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von Willebrand disease (VWD) is the most common inherited bleeding disorder. The management of patients with VWD who are undergoing surgeries is crucial to prevent bleeding complications. We systematically summarized the evidence on the management of patients with VWD who are undergoing major and minor surgeries to support the development of practice guidelines. We searched Medline and EMBASE from inception through October 2019 for randomized clinical trials (RCTs), comparative observational studies, and case series that compared maintaining factor VIII (FVIII) levels or von Willebrand factor (VWF) levels at >0.50 IU/mL for at least 3 days in patients undergoing major surgery, and those with options for perioperative management of patients undergoing minor surgery. Two authors screened and abstracted data and assessed the risk of bias. We conducted meta-analyses when possible. We evaluated the certainty of the evidence using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. We included 7 case series for major surgeries and 2 RCTs and 12 case series for minor surgeries. Very-low-certainty evidence showed that maintaining FVIII levels or VWF levels of >0.50 IU/mL for at least 3 consecutive days showed excellent hemostatic efficacy (as labeled by the researchers) after 74% to 100% of major surgeries. Low- to very-low-certainty evidence showed that prescribing tranexamic acid and increasing VWF levels to 0.50 IU/mL resulted in fewer bleeding complications after minor procedures compared with increasing VWF levels to 0.50 IU/mL alone. Given the low-quality evidence for guiding management decisions, a shared-decision model leading to individualized therapy plans will be important in patients with VWD who are undergoing surgical and invasive procedures.

Background: von Willebrand disease (VWD) is a common inherited bleeding disorder. Significant variability exists in management options offered to patients. Objective: These evidence-based guidelines from the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis (ISTH), the National Hemophilia Foundation (NHF), and the World Federation of Hemophilia (WFH) are intended to support patients, clinicians, and health care professionals in their decisions about management of VWD. Methods: ASH, ISTH, NHF, and WFH formed a multidisciplinary guideline panel. Three patient representatives were included. The panel was balanced to minimize potential bias from conflicts of interest. The University of Kansas Outcomes and Implementation Research Unit and the McMaster Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline development process, including performing and updating systematic evidence reviews (through November 2019). The panel prioritized clinical questions and outcomes according to their importance to clinicians and patients. The panel used the GRADE approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. Results: The panel agreed on 12 recommendations and outlined future research priorities. Conclusions: These guidelines make key recommendations regarding prophylaxis for frequent recurrent bleeding, desmopressin trials to determine therapy, use of antiplatelet agents and anticoagulant therapy, target VWF and factor VIII activity levels for major surgery, strategies to reduce bleeding during minor surgery or invasive procedures, management options for heavy menstrual bleeding, management of VWD in the context of neuraxial anesthesia during labor and delivery, and management in the postpartum setting.

Essential thrombocythemia (ET) is characterized by abnormal megakaryopoiesis and enhanced thrombotic risk. Once-daily low-dose aspirin is the recommended antithrombotic regimen, but accelerated platelet generation may reduce the duration of platelet cyclooxygenase-1 (COX-1) inhibition. We performed a multicenter double-blind trial to investigate the efficacy of 3 aspirin regimens in optimizing platelet COX-1 inhibition while preserving COX-2–dependent vascular thromboresistance. Patients on chronic once-daily low-dose aspirin (n = 245) were randomized (1:1:1) to receive 100 mg of aspirin 1, 2, or 3 times daily for 2 weeks. Serum thromboxane B2 (sTXB2), a validated biomarker of platelet COX-1 activity, and urinary prostacyclin metabolite (PGIM) excretion were measured at randomization and after 2 weeks, as primary surrogate end points of efficacy and safety, respectively. Urinary TX metabolite (TXM) excretion, gastrointestinal tolerance, and ET-related symptoms were also investigated. Evaluable patients assigned to the twice-daily and thrice-daily regimens showed substantially reduced interindividual variability and lower median (interquartile range) values for sTXB2 (ng/mL) compared with the once-daily arm: 4 (2.1-6.7; n = 79), 2.5 (1.4-5.65, n = 79), and 19.3 (9.7-40; n = 85), respectively. Urinary PGIM was comparable in the 3 arms. Urinary TXM was reduced by 35% in both experimental arms. Patients in the thrice-daily arm reported a higher abdominal discomfort score. In conclusion, the currently recommended aspirin regimen of 75 to 100 once daily for cardiovascular prophylaxis appears to be largely inadequate in reducing platelet activation in the vast majority of patients with ET. The antiplatelet response to low-dose aspirin can be markedly improved by shortening the dosing interval to 12 hours, with no improvement with further reductions (EudraCT 2016-002885-30).

