Impacto del perfil mutacional sobre el riesgo trombótico en pacientes con cáncer / Impact of the mutation profile on thrombotic risk in cancer patients

Los pacientes con cáncer presentan un riesgo elevado de trombosis, que condiciona una elevada morbimortalidad. Se han desarrollado diversas escalas predictivas para la identificación de aquellos con alto riesgo trombótico, incorporando datos clínicos y biológicos, pero, en general, no permiten una selección óptima de los sujetos candidatos para recibir tromboprofilaxis. Estudios recientes demuestran que el perfil mutacional tiene un alto impacto sobre el riesgo trombótico, lo que va a facilitar el desarrollo de nuevos modelos predictivos de trombosis en pacientes con cáncer (AU)

Patients with cancer present with an elevated risk of thrombosis, which entails high morbidity and mortality. Various predictive scales that incorporate clinical and biological data have been developed to identify those at high risk of thrombosis, but, in general, they do not allow for the optimal selection of subjects who are candidates for thromboprophylaxis. Recent studies have demonstrated that the mutation profile has a high impact on the risk of thrombosis; this will facilitate developing new predictive models of thrombosis in patients with cancer (AU)

SEA 2022 Standards for Global Control of Cardiovascular Risk. / Estándares SEA 2022 para el control global del riesgo cardiovascular.

One of the objectives of the Spanish Society of Arteriosclerosis is to contribute to better knowledge of vascular disease, its prevention and treatment. It is well known that cardiovascular diseases are the leading cause of death in our country and entail a high degree of disability and health care costs. Arteriosclerosis is a multifactorial disease and therefore its prevention requires a global approach that takes into account the different risk factors with which it is associated. Therefore, this document summarizes the current level of knowledge and includes recommendations and procedures to be followed in patients with established cardiovascular disease or at high vascular risk. Specifically, this document reviews the main symptoms and signs to be evaluated during the clinical visit, the laboratory and imaging procedures to be routinely requested or requested for those in special situations. It also includes vascular risk estimation, the diagnostic criteria of the different entities that are cardiovascular risk factors, and makes general and specific recommendations for the treatment of the different cardiovascular risk factors and their final objectives. Finally, the document includes aspects that are not usually referenced in the literature, such as the organization of a vascular risk consultation.

Impact of the mutation profile on thrombotic risk in cancer patients.

Patients with cancer present with an elevated risk of thrombosis, which entails high morbidity and mortality. Various predictive scales that incorporate clinical and biological data have been developed to identify those at high risk of thrombosis, but, in general, they do not allow for the optimal selection of subjects who are candidates for thromboprophylaxis. Recent studies have demonstrated that the mutation profile has a high impact on the risk of thrombosis; this will facilitate developing new predictive models of thrombosis in patients with cancer.

[Coagulopathy and thrombosis: similarities and differences among pathogenic coronaviruses].

One of the most significant negative prognostic factors in patients suffering from the disease caused by SARS-CoV-2 (COVID-19) is the development of coagulopathy, associated with abnormal laboratory findings, such as increased D-dimer, and venous thromboembolic complications, requiring thromboprophylactic strategies. The main clinical characteristics of COVID-19 patients are revised here as compared to other coronavirus infections, such as Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS), emphasizing clinical, diagnostic and therapeutic aspects.

Neutrophils as instigators of thrombosis: Beyond antimicrobial protection. / Neutrófilos como instigadores de trombosis: más allá de la protección antimicrobiana.

When activated, neutrophils release structures (NETs) composed of DNA, histones and granular proteins that provide an ideal matrix for platelet activation and coagulation mechanisms, thereby contributing to the pathogenesis of thrombosis in venous and arterial territories, as well as cancer-associated thrombosis. NETs play a key role in immunothrombosis, a term that describes the relationship between the immune response and coagulation.

Safety and effectiveness of a prothrombin complex concentrate in approved and off-label indications.

