M. Ozelo - Academia.edu (original) (raw)
Papers by M. Ozelo
Blood, 2011
1156 Introduction: Bernard-Soulier syndrome (BSS) is a rare hereditary bleeding disorder, caused ... more 1156 Introduction: Bernard-Soulier syndrome (BSS) is a rare hereditary bleeding disorder, caused by mutations within the glycoprotein (GP) Ib alpha, GP Ib beta and GP IX genes that encode three of four subunits of the platelet GP Ib-V-IX adhesion receptor. In the present study we evaluated the mutations involved in the diagnosis of BSS from twenty-two unrelated patients. Patients and Methods: All patients were followed in two large bleeding disorder reference centers in Brazil. The diagnosis of BSS was established based on the presence of mucocutaneous bleeding and macrotrombocytopenia, and was confirmed by platelet ristocetin aggregation and flow cytometry for the platelet GP Ib alpha (CD 42b), GP Ib beta (CD 42c), and GP IX (CD 42a). Available first- and second-degree relatives were also contacted for clinical, laboratory and molecular evaluation. Genomic DNA from all index cases was used for sequence analysis of the three genes, GP1BA, GP1BB and GP9, and the results were confirme...
Research and Practice in Thrombosis and Haemostasis
Research and Practice in Thrombosis and Haemostasis
Research and Practice in Thrombosis and Haemostasis
Research and Practice in Thrombosis and Haemostasis
GTH Congress 2023 – 67th Annual Meeting of the Society of Thrombosis and Haemostasis Research – The patient as a benchmark
Blood, 2014
Introduction: Prophylaxis with replacement factor IX (FIX) therapies can reduce the frequency of ... more Introduction: Prophylaxis with replacement factor IX (FIX) therapies can reduce the frequency of bleeding episodes in patients with severe hemophilia B. There is currently a lack of data on factor activity levels in patients that treat bleeding episodes while adhering to a prophylactic regimen. The phase 3 B-LONG study (Powell et al. NEJM 2013) demonstrated that recombinant factor IX Fc fusion protein (rFIXFc) had a prolonged half-life relative to recombinant FIX, and that rFIXFc was efficacious and safe for prophylaxis and treatment of bleeding in subjects with hemophilia B; previous reports have evaluated treatment of bleeding in all subjects in B-LONG, including those receiving episodic treatment with rFIXFc. The purpose of this analysis was to assess the efficacy of rFIXFc for the treatment of bleeding in patients that received rFIXFc prophylaxis in the B-LONG study. Additionally, FIX activity levels were predicted under scenarios where treatment of bleeding occurred in close pr...
Transfusion and Apheresis Science, 2004
To evaluate, in vitro, the effects of collecting and cryopreserving fresh dry platelet concentrat... more To evaluate, in vitro, the effects of collecting and cryopreserving fresh dry platelet concentrates (PCs). Standard and dry PCs were collected in the same apheresis procedure. PCs were evaluated by mean platelet volume (MPV), pH, glucose and LDH levels. Activation was examined by flow cytometry using anti-CD41, anti-CD42 and anti-CD62p monoclonal antibodies and annexin binding assay. Platelet function was assessed by aggregation using ADP, collagen and arachidonic acid as agonists. Dry PCs were compared to standard PCs and to cryopreserved dry PCs. We also compared the use of ThromboSol to 5% DMSO as cryoprotectives. Dry PCs presented a significantly reduced pH and glucose (p<0.001), increased LDH levels and CD62p expression (p<0.001) and diminished aggregation response to ADP (p<0.001). Platelet cryopreservation was associated with platelet lysis, activation and loss of function. Dry PCs cryopreserved with TS were associated with statistically higher LDH levels (p<0.001) and a higher percentage of annexin binding (p=0.005), in addition to a lower number of CD42 positive platelets (p=0.01). Dry PCs should be rapidly frozen after collection to avoid a fall in pH and platelet activation. 5% DMSO performed better than TS to cryopreserve dry PCs.
Sem informação21267688th Annual Congress of the European-Association-for-Haemophilia-and-Allied-D... more Sem informação21267688th Annual Congress of the European-Association-for-Haemophilia-and-Allied-Disorder
Blood, 2003
Based on the natural history of disease in patients with baseline factor levels more than 1% and ... more Based on the natural history of disease in patients with baseline factor levels more than 1% and on studies of hemophilia patients treated with routine administration of clotting factor concentrates to maintain levels more than ...
Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis, Jan 20, 2016
The main objective of this study is to investigate the utility of International Society on Thromb... more The main objective of this study is to investigate the utility of International Society on Thrombosis and Haemostasis-Bleeding Assessment Tool (ISTH-BAT) in comparison with the condensed form of Molecular and Clinical Markers for the Diagnosis and Management of type 1 and WHO BATs, in assessing bleeding in two well known and clinically significant platelet function defects. Thirty-eight patients previously diagnosed with Glanzmann's thrombasthenia and 10 with Bernard-Soulier syndrome (BSS) were analyzed. Bleeding scores were significantly higher than that of controls using both electronic bleeding questionnaire (eBQ) and ISTH-BAT with no significant difference between both tools. ISTH-BAT had a sensitivity, specificity, positive predictive value and negative predictive value of 100%, 76.2%, 0.9 and 1. This was closely similar to eBQ. Both ISTH-BAT and eBQ are efficient in BSS and Glanzmann's thrombasthenia. However, given the ISTH recommendation, ISTH-BAT should be adopted. ...
Blood transfusion = Trasfusione del sangue
Significant advances in the management of haemophilia have been achieved in the past several deca... more Significant advances in the management of haemophilia have been achieved in the past several decades. These include the development of safe and efficacious plasma-derived and recombinant clotting factor products, use of prophylaxis as standard of care in bleeding prevention and appropriate surgical management of haemophilic arthropathy. Despite these advances, the development of high-titre anti-factor antibodies (inhibitors) remains an unresolved challenge in the management of people with haemophilia. Inhibitors develop in 25–30% of patients with severe haemophilia A and in 1–5% of those with severe haemophilia B1–3. They were first described by Lawrence and Johnson in 19414, and in the seven decades that followed our knowledge of their pathophysiology and risk factors remains incomplete and continues to evolve. This is partly a result of the small inhibitor population with significant intra- and inter-individual variability making the conduct of studies and interpretation of results difficult. The main reason for our incomplete knowledge in this area is that inhibitor development is a multi-factorial event resulting from the variable interplay between several genetic (non-modifiable) and non-genetic (modifiable to some extent) risk factors. Despite these limitations, a number of clinical evaluations analysing treatment of inhibitor patients have been performed including randomised controlled prospective studies5,6. These studies provide, in part, the evidence basis for our current inhibitor management principles and practice. Inhibitors remain a popular subject of haemostasis scientific meetings and many issues related to their pathophysiology and management are discussed and debated in the published literature. The main issues include: (i) the identification of clinically relevant risk factors for inhibitor development, (ii) the definition of the bleeding phenotype and clinical management of these patients, (iii) the usefulness and feasibility of prophylaxis with bypassing agents in the treatment of patients with inhibitors, (iv) the identification of predictive factors for inhibitor eradication, and (v) novel therapeutic approaches and molecules for the treatment and/or eradication of inhibitors. The aim of this review is to give an update on each of these issues with a focus on the current state-of-the-art knowledge and practice from the authors’ personal perspective. This review focuses mainly on factor VIII inhibitors as these occur much more frequently in clinical practice.