Type 3 von Willebrand disease (VWD3) is a rare and severe bleeding disorder characterized by often undetectable von Willebrand factor (VWF) plasma levels, a recessive inheritance pattern, and heterogeneous genotype. The objective of this study was to identify the VWF defects in 265 European and Iranian patients with VWD3 enrolled in 3WINTERS-IPS (Type 3 Von Willebrand International Registries Inhibitor Prospective Study). All analyses were performed in centralized laboratories. The VWF genotype was studied in 231 patients with available DNA (121 [115 families] from Europe [EU], and 110 [91 families] from Iran [IR]). Among 206 unrelated patients, 134 were homozygous (EU/IR = 57/77) and 50 were compound heterozygous (EU/IR = 43/7) for VWF variants. In 22 patients, no or only one variant was found. A total of 154 different VWF variants (EU/IR = 101/58 [5 shared]) were identified among the 379 affected alleles (EU/IR = 210/169), of which 48 (EU/IR = 18/30) were novel. The variants p.Arg1659*, p.Arg1853*, p.Arg2535*, p.Cys275Ser, and delEx1_Ex5 were found in both European and Iranian VWD3 patients. Sixty variants were identified only in a single allele (EU/IR = 50/10), whereas 18 were recurrent (≥3 patients) within 144 affected alleles. Nine large deletions and one large insertion were found. Although most variants predicted null alleles, 21% of patients carried at least 1 missense variant. VWD3 genotype was more heterogeneous in the European population than in the Iranian population, with nearly twice as many different variants. A higher number of novel variants were found in the Iranian VWD3 patients.

Introduction: Anticoagulation plays a crucial role in the treatment of splanchnic vein thrombosis (SVT), including thrombosis of the portal (PVT), mesenteric (MVT) and splenic (SpVT) veins. Rivaroxaban is a potential alternative to heparins and vitamin K antagonists (VKA) in these patients, but data to support its use are scant. Several recent guidelines highlighted the limited evidence available for the use of the direct oral anticoagulants in these patients. In addition, despite anticoagulation, SVT patients carry high risk of recurrent venous thromboembolic events. The aim of this study was to evaluate the safety and efficacy of rivaroxaban for the acute-phase treatment of SVT (first 3 months of treatment). Methods: RIVASVT-100 (NCT02627053) was a prospective cohort study of adult patients with a first episode of symptomatic, objectively diagnosed PVT, MVT or SpVT. Exclusion criteria were known liver cirrhosis, Budd-Chiari syndrome, previous or ongoing variceal bleeding, portal cavernoma, thrombocytopenia, severe renal failure, life expectancy 7 days, ongoing VKA treatment. Patients received rivaroxaban 15 mg twice daily for 3 weeks, followed by 20 mg once daily for a total of 3 months. Afterwards, the decision to continue any available anticoagulant drug was left to the discretion of the attending physicians. Follow-up was performed at 3 weeks, 2 months, 3 months and 6 months. Primary outcome was the occurrence of ISTH-defined major bleeding events during the 3 months of active treatment and up to 2 days after the end of study treatment. Secondary outcomes included death, clinically relevant non-major bleeding (CRNMB), recurrent SVT or symptomatic venous thromboembolism in other sites. We here report the results of the 3-month follow-up. Results: Between June 2015 and March 2021, 103 patients were enrolled from 18 participating centres. After excluding 3 patients who did not meet the criteria for eligibility, 100 patients were included in the analysis. Mean (SD) age was 54.4 (± 15.5) years; 64% were males. Overall, 74% of patients had PVT, 61% MVT and 48% SpVT; 53% of SVT occurred in multiple sites. The most common risk factors were abdominal inflammation/infection (26%), followed by solid cancer (9%), overt myeloproliferative neoplasms (9%) and oestrogen hormonal therapy (9%), while 43% of cases were unprovoked. The