4402 The effects of hemodilution in vitro on coagulation in term parturients using thromboelastometry

OBJECTIVES/GOALS: Little is known about the effect of hemodilution with crystalloid on blood coagulation in obstetric patients. The purpose of our study was to examine the impact of hemodilution on components of blood coagulation using rotational thromboelastometry (ROTEM®) in term parturients METHODS/STUDY POPULATION: This is a prospective, observational pilot study including 35 healthy, pregnant patients at term (≥37 weeks) without history of bleeding or clotting disorder or on medication affecting coagulation. Venous blood samples were collected from all patients and divided into specimen tubes to generate varying degrees of hemodilution with Plasma-Lyte (0%, 20%, 25%, 30%, 35%, 40%, 45%, 55%, 60%, 65%, 70%, 75%, 80%). Rotational thromboelastometry was then performed on samples to assess for coagulation changes. RESULTS/ANTICIPATED RESULTS: EXTEM (extrinsically activated assay) clotting time (CT) became prolonged at 65% hemodilution and above, and the median CT was in the coagulopathic range (>80 seconds) at a dilution of 80%. FIBTEM (extrinsically activated assay with platelet inhibitor, primarily measuring contribution of fibrinogen to coagulation) amplitude at 5 minutes (A5) began to diminish at 35% hemodilution, with the median A5 in the coagulopathic range (<12 mm) at 55% hemodilution. The area under the curve (AUC), a marker of clot strength, for EXTEM and FIBTEM consistently declined as hemodilution increased. Greater decreases in FIBTEM AUC were seen compared to EXTEM AUC, with the ratio of FIBTEM:EXTEM AUC at each dilution demonstrating a statistically significant difference from baseline. DISCUSSION/SIGNIFICANCE OF IMPACT: All thromboelastometry values demonstrated a hypocoagulable trend as hemodilution increased. However, the samples analyzed by the FIBTEM assay trended toward a coagulopathy at a lower degree of hemodilution compared to the EXTEM assay. As FIBTEM tests analyze the role of fibrinogen in hemostasis and EXTEM tests analyze the role of platelets, our findings suggest that platelets may be able to withstand higher degrees of hemodilution before impairing hemostasis compared to fibrinogen. These findings support the growing body of literature that in early stages of severe obstetric hemorrhage, the prioritization of fibrinogen replacement may be critical in preventing further coagulopathy. CONFLICT OF INTEREST DESCRIPTION: All authors have no conflicts of interest to report.

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Inhibition of Plasmin Generation in Plasma By Heparin, Low Molecular Weight Heparin and a Covalent Antithrombin-Heparin Complex (ATH)

Blood ◽

10.1182/blood.v124.21.4217.4217 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4217-4217

Author(s):

Gabriela Chang ◽

Helen M. Atkinson ◽

Leslie R. Berry ◽

Anthony K.C. Chan

Keyword(s):

