Direct oral anticoagulants in oral surgery: a prospective cohort.

BACKGROUND: Quantitative assessment of bleeding in dental extractions is rarely reported in the literature. The assessment of bleeding might provide additional evidence to predict and minimize postoperative outcomes. The aim of this study was to evaluate the pattern of bleeding in individuals taking direct oral anticoagulants (DOACs) submitted to dental extractions. METHODS: Intraoperative bleeding was evaluated by using total collected bleeding corrected by absorbance reading (dental bleeding score). To monitoring bleeding episodes from the day of surgery, this cohort was followed up until the seventh postoperative day. RESULTS: Forty-five procedures were performed in three comparative groups, patients under DOACs, individuals taking vitamin K antagonists (VKAs) and without anticoagulant therapy. No bleeding events were observed in procedures carried out in individuals of the DOAC group. Additional hemostatic measures were required in two procedures in the VKA group and one in the non-anticoagulated group. The dental bleeding scores obtained for the DOAC and VKA groups were similar. CONCLUSIONS: Our data suggest that the DOAC therapy did not result in increased bleeding outcomes in this sample.

Risk of recurrent venous thromboembolism related to prior risk situations: re-evaluation of a cohort study with a longer follow-up.

: Venous thromboembolism (VTE) is a chronic disease. Strategies to assess groups at a high risk of recurrence are needed. We reported that patients without prior risk situation for VTE had an incidence rate ratio (IRR) three times higher when compared with those with this history. The aim of this study was to re-evaluate the cohort, with a longer follow-up and evaluated the association between the absence of a prior risk situation for VTE with an increased risk for recurrence. A total of 289 patients with a previous VTE were followed for 116 months. Patients were advised to attend the outpatients' clinic in case of suspected VTE recurrence. Incidence rates of recurrent thrombotic events were calculated as the number of events over the accumulated observation time. Recurrent VTE occurred in 52 (18%) patients. Patients with a provoked first event and positive prior risk situations for VTE had an incidence rate for recurrence of 1.2 [95% confidence interval (95% CI), 0.7-1.9] per 100 patient-years. The IRR of this subgroup compared with patients with a provoked event without prior risk situations for VTE was 0.9 (95% CI 0.4-2.4). IRR was 2.5 (95% CI, 1.3-4.9) in patients with an unprovoked event and positive prior risk situations and 5.9 (95% CI, 32.8-12.5) in patients with an unprovoked event and no prior risk situations compared with patients with a provoked event without other prior risk situations for VTE. Exposure to prior risk situations for VTE was a protective factor among those patients whose first VTE event was unprovoked.

Non-genetic factors and polymorphisms in genes CYP2C9 and VKORC1: predictive algorithms for TTR in Brazilian patients on warfarin.

PURPOSE: This study was designed to evaluate the association of non-genetic factors and polymorphisms CYP2C9*2 (rs1799853), CYP2C9*3 (rs1075910), and VKORC1-G1639A (rs9923231) with time in therapeutic range (TTR), and to build a regression model to predict the quality of oral anticoagulation control in a sample of Brazilian patients. METHODS: This is a retrospective cohort study developed at an anticoagulation clinic of a university hospital. Overall, 312 patients were included. The quality of oral anticoagulation control was evaluated by TTR. TTR was dichotomized for analysis, using two cutoff points for classification as inadequate (TTR ≤ 60.0%) and optimal (TTR ≥ 75.0%) control. RESULTS: The average age was 60.4 ± 13.5 years, with a predominance of women (187; 59.9%). The -G1639A polymorphism of the VKORC1 gene, when evaluated, based on the recessive inheritance pattern [AA × (GA + GG)], patients with AA genotype exhibited a higher TTR (68.2% versus 62.8%, p = 0.017). TTR ≤ 60.0% was associated with number of drugs in chronic use, assistance for warfarin administration, reports of not taking warfarin, absenteeism, sex (female), and target INR (International Normalized Ratio; 2.00-3.00). TTR ≥ 75.0% was associated with sex (male), target INR (2.00-3.00), assistance for warfarin administration, reports of not taking warfarin, and absenteeism. The two algorithms proposed showed adequate ability to predict TTR presenting good sensitivity and specificity. CONCLUSIONS: Our findings provided useful information for risk stratification depending on TTR level and for future investigations on the quality of oral anticoagulation control in Brazilian anticoagulation clinics.

