Venous Thrombotic Events (VTEs) in Acute Myeloid Leukemia (AML) Patients During Induction Therapy (IT): Identifying Risk Factors, and Safety of Using Anticoagulation Therapy

Abstract Abstract 3148 Background: VTEs are common complications in association with IT which may cause additional morbidity and mortality in AML patients. However, treating patients with AML is challenging because of the cytopenias due to chemotherapy and the high risk for bleeding during IT. This study investigates frequency, risk factors, and safety of using anticoagulation (AC) therapy for VTEs during IT. Method: We retrospectively reviewed the charts of AML patients who received IT between January, 2000-January, 2011 at William Beaumont Health Systems. Exclusion criteria included a documented personal history of inherited thrombophilia. Data retrieved included the following: patient characteristics, leukemia subtype, cytogenetic risk, location of the VTEs, FLT3 mutations, IT regimen used (cytarabine and anthracycline regimens or hypomethylating agents), AC therapy, bleeding complications, mortality related to AC therapy. All patients who received AC were initially treated with regular intravenous unfractionated heparin or subcutaneous low molecular weight heparin. Patients were subsequently started on oral warfarin during the first 10 days of the initial treatment with a targeted INR of 2.0–3.0. Results: We found 48 of 363 (13.2%) AML patients developed VTEs during IT. Of those patients, 56.3 % were female. The VTEs occurred most frequently in upper extremities (58%) and were catheter-related. Other locations for VTEs included lower extremities (21%), pulmonary embolism (15%), and mesenteric or portal veins (6%). We note that 41 patients (87%) received AC therapy. Of these, three patients (7.3%) had bleeding complications and no AC therapy-related deaths were observed. When the three cytogenetic risk groups were compared, there was no difference in the incidence of VTEs (good vs intermediate vs poor). Patients with FLT 3 mutations, however, had a significant higher incidence of VTEs when compared to patients without FLT3 mutations (55.3% vs 12% p <0.001). Finally, patients treated with cytarabine + anthracycline regimen had a higher incidence of VTEs compared to patients treated with hypomethylating agents (81.3% vs 4.2 % p <0.001.) Conclusions: We found that 13% of AML patients developed VTEs during IT, most commonly in upper extremities and were catheter-related. The risk for VTEs was markedly increased in patients with FLT3 mutations. Furthermore, using a cytarabine + anthracycline regimens carried a higher risk for VTEs when compared to regimens using a hypomethylating agents. Finally, using AC therapy during IT is relatively safe and is associated with low risk of bleeding complications. Disclosures: No relevant conflicts of interest to declare.

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Playing-Related Musculoskeletal Disorders, Risk Factors, and Treatment Efficacy in a Large Sample of Oboists

Frontiers in Psychology ◽

10.3389/fpsyg.2021.772357 ◽

2022 ◽

Vol 12 ◽

Author(s):

Heather M. Macdonald ◽

Stéphanie K. Lavigne ◽

Andrew E. Reineberg ◽

Michael H. Thaut

Keyword(s):

Risk Factors ◽

Musculoskeletal Disorders ◽

Risk Groups ◽

The Body ◽

Upper Extremities ◽

Online Questionnaire ◽

Severe Injuries ◽

Instrument Choice ◽

Linear Relationships ◽

The Right

ObjectivesDuring their lifetimes, a majority of musicians experience playing-related musculoskeletal disorders (PRMD). PRMD prevalence is tied to instrument choice, yet most studies examine heterogeneous groups of musicians, leaving some high-risk groups such as oboists understudied. This paper aims to (1) ascertain the prevalence and nature of PRMDs in oboists, (2) determine relevant risk factors, and (3) evaluate the efficacy of treatment methods in preventing and remedying injuries in oboe players.MethodsA 10-question online questionnaire on PRMDs and their treatments was completed by 223 oboists. PRMDs were compared across gender, weekly playing hours, career level, age, and years of playing experience.ResultsOf all respondents, 74.9% (167/223) reported having had at least one PRMD in their lifetime. A majority of these injuries (61.9% of all respondents) were of moderate to extreme severity (5 or higher on a scale of 1 to 10). Females (mean = 5.88) reported significantly more severe injuries than males. No significant effects of career level (i.e., professional vs. student vs. amateur), age, or years of playing experience were observed. We found significant non-linear relationships between weekly playing hours and PRMD prevalence and severity. Injuries were most commonly on the right side of the body, with the right thumb, wrist, hand, and forearm being most affected in frequency and severity. Of those injuries for which recovery information was provided, only 26.1% of injuries were “completely recovered.” The perceived effectiveness of a few treatments (physical therapy, rest, stretching, occupational therapy, massage) tended to be ranked more highly than others.ConclusionThe oboists in this study experienced high rates of PRMD, particularly in the right upper extremities. Females and those playing 7-9 and 16-18 h per week reported a significantly higher severity of injuries than other groups.

