Francisco Martín-Herrero

Identification of serum endoglin as a novel prognostic marker after acute myocardial infarction.

Endoglin is a proliferation‐associated and hypoxia‐inducible protein expressed in endothelial cells. The levels of soluble circulating endoglin and their prognostic significance in patients with acute myocardial infarction (AMI) are not known. In this observational prospective study serum endoglin levels were measured by ELISA in 183 AMI patients upon admission to hospital and 48 hrs later and in 72 healthy controls. Endoglin levels in AMI patients on admission were significantly lower than in healthy controls (4.25 ± 0.99 ng/ml versus 4.59 ± 0.87 ng/ml; P= 0.013), and decreased further in the first 48 hours (3.65 ± 0.76 ng/ml, P < 0.001). Upon follow‐up (median 319 days), patients who died had a significantly greater decrease in serum endoglin level over the first 48 hrs than those who survived (1.03 ± 0.91 versus 0.54 ± 0.55 ng/ml; P= 0.025). Endoglin decrease was an independent predictor of short‐term (30 days) (hazard ratio 2.33;95% CI = 1.27–4.23; P= 0.006) cardiovascular mortality, and also predicts overall cardiovascular mortality during the follow‐up (median 319 days) in AMI patients (hazard ratio 2.13;95% CI = 1.20–3.78; P= 0.01). In conclusion, early changes in serum endoglin may predict mortality after AMI.

Analysis of incidence, risk factors and clinical outcome of thromboembolic and bleeding events in 431 allogeneic hematopoietic stem cell transplantation recipients

Allogeneic hematopoietic stem cell transplantation recipients have an increasing risk of both hemorrhagic and thrombotic complications. However, the competing risks of two of these life-threatening complications in these complex patients have still not been well defined. We retrospectively analyzed data from 431 allogeneic transplantation recipients to identify the incidence, risk factors and mortality due to thrombosis and bleeding. Significant clinical bleeding was more frequent than symptomatic thrombosis. The cumulative incidence of a bleeding episode was 30.2% at 14 years. The cumulative incidence of a venous or arterial thrombosis at 14 years was 11.8% and 4.1%, respectively. The analysis of competing factors for venous thrombosis revealed extensive chronic graft-versus-host disease to be the only independent prognostic risk factor. By contrast, six factors were associated with an increased risk of bleeding; advanced disease, ablative conditioning regimen, umbilical cord blood transplantation, anticoagulation, acute III-IV graft-versus-host disease, and transplant-associated microangiopathy. The development of thrombosis did not significantly affect overall survival (P=0.856). However, significant clinical bleeding was associated with inferior survival (P<0.001). In allogeneic hematopoietic stem cell transplantation, significant clinical bleeding is more common than thrombotic complications and affects survival.

The role of immature platelet fraction in acute coronary syndrome

Dear Sir, Activated platelets play a crucial role in the pathogenesis of acute coronary syndrome (ACS) (1), and platelet size can be a determinant of platelet function. Thus, large platelets are metabolically more active than small platelets and have greater pro-thrombotic potential (2). However, the clinical influence of platelet size, measured as mean platelet volume (MPV), is controversial (3–6). An alternative to MPV measurement is the analysis of immature platelet fraction (IPF). Newly formed platelets can be distinguished from mature platelets that are poor in RNA by flow cytometric quantification using fluorescent dyes that bind RNA (7). However, this method produces high intra-assay reproducibility coefficients of variation (8) and requires specialist personnel to perform it. A new, rapid and fully automated method for the measurement of reticulated platelets, expressed as the immature platelet fraction (IPF), using the Sysmex XE-2100 blood cell counter has been under development. Recently, Grove et al showed that measurements of IPF made with the Sysmex XE-2100 were significantly higher in patients with ACS than in healthy subjects (9), although further studies were required. Therefore, the aim of this study is to examine the relationship between IPF and ACS in a case-control study. A total of 404 individuals were enrolled in the study. A total of 202 patients with a documented first episode of ACS were prospectively recruited upon admission to the Coronary Unit. The diagnosis of ACS included ST segment elevation myocardial infarction (STEMI, n = 129) and non-ST segment elevation ACS (NST ACS, n = 73). The latter group included non-ST segment elevation myocardial infarction (NSTEMI) and unstable angina (UA) patients. Diagnosis of STEMI, NSTEMI and UA was made according to the new ESC/ACC consensus definition (10). The control group for our study included 202 unrelated healthy persons without a history of vascular or thromboembolic disease and a normal electrocardiogram. All subjects gave their informed consent to enter the study. Blood was collected from the antecubital vein at 08:00 a.m. on day 1 or 2 after admission. IPF was calculated as the ratio of immature platelets to the total number of platelets in a fully automated haematology analysis system (Sysmex XE-2100; Sysmex,