New England Journal of Medicine, 2013
Background Prophylactic factor replacement in patients with hemophilia B improves outcomes but re... more Background Prophylactic factor replacement in patients with hemophilia B improves outcomes but requires frequent injections. A recombinant factor IX Fc fusion protein (rFIXFc) with a prolonged half-life was developed to reduce the frequency of injections required. Methods We conducted a phase 3, nonrandomized, open-label study of the safety, efficacy, and pharmacokinetics of rFIXFc for prophylaxis, treatment of bleeding, and perioperative hemostasis in 123 previously treated male patients. All participants were 12 years of age or older and had severe hemophilia B (endogenous factor IX level of ≤2 IU per deciliter, or ≤2% of normal levels). The study included four treatment groups: group 1 received weekly dose-adjusted prophylaxis (50 IU of rFIXFc per kilogram of body weight to start), group 2 received interval-adjusted prophylaxis (100 IU per kilogram every 10 days to start), group 3 received treatment as needed for bleeding episodes (20 to 100 IU per kilogram), and group 4 received treatment in the perioperative period. A subgroup of group 1 underwent comparative sequential pharmacokinetic assessments of recombinant factor IX and rFIXFc. The primary efficacy end point was the annualized bleeding rate, and safety end points included the development of inhibitors and adverse events. Results
Microvascular Research, 2013
The endothelium plays an important role in sickle cell anemia (SCA) pathophysiology, interacting ... more The endothelium plays an important role in sickle cell anemia (SCA) pathophysiology, interacting with red cells, leukocytes and platelets during the vaso-occlusive process and undergoing activation and dysfunction as a result of intravascular hemolysis and chronic inflammation. Blood outgrowth endothelial cells (BOECs) can be isolated from adult peripheral blood and have been used in diverse studies, since they have a high proliferative capacity and a stable phenotype during in vitro culture. This study aimed to establish BOEC cultures for use as an in vitro study model for endothelial function in sickle cell anemia. Once established, BOECs from steady-state SCA individuals (SCA BOECs) were characterized for their adhesive and inflammatory properties, in comparison to BOECs from healthy control individuals (CON BOECs). Cell adhesion assays demonstrated that control individual red cells adhered significantly more to SCA BOEC than to CON BOEC. Despite these increased adhesive properties, SCA BOECs did not demonstrate significant differences in their expression of major endothelial adhesion molecules, compared to CON BOECs. SCA BOECs were also found to be pro-inflammatory, producing a significantly higher quantity of the cytokine, IL-8, than CON BOECs. From the results obtained, we suggest that BOEC may be a good model for the in vitro study of SCA. Data indicate that endothelial cells of sickle cell anemia patients may have abnormal inflammatory and adhesive properties even outside of the chronic inflammatory and vaso-occlusive environment of patients.
65th Annual Meeting of the Society of Thrombosis and Haemostasis Research
Thrombosis and …, 2006
Emerging findings have demonstrated the critical role of blood clotting factors in the formation ... more Emerging findings have demonstrated the critical role of blood clotting factors in the formation and stabilization of embryonic blood vessels. Whether a similar role is true during post-natal angiogenesis remains to be determined. Here we sought to determine whether the ...
Hematology, Transfusion and Cell Therapy
Blood, 2011
1156 Introduction: Bernard-Soulier syndrome (BSS) is a rare hereditary bleeding disorder, caused ... more 1156 Introduction: Bernard-Soulier syndrome (BSS) is a rare hereditary bleeding disorder, caused by mutations within the glycoprotein (GP) Ib alpha, GP Ib beta and GP IX genes that encode three of four subunits of the platelet GP Ib-V-IX adhesion receptor. In the present study we evaluated the mutations involved in the diagnosis of BSS from twenty-two unrelated patients. Patients and Methods: All patients were followed in two large bleeding disorder reference centers in Brazil. The diagnosis of BSS was established based on the presence of mucocutaneous bleeding and macrotrombocytopenia, and was confirmed by platelet ristocetin aggregation and flow cytometry for the platelet GP Ib alpha (CD 42b), GP Ib beta (CD 42c), and GP IX (CD 42a). Available first- and second-degree relatives were also contacted for clinical, laboratory and molecular evaluation. Genomic DNA from all index cases was used for sequence analysis of the three genes, GP1BA, GP1BB and GP9, and the results were confirme...
Research and Practice in Thrombosis and Haemostasis
Research and Practice in Thrombosis and Haemostasis
Research and Practice in Thrombosis and Haemostasis
Research and Practice in Thrombosis and Haemostasis
GTH Congress 2023 – 67th Annual Meeting of the Society of Thrombosis and Haemostasis Research – The patient as a benchmark
Blood, 2014
Introduction: Prophylaxis with replacement factor IX (FIX) therapies can reduce the frequency of ... more Introduction: Prophylaxis with replacement factor IX (FIX) therapies can reduce the frequency of bleeding episodes in patients with severe hemophilia B. There is currently a lack of data on factor activity levels in patients that treat bleeding episodes while adhering to a prophylactic regimen. The phase 3 B-LONG study (Powell et al. NEJM 2013) demonstrated that recombinant factor IX Fc fusion protein (rFIXFc) had a prolonged half-life relative to recombinant FIX, and that rFIXFc was efficacious and safe for prophylaxis and treatment of bleeding in subjects with hemophilia B; previous reports have evaluated treatment of bleeding in all subjects in B-LONG, including those receiving episodic treatment with rFIXFc. The purpose of this analysis was to assess the efficacy of rFIXFc for the treatment of bleeding in patients that received rFIXFc prophylaxis in the B-LONG study. Additionally, FIX activity levels were predicted under scenarios where treatment of bleeding occurred in close pr...