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Orale Antikoagulation bei chronischer Beinischämie

VASA ◽

10.1024/0301-1526.30.2.83 ◽

2001 ◽

Vol 30 (2) ◽

pp. 83-88

Author(s):

U. Mueller-Kolck

Keyword(s):

Oral Anticoagulation ◽

Clinical Decision Making ◽

Risk Model ◽

Anticoagulation Therapy ◽

Limb Ischemia ◽

Risk Groups ◽

Clinical Decision ◽

Arterial Disease ◽

Bleeding Complications ◽

Minor Bleeding

This review article summarizes clinical data on adjuvant long-term oral anticoagulation therapy (OAC) of peripheral arterial disease (PAD). It analyzes the underlying risk model of oral anticoagulation. Definitions of runoff patterns, of major and minor bleeding complications, of predictors of major bleedings as well as a classification of patient risk groups are described. The indication for OAC treatment of chronic limb ischemia remains still due to an individual decision. Clinical decision making is facilitated by the risk model. Improved oral anticoagulation control results in fewer bleeding complications. Studies on patient weekly self-testing and self-dosing which support this hypothesis are reviewed in the context of adjuvant OAC therapy.

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Frequency and Determinants of Thrombotic and Bleeding Complications in Ph Negative Myeloproliferative Neoplasms (MPN): The Role of Adamts-13 and VWF Activities in an Italian Cohort 0f 88 Well Characterized Patients

Blood ◽

10.1182/blood.v120.21.3369.3369 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3369-3369

Author(s):

Augusto B. Federici ◽

Maria C Carraro ◽

Antonella Lattuada ◽

Chiara Vanelli ◽

Veronica Sciumbata ◽

...

Keyword(s):

Risk Factors ◽

Multivariate Analysis ◽

Conflicts Of Interest ◽

Myeloproliferative Neoplasms ◽

Thrombotic Event ◽

Previous History ◽

Bleeding Complications ◽

Post Surgery ◽

Bleeding Episodes

Abstract Abstract 3369 Background: Patients with Ph-negative Myeloproliferative Neoplasms (MPN) such as Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF) can be exposed during the course of these MPN to thrombotic and bleeding complications, with increased morbidity and mortality. Age, previous history of thrombosis, increased White Blood Cell (WBC) and Jak2 allele burden have been proposed as risk factors for Venous (VTE) and Arterial (ATE) thromboses while bleeding has been previously associated with abnormalities of the von Willebrand factor (VWF). Aims: To investigate any significant role of ADAMTS-13 and VWF activities in the thrombotic and bleeding complications observed in a small but well characterized cohort of MPN patients. Patients and Methods: 88 consecutive patients were diagnosed at the Hematology and Transfusion Medicine Division, L.SACCO University Hospital of Milan, according to WHO criteria. Patients signed an informed consent to participate in this clinical study with a protocol approved by local IRB and they showed MPN type (%), mean age (range), gender M/F and Jak2 positivity (%) as follows: PV[n=42 (48%), 68 (36–86), 18/24; 85.7%]; ET [n=34 (38%), 66 (30–93), 10/24, 61.7%]; PMF [n=12 (14%), 67 (37–88), 7/5, 58%]. Thrombotic and bleeding episodes were recorded and managed from the time of diagnosis and associated with the use of aspirin (ASA) and of other MPN therapies. Among additional lab parameters, plasmatic ADAMTS-13 and VWF activities were also measured at enrolment as endothelial/platelet marker. These activities were assayed with Technozym ADAMTS-13 activity (Technoclone GmbH, Austria), Innovance VWF-GPIb activity (Siemens AG, Germany) and HemosIL-VWF antigen (Instrumentation Laboratory, USA). Multimeric analyses were also tested using very sensitive intermediate SDS-agarose gel electrophoresis. Statistical analyses were performed by SPSS-17.2. Results: 59/88 (67%) patients did not show any thrombotic or bleeding complications during the 6-year follow-up. In these cases mean (range) values of VWF:GPIb and VWF:Ag were 104 (29–202) and 133 (52–288) U/dL while ADAMTS-13 was 102 (63–143). 20/88 (23%) cases showed at least one thrombotic event (13ATE/7VTE): AMI (6), STROKE (6), TIA (2), PE (1), DVT (7). Patients with thromboses showed relatively higher values VWF:GPIb and lower ADAMTS-13 and this was confirmed in multivariate analysis especially for ET [VWF:GPIb=135 (61–237) U/dL, p=0.004 and ADAMTS-13=89(62–134), p=0.009]. Major bleeding episodes mainly mucosal (5 gastrointestinal, 3 post-surgery, 1 severe menorrhagia) requiring blood transfusions or hysterectomy were observed in 9/88 (10%) patients. At the multivariate analysis, major bleedings were significantly associated with lower VWF:GPIb [68 (25–111) U/dL, p=0.022), lower VWF:Ag [93 (35–146) U/dL, p=0.016] and to the ASA intake (p=0.006). Most of these bleeders showed also a relative loss of the highest molecular weight multimers. Conclusions: Based on these observations, we confirm that thrombotic events in MPN may certainly have multiple risk factors: however, lower ADAMTS-13 and higher VWF activities might play a role as additional risk factors especially in ET. Conversely, lower levels of VWF with loss of the largest multimers are important risk factors for bleeding in MPN especially in patients treated with ASA. Disclosures: No relevant conflicts of interest to declare.

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Absence of High-Dose Consolidation Courses and Low Numbers of Allogeneic HSCTs Did Not Affect Overall Optimistic Results in B-Cell Precursor Ph-Negative Adult ALL Patients Treated By Non-Intensive but Non-Interruptive ALL-2009 Protocol: Data of the Russian ALL Study Group

Blood ◽

10.1182/blood.v126.23.2497.2497 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2497-2497

Author(s):

Elena N. Parovichnikova ◽

Vera V. Troitskaya ◽

Andrey Sokolov ◽

Galina Kliasova ◽

Larisa A. Kuzmina ◽

...

Keyword(s):

Risk Factors ◽

High Risk ◽

Conflicts Of Interest ◽

Univariate Analysis ◽

Normal Karyotype ◽

Risk Groups ◽

High Dose ◽

Late Response ◽

Allogeneic Hsct ◽

Blast Cells

Abstract Introduction It is postulated that the improvement in the overall treatment outcome in adult Ph-negative ALL came from the implementation of more aggressive pediatric-like protocols and higher portion of allogeneic HSCT. Here we report the results of the adult (15-55 yy) Ph-negative ALL protocol based on the opposite approaches: less intensive but non-interruptive treatment with low numbers of allo-HSCT. The study is registered on the ClinicalTrials.gov public site; NCT01193933. Patients and Methods The ALL-2009 is based on: (1) the replacement of prednisolone (Pdn) 60 mg/m2 with dexamethazone (Dexa) 10 mg/m2 if blast cells are >25% in b/m after prephase (7d); (2) de-intensified but non-interruptive 5 months induction/consolidation treatment (5 wks prd/dexa with 3 instead of 4 dauno/vncr pulses, 4 weeks of 6MP with 5 L-asp, 2 instead of 4 ARA-C blocks, 1 instead of 2 Cph injections during induction; induction-like 3 consolidations for 3wks, 2wks, 4wks-continuously without intervals), followed by (3) 2 late (at 6 mo) intensifications- with 1 day HD MTX and with 1 d HD ARA-C, both with L-asp and 3 ds dexa and (4) 2-yrs continuous 6MP/MTX maintenance with doses modification according to myelosuppression with monthly 3-days dexa/vncr/L-asp pulses (∑ L-asp = 590.000 IU/m2). The protocol was identical for all risk groups. Allo-HSCT was indicated only for extremely high-risk BCP-ALL (t(4;11),L>100). No central MRD monitoring was performed. Since Apr 2009 till June 2015 20 centers had recruited 168 BCP-Ph-negative ALL pts with a median age 28 years (15-54), 84f/84 m. Full cytogenetics was available in 67,3% (n=113), 43,4% of them (n=49) had normal karyotype (NK), 10% (n=9%) had no mitosis, 47,6% (n=54) - different abnormalities (hypoploid-1, hyperploid-12, t(11q23)/MLL-8, del11q23-2, t(1;19)-2, t(12;21)-1;others-28). 26,7% of pts (n=45) were in the standard risk (SR) group (WBC <30, EGIL BII-III, LDH < 2N; no late CR; t(4;11)-negative), 56,5% (n=95) - in the high risk (HR) group (WBC >30; EGIL BI, LDH > 2N; late CR; t(4;11)-positive), 28 patients (n=16,8%) were not qualified by the risk. The analysis was performed in June 2015. 158 pts were available for analysis. Results CR rate in 158 available for analysis pts was 87,7% (n=139), induction death occurred in 9,1% (n=14), resistance was registered in 3,2% (n=5). The majority of CR pts (87,8%) achieved it after prephase (12,2%, n=17) and the 1st phase of induction (75,6%, n=105). Late responders constituted 12,2% (n=17). Allogeneic BMT was performed only in 9 of 144 patients who survived induction (6,2%). Totally 31 pts (22,3%) had relapsed. At 60 mo OS for the whole group constituted - 50%, DFS - 51.3%. In a univariate analysis among various risk factors (age <> 30y, initial risk group, WBC, LDH, immunophenotype, late response >35d, PRD resistance) age (>30 y) became statistically significant for OS, DFS and relapse probability (RP) (pic.1), abnormal karyotype - for DFS (30% vs 68%, p=0,04) and RP (42% vs 19%, p= 0,04). In a multivariate analysis no common risk factors were significant. Conclusions Our data demonstrate that the proposed treatment approach is rather effective. We believe that constant non-interruptive treatment without intensive highly myelosuppressive consolidation courses and high portion of allogeneic HSCT may become an alternative and reproducible approach in adult Ph-negative ALL, though we have to stress that it should be very strict compliance of the pts to the protocol. All pts, mostly from the region hospitals who refused prolonged and constant treatment (~5%), relapsed. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

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Comparison of Prognostic Models for Autologous Hematopoietic Stem Cell Transplantation (AHCT) for Relapsed Hodgkin Lymphoma.

Blood ◽

10.1182/blood.v114.22.1215.1215 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1215-1215

Author(s):

Theresa Hahn ◽

Philip L. McCarthy ◽

Jeanette Carreras ◽

Mei-Jie Zhang ◽

Hillard M. Lazarus ◽

...

Keyword(s):

Risk Factors ◽

High Risk ◽

Risk Group ◽

Patient Characteristics ◽

Risk Groups ◽

High Risk Group ◽

Prognostic Models ◽

Brier Score ◽

Model Risk ◽

Resistant Disease

Abstract Abstract 1215 Poster Board I-237 AHCT is standard therapy for relapsed or refractory Hodgkin Lymphoma (HL). Prognostic risk score models for HL patients receiving AHCT aim to predict post transplant outcomes based on factors measured at the time of AHCT. We performed a comparison of 3 such models from Dana-Farber Cancer Institute (DFCI), Roswell Park Cancer Institute (RPCI) and University of Minnesota (UMinn) in an independent multicenter dataset of 597 relapsed or refractory HL patients receiving AHCT from 1996-2004, reported to the CIBMTR by 150 centers. Patient characteristics at diagnosis: 60% male, 52% stage III-IV, 59% B symptoms, 33% extranodal disease. Patient characteristics at AHCT: median (range) age 32 (7-74) years; 73% KPS≥90; 19% with extranodal disease; 39% had ≥3 prior chemotherapy regimens; 18% had resistant disease; median (range) time from diagnosis to AHCT 22 (3-238) months. High dose therapy regimens were primarily BEAM (72%) or CBV (12%) with 91% receiving peripheral blood stem cells. Progression free (PFS) and overall survival (OS) estimates at 3 years were 59% and 72%, respectively. The 3 prognostic models each measured 3 prognostic variables at AHCT that were combined into a prognostic score and assigned to a risk group (low, intermediate, high). The DFCI model risk factors were: chemo-resistant disease, KPS<90, ≥1 extranodal site; with corresponding risk groups low (0 factors), intermediate, (1 factor) and high (2-3 factors). The RPCI model risk factors were: chemo-resistant disease, KPS<90, ≥3 prior regimens with risk groups low (0-1 factor) and high (2-3 factors). The UMinn model risk factors were: chemo-resistant disease, B symptoms, not in CR at BMT with risk groups low (0-1 factor), intermediate (2 factors) and high (3 factors). Only 1 factor (chemo- resistant disease) was included in all 3 models. We quantified the predictive capabilities of the models using Brier score (B) and R2 for each model. Brier score as a function of time is a measure of the accuracy of the model calculated as the average deviation between the predicted probabilities and the actual outcome. R2 measures goodness of fit based on the observed vs. predicted difference in the regression model. A smaller Brier score and a larger R2 indicate better predictive performance. The models are compared in Table 1 with regards to prediction of 36 month PFS: Table 1 DFCI Model RPCI model UMinn model Brier Score 0.2344 0.2360 0.2394 R2 3.24% 2.57% 1.17% The high risk group PFS (Figure 1) was similar for the DFCI and RPCI models but the DFCI model separated a low and intermediate risk group which were not significantly different from each other. The UMinn model high risk group had a higher PFS than either of the other 2 models' high risk group and the intermediate group in this model was not significantly different from the high risk group. The relative incremental change in R2 was 26% higher for the DFCI than the RPCI model and 120% higher for the RPCI than the UMinn model. From the B and R2 values, the DFCI model had marginal superiority over RPCI model while both performed better than the UMinn model. Newer prognostic systems incorporating other prognostic variables are needed to distinguish lower and intermediate risk patients. Figure 1 Figure 1. Disclosures: No relevant conflicts of interest to declare.

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Outcomes Of Relapse Of AML Post Allogeneic Transplantation In The Era Of Hypomethylating Agents: An Analysis Of 162 Allogeneic Transplants From a Single Center

Blood ◽

10.1182/blood.v122.21.2086.2086 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2086-2086

Author(s):

Justin LaPorte ◽

Xu Zhang ◽

Zaamin Hussain ◽

Stacey Brown ◽

Connie A. Sizemore ◽

...

Keyword(s):

Conflicts Of Interest ◽

Patient Characteristics ◽

Hypomethylating Agents ◽

Term Survival ◽

Long Term Outcome ◽

Post Transplant ◽

Hypomethylating Agent ◽

One Year ◽

Relapse Therapy

Abstract Allogeneic hematopoietic cell transplantation (allo-HCT) can be curative in many patients with intermediate and high risk AML. However, post-transplant relapse remains an important cause of treatment failure. Patients with AML who relapse post allo-HCT typically have a dismal prognosis with limited therapeutic options. Hypomethylating agents alone are increasingly being used to treat AML in patients who are elderly or otherwise unfit for chemotherapy. They may also be used for maintenance/consolidation following induction chemotherapy. The activity and minimal toxicity associated with hypomethylating agents makes them potentially useful in the management of AML patients who relapse following allo-HCT. However, their use in this setting has not been well studied. We assessed one hundred and sixty two consecutive patients who underwent a first allo-HCT for AML at our center during a period when hypomethylating agent therapy was widely available (February 2005 through May 2013). Patient characteristics were: median age, 53 (range18-74); M=75, F=87; donor-matched-sibling (MRD) =59, matched-unrelated (MUD) =67, HLA-haploidentical (Haplo) =36; ablative conditioning=98, RICT/NST=64; PBSC=142, BM=20; CIBMTR risk category- high=53, intermediate=28, low=74, unknown=7. Post-relapse therapy was determined by the attending physician and patient preference. Patient characteristics, post-relapse therapy, GVHD and survival were prospectively collected as part of our comprehensive HCT database. With a median follow-up for surviving patients of 22.4 months, relapse of AML post-allo-HCT was experienced by fifty-five patients (22 MRD, 24 MUD, 9 Haplo; cytogenetic risk 23 poor, 31 intermediate, 1 unknown) at a median of 113 days (range 25-1106) post-transplant. Thirty-four patients (62%) were treated with a hypomethylating agent post-relapse (17 azacitidine, 10 decitabine, 7 both) (12 hypomethylating agent alone, 11 combined with chemotherapy, 11 sequentially with chemotherapy). Median number of cycles of hypomethylating agent therapy was 2 (range 1-9). Of the 23 patients that received at least 2 cycles of hypomethylating agents, 14 achieved CR or CRi. Donor lymphocyte infusions (DLI) were administered in 15 of the 55 relapsed patients and 16 patients received a second allo-HCT. Estimated Kaplan-Meier probability of post-relapse survival (PRS) at 6, 12 and 24 months post-relapse for all patients was 53%, 36% and 19% and was not significantly different for patients who developed any versus no GVHD following post-relapse therapy. However, PRS at 6 and 12 months was 62% (95% CI 43-76%) and 38% (95% CI 22-54%) in patients who received hypomethylating agent therapy post-relapse versus 38% (95% CI 18-58%) and 33% (95% CI 15-53%) in patients who did not (p=0.063 Gehan’s test). PRS was not different between the two groups at 24 months. Survival > 1 year post relapse was achieved in 19 of 55 relapsing patients (35%). Of these patients, 9 received a second allo-HCT, 9 received DLI and 12 were treated with a hypomethylating agent. At the time of writing 6 patients are alive and in complete remission at a median of 49 months (10-72) following relapse. Of the 6 patients (5 MRD, 1 MUD; cytogenetic risk 2 poor, 4 intermediate), 4 received hypomethylating agents, 3 received a second transplant, 1 received DLI, and 4 have active GVHD. These data demonstrate that relapse post allo-HCT remains a major obstacle to long-term survival in patients transplanted for AML. Hypomethylating agents can be used in the majority of relapsed patients in this setting and appear effective in inducing responses. The use of hypomethylating agents may be associated with a prolongation of early post-relapse survival although it does not appear to increase survival beyond one year post-relapse. Survival beyond one year post-relapse can be achieved even without a second allogeneic transplant, but is only achieved in a minority of relapsing patients. Combination of therapy with hypomethylating agents and novel agents may be necessary to impact long-term outcome. Disclosures: No relevant conflicts of interest to declare.

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New Insights Into Factor XI Function: From Biochemistry to Animal Models

Blood ◽

10.1182/blood.v116.21.sci-20.sci-20 ◽

2010 ◽

Vol 116 (21) ◽

pp. SCI-20-SCI-20

Author(s):

David Gailani

Keyword(s):

