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Early descriptions of COVID-19 associated coagulopathy identified it as a disseminated intravascular coagulation (DIC). However, recent studies have highlighted the potential role of endothelial cell injury in its pathogenesis, and other possible underlying mechanisms are being explored. This study aimed to analyse the coagulation parameters of critically and noncritically ill patients with COVID-19 bilateral pneumonia, determine if coagulation factors consumption occurs and explore other potential mechanisms of COVID-19 coagulopathy. Critically and noncritically ill patients with a diagnosis of COVID-19 bilateral pneumonia were recruited. For each patient, we performed basic coagulation tests, quantification of coagulation factors and physiological inhibitor proteins, an evaluation of the fibrinolytic system and determination of von Willebrand Factor (vWF) and ADAMTS13. Laboratory data were compared with clinical data and outcomes. The study involved 62 patients (31 ICU, 31 non-ICU). The coagulation parameters assessment demonstrated normal median prothrombin time (PT), international normalized ratio (INR) and activated partial thromboplastin time (APTT) in our cohort and all coagulation factors were within normal range. PAI-1 median levels were elevated (median 52.6 ng/ml; IQR 37.2-85.7), as well as vWF activity (median 216%; IQR 196-439) and antigen (median 174%; IQR 153.5-174.1). A mild reduction of ADAMTS13 was observed in critically ill patients and nonsurvivors. We demonstrated an inverse correlation between ADAMTS13 levels and inflammatory markers, D-dimer and SOFA score in our cohort. Elevated vWF and PAI-1 levels, and a mild reduction of ADAMTS13 in the most severe patients, suggest that COVID-19 coagulopathy is an endotheliopathy that has shared features with thrombotic microangiopathy.

Background A factor XIII (FXIII) level >30% is considered necessary to prevent spontaneous bleeding. Bleeding is also a risk in patients with acquired FXIII deficiency, but the hemostatic level of FXIII in this context remains to be determined. Methods We retrospectively analyzed all patients diagnosed with acquired FXIII deficiency at a large hospital over 3 years (study ID NCT04416594, http://www.clinicaltrials.gov) and assessed clinical data to identify the best cut-off point for FXIII activity to distinguish between low and high risk of major bleeding in a mixed medical and surgical population. Results Of the 97 patients who experienced bleeding despite a normal coagulation test, 43.2% had FXIII activity Conclusion Acquired FXIII deficiency is associated with high morbidity. The hemostatic level of FXIII in the setting of acquired FXIII deficiency might be above 30%.

Acquired thrombotic thrombocytopenic purpura (aTTP) is still associated with a 10% to 20% death rate and its clinical course is characterized by recurrent episodes in up to 50% of cases. Over the last decade, mortality predicting models like the French TMA Reference Center Score and the Mortality In TTP Score (MITS) have been developed in an attempt to personalize treatment. The objective of the present study was to compare the results in both scores of de novo and relapsed aTTP episodes. For such purpose, a total of 29 episodes of aTTP (16 de novo and 13 relapses) were analyzed. All patients were homogeneously diagnosed and treated. First episodes had a higher score in both models in comparison with relapsed aTTP, (MITS median, 1 r: 1-4 vs 0 r: 1-2, P = .038 and French TMA Reference Center Score median, 2 r: 1-3 vs 1 r: 0-1, P = .006). The prevalence of neurological symptoms was significantly higher in the first episodes (P = .001) and patients >60 years old were more common in this group (P = .013), which may have been related to the results. Platelet count at presentation was higher in recurrences than in the first disease episode (P = .016) and ADAMTS13 activity

Introduction: Idarucizumab is a humanized monoclonal antibody fragment that binds to dabigatran and reverses its anticoagulant activity. It has been available in Spain since June 2016 and is indicated for imminent surgery or invasive procedures and life-threatening bleeding. The aim of the study was to describe the actual experience with idarucizumab in different centers in Madrid. Methods: Patients with electronic prescription of idarucizumab between June 2016 and July 2021 were included. Demographic information, comorbidities, laboratory parameters, dabigatran indication, anticoagulation resumption, adverse events related to idarucizumab and death within 30 days were collected from medical records. Qualitative data are presented as frequencies and percentages. Quantitative data are presented as mean ± standard deviation (SD) or median (interquartile range -IQR-). Cumulative survival was calculated by dividing the number of patients alive by the number of patients in each indication category for idarucizumab in a 30-day post-infusion period. Results: A total of 69 patients from 8 hospitals in Madrid were included. Ninety-six percent received dabigatran for prevention of stroke and embolism in nonvalvular atrial fibrillation and 4% received it for the treatment of thromboembolic disease. The mean age was 73.5 ± 13.9 years, and 55.6% were men. Median aPTT was 45.6 seconds and was prolonged in 72.1% (49). Patient characteristics, concomitant conditions and laboratory parameters are reviewed in Table 1. The main indication for idarucizumab was reversal of anticoagulation for persistent bleeding (46.4%), followed by surgery (44.9%). Fibrinolysis due to ischemic stroke was performed in 3 patients (4.3%), dabigatran intoxication occurred in 3 patients due to acute renal failure (4.3%). Gastrointestinal bleeding was the most common type of bleeding. Two of the patients intoxicated with dabigatran also had gastrointestinal bleeding. Cardiac surgery was the most common type of intervention, with heart transplant being a common indication (9/13). Minor surgical procedures included 2 lumbar punctures and 1 central venous catheterization. In one case, the type of surgery was not available. Figure 1 A and B summarize the bleeding location and type of surgery. The median time between infusion of idarucizumab and cessation of bleeding or onset of surgery was 3 hours, however this information was only available in 43 patients. No reports of excessive bleeding during surgery or after fibrinolysis were noted. One patient with dabigatran intoxication was reported to have an episode of persistent melena in which the trough plasma level was 1178.1 ng/mL. This patient died of an aggressive lymphoproliferative disorder that couldn´t be biopsied due to altered coagulation. A case of auricular thrombosis occurred in a patient with a heart transplant due to hyperthophic cardiomiopathy and end-stage heart failure requiring thrombectomy. The patient required a biventricular assistance and died of myocardial infarction. Full 30-day follow-up was available for 68 patients, during this period 11 died. Five patients in the bleeding group died, 3 from hypovolemic shock, 1 from intraparenchymal hemorrhage and data were missing for 1. Two patients who received a heart transplant died, one as described previously 10 days after the transplant and the other 2 days after the transplant from hemorrhagic shock. Three patients who underwent abdominal surgery died of septic shock. One patient with dabigatran intoxication died. Cumulative survival after a follow-up period of 30 days was 86% (Figure 2). Seventy-seven percent (53) resumed anticoagulation after a median of 3 days (0-180), and 62.3% (33) were bridged with low molecular weight heparin (LMWH) at prophylactic doses. Finally, 75% (40) maintained LMWH (7) or restarted dabigatran or another direct oral anticoagulant (33). A total of 13 patients didn´t resume any anticoagulation. Conclusions: Idarucizumab is an effective drug for reversal of dabigatran anticoagulation in bleeding or imminent surgery/invasive procedures. In this cohort it was used safely in patients awaiting a heart transplant. No cases of bleeding after infusion or during surgery were reported, except for a single case of auricular thrombosis. Most patients resumed anticoagulation at discharge. The experience described confirms the safety of idarucizumab in daily clinical practice. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