Risk factors associated with recurrent venous thromboembolism after a first cerebral venous thrombosis event: A cohort study.

BACKGROUND: Cerebral venous thrombosis (CVT), although rare, is potentially fatal. Few studies have investigated risk factors associated with recurrent venous thromboembolism (VTE) after a first CVT event of which most are from Caucasian populations. The aim of this study was to evaluate risk factors associated with recurrent VTE after a first CVT event in a South American-population. PATIENTS/METHODS: In this cohort, multicenter study, patients aged >18 years and objectively-diagnosed with CVT were included, with follow-up starting after discontinuing anticoagulant therapy. The primary outcome was symptomatic VTE recurrence at any venous site. RESULTS: We included 203 patients with a median age of 30.8 (interquartile range [IQR], 24.7-40.9) years and a follow-up of 3.0 (IQR, 1.2-5.6) years. Most patients (86.2%) were women, and among those of reproductive age (n = 162), 65.4% developed CVT during oral contraceptive use, and 9.2% during pregnancy/puerperium. Thirteen patients (6.9%) developed VTE recurrence after a first CVT, yielding an overall rate of 1.6/100 patient-years (95% confidence interval [CI], 0.8-2.8). Recurrence rate was higher in males (4.6/100 patient-years; 95% CI, 1.2-11.7) than in females (1.2/100 patient-years; 95% CI, 0.6-2.4), and in patients with factor V Leiden mutation (9.2/100 patient-years; 95% CI, 1.1-33.1) than in those without it (1.2/100 patient-years; 95% CI, 0.5-2.4). CONCLUSIONS: VTE recurrence after a first CVT was low. In spite of the limitation of small sample size, male sex and factor V Leiden mutation were the only factors associated with a significant higher risk of recurrent VTE after a first CVT in a multivariate analysis.

Apolipoprotein E and PAI-1 gene polymorphisms and no association with arterial ischemic stroke and peripheral arterial disease manifestations / Polimorfismos nos genes da apolipoproteína E e do PAI-1 e não associação com as manifestações de acidente vascular cerebral e doença arterial periférica

ABSTRACT Introduction: Arterial thrombosis is considered a multifactorial disease, resulting from the interaction of genetic and acquired risk factors. Objectives: The aim of this study was to investigate the presence of the polymorphism in inhibitor of plasminogen activator type 1 (PAI-1) and apolipoprotein E (ApoE) genes and its interactions with PAI-1 levels and lipids and apolipoprotein profiles, respectively, as well as the frequencies of these polymorphisms and their association with thrombosis. Methods: Ninety-seven patients [48 with arterial ischemic stroke (IS) and 49 with peripheral arterial disease (PAD)], treated at the hematology medical service were included in this study. Polymorphisms were also investigated in 201 control subjects. Polymorphisms were investigated by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: For the PAI-1 polymorphism, there were 54.2% heterozygous (HT) genotypes and 12.5% homozygous (HM) genotypes in the patients' group, and 52.7% HT genotypes and 21.3% HM genotypes in the controls. For the ApoE polymorphism, there were 56.3% (ε3ε3), 6.3% (ε4ε4), 8.3% (ε2ε3), 4.2% (ε2ε4) and 24.9% (ε3ε4) in the patients, and 61.2% (ε3ε3), 4.5% (ε4ε4), 8% (ε2ε3), 4.5% (ε2ε4) and 21.8% (ε3ε4) in the controls. Conclusion: No significant difference was observed by comparing patients and controls. In this study, no association was found between the presence of the evaluated polymorphisms and the occurrence of thrombotic events.