Molecular Weight ◽

Plasminogen Activator ◽

Low Molecular Weight Heparin ◽

Conflicts Of Interest ◽

Area Under The Curve ◽

Low Molecular Weight ◽

Plasminogen Activator Inhibitor 1 ◽

Significant Difference

Abstract Introduction: Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are widely used anticoagulants for thrombosis treatment. However, these anticoagulants have limitations such as increased bleeding, variable dose response, required frequent monitoring, and, in the case of LMWH, inability to inhibit thrombin. This has led to the development of a covalent complex of antithrombin and heparin (ATH), which has been shown to overcome many of these shortcomings. ATH has faster rates of inhibition of many coagulation factors, is able to inhibit clot-bound thrombin, and is a more effective inhibitor of both venous and arterial thrombosis in animal models. Moreover, in a rabbit thrombosis model, ATH has been shown to decrease clot mass and fibrin accretion, while the contrary was observed for UFH. From these observations, it was suggested that ATH may enhance fibrin breakdown and thus led to investigations into the effects of UFH and ATH on fibrinolysis. In vitro studies have shown that UFH enhances antithrombin inhibition of plasmin. In addition, ATH displays a slightly greater inhibition of plasmin generation and activity. Such studies were conducted in purified systems, in the absence of other plasmin inhibitors naturally present in plasma. Therefore, the aim of the present study was to compare the effects of UFH, LMWH, and ATH on plasmin generation in plasma. Methods: At 37°C tissue plasminogen activator (tPA) and soluble fibrin fragments (fib) were added to normal adult pooled platelet poor plasma supplemented with 0.35, 0.7, 1.4, or 2.1 U anti-Xa/ml UFH, LMWH, or ATH, to initiate plasmin generation (8.93nM tPA and 300µg/ml fib). At various time points, subsamples were mixed with excess plasminogen activator inhibitor 1 (PAI-1) (55.12nM) to stop further plasmin generation. The plasmin concentration at each time point was determined using a plasmin-specific chromogenic substrate and a standard curve produced from purified plasmin. Results: Comparisons of mean area under the curve (AUC) for plasmin generation displayed a significant decrease in plasmin generation in the presence of all three anticoagulants at all doses tested (p<0.05). Comparing the anticoagulants at similar doses, plasmin generation was significantly decreased in the presence of ATH (15384.66±1930.23nM/min) compared to LMWH (23892.28±3090.54nM/min) at 0.7 U/ml (p<0.05). At a dose of 1.4 U/ml, there was significantly less plasmin generated, over time, in the presence of UFH (20089.49±3022.1623nM/min) and ATH (19273.86±1805.7323nM/min) when compared to LMWH (24743.18±1265.1023nM/min) (p<0.05). There was no significant difference in plasmin inhibition between UFH and ATH at any of the doses tested. Conclusion: The present study supports previous findings that UFH and ATH can facilitate antithrombin inhibition of plasmin. It is also observed that LMWH catalyzes the inhibition of plasmin by antithrombin but possibly to a lesser extent. These findings suggest that ATH has a similar inhibitory effect on plasmin generation and activity in plasma compared to UFH, despite its overall superior anticoagulant properties. Therefore, previous in vivo observations displaying decrease in clot mass with administration of ATH was due to its enhanced anticoagulant abilities and not fibrinolysis enhancement. These findings add to our understanding of ATH mechanisms of action and aid in its development for clinical use. Disclosures No relevant conflicts of interest to declare.

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Leukemia-Induced Alterations of Bone Marrow Microenvironment Contribute to Leukemogenesis.

Blood ◽

10.1182/blood.v116.21.2597.2597 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2597-2597

Author(s):

Jae-Seung Shim ◽

Myungshin Kim ◽

Jong Wook Lee ◽

Il-Hoan Oh

Keyword(s):

Conflicts Of Interest ◽

Growth Arrest ◽

Normal Growth ◽

Qualitative Change ◽

Myelogenous Leukemia ◽

Cd34 Cells ◽

Significant Difference ◽

Acute Myelogenous ◽

The Impact

Abstract Abstract 2597 The impact of microenvironment on the regulation of normal hematopoietic process is being unveiled, but their role during leukemogenesis have been poorly understood. In this study, to characterize the leukemic microenvironment, we have analyzed mesenchymal stromal cells (MSC) of bone marrows from 55 cases of acute myelogenous leukemia (AML), and 17 of AML in the remission. When the colonogenic activity of MSCs were compared, 43% of AML-derived BM exhibited defect in colony (CFU-F) formation, where no colony formation or premature growth arrest of colonies were observed, whereas only 11% of normal BM exhibited growth arrest of colonies. In the AML subtypes, M3 type (FAB classification) exhibited most profound loss of CFU-Fs, where none of them (n=9) exhibited normal growth of colonies. In addition, numbers of colony (CFU-F) in AML was significantly lower than normal BM (52 vs. 155 per each ml of BM, respectively for AML and normal, p<0.05). In contrast, BMs of AML in remission did not exhibit significant difference in the number of CFU-F compared to numbers of normal BM (88 vs. 71.4 per 5×106 MNCs, respectively for normal and remission), indicating that the quantitative loss of CFU-F is correlated to disease activity of AML. We next examined the qualitative changes of MSCs in AML, i.e., 83% of MSCs in AML (5/6) exhibited poor osteogenic differentiation, and all examined AML MSCs (6/6) exhibited lower adipogenic differentiaton compared to normal MSCs. During in-vitro culture, MSCs from AML showed accelerated loss of colonogenic activity during passage cultures compared to normal MSCs and lower intensity levels of CD146 in the cell surface. Moreover, MSCs from AML showed significantly higher levels of senescence-associated beta-galactosidase without changes in telomere length, indicating that the MSC has undergone qualitative change during leukemogenesis. When co-cultured with umbilical cord blood-derived CD34+ cells, AML-derived MSCs inhibited proliferation of CD34+ cells and caused significantly lower levels of hematopoietic cell expansion compared to the levels from co-culture with normal BM-derived MSCs or stroma-free cultures, indicating that leukemic MSCs should contribute to the loss of normal hematopoietic cells in leukemia. Taken together, our study shows that microenvironment of BM undergoes quantitative and qualitative alteration during leukemogenesis and that such leukemic microenvironment contributes to the pathology of leukemia. Disclosures: No relevant conflicts of interest to declare.