OBJECTIVE: To evaluate the effectiveness and safety of prothrombin complex concentrates (PCCs) in approved and off-label indications. BACKGROUND: PCCs are approved for the urgent reversal of vitamin K antagonists (VKAs). Data concerning the efficacy, safety and dosing for off-label indications are limited, but they are included in massive bleeding protocols. METHODS: This was a retrospective review of cases treated with four-factor PCCs (4F-PCCs) between January 2009 and 2016. Efficacy end-points include: (i) VKA reversal efficacy assessed by international normalised ratio (INR) normalisation (<1·5) and (ii) clinical efficacy as bleeding cessation and/or decreased number of transfused blood components and 24-h mortality in bleeding coagulopathy. The safety end-point is the incidence of thromboembolic events. RESULTS: A total of 328 patients were included (51·8% male, median age 78 years old). Indications were as follows: VKA reversal (66·6%), bleeding coagulopathy (30·5%) and direct anticoagulant (DOAC) reversal due to bleeding (2·5%). VKA reversal was effective in 97·1% of patients, and 76·5% demonstrated complete reversal (INR < 1·5); only 34·3% patients needed hemoderivatives. Prior to emergency procedures, PCCs achieved global responses in 83% of patients, with no bleeding complication during intervention. DOAC reversal was effective in 88·9% of patients. Bleeding cessation was associated with the dose administered (P = 0·002). In coagulopathy bleeding, haemorrhage cessation, established by the International Society of Thrombosis and Haemostais (ISTH) definition, occurred in 56·7% of massive bleeding events and in 42·5% of other coagulopathies; 24-h mortality was 30%, mainly related to active bleeding. Ten thrombotic episodes were observed (3·1%). CONCLUSION: 4F-PCC was effective as adjuvant treatment with an acceptable safety profile, not only for the emergent reversal of VKAs but also for refractory coagulopathy associated with major bleeding.

Improvement of appropriate pharmacological prophylaxis in hospitalised cancer patients with a multiscreen e-alert system: a single-centre experience.

PURPOSE: Thromboprophylaxis use among medical inpatients, including cancer patients, is suboptimal. We aimed to evaluate the impact of a novel multiscreen version (v2.0) of an e-alert system for VTE prevention in hospitalised cancer medical patients compared to the original software. METHODS: Prospective study including 989 consecutive adult cancer patients with high-risk of VTE. Patients were followed-up 30 days post-discharge. Two periods were defined, according to the operative software. RESULTS: E-alert v2.0 was associated with an increase in the use of LMWH prophylaxis (65.5% vs. 72.0%); risk difference (95% CI) 0.064 (0.0043-0.12). Only 16% of patients in whom LMWH prophylaxis was not prescribed lacked a contraindication. No significant differences in the rates of VTE (2.9% vs. 3.2%) and major bleeding (2.7% vs. 4.0%) were observed. CONCLUSIONS: E-alert v2.0 further increased the use of appropriate thromboprophylaxis in hospitalised cancer patients, although was not associated with a reduction in VTE incidence.

[Patients with vulnerable coronary plaques have higher serum metalloproteinase-1 levels]. / Los pacientes con placas coronarias vulnerables presentan mayores niveles séricos de metaloproteinasa-1.

BACKGROUND: Most acute coronary syndromes are caused by the fracture of a vulnerable atherosclerotic plaque. These plaques are thin cap fibroatheromas, which can only be detected with invasive coronary imaging techniques. It is necessary to find a non-invasive biomarker of these vulnerable plaques in order to identify patients at risk without a coronary angiography. Metalloproteinase-1 is an enzyme involved in extracellular matrix metabolism which has been correlated with the rupture of atherosclerotic plaques. Its serum levels in patients with vulnerable plaques remain unknown. METHODS: Patients with suspected stable coronary artery disease undergoing coronary angiography in our hospital were in-cluded. The coronary arteries were studied with optical coherence tomography to detect vulnerable plaques. Blood samples were taken from a peripheral vein and from the coronary sinus, to assess metalloproteinase-1 levels. RESULTS: Fifty-one patients were included, 13 of whom had at least one vulnerable plaque. There were not significant dif-ferences in clinical characteristics, lipid profile or C reactive protein levels, between patients with or without vulnerable plaques. Patients with vulnerable plaques had significant higher metalloproteinase-1 levels both in peripheral (7330±5541 vs 2894±1783 pg/ml, p=0.025) and coronary sinus serum (6012±3854 vs 2707±1252 pg/ml, p=0.047). CONCLUSIONS: Patients with vulnerable plaques had significantly higher metalloproteinase-1 serum levels. Further studies with clinical follow up are needed to assess the prognostic value of serum metalloproteinase-1.

Durable complete remission with aromatase inhibitor therapy in a patient with metastatic uterine carcinosarcoma with poor performance status and coagulation disorders: a case report.

BACKGROUND: Chemotherapy is considered the most appropriate treatment for metastatic uterine sarcoma, despite its limited efficacy. No other treatment has been conclusively proved to be a real alternative, but some reports suggest that anti-hormonal therapy could be active in a small subset of patients. We report the case of a patient with metastatic uterine carcinosarcoma with positive hormonal receptors and a complete pathological response. CASE PRESENTATION: A 54-year-old white woman presented to our emergency room with hypovolemic shock and serious vaginal bleeding. After stabilization, she was diagnosed as having a locally advanced uterine carcinosarcoma with lymph nodes and bone metastatic disease. In order to control the bleeding, palliative radiotherapy was administered. Based on the fact that positive hormone receptors were found in the biopsy, non-steroidal aromatase inhibitor therapy with letrozole was started. In the following weeks, her general status improved and restaging imaging tests demonstrated a partial response of the primary tumor. Ten months after initiating aromatase inhibitor therapy, she underwent a radical hysterectomy and the pathological report showed a complete response. After completing 5 years of treatment, aromatase inhibitor therapy was stopped. She currently continues free of disease, without further therapy, and maintains a normal and active life. CONCLUSIONS: This case shows that patients with uterine carcinosarcoma and positive hormone receptors may benefit from aromatase inhibitor therapy. A multidisciplinary strategy that includes local therapies such as radiation and/or surgery should be considered the mainstay of treatment. Systemic therapies such as hormone inhibitors should be taken into consideration and deserve further clinical research in the era of precision medicine.

Implementation of a management protocol for massive bleeding reduces mortality in non-trauma patients: Results from a single centre audit.

OBJECTIVE: To audit the impact upon mortality of a massive bleeding management protocol (MBP) implemented in our center since 2007. DESIGN: A retrospective, single-center study was carried out. Patients transfused after MBP implementation (2007-2012, Group 2) were compared with a historical cohort (2005-2006, Group 1). BACKGROUND: Massive bleeding is associated to high mortality rates. Available MBPs are designed for trauma patients, whereas specific recommendations in the medical/surgical settings are scarce. PATIENTS: After excluding patients who died shortly (<6h) after MBP activation (n=20), a total of 304 were included in the data analysis (68% males, 87% surgical). INTERVENTIONS: Our MBP featured goal-directed transfusion with early use of adjuvant hemostatic medications. VARIABLES OF INTEREST: Primary endpoints were 24-h and 30-day mortality. Fresh frozen plasma-to-red blood cells (FFP:RBC) and platelet-to-RBC (PLT:RBC) transfusion ratios, time to first FFP unit and the proactive MBP triggering rate were secondary endpoints. RESULTS: After MBP implementation (Group 2; n=222), RBC use remained stable, whereas FFP and hemostatic agents increased, when compared with Group 1 (n=82). Increased FFP:RBC ratio (p=0.053) and earlier administration of FFP (p=0.001) were also observed, especially with proactive MBP triggering. Group 2 patients presented lower rates of 24-h (0.5% vs. 7.3%; p=0.002) and 30-day mortality (15.9% vs. 30.2%; p=0.018) - the greatest reduction corresponding to non-surgical patients. Logistic regression showed an independent protective effect of MBP implementation upon 30-day mortality (OR=0.3; 95% CI 0.15-0.61). CONCLUSIONS: These data suggest that the implementation of a goal-directed MBP for prompt and aggressive management of non-trauma, massive bleeding patients is associated to reduced 24-h and 30-day mortality rates.

[Multidisciplinary consensus document on the management of massive haemorrhage (HEMOMAS document)]. / Documento multidisciplinar de consenso sobre elmanejo de la hemorragia masiva (document HEMOMAS)

Massive haemorrhage is common and often associated with high morbidity and mortality. We perform a systematic review of the literature, with extraction of the recommendations from the existing evidences because of the need for its improvement and the management standardization. From the results we found, we wrote a multidisciplinary consensus document. We begin with the agreement in the definitions of massive haemorrhage and massive transfusion, and we do structured recommendations on their general management (clinical assessment of bleeding, hypothermia management, fluid therapy, hypotensive resuscitation and damage control surgery), blood volume monitoring, blood products transfusion (red blood cells, fresh frozen plasma, platelets and their best transfusion ratio), and administration of hemostatic components (prothrombin complex, fibrinogen, factor VIIa, antifibrinolytic agents).

Multidisciplinary consensus document on the management of massive haemorrhage (HEMOMAS document).

Massive haemorrhage is common and often associated with high morbidity and mortality. We perform a systematic review of the literature, with extraction of the recommendations from the existing evidences because of the need for its improvement and the management standardization. From the results we found, we wrote a multidisciplinary consensus document. We begin with the agreement in the definitions of massive haemorrhage and massive transfusion, and we do structured recommendations on their general management (clinical assessment of bleeding, hypothermia management, fluid therapy, hypotensive resuscitation and damage control surgery), blood volume monitoring, blood products transfusion (red blood cells, fresh frozen plasma, platelets and their best transfusion ratio), and administration of hemostatic components (prothrombin complex, fibrinogen, factor VIIa, antifibrinolytic agents).

Lack of TAFI increases brain damage and microparticle generation after thrombolytic therapy in ischemic stroke.

BACKGROUND: Thrombin-activatable fibrinolysis inhibitor (TAFI) plays an important role in coagulation and fibrinolysis. Whereas TAFI deficiency may lead to a haemorrhagic tendency, data from TAFI knockout mice (TAFI-/-) are controversial and no differences have been reported in these animals after ischemic stroke. There are also no data regarding the role of circulating microparticles (MPs) in TAFI-/-. OBJECTIVES: to examine the effect of tPA on the rate of intracranial haemorrhage (ICH) and on MPs generated in a model of ischemic stroke in TAFI-/- mice. METHODS: Thrombin was injected into the middle cerebral artery (MCA) to analyse the effect of tPA (10mg/Kg) on the infarct size and haemorrhage in the absence of TAFI. Immunofluorescence for Fluoro-Jade C was performed on frozen brain slides to analyse neuronal degeneration after ischemia. MPs were isolated from mouse blood and their concentrations calculated by flow cytometry. RESULTS: Compared with saline, tPA significantly increased the infarct size in TAFI-/- mice (p<0.05). Although plasma fibrinolytic activity (fibrin plate assay) was higher in these animals, no macroscopic or microscopic ICH was detected. A positive signal for apoptosis and degenerating neurons was observed in the infarct area, being significantly higher in tPA treated TAFI-/- mice (p<0.05). Interestingly, higher numbers of MPs were found in TAFI-/- plasma as compared to wild type, after stroke (p<0.05). CONCLUSIONS: TAFI deficiency results in increased brain damage in a model of thrombolysis after ischemic stroke, which was not associated with bleeding but with neuronal degeneration and MP production.

Haemostatic activation and inflammatory response after three methods of treatment of great saphenous vein incompetence.

OBJECTIVE: The purpose of this study was to compare the activation of haemostasis and inflammatory response after three different methods of treatment of great saphenous vein (GSV) incompetence. MATERIAL AND METHODS: Forty-five patients with GSV incompetence were assigned to one of the three types of treatment: high ligation and stripping (HL&S), radiofrequency ablation with ClosureFast (RFA) and endovenous laser ablation (EVLA) with 810 nm diode laser with miniphlebectomy if required. Peripheral blood samples were obtained in the morning before the surgery and 24 hours and 10 days after the procedure. The concentrations of C-reactive protein (CRP), D-dimer, prothrombin fragment 1 + 2 (F1 + 2), antigen of tissue plasminogen activator (t-PA) and von Willebrand factor (vWF) antigen and activity of plasminogen activator inhibitor (PAI-1) were determined. The results were statistically analysed with SPSS for Windows 15.0. RESULTS: Thirty-eight patients completed the study: 13 from RFA, 14 from EVLA and 11 from HL&S group. The baseline data did not differ among groups. There was a significant increase of D-dimer in HL&S group after 24 hours (P = 0.002). The changes in RFA and EVLA groups did not show statistical significance (P = 0.092). PAI-1 decreased in RFA patients after 24 hours (P = 0.02), did not change in EVLA patients, and tended to increase after HL&S (P = 0.08). The highest CRP increase was observed in HL&S group (P = 0.003). No significant changes in F1 + 2, t-PA and vWF were observed in any group of patients at 24 hours. At 10 days, a further significant increase of D-dimer (P = 0.04) and CRP (P = 0.018) concentrations in HL&S but not RFA and EVLA patients was observed. CONCLUSIONS: Endovenous thermal ablation is associated with significantly less activation of haemostasis and inflammatory response when compared with HL&S.

proMetalloproteinase-10 is associated with brain damage and clinical outcome in acute ischemic stroke.

BACKGROUND: Matrix metalloproteinases (MMPs) mediate tissue injury during stroke but also neurovascular remodeling and we have shown that MMP-10 is involved in atherothrombosis. OBJECTIVE: The purpose of this study was to examine the relationship between proMMP-10 and clinical outcome, assessing inflammatory and proteolytic markers, in patients with acute ischemic stroke. METHODS: We prospectively studied 76 patients with ischemic stroke treated with tPA within the first 3 h from symptom onset, compared with 202 non-tPA-treated ischemic stroke patients and 83 asymptomatic subjects. Stroke severity was assessed with the National Institutes of Health Stroke Scale (NIHSS). Hemorrhagic transformation (HT) and severe brain edema were diagnosed by cranial CT. Good functional outcome was defined as a modified Rankin scale score ≤ 2 at 90 days. Serum levels of MMP-9, proMMP-10, TIMP-1, tumor necrosis factor-α (TNFα), interleukin-6 and cellular fibronectin were measured at admission. The effect of TNFα on endothelial proMMP-10 was assessed in vitro. RESULTS: Serum proMMP-10 concentration in ischemic stroke patients, non-treated or treated with t-PA, which was higher than age-matched healthy subjects (P < 0.0001), was independently associated with higher infarct volume, severe brain edema, neurological deterioration and poor functional outcome at 3 months (all P < 0.05), but not with HT. proMMP-10 levels were also independently and positively associated with circulating levels of TNFα (P < 0.0001), which induced its endothelial expression in vitro, both mRNA and protein. MMP-9, however, was only associated with HT and severe edema (all P < 0.05). CONCLUSIONS: Increased serum proMMP-10 after acute ischemic stroke, associated with TNFα, is a new marker of brain damage and poor outcome.

Tissue factor expressed by microparticles is associated with mortality but not with thrombosis in cancer patients.

A prothrombotic state is one of the hallmarks of malignancy and a major contributor to morbidity and mortality in cancer patients.Tissue factor (TF) is often overexpressed in malignancy and is a prime candidate in predicting the hypercoagulable state. Moreover, increased number of TF-exposing microparticles (MPs) in cancer patients may contribute to venous thromboembolism (VTE). We have conducted a prospective cohort study to determine whether elevated TF antigen, TF activity and TF associated to MPs (MPs-TF) are predictive of VTE and mortality in cancer patients. The studied population consisted of 252 cancer patients and 36 healthy controls. TF antigen and activity and MPs-TF were determined by ELISA and chromogenic assays. During a median follow-up of 10 months, 40 thrombotic events were recorded in 34 patients (13.5%), and 73 patients (28.9%) died. TF antigen and activity were significantly higher in patients than in controls (p<0.01) mainly in patients with advanced stages, whereas no differences were observed for TF activity of isolated MPs. We did not find a statistically significant association of TF variables with the risk of VTE. Multivariate analysis adjusting for age, sex, type of cancer and other confounding variables showed that TF activity (p<0.01) and MPs-TF activity (p<0.05) were independently associated with mortality. In conclusion, while TF variables were not associated with future VTE in cancer patients, we found a strong association of TF and MPs-TF activity with mortality, thus suggesting they might be good prognostic markers in cancer patients.