RESUMO Introdução: A trombose arterial é considerada uma doença multifatorial, resultante da interação de fatores de risco genéticos e adquiridos. Objetivos: O objetivo deste estudo foi investigar a presença dos polimorfismos nos genes do inibidor da ativação do plasminogênio tipo 1 (PAI-1) e da apolipoproteína E (ApoE), bem como suas interações com níveis de PAI-1 e lipídios e perfis de apolipoproteína, respectivamente, além das frequências desses polimorfismos e sua associação com trombose. Métodos: Noventa e sete pacientes [48 com acidente vascular cerebral isquêmico arterial (AVC) e 49 com doença arterial periférica (DAP)], tratados no serviço médico de hematologia, foram incluídos neste estudo. Os polimorfismos também foram investigados em 201 indivíduos-controle. Os polimorfismos foram investigados por reação em cadeia da polimerase-fragmento de restrição polimorfismo (PCR-RFLP). Resultados: Para o polimorfismo PAI-1, havia 54,2% genótipos heterozigotos (HT) e 12,5% genótipos de homozigoto (HM) no grupo dos pacientes, e 52,7% genótipos HT e 21,3% genótipos HM nos grupos-controle. Para o polimorfismo da ApoE, havia 56,3% (ε3ε3), 6,3% (ε4ε4), 8,3% (ε2ε3), 4,2% (ε2ε4) e 24,9% (ε3ε4) nos pacientes, e 61,2% (ε3ε3), 4,5% (ε4ε4), 8% (ε2ε3), 4,5% (ε2ε4) e 21,8% (ε3ε4) nos controles. Conclusão: Nenhuma diferença significativa foi observada comparando pacientes e controles. Neste estudo, não foi encontrada associação entre a presença dos polimorfismos avaliados e a ocorrência de eventos trombóticos.

Oral surgery in patients under antithrombotic therapy: perioperative bleeding as a significant risk factor for postoperative hemorrhage.

: To investigate perioperative and postoperative bleeding, complications in patients under therapy with anticoagulant or antiplatelet drugs submitted to oral surgery. To evaluate the risk of bleeding and safety for dental surgery, a retrospective chart review was performed. Medical and dental records of patients taking oral antithrombotic drugs undergoing dental surgery between 2010 and 2015 were reviewed. Results were statistically analyzed using Fisher's exact test, t test or the χ test. One hundred and seventy-nine patients underwent 293 surgical procedures. A total of eight cases of perioperative and 12 episodes of postoperative bleeding were documented. The complications were generally managed with local measures and did not require hospitalization. We found significant association of postoperative hemorrhage with increased perioperative bleeding (P = 0.043) and combination of anticoagulant and antiplatelet therapy (P < 0.001). The chance of postoperative hemorrhage for procedures with increased perioperative bleeding is 8.8 times bigger than procedures without perioperative bleeding. Dental surgery in patients under antithrombotic therapy might be carried out without altering the regimen because of low risk of perioperative and postoperative bleeding. However, patients with increased perioperative bleeding should be closely followed up because of postoperative complications risk.

Effects of Tityus serrulatus scorpion venom on thromboelastogram in rats.

Thromboelastometry was used to evaluate blood coagulation in anesthetized rats after intravenous administration of Tityus serrulatus scorpion venom (Tx). Tracheostomy followed by catheterization of the left jugular vein and right carotid artery were performed for Tx or Ringer's lactate solution injection and blood sample harvesting, respectively. Blood samples were obtained at the beginning of the experiments (baseline) and at two, five, 15, 30, and 60 min after intoxication. The following coagulation parameters were analyzed: CT (Clotting Time), CFT (Clotting Formation Time), Alpha Angle (α), MCF (Maximum Clot Firmness) and TPI (Thrombodynamic Potential Index). Toxin-induced hypercoagulability was demonstrated at the 15 and 60 min. We hypothesize Tx-induced hypercoagulability and enhanced clot formation could be explained by catecholamine release, systemic inflammatory response, and complement system activation, at least in the first hour after envenomation. Further studies are needed to determine the molecular mechanism of Tx-induced coagulopathy.

Protein S levels and the risk of venous thrombosis: results from the MEGA case-control study.

