Definition of major bleeding: Prognostic classification.

BACKGROUND: In patients on anticoagulant treatment, the major bleeding (MB) definition released by the International Society of Thrombosis and Haemostasis (ISTH) is widely accepted. However, this definition identifies MBs with highly variable short-term risk of death. OBJECTIVES: The study aims were to derive and validate a classification of ISTH-defined MBs for the risk of short-term death. METHODS: Consecutive patients admitted for ISTH-defined MB occurring while on treatment with oral anticoagulants were included in the study and divided into a derivation and a validation cohort. Death within 30 days was the primary study outcome. RESULTS: Among 1077 patients with MB, 64/517 and 63/560 patients in the derivation and validation cohort died, respectively. In the derivation cohort, Glasgow coma scale (GCS) <14 and shock were predictors of death; critical site bleeding and hemoglobin decrease ≥2 g/dL, or transfusion ≥ 2 units were not. GCS <14 (hazard ratio [HR], 8.67; 95% confidence interval [CI], 3.93-19.13) was predictor of death in intracranial hemorrhage (ICH) and shock at admission (HR, 4.84; 95% CI, 2.01-11.70) and pericardial bleeding (HR, 11.37; 95% CI, 1.33-97.31) in non-ICH MBs. The predictive value of GCS <14 in ICH and shock and pericardial bleeding in non-ICH MBs was confirmed in the validation cohort. None of the patients with isolated ocular or articular bleeding died. A prognostic classification of ISTH-defined MBs for the risk of short-term death is proposed as "serious," "severe," and "life-threatening" (ICH with GCS <14 or non-ICH with shock) MBs. CONCLUSION: According to our study, ISTH-defined MBs can be stratified for the risk of death within 30 days.

Mortality in patients with intracerebral hemorrhage associated with antiplatelet agents, oral anticoagulants or no antithrombotic therapy.

The association between preceding treatment with antiplatelet agents (APs), vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) and mortality after intracerebral hemorrhage (ICH) remains unclear. The aim of this multicenter, prospective cohort study was to assess the risk for death after ICH in consecutive patients who were on treatment with APs, VKAs, DOACs, or no antithrombotic agent. The primary outcome was in-hospital death by day 30. ICH volume at admission and volume expansion were centrally assessed. Out of 598 study patients, in-hospital death occurred in 21% of patients who were on treatment with APs, 25% with VKAs, 30% with DOACs, and 13% with no antithrombotics. Crude death rate was higher in patients on antithrombotics as compared to patients receiving no antithrombotic agent. At multivariate analysis, age (HR 1.07; 95% CI 1.04-1.10), previous stroke (HR 1.83; 95% CI 1.14-2.93), GCS ≤8 at admission (HR 6.06; 95% CI 3.16-9.74) and GCS 9-12 (HR 3.38; 95% CI 1.81-6.33) were independent predictors of death. Treatment with APs (HR 1.29; 95% CI 0.61-2.76), VKAs (HR 1.42; 95% CI 0.70-2.88) or DOACs (HR 1.28; 95% CI 0.61-2.73) were not predictors of death in the overall study population, in non-trauma associated ICH as well as when GCS was not included in the model. ICH volume and volume expansion were independent predictors of death. In conclusion, preceding treatment with antithrombotic is associated with the severity of ICH. Age, previous stroke and clinical severity at presentation were independent predictors of in-hospital death in patients with ICH.

Impact of residual pulmonary obstruction on the long-term outcome of patients with pulmonary embolism.