Hemodynamic and Inflammatory Markers of Sleep Apnea-Hypopnea Syndrome and Nocturnal Hypoxemia: Effects of Treatment With Nasal Continuous Positive Airway Pressure

OBJECTIVE In this study, we assessed factors associated with cardiovascular risk in patients with sleep apnea-hypopnea syndrome (SAHS) through analysis of plasma concentrations of N-terminal prohormone brain natriuretic peptide (NTproBNP) and high-sensitivity C-reactive protein (hsCRP). In addition, we analyzed the effect of nasal continuous positive airway pressure (nCPAP) on these markers. PATIENTS AND METHODS Forty-two patients with SAHS (mild to moderate in 15 cases and severe in 27) were compared with 14 individuals without SAHS. The participants were not receiving drug treatment and they did not have diabetes, hypertension, marked dyslipidemia, or cardiovascular disease, which was ruled out both clinically and by echocardiography and (99m)Tc-tetrofosmin scintigraphy at rest and during exercise. The effects of nCPAP in patients with severe SAHS were analyzed after 6 months of treatment. RESULTS Following adjustment for age, body mass index, and smoking habit, the mean concentrations of markers were not significantly higher in patients with severe SAHS than in those with mild-to-moderate SAHS or in control subjects. Nevertheless, in patients with SAHS the main factor influencing NTproBNP concentrations was the percentage of time with a nocturnal arterial oxygen saturation of less then 90% (r=0.37, P=.017). No variables predictive of hsCRP concentration were identified. The concentrations of the markers were reduced by nCPAP, but the differences were not statistically significant. CONCLUSIONS While nocturnal hypoxemia in SAHS is responsible for variations in the plasma concentration of NTproBNP (as a result of cardiovascular changes), SAHS appears not to be associated with the inflammatory marker hsCRP when patients with heart disease, cardiovascular risk factors, or those receiving pharmacologic treatment are excluded.

Infective Endarteritis in Patent Ductus Arteriosus and Septic Pulmonary Embolism

Infective endarteritis was the most common cause of death in patients with patent ductus arteriosus (PDA) prior to the introduction of antibiotic therapy and surgical closure of the defect, though nowadays it is a rare complication. Infective endarteritis is especially unusual in asymptomatic patients, more so when the PDA is silent on cardiac auscultation, with very few reports of this type of case to be found in the relevant literature. We present the case of a 56 year old woman who had a history of PDA detected during adolescence during auscultation for a cardiac murmur. She presented to the emergency service with fluctuating fever of no apparent origin and a poor response to habitual antipyretic agents, as well as a 5 kg weight loss over 2 months. Following her admission, 3 blood cultures were positive for Streptococcus viridans. A transthoracic echocardiogram showed the left ventricle with conserved systolic function, slight aortic insufficiency, and a fixed structure on the wall of the pulmonary artery with erratic movement indicative of a vegetation (Figure). The patient was diagnosed with subacute bacterial infective endocarditis and treatment was started with penicillin G and gentamicin. The course of the patient was initially satisfactory. Ten days after admission she had another fever peak accompanied by a pleuritic type pain in her left side. A chest radiograph showed increased density in the lower lobe of the right lung. A further transthoracic echocardiogram revealed the disappearance of the vegetation that had been seen previously. A suspicion of pulmonary embolism, of probable septic origin, was confirmed by means of ventilation-perfusion pulmonary scintigraphy. A diagnosis of subacute bacterial endarteritis on PDA was confirmed, complicated by septic pulmonary embolism. Antibiotic therapy was continued with penicillin for 4 weeks and gentamicin for 2 weeks. The patient was discharged from the hospital pending closure of the PDA. The incidence of PDA has increased spectacularly over the last 20 years, due to the increase in the survival of premature infants. The incidence is currently in the range of 0.02%-0.04% of live term births. The most common complications associated with PDA are left heart failure and infective endocarditis (endarteritis). Surgical or percutaneous closure of the PDA is indicated in practically all cases, except in those patients who have developed severe, irreversible pulmonary hypertension or in those whose PDA is silent (asymptomatic patients or with no audible murmur). Patients should also undergo surgery if they have had an episode of endarteritis. In patients with a small, asymptomatic PDA that is audible on auscultation, closure is controversial and no clear recommendation exists in the clinical practice guidelines. The case reported here concerned a patient with a small, asymptomatic PDA, with no previous risk procedure, who developed infective endarteritis, complicated by septic pulmonary embolism. Thus, infectious endarteritis is shown to be able to appear as a complication of PDA, although it is exceptional in asymptomatic patients. As the case reported shows, the risk for infection is present even in small, asymptomatic ducts, and prophylactic closure of the PDA should be considered.