In thrombophilic families, protein S deficiency is clearly associated with venous thrombosis. We aimed to determine whether the same holds true in a population-based case-control study (n = 5317). Subjects were regarded protein S deficient when protein S levels were < 2.5th percentile of the controls. Free and total protein S deficiency was not associated with venous thrombosis: free protein S < 53 U/dL, odds ratio [OR] 0.82 (95% confidence interval [CI], 0.56-1.21) and total protein S < 68 U/dL, OR 0.90 (95% CI, 0.62-1.31). When lower cutoff values were applied, it appeared that subjects at risk of venous thrombosis could be identified at levels < 0.10th percentile of free protein S (< 33 U/dL, OR 5.4; 95% CI, 0.61-48.8). In contrast, even extremely low total protein S levels were not associated with venous thrombosis. PROS1 was sequenced in 48 subjects with free protein S level < 1st percentile (< 4 6 U/dL), and copy number variations were investigated in 2718 subjects, including all subjects with protein S (free or total) < 2.5th percentile. Mutations in PROS1 were detected in 5 patients and 5 controls reinforcing the observation that inherited protein S deficiency is rare in the general population. Protein S testing and PROS1 testing should not be considered in unselected patients with venous thrombosis.

Rifampicin-warfarin interaction leading to macroscopic hematuria: a case report and review of the literature.

BACKGROUND: Rifampicin remains one of the first-line drugs used in tuberculosis therapy. This drug's potential to induce the hepatic cytochrome P450 oxidative enzyme system increases the risk of drug-drug interactions. Thus, although the presence of comorbidities typically necessitates the use of multiple drugs, the co-administration of rifampicin and warfarin may lead to adverse drug events. We report a bleeding episode after termination of the co-administration of rifampicin and warfarin and detail the challenges related to international normalized ratio (INR) monitoring. CASE PRESENTATION: A 59-year-old Brazilian woman chronically treated with warfarin for atrial fibrillation (therapeutic INR range: 2.0-3.0) was referred to a multidisciplinary anticoagulation clinic at a university hospital. She showed anticoagulation resistance at the beginning of rifampicin therapy, as demonstrated by repeated subtherapeutic INR values. Three months of sequential increases in the warfarin dosage were necessary to reach a therapeutic INR, and frequent visits to the anticoagulation clinic were needed to educate the patient about her pharmacotherapy and to perform the warfarin dosage adjustments. The warfarin dosage also had to be doubled at the beginning of rifampicin therapy. However, four weeks after rifampicin discontinuation, an excessively high INR was observed (7.22), with three-day macroscopic hematuria and the need for an immediate reduction in the warfarin dosage. A therapeutic and stable INR was eventually attained at 50% of the warfarin dosage used by the patient during tuberculosis therapy. CONCLUSIONS: The present case exemplifies the influence of rifampicin therapy on warfarin dosage requirements and the increased risk of bleeding after rifampicin discontinuation. Additionally, this case highlights the need for warfarin weekly monitoring after stopping rifampicin until the maintenance dose of warfarin has decreased to the amount administered before rifampicin use. In particular, patients with cardiovascular diseases and active tuberculosis represent a group with a substantial risk of drug-drug interactions. Learning how to predict and monitor drug-drug interactions may help reduce the incidence of clinically significant adverse drug events.

Risk of recurrent venous thrombosis related to past provoking risk situations: follow-up of a cohort study.

Strategies targeting at classifying the risk for recurrent venous thrombosis are needed. We previously hypothesized, by studying a cohort of patients, that those who had 'survived' risk situations for venous thrombosis without developing it would, after a first venous thrombosis, have a low recurrence risk. Therefore, we re-evaluated the same cohort, now with a longer follow-up. Patients, after a first confirmed venous thrombosis event, were followed for an average of 43 months after suspension of anticoagulation. Patients with indication for indefinite anticoagulation were not included. The primary endpoint was objective recurrent venous thrombosis. Recurrent venous thrombosis was recorded in 9% of 378 eligible patients. Patients with a provoked first event and positive past risk situations for venous thrombosis had an incidence rate of recurrence of 1.26 (95% CI, 0.60-2.31) per 100 patient-years. The incidence rate ratio (IRR) of this subgroup compared with patients with a provoked event without other past risk situations for venous thrombosis was 0.8 (95% CI 0.2-2.9). This IRR was 2.8 (95% CI, 1.2-6.5) in patients with an unprovoked event and positive past risk situations and 7.1 (95% CI, 3.0-17.1) in patients with an unprovoked event and no past risk situations. When only idiopathic first events were evaluated the IRR was 2.5 (95% CI, 1.1-5.9) for patients without past risk situation compared with those with these history. In this study, asking a patient about past exposure to risk factors for venous thrombosis long before the occurrence of a first venous thrombosis occurred, could be used to classify patients with a first unprovoked venous thrombosis at higher risk for recurrence of venous thrombosis.

Agreement among four drug information sources for the occurrence of warfarin drug interactions in Brazilian heart disease patients with a high prevalence of Trypanosoma cruzi infection.

PURPOSE: The aim of this study was to assess the agreement of four renowned interaction lists on potentially severe warfarin drug interactions (DI) in outpatients at a university hospital in Brazil, specifically in subgroups of Trypanosoma cruzi-infected and non-infected patients and those with previous bleeding episodes. METHODS: This was a cross-sectional study in which adult outpatients with heart disease and indications for chronic warfarin use were enrolled. The occurrence of potentially severe warfarin DI was evaluated based on the lists provided by three compendia, i.e., Drug Interaction Facts (DIF), Drug Interactions: Analysis and Management (DIAM) and DRUG-REAX, and by the World Health Organization (WHO) Model Formulary. A kappa coefficient was used to calculate the agreement among the sources. RESULTS: A total of 280 patients were studied. Most patients were female (54.6 %) with an average age of 56.8 (standard deviation 13.1) years. The agreement among the four sources was fair (Fleiss' kappa coefficient = 0.295). T. cruzi-infected individuals were less likely to have severe warfarin DI than non-infected patients (p < 0.05 for DIAM, DRUG-REAX and the WHO Model Formulary). Potentially severe DI were more frequent in patients with previous bleeding episodes, based on the DIF compendia (p = 0.007). CONCLUSIONS: This evaluation of warfarin DI revealed that the disagreement between compendia is also observed in clinical practice. T. cruzi infection is associated with a lower prevalence of potentially severe warfarin DI, but with a wider variation in its detection. Our results suggest a wide spectrum of discrepancies in detecting heart disease patients at higher risk for severe warfarin DI and a possible heterogeneity in clinical guidance.

Warfarin drug interactions: a comparative evaluation of the lists provided by five information sources.

PURPOSE: Detecting potential drug interactions can lead to early interventions that protect patients from serious drug-related problems. The aim of this study was to evaluate the agreement among the lists of warfarin interactions provided by five information sources. METHODS: The lists of warfarin interactions and the corresponding severity ratings and documentation levels presented by the three compendia and by the World Health Organization (WHO) Model Formulary were all compared, and each list was compared to that provided on the package insert of Marevan, a brand of warfarin. The compendia used were: Drug Interaction Facts, Drug Interactions: Analysis and Management and DRUG-REAX. A kappa coefficient was used to calculate the agreement among the sources. RESULTS: A total of 537 interactions were listed. Only 13 (2.4%) were common to the five sources. The global Fleiss' kappa coefficient was -0.0080, which indicated poor agreement. Eleven warfarin interactions appeared only in the Marevan package insert. Importantly, 243 interactions (45.3% of the total) were deemed significant in at least one compendium. Only two warfarin interactions were reported as critical by all three compendia and by WHO. The most critical interactions cited by the compendia were missing from the package insert. CONCLUSIONS: Poor agreement was found among five sources listing warfarin interactions. Potentially severe clinical consequences might occur due to these discrepant recommendations. Finally, the lack of standard terminology and clinical guidance, as well as the possible inaccuracy of severity ratings and documentation might contribute to heterogeneous procedures in clinical practice.

Past provoking venous thrombosis risk situations on the risk of a recurrent thrombotic event: a cohort study.

OBJECTIVE: Strategies that can classify the risk for recurrent venous thrombosis are needed. Some patients may have experienced many risk situations during their life time without developing venous thrombosis (VT), while others may have experienced few of such risk factors and then develop VT idiopathically or after a single provoked risk factor. We hypothesized that those who had 'survived' many risk situations without developing VT would, after a first VT, have a low recurrence risk. METHODS: Brazilian tertiary hospital cohort was followed for an average of 30 months after anticoagulation withdrawal for a first VT. Patients with indication for indefinite anticoagulation were not included. The primary end point was objective recurrent VT. RESULTS: Recurrent VT was recorded in 7% of 378 eligible patients. Patients with a provoked first event and positive past risk situations for VT had an incidence rate of recurrence of 1.16 (95% confidence interval [CI], 0.47-2.39) per 100 patient-years. The incidence rate ratio (IRR) of this subgroup compared to patients with a provoked event without other past risk situations for VT was 1.1 (95% CI, 0.3-4.4). This IRR was 3.3 (95% CI, 1.3-8.7) in patients with an unprovoked event and positive past risk situations and 5.1 (95% CI, 1.6-16.1) in patients with an unprovoked event and no past risk situations. CONCLUSIONS: Asking a patient about past exposure of venous thrombosis risk factors long before the occurrence of a first venous thrombosis occurred, does not provide information to classify patients at lower risk for recurrence of venous thrombosis.

Permissive hypotension and desmopressin enhance clot formation.

BACKGROUND: Experimental studies of uncontrolled hemorrhage demonstrated that permissive hypotension (PH) reduces blood loss, but its effect on clot formation remains unexplored. Desmopressin (DDAVP) enhances platelet adhesion promoting stronger clots. We hypothesized PH and DDAVP have additive effects and reduce bleeding in uncontrolled hemorrhage. METHODS: Rabbits (n = 42) randomized as follows: sham; normal blood pressure (NBP) resuscitation; PH resuscitation-60% baseline mean arterial pressure; NBP plus DDAVP 1 hour before (DDAVP NBP) or 15 minutes after beginning of shock (DDAVP T1 NBP); and PH plus DDAVP 1 hour before (DDAVP PH) or 15 minutes after beginning of shock (DDAVP T1 PH). Fluid resuscitation started 15 minutes after aortic injury and ended at 85 minutes. Intraabdominal blood loss was calculated, aortic clot sent for electron microscopy. Activated partial thromboplastin time, platelet count, thromboelastometry, arterial blood gases, and complete blood count were performed at baseline and 85 minutes. Analysis of variance was used for comparison. RESULTS: NBP received more fluid volume and had greater intraabdominal blood loss. DDAVP, when administered preshock, significantly reduced blood loss in NBP and fluid requirement when given postshock. Platelets, arterial blood gas, complete blood count, and activated partial thromboplastin time were similar at 85 minutes. NBP delayed clot formation and worsened thrombodynamic potential on thromboelastometry, whereas PH and DDAVP improved. Electron microscopy showed lack of fibrin on NBP clots, whereas DDAVP and PH clots displayed exuberant fibrin/platelet aggregates. DDAVP NBP presented intermediate clots. CONCLUSION: PH reduced bleeding and improved hemostasis compared with normotensive resuscitation. DDAVP given preshock exerted similar effects with normotensive resuscitation.

Polymorphisms in exons 6 and 7 of the ABO locus and their association with venous thrombosis in young Brazilian patients.

The A1 and B alleles of the ABO blood system have been associated with high levels of both factor VIII and von Willebrand factor and with a predisposition to venous thromboembolism (VTE). In this study, genotypes of the ABO system were determined by PCR-restriction fragment length polymorphism for 148 young VTE Brazilian patients and 233 unrelated control individuals. The blood group O was more frequent among the controls [odds ratio (OR), 0.21; 95% confidence interval (CI), 0.13-0.34; P = 0.000) and groups A and B (OR, 2.24; 95%, CI, 1.46-3.42; P = 0.000 and OR, 2.52; 95% CI, 1.42-4.48; P = 0.002, respectively) among patients. The patients' group was under Hardy-Weinberg equilibrium, whereas the control group was not (P < 0.0051), suggesting that natural selection might be acting in favor of carriers of the O blood group. When the allelic frequencies were compared through multivariate logistic regression analysis for adjustments of covariates, the alleles A1 (OR, 1.69; 95% CI, 1.17-2.45; P = 0.006), A2 (OR, 2.19; 95% CI, 1.24-3.87; P = 0.010), and B (OR, 2.65; 95% CI, 1.64-4.26; P = 0.000) were independently associated with VTE and may represent important risk factors to the development of VTE among young Brazilian patients. Thus, the inclusion of ABO blood group determination may be helpful to discriminate individuals with high risk for VTE allowing target intervention as well as to manage VTE in young patients.