Causes and consequences of coagulation activation in sepsis: an evolutionary medicine perspective.

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. 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.

Elevated hypercoagulability markers in hemoglobin SC disease.

Hemoglobin SC disease is a very prevalent hemoglobinopathy; however, very little is known about this condition specifically. There appears to be an increased risk of thromboembolic events in hemoglobin SC disease, but studies evaluating the hemostatic alterations are lacking. We describe the findings of a cross-sectional observational study evaluating coagulation activation markers in adult patients with hemoglobin SC, comparing them with those in sickle cell anemia patients and healthy controls. A total of 56 hemoglobin SC and 39 sickle cell anemia patients were included in the study, all in steady state, and 27 healthy controls. None of the patients was taking hydroxyurea. Hemoglobin SC patients had a significantly up-regulated relative expression of tissue factor, as well as elevations in thrombin-antithrombin complex and D-dimer, in comparison to controls (P<0.01). Hemoglobin SC patients had lower tissue factor expression, and thrombin-antithrombin complex and D-dimer levels when compared to sickle cell anemia patients (P<0.05). Markers of endothelial activation (soluble thrombomodulin and soluble vascular cell adhesion molecule-1) and inflammation (tumor necrosis factor-alpha) were both significantly elevated in hemoglobin SC patients when compared to controls, being as high as the levels seen in patients with sickle cell anemia. Overall, in hemoglobin SC patients, higher hemolytic activity and inflammation were associated with a more intense activation of coagulation, and hemostatic activation was associated with two very prevalent chronic complications seen in hemoglobin SC disease: retinopathy and osteonecrosis. In summary, our results demonstrate that hemoglobin SC patients have a hypercoagulable state, although this manifestation was not as intense as that seen in sickle cell anemia.

Folate, vitamin B12 and Homocysteine status in the post-folic acid fortification era in different subgroups of the Brazilian population attended to at a public health care center.

BACKGROUND: Folate and vitamin B12 are essential nutrients, whose deficiencies are considerable public health problems worldwide, affecting all age groups. Low levels of these vitamins have been associated with high concentrations of homocysteine (Hcy) and can lead to health complications. Several genetic polymorphisms affect the metabolism of these vitamins. The aims of this study were to assess folate, vitamin B12 and homocysteine status in distinct Brazilian individuals after the initiation of folic acid fortification by Brazilian authorities and to investigate the effects of RFC1 A80G, GCPII C1561T and MTHFR C677T polymorphisms on folate, vitamin B12 and Hcy levels in these populations. METHODS: A total of 719 individuals including the elderly, children, as well as pregnant and lactating women were recruited from our health care center. Folate, vitamin B12 and Hcy levels were measured by conventional methods. Genotype analyses of RFC1 A80G, GCPII C1561T and MTHFR C677T polymorphisms were performed by PCR-RFLP. RESULTS: The overall prevalence of folate and vitamin B12 deficiencies were 0.3% and 4.9%, respectively. Folate deficiency was observed only in the elderly (0.4%) and pregnant women (0.3%), whereas vitamin B12 deficiency was observed mainly in pregnant women (7.9%) and the elderly (4.2%). Plasma Hcy concentrations were significantly higher in the elderly (33.6%). Pregnant women carrying the MTHFR 677TT genotype showed lower serum folate levels (p = 0.042) and higher Hcy levels (p = 0.003). RFC1 A80G and GCPII C1561T polymorphisms did not affect folate and Hcy levels in the study group. After a multivariate analysis, Hcy levels were predicted by variables such as folate, vitamin B12, gender, age and RFC1 A80G polymorphism, according to the groups studied. CONCLUSION: Our results suggest that folate deficiency is practically nonexistent in the post-folic acid fortification era in the subgroups evaluated. However, screening for vitamin B12 deficiency may be particularly relevant in our population, especially in the elderly.

Angiopoietin2 is associated with coagulation activation and tissue factor expression in extracellular vesicles in COVID-19.