Immature Platelet Fraction: A New Prognostic Marker in Acute Coronary Syndrome

The role of platelets in the pathogenesis of acute coronary syndrome (ACS) is well recognized. Persistent platelet activation despite antithrombotic therapy has an influence on the severity of ischemic cardiomyopathy. Reticulated platelets are the youngest form of circulating platelets. They are larger than senescent platelets, contain residual RNA that confers a reticulated appearance, and are hemostatically more active because they express more glycoprotein Ib and IIb/IIIa receptors. Currently, a fast, automated method is available to quantify reticulated platelets by the immature platelet fraction (IPF), calculated as the ratio between immature platelets and total platelets. The mean platelet volume is an indicator of platelet reactivity. An elevated mean platelet volume in the acute phase of myocardial infarction is associated with a poorer short-term prognosis. IPF determination may be more sensitive and specific than the mean platelet volume for evaluating platelet reactivity. It has been observed that, in patients with coronary disease, the IPF is elevated relative to the healthy population, and it is also increased in ACS with respect to stable coronary disease. In our study, reticulated platelets were analyzed by plasma IPF determination in hospitalized ACS patients with the aim of determining the short-term prognostic value (predictor of inhospital mortality) of this parameter. Between January 2007 and April 2008, 251 hospitalized ACS patients were studied. ACS was established based on symptoms of myocardial ischemia in the 24 h prior to admission together with elevated cardiac biomarkers and/or electrocardiographic abnormalities (ST deviation 0.5 mm and/or T wave changes, consisting of negative T waves 2 mm in 2 or more contiguous leads). The sample for IPF determination was obtained in the morning of the first day of hospitalization. IPF was determined with a Sysmex XE-2100 automated hematology analyzer (Sysmex; Kobe, Japan), which, in relation to the platelet volume and RNA content, distinguishes the percentage of immature platelets. A descriptive statistical analysis was performed. We calculated descriptive statistics of frequency of the continuous variables studied (median [interquartile range]) and the categorical variables (percentages). The Mann-Whitney U test was used to compare quantitative variables, and the Pearson chi-square test to determine associations between qualitative variables. The predictive factors of in-hospital mortality were established by univariate analysis, and statistically significant variables were included in a binary multivariate logistic regression analysis. All statistical analyses were carried out with the IBM SPSS Statistics 18 program. Statistical significance was set at a P-value of<.05. The characteristics of the study population are shown in Table 1. The comparison of IPF values in ACS patients with and without ST segment elevation showed no significant differences between the 2 groups: 5.20% [3.60%-7.60%] vs 4.75% [3.12%-7.42%] (P=.289). Thirty-one patients (12.3%) died during hospitalization. The IPF value was higher in patients who died than in those who survived: 6.60% [4.20%-10.80%] vs 4.80% [3.10%-6.95%] (P=.002). In-hospital mortality increased as the IPF tertile increased, such that the probability of death was higher in patients in the third tertile (IPF>6.2%) than in those in the first (IPF<3%) (22% vs 6%; P=.003). Mortality observed in the high-risk group determined by the global registry of acute coronary events (GRACE) risk score ( 140) was 10%, 15.7%, and 25% (P=.148) for the first, second, and third IPF tertiles, respectively, and in the non-highrisk group (GRACE score<140), mortality was 2.3%, 3.1%, and 15.3% (P=.057) for the first, second, and third tertiles, respectively. After adjusting for other covariables (age, diabetes mellitus, heart failure at hospitalization, ST deviation on electrocardiographic study, and troponin elevation) multivariate analysis showed that the third tertile of IPF remained as an independent predictor of in-hospital mortality: odds ratio=2.42 (95% confidence interval, 1.08-5.43; P=.032) (Table 2). Table 1 Characteristics of the Population