The impact of residual pulmonary obstruction on the outcome of patients with pulmonary embolism is uncertain.We recruited 647 consecutive symptomatic patients with a first episode of pulmonary embolism, with or without concomitant deep venous thrombosis. They received conventional anticoagulation, were assessed for residual pulmonary obstruction through perfusion lung scanning after 6 months and then were followed up for up to 3 years. Recurrent venous thromboembolism and chronic thromboembolic pulmonary hypertension were assessed according to widely accepted criteria.Residual pulmonary obstruction was detected in 324 patients (50.1%, 95% CI 46.2-54.0%). Patients with residual pulmonary obstruction were more likely to be older and to have an unprovoked episode. After a 3-year follow-up, recurrent venous thromboembolism and/or chronic thromboembolic pulmonary hypertension developed in 34 out of the 324 patients (10.5%) with residual pulmonary obstruction and in 15 out of the 323 patients (4.6%) without residual pulmonary obstruction, leading to an adjusted hazard ratio of 2.26 (95% CI 1.23-4.16).Residual pulmonary obstruction, as detected with perfusion lung scanning at 6 months after a first episode of pulmonary embolism, is an independent predictor of recurrent venous thromboembolism and/or chronic thromboembolic pulmonary hypertension.

Recanalization rate in patients with proximal vein thrombosis treated with the direct oral anticoagulants.

BACKGROUND: The recanalization rate in patients with deep venous thrombosis (DVT) of the legs treated with the direct oral anticoagulants (DOAC) is unknown. METHODS: In an Italian cohort, we investigated the rate of residual vein thrombosis (RVT) after three and/or six months in 352 patients with proximal DVT who had been treated with the DOACs as a stand-alone therapy or lead-in parenteral anticoagulants, and compared it to that recorded in a historical cohort of 1094 patients in which vitamin K antagonists (VKAs) had been employed. In both cohorts, RVT was defined as the ultrasound persistence of thrombotic material resulting in a diameter of at least 4mm of incompressibility of the proximal veins. RESULTS: RVT was detected in 143 patients treated with DOACs (41.2%) after three months and in 58 patients (21.1%) after six months; the corresponding figure in patients treated with conventional anticoagulation was 52.3% and 54.5%, respectively. After adjusting for the baseline characteristics, the odds ratio of RVT in patients treated with the DOACs as compared with those treated with conventional anticoagulation was 0.63 (95% CI, 0.48-0.81) after three months, and 0.17 (95% CI; 0.11-0.26) after six months. CONCLUSIONS: In patients with proximal DVT treated with the DOACs, the persistence of ultrasound detectable RVT is likely to occur less frequently than in patients treated with conventional anticoagulation. These results may have implications for the prognosis of patients with DVT.

Major bleeding with vitamin K antagonists or direct oral anticoagulants in real-life.

BACKGROUND: Limited data are available on major bleeding (MB) occurring during treatment with vitamin K (VKAs) or direct oral anticoagulants (DOACs) outside clinical trials. METHODS: Patients hospitalized for MB while on treatment with VKAs or DOACs were included in a multicenter study to compare clinical presentation, management and outcome of bleeding. The primary study outcome was death at 30days. RESULTS: Between September 2013 and September 2015, 806 patients were included in the study, 76% on VKAs and 24% on DOACs. MB was an intracranial hemorrhage in 51% and 21% patients on VKAs or DOACs, respectively (Odds Ratio [OR] 3.79; 95% confidence interval [CI] 2.59-5.54) a gastrointestinal bleeding in 46% and 25% patients on DOACs and VKAs, respectively (OR 2.62; 95% CI 1.87-3.68). Death at 30days occurred in 130 patients (16%), 18% and 9% of VKA and DOAC patients (HR 1.95; 95% CI 1.19-3.22, p=0.008). The rate of death at 30days was similar in VKA and DOAC patients with intracranial hemorrhage (26% and 24%; HR 1.05, 95% CI 0.54-2.02) and gastrointestinal bleeding (11% and 7%; HR 1.46, 95% CI 0.57-3.74) and higher in VKA than DOAC patients with other MBs (10% and 3%; HR 3.42, 95% CI 0.78-15.03). CONCLUSIONS: Admission for ICH is less frequent for DOAC patients compared with VKA patients. Admission for gastrointestinal MB is more frequent for DOAC as compared to VKA patients. Mortality seems lower in patients with MBs while on DOACs than VKAs but this finding varies across different types of MBs.

