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Extracorporeal photopheresis (ECP) is an established treatment strategy in steroid-refractory graft-versus-host disease (GVHD). This study's main objective was to analyze the clinical response and impact of ECP therapy in steroid dose reduction. A retrospective observational series of 113 patients from 7 transplantation centers was analyzed. Sixty-five patients (58%) had acute GVHD (aGVHD), and 48 (42%) had chronic GVHD (cGVHD). All ECP procedures were performed with the off-line system. The median number of procedures until achievement of initial response was 3 for both patients with aGVHD and those with cGVHD. ECP was the second-line therapy in 48% of the aGVHD cases and in 50% of the cGVHD cases. 71% of the cases of aGVHD were grade III-IV, and 69% of the cases of cGVHD were severe. The overall response rate on day 28 was 53% (complete response [CR] rate, 45%) in the patients with aGVHD and 67% (CR, 23%) in those with cGVHD. Skin was the most frequently involved organ, with a response rate of 58% (CR, 49%) in the patients with aGVHD and 69% (CR 29%) in those with cGVHD. At the end of ECP treatment, 60% of patients treated for aGVHD who responded were able to stop steroid therapy, with a median dose reduction of 100%. Significant differences in overall survival were observed for patients responding to ECP with aGVHD (hazard ratio [HR], 4.3; P.001) and with cGVHD (HR, 4.8; P = .003). Our data indicate that ECP is a valid therapeutic alternative in patients with steroid-refractory aGVHD and cGVHD, permitting significant steroid dosage reductions.

Very few data exist on when a particular thrombopoietin-receptor agonist (TPO-RA) is favored in clinical practice for the treatment of patients with immune thrombocytopenia (ITP), about novel risk factors for vascular events (VE) with these drugs, nor about predictive factors for therapy free responses (TFR). We conducted an observational, retrospective, long-term follow-up multicenter study from November 2016 to January 2018 of 121 adult ITP patients initiating TPO-RA between January 2012 to December 2014. Data reflected that a platelet count ≤25 × 109/l at the time when the TPO-RA was initiated was associated with a 2.8 higher probability of receiving romiplostim vs. eltrombopag (P = 0.010). VE on TPO-RA was related to previous neoplasia in patients over 65 years (50% vs. 2.2%, P vs. 33%, P = 0.001). Receiving romiplostim as first TPO-RA with no subsequent TPO-RA switching was associated with a 50% likelihood of TFR after 2.9 years of therapy (3.3 years in chronic ITP patients). These real-world data help deciphering some areas of uncertainty, and offer insight into some of the most relevant challenges of ITP which may help clinicians make appropriate treatment decisions in the management of adult ITP patients with TPO-RA.

During platelet activation, arachidonic acid (AA) is released from membrane phospholipids and metabolized to thromboxane A2 (TXA2) through the actions of cyclooxygenase-1 (COX-1) and TXA2 synthase. Note, TXA2 binds to the platelet TXA2 receptor, causing shape change, secretion and platelet aggregation.1 Also, COX-1 (599aa; 70 kDa) has cyclooxygenase and peroxidase activities and it is functionally active as a homodimer, with each COX-1 monomer consisting of four highly conserved domains: an N-terminal signal peptide, a dimerization domain, a membrane-binding domain (MBD) and a large C-terminal catalytic domain2 (Figure 1A). Irreversible COX-1 inhibition by aspirin is a widely established anti-platelet therapy in cardiovascular disease., Fundación Mutua Madrileña, Grant/Award Number: AP172142019; Fundación Séneca, Grant/Award Number: 19873/GERM/15; Gerencia Regional de Salud, Grant/Award Numbers: 1647/A/17, 2061A/19; Instituto de Salud Carlos III (ISCIII) & Feder, Grant/Award Numbers: CB15/00055, PI17/01966, PI18/00598, PI20/00926, PI17/01311; Junta de Castilla y León; British Heart Foundation, Grant/Award Number: PG/17/40/33028; Ayuda a Grupos de Trabajo en Patología Hemorrágica; Premio López Borrasca 2019; Sociedad Española de Trombosis y Hemostasia.

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.

Platelets play a major role in hemostasis as ppwell as in many other physiological and pathological processes. Accordingly, production of about 1011 platelet per day as well as appropriate survival and functions are life essential events. Inherited platelet disorders (IPDs), affecting either platelet count or platelet functions, comprise a heterogenous group of about sixty rare diseases caused by molecular anomalies in many culprit genes. Their clinical relevance is highly variable according to the specific disease and even within the same type, ranging from almost negligible to life-threatening. Mucocutaneous bleeding diathesis (epistaxis, gum bleeding, purpura, menorrhagia), but also multisystemic disorders and/or malignancy comprise the clinical spectrum of IPDs. The early and accurate diagnosis of IPDs and a close patient medical follow-up is of great importance. A genotype–phenotype relationship in many IPDs makes a molecular diagnosis especially relevant to proper clinical management. Genetic diagnosis of IPDs has been greatly facilitated by the introduction of high throughput sequencing (HTS) techniques into mainstream investigation practice in these diseases. However, there are still unsolved ethical concerns on general genetic investigations. Patients should be informed and comprehend the potential implications of their genetic analysis. Unlike the progress in diagnosis, there have been no major advances in the clinical management of IPDs. Educational and preventive measures, few hemostatic drugs, platelet transfusions, thrombopoietin receptor agonists, and in life-threatening IPDs, allogeneic hematopoietic stem cell transplantation are therapeutic possibilities. Gene therapy may be a future option. Regular follow-up by a specialized hematology service with multidisciplinary support especially for syndromic IPDs is mandatory.

An in-depth focused study of specific cases of patients with recurrent thrombosis may help to identify novel circumstances, genetic and acquired factors contributing to the development of this disorder. The aim of this study was to carry out a detailed and sequential analysis of samples from a patient suffering from early and recurrent venous and arterial thrombosis. We performed thrombophilic tests, biochemical, functional, genetic and glycomic analysis of antithrombin and other plasma proteins. The patient carried a new type I antithrombin mutation (p.Ile218del), whose structural relevance was verified in a recombinant model. Experiments with N-glycosidase F and neuraminidase suggested a nearly full desialylation of plasma proteins, which was confirmed by mass spectrometry analysis of transferrin glycoforms. However, partial desialylation and normal patterns were detected in samples collected at other time-points. Desialylation was noticeable after arterial events and was associated with low antithrombin activity, reduced platelet count and glomerular filtration rate. This is the first description of a global and transient desialylation of plasma proteins associated with thrombosis. The decrease in the strong electronegative charge of terminal glycans may modulate hemostatic protein-protein interactions, which in combination with a strong prothrombotic situation, such as antithrombin deficiency, could increase the risk of thrombosis.

Background . In clinical practice, tapering off thrombopoietin receptor agonists (TPO-RA) in immune thrombocytopenia (ITP) is considered if therapy is no longer needed due to a decrease in the disease activity favoring sustained treatment-free responses (TFR). To date, there are no predictors to identify when this approach is likely to be successful, other than earlier start of TPO-RA, and robust platelet responses. Aim. To evaluate clinical predictors of TFR in a real-world cohort of ITP patients treated with TPO-RA by dealing with confounding variables that could be minimized at the stage of the analysis. Methods. In this retrospective, multicenter study from 19 secondary and tertiary Spanish hospitals, patients aged >18 years with chronic ITP who had initiated TPO-RA (eltrombopag [EPG] or romiplostim [ROM]) between January 2012 and December 2014 were included. Data were collected from medical records (November 2016 to January 2018) on patient characteristics, history of disease and previous therapies, TPO-RA administration, response and discontinuation. Results. A total of 82 patients with a median age of 63 years (range 19-90 years), 59.9% females initiated TPO-RA (ROM, n=37; EPG, n=45). The median time from diagnosis of ITP to therapy with TPO-RA was 5.5 years (1.1-50.3 years). In all cases the TPO-RA was started with intention to treat indefinitely; the median initial doses of EPG were 350 mg/week (175-525 mg/week), and those of ROM 2.0 μg/kg/week (1.0-7.0 μg/kg/week). The median time on TPO-RA treatment was 2.9 years (0.1 to 5.6 years), and the median follow-up from start of TPO-RA until collection of data was of 3.9 years (1.3 to 5.6 years). A total of 29 patients (35.4%) switched TPO-RA during follow-up. The most frequent cause for switching was lack of efficacy (44.8% of cases -in all cases the initial TPO-RA was EPG-). Due to switching, 58 patients received ROM, and 53 were treated with EPG, yielding 122.3, and 100.8 patient-years of total exposure, respectively. During follow-up almost one half of the patients (47.6%, n=39) stopped TPO-RA. After a median of 1.4 years (0.1-3.3 yrs) under TPO-RA treatment, 19 patients (23.2% of the whole cohort) maintained TFR defined as platelet counts >50x109/l for a median follow-up of 2.8 years (1.5-4.4 years) in the absence of any platelet increasing drug. Remarkably, while the specific TPO-RA that was discontinued did not influence the probability to achieve TFR (P=0.582), there was a trend towards receiving ROM as first TPO-RA and attaining sustained responses (P=0.073), while switching TPO-RA negatively predicted TFR (P=0.010). In univariate analysis with logistic regression, switching TPO-RA was associated with a 6.4 risk of not achieving TFR (P= 0.019). The overall comparison of the Kaplan-Meier curves indicated an association (log-rank P=0.041) among the initial TPO-RA that was prescribed and the probability of TFR (Fig 1A), but the estimated median time to achieve TFR was not reached for either TPO-RA. When switching and initial TPO-RA were considered, patients receiving ROM and not experiencing switching were the best performing group in terms of achieving TFR; the median time to taper off the drug and sustain platelet responses was 3.3 years (95% CI 2.7-4.0 years) (Fig. 1B). Conclusion. In this observational research analysis, we have tried to minimize the possible bias of some studies that could mistakenly attribute TPO-RA induced TFR, when in fact it may be the natural course of the underlying disease. By analyzing a group of chronic ITP patients with a particularly poor baseline prognosis (median time from diagnosis 5.5 years) we address potential confounding variables by disease severity. Our data show that assuring that long duration under TPO-RA therapy is provided (median of 3.3 years), one half of chronic ITP patients treated with ROM and not undergoing switching can achieve TFR. Disclosures Mingot-Castellano: Roche: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Sobi: Consultancy; Amgen: Consultancy; Novonordisk: Consultancy; CSL Behring: Consultancy. Jarque:Abbie: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Grifols: Consultancy; Gilead: Consultancy, Speakers Bureau; CellTrion: Consultancy; Celgene: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Servier: Speakers Bureau; Roche: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Shire: Consultancy, Speakers Bureau; Shionogi: Consultancy, Speakers Bureau. Campos:Novartis: Speakers Bureau; Amgen: Speakers Bureau. Lopez Fernandez:Amgen: Consultancy, Speakers Bureau. Casado:Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Álvarez Roman:Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Speakers Bureau; Sobi: Consultancy, Speakers Bureau; Takeda: Research Funding; NovoNordisk: Consultancy, Speakers Bureau.

