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Introduction: There is no consensus on the management of the coronavirus disease (COVID-19) in patients with secondary immunosuppression due to either an underlying hematological disease or to the effects of immunochemotherapy (ICT). Some of them may present persistent infection with multiple relapses of COVID-19, requiring several admissions. This study evaluated the clinical characteristics and outcomes after treatment of 5 patients with follicular lymphoma (FL), previously treated with ICT, who developed several episodes of COVID-19. Methods: We analyzed the clinical evolution and response to treatment with antiviral agent, steroids, and convalescent plasma in 5 patients with FL and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persistent infection. Reverse transcriptase polymerase chain reaction tests and peripheral blood immunophenotype were performed for all patients. Results: All patients required hospitalization due to pneumonia with severity criteria and were re-admitted after a median of 22 days (13–42) from the previous discharge. They all showed B-cell depletion by immunophenotyping, and no traces of immunoglobulin antibodies against SARS-CoV-2 were detected in any of the cases. The survival rate was 80%. Conclusion: The combination therapy evidenced clinical benefits, demonstrating its capacity to control infection in immunosuppressed FL patients treated with ICT.

Background COVID-19 related in-hospital venous thromboembolism (VTE) incidence is high but data reported vary significantly. Some studies show that up to half of the events are diagnosed early after admission. Objectives To study symptomatic VTE incidence in acute COVID-19 hospitalized patients and to describe timing of VTE diagnosis. Methods Multicenter cohort of 5966 patients hospitalized with acute COVID-19. Multicenter Registry of 844 hospitalized patients with acute COVID-19 and associated acute VTE. Results By the time of cohort data collection, 68 patients (1.14%) were still hospitalized, 19.8% had died, and 5.4% required ICU. During a median follow-up of 6 days (IQR, 4–12), 183 patients (3.07%; 95% CI, 2.64–3.55) presented a symptomatic VTE event. The cumulative incidences of VTE at 7, 14 and 21 days in wards [2.3% (95% CI, 1.9–2.7), 3.6% (95% CI, 3.0–4.3), and 4.3% (95% CI, 3.5–5.1)] were similar to the ones reported in ICU [2.2% (95% CI, 1.0–4.4), 2.9% (95% CI, 1.5–5.3), and 4.1% (95% CI, 2.2–6.8)], but at 30 and 60 days were higher in ICU [6.9% (95% CI, 4.2–10.5), and 12.8% (95% CI, 8.1–18.5)] than in wards. Eighty-eight VTE events (48%) were diagnosed early, within 48 h of admission. VTE was not associated with death (HR, 0.79; 95% CI, 0.55–1.12). Conclusions Incidence of symptomatic VTE in our COVID-19 cohort is consistent with that of other real-life studies recently published. Early VTE events are, along with COVID-19, the reason for admission rather than an in-hospital complication.

Vitamin K antagonists (VKA) are the most widely used anticoagulants for the prevention of thrombotic events. Several renal adverse effects have been associated with the use of VKA. The main aim of our study was to explore the association between international normalized ratio (INR) levels and microscopic hematuria in patients with VKA.We performed a cross-sectional study of patients treated with VKA that attended the outpatient clinic for routine INR control. A simple urinalysis was performed on the day of the INR control and the precise number of red cells in the urine sediment was quantified. Demographic data, kidney function tests, comorbidities, anticoagulant dose and concomitant treatment were registered.A total of 337 patients were included with median INR levels of 2.6 (IQR 2.1-3.3). 11.9% of the patients presented microscopic hematuria (≥14 RBCs/µl). There was a significant correlation between INR levels and the number of red blood cells in the urine sediment (r = 0.201, p = 0.024). In the univariate analysis, microscopic hematuria was associated with having an INR3.5 (19% vs. 10.2%, p = 0.046), bacteriuria (15.2% vs. 3.6%, p = 0.015), leukocyturia (14.8% vs. 6.6%, p = 0.026), hypertension (16.2% vs. 9.5%, p = 0.053), and the use of renin-angiotensin system (RAS) blockers (6.9% vs. 17.2%, p = 0.004). Multivariate logistic regression showed an association between microscopic hematuria and RAS blockade (OR 0.38, CI 95% 0.163-0.886, p = 0.025), independent from INR levels, hypertension, leukocyturia or bacteriuria.INR overdose was significantly associated with the presence of microscopic hematuria. RAS blockade is an independent protective factor for the presence of microscopic hematuria in anticoagulated patients.

