Erich de Paula - Academia.edu (original) (raw)

Papers by Erich de Paula

BMC Medicine, 2015

Background: Coagulation and innate immunity have been linked together for at least 450 million ye... more Background: Coagulation and innate immunity have been linked together for at least 450 million years of evolution. Sepsis, one of the world's leading causes of death, is probably the condition in which this evolutionary link is more evident. However, the biological and the clinical relevance of this association have only recently gained the attention of the scientific community. Discussion: During sepsis, the host response to a pathogen is invariably associated with coagulation activation. For several years, coagulation activation has been solely regarded as a mechanism of tissue damage, a concept that led to several clinical trials of anticoagulant agents for sepsis. More recently, this paradigm has been challenged by the failure of these clinical trials, and by a growing bulk of evidence supporting the concept that coagulation activation is beneficial for pathogen clearance. In this article we discuss recent basic and clinical data that point to a more balanced view of the detrimental and beneficial consequences of coagulation activation in sepsis. Summary: Reappraisal of the association between coagulation and immune activation from an evolutionary medicine perspective offers a unique opportunity to gain new insights about the pathogenesis of sepsis, paving the way to more successful approaches in both basic and clinical research in this field.

Recent Patents on Biomarkerse, 2012

1 Imunodeficiência humoral é uma característica intrínseca da leucemia linfocítica crônica B. A q... more 1 Imunodeficiência humoral é uma característica intrínseca da leucemia linfocítica crônica B. A quimioterapia, principalmente quando o paciente é politratado, e em especial os análogos da purina, ampliam o espectro de susceptibilidade destes pacientes a agentes infecciosos oportunistas devido ao efeito imunossupressor celular destas drogas. Relatamos um paciente com leucemia linfocítica crônica submetido a várias linhas de quimioterapia, inclusive o 2-CdA, que apresentou múltiplas complicações infecciosas associadas a grave imunodeficiência celular. Rev.bras.hematol.hemoter., 2000, 22(3): 420-423 Palavras-chave:

Rev Bras Hematol Hemoter, 2012

Platelets share antigens with other cells such as ABH and HLA class I antigens, but also express ... more Platelets share antigens with other cells such as ABH and HLA class I antigens, but also express specific antigens. Platelet specific antigens are identified according to a nomenclature devised by the International Society of Blood Transfusion and are referred to as Human Platelet Antigens (HPA). These include glycoproteins expressed on platelet surfaces such as GPIIb/IIIa, the von Willebrand factor receptor GP Ib/IX, among others. Polymorphisms in the genes that code for these proteins result in different HPA patterns, which can result in the exposure of humans to incompatible HPA during platelet transfusions or pregnancy of an HPA-incompatible fetus. Significant differences in the prevalence of HPA polymorphisms have been described in different populations and HPA polymorphism frequencies in Brazil have been elegantly described in different ethnic groups (1) . Alloimmunization to HPA can result in clinically significant problems such as neonatal alloimmune thrombocytopenia and post-transfusion purpura. The former occurs when an alloimmunized mother gives birth to an HPA-incompatible newborn resulting in neonatal thrombocytopenia. The latter is an extremely rare condition in which the development of anti-HPA antibodies, usually anti-HPA-1a, results in sudden (within 7-10 days after a transfusion), severe and self-limiting thrombocytopenia, with destruction of both autologous and allogeneic platelets. In addition to these two well-recognized HPA-related disorders, HPA alloimmunization is sometimes associated with platelet refractoriness, although the role of HPA antibodies in this context is less straightforward .