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The Janus Face of Neutrophil Specific Antigen CD177 in Bacterial Infection: Focal Disease Versus Systemic Disease

Blood ◽

10.1182/blood.v118.21.1108.1108 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1108-1108

Author(s):

Behnaz Bayat ◽

Vanessa Santoso ◽

Beate Kehrel ◽

Ulrich J Sachs ◽

Sentot Santoso

Keyword(s):

Bacterial Infection ◽

Conflicts Of Interest ◽

Systemic Disease ◽

Specific Antigen ◽

Favourable Effect ◽

Bacterial Sepsis ◽

Migration Ability ◽

Significant Difference ◽

The Impact

Abstract Abstract 1108 CD177, also known as NB1 (or HNA-2) is a GPI-linked glycoprotein, which is exclusively expressed on neutrophils. Approximately 3 to 5% of healthy individuals do not express this antigen on their neutrophils (NBnull). Recent data demonstrated a strong upregulation of NB1 on neutrophils in patients with bacterial, but not viral infections. The mechanism underlying this phenomenon, however, is unknown. Our previous studies showed that NB1 functions as a partner of endothelial PECAM-1 and therefore plays a role on neutrophil diapedesis. Consequently, neutrophils carrying NB1 (NB1plus) migrate faster through endothelial cells than NBnull neutrophils. However, several studies have documented an abrogation of neutrophil migratory abilities in sepsis conditions. In this study, we aim to clarify the impact of neutrophil NB1 expression in bacterial sepsis. To mimic this condition in vitro, we first compared the transendothelial migration ability of NB1 phenotyped neutrophils after stimulation with the bacterial peptide fMLP in a transwell system. Lower transmigration ability (75% vs. 40%) was observed in fMLP-treated NB1plus neutrophils (n = 5) in comparison to untreated neutrophils. In contrast, no significant difference in the migration ability was observed between fMLP-treated and untreated NB1null neutrophils (n = 3). Expression analysis by flow cytometry showed a dose-dependent upregulation of NB1 after stimulation with fMLP (10−6 to 10−8 μM) in NB1plus neutrophils. Interestingly, down regulation of PECAM-1 expression was observed in these treated cells. Contrary, no PECAM-1 downregulation was detected in NBnull fMLP-treated neutrophils. These results could be confirmed by immunoblotting analysis using specific antibodies directed against different epitopes on NB1 (mabs 7D8, MEM166) and against different PECAM-1 Ig domains (mabs PECAM1.1, 1.2 and 1.3). Analysis of the supernatants of fMLP-treated neutrophils demonstrated the shedding of PECAM-1 from NB1plus, but not from NB1null neutrophils. These results indicate that shedding of PECAM-1 from neutrophils during bacterial infections depends on NB1 expression. Recent studies showed that a single nucleotide polymorphism (42C>G) located in NB1 promoter region is associated with the regulation of NB1 expression. Individuals homozygous for C allele express high NB1 surface density in comparison to individuals homozygous for G allele. Our association study showed higher frequency of C allele in patients with bacterial sepsis (n=98) compared with healthy cohort (n = 132) (8.16% vs. 12.88%; P<0.03). This observation indicates the role of C42 allele (or high NB1 expression) as genetic risk factor for bacterial sepsis. All together, these data demonstrate a reverse role of NB1 expression in focal and systemic infection, indicating favourable effect of low NB1 in systemic bacterial infection. This phenomenon may be caused by reduction of neutrophil directionality and motility due to NB1-mediated PECAM-1 shedding. Disclosures: No relevant conflicts of interest to declare.

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Flt3 Is Required for MLL-ENL-Induced Leukemogenesis In Vivo, but Not for LSC Function in Vitro

Blood ◽

10.1182/blood.v118.21.2450.2450 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2450-2450

Author(s):

Kenjiro Kamezaki ◽

Hans-Willem Snoeck

Keyword(s):

Kinase Inhibitors ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Tyrosine Kinase Receptor ◽

Mouse Bone Marrow ◽

Retroviral Transduction ◽

Significant Difference

Abstract Abstract 2450 Flt3 is a type III tyrosine kinase receptor expressed on hematopoietic multipotential progenitors and more downstream progenitor cells in the mouse bone marrow (BM).Flt3 is one of the most frequently mutated genes in acute myeloblastic leukemia (AML) patients, leading to constitutive activation. Several Flt3 kinase inhibitors are in clinical development in AML with Flt3 mutations, although disappointing results suggest that Flt3-inhibitors as monotherapy are unlikely to become reality. Wild type (wt) Flt3, which differs in its signaling characteristics and downstream targets from mutated Flt3, is highly expressed in particular in AML and ALL (acute lymphoblastic leukemia) with MLL (Mixed Lineage Leukemia) rearrangements. These observations suggest a role for wt Flt3 in pathogenesis as well, although little experimental or clinical evidence has been published yet supporting this notion. To our knowledge, there is only one report suggesting that wt Flt3 is required for the development of leukemia in a murine model of c-cbl mutation-induced leukemogenesis (Rathinam C, et al. Cancer Cell 2010). For this reason, we focused on the role of wt Flt3 in leukemogenesis and using leukemia mouse models established by retroviral transduction of MLL-ENL, MLL-AF9 and AML1-ETO9a. Mice transplanted with MLL-ENL-transduced Flt3−/− BM cells showed a higher survival rate (wt 61.3%, n=34 vs Flt3−/− 96.8%, n=31, median follow-up period; 255 days, p=0.038). No difference in survival was observed in the MLL-AF9 and AML1-ETO9a models however. Surprisingly, MLL-ENL-transduced Flt3−/− BM cells showed no significant difference in serial replating capacity of BM cells in methylcellulose colony forming assays in vitro compared to wt BM cells, and putative lin-kit+ leukemic stem cells (LSCs) did not express Flt3. In vivo, however, putative MLL-ENL LSCs, but not MLL-AF9 LSCs expressed Flt3. Furthermore, in non- and pre-leukemic MLL-ENL-transduced mice BM cells the frequency of lin-kit+ putative LSCs among MLL-ENL positive populations was decreased in Flt3−/− group (wt 1.468% vs Flt3−/− 0.466%, p=0.031). Flt3+ lin-kit+ populations were increased in MLL-ENL transduced leukemic wt mice compared to non-leukemic mice (leukemic mice 26.7% vs non-leukemic mice 9.9%, p=0.028). These results suggest that Flt3 signaling is required for MLL-ENL-induced leukemogenesis and maintenance of LSCs in vivo, but not in vitro. Importantly, the data suggest that the in vitro replatable leukemia stem cell (LSC) paradigm might not reflect LSC function or phenotype in vivo. Disclosures: No relevant conflicts of interest to declare.

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Amylase-Producing Myeloma Cells Reduced Sensitivity to Dexamethasone and Bortezomib.

Blood ◽

10.1182/blood.v124.21.5690.5690 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5690-5690

Author(s):

Shohei Mizuno ◽

Ichiro Hanamura ◽

Akinobu Ota ◽

Karnan Sivasundaram ◽

Tomoko Narita ◽

...

Keyword(s):

Tumor Growth ◽

Conflicts Of Interest ◽

Constitutive Expression ◽

Proliferation Rate ◽

Specific Gene ◽

Significant Difference ◽

Mock Control ◽

The Impact

Abstract Despite recent progress in treatment for multiple myeloma (MM), a complete cure remains elusive. To further improve the therapeutic outcome of patients with MM, elucidation of the pathology of refractory cases is important. Hyperamylasemia, which is associated with ectopic amylase (AMY) production by MM cells, is a rare condition, and it has been reported to present with poor prognosis showing rapid tumor growth, extramedullary tumor mass formation, and refractoriness of the condition. However, to date, there have been no biological analyses of MM cells ectopically producing AMY. In this study we generated transfectants that stably expressed AMY with human MM cells, and investigated the impact that ectopic AMY production has on tumor proliferation and changes in drug susceptibility in vitro and in vivo. Two human MM cell lines (RPMI8226 and KMS11) and the cDNA encoding AMY1 were used to establish transfectants with ViraPower™ Lentiviral Gateway Expression Kit (Invitrogen), because the increased AMY isotype was salivary type, which is coded in AMY1, in all MM patients previously reported. The constitutive expression and production of AMY1 were confirmed in the AMY-transfectants (8226/AMY and KMS11/AMY), while they were not in the mock controls. These transfectants were assayed for proliferation and apoptosis after exposure to dexamethasone (Dex), bortezomib (Bz) and lenalidomide (Len) in vitro. The anti-myeloma activity of Bz was also tested in vivo in a xenograft model generated by injecting 8226/AMY or the mock cells into NOD-SCID mice. 8226/AMY had no growth advantage in vitro but grew rapidly when subcutaneously transplanted in mice compared with the mock control (2,177±878 vs 970±131 mm3, p = 0.044). 8226/AMY showed a higher cell proliferation rate than the mock control in vitro when treated with Dex (40uM), Bz (2nM), and Len (1mM). The number of apoptotic 8226/AMY cells decreased after exposure to Bz and Len, but the number after exposure to Dex was equivalent compared with the mock control by the Annexin / Propidium Iodide assay. Therefore, 8226/AMY became less sensitive to Bz and Len partly through the inhibition of apoptosis induced by these drugs. 8226/AMY grew rapidly subcutaneously in mice compared with the mock control when treated with Bz (0.3mg/kg, twice weekly) (p = 0.017). As for KMS11/AMY, the AMY-transfectant showed a higher proliferation rate than the mock control in vitro. KMS11/AMY showed reduced susceptibility to Dex, no change in the susceptibility to Bz, and an enhanced susceptibility to Len unexpectedly in comparison with the mock control. The reason for a difference in the effect of ectopic AMY expression on the susceptibility to anti-MM drugs between 8226/AMY and KMS11/AMY is unclear; however, it might be due to the nature of their parental cells. No significant difference was observed in the gene expression profiling between both AMY-transfectants and each of the respective mock controls, except for AMY1, suggesting that ectopic AMY expression did not affect the expression level of the specific gene in MM. In conclusion, we found that 8226/AMY had reduced susceptibility to Dex, Bz, and Len in vitro and also rapid tumor growth with a weakened anti-tumor effect of Bz in vivo. All of these were consistent with the clinical course of previously reported patients with ectopic AMY-producing MM. On the other hand, KMS11/AMY showed an enhanced susceptibility to Len compared with the mock control, indicating that Len might be effective for some patients with AMY-producing MM. Our data provided beneficial clues for elucidating the molecular pathology and developing a treatment strategy for this clinical setting. Disclosures No relevant conflicts of interest to declare.

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Stress, Cortisol and Suicide Risk

10.31234/osf.io/92b7z ◽

2019 ◽

Author(s):

Daryl Brian O'Connor

Keyword(s):

Risk Factors ◽

Suicidal Behavior ◽

Suicide Risk ◽

Stressful Events ◽

Additional Risk ◽

Global Health Issue ◽

History Of ◽

Hpa Axis Activity ◽

The Impact

Suicide is a global health issue accounting for at least 800,000 deaths per annum. Numerous models have been proposed that differ in their emphasis on the role of psychological, social, psychiatric and neurobiological factors in explaining suicide risk. Central to many models is a stress-diathesis component which states that suicidal behavior is the result of an interaction between acutely stressful events and a susceptibility to suicidal behavior (a diathesis). This article presents an overview of studies that demonstrate that stress and dysregulated hypothalamic-pituitary-adrenal (HPA) axis activity, as measured by cortisol levels, are important additional risk factors for suicide. Evidence for other putative stress-related suicide risk factors including childhood trauma, impaired executive function, impulsivity and disrupted sleep are considered together with the impact of family history of suicide, perinatal and epigenetic influences on suicide risk.

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Setting the Stage

10.1093/oso/9780198777168.003.0002 ◽

2017 ◽

Author(s):

Fred L. Borch

Keyword(s):

World War Ii ◽

Japanese Occupation ◽

East Indies ◽

Indonesian Archipelago ◽

Ethical Policy ◽

Netherlands East Indies ◽

History Of ◽

Colonial Economy ◽

The Impact

Explores the role of the Dutch in the Indies from 1595, when sailors from Amsterdam first arrived in the islands, to 1942, when the Japanese invaded the colony and inflicted a devastating defeat upon the Dutch. The history of the Dutch in the Indonesian archipelago is critical to understanding the impact of the Japanese occupation after 1942, and the nature of the war crimes committed by the Japanese. This is because the ultimate goal of the Japanese occupiers was to erase all aspects of Dutch culture and influence the islands. The chapter begins with an examination of the early Dutch settlement of the islands, and the development of the colonial economy. It then discusses the so-called “Ethical Policy,” which sought to unify the islands under Dutch rule and implement European ideas about civilization, culture, and prosperity. The chapter looks at the colony’s social structure prior to World War II and closes with a discussion of the colony’s preparations for war with the Japanese in 1942. A short postscript explains what occurred between August 1945, when the Japanese surrendered, and December 1949, when the Netherlands East Indies ceased to exist.

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The Role of Oil and Gas in the Economic Development of the Global Economy

10.1093/oso/9780198817369.003.0004 ◽

2018 ◽

Author(s):

Paul Stevens

Keyword(s):

Economic Development ◽

Global Economy ◽

Oil And Gas ◽

Primary Energy ◽

Oil And Gas Producers ◽

The Future ◽

History Of ◽

Factor Inputs ◽

The Impact

This chapter is concerned with the role of oil and gas in the economic development of the global economy. It focuses on the context in which established and newer oil and gas producers in developing countries must frame their policies to optimize the benefits of such resources. It outlines a history of the issue over the last twenty-five years. It considers oil and gas as factor inputs, their role in global trade, the role of oil prices in the macroeconomy and the impact of the geopolitics of oil and gas. It then considers various conventional views of the future of oil and gas in the primary energy mix. Finally, it challenges the drivers behind these conventional views of the future with an emphasis on why they may prove to be different from what is expected and how this may change the context in which producers must frame their policy responses.

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NLRP7 Promotes Choriocarcinoma Growth and Progression through the Establishment of an Immunosuppressive Microenvironment

Cancers ◽

10.3390/cancers13122999 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2999

Author(s):

Deborah Reynaud ◽

Roland Abi Nahed ◽

Nicolas Lemaitre ◽

Pierre-Adrien Bolze ◽

Wael Traboulsi ◽

...

Keyword(s):

Immune Response ◽

Tumor Cells ◽

Major Gene ◽

Critical Role ◽

Orthotopic Model ◽

Independent Manner ◽

Maternal Immune Response ◽

The Impact

The inflammatory gene NLRP7 is the major gene responsible for recurrent complete hydatidiform moles (CHM), an abnormal pregnancy that can develop into gestational choriocarcinoma (CC). However, the role of NLRP7 in the development and immune tolerance of CC has not been investigated. Three approaches were employed to define the role of NLRP7 in CC development: (i) a clinical study that analyzed human placenta and sera collected from women with normal pregnancies, CHM or CC; (ii) an in vitro study that investigated the impact of NLRP7 knockdown on tumor growth and organization; and (iii) an in vivo study that used two CC mouse models, including an orthotopic model. NLRP7 and circulating inflammatory cytokines were upregulated in tumor cells and in CHM and CC. In tumor cells, NLRP7 functions in an inflammasome-independent manner and promoted their proliferation and 3D organization. Gravid mice placentas injected with CC cells invalidated for NLRP7, exhibited higher maternal immune response, developed smaller tumors, and displayed less metastases. Our data characterized the critical role of NLRP7 in CC and provided evidence of its contribution to the development of an immunosuppressive maternal microenvironment that not only downregulates the maternal immune response but also fosters the growth and progression of CC.