BACKGROUND Graft-versus-host disease (GvHD) remains an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation, despite the improvements in GvHD prophylaxis. First line treatment of GvHD (acute or chronic) consists of high dose corticosteroids, with a response rate of around 50%. Extracorporeal photopheresis (ECP) is an effective and safe treatment strategy in corticosteroid refractory GvHD, although most of the studies are limited to retrospective series. The main objectives of this study were to analyze the clinical response and impact of ECP therapy in corticosteroid dose reduction. METHODS 114 patients from 7 Spanish transplantation centers were analyzed retrospectively. The characteristics of the patients are shown on Table 1. A total of 1940 ECP procedures were performed from January-2011 to June-2017 in 65 patients (57%) with acute GvHD (aGvHD) and 49 (43%) with chronic GvHD (cGvHD). Glucksberg and the NIH criteria were used for the diagnosis and grading of acute and chronic GvHD, respectively. All ECP procedures were performed with the off-line system: after the lymphoapheresis, 8-MOP was added to the apheresis product and finally photoinactivated in the Macogenic G1 (Macopharma®) irradiator. During the first 4 weeks, patients underwent 1-2 weekly procedures, followed by 1-2 procedures every 2 weeks and tailored by clinical response. The response was classified as complete response (CR), partial response (PR) or no response (NR). % of the initial corticosteroid dose reduction was registered at the end of treatment. RESULTS Patients with aGvHD underwent a median of 13 processes (interquartile range 9-19), and those with cGvHD a median of 19 processes (IQR 13-24). The median number of processes until response was 3 in patients with aGvHD and 4 for patients with cGvHD. ECP was the second line therapy in the 47% of aGvHD cases and 49% in cGvHD. 71% of the cases of aGvHD were grade 3-4, and 69% of the cases of cGvHD corresponded to severe forms. The overall response rate in aGvHD was 66% (CR 55%), whereas in cGvHD the rate was 67% (CR 22%). The most involved organ was the skin, with a response rate of 80% (CR 68%) in aGvHD and 69% (CR 22%) in cGvHD. In acute digestive GvHD, the response rate was 61% (CR 50%), and 75% (CR 50%) in the chronic form. For liver involvement, response rates were 67% (CR 57%) in acute and 70% (CR 30%) in cGvHD. 80% of the patients with chronic lung involvement showed an overall response (20%CR). At the end of ECP treatment, 71% of the patients treated for aGvHD and 61% of patients with cGvHD were able to reduce the corticosteroid dose, with a median dose reduction of 90% and 100% in all patients, respectively. With a median follow-up of 31 months in aGvHD and 68 months in cGvHD, the 2-year overall survival (OS) was 47% and 83%, respectively. Significant OS differences were noted between responding (CR+PR, 2-year OS 62%) and no responding (NR, 2 year OS 18%, HR=2.5, p CONCLUSIONS ECP is a valid therapeutic alternative in patients with corticosteroid refractory acute and cGvHD, with higher CR rates in patients with aGvHD. ECP allowed for significant corticosteroid dose reductions in more than 2/3 of the patients in both GvHD settings, and granted longer OS in responding patients. The results obtained are similar to those published by other groups. Disclosures No relevant conflicts of interest to declare.

Very few data exist on the management of adult patients diagnosed with primary immune thrombocytopenia (ITP). The objectives of this study were to describe the diagnostic and treatment patterns for ITP and to compare the findings to recent ITP guidelines. We retrospectively analyzed the medical records of adult ITP patients diagnosed with primary ITP between January 2011 and June 2012 and examined whether management strategies were consistent or not with eight recent guideline-recommended practices. Overall, median age at the diagnosis of the disease (n = 101) was 58 years and median platelet count 12 x 10(9)/L with 75.2 % of patients having symptoms of ITP. The study perceived two major shortcomings in the diagnostic approach: (1) failure to perform peripheral blood film examination in 22.8 % of patients, a test that is mandatory by all guidelines, and (2) ordinary bone marrow assessment in more than half of the patients at diagnosis (50.5 %), a test not routinely recommended by guidelines. Low appropriateness in therapeutic management of patients included (1) unjustified use of intravenous immunoglobulin in the absence of bleeding in 54.8 % of patients and (2) splenectomy not being deferred until 6-12 months from diagnosis (median 161 days). Data also reflect a trend towards the early use of thrombopoietin receptor agonists in the treatment of patients who are refractory to any first-line therapy. We have recognized important areas of inapropriateness in the diagnostic and therapeutic management of adult ITP patients. Compliance with established guidelines should be encouraged in order to improve patient outcomes.