Coagulation activation in immunothrombosis involves various pathways distinct from classical hemostasis, offering potential therapeutic targets to control inflammation-induced hypercoagulability while potentially sparing hemostasis. The Angiopoietin/Tie2 pathway, previously linked to embryonic angiogenesis and sepsis-related endothelial barrier regulation, was recently associated with coagulation activation in sepsis and COVID-19. This study explores the connection between key mediators of the Angiopoietin/Tie2 pathway and coagulation activation. The study included COVID-19 patients with hypoxia and healthy controls. Blood samples were processed to obtain platelet-free plasma, and frozen until analysis. Extracellular vesicles (EVs) in plasma were characterized and quantified using flow cytometry, and their tissue factor (TF) procoagulant activity was measured using a kinetic chromogenic method. Several markers of hemostasis were assessed. Levels of ANGPT1, ANGPT2, and soluble Tie2 correlated with markers of coagulation and platelet activation. EVs from platelets and endothelial cells were increased in COVID-19 patients, and a significant increase in TF+ EVs derived from endothelial cells was observed. In addition, ANGPT2 levels were associated with TF expression and activity in EVs. In conclusion, we provide further evidence for the involvement of the Angiopoietin/Tie2 pathway in the coagulopathy of COVID-19 mediated in part by release of EVs as a potential source of TF activity.

Reduced thrombin formation and excessive fibrinolysis are associated with bleeding complications in patients with dengue fever: a case-control study comparing dengue fever patients with and without bleeding manifestations.

BACKGROUND: Dengue cases have been classified according to disease severity into dengue fever (DF) and dengue hemorrhagic fever (DHF). Although DF is considered a non-severe manifestation of dengue, it has been recently demonstrated that DF represents a heterogeneous group of patients with varied clinical complications and grades of severity. Particularly, bleeding complications, commonly associated to DHF, can be detected in half of the patients with DF. Although a frequent complication, the causes of bleedings in DF have not been fully addressed. Thus, the aim of this study was to perform a comprehensive evaluation of possible pathophysiological mechanisms that could contribute to the bleeding tendency observed in patients with DF. METHODS: This is a case-control study that enrolled adults with DF without bleeding and adults with DF and bleeding complications during the defervescence period. Healthy controls were also included. Peripheral blood counts, inflammatory, fibrinolysis and endothelial cell activation markers, and thrombin generation were evaluated in patients and controls. RESULTS: We included 33 adults with DF without complications, 26 adults with DF and bleeding and 67 healthy controls. Bleeding episodes were mild in 15 (57.6%) and moderate in 11 (42.4%) patients, 8 (30.7%) patients had bleedings in multiple sites. Patients with DF and bleedings had lower platelet counts than DF without bleeding (median = 19,500 vs. 203,500/mm3, P < 0,0001). Levels of TNF-α, thrombomodulin and VWF were significantly increased in the two dengue groups than in healthy controls, but similar between patients with and without bleedings. Plasma levels of tPA and D-dimer were significantly increased in patients with bleedings (median tPA levels were 4.5, 5.2, 11.7 ng/ml, P < 0.0001 and median D-dimer levels were 515.5, 1028 and 1927 ng/ml, P < 0.0001). The thrombin generation test showed that patients with bleeding complications had reduced thrombin formation (total thrombin generated were 3753.4 in controls, 3367.5 in non-bleeding and 2274.5nM in bleeding patients, P < 0.002). CONCLUSIONS: DF can manifest with spontaneous bleedings, which are associated with specific coagulation and fibrinolysis profiles that are not significantly present in DF without this complication. Particularly, thrombocytopenia, excessive fibrinolysis and reduced thrombin formation may contribute to the bleeding manifestations in DF.

A high angiopoietin-2/angiopoietin-1 ratio is associated with a high risk of septic shock in patients with febrile neutropenia.

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.

Circulating progenitor and mature endothelial cells in deep vein thrombosis.

INTRODUCTION: Mature circulating endothelial cells (CEC) and circulating endothelial progenitor cells (EPC) have been described in several conditions associated with endothelial injury. Their role in deep vein thrombosis (DVT) has not been previously evaluated. PATIENTS AND METHODS: In this pilot study we evaluated the time course of CEC and EPC release after vena cava experimental DVT in mice, using the FeCl3 model. We also evaluated their presence in patients with DVT at different phases of the disease (acute and chronic phase). CEC and EPC were evaluated by Flow Cytometry. RESULTS: In mice, both CEC and EPC were increased 24 hours after DVT induction, peaking 48 hours thereafter. After 72 hours, CEC counts decreased sharply, whereas EPC counts decreased less substantially. In DVT patients we observed a significant increase in CEC counts immediately after DVT compared to healthy individuals. Patients with chronic disease also presented a significant elevation of these cell count. In a subgroup of patients for whom serial samples were available, CEC counts decreased significantly after 9-15 months of the acute event. CONCLUSIONS: Our results suggest the participation of these cells in the reparative processes that follows DVT, both at immediate and late time-points. The different kinetics of CEC and EPC release in experimental DVT suggests a heterogeneous role for these cells in the reparative events after DVT.

Association of heme-oxygenase 1, hemopexin, and heme levels with markers of disease severity in COVID-19.

Heme-oxygenase 1 (HO-1) is an enzyme with well-known anti-inflammatory and antioxidant properties, whose levels have been previously associated with disease severity in the context of sterile and infectious diseases. Moreover, the heme/HO-1 pathway has been associated with prothrombotic changes in other diseases. Accordingly, the potential of modulating HO-1 levels for the treatment of COVID-19 was extensively speculated during the COVID-19 pandemic, but very few actual data were generated. The aim of our study was to explore the association of HO-1, heme, and hemopexin (HPX) levels with COVID-19 severity and with markers of inflammation and coagulation activation. The study was conducted in 30 consecutive patients with COVID-19 admitted due to hypoxemia, and 30 healthy volunteers matched by sex, age, and geographic region. HO-1 and HPX levels were measured by enzyme immunoassay (ELISA) and heme levels were measured by a colorimetric method. A comprehensive panel of coagulation and fibrinolysis activation was also used. Patients with COVID-19 presented increased levels of HO-1 when compared to controls (5741 ± 2696 vs 1953 ± 612 pg/mL, respectively, P < 0.0001), as well as a trend toward increased levels of HPX (3.724 ± 0.880 vs 3.254 ± 1.022 mg/mL, respectively; P = 0.06). In addition, HO-1 and HPX levels reduced from admission to day + 4. HO-1 levels were associated with duration of intensive care unit stay and with several markers of coagulation activation. In conclusion, modulation of HO-1 could be associated with the prothrombotic state observed in COVID-19, and HO-1 could also represent a relevant biomarker for COVID-19. New independent studies are warranted to explore and expand these findings.

Podoplanin and CLEC-2 levels in patients with COVID-19.

Introduction: Podoplanin (PDPN gene) and CLEC-2 are involved in inflammatory hemostasis and have also been related with the pathogenesis of thrombosis. Emerging evidence also suggest that podoplanin can exert protective effects in sepsis and in acute lung injury. In lungs, podoplanin is co-expressed with ACE2, which is the main entry receptor for SARS-CoV-2. Aim: To explore the role of podoplanin and CLEC-2 in COVID-19. Methods: Circulating levels of podoplanin and CLEC-2 were measured in 30 consecutive COVID-19 patients admitted due to hypoxia, and in 30 age- and sex-matched healthy individuals. Podoplanin expression in lungs from patients who died of COVID-19 was obtained from two independent public databases of single-cell RNAseq from which data from control lungs were also available. Results: Circulating podoplanin levels were lower in COVID-19, while no difference was observed in CLEC-2 levels. Podoplanin levels were significantly inversely correlated with markers of coagulation, fibrinolysis and innate immunity. scRNAseq data confirmed that PDPN is co-expressed with ACE2 in pneumocytes, and showed that PDPN expression is lower in this cell compartment in lungs from patients with COVID-19. Conclusion: Circulating levels of podoplanin are lower in COVID-19, and the magnitude of this reduction is correlated with hemostasis activation. We also demonstrate the downregulation of PDPN at the transcription level in pneumocytes. Together, our exploratory study questions whether an acquired podoplanin deficiency could be involved in the pathogenesis of acute lung injury in COVID-19, and warrant additional studies to confirm and refine these findings.

Venous thromboembolism in critically ill patients with pneumonia in the pre-COVID-19 era: Data from a large public database.

Background: The magnitude of venous thromboembolism (VTE) risk in severe COVID-19 is a matter of debate because of study heterogeneity, changes in VTE management, and scarce evidence of VTE risk in critically ill patients with pneumonia in the pre-COVID-19 era. Objectives: To evaluate VTE risk in the pre-COVID-19 era in a large intensive care unit (ICU) database. Patients/Methods: Data from consecutive pneumonia patients admitted to the ICU were retrieved from the Medical Information Mart for Intensive Care III. VTE risk was described in the entire cohort and in subgroups. Results: Among 6842 pneumonia patients admitted to the ICU, 486 patients were diagnosed with VTE after a median of 3 (IQR 1-11) days in the ICU. The 30-day cumulative incidence of VTE was 7% and remained at this level across different age groups, sex, and type of ICU. After adjusting for death, the overall cumulative incidence of VTE was 5%. A total of 1788 patients received thromboprophylaxis (of 2958 for whom that data were available). VTE occurred in 10.7% (95% CI 9.0-12.6) of patients without thromboprophylaxis and in 6.4% (95% CI 5.4-7.6) of those with thromboprophylaxis. Mortality was 20.6% among patients with VTE and 19.2% among those without VTE. Conclusions: In the pre-COVID-19 era, VTE risk in ICU patients with pneumonia was high and decreased with thromboprophylaxis. These findings can serve as comparators for future studies aiming at evaluating the impact of COVID-19 or other emerging infections on VTE risk.

Extracellular matrix-derived and low-cost proteins to improve polyurethane-based scaffolds for vascular grafts.

Vascular graft surgeries are often conducted in trauma cases, which has increased the demand for scaffolds with good biocompatibility profiles. Biodegradable scaffolds resembling the extracellular matrix (ECM) of blood vessels are promising vascular graft materials. In the present study, polyurethane (PU) was blended with ECM proteins collagen and elastin (Col-El) and gelatin (Gel) to produce fibrous scaffolds by using the rotary jet spinning (RJS) technique, and their effects on in vitro properties were evaluated. Morphological and structural characterization of the scaffolds was performed using scanning electron microscopy (SEM) and atomic force microscopy (AFM). Micrometric fibers with nanometric rugosity were obtained. Col-El and Gel reduced the mechanical strength and increased the hydrophilicity and degradation rates of PU. No platelet adhesion or activation was observed. The addition of proteins to the PU blend increased the viability, adhesion, and proliferation of human umbilical vein endothelial cells (HUVECs). Therefore, PU-Col-El and PU-Gel scaffolds are promising biomaterials for vascular graft applications.

Contact and intrinsic coagulation pathways are activated and associated with adverse clinical outcomes in COVID-19.

Coagulation activation is a prominent feature of severe acute respiratory syndrome coronavirus 2 (COVID-19) infection. Activation of the contact system and intrinsic pathway has increasingly been implicated in the prothrombotic state observed in both sterile and infectious inflammatory conditions. We therefore sought to assess activation of the contact system and intrinsic pathway in individuals with COVID-19 infection. Baseline plasma levels of protease:serpin complexes indicative of activation of the contact and intrinsic pathways were measured in samples from inpatients with COVID-19 and healthy individuals. Cleaved kininogen, a surrogate for bradykinin release, was measured by enzyme-linked immunosorbent assay, and extrinsic pathway activation was assessed by microvesicle tissue factor-mediated factor Xa (FXa; MVTF) generation. Samples were collected within 24 hours of COVID-19 diagnosis. Thirty patients with COVID-19 and 30 age- and sex-matched controls were enrolled. Contact system and intrinsic pathway activation in COVID-19 was demonstrated by increased plasma levels of FXIIa:C1 esterase inhibitor (C1), kallikrein:C1, FXIa:C1, FXIa:α1-antitrypsin, and FIXa:antithrombin (AT). MVTF levels were also increased in patients with COVID-19. Because FIXa:AT levels were associated with both contact/intrinsic pathway complexes and MVTF, activation of FIX likely occurs through both contact/intrinsic and extrinsic pathways. Among the protease:serpin complexes measured, FIXa:AT complexes were uniquely associated with clinical indices of disease severity, specifically total length of hospitalization, length of intensive care unit stay, and extent of lung computed tomography changes. We conclude that the contact/intrinsic pathway may contribute to the pathogenesis of the prothrombotic state in COVID-19. Larger prospective studies are required to confirm whether FIXa:AT complexes are a clinically useful biomarker of adverse clinical outcomes.

Time-course of sFlt-1 and VEGF-A release in neutropenic patients with sepsis and septic shock: a prospective study.

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. METHODS: We prospectively evaluated concentrations of sFlt-1 and VEGF-A at different time-points during febrile neutropenia, and evaluated the association of these levels with sepsis severity and septic shock development. RESULTS: Neutropenic patients that evolved with septic shock (n = 10) presented higher levels of sFlt-1 and VEGF-A measured 48 hours after fever onset than patients with non-complicated sepsis (n = 31) and levels of these biomarkers correlated with sepsis severity scores. Estimation of the diagnostic accuracy of sFlt-1 levels for the discrimination of patients that evolved to septic shock yielded promising results in our study population. DISCUSSION: Our data suggest that sFlt-1 and VEGF-A could be useful biomarkers for sepsis severity in patients with febrile neutropenia. In addition, the kinetics of sFlt-1 release in patients that evolve to septic shock suggest that the sFlt-1 could be a salvage compensatory mechanism in patients with septic shock, but that the magnitude of the sFlt-1 release observed in human sepsis is not sufficient to reproduce the beneficial anti-VEGF-A effects observed in animal models of sepsis.

Evaluation of mild hyperhomocysteinemia during the development of atherosclerosis in apolipoprotein E-deficient and normal mice.

We focused on the effect of mild hyperhomocysteinemia (HHcy) on the development of atherosclerosis, using apolipoprotein E-deficient (apoE(-/-)) and normal mice. Mice received diets enriched in methionine with low or high levels of folate, B(12) and B(6) (diets B and C, respectively), and diet only with low levels of folate, B(12) and B(6) (diets D), to induce mild HHcy. Normal mice fed on diets B, C and D presented mild HHcy, but they did not develop atherosclerotic lesions after 24 weeks of diet. In addition, increased endoplasmic reticulum stress was present in normal mice fed on diet B, compared to others groups. ApoE(-/-) mice fed on diet B for 20 weeks presented the greatest atherosclerotic lesion area at the aortic sinus than other groups. These results suggest that the methionine may have a toxic effect on endothelium, and the B-vitamins addition on diet may have a protective effect in the long term, despite the increase on homocysteine levels. Mild HHcy accelerated the development of atherosclerosis in apoE(-/-) mice, and supplementation with B-vitamins is important for prevention of vascular disease, principally in the long term.

A case series of platelet rich plasma in chronic venous ulcers.

INTRODUCTION: Venous ulcers are the most common type of leg wounds (80%) and the main cause is chronic venous insufficiency. Autologous platelet-rich plasma (PRP) is a potential wound healing treatment due to its great variety of growth factors. The aim of this study was to describe in a case series the results of poor-leukocyte PRP (P-PRP) or saline for the treatment of chronic non-healing ulcers of the lower extremity. METHODS: Eight patients were treated according to the topical therapy: saline solution or P-PRP gel. All patients used double compression stocks and were assisted by a vascular practitioner for up to 12 months or until wound healing. The treatment was performed weekly with cleaning of the affected area, macroscopic evaluation (area measurement and photos) and P-PRP or saline application, and closure with Tegaderm®. Trial Registration: Retrospectively approved by Brazilian Clinical Trials, register number RBR-7zhgb3 (http://www.ensaiosclinicos.gov.br/rg/RBR-7zhgb3/). RESULTS: All patients showed signs of wound healing with a reduction in wound size and ulcer numbers, but more evident with P-PRP application. CONCLUSIONS: The results suggested that P-PRP presented a better result when compared to saline solution in the healing process of long clinical course chronic venous ulcers, when associated to compressive stocks and topical care.

A retrospective analysis of 122 immune thrombocytopenia patients treated with dapsone: Efficacy, safety and factors associated with treatment response.

BACKGROUND: The optimum second-line treatment or best sequence of treatments for immune thrombocytopenia (ITP) are yet to be determined. Our institution has accumulated extensive experience regarding the use of dapsone as second-line therapy for ITP. OBJECTIVES: We aimed to assess the efficacy rate and safety of dapsone treatment in ITP patients. PATIENTS/METHODS: Here we report our experience in a retrospective study, including 122 patients, with a median treatment duration with dapsone of 6 months and a median follow-up period of 3.4 years. RESULTS: The overall response rate in this cohort was 66%, including 24% of complete responses. Among responders, in 24% a relapse occurred while on treatment. Therefore, a sustained response was observed in 51% of patients. Interestingly, 81% of the responders maintained the response after the interruption of treatment, for a median time of 26 months. Side effects were reported in 16% of the patients in this cohort and treatment was interrupted due to side effects in 11% of patients. The main cause in these cases was hemolytic anemia and methemoglobinemia. Reductions in hemoglobin levels during the use of dapsone were seen in 94% of the patients. Responders presented significantly greater reductions in their hemoglobin levels than nonresponders did: median hemoglobin drop of 1.9 g/dl vs. 1.2 g/dl (p = .004). CONCLUSIONS: Our findings suggest that dapsone has adequate efficacy and is well tolerated. Although the mechanism of action is still unclear, our observation that the degree in the drop of hemoglobin is greater in responders suggest a possible role of the blockage of the reticuloendothelial system in the therapeutic effect of the drug.

A novel association of acquired ADAMTS13 inhibitor and acute dengue virus infection.

BACKGROUND: Dengue is a mosquito-borne viral disease with an increasing incidence worldwide. Thrombocytopenia is a common finding in dengue virus (DV) infection; however, the underlying mechanisms remain unknown. CASE REPORT: Here we provide the first evidence of a case of antibody formation against ADAMTS13 (ADAMTS13 inhibitor) in the course of a severe acute DV infection resulting in thrombotic microangiopathy (TMA). The patient presented with classical dengue symptoms (positive epidemiology, high fever, myalgia, predominantly in the lower limbs and lumbar region for 1 week) and, after 11 days of initial symptoms, developed TMA. Clinical and laboratorial investigation of dengue and TMA was performed. RESULTS: The patient presented with ADAMTS13 inhibitor (IgG) during the acute phase of the disease, without anti-platelet antibodies detectable. Dengue infection had laboratorial confirmation. There were excellent clinical and laboratory responses to 11 serial plasma exchanges. Anti-ADAMTS13 inhibitor disappeared after remission of TMA and dengue resolution. No recurrence of TMA symptoms was observed after 2-year follow-up. CONCLUSIONS: Although the real incidence of dengue-related TMA is unknown, this case provides the basis for future epidemiologic studies on acquired ADAMTS13 deficiency in DV infection. The prompt clinical recognition of this complication and early installment of specific therapy with plasma exchange are likely to improve the outcome of severe cases of dengue.

Imbalances in serum angiopoietin concentrations are early predictors of septic shock development in patients with post chemotherapy febrile neutropenia.

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. METHODS: We prospectively evaluated concentrations of Ang-1 and Ang-2 at different time-points during febrile neutropenia, and explored the diagnostic accuracy of these mediators as potential predictors of poor outcome in this clinical setting before the development of sepsis complications. RESULTS: Patients that evolved with septic shock (n = 10) presented higher levels of Ang-2 measured 48 hours after fever onset, and of the Ang-2/Ang-1 ratio at the time of fever onset compared to patients with non-complicated sepsis (n = 31). These levels correlated with sepsis severity scores. CONCLUSIONS: Our data suggest that imbalances in the concentrations of Ang-1 and Ang-2 are independent and early markers of the risk of developing septic shock and of sepsis mortality in febrile neutropenia, and larger studies are warranted to validate their clinical usefulness. Therapeutic strategies that manipulate this Ang-2/Ang-1 imbalance can potentially offer new and promising treatments for sepsis in febrile neutropenia.

Low prevalence of Post-thrombotic syndrome in patients treated with rivaroxaban.

Post-thrombotic syndrome (PTS) is a complication of deep vein thrombosis (DVT). Residual vein thrombus (RVT) on Doppler Ultrasound can be associated with PTS. Limited data are available on the effect of direct oral anticoagulants (DOACs) on the long-term outcome of PTS. This study aimed to compare the prevalence of PTS and RVT, in patients with previous DVT treated with rivaroxaban or enoxaparin/warfarin. A total of 129 patients with previous proximal lower limb DVT and treated with rivaroxaban (n = 71) or enoxaparin/warfarin (n = 58) for at least 3 months were included. The Villalta scale for PTS was performed after treatment. The median duration of the DVT symptoms before anticoagulation was 7 days for both groups. The rate of PTS was 50.7% in the patients treated with rivaroxaban and 69% in the enoxaparin/warfarin group. Enoxaparin/warfarin showed an increased prevalence of PTS (P = .018). An analysis in 3 different models showed that the relative risk of PTS decreased by 76% with rivaroxaban use when compared with enoxaparin/warfarin treatment. In addition, 93 of the 129 patients were evaluated regarding the presence of RVT, of which, 11 (24.4%) and 31 (64.6%) presented with RVT for rivaroxaban and enoxaparin/warfarin, respectively (P < .0001). The RVT analysis excluded the possibility of RVT as a mediator of the association between type of treatment and PTS when comparing rivaroxaban with enoxaparin/warfarin (odds ratio (OR) = 0.14; 95% confidence interval (CI): 0.1-1.0, P = .051) with rivaroxaban compared with enoxaparin/warfarin. Rivaroxaban treatment was associated with a lower risk of PTS when compared to enoxaparin/warfarin; RVT however, was not a mediator in the association between PTS and type of treatment.

Assessing the coagulation factor levels, inherited thrombophilia, and ABO blood group on the risk for venous thrombosis among Brazilians.

Increased coagulation factor levels have been demonstrated to be a risk factor for venous thromboembolism in patients of Caucasian origin. Coagulation factors, hereditary thrombophilia, and ABO blood group were evaluated for venous thrombosis risk in a heterogeneous Brazilian population consisting of 122 women and 53 men, with a median age of 36 years (range 13-63), matched to a control group by age, sex, and ethnicity. Increased levels of factor VIII (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.6-6.0), von Willebrand factor (OR, 2.8; 95% CI, 1.4-5.4), non-O blood group (OR, 2.1; 95% CI, 1.3-3.4), and thrombophilia (OR, 3.4; 95% CI, 1.6-7.1) emerged as independent risk factors for venous thromboembolism. The interaction of high levels of factor IX and factor XI with other independent variables increased the potential for thrombosis synergistically. Therefore, the ability of identifying underlying thrombophilia risk factors in our population was enhanced by the inclusion of these factors in the prothrombotic laboratory workup.