Background and Aims Vitamin K antagonists (VKA) are the most widely used anticoagulants in the daily clinical practice for the prevention of thrombotic events. Several renal adverse effects have been associated with the use of VKA, from hemodynamic effects due to massive urological hemorrhage associated with VKA overdose, to non-hemodynamic effects that include glomerular hemorrhage and renal tubular obstruction due to red cell casts. The main aim of our study was to establish an association between INR levels and microscopic hematuria in patients with VKA, and identify possible risk and protective factors associated with development of microscopic hematuria in these patients. Method We performed a transversal study that included patients with oral anticoagulation with coumarin derivatives (warfarin or acenocoumarol), that attended the Hematology outpatient clinic from October to December 2019 for routine INR control. A urine specimen was collected on the day of the INR control. We performed a simple urinalysis to all patients and quantified the precise number of red cells in the urine sediment by flow cytometry. Demographic data, kidney function tests including serum creatinine and albuminuria, comorbidities, anticoagulant dose and concomitant treatment were registered. Results 337 patients were included in the study, with an average age of 68.6 ± 12.2 years, 51% were females, 95% were treated with acenocoumarol and 5% with warfarin. Median INR levels were 2.6 (IQR 2.1-3.3) and the median number of urine red cells in the sediment were 11 RBCs/µl (IQR 0-13). 11.9% of the patients presented microscopic hematuria (≥14 RBCs/µl). There was a significant correlation between INR levels and the number of RBCs in the urine sediment (Spearman’s rho= 0.119, p= 0.029), independent from the type of anticoagulant used. This correlation was stronger after excluding those patients who had concomitant bacteriuria (Spearman’s rho= 0.201, p= 0.024). We found no correlation between time elapsed from start of anticoagulation or total weekly dose with the intensity of microscopic hematuria. In the univariate analysis, microhematuria was associated with having an INR >3.5 (19% vs. 10.2%, p=0.046), bacteriuria (15.2% vs. 3.6%, p=0.015), leukocyturia (14.8% vs. 6.6%, p= 0.026), hypertension (16.2% vs. 9.5%, p=0.053), and the use of RAAS blockers (17.2% vs. 6.9%, p=0.004). After performing a multivariate logistic regression that included the aforementioned variables, the association between microhematuria and RAAS blockade with either an ACE inhibitor or ARB was maintained (OR 0.38, CI 95% 0.163-0.886, p=0.025), independent from INR levels, hypertension, leukocyturia or bacteriuria. We found no association between serum creatinine, albuminuria or antiplatelet treatment with the presence of microscopic hematuria. Conclusion INR overdose is significantly associated with the presence of microscopic hematuria, independent from the type of VKA used or the total weekly dose. RAAS blockade is an independent protective factor for the presence of microscopic hematuria in anticoagulated patients.

The clinical diagnosis of von Willebrand disease (VWD), particularly type 1, can be complex because several genetic and environmental factors affect von Willebrand factor (VWF) plasma levels. An estimated 60% of the phenotypic variation is attributable to hereditary factors, with the ABO blood group locus being the most influential. However, recent studies provide strong evidence that nonsynonymous single nucleotide variants (SNVs) contribute to VWF and factor VIII phenotypic variability in healthy individuals. This study aims to investigate the role of common VWF SNVs on VWD phenotype by analyzing data from 219 unrelated patients included in the “Molecular and Clinical Profile of von Willebrand Disease in Spain project.” To that end, generalized linear mixed-effects regression models were fitted, and additive and epistatic analyses, and haplotype studies were performed, considering five VWD-related measures (bleeding score, VWF:Ag, VWF:RCo, factor VIII:C, and VWF:CB). According to these analyses, homozygotes: for p.Thr789Ala(C) would be expected to show 39% higher VWF:Ag levels; p.Thr1381Ala(C), 27% lower VWF:Ag levels; and p.Gln852Arg(C), 52% lower VWF:RCo levels. Homozygotes for both p.Thr789Ala(C) and p.Gln852Arg(T) were predicted to show 185% higher VWF:CB activity, and carriers of two copies of the p.Thr1381Ala(T)/p.Gln852Arg(T) haplotype would present a 100% increase in VWF:RCo activity. These results indicate a substantial effect of common VWF variation on VWD phenotype. Although additional studies are needed to determine the true magnitude of the effects of SNVs on VWF, these findings provide new evidence regarding the contribution of common variants to VWD, which should be taken into account to enhance the accuracy of the diagnosis and classification of this condition. ClinicalTrials.gov identifier: NCT02869074.

Background Antithrombotic prophylaxis in hospitalised patients with SARS-CoV-2 acute infection has increased. Currently, most of the evidence relates to patients in intensive care units; however, there is little information on patients admitted to hospital wards and there is no consensus protocol on thromboprophylaxis during admission and after discharge. Objective To assess the effectiveness of antithrombotic prophylaxis in patients admitted with COVID-19 and 30 days after discharge. Method A prospective observational study was conducted of patients admitted with COVID-19 in which the hospital thromboprophylaxis protocol was applied, classifying the patients as having a standard or high risk of thrombosis. Pharmacists performed a daily follow-up and actively intervened during admission and at discharge. The main outcome measure was the global incidence of symptomatic venous thromboembolism (VTE) related to hospitalisation. Results A total of 113 patients were included, 98.23% of whom were admitted to a hospital ward. The incidence of hospital-acquired VTE was 1.77%. In 75.22% of the subjects, thromboprophylaxis was adjusted to the protocol during admission. A total of 23 pharmaceutical interventions were conducted, with an adherence of 52.17%. At discharge, 94.28% of the patients who had no haemorrhage and ≥4 points on the Padua Prediction Score required thromboprophylaxis, aligning with the protocol. The global incidence of haemorrhagic events during the follow-up period was 0.88%. Conclusion The incidence of hospital-acquired VTE was lower than that described in the literature. Although it cannot be certain that it is directly related to the instituted protocol, the data can show that the management of prevention of VTE is being optimally performed at the hospital. Long-term studies are needed to evaluate the incidence after discharge, as well as to agree on a specific protocol in the COVID-19 population for the prevention of these events during hospitalisation and post-discharge.

SummaryThe diagnosis of von Willebrand disease (VWD) remains difficult in a significant proportion of patients. A Spanish multicentre study investigated a cohort of 556 patients from 330 families who were analysed centrally. VWD was confirmed in 480. Next generation sequencing (NGS) of the whole coding VWF was carried out in all recruited patients, compared with the phenotype, and a final diagnosis established. A total of 238 different VWF mutations were found, 154 were not included in the Leiden Open Variation Database (LOVD). Of the patients, 463 were found to have VWF mutation/s. A good phenotypic/ genotypic association was estimated in 96.5 % of the patients. One hundred seventy-four patients had two or more mutations. Occasionally a predominant phenotype masked the presence of a second abnormality. One hundred sixteen patients presented with mutations that had previously been associated with increased von Willebrand factor (VWF) clearance. RIPA unavailability, central phenotypic results disagreement and difficult distinction between severe type 1 and type 3 VWD prevented a clear diagnosis in 70 patients. The NGS study facilitated an appropriate classification in 63 of them. The remaining seven patients presented with a VWF novel mutation pending further investigation. In five patients with a type 3 and two with a type 2A or 2B phenotype with no mutation, an acquired von Willebrand syndrome (AVWS) was suspected/confirmed. These data seem to support NGS as a first line efficient and faster paradigm in VWD diagnosis.Supplementary Material to this article is available online at www.thrombosis-online.com.

The correct diagnosis and classification of von Willebrand disease (VWD) is difficult because of the variability of its clinical expression and limitations of laboratory methods. However, correctly diagnosing VWD is important for therapy and genetic counselling. A survey related to the referred VWD patients in Spain revealed local diagnostic problems in at least one third of the cases of VWD. Consequently, a Spanish multicenter study was carried out in which a cohort of 556 patients from 330 families was analyzed centrally. VWD was confirmed in 480 patients. Next generation sequencing (NGS) of the whole coding von Willebrand factor gene ( VWF ) was carried out in all recruited patients, compared with the phenotype, and a final diagnosis was established. A total of 238 different VWF mutations were found: 154 were not included in the Leiden Open Variation Database (LOVD). Of the patients, 467 were found to have a VWF mutation/s. A good phenotype/genotype association was estimated in 94.6% of the cases. One hundred and eighty patients had two or more mutations. Occasionally a predominant phenotype masked the presence of a second abnormality. One hundred and sixteen patients presented with mutations that had previously been associated with an increased VWF clearance. Ristocetin induced platelet agglutination (RIPA) unavailability, central phenotypic results disagreement and difficult distinction between severe type 1 and type 3 VWD prevented a clear diagnosis in 74 patients. A local/central disagreement over diagnosis occurred in 42.3% of the whole cohort. The NGS study facilitated an appropriate classification in 60 of them. Based on these results, a proposal for a change in the VWD diagnostic paradigm, suggesting the inclusion of the analysis of VWF at the initial diagnostic process, has been made. An extension of this project to include 400 new VWD patients has begun. A diagnostic strategy has been developed, and a Spanish consensus guideline for optimal treatment of VWD was developed in Spain. Desmopressin (DDAVP) is the treatment of choice in responsive VWD patients. VWF concentrates (VWF/FVIII) are used in individuals unresponsive to DDAVP, when DDAVP is contraindicated, or in VWD types 2B and 3, and for long term management needs (e.g., post major surgery).

Objectives Patients with aggressive non-Hodgkin’s lymphoma (NHL) and acute lymphoblastic leukemia (ALL) with high risk of CNS infiltration or recurrence may receive prophylaxis or be treated with intrathecal injections (IT) of liposomal cytarabine (LC) once every 2 weeks (due to its sustained release of cytarabine). Sequential flow cytometric studies in patients with CNS involvement and treated with LC, allow to detect tumor cells as well as LC liposomes (LCL) in the CSF. The true meaning of the presence of these liposomes during the treatment with LC is still unknown. Patients and Methods In this study, we aimed to investigate the presence of LCL detected by Flow Cytrometry (FC) among 166 CSF samples of 69 patients treated with LC. Samples were taken before each administration of intrathecal LC and centrally processed. Results Results are shown in the below table. | | N | | | -------------------------------------------------------------------------------------- | -------- | ------------------------------------------------------------------------------------- | ----------------------- | | Patients | 69 | | | Samples | 166 | | | Liposomal Cytarabine Liposomes (LCL) in CSF | | | N | % | | | Patients | 13 | 19% | | | DLBCL | 6 | 46% | | | LLT | 2 | 15% | | | ALL | 2 | 15% | | | MCL | 1 | 8% | | | MM | 1 | 8% | | | CLL | 1 | 8% | | | Samples | 26 | 16% | | | Males | 8 | 62% | | | | 26 | 16% | | | Age | 66 years | [33-84] | | | LCL in CSF of patients receiving Liposomal Cytarabine PROPHYLAXIS | | | N | Toxycity | Total no of IT LC doses | | Patients | 7 | | | | no of IT LC doses* | 3 (2-5). | | | | LCL | 7 | | | | After 1st dose | 5 | | | | After 2nd dose | 2 | 1 LLT patient: arachnoiditis, high intrathecal pressure, papillitis, without sequelae | 5 | | After 3rd dose | 2 | | | | After 5th dose | 1 | | | | LCL in CSF of patients receiving Liposomal Cytarabine leptomeningeal disease TREATMENT | | | N | Tumor: Toxycity | Total no of IT LC doses | | Patients | 6 | | | | no of IT LC doses* | 6 (4-7) | | | | LCL | 6 | | | | After 1st dose | 3 | 1 DLBCL patient: Headache, dizziness and instability | 5 | | | | 1 MM patient: Headache, dizziness and instability | 4 | | After 3rd dose | 2 | | | | After 5th dose | 1 | 1 ALL patient: Headache, dizziness and instability | 7 | | * Median [range] | Abstract 5444. Table 1 Patients with NHL/ALL, treated with Intrathecal Liposomal Cytarabine The thirteen patients were simultaneously treated with LC and IT + IV dexamethasone. It was found no relationship between the amount of LCL and toxicity. Conclusions: Presence of LCL in CSF is detected in 15-20% of patients receiving IT LC as prophylaxis / treatment and it does not show a direct relationship with presence of toxicity. Although the true clinical significance of the presence of LCL in CSF remains unknown, their monitoring could be useful to individualize the treatment with CL IT (dose and time between doses). Disclosures Off Label Use: Liposomal cytarabine is not approved for prophylaxys of lymphomatous meningitis..