Transfusion and Apheresis Science, 2004
To evaluate, in vitro, the effects of collecting and cryopreserving fresh dry platelet concentrat... more To evaluate, in vitro, the effects of collecting and cryopreserving fresh dry platelet concentrates (PCs). Standard and dry PCs were collected in the same apheresis procedure. PCs were evaluated by mean platelet volume (MPV), pH, glucose and LDH levels. Activation was examined by flow cytometry using anti-CD41, anti-CD42 and anti-CD62p monoclonal antibodies and annexin binding assay. Platelet function was assessed by aggregation using ADP, collagen and arachidonic acid as agonists. Dry PCs were compared to standard PCs and to cryopreserved dry PCs. We also compared the use of ThromboSol to 5% DMSO as cryoprotectives. Dry PCs presented a significantly reduced pH and glucose (p<0.001), increased LDH levels and CD62p expression (p<0.001) and diminished aggregation response to ADP (p<0.001). Platelet cryopreservation was associated with platelet lysis, activation and loss of function. Dry PCs cryopreserved with TS were associated with statistically higher LDH levels (p<0.001) and a higher percentage of annexin binding (p=0.005), in addition to a lower number of CD42 positive platelets (p=0.01). Dry PCs should be rapidly frozen after collection to avoid a fall in pH and platelet activation. 5% DMSO performed better than TS to cryopreserve dry PCs.
Sem informação21267688th Annual Congress of the European-Association-for-Haemophilia-and-Allied-D... more Sem informação21267688th Annual Congress of the European-Association-for-Haemophilia-and-Allied-Disorder
Blood, 2003
Based on the natural history of disease in patients with baseline factor levels more than 1% and ... more Based on the natural history of disease in patients with baseline factor levels more than 1% and on studies of hemophilia patients treated with routine administration of clotting factor concentrates to maintain levels more than ...
Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis, Jan 20, 2016
The main objective of this study is to investigate the utility of International Society on Thromb... more The main objective of this study is to investigate the utility of International Society on Thrombosis and Haemostasis-Bleeding Assessment Tool (ISTH-BAT) in comparison with the condensed form of Molecular and Clinical Markers for the Diagnosis and Management of type 1 and WHO BATs, in assessing bleeding in two well known and clinically significant platelet function defects. Thirty-eight patients previously diagnosed with Glanzmann's thrombasthenia and 10 with Bernard-Soulier syndrome (BSS) were analyzed. Bleeding scores were significantly higher than that of controls using both electronic bleeding questionnaire (eBQ) and ISTH-BAT with no significant difference between both tools. ISTH-BAT had a sensitivity, specificity, positive predictive value and negative predictive value of 100%, 76.2%, 0.9 and 1. This was closely similar to eBQ. Both ISTH-BAT and eBQ are efficient in BSS and Glanzmann's thrombasthenia. However, given the ISTH recommendation, ISTH-BAT should be adopted. ...