JAK2 V617F mutation was detected in 13 out of 50 tested patients (26%). Rivaroxaban was the sole anticoagulant agent used in 21% of patients, whereas the remaining received a combination of anticoagulants, which included low molecular weight heparin, unfractionated heparin or fondaparinux for a median of 5.0 days before transitioning to rivaroxaban. Three patients were lost to follow-up but known to be alive at the end of the study. At 3-month follow-up, 1 (1.0%) patient died due to a non-SVT related cause. Two patients (2.06%; 95% CI, 0.57-7.21) had major bleeding events (both gastrointestinal), while 3 patients (3.09%) had CRNMB. There were 2 recurrent SVT (2.06%) during rivaroxaban treatment, one of these occurred in a patient with metastatic solid cancer. The 6-month follow-up for the last enrolled patient is ongoing. Conclusions: Rivaroxaban appears to be safe and effective for the acute-phase treatment of SVT in non-cirrhotic patients. Disclosures Beyer-Westendorf: Bayer: Other: Personal fees; Daiichi Sankyo: Other: Personal fees; Pfizer: Other: Personal fees; Portola-Alexion: Other: Personal fees. Carrier: BMS: Honoraria, Research Funding; Leo Pharma: Honoraria, Research Funding; Bayer: Honoraria; Pfizer: Honoraria, Research Funding; Servier: Honoraria; Sanofi: Honoraria. Bertoletti: BMS: Honoraria, Other: Personal Fees; Pfizer: Honoraria, Other: Personal fees; Aspen: Other: Personal Fees; Bayer: Other: Personal Fees; Leo Pharma: Other: Personal Fee. Di Nisio: Bayer, Daiichi Sankyo, BMS-Pfizer, Leo Pharma, and Sanofi: Other: Personal fees. Ageno: Bayer: Research Funding; Bayer, Portola, Janssen, Aspen, Norgine, Sanofi.: Other: Advisory Board. OffLabel Disclosure: The use of rivaroxaban in splanchnic vein thrombosis is off label in most countries.

Background Although combined oral contraceptives (COC) are considered a transient risk factor for venous thromboembolism (VTE), the risk of recurrence after discontinuation of anticoagulation is unclear. Few studies have focused on the risk of recurrence in this group; studies report variable results and are limited by small sample size. The risk of recurrence appears to be low, but this could relate to the young age of affected women. Deciphering the absolute VTE recurrence risk after a COC-associated VTE is crucial in helping clinicians and patients decide if anticoagulation could be discontinued after the initial treatment period. Objectives The objectives of this systematic review and meta-analysis are to estimate the incidence of recurrent VTE among women with COC-associated VTE, compared with women with unprovoked VTE. Methods We searched the following databases: Cochrane Central Register of Controlled Trial, Cochrane Database of Systematic Reviews, Embase Classic +Embase, and Medline ALL, all from the OvidSP platform, from the database's inception to July 2020. Additional studies were identified by screening citations from included studies. Prospective cohort studies, randomized controlled trials (RCTs), and meta-analyses of prospective cohort studies or RCTs were reviewed by two authors for study inclusion (Figure 1). Studies were included if women had objectively confirmed COC-associated VTE, received a minimum of three months of anticoagulation, discontinued COC prior to or at time of discontinuation of anticoagulation, time of follow-up began after anticoagulation was stopped, and recurrent VTE data was available. Studies were excluded if patients were systematically treated with an alternative pharmacologic agent intended to reduce the risk of recurrent VTE such as aspirin. Authors of identified papers were contacted for additional data on critical variables. If there were multiple publications from a cohort, the study with the longest follow up was included. Two authors extracted study data and assessed included studies for risk of bias using the Newcastle Ottawa Scale. Meta-analysis was done using a random effects Poisson regression model. Heterogeneity