thrombin generated. CONCLUSIONS: Our studies demonstrate the critical impact of rheological conditions on the antithrombotic effects of apixaban. Studies under flow conditions combined with modified thrombin generation assays could help discriminating concentrations of apixaban that prevent excessive platelet accumulation, from those that deeply impair fibrin formation and may unnecessarily compromise hemostasis.

Altered Hypercoagulability Factors in Patients with Chronic Chagas Disease: Potential Biomarkers of Therapeutic Response.

Thromboembolic events were described in patients with Chagas disease without cardiomyopathy. We aim to confirm if there is a hypercoagulable state in these patients and to determine if there is an early normalization of hemostasis factors after antiparasitic treatment. Ninety-nine individuals from Chagas disease-endemic areas were classified in two groups: G1, with T.cruzi infection (n = 56); G2, healthy individuals (n = 43). Twenty-four hemostasis factors were measured at baseline. G1 patients treated with benznidazole were followed for 36 months, recording clinical parameters and performance of conventional serology, chemiluminescent enzyme-linked immunosorbent assay (trypomastigote-derived glycosylphosphatidylinositol-anchored mucins), quantitative polymerase chain reaction, and hemostasis tests every 6-month visits. Prothrombin fragment 1+2 (F1+2) and endogenous thrombin potential (ETP) were abnormally expressed in 77% and 50% of infected patients at baseline but returned to and remained at normal levels shortly after treatment in 76% and 96% of cases, respectively. Plasmin-antiplasmin complexes (PAP) were altered before treatment in 32% of G1 patients but normalized in 94% of cases several months after treatment. None of the patients with normal F1+2 values during follow-up had a positive qRT-PCR result, but 3/24 patients (13%) with normal ETP values did. In a percentage of chronic T. cruzi infected patients treated with benznidazole, altered coagulation markers returned into normal levels. F1+2, ETP and PAP could be useful markers for assessing sustained response to benznidazole.

Procoagulant microparticles are increased in patients with Behçet's disease but do not define a specific subset of clinical manifestations.

Microparticles (MP) are considered a key component in the haemostatic response. Beyond their in vitro procoagulant properties, a number of pieces of evidence points to procoagulant MP as efficient effectors in the haemostatic response and as pathogenic markers of thrombotic disorders and vascular damage. The aim of the present study was to analyze the procoagulant activity of MP and its correlation with clinical manifestations focusing on vascular involvement in patients with Behçet's disease (BD). We analyzed 55 BD patients in inactive phase of the disease (26 men; mean age, 35 ± 15 years) of which 19 had previously suffered from thrombosis (deep venous thrombosis in 17 and ischemic stroke in 2), and 73 healthy controls matched for age and sex. Procoagulant MP were assessed by a functional assay. BD patients showed higher procoagulant MP values than controls (22.89 ± 15.74 nM versus 14.47 ± 7.34 nM; p < 0.0001). Conversely, we did not find differences in the levels of procoagulant MP according to the gender of patients (22.22 ± 16.23 nM for men versus 21.46 ± 16.47 for women; p = 0.846) or to previous and current treatments. Moreover, the plasmatic concentration of MP does not define any clinical phenotype and it was not related to the time of evolution of the disease. Although inactive BD patients had high values of procoagulant MP, they did not differentiate between BD patients with or without thrombosis.

Coagulation Factor Concentrates Fail to Restore Alterations in Fibrin Formation Caused by Rivaroxaban or Dabigatran in Studies With Flowing Blood From Treated Healthy Volunteers.

We evaluated the hemostatic alterations in blood from healthy individuals treated for 5 days with direct oral anticoagulants (DOACs) rivaroxaban (20 mg/d) or dabigatran (150 mg/12 h) in a single-blind clinical trial with crossover assignment (NCT01478282). We assessed the potential of prothrombin complex concentrates, activated prothrombin complex concentrates, or recombinant activated factor VII, when added ex vivo, to reverse the alterations caused by these DOACs. Blood was drawn at maximum plasma concentration after the last dose of each DOAC, and modifications in coagulation biomarkers were evaluated using a series of tests performed under steady conditions including routine coagulation, thrombin generation, and thromboelastometry assays. Additional studies in standardized flow devices were applied to evaluate alterations on platelet deposition and fibrin formation on damaged vascular surfaces exposed to flowing blood. Both DOACs caused important modifications of all coagulation biomarkers and significantly reduced fibrin formation in flow studies. Alterations in biomarkers observed in steady laboratory tests were normalized and occasionally overcompensated by procoagulant strategies. In contrast, reductions in fibrin formation observed in studies with flowing blood were improved, although never completely restored to baseline levels. Effects of dabigatran in flow studies appeared more resistant to reversal strategies than those of rivaroxaban. Inconsistencies between results of coagulation studies in steady or flowing assays not only raise concerns about the adequacy of the earlier tests to predict the restoration of the coagulopathy induced by DOACs but also suggest limitations of nonspecific procoagulant strategies to control severe coagulopathy in patients inadvertently overexposed these agents.

ADAMTS-13 in Critically Ill Patients With Septic Syndromes and Noninfectious Systemic Inflammatory Response Syndrome.

PURPOSE: Decreased ADAMTS-13 (A Disintegrin and Metalloprotease with a ThromboSpondin type 1 motif, member 13) seems to be associated with a poor prognosis in sepsis. However, its role in different septic syndromes and other causes of systemic inflammatory response syndrome (SIRS) remains unclear. The aims of this study were to assess ADAMTS-13 levels in patients with septic syndromes or noninfectious SIRS and to determine their association with morbidity and mortality. METHODS: The study population consisted of 178 patients admitted to the medical intensive care unit presenting either septic syndromes or noninfectious SIRS. ADAMTS-13 levels were analyzed. RESULTS: Patients with septic syndromes showed significantly lower levels of ADAMTS-13 compared with those with noninfectious SIRS (P = 0.014). Patients with severe sepsis or septic shock presented lower levels than those of patients with sepsis (P = 0.086). A significant negative correlation was found between ADAMTS-13 levels and delta Sequential Organ Failure Assessment and Acute Physiology and Chronic Health Evaluation II scores at admission in the septic patients. Patients who died had significantly lower levels of ADAMTS-13 compared with survivors, both in the whole population and among the septic patients (P = 0.002 and P = 0.009, respectively). Logistic regression analysis showed that decreased ADAMTS-13 levels were associated with an increased risk of in-intensive care unit mortality (odds ratio, 0.985; 95% confidence interval, 0.973-0.998; P = 0.023). CONCLUSIONS: Septic patients have lower levels of ADAMTS-13 than do patients with noninfectious SIRS. Levels of ADAMTS-13 are correlated with illness severity in patients with septic syndromes. ADAMTS-13 levels were associated with an increased risk of mortality in critically ill patients with SIRS especially those with septic syndromes.