Blood transfusion = Trasfusione del sangue
Significant advances in the management of haemophilia have been achieved in the past several deca... more Significant advances in the management of haemophilia have been achieved in the past several decades. These include the development of safe and efficacious plasma-derived and recombinant clotting factor products, use of prophylaxis as standard of care in bleeding prevention and appropriate surgical management of haemophilic arthropathy. Despite these advances, the development of high-titre anti-factor antibodies (inhibitors) remains an unresolved challenge in the management of people with haemophilia. Inhibitors develop in 25–30% of patients with severe haemophilia A and in 1–5% of those with severe haemophilia B1–3. They were first described by Lawrence and Johnson in 19414, and in the seven decades that followed our knowledge of their pathophysiology and risk factors remains incomplete and continues to evolve. This is partly a result of the small inhibitor population with significant intra- and inter-individual variability making the conduct of studies and interpretation of results difficult. The main reason for our incomplete knowledge in this area is that inhibitor development is a multi-factorial event resulting from the variable interplay between several genetic (non-modifiable) and non-genetic (modifiable to some extent) risk factors. Despite these limitations, a number of clinical evaluations analysing treatment of inhibitor patients have been performed including randomised controlled prospective studies5,6. These studies provide, in part, the evidence basis for our current inhibitor management principles and practice. Inhibitors remain a popular subject of haemostasis scientific meetings and many issues related to their pathophysiology and management are discussed and debated in the published literature. The main issues include: (i) the identification of clinically relevant risk factors for inhibitor development, (ii) the definition of the bleeding phenotype and clinical management of these patients, (iii) the usefulness and feasibility of prophylaxis with bypassing agents in the treatment of patients with inhibitors, (iv) the identification of predictive factors for inhibitor eradication, and (v) novel therapeutic approaches and molecules for the treatment and/or eradication of inhibitors. The aim of this review is to give an update on each of these issues with a focus on the current state-of-the-art knowledge and practice from the authors’ personal perspective. This review focuses mainly on factor VIII inhibitors as these occur much more frequently in clinical practice.
New England Journal of Medicine, 2013
Background Prophylactic factor replacement in patients with hemophilia B improves outcomes but re... more Background Prophylactic factor replacement in patients with hemophilia B improves outcomes but requires frequent injections. A recombinant factor IX Fc fusion protein (rFIXFc) with a prolonged half-life was developed to reduce the frequency of injections required. Methods We conducted a phase 3, nonrandomized, open-label study of the safety, efficacy, and pharmacokinetics of rFIXFc for prophylaxis, treatment of bleeding, and perioperative hemostasis in 123 previously treated male patients. All participants were 12 years of age or older and had severe hemophilia B (endogenous factor IX level of ≤2 IU per deciliter, or ≤2% of normal levels). The study included four treatment groups: group 1 received weekly dose-adjusted prophylaxis (50 IU of rFIXFc per kilogram of body weight to start), group 2 received interval-adjusted prophylaxis (100 IU per kilogram every 10 days to start), group 3 received treatment as needed for bleeding episodes (20 to 100 IU per kilogram), and group 4 received treatment in the perioperative period. A subgroup of group 1 underwent comparative sequential pharmacokinetic assessments of recombinant factor IX and rFIXFc. The primary efficacy end point was the annualized bleeding rate, and safety end points included the development of inhibitors and adverse events. Results
Microvascular Research, 2013
The endothelium plays an important role in sickle cell anemia (SCA) pathophysiology, interacting ... more The endothelium plays an important role in sickle cell anemia (SCA) pathophysiology, interacting with red cells, leukocytes and platelets during the vaso-occlusive process and undergoing activation and dysfunction as a result of intravascular hemolysis and chronic inflammation. Blood outgrowth endothelial cells (BOECs) can be isolated from adult peripheral blood and have been used in diverse studies, since they have a high proliferative capacity and a stable phenotype during in vitro culture. This study aimed to establish BOEC cultures for use as an in vitro study model for endothelial function in sickle cell anemia. Once established, BOECs from steady-state SCA individuals (SCA BOECs) were characterized for their adhesive and inflammatory properties, in comparison to BOECs from healthy control individuals (CON BOECs). Cell adhesion assays demonstrated that control individual red cells adhered significantly more to SCA BOEC than to CON BOEC. Despite these increased adhesive properties, SCA BOECs did not demonstrate significant differences in their expression of major endothelial adhesion molecules, compared to CON BOECs. SCA BOECs were also found to be pro-inflammatory, producing a significantly higher quantity of the cytokine, IL-8, than CON BOECs. From the results obtained, we suggest that BOEC may be a good model for the in vitro study of SCA. Data indicate that endothelial cells of sickle cell anemia patients may have abnormal inflammatory and adhesive properties even outside of the chronic inflammatory and vaso-occlusive environment of patients.
65th Annual Meeting of the Society of Thrombosis and Haemostasis Research
Thrombosis and …, 2006
Emerging findings have demonstrated the critical role of blood clotting factors in the formation ... more Emerging findings have demonstrated the critical role of blood clotting factors in the formation and stabilization of embryonic blood vessels. Whether a similar role is true during post-natal angiogenesis remains to be determined. Here we sought to determine whether the ...
Hematology, Transfusion and Cell Therapy