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THU0433 TREATMENT WITH PEGLOTICASE IMPROVES HEPATIC FIBROSIS ESTIMATED BY FIBROSIS-4 INDEX IN SUBJECTS WITH CHRONIC REFRACTORY GOUT

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.2360 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 454.1-454

Author(s):

N. Schlesinger ◽

A. Yeo ◽

P. Lipsky

Keyword(s):

Liver Disease ◽

Linear Regression ◽

Rank Order ◽

Linear Regression Analysis ◽

Area Under The Curve ◽

Serum Urate ◽

Complete Analysis ◽

Alcoholic Fatty Liver ◽

Significant Difference ◽

The Impact

Background:Hyperuricemia is associated with non-alcoholic fatty liver disease (NAFLD)1,2, but the relationship to fibrosis remains uncertain3. Moreover, it is not known whether lowering serum urate will affect the course of NAFLD. The availability of data from two randomized trials of pegloticase, a pegylated recombinant mammalian uricase, that profoundly decreases serum urate afforded the opportunity to test the hypothesis that lowering urate might improve NAFLD.Objectives:To determine whether treatment of chronic refractory gout patients with pegloticase was associated with improvement in NAFLD determined by Fibrosis 4 index (Fib4).Methods:Databases from patients with chronic refractory gout who participated in two randomized 6 month clinical trials (RCTs) of pegloticase were analyzed4. Sub-sets who had persistent urate lowering to levels <1 mg/dL in response to biweekly pegloticase (Responders, n=36) were compared to those who received placebo (n=43). Since liver biopsy information was not available on these subjects, we relied on Fib4, a validated non-invasive estimate of liver fibrosis in a variety of liver diseases5,6calculated from measurements of AST, ALT, platelet count and age (Age x AST/platelets x √ALT). A Fib4 value of 1.3 is an indication that further evaluation of liver disease is warranted.Results:At baseline, the mean Fib4 values were 1.40 ± 0.86 in pegloticase responders and 1.04 ± 0.53 in subjects receiving placebo. As shown in figure 1, subjects receiving placebo exhibited a change of 0.26 ± 0.41 in the Fib4 score over the six months of the RCTs compared with 0.13 ± 0.62 in the pegloticase responders (p=0.048; by linear regression). When only the subjects with a Fib4 value > 1.3 were considered, a significant difference in the change in the Fib4 values over the 6 months of the trial between pegloticase responders and those receiving placebo was also observed (-0.15 ± 0.67 vs 0.37 ± 0.42, p=0.004, by linear regression). The correlations between serum urate area under the curve (AUC) over the 6 months of the trial and the change in Fib4 value was rs=0.33, p=0.0.0004 (Spearman rank-order correlation coefficient). Finally, multiple linear regression analysis indicated serum urate AUC (as a surrogate measure for group) is the main contributor to the change in Fib4 (p=0.018 by linear regression).Conclusion:The data are consistent with the conclusion that persistent lowering of serum urate had a significant impact on Fib4 levels, implying a possible effect on the course of NAFLD. The results support a more complete analysis involving biopsy examination of the impact of urate on liver inflammation and fibrosis.References:[1]Yang C et al. PlosOne2017; 12:e0177249[2]Jaruvongvanich V et al. Eur J Gastroenterol Hepatol 2017; 29:1031[3]Jaruvongvanich V et al. Eur J Gastroenterol Hepatol 2017; 29:694[4]Sundy JS, et al. JAMA. 2011; 306 (7):711-20[5]Sterling RK et al. Hepatol 2006; 43:1317[6]Shah AG et al. Clin Gastroenterol Hepatol 2009;7:1104Disclosure of Interests: :Naomi Schlesinger Grant/research support from: Pfizer, Amgen, Consultant of: Novartis, Horizon Therapeutics, Selecta Biosciences, Olatec, IFM Therapeutics, Mallinckrodt Pharmaceuticals, Anthony Yeo Employee of: Horizon Therapeutics, Peter Lipsky Consultant of: Horizon Therapeutics

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