[Background]: Eltrombopag is useful for immune thrombocytopenia (ITP). However, results of clinical trials may not accurately mirror clinical practice reality. Here we evaluated eltrombopag for primary and secondary ITP in our ≥65‐year‐old population., [Methods]: A total of 106 primary ITP patients (16 with newly diagnosed ITP, 16 with persistent ITP, and 74 with chronic ITP) and 39 secondary ITP patients (20 with ITP secondary to immune disorders, 7 with ITP secondary to infectious diseases, and 12 with ITP secondary to lymphoproliferative disorders [LPD]) were retrospectively evaluated., [Results]: Median age of our cohort was 76 (interquartile range, IQR, 70‐81) years. 75.9% of patients yielded a platelet response including 66.2% complete responders. Median time to platelet response was 14 (IQR, 8‐21) days. Median time on response was 320 (IQR, 147‐526) days. Sixty‐three adverse events (AEs), mainly grade 1‐2, occurred. The most common were hepatobiliary laboratory abnormalities (HBLAs) and headaches. One transient ischemic attack in a newly diagnosed ITP and two self‐limited pulmonary embolisms in secondary ITP were the only thrombotic events observed., [Conclusion]: Eltrombopag showed efficacy and safety in ITP patients aged ≥65 years with primary and secondary ITP. However, efficacy results in LPD‐ITP were poor. A relatively high number of deaths were observed.

INTRODUCTION COVID-19 is associated with coagulopathy that correlates with poor prognosis. Although the underlying mechanism of COVID-19 coagulopathy remains unknown, early reports suggested that it may be a form of disseminated intravascular coagulation (DIC). However, recent studies have highlighted the potential role of endothelial cell injury in its pathogenesis. AIMS The aims of our study were to analyze the coagulation parameters of critically and non-critically ill patients with COVID-19 pneumonia admitted to our hospital, determine if coagulation factors consumption occurs, identify potential prognostic biomarkers of this new disease and explore possible underlying mechanisms of COVID-19 coagulopathy. METHODS We conducted a retrospective cohort study performed at Gregorio Marañon Hospital in Madrid, Spain. Adult patients with a diagnosis of COVID-19 hospitalized in our center were recruited, including those admitted to the ICU and to general wards. Patients were randomly selected from blood samples that arrived at our Hemostasis laboratory during April 2020. For each patient, we conducted a complete analysis of coagulation parameters, including basic coagulation tests, quantification of coagulation factors and physiological inhibitor proteins, evaluation of the fibrinolytic system and determination of von Willebrand Factor (vWF) and ADAMTS13. Laboratory data were compared with clinical data and outcomes. Data were analyzed using IBM SPSS Statistics for Mac, version 24. This study was approved by our institutional Ethics Committee and it was executed along with the international ethics recommendations for conducting research in humans following the latest revision of Declaration of Helsinki. RESULTS A total of 62 patients (31 ICU, 31 non-ICU) were analyzed. Mean age of the sample was 61.8 (SD 15.2) years and 69.4% of the patients were male. The coagulation parameters assessment demonstrated normal median PT, INR and APTT in our cohort and all coagulation factors were within normal range. Factor VIII showed an increasing trend (194.5±71.9) which could be interpreted as an acute phase reactant, and it was significantly higher in non-survivors (p=0.003). Similarly, we did not observe consumption of physiological inhibitor proteins and platelet counts were also within the normal limits, despite being slightly lower in non-survivor patients (p=0.006) (Table 1). Von Willebrand Factor (vWF) was above the normal range (median 216%, IQR 196-439, normal range 62-175%) in our cohort and higher levels of vWF-antigen (p=0.001) and vWF-activity (p=0.02) were associated with poor prognosis. Likewise, a lower ADAMTS13 activity was observed in non-survivors (p=0.008). Regarding the fibrinolytic pathway, PAI levels were above the normal range (median 52.6ng/ml, IQR 37.2-85.7, normal range 4-40ng/ml), but we found no statistically significant differences based on survival. The remaining parameters of the fibrinolytic pathway (plasminogen and alpha-2 antiplasmin) were within normal range (Table 1). ICU-patients had a poorer prognosis, with a higher rate of mortality (p=0.003). Likewise, they showed more elevated acute phase reactants (p CONCLUSIONS COVID-19 infection is associated with coagulopathy that correlates with poor prognosis. However, coagulation factors, physiological inhibitory proteins and alpha-2-antplasmin levels were preserved in our study. Similarly, we did not observe platelets or fibrinogen consumption, which leads us to assume that COVID-19 coagulopathy is not a form of DIC. Increased vWF and decreased ADAMTS13 activity in our cohort could indicate that the underlying mechanism of this coagulopathy may reside in the endothelial cells and share a similar pathogenesis with thrombotic microangiopathy (TMA), as it has been recently suggested in some scientific reports. Disclosures No relevant conflicts of interest to declare.