Management of new oral anticoagulants related life threatening or major bleedings in real life: a brief report.

Although new oral anticoagulants (NOAs) have been marketed in many countries, concern exists about the management of bleedings related to these drugs due to the lack of specific antidotes. The aim of our study was to report on real life management of NOAs-related life-threatening or major bleedings. We report data from consecutive cases of NOAs related major bleedings admitted to 4 hospitals since NOAs became marketed in Italy. We treated 8 patients, 4 males, with mean age 84 ± 7 years, 7 of whom were on dabigatran and one on rivaroxaban. The indication for NOA was atrial fibrillation. All bleedings were spontaneous and involving the gastro-intestinal tract. At the time of bleeding all patients had a drop in hemoglobin levels over 20 g/L. Creatinine clearance was ≤30 mL/min in 4 patients. All patients received general supportive measures, 4 of 8 patients were transfused with packed red cells and one patient received platelet transfusion. Three patients were treated with tranexamic acid and one patient on dabigatran received 4-factor prothrombin complex concentrate (PCC) with bleeding cessation, although coagulation parameters were not corrected. The median time for normalization of coagulation parameters was 3 days (range 1-6 days). All patients were discharged alive and NOAs were discontinued. In NOAs related major gastro-intestinal bleeding general supportive measures seem to be effective for the majority of patients. Despite promoting bleeding cessation, 4-factor PCC does not reverse abnormal coagulation parameters.

The practical management of intracerebral hemorrhage associated with oral anticoagulant therapy.

Oral anticoagulant-associated intracerebral hemorrhage is increasing in incidence and is the most feared complication of therapy with vitamin K1 antagonists. Anticoagulant-associated intracerebral hemorrhage has a high risk of ongoing bleeding, death, or disability. The most important aspect of clinical management of anticoagulant-associated intracerebral hemorrhage is represented by urgent reversal of coagulopathy, decreasing as quickly as possible the international normalized ratio to values ≤1·4, preferably ≤1·2, together with life support and surgical therapy, when indicated. Protocols for anticoagulant-associated intracerebral hemorrhage emphasize the immediate discontinuation of anticoagulant medication and the immediate intravenous administration of vitamin K1 (mean dose: 10-20 mg), and the use of prothrombin complex concentrates (variable doses calculated estimate circulating functional prothrombin complex) or fresh-frozen plasma (15-30 ml/kg) or recombinant activated factor VII (15-120 µg/kg). Because of cost and availability, there is limited randomized evidence comparing different reversal strategies that support a specific treatment regimen. In this paper, we emphasize the growing importance of anticoagulant-associated intracerebral hemorrhage and describe options for acute coagulopathy reversal in this setting. Additionally, emphasis is placed on understanding current consensus-based guidelines for coagulopathy reversal and the challenges of determining best evidence for these treatments. On the basis of the available knowledge, inappropriate adherence to current consensus-based guidelines for coagulopathy reversal may expose the physician to medico-legal implications.

Prognostic stratification of acute pulmonary embolism: focus on clinical aspects, imaging, and biomarkers.

Pulmonary embolism (PE) represents a common disease in emergency medicine and guidelines for diagnosis and treatment have had wide diffusion. However, PE morbidity and mortality remain high, especially when associated to hemodynamic instability or right ventricular dysfunction. Prognostic stratification to identify high risk patients needing to receive more aggressive pharmacological and closer monitoring is of utmost importance. Modern guidelines for management of acute PE are based on risk stratification using either clinical, radiological, or laboratory findings. This article reviews the modern treatment of acute PE, which is customized upon patient prognosis. Accordingly the current risk stratification tools described in the literature such as clinical scores, echocardiography, helical computer tomography, and biomarkers will be reviewed.

The Risk-based Treatment of Acute Pulmonary Embolism.