Animal Models ◽

Arterial Thrombosis ◽

Conflicts Of Interest ◽

Thrombus Formation ◽

Anticoagulation Therapy ◽

Factor Ix ◽

Bleeding Complications ◽

Contact Activation ◽

Factor Xi ◽

Deficient Mice

Abstract Abstract SCI-20 Factor XI (fXI) is the zymogen of an enzyme (fXIa) that contributes to blood coagulation through activation of factor IX (fIX). FXI has structural and mechanistic features that distinguish it from the vitamin K-dependent proteases of coagulation. The protein is a dimer of identical 80 kDa subunits, each containing four apple domains (A1-A4) that form a platform at the base of the trypsin-like protease domain. The apple domains contain binding sites for fIX, platelet receptors, and high molecular weight kininogen. FXI is converted to fXIa by cleavage of a single bond on each subunit, unmasking exosites required for fIX binding. Conversion of fXI to fXIa proceeds through an intermediate with only one activated subunit (1/2-fXIa). 1/2-fXIa, and monomeric forms of fXIa, activate fIX in a manner similar to fully activated fXIa, indicating each subunit functions as a complete enzyme. The importance of the dimeric structure of fXI is not clear at this point. It may facilitate activation, or allow fXIa to bind simultaneously to fIX and a surface (a platelet for example) at a wound site. Congenital fXI deficiency is associated with a variable propensity to bleed excessively after trauma to certain tissues. Symptoms are usually milder than in fIX deficiency (hemophilia B), and many affected individuals are asymptomatic. In the cascade-waterfall model of coagulation, fXI is activated by factor XIIa (fXIIa) during a process called contact activation. However, current models often omit contact activation, because fXII deficiency is not associated with abnormal hemostasis. Thrombin activates fXI, providing an explanation for normal hemostasis in fXII deficiency. In contrast to its modest role in hemostasis, fXI may serve an important role in thromboembolic diseases. High fXI levels are a risk factor for arterial and venous thrombosis in humans; and deficiency or inhibition of fXI confers resistance to thrombosis in animal models. FXI deficient mice are as resistant to arterial thrombosis as fIX deficient mice, or wild type mice treated with a supra-therapeutic dose of heparin. In arterial thrombosis models in mice, rabbits and baboons, lack of fXI activity results in instability of platelet rich thrombi, preventing vessel occlusion. FXI deficiency also prolongs survival and lessens the severity of disseminated intravascular coagulation in a mouse polymicrobial sepsis model. Interestingly, mice with combined deficiencies of fXI and fIX are more resistant to arterial thrombus formation than mice deficient in only one of these proteins, indicating fXIa has proteolytic targets other than fIX. The observation that fXII deficient mice are resistant to arterial thrombosis suggests that activation of fXI by contact activation, while unnecessary for hemostasis, contributes to thrombin generation in some pathologic processes. If the observations in mice apply to thromboembolism in humans, then fXIa and/or fXIIa may be excellent targets for novel antithrombotic strategies. In contrast to drugs such as heparin and warfarin, agents targeting fXIa or fXIIa would likely be associated with relatively few bleeding complications, and could be employed in clinical situations where anticoagulation therapy is currently contraindicated. Disclosures: No relevant conflicts of interest to declare.

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Role Of Hypomethylating Agents For Patients With Lower-Risk Myelodysplastic Syndrome Defined By IPSS and IPSS-R

Blood ◽

10.1182/blood.v122.21.2782.2782 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2782-2782

Author(s):

Joon Ho Moon ◽

Sang Kyun Sohn ◽

Jae Sook Ahn ◽

Yeo-Kyeoung Kim ◽

Hyeoung Joon Kim ◽

...

Keyword(s):

Myelodysplastic Syndrome ◽

Lower Risk ◽

Conflicts Of Interest ◽

Risk Groups ◽

International Prognostic Scoring System ◽

Hypomethylating Agents ◽

Risk Patients ◽

Very High ◽

Prognostic Power

Abstract Background International Prognostic Scoring System (IPSS) is commonly used to distinguish various subgroups of myelodysplastic syndrome (MDS) patients with different prognosis and to make a therapeutic decision. However, the classic IPSS, defining lower-risk as low and intermediate-1 IPSS, seems to be insufficient to discriminate the prognostic groups of lower-risk MDS. Recently, IPSS was updated into the revised score (IPSS-R) to refine the IPSS by reassessing the major predictive features of MDS. The hypomethylating agents (HMA) are usually recommended for patients with lower-risk MDS who is not responsive to other therapies. However the role of HMA for the patients with lower-risk IPSS are still on debate. This study was conducted to find the rationale to treat HMA for the patients with lower-risk IPSS and to know whether IPSS-R further discriminate the prognosis of patients treated with HMA. Methods The data of 334 patients diagnosed with MDS lower-risk defined by IPSS after Jan 2006 were retrospectively reviewed. Lower-risk IPSS was revised into IPSS-R to know whether it could further discriminate the prognosis of this group of patients. The prognosis of lower-risk by IPSS and IPSS-R were analyzed in terms of overall survival (OS) and prognostic power was calculated with time-dependent Cox-hazard models. To define the role of HMA for patients with lower-risk IPSS, we categorized the lower risk patients into No-HMA group, early HMA group (HMA within 2 mo.), and late HMA group (HMA after 2 mo). Results Out of 334 lower-risk patients (39 low and 295 intermediate-1), 195 patients (58.4%) were treated with HMA (azacitidine 163, decitabine 32). Median time to HMA treatment was 43 days (range 0-1778 days). 3yr-OS rate was not significantly different between HMA group (43.1¡¾4.2%) and non-HMA group (62.3¡¾5.9%) (p=0.099). Early HMA treatment (3yr-OS 36.4¡¾5.4%) didn't show survival benefits compared to late HMA group (54.6¡¾6.3%) or no-HMA group (62.3¡¾5.9%) (p=0.003). Plus, HMA response (CR/PR/HI) didn't guarantee OS benefits: 3yr-OS of 45.2¡¾7.4% in responders (CR/PR/HI, n=74) and 43.4¡¾5.0 in non-responders (SD/PD, n=121) (p=0.239). Among 39 patients with IPSS low, 11 patients (28.2%) were revised into IPSS-R very low, 24 (61.5%) into low, 3 (7.7%) into intermediate, and 1 (2.6%) into high. Among 295 patients with IPSS intermediate-1, 4 patients (1.4%) were revised into IPSS-R very low, 84 (28.5%) into low, 133 (45.1%) into intermediate, 71 (24.1%) into high and 3 (1.0%) into very high. IPSS-R could further discriminate the IPSS lower-risk patients with regard to OS: 3yr-OS rates of 100% in very low, 64.5¡¾5.9% in low, 46.1¡¾5.5% in intermediate, 26.1¡¾6.6% in high, and 0% in very high (p<0.001). The survival benefits of HMA for lower risk groups (very low and low) defined by IPSS-R (n=123) was not defined in the current study, where 3yr-OS was 83.8¡¾6.4% in no-HMA group (n=60) vs. 60.5¡¾7.1% in HMA group (n=63) (p=0.198). Conclusion The prognosis of the patients with lower-risk IPSS (low and intermediate-1) were successfully refined by IPSS-R. The IPSS intermediate-1 risk was heterogeneous group, which subdivided into very low to very high by IPSS-R. However, the beneficial effect of HMA for patients with lower-risk MDS, defined by IPSS (low and intermedite-1) and IPSS-R (very low and low), should be elucidated in the future studies. Disclosures: No relevant conflicts of interest to declare.

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P44 Liver injury in children on long-term low dose methotrexate

Rheumatology ◽

10.1093/rheumatology/kez416.011 ◽

2019 ◽

Vol 58 (Supplement_4) ◽

Cited By ~ 1

Author(s):

Chayarani Kelgeri ◽

Somashekhar HR ◽

Rachel Brown ◽

Eslam Al-Abadi ◽

Girish Gupte

Keyword(s):

Risk Factors ◽

Liver Injury ◽

Liver Biopsy ◽

Conflicts Of Interest ◽

Total Duration ◽

Patient Characteristics ◽

Base Line ◽

Liver Biopsies ◽

Dose Modifications ◽

Elevated Transaminases

Abstract Background Liver injury is known in patients on methotrexate (MTX). We retrospectively reviewed records of patients who had liver biopsy for suspected MTX induced liver injury and identify risk factors if any. Methods Children (≤ 16 years) referred to us from 2002 to 2015 with suspected MTX induced liver injury were identified and data related to their underlying diagnosis, biochemical parameters, Body Mass Index (BMI), dose and duration of MTX at the time of liver biopsy, use of concomitant drugs, duration and other causes for elevated transaminases, liver histology including clinical decisions to continue or stop MTX were extracted from the data base. All the liver biopsies were re-analysed for this study and scored using the Roenigk classification by a single histopathologist blinded to patient characteristics. Results Seventeen liver biopsies were performed in 14 children (3 had repeat biopsies) who were referred for frequent/persistent transaminitis (> 2 times upper limit normal). The base line bilirubin, transaminases and synthetic liver function were normal in all prior to MTX therapy. All were on MTX at the time of biopsy except two who had been off the drug for 3 and 8 months following frequent transaminitis. They had liver biopsy to guide reintroduction of MTX in their treatment regime. None of the patients had renal impairment, diabetes or underlying liver disease. Thirteen biopsies (82 %) had none (n = 6) to mild liver injury (n = 7) and were advised to continue MTX. Four biopsies (18%) showed significant liver injury (grade 3b and 4). Of these 3 patients were advised to stop MTX while one was advised to continue and repeat liver biopsy in 6 months. He however, stopped MTX soon thereafter. All biopsies of children (n = 3) with BMI ≥ 91st centile had liver damage. Two of thirteen biopsies with BMI < 91 centile had moderate-severe damage. No correlation was seen between the histologic findings or their severity with dose or duration of MTX, concomitant use of other drugs, severity/highest transaminase peak, total duration of transaminase abnormality, longest single episode of transaminase abnormality or frequency/number of peaks of abnormal transaminases. Of the 3 with repeat biopsies, fibrosis had progressed in 2, necessitating discontinuation of MTX in 1. Conclusion The finding of significant liver injury in our cohort is not entirely in keeping with previous paediatric studies which report non-significant fibrosis or cirrhosis. We could not identify any risk factors though children with BMI ≥ 91st centile seemed more likely to have liver injury. This finding is similar to adult studies implicating obesity as risk factor though it is difficult to draw definitive conclusions given the small size of our cohort. Other limitations include the retrospective nature of the study, bias as MTX dose modifications and referral were at the discretion of the rheumatologist and no information on alcohol intake in the teenagers. This study emphasises the need for careful monitoring to prevent severe fibrosis and cirrhosis. Conflicts of Interest The authors declare no conflicts of interest.

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Burden of Cardiovascular Events and Bleeding Is High in Myelodysplastic Syndromes

Blood ◽

10.1182/blood-2020-143319 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 34-35

Author(s):

Rakchha Chhetri ◽

Oisin Friel ◽

Monika M Kutyna ◽

Kathleen Pao Lynn Cheok ◽

Li Yan A Wee ◽

...

Keyword(s):

Risk Factors ◽

Antiplatelet Therapy ◽

Myelodysplastic Syndromes ◽

Anticoagulation Therapy ◽

Bleeding Complications ◽

Severe Thrombocytopenia ◽

Bleeding Events ◽

Platelet Counts ◽

Risk Of Bleeding ◽

Rbc Transfusion

Background: Myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) patients are older and suffer with cardiovascular (CV) diseases. Management of these patients with antiplatelet and anticoagulation therapy is challenging as thrombocytopenia can increase the risk of bleeding. Aim: To assess burden and CV disease related mortality, review of anticoagulant /antiplatelet therapy and bleeding complications in MDS and oligoblastic AML patients. Methods: Electronic medical records of 910 MDS and oligoblastic AML patients enrolled in the South Australian MDS (SA-MDS) registry were reviewed. CV risk factors, CV and bleeding events requiring or occurring during hospitalisation, anticoagulation and/or antiplatelet therapy information were collected. Platelet counts of <100, <50 and <20 (x109/L) were defined as mild, moderate and severe thrombocytopenia respectively. Severity of bleeding events was classified using modified International Society of Thrombosis and Hemostasis (ISTH) classification. MDS patients require regular RBC transfusion, hence fall in hemoglobin ≥20 gm/L or ≥2 units of RBC transfusion were not used for defining major bleeding. Results: At the time of MDS diagnosis, 72% (658/910) and 42% (386/910) patients had ≥1 and ≥2 CV risk factors. Twenty-five percent patients required hospitalization for CV events prior to the MDS diagnosis and their median OS was significantly poor compared to patients who did not have CV events (Figure 1A). During median follow up of 28 months after MDS diagnosis, 27.5% (251/910) patients were admitted with or developed CV events during hospitalization. In a Cox-regression analysis age, absolute monocyte count, CV risk factors and prior CV events were independent predictors of CV events following MDS diagnosis (Figure 1B). The most frequent CV events were arrhythmia (137/399; 34%), congestive cardiac failure (129/399; 32%), and ischemic heart disease (94/399; 23%). Atrial fibrillation (AF) contributed towards 78% (108/137) of all arrhythmias. 39% of AF occurred in the setting of infections and 12% patients died during the same hospitalization or were palliated. 89% of AF patients had a CHADS2VASc2 score ≥2, however only 30% (20/65) and 24% (16/65) events with available information were treated with anticoagulation and antiplatelet therapy respectively. While 60% (39/65) AF events did not receive antiplatelet or anticoagulation therapies. Four AF patients developed ischemic stroke following MDS diagnosis and five patients had stroke before MDS diagnosis and were subsequently diagnosed with AF. Importantly, 36% (34/94) AF patients developed 45 bleeding events. The frequency of bleeding events was not significantly different between patients treated with anticoagulation/antiplatelet therapy versus who were not treated (13.8% vs. 13.6%). Although, cumulative incidence of bleeding and CV events was similar at 29% and 28% at five-years (Figure 1C-D), only some patients had both events. Of the 387 patients, 39% (n= 152) and 39% (n=153) patients required hospitalization only for CV or bleeding events, while only 21% (82/387) required hospitalization for both bleeding and CV events. Identifying these three groups early is crucial to optimize their outcome. Of the 387 bleeding events, 88 (24%) were major and 296 (76%) were clinically relevant minor bleeding. Notably, 127, 47 and 15 bleeding events were gastrointestinal, intracranial and intraocular respectively. While 50% bleeding events occurred in the setting of moderate to severe thrombocytopenia, 19% and 31% of bleeding events occurred at platelet counts of >50-100 and >100x109/L respectively (Figure 1E). Details of anticoagulation/antiplatelet therapy were available for 66% (161/243) of bleeding events. Importantly, 76% of bleeding events occurred without anticoagulation and antiplatelet therapy, while 10% and 13% bleeding occurred while on anticoagulation therapy and antiplatelet therapy respectively. Conclusions: Our analysis demonstrates a significant burden of CV and bleeding in MDS. Only 23% of all bleeding events occurred while on anticoagulation therapy and some patients with recurrent CV events did not require hospitalization for bleeding. However, large numbers of CV events are sub-optimally managed due to perceived excess risk of bleeding. Therefore, guidelines for anticoagulation and/or antiplatelet therapy are required for MDS patients. Disclosures Hiwase: Novartis Australia: Research Funding.

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