Eltrombopag is effective and safe in immune thrombocytopenia (ITP). Some patients may sustain their platelet response when treatment is withdrawn but the frequency of this phenomenon is unknown. We retrospectively evaluated 260 adult primary ITP patients (165 women and 95 men; median age, 62 years) treated with eltrombopag after a median time from diagnosis of 24 months. Among the 201 patients who achieved a complete remission (platelet count >100 × 109/l), eltrombopag was discontinued in 80 patients. Reasons for eltrombopag discontinuation were: persistent response despite a reduction in dose over time (n = 33), platelet count >400 × 109/l (n = 29), patient's request (n = 5), elevated aspartate aminotransferase (n = 3), diarrhea (n = 3), thrombosis (n = 3), and other reasons (n = 4). Of the 49 evaluable patients, 26 patients showed sustained response after discontinuing eltrombopag without additional ITP therapy, with a median follow-up of 9 (range, 6–25) months. These patients were characterized by a median time since ITP diagnosis of 46.5 months, with 4/26 having ITP

Eltrombopag is safe and effective in primary chronic ITP. However, lack of clinical trials avoids a clear demonstration of its utility in newly diagnosed and persistent ITP. Our aim here is to report Spanish results for this type of patients. We retrospectively evaluated 220 adult primary ITP patients. According to standard definition, patients were allocated to newly diagnosed (n = 30), persistent (n = 30), and chronic (n = 160) ITP. Groups were homogenous regarding most relevant parameters. 180 (90%) of 220 patients achieved a platelet response (R) with 167 (75.9%) complete responses (CR) after a 15-month follow-up. No statistical significant differences among groups but a trend towards a greater efficacy in newly diagnosed ITP were observed (93.3% of responses with 86.7% of CR). Efficacy in persistent ITP (83.3% of responses with 80.0% of CR) and chronic ITP (79.4% of responses with 73.1% of CR) was similar. 70 patients (31.8%) experienced adverse events. 15 of them were grade 3–4. Most common adverse effects were headache and hepatobiliary laboratory abnormalities (HBLAs). One persistent ITP had a venous thrombosis and one chronic ITP had grade II myelofibrosis. We consider Eltrombopag use for the early stage ITP as effective and safe as it is in chronic ITP.

Background Despite the favorable results of imatinib front line in chronic-phase chronic myeloid leukemia there is room for improvement. Design and Methods Early intervention during imatinib therapy was undertaken in 210 adults with chronic-phase chronic myeloid leukemia less than three months from diagnosis (Sokal high risk: 16%). Patients received imatinib 400 mg/day. At three months, dose was increased if complete hematologic response was not achieved. At six months, patients in complete cytogenetic response were kept on 400 mg and the remainder randomized to higher imatinib dose or 400 mg plus interferon-alfa. At 18 months, randomized patients were switched to a 2nd generation tyrosine kinase inhibitor if not in complete cytogenetic response and imatinib dose increased in non-randomized patients not in major molecular response. Results Seventy-two percent of patients started imatinib within one month from diagnosis. Median follow-up is 50.5 (range: 1.2–78) months. At three months 4 patients did not have complete hematologic response; at six months 73.8% were in complete cytogenetic response; among the remainder, 9 could not be randomized (toxicity or consent withdrawal), 17 were assigned to high imatinib dose, and 15 to 400 mg + interferon-alpha. The low number of randomized patients precluded comparison between the two arms. Cumulative response at three years was: complete hematologic response 98.6%, complete cytogenetic response 90% and major molecular response 82%. On an intention-to-treat basis, complete cytogenetic response was 78.8% at 18 months. At five years, survival was 97.5%, survival free from accelerated/blastic phase 94.3%, failure free survival 82.5%, and event free survival (including permanent imatinib discontinuation) 71.5%. Conclusions These results indicate the benefit of early intervention during imatinib therapy ( ClinicalTrials.gov Identifier: [NCT00390897][1] ). [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00390897&atom=%2Fhaematol%2F95%2F8%2F1317.atom

BackgroundEltrombopag is effective and safe in chronic immune thrombocytopenia (ITP). However, clinical trials may not accurately reflect what happens in clinical practice. We evaluated the efficacy and safety of eltrombopag in primary chronic ITP in a real-world setting. MethodsA total of 164 primary patients with chronic ITP from 40 Spanish centers, who had been treated with eltrombopag, were retrospectively evaluated. ResultsThe median age of our cohort (72% women) was 63 yr (interquartile range, IQR, 45-75 yr). The median time with ITP diagnosis was 81 months (IQR, 30-192 months). The median number of therapies prior to eltrombopag was 3 (IQR, 2-4). At the time of eltrombopag start, 45 patients (30%) were receiving concomitant treatment for ITP. Forty-six patients (30%) had bleeding signs/symptoms the month before the treatment started. The median platelet count at eltrombopag initiation was 22 x 10(9)/L (IQR, 8-39 x 10(9)/L). A total of 135 patients (88.8%) achieved a platelet response. The median time to platelet response was 12 d (95% CI, 9-13 d). Maintained platelet response rate during the 15-month period under examination was 75.2%. Twenty-eight patients (18.4%) experienced adverse events, mainly grades 1-2. ConclusionEltrombopag is highly effective and well tolerated in unselected patients with primary chronic ITP.