UNLABELLED: Risk evaluation and prognostic stratification based upon clinical and radiological findings and new cardiac biomarkers, such as natriuretic peptides (NP) and troponins, represent key points in modern management of acute pulmonary embolism (PE). Literature evidence shows that normotensive PE with right heart dysfunction (RHD), defined as submassive PE, has poorer prognosis when compared to normotensive PE without RHD, defined as non-massive PE; thus whether submassive PE should be managed more aggressively and with closer monitoring represents the crucial question about acute PE treatment. Although the answer is yet unclear, the most recent guidelines address to thrombolysis as treatment choice in selected high risk patients with submassive PE. Guidelines also clarify the indications for unfractioned and low molecular weight heparins and fondaparinux. Therefore, in the present article, the authors focus on modern risk-based therapeutic guidelines of acute PE. KEYWORDS: Pulmonary embolism; Treatment; Prognosis; Biomarkers; Chocardiography; Hemodynamic; Guidelines.

Pulmonary embolism in the elderly: a review on clinical, instrumental and laboratory presentation.

OBJECTIVE: Diagnosis of pulmonary embolism (PE) remains difficult and is often missed in the elderly due to nonspecific and atypical presentation. Diagnostic algorithms able to rule out PE and validated in young adult patients may have reduced applicability in elderly patients, which increases the number of diagnostic tools use and costs. The aim of the present study was to analyze the reported clinical presentation of PE in patients aged 65 and more. MATERIALS AND METHODS: Prospective and retrospective English language studies dealing with the clinical, instrumental and laboratory aspects of PE in patients more than 65 and published after January 1987 and indexed in MEDLINE using keywords as pulmonary embolism, elderly, old, venous thromboembolism (VTE) in the title, abstract or text, were reviewed. RESULTS: Dyspnea (range 59%-91.5%), tachypnea (46%-74%), tachycardia (29%-76%), and chest pain (26%-57%) represented the most common clinical symptoms and signs. Bed rest was the most frequent risk factor for VTE (15%-67%); deep vein thrombosis was detected in 15%-50% of cases. Sinus tachycardia, right bundle branch block, and ST-T abnormalities were the most frequent ECG findings. Abnormalities of chest X-ray varied (less than 50% in one-half of the studies and more than 70% in the other one-half). Arterial blood gas analysis revealed severe hypoxemia and mild hypocapnia as the main findings. D-Dimer was higher than cut-off in 100% of patients in 75% of studies. Clinical usefulness of D-Dimer measurement decreases with age, although the strategies based on D-Dimer seem to be cost-effective at least until 80 years. CONCLUSION: Despite limitations due to pooling data of heterogeneous studies, our review could contribute to the knowledge of the presentation of PE in the elderly with its diagnostic difficulties. A diagnostic strategy based on reviewed data is proposed.

Serial 2-point ultrasonography plus D-dimer vs whole-leg color-coded Doppler ultrasonography for diagnosing suspected symptomatic deep vein thrombosis: a randomized controlled trial.

CONTEXT: Patients with suspected deep vein thrombosis (DVT) of the lower extremities are usually investigated with ultrasonography either by the proximal veins (2-point ultrasonography) or the entire deep vein system (whole-leg ultrasonography). The latter approach is thought to be better based on its ability to detect isolated calf vein thrombosis; however, it requires skilled operators and is mainly available only during working hours. No randomized comparisons are yet available evaluating the relative values of these 2 strategies. OBJECTIVE: To assess if the 2 diagnostic strategies are equivalent for the management of symptomatic outpatients with suspected DVT of the lower extremities. DESIGN, SETTING, AND PATIENTS: A prospective, randomized, multicenter study of consecutive symptomatic outpatients (n = 2465) with a first episode of suspected DVT of the lower extremities who were randomized to undergo 2-point or whole-leg ultrasonography. Data were taken from ultrasound laboratories of 14 Italian universities or civic hospitals between January 1, 2003, and December 21, 2006. Patients with normal ultrasound findings were followed up for 3 months, with study completion on March 20, 2007. MAIN OUTCOME MEASURE: Objectively confirmed 3-month incidence of symptomatic venous thromboembolism in patients with an initially normal diagnostic workup. RESULTS: Of 2465 eligible patients, 345 met 1 or more exclusion criteria and 22 refused to participate; therefore, 2098 patients were randomized to either 2-point (n = 1045) or whole-leg (n = 1053) ultrasonography. Symptomatic venous thromboembolism occurred in 7 of 801 patients (incidence, 0.9%; 95% confidence interval [CI], 0.3%-1.8%) in the 2-point strategy group and in 9 of 763 patients (incidence, 1.2%; 95% CI, 0.5%-2.2%) in the whole-leg strategy group. This met the established equivalence criterion (observed difference, 0.3%;95% CI, -1.4% to 0.8%). CONCLUSION: The 2 diagnostic strategies are equivalent when used for the management of symptomatic outpatients with suspected DVT of the lower extremities. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00353093.

Comparison of blood viscosity using a torsional oscillation viscometer and a rheometer.

The absence of a simple and clinically practical method to determine whole blood viscosity can partly justify why the medical community has been slow in realizing the significance of whole blood viscosity. For this reason, the availability of a technique able to evaluate blood viscosity in a rapid and direct manner is welcome. To evaluate the feasibility in hemorheological laboratory of a new torsional oscillation viscometer, it was compared with a conventional cone-plate system. The viscosity comparison has been related to hematocrit value both on whole blood and suspended blood in a saline solution. The results showed a good repeatability and reproducibility of the new equipment, with a best-fitting data of the hematocrit 0-100% range characterized by coefficient of determinations, r2>0.95. Furthermore, a comparison of whole blood viscosity as measured by the two instruments was done on blood samples collected from hospitalized patients. Reasonable agreement for the viscosity values was found between the two methods with linear determination coefficients between the two measurement methods comprised between r2=0.7329 and 0.9263, depending on shear stress phase and the corresponding shear rate.

Prevalence of factor V Leiden and prothrombin G20210A in patients with gastric cancer.

AIM: To analyze the prevalence of the two commonest thrombophilic mutations, factor V Leiden and prothrombin G20210A, in patients with gastric cancer. METHODS: One hundred and twenty-one patients with primary gastric carcinoma and 130 healthy subjects, comparable for age and sex, were investigated. Factor V Leiden was detected by using polymerase chain reaction and restriction enzyme digestion, and prothrombin G20210A gene mutation by allele-specific PCR. RESULTS: Among the 121 cancer patients, factor V Leiden was found in 4 cases (GA genotype: 3.3%) and prothrombin G20210A in 10 cases (GA genotype: 8.3%). Of the 130 control subjects, factor V Leiden was detected in 6 cases (GA genotype: 4.6%) and prothrombin G20210A in 8 cases (GA genotype: 6.1%). No double heterozygous carriers of both mutations were found in either group. The prevalence of both factor V Leiden and prothrombin G20210A variant was not statistically different between the cancer patients and the healthy subjects. CONCLUSION: Our study suggests that, in gastric cancer, the risk factors of thrombophilic cancer state are on acquired rather than on a genetic basis and that prothrombin G20210A does not seem to be a cofactor in gastric cancer pathogenesis.

[Acquired factor VIII hemophilia in a geriatric patient]. / Emofilia A acquisita: descrizione di un caso clinico in età geriatrica.

Acquired hemophilia is a rare coagulopathy in adults, associated with bleeding complications. Although the etiology of this disorder remains obscure, an autoimmune mechanism produces the development of autoantibodies against factor VIII. About half of cases are associated with other conditions, mainly post-partum, underlying cancer, autoimmune disease. An 81-year-old male was admitted to the hospital with extensive hematomas (neck, chest, arms and lower limbs). There was no family or personal history of congenital bleeding diathesis. He had chronic bronchitis and cerebrovascular disease; no drugs had been used during the month prior to noted symptoms. Laboratory parameters revealed: hemoglobin 10.9 g%, normal platelet count and white blood cells, prolonged activated partial thromboplastin time (98 s), with normal prothrombin time and fibrinogen concentration. An activated partial thromboplastin time mixing study did not show any correction, suggesting a coagulation inhibitor. Lupus anticoagulant and anticardiolipin antibodies were negative. Biochemical, immunological tests and tumor markers were normal. Thoracic and abdominal computed tomographic scan did not reveal pathological images or hematomas. Analysis of clotting factors revealed decreased factor VIII (< 2%) and elevated factor VIII inhibitor (55 Bethesda units). Idiopathic acquired hemophilia diagnosis was made. Red blood cell transfusion and human factor VIII (2000 U/day for 7 days) infusion were initiated, intravenously with methylprednisolone. A progressive improvement in clinical conditions and laboratory parameters was observed. After 18 days the patient was discharged and treated with prednisone. At follow-up control the clinical conditions and laboratory parameters were normal.

Evaluation of C-reactive protein measurement for assessing the risk and prognosis in ischemic stroke: a statement for health care professionals from the CRP Pooling Project members.

BACKGROUND AND PURPOSE: Several studies have shown, in different populations, that modest elevation of plasma C-reactive protein (CRP) in the range seen in apparently healthy individuals is a strong predictor of future vascular events. Elevated plasma CRP concentrations are also associated with an increased risk of cerebrovascular events and an increased risk of fatal and nonfatal cardiovascular events in ischemic stroke patients. These epidemiological and clinical observations suggest that determination of plasma CRP concentrations could be used as an adjunct for risk assessment in primary and secondary prevention of cerebrovascular disease and be of prognostic value. The aim of this review is to summarize the evidence for CRP as an independent predictor of cerebrovascular events in at-risk individuals and ischemic stroke patients and to consider its usefulness in evaluating prognosis after stroke. SUMMARY OF REVIEW: CRP fulfils most of the requirements of a new risk and prognostic predictor, but several issues await further confirmation and clarification before this marker can be included in the routine evaluation of stroke patients and subjects at risk for cerebrovascular disease. Potentially important associations have been established between elevated plasma CRP concentrations and increased efficacy of established therapies, particularly lipid-lowering therapy with statins. CONCLUSIONS: At present, there is not sufficient evidence to recommend measurement of CRP in the routine evaluation of cerebrovascular disease risk in primary prevention, because there is insufficient evidence as to whether early detection, or intervention based on detection, improves health outcomes, although shared risk of cardiovascular disease indicates this may be of value. In secondary prevention of stroke, elevated CRP adds to existing prognostic markers, but it remains to be established whether specific therapeutic options can be derived from this.

[Thoracic outlet syndrome: clinical staging]. / Sindrome dello stretto toracico superiore: stadiazione clinica.

The clinical and instrumental manifestations of thoracic outlet syndrome are well known but the therapeutic choices frequently differ in relation to the physician's experience. Thus, there is no univocal opinion regarding the therapy of this complex syndrome. To solve this problem we have attempted to bring together the clinical and instrumental pictures in a single classification that includes the three fundamental aspects of the syndrome, namely nerve, artery and vein injury (NAV). Our goal was to achieve a universally accepted therapy-oriented staging system, as is the case with the TNM system for malignant tumours. From 1984 to 2002, in our institution 156 patients with thoracic outlet syndrome were evaluated. These were grouped in 4 stages depending on their NAV status. Subsequent therapy was in accordance with stage. Our results confirmed the accuracy of NAV. On the basis of our preliminary experience, the NAV staging system is useful for correct patient grouping. Now a prospective multicentre study is needed for universal scientific validation.