Rev. Bras. Hematol. Hemoter., 2000

Revista Brasileira de Hematologia e Hemoterapia, 2014

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Revista Brasileira de Hematologia e Hemoterapia, 2012

Translational Research, 2009

The protein infusion of basic fibroblast growth factor-2 (FGF-2) and platelet derived growth fact... more The protein infusion of basic fibroblast growth factor-2 (FGF-2) and platelet derived growth factor-BB (PDGF-BB) have been shown to promote the formation of a stable and functional vascular network in small and large animal models of ischemia. Here, we sought to determine whether a similar effect could be obtained using a gene-therapy-based strategy with nonviral vectors. Rats underwent a surgical procedure to create hindlimb ischemia and were injected with a combination of plasmids that expressed FGF-2 and PDGF-BB. Anatomical and functional parameters of the angiogenesis and arteriogenesis response were evaluated after 4 weeks. The results were compared with rats injected with plasmids that expressed a reporter gene or the extensively studied vascular endothelial growth factor (VEGF165) alone. Treatment with the FGF-2/PDGF-BB combination increased the angiogenesis and arteriogenesis response compared with the empty plasmid, and it was as effective as VEGF165. In terms of safety, the combination allowed the use of a 50% lower individual dose of each plasmid and in addition promoted the formation of more stable vessels than VEGF165. In conclusion, the dual gene transfer of FGF-2 and PDGF-BB using nonviral vectors is safe and effective in promoting the formation of a functional vascular network in a rodent model of hindlimb ischemia.

Thrombosis Research, 2012

Deep vein thrombosis (DVT) is a multi-causal disease associated with high morbidity and mortality... more Deep vein thrombosis (DVT) is a multi-causal disease associated with high morbidity and mortality due to complications, and 25% of patients present recurrence within 5 years. The identification of factors involved with DVT can help in the management of patients, prevention of recurrence and in the development of new therapies. The evaluation of plasma components using proteomics potentially provides a window into the individual&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s state of health. We analyzed the protein profile of plasma samples from 3 DVT patients and compared results to those obtained from 1 sibling and 1 neighbor of each patient. These patients were selected as they presented a personal and family history of spontaneous and recurrent episodes of proximal DVT. Albumin was removed using Affi-Gel Blue Gel, and the proteins were alkylated, reduced, precipitated and hydrolyzed. The peptides were fractionated by SCX chromatography, the 7 fractions obtained were directed to the ESI Q-TOF Premier mass spectrometer. Protein search was performed using the Mascot engine against the IPI human database. Proteins that were statistically overexpressed in DVT patients included C4-A plasma protease, C1 inter-alpha-trypsin inhibitor, heavy chain H inhibitor and serum amyloid A. Proteins that were statistically reduced in DVT patients included alpha-2-HS-glycoprotein, isoform 2 of inter-alpha-trypsin inhibitor heavy chain H4 and apolipoprotein A-IV. The evaluation of plasma from patients with spontaneous DVT allows the identification of differently expressed proteins when compared to controls; this expression may be of pathological importance for immune and inflammatory processes in DVT.

Journal of Translational Medicine, 2011

Background: Septic shock is the most feared complication of chemotherapy-induced febrile neutrope... more Background: Septic shock is the most feared complication of chemotherapy-induced febrile neutropenia. So far, there are no robust biomarkers that can stratify patients to the risk of sepsis complications. The VEGF-A axis is involved in the control of microvascular permeability and has been involved in the pathogenesis of conditions associated with endothelial barrier disruption such as sepsis. sFlt-1 is a soluble variant of the VEGF-A receptor VEGFR-1 that acts as a decoy receptor down-regulating the effects of VEGF-A. In animal models of sepsis, sFlt-1 was capable to block the barrier-breaking negative effects of VEGF-A and to significantly decrease mortality. In non-neutropenic patients, sFlt-1 has been shown to be a promising biomarker for sepsis severity.

Journal of Thrombosis and Haemostasis, 2007

Journal of Critical Care, 2014

The purpose was to investigate the presence of hypercoagulability in the very early phase of the ... more The purpose was to investigate the presence of hypercoagulability in the very early phase of the host response to an infection in the clinical course of sepsis and septic shock. Twenty-four patients with chemotherapy-associated febrile neutropenia were evaluated at baseline, at the time of fever onset, and 48 hours thereafter using the thrombin generation test, a more physiological and global assay of hemostasis. The rate of thrombin generation was decreased and no signals of systemic hypercoagulability could be observed during the first 48 hours of sepsis. Moreover, patients that evolved to septic shock presented a more significant impairment in thrombin generation than those with noncomplicated sepsis. Patients with sepsis and febrile neutropenia present an impairment in thrombin generation from very early stages of their disease course. These results suggest that the procoagulant in vitro alterations described during sepsis do not necessarily translate into a clinically relevant systemic hypercoagulable state. These findings could help explain why treatment with systemic anticoagulants did not translate to clinical benefits in human sepsis and highlight the need for a better understanding of the hemostatic alterations in sepsis before new treatments targeting coagulation activation are developed.

Haemophilia, 2012

Acquired von Willebrand syndrome (AVWS) is a rare hemorrhagic condition for which very little inf... more Acquired von Willebrand syndrome (AVWS) is a rare hemorrhagic condition for which very little information is available regarding the management of extreme challenges to Haemostasis. The AVWS is more common in the elderly, who are frequently exposed to invasive procedures and/or chemotherapy. Haematopoietic stem cell transplantation (HSCT) is a situation in which the haemostatic capacity is challenged by severe thrombocytopaenia, chemotherapy-associated mucosal barrier breakdown and the need for invasive procedures. In our report, we present and discuss the haemostatic management of a patient with AVWS who was refractory to Von Willebrand factor concentrate replacement during the course of an autologous HSCT to treat multiple myeloma. Patients with AVWS are frequently exposed to high-risk haemostatic challenges, and additional information about the haemostatic management of these situations is necessary.

Critical Care, 2013

Introduction: Endothelial barrier breakdown is a hallmark of septic shock, and proteins that phys... more Introduction: Endothelial barrier breakdown is a hallmark of septic shock, and proteins that physiologically regulate endothelial barrier integrity are emerging as promising biomarkers of septic shock development. Patients with cancer and febrile neutropenia (FN) present a higher risk of sepsis complications, such as septic shock. Nonetheless, these patients are normally excluded or under-represented in sepsis biomarker studies. The aim of our study was to validate the measurement of a panel of microvascular permeability modulators as biomarkers of septic shock development in cancer patients with chemotherapy-associated FN. Methods: This was a prospective study of diagnostic accuracy, performed in two distinct in-patient units of a university hospital. Levels of vascular endothelial growth factor A (VEGF-A), soluble fms-like tyrosine kinase-1 (sFlt-1) and angiopoietin (Ang) 1 and 2 were measured after the onset of neutropenic fever, in conditions designed to mimic the real-world use of a sepsis biomarker, based on our local practice. Patients were categorized based on the development of septic shock by 28 days as an outcome. Results: A total of 99 consecutive patients were evaluated in the study, of which 20 developed septic shock and 79 were classified as non-complicated FN. VEGF-A and sFlt-1 levels were similar between both outcome groups. In contrast, Ang-2 concentrations were increased in patients with septic shock, whereas an inverse finding was observed for Ang-1, resulting in a higher Ang-2/Ang-1 ratio in patients with septic shock (5.29, range 0.58 to 57.14) compared to non-complicated FN (1.99, range 0.06 to 64.62; P = 0.01). After multivariate analysis, the Ang-2/Ang-1 ratio remained an independent factor for septic shock development and 28-day mortality. Conclusions: A high Ang-2/Ang-1 ratio can predict the development of septic shock in cancer patients with febrile neutropenia.

Clinical and Applied Thrombosis/Hemostasis, 2013

Increased levels of factor VIII (FVIII) are a prevalent and independent risk factor for deep veno... more Increased levels of factor VIII (FVIII) are a prevalent and independent risk factor for deep venous thrombosis (DVT). After a median of 10 years of the first DVT, we evaluated FVIII coagulation levels in 55 patients with DVT of the lower limbs and previous high levels of FVIII and in 74 controls. Subsequently, we analyzed the presence of post-thrombotic syndrome (PTS) in patients and its relationship with FVIII levels. After a median of 10 years of the first DVT, the FVIII levels were still significantly higher in patients when compared to controls (P < .001). Patients with severe PTS showed increased levels of FVIII when compared to patients with moderate or absent PTS (P < .001). We demonstrated a persistent increase in FVIII levels in a subset of patients with DVT, but in a lower magnitude after 10 years of the first DVT episode. Moreover, we observed a significant association between increased FVIII levels and severe PTS.

BMC Infectious Diseases, 2010

Background: Febrile neutropenia carries a high risk of sepsis complications, and the identificati... more Background: Febrile neutropenia carries a high risk of sepsis complications, and the identification of biomarkers capable to identify high risk patients is a great challenge. Angiopoietins (Ang -) are cytokines involved in the control microvascular permeability. It is accepted that Ang-1 expression maintains endothelial barrier integrity, and that Ang-2 acts as an antagonizing cytokine with barrier-disrupting functions in inflammatory situations. Ang-2 levels have been recently correlated with sepsis mortality in intensive care units.

Biomarkers in Cardiovascular Disease, 2015

Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis, Jan 28, 2016

Postthrombotic syndrome (PTS) may affect 50% of patients with deep venous thrombosis, 5-10% of th... more Postthrombotic syndrome (PTS) may affect 50% of patients with deep venous thrombosis, 5-10% of them may present severe manifestations. The causes for PTS development and severity have not been well established. This study evaluated whether PTS may be associated with the presence, and echogenicity, of the residual vein thrombosis (RVT). We included patients with a history of deep venous thrombosis in the past 58 months. These patients were further evaluated for PTS diagnosis, clinical comorbidities, plasma levels of D-dimer, serum levels of C-reactive protein and for the presence of RVT. Particularly, RVT was detected by ultrasound examination and the residual thrombi echogenicity was determined by grayscale median (GSM). Fifty-six patients were included, of which 41 presented PTS. Mild PTS was detected in 23 patients, moderate PTS in 11 and severe PTS in seven patients. Patients with severe PTS showed higher body mass index, higher abdominal circumference and higher C-reactive prote...

Journal of Thrombosis and Thrombolysis, 2016

The home prothrombin time/international normalized ratio (PT/INR) self-management could be conven... more The home prothrombin time/international normalized ratio (PT/INR) self-management could be convenient for patients, enhancing treatment compliance and improving the quality of the oral anticoagulation. However, patient self-management (PSM) of oral anticoagulation may not be feasible for up to half of the patients due to cognitive or educational issues. In the present study, we aimed to evaluate the feasibility of a PSM program in a public health medical center that provides care for low-income patients. We also aimed to determine the accuracy of individual point-of-care devices (CoaguChek XS(®)) during long-term of home manipulation. Patients&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; time-in-therapeutic range (TTR) and perception of quality of life, were evaluated at scheduled study-visits to the center. Additionally, the accuracy of individual CoaguChek XS(®) was evaluated in comparison to the standard automated coagulometer at scheduled study-visits to the center. Twenty-five patients were included in the PSM program. The median TTR of patients was 75 % before inclusion, 72 % at 3 months, 75 % at 6 months and 100 % at 12 months after the beginning of self-management (P = 0.14).The median DASS scores were 64, 63, 61.5 and 71.5 before inclusion and at 3, 6 and 12 months, respectively (P = 0.09). One hundred paired INR values were obtained. Correlation between INR values delivered by individual CoaguChek XS(®) and the automated coagulometer was 94 % and the mean result bias was 0.07 INR units. The coefficient of correlation and the mean bias between methods was stable during 24 months of follow-up. The present study suggests that PSM is feasible for patients treated in the public health system and that the results delivered by CoaguChek XS(®) have long-term reliability.