Background: Eltrombopag is effective and safe for treating chronic immune thrombocytopenia (ITP) patients who have not responded to previous therapy. Interestingly, some patients in whom hemostatic platelet counts are achieved with eltrombopag may sustain the platelet response when eltrombopag ceases to be administered. However, the frequency of sustained responses after discontinuing eltrombopag without additional therapy for ITP is largely unknown. Methods: A total of 260 adult patients (aged 18 years or more) with primary ITP treated with eltrombopag included in the Spanish Eltrombopag Registry were retrospectively evaluated. The study was performed in accordance with the standards of the Helsinki declaration and approved by the Hospital Universitario de Burgos Ethics Committee. Results: The median age was 62 [range, 18–93] years. There were 165 women and 95 men. According to the standard definition, patients were allocated to newly diagnosed (n=29), persistent (n=36) and chronic (n=195) ITP groups. The median time from diagnosis to eltrombopag initiation was 24 [range, 1–480] months. The median number of previous therapies was 3 [range, 0–10], including splenectomy (22%), rituximab (23%) and romiplostim (19%). The initial response rate to eltrombopag was 231/260 (89%), including 77% (n=201) cases of complete remission (platelet count ≥100 x 109/L). The median duration of eltrombopag treatment was 6 [range, 1–54] months. Eltrombopag was discontinued in 80 out of 201 (39.8%) patients who achieved CR. Reasons for eltrombopag discontinuation were: persistent response despite a reduction in dose over time (n=33), platelet count >400x109/L (n=29), patient’s request (n=5), aspartate aminotransferase elevation (n=3), diarrhea (n=3), thrombosis (n=3) and other reasons (n=4). For analysis of discontinuation, patients with follow-up < 6 months (n=15), newly diagnosed ITP (n=11) or patients who received concomitant or previous (6 months before) treatments at the start of eltrombopag use (n=5) were excluded. Of the 49 evaluable patients, 22 (45%) had an immediate relapse after stopping eltrombopag. One patient with sustained response after stopping treatment relapsed at 10 months. A total of 26 patients (53%) showed sustained response after discontinuing eltrombopag without additional ITP therapy, with a median follow-up of 9 [range, 6–25] months. These patients were characterized by a median time since ITP diagnosis of 46.5±114.1 months, with 4/26 having ITP The main characteristics (age, gender, duration of ITP, prior anti-ITP lines, prior splenectomy, prior rituximab, prior romiplostim, platelet count before starting eltrombopag, duration of eltrombopag treatment, and platelet count before eltrombopag withdrawal) of the 26 patients with sustained response after stopping eltrombopag were compared with those of the 23 patients relapsing after eltrombopag withdrawal. No predictive factors of sustained response after eltrombopag withdrawal could be identified. Conclusion: Platelet response following eltrombopag cessation may be sustained in nearly half of adult patients with primary ITP after CR with eltrombopag. However, reliable markers for predicting which patients will have this response are lacking. Disclosures No relevant conflicts of interest to declare.

Rozrolimupab, a recombinant mixture of 25 fully human RhD-specific monoclonal antibodies, represents a new class of recombinant human antibody mixtures. In a phase 1 or 2 dose escalation study, RhD+ patients (61 subjects) with primary immune thrombocytopenia received a single intravenous dose of rozrolimupab ranging from 75 to 300 μg/kg. The primary outcome was the occurrence of adverse events. The principal secondary outcome was the effect on platelet levels 7 days after the treatment. The most common adverse events were headache and pyrexia, mostly mild, and reported in 20% and 13% of the patients, respectively, without dose relationship. Rozrolimupab caused an expected transient reduction of hemoglobin concentration in the majority of the patients. At the dose of 300 μg/kg platelet responses, defined as platelet count ≥ 30 × 109/L and an increase in platelet count by > 20 × 109/L from baseline were observed after 72 hours and persisted for at least 7 days in 8 of 13 patients (62%). Platelet responses were observed within 24 hours in 23% of patients and lasted for a median of 14 days. Rozrolimupab was well tolerated and elicited rapid platelet responses in patients with immune thrombocytopenia and may be a useful alternative to plasma-derived products. This trial is registered at www.clinicaltrials.gov as #NCT00718692.

Background: Eltrombopag is an oral thrombopoietin receptor agonist (TPO-RA) drug approved in primary chronic ITP. Lack of clinical trials in secondary ITP avoids a clear demonstration of its potential in terms of safety and efficacy on secondary ITP. Aims: To evaluate the efficacy and safety of eltrombopag in secondary ITP patients in daily clinical practice in Spain. Methods: Ninety-eight secondary ITP patients (aged 18 years or more) from 30 Spanish centers, treated with eltrombopag and included in the Spanish Eltrombopag Registry were retrospectively evaluated. Our study was performed in accordance with the standards of the Helsinki declaration and approved by the Hospital Universitario de Burgos Ethics Committee. Results: Our case series included 98 patients we allocated to four categories: immune disorders (n=47), infections (n=23), lymphoproliferative disorders (n=20), and neoplasms (n=8). The median age of the cohort was 62 (IQR, 40-71) years with 38 men and 60 women. At diagnosis, 34 patients had a Charlson Comorbidity Index score of 2 or more. Median time from ITP diagnosis to eltrombopag initiation was 13 (IQR, 2-66) months. Median number of therapies against thrombocytopenia before eltrombopag was 2 (IQR, 1-3), including rituximab (24), splenectomy (18) and romiplostim (13). Median platelet count when treatment started was 15 x 109/L (IQR, 5-43 x 109/L). Meanwhile, 44 patients had bleeding symptoms. Concomitant therapy was administered to 55 ITP (corticoids in 33) (Table I). Whole cohort eltrombopag response rate was 59% of responses (R; platelet count ≥30 x109/L and at least 2-fold increase the baseline count and absence of bleeding) with 52% of complete responses (CR; platelet count >100 x 109/L). Regarding the disease associated to ITP we observed high response rates in immune disorders and infection groups (67% of R, 76 % of R, respectively). Nevertheless, in lymphoproliferative disorders and neoplastic groups efficacy rates were much lower (36 % of R, 37 % of R respectively). The proportion of patients achieving platelet response was quite similar regardless the other studied parameters: age, sex, concomitant treatment, bleeding and platelet count at start of eltrombopag treatment. 30 adverse events were reported with eltrombopag, being 18 of them grade 3-4. 14 deaths were observed but only two were caused by bleeding. The remaining causes of death were: 4 because of bacterial sepsis and another 4 due to progression of basal disease. 2 secondary neoplasms, 1 aspergillosis and one death due to a non-treated severe anemia were also reported (Table II). Conclusion: The use of eltrombopag for treating secondary ITP is effective and safe. To point out, its efficacy in lymphoproliferative disorders and in neoplasm-associated ITP is lower than in benign diseases. Certainly, more studies are needed to confirm usefulness of TPO-RAs in secondary ITP cases. Table 1. Patient characteristics Variable Total(n = 98) Type of disease, n Immune disorders SLE 13 Evans Syndrome 8 Antiphospholipid Syndrome 6 Sjögren Syndrome 5 Rheumatoid Arthritis 3 Immunodeficiencies 3 Autoimmune Hepatitis 2 Primary Biliary Cirrhosis 2 Psoriatic arthritis 1 Evans Syndrome-Immunodeficiencies 1 Evans Syndrome-HCV 1 Graves-Basedow disease 1 Inflammatory Bowel disease 1 Lymphoproliferative disorders Lymphoproliferative diseases 16 HCV-Lymphoma 3 HIV-Lymphoma 1 Infections Hepatitis C Virus 16 HIV 5 HCV-HIV 2 Neoplasms Myeloid Neoplasms 8 Age, years, median [Q1;Q3] 62[40;71] Men/Women n 38/60 Bleeding at start of eltrombopag treatment, n 44 Concomitant treatment, n 55 Corticoids 33 Immunoglobulins 6 Corticoids and Immunoglobulins 7 Table 2. Adverse events with Eltrombopag Variable n Total, n 30 Serious Adverse Events (Grade 3-4), n 18 Progression of basal disease 4 Severe Bacterial Infections 3 Deep venous thrombosis 3 Stroke 2 Medullary fibrosis 2 Severe Bleeding 1 Aspergillosis 1 Pulmonary Embolism 1 Secondary neoplasms 1 Acute Pancreatitis 1 Acute Myocardial Infarction 1 Deaths, n 14 Bacterial Infections 4 Progression of basal disease 4 Secondary neoplasms 2 Severe Bleeding 2 Aspergillosis 1 Severe Anemia due to negative of patient to transfusion 1 Disclosures Off Label Use: We describe the possibility of using eltrombopag, an oral thrombopoietin receptor analog, for secondary ITP patients..

Background: Eltrombopag is a thrombopoietin receptor agonist approved for primary chronic ITP patients. Due to the non-existence of clinical trials using eltrombopag in persistent and newly diagnosed ITP, there are no clear data about its usefulness in this setting. Aims: To evaluate efficacy and safety of eltrombopag in persistent, newly diagnosed and chronic ITP in routine clinical practice in Spain. Methods: Two hundred and twenty adult ITP patients from thirty Spanish centers who had been treated with eltrombopag and included in the Spanish Eltrombopag Registry were retrospectively evaluated. This study was performed in accordance with the standards of the Helsinki declaration and approved by the Hospital Universitario de Burgos Ethics Committee. Results: Here we report efficacy and safety results of primary ITP Spanish Eltrombopag Registry cohort. According to the standard definition, patients were allocated to newly diagnosed (n=30), persistent (n=30) and chronic (n=160) ITP groups. Each group is described separately in Table I. There are no statistical significant differences regarding response and duration of response among ITP groups. There is a trend towards a greater efficacy in newly diagnosed ITP with 93.3% of responses (platelet count ≥30 x109/L and at least two-fold increase the baseline count and absence of bleeding) and 86.7% of complete responses (CR; platelet count >100 x 109/L). Persistent ITP achieved 83.3% of responses and 80.0% of CR. Similarly 79.4% of responses with 73.1 of CR were observed in chronic ITP. Response rates were similar in all groups regardless all other studied parameters. Another trend towards a longer response duration in persistent ITP was found, with a median of 424 (IQR, 288-664) days. Response durations were similar in chronic ITP (median, 370 days; IQR, 174-624) and in newly diagnosed ITP (median, 378 days; IQR, 154-485). In newly diagnosed ITP, eight adverse events (AEs) with only three grade 3-4 AEs were observed. We reported three deaths; Two of them were due to upper respiratory tract infections in previously diagnosed pulmonary patients. A cerebral hemorrhage was the only death directly related to thrombocytopenia. In persistent ITP, four grade 1-2 AEs and two grade 3-4 AEs (one stroke, one cerebral bleeding) were reported. The only observed death was secondary to the mentioned cerebral hemorrhage. Twenty-one grade 1-2 AEs, ten grade 3-4 AEs and eight deaths (only two caused by bleeding) occurred in chronic ITP. Conclusion: Use of eltrombopag for treating persistent and newly diagnosed ITP is effective and safe. However, more studies are needed to confirm usefulness of TPO-RAs in this setting. | Variable | Newly-Diagnosed ITP (n = 30) | Persistent ITP (n=30) | Chronic ITP (n=160) | | | ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | -------------------------------------------------------------------------------- | --------------------------------------------------------------------------------- | ------------------------------------------------------------------------------------------------ | | | Age, years, median [Q1;Q3] | 66[46;79] | 66[47;76] | 61[47;75] | | | Men/Women n | 12/18 | 15/15 | 47/113 | | | Charlson comorbidity Index > 1, n (%) | 7(25.9) | 5(17.2) | 25(16.7) | | | Months with ITP, median [Q1;Q3] | 1[1;2] | 6[4;10] | 79[30;193] | | | Past ITP treatments, median [Q1;Q3] Rituximab, n (%) Splenectomy, n (%) Romiplostim, n (%) | 2[1;3] 3(10.7) 2(7.1) 3(10.7) | 2[1;3] 5(17.2) 4(13.8) 4(13.8) | 3[2;4] 43(28.3) 47(30.7) 37(24.3) | | | Platelet count at start of eltrombopag treatment, (x109/L), median [Q1;Q3] Bleeding at start of eltrombopag treatment , n (%) Concomitant treatment, n (%) Corticoids Immunoglobulins Corticoids and Immunoglobulins | 15[7;29] 13(43.3) 10(33.3) 6(60) 0 2(20) | 14[6;26] 10(33.3) 9(30) 7(77.8) 0 2(22.2) | 22 [9;38] 50 (31.3) 46 (28.8) 27 (57.4) 10 (21.3) 8 (17) | | Table 1. Patient characteristics Disclosures Off Label Use: We describe the possibility of using eltrombopag, an oral thrombopoietin receptor analog, for persistent and newly diagnosed ITP patients..

Background: The trombopoietin receptor agonists (TRAs) romiplostim and eltrombopag are effective and safe in the treatment of chronic immune thrombocytopenia (ITP). However, when no response is achieved or when adverse events occur with one TRA the value of the sequential use of romiplostim and eltrombopag has not been clearly established. Here we have evaluated the efficacy and tolerance of using eltrombopag after romiplostim in ITP. Methods: Fifty-one primary ITP patients (aged 18 years or more) who had been sequentially treated first with romiplostim and then with eltrombopag in the Spanish Eltrombopag Registry were retrospectively evaluated. In accordance with the usual standards, complete response was defined as a platelet count of 100x109/L and a response as a platelet count of 30x109/L or a count of at least twice the initial (pre-treatment) value. This study was performed in accordance with the standards of the Helsinki declaration and approved by the Hospital Universitario de Burgos Ethics Committee. Results: The median age of our cohort was 49 [range, 18–83] years. There were 32 women and 19 men. According to the standard definition, patients were allocated to newly diagnosed (n=2), persistent (n=5) and chronic (n=44) ITP groups. The median number of therapies prior to administration of eltrombopag was 4 [range, 2–9], including splenectomy (39%), rituximab (33%) and romiplostim (100%). The median duration of romiplostim use before switching to eltrombopag was 12 (IQR 5–21) months. The reasons for switching from the romiplostim to eltrombopag were: lack of efficacy of romiplostim (n=25), patient's preference (n=16), platelet-count fluctuation (n=6), and side-effects (n=4). The initial response rate to eltrombopag was 41/51 (80.5%), including 67% (n=34) of cases with complete remission. After a median follow-up of 13 months with eltrombopag, 39 patients maintained their response. When eltrombopag was used for patients who were refractory to the maximum romiplostim dose the initial response rate of eltrombopag was 25%. However, 83% of patients who relapsed after their initial response to romiplostim responded to eltrombopag. Sixteen romiplostim responders requested their physicians to switch them to eltrombopag because they preferred an oral drug. The efficacy was maintained after switching in all 16 patients. In the platelet-count fluctuation group, the initial response rate was also 100%. All 4 patients who were switched to eltrombopag because they experienced side-effects of romiplostim achieved complete remission with eltrombopag and their adverse events were resolved. 16 / 51 (33%) patients experienced one or more adverse event during treatment with eltrombopag. The frequency of grade 3–4 adverse events during treatment with eltrombopag was 9.8%. Conclusion: The use of eltrombopag after romiplostim for treating ITP is effective and safe. The reason for discontinuing romiplostim was associated with the response to eltrombopag. Disclosures No relevant conflicts of interest to declare.

Abstract 4676 INTRODUCTION: Bernard Soulier Syndrome (BSS) is a rare qualitative and quantitative autosomal recessive platelet disorder molecularly characterized by defective GPIb-IX-V membrane glycoprotein that is related to platelet adhesion and interaction with both Von Willebrand factor and endothelium. It is usually expressed by an enlarged bleeding time and decreased yet giant sized platelets, and can cause severe hemorrhagic complications during pregnancy. CASE REPORT: We present two successful pregnancies and labour management on a 33-year-old woman diagnosed in her childhood with BSS. Ristocetin induced platelet agglutination test and membrane glycoprotein study were performed to get the diagnosis. Furthermore, in the last year we have completed the diagnosis with platelet receptor expression flow citometry analysis, finding out depleted antiGPIbα and antiGPIX antibodies. Changes which prevent GPIbα for correct expression and processing were observed. Also integrin αIIbβ3 levels were risen due to the big sized platelets. A PCR product was obtained from genomic DNA using the GPIbα oligonucleotide pair; sense and antisense, and direct DNA sequencing of the amplification was performed in a model ABIprism 377 DNA sequencer (Perkin-Elmer Cetus). The direct sequencing of the sense strand of the 5x fragment shows in the patient the simultaneous presence of G and C nucleotids in 688 position, and the T and A nucleotids in 715 position. These punctual mutations give Ala200Pro substitutions and Cys209Ser in heterozygosis in mature peptide, respectively, Figure 1. The Ala200Pro mutation has not been reported in others cases of Bernard-Soullier, previously. The Cys209Ser has been described in other two Spanish patients: one in homozygosis and the other in heterozygosis associated to the mutation. Our patient presented hemorrhagic symptoms from 18 month old with an average of 40×103/μ l platelet count and increased platelet volume who required multiple platelet transfusions during her childhood. In the menarche main hemorrhagic manifestations consisted on methrorragia and epistaxis which were controlled with tranexamic acid. At the age of 26 a spontaneous ovarian cyst rupture required urgent hospital admission and two platelet pool transfusion. On December 2007 she consulted for epistaxis, and on September 2008 cesarean delivery was planned at 38th week of pregnancy; platelet count was 40×103/μ l, antiplatelet antibodies were negative for membrane glycoproteins and antiHLA-1 was positive against 98% donors tested. As a result, an HLA-compatible donor was searched, and two platelet apheresis were transfused one hour before surgery and every 12 hours after the procedure. The next 4 days one apheresis every 48 hours were transfused with no hemorrhagic symptoms. On January 2010, she presented with her second pregnancy; the patient had severe anemia, with high transfusion requirements; neither hemorrhage or hemolysis was detected, and even the possibility of a Munchausen syndrome was questioned. Unplanned caesarean was performed at 32th week because of the clinical instability of the patient, and this time we could not find on time an HLA-compatible donor, so two random platelet pools were transfused one hour before surgery and one platelet apheresis every day during 4 days after caesarean deliver, without any hemorrhagic complication. The newborn was asymptomatic with normal platelet count. The patientxs haemoglobin level returned to normal after five days of delivery. CONCLUSIONS: We present the successful labour management of two consecutive pregnancies on a young woman diagnosed with BSS. The low prevalence of this syndrome (less than one case per million population) explains the absence of well-established protocols for the management of pregnancy in this disease. Up to date there are only twelve reported cases of pregnancy and delivery in BSS patients, most of them presenting with severe hemorrhagic complications. Correct platelet transfusion is the mainstay of treatment, and screening for anti-platelet antibodies study is mandatory due to its high prevalence in these patients. Disclosures: No relevant conflicts of interest to declare.

Abstract 3358 INTRODUCTION: Non-neoplastic chronic portal vein thrombosis (PVT) is a frecuent diagnosis in the course of liver cirrhosis, with reported prevalences of 0.6% to 15,8%. PVT can motivate life-threatening complications due to worsening portal hypertension, so anticoagulation therapy is challenging in these patients. OBJECTIVE: To analyze the response to antithrombotic therapy and changes in liver function tests in 28 patients with chronic PVT associated with cirrhosis. PATIENTS AND METHODS: 28 consecutive patients with liver cirrhosis and chronic PVT were treated with antithrombotic therapy from 2004 to 2009. Hepatocellular carcinoma and known thrombophilic risks were ruled out. Therapy consisted in 15 days of therapeutic doses of low molecular weight heparin (LMWH) (enoxaparin) adjusted according to baseline coagulability (Table 1), followed by either prophylactic doses (40mg/day) of LMWH or acenocoumarol (target INR 2–3), during 6 months. Response was evaluated after 6 months. If recanalization was complete, therapy was suspended. If recanalization was partial or no recanalization was observed, therapy was continued until response. RESULTS: From the 28 patients studied, 19 (68%) were males with a median age of 53 years (range 35–77). Cirrhosis was due to alcoholism (25%), virus (54%), mixed in 1 patient and other causes in 3 patients. PVT involved the portal trunk and/or branches in 19/28 (68%) patients, mesenteric vein in 2 patients and portal trunk and/or branches, mesenteric and/or splenic vein thrombosis coexisted in 7 patients. 19/28 (68%) of the patients had moderate or moderate-severe hypocoagulability range. Complete and partial thrombosis was seen in 18 and 10 patients at diagnosis, respectively. From the 28 patients, 18 (64%) responded to antithrombotic therapy after 6 months, with a complete recanalization in 13 patients 13/18 (72%) and partial in 5/18 patients (28%). None of the 28 patients presented hemorrhagic complications and none showed platelets counts below baseline values. 17 from the 18 patients who responded, showed altered liver function tests before therapy. After 6 months, 8/17 (47%) improved liver function (only one patient had received antiviral therapy). After a median follow up of 42 months (range 7–67), 15/18 (83%) patients continued showing complete or partial response while 3 patients progressed. Of note, 3 patients of this group could proceed to further liver transplantation. CONCLUSIONS: Antithrombotic therapy in chronic PVT in cirrhotic patients resulted in a high response rate (64%) in our study, with a complete recanalization in 72% of the cases. Adjusted dose scheme according to level of hypocoagulability seems to be effective and safe, since 63% of the subgroups of moderate and moderate-severe hypocoagulability responded with no haemorrhagic complications. Disclosures: No relevant conflicts of interest to declare.

Abstract 4397 OBJECTIVES Thrombotic events have been reported as a major cause of morbidity after the Fontan procedure. There is no consensus about the type and duration of postoperative anticoagulation prophylaxis, due to the high risk of bleeding complications, the difficulties in monitoring and the questionable therapeutic compliance in children. In spite of the lack of long term prospective studies in this situation, the ACCP has recommended in their guidelines OAT following Fontan or Glenn operation for at least 6 months. This has also been our practice in our institution during the period of study. AIM OF THE STUDY To analyze the efficacy and complications of OAT in our pediatric patients after undergoing the Fontan operation. METHODS Retrospective chart review of all the children treated with OAT in our institution between 1995 and 2009. All patients were treated initially with acenocumarol 0,2 mg/kg, except the Fontan patients, who received 0,1 mg/kg. Target INR was 2–3 for all patients. The Mann-Whitney test was used to compare the rate of complications, and the percentage of visits out of target INR between the Fontan patients and the rest of the cohort. RESULTS There were 61 children (26 female/35 males) aged between 1 month and 17 years, who received OAT with a range of follow up between 4 months and 14 years: 27 after Fontan operation (Group A), an 34 for other reasons (Group B: n=13 non prothetic valve cardiopathy, n=21 treatment of thromboembolic disease). The average follow-up was similar in both groups (median of 6.5 months in group A vs.7.5 months in group B). There were few complications: 1 mild epistaxis and 1 thrombotic event in group B, and none in group A. There were no differences in the proportion of controls in normal range between both groups; there was a moderate proportion of controls outside the target range of INR, with higher distribution below the range than above the range. The median dose used to achieve the target INR was 0.3 mg/kg/d in Group A and 0.4 mg/kg/d in Group B. CONCLUSIONS Oral Anticoagulant therapy is safe and effective in pediatric patients,with very low rates of thrombotic or hemorragic complications including those undergoing the Fontan surgery. There were not any differences between both groups in any of the analizyed parameters. Disclosures: No relevant conflicts of interest to declare.

Abstract 1113 Poster Board I-135 Currently, imatinib (IM) 400 mg daily is the frontline therapy for patients with CP-CML. In an attempt to improve the therapeutic response to IM, the Spanish collaborative PETHEMA group undertook a study of early optimization of therapy, in which 210 adult patients newly diagnosed with CP-CML (< 3 months from diagnosis) were included. Median age was 44 (range: 18-71) years and distribution by Sokal groups: low risk 56%, intermediate risk 28%, and high risk 16%. Hydroxyurea was permitted before IM. Patients initially received IM 400 mg daily for 3 months and then those failing to achieve a complete hematologic response (CHR) had the dose increased (to 600 and then 800 mg daily), while the remainder were maintained on 400 mg daily for three more months. At 6 months, depending on cytogenetic response, patients were kept on IM 400, if they had achieved a complete cytogenetic response (CCyR), or randomized to receive higher IM doses (600 and then 800 mg) or IM 400 plus low dose interferon (IFN, 3 million units 3 times a week) in case that a CCyR had not been attained by that time. In patients already in CCyR at 6 months, the IM dose was increased if a major molecular response (MMolR) according to the international scale had not been achieved at 18 months, whereas in patients not in CCyR and randomized at 6 months, a switch to a second generation TKI (dasatinib or nilotinib) was permitted if a CCyR was not achieved at one year of randomization. At standard intervals, cytogenetic response was assessed in bone marrow by chromosome banding analysis and molecular response determined in peripheral blood by RT-Q-PCR performed in three reference laboratories. At the time of the analysis, median follow-up was 48.3 (range: 1.2-73) months. Median time from diagnosis to IM start was 0.5 (range: 0-2.8) months; 72% of patients started IM within one month from diagnosis. At 3 months of treatment, 4 patients had not achieved a CHR; two of them failed to achieve a favorable response following the increase in the IM dose. At 6 months, a CCyR was obtained in 79% of patients; of the 41 patients not in CCyR, 9 could not be randomized because of toxicity (n= 3) or withdrawal of consent (n=6), 17 were assigned to higher IM dose, and 15 to IM 400 + IFN, but only 9 of the latter actually started IFN. Due to the scarce number of patients randomized, no comparison could be established between the two arms. Overall, cumulative incidence of response at 3 years was: CHR 98.6%, CCyR 90%, and MMolR 82%. Based on an intention-to-treat analysis, CCyR was 70% at 18 months. With current follow-up, only 5 patients have died and 9 have progressed to the accelerated or blastic phases (AP/BP). At 5 years, overall survival rate is 97.5%, survival free from AP/BP 95.5%, survival free from failure (including death, progression to AP/BP and the lack of achievement or the loss of a previously obtained CHR and CCyR) 82%, and event-free survival (including the above plus the permanent IM discontinuation for any reason) 80%. Twenty-seven patients (12.8% of the overall group) had grade 3-4 hematological toxicity and 26 (12.4%) grade 3-4 nonhematological side effects, in most cases during the first year of treatment. The presentresults show the benefit of prompt institution and early optimization of IM therapy in patients with newly diagnosed CP-CML. Disclosures Cervantes: Novartis: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau.