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.
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'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.
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.
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.
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...
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' 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.
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.
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'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.
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.
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.
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...
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' 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.
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Papers by Erich de Paula