Risk of placenta-mediated pregnancy complications or pregnancy-related VTE in VTE-asymptomatic families of probands with VTE and heterozygosity for factor V Leiden or G20210 prothrombin mutation

Few studies have evaluated the risk of pregnancy‐related adverse events in asymptomatic relatives of probands for VTE and factor V Leiden or the G20210A variant. The antepartum management of this population ranges from antepartum anticoagulation therapy to clinical surveillance.

Anaphylaxis and Recurrent Hydatid Disease

A 62-year-old woman presented to the emergency department with anaphylaxis. Three years before this, she had been diagnosed with multivesicular hepatic hydatid cystic disease and an associated pericardial effusion.1 The cyst was resected, her pericardial effusion was drained, and she completed a course of albendazole therapy. In the interim period, she remained asymptomatic, and annual echocardiographic studies were unremarkable. On this occasion she presented with a 4-week history of recurrent episodes of transient chest pain, generalized pruritus, flushing, and urticaria. Initial management comprised intravenous …

C3G promotes a selective release of angiogenic factors from activated mouse platelets to regulate angiogenesis and tumor metastasis

Previous observations indicated that C3G (RAPGEF1) promotes α-granule release, evidenced by the increase in P-selectin exposure on the platelet surface following its activation. The goal of the present study is to further characterize the potential function of C3G as a modulator of the platelet releasate and its implication in the regulation of angiogenesis. Proteomic analysis revealed a decreased secretion of anti-angiogenic factors from activated transgenic C3G and C3G∆Cat platelets. Accordingly, the secretome from both transgenic platelets had an overall pro-angiogenic effect as evidenced by an in vitro capillary-tube formation assay with HUVECs (human umbilical vein endothelial cells) and by two in vivo models of heterotopic tumor growth. In addition, transgenic C3G expression in platelets greatly increased mouse melanoma cells metastasis. Moreover, immunofluorescence microscopy showed that the pro-angiogenic factors VEGF and bFGF were partially retained into α-granules in thrombin- and ADP-activated mouse platelets from both, C3G and C3GΔCat transgenic mice. The observed interaction between C3G and Vesicle-associated membrane protein (Vamp)-7 could explain these results. Concomitantly, increased platelet spreading in both transgenic platelets upon thrombin activation supports this novel function of C3G in α-granule exocytosis. Collectively, our data point out to the co-existence of Rap1GEF-dependent and independent mechanisms mediating C3G effects on platelet secretion, which regulates pathological angiogenesis in tumors and other contexts. The results herein support an important role for platelet C3G in angiogenesis and metastasis.

Hemorrhagic pericardial effusion as the debut of acquired hemophilia in a chronic lymphocytic leukemia patient: A case report, and a review of acquired hemophilia A-related hematological malignancies

Background: Acquired hemophilia A (AHA) is a rare bleeding disease caused by autoantibodies against factor VIII. Spontaneous bleeding symptoms usually affect the skin and muscle, while pericardial effusion is an extremely rare manifestation. In the elderly, anticoagulant treatment is frequent and bleeding symptoms are usually associated with this. Clinical findings: We report a hemorrhagic pericardial effusion as the AHA debut in a patient with untreated chronic lymphocytic leukemia and anticoagulated with apixaban for atrial fibrillation and chronic arterial ischemia. The patient was treated with recombinant activated factor VII to control the active bleeding and corticosteroids and cyclophosphamide to eradicate the inhibitor. In addition, a briefly review of hematological malignancies associated to acquired hemophilia was performed. Particularities: a) anticoagulant treatment may confuse the suspicion of AHA and its diagnosis; b) hemorrhagic pericardial effusion is an extremely rare presentation; c) bypassing agents raise the risk of thromboembolism; d) hematological malignancies rarely cause AHA (<20% of cases). Conclusion: A multidisciplinary team is needed to diagnose and manage AHA effectively. The use of anticoagulants may lead to the misdiagnosis of clinical symptoms. Chronic lymphocytic leukemia is one of the main causes of hematological malignancies associated. The specific treatment of CLL is still recommended in the event of active disease.