was assessed using the I-squared measure. Results Our systematic review included 19 studies with a total of 1,537 women (5,828 patient years of follow up) with an index COC-associated VTE, and 1,974 women (7,798 patient years of follow up) with an index unprovoked VTE. Authors contributed additional unpublished data in 16 of the 19 studies. Overall, studies were at low risk of bias, with a mean of 7 stars (out of a possible 9) in the Newcastle Ottawa Scale. Among the 19 studies, the incidence rate of VTE recurrence in women with COC-associated VTE was 1.22 per patient year (95% confidence interval (CI) 0.94 to 1.59, I 2 = 6.4%, 95% prediction interval (PI) 0.81 to 1.85) (Figure 2). The incidence rate of VTE recurrence in women with an index unprovoked VTE not associated with COC was 3.89 per patient year (95% CI 2.98 to 5.07, I 2 =74.2%, 95% PI 1.37 to 11.03). The unadjusted incidence rate ratio of recurrent VTE comparing women with COC-associated events to women with unprovoked events was 0.34 (95% CI 0.26 to 0.45, I 2 = 2.6%, 95% PI 0.26 to 0.46). Only three studies had age-adjusted comparisons, but each with a different effect measure so they could not be combined, with a relative risk ratio 0.4 (95% CI 0.2 to 0.8) (also adjusted for site of VTE and congenital thrombophilia) (Eischer 2014), a hazard ratio of 0.11 (95% CI 0.01 to 0.85) (Kearon 2019), and an incidence rate ratio of 1 (95% CI 0.3 to 3.2) (Le Moigne 2013). Conclusions The estimated risk of VTE recurrence after a COC-associated VTE is low, and is lower compared to women with unprovoked VTE, however this comparison may be confounded by age. With only a minority of studies providing age adjusted analyses, the true difference remains unknown. Our meta-analysis is strengthened by the substantial contribution of unpublished data from individual study authors. This can help to guide clinicians and patient shared decision-making on the duration of anticoagulation. Figure 1 Figure 1. Disclosures Le Gal: LEO Pharma: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Bayer: Honoraria; Aspen: Honoraria; Sanofi: Honoraria. Schulman: Boehringer-Ingelheim: Research Funding; Octapharma: Research Funding. Skeith: CSL Behring: Research Funding; Leo Pharma: Honoraria; Sanofi: Honoraria.

Rivaroxaban is an effective and safe alternative to warfarin in patients with atrial fibrillation and venous thromboembolism. We tested the efficacy and safety of rivaroxaban compared with warfarin in high-risk patients with thrombotic antiphospholipid syndrome. This is a randomized open-label multicenter noninferiority study with blinded end point adjudication. Rivaroxaban, 20 mg once daily (15 mg once daily based on kidney function) was compared with warfarin (international normalized ratio target 2.5) for the prevention of thromboembolic events, major bleeding, and vascular death in patients with antiphospholipid syndrome. Only high-risk patients triple positive for lupus anticoagulant, anti-cardiolipin, and anti-β2-glycoprotein I antibodies of the same isotype (triple positivity) were included in the study. The trial was terminated prematurely after the enrollment of 120 patients (59 randomized to rivaroxaban and 61 to warfarin) because of an excess of events among patients in the rivaroxaban arm. Mean follow-up was 569 days. There were 11 (19%) events in the rivaroxaban group, and 2 (3%) events in the warfarin group. Thromboembolic events occurred in 7 (12%) patients randomized to rivaroxaban (4 ischemic stroke and 3 myocardial infarction), whereas no event was recorded in those randomized to warfarin. Major bleeding occurred in 6 patients: 4 (7%) in the rivaroxaban group and 2 (3%) in the warfarin group. No death was reported. The use of rivaroxaban in high-risk patients with antiphospholipid syndrome was associated with an increased rate of events compared with warfarin, thus showing no benefit and excess risk. This trial was registered at www.clinicaltrials.gov as #NCT02157272.

The PROLONG randomized trial showed that a normal D-dimer (D-d) 1 month after anticoagulation suspension for unprovoked venous thromboembolism (VTE) was associated with a low risk of late recurrences (4.4% patient years). However, it is unknown whether D-d changes subsequently. The aim of this prospective multicenter study was to assess D-d time course and its relation with late recurrences in patients with normal D-d 1 month after anticoagulation suspension for a first episode of unprovoked VTE. D-d was measured with a qualitative method (Clearview Simplify D-dimer; Inverness Medical Professional Diagnostics). Patients with a normal D-d 1 month after stopping anticoagulation repeated D-d testing every 2 months for 1 year. D-d was normal in 68% (243/355) of patients 1 month after anticoagulation suspension. Patients in whom D-d became abnormal at the third month and remained abnormal afterward had a higher risk of recurrence (7/31; 27% patient years; 95% confidence interval [CI]: 12-48) than patients in whom D-d remained normal at the third month and afterward (4/149; 2.9% patient years; 95% CI: 1-7; adjusted hazard ratio: 7.9; 95% CI: 2.1-30; P = .002). Repeated D-d testing after anticoagulation suspension for a first episode of unprovoked VTE could help tailor the duration of treatment. This trial is registered at http://clinicaltrials.gov as NCT00266045.

In a previous publication on new terminology, definitions, and outcome criteria for immune thrombocytopenia (ITP), the International Working Group (IWG) on ITP acknowledged that response to treatment should consist of clinically meaningful end points such as bleeding manifestations and that platelet count may not be the ideal parameter for capturing the benefits of therapy. The IWG now proposes a consensus-based ITP-specific bleeding assessment tool (ITP-BAT) with definitions and terminology consistent with those adopted for other bleeding disorders. Bleeding manifestations were grouped into three major domains: skin (S), visible mucosae (M), and organs (O), with gradation of severity (SMOG). Each bleeding manifestation is assessed at the time of examination. Severity is graded from 0 to 3 or 4, with grade 5 for any fatal bleeding. Bleeding reported by the patient without medical documentation is graded 1. Within each domain, the same grade is assigned to bleeding manifestations of similar clinical impact. The “worst bleeding manifestation since the last visit” (observation period) is graded (a suitable database collection form is provided), and the highest grade within each domain is recorded. The SMOG system provides a consistent description of the bleeding phenotype in ITP, and the IWG unanimously supports its adoption and validation in future clinical studies.

Although rare, type 3 von Willebrand disease (VWD3) is of major interest because of its severe clinical presentation, the need for replacement therapy with von Willebrand Factor (VWF) concentrates and the risk of anti-VWF inhibitors. To better characterize the clinical and laboratory features of this rare inherited bleeding disorder, a large cohort of VWD3 patients has been enrolled into the type 3 Von Willebrand International RegistrieSInhibitor Prospective Study. 3WINTERS-IPS is a no-profit, investigators initiated, multicenter, European-Iranian (EU-IR) observational, retrospective and prospective study on patients with VWD3 diagnosis. One of the aims of 3WINTERS-IPS is to assess the efficacy and safety of VWF concentrates with or without FVIII, including the risk of anti-VWF antibodies, in a large cohort of centrally confirmed VWD3 patients. A total of 260 previously diagnosed VWD3 cases were enrolled into the study from 18-EU and 7-IR investigation sites (retrospective registries) and reassessed by 5 expert labs for phenotypic and genotypic analyses to confirm VWD3 diagnosis (central confirmation). Only 201/260 (77%) cases with centrally confirmed VWD3 diagnosis were included into the 24-month clinical observation (prospective phase) registered as NCT02460458 into Clinical-Trials.gov. All the clinical and laboratory data were reported by investigators into the database online organized by a CRO under the direct supervision of the Scientific Coordinators. Clinical results on the efficacy and safety of VWF concentrates during the first 18-month observation are currently available on 149/201 (74%) VWD3 patients (EU=62/IR=87) with the following sex (M/F) and age (Mean-SD, Median) distribution: 86/115 and 28.9-18, 27. Anti-VWF antibodies were confirmed in 16/201 (8%) VWD3: these patients are under treatment with recombinant FVIII without VWF or recombinant activated Factor VII. Being 3WINTERS-IPS a non-interventional study, the therapeutic approaches such as on demand (OD) or secondary long-term prophylaxis (SLTP) with the assigned VWF concentrates with or without FVIII (FANHDI, HAEMATE-P, WILATE, WILFACTIN) were decided by local investigators. The number of VWD3 treated OD/SLTP were 106/43 with more cases under SLTP at EU than at IR sites (28/15). Cases under OD/SLTP with bleeds were 73/106(69%) of OD and 21/43(48%) of SLTP. To compare the results of OD/SLTP groups, data obtained were divided by case number and by months to calculate the mean (range) annual bleeding rate (ABR). ABR observed so far in OD/SLTP is 4.3 (2.8-5.8)/3.1(1.4-3.8) with nose (29/28%), joint (19/24%), uterus (13/23%) bleeds being the most frequent sites. To manage (OD) or prevent (SLTP) bleeds the mean (range) consumption of VWF:RCo units of VWF concentrates per patient were 4800 (1800-15.500) and 8000 (5000-10.500) units, respectively. During follow-up VWD3 patients under OD/SLTP were exposed to 17/10 minor/major surgeries with 14.900 (9.500-22.000)/17.200 (12.800-31.000) VWF:RCo Units used per surgery. Efficacy of the different VWF concentrates was reported as good/excellent during bleeds and surgeries. No side effects related to VWF concentrates were reported by investigators: no additional anti-VWF antibodies were found after the use of VWF concentrates. Based on this interim analyses on the largest cohort of VWD3 currently under prospective observation, the frequency of spontaneous bleeds assessed by ABR seems lower than expected by the severe VWF defect of VWD3. So far, the use of SLTP seems to reduce the ABR. However, a longer prospective observation (from 2 to 5 years) with 3WINTERS-IPS-EXTENDED is required to characterize bleeding phenotype of VWD3 patients and to prepare recommendations on the appropriate use (OD/SLTP) of the VWF concentrates Disclosures Leebeek: Uniqure: Research Funding; Baxalta/Shire: Research Funding; CSL Behring: Research Funding. Peyvandi:Kedrion: Consultancy; Kedrion: Consultancy; Kedrion: Consultancy; Novo Nordisk: Speakers Bureau; Novo Nordisk: Speakers Bureau; Grifols: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Grifols: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Octapharma US: Honoraria; Roche: Speakers Bureau; Shire: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Kedrion: Consultancy; Grifols: Speakers Bureau; Kedrion: Consultancy; Novo Nordisk: Speakers Bureau; Grifols: Speakers Bureau; Grifols: Speakers Bureau; Novo Nordisk: Speakers Bureau; Roche: Speakers Bureau; Novo Nordisk: Speakers Bureau; Roche: Speakers Bureau; Roche: Speakers Bureau; Shire: Speakers Bureau; Sobi: Speakers Bureau; Roche: Speakers Bureau; Shire: Speakers Bureau; Shire: Speakers Bureau; Octapharma US: Honoraria; Sobi: Speakers Bureau; Sobi: Speakers Bureau; Shire: Speakers Bureau; Sobi: Speakers Bureau; Octapharma US: Honoraria; Octapharma US: Honoraria; Sobi: Speakers Bureau; Octapharma US: Honoraria. Eikenboom:CSL: Research Funding.

Type I von Willebrand disease (VWD) is the most frequent bleeding disorder, with a prevalence of 10-50 cases per 10,000 persons. VWD usually shows an autosomal dominant inheritance pattern, at least in families having VWF:Ag levels below 30 IU/dL. There is considerable uncertainty whether patients having only mildly reduced VWF levels (in the range 30-50 IU/dL) should be diagnosed as having VWD or if they should be considered as a separate clinical entity, broadly referred to as "reduced VWF patients." We hypothesize that these patients may have a clinically distinct bleeding pattern, in terms of presenting symptoms at diagnosis, bleeding severity, and possibly even clinical. We pooled data from three cohorts of patients. The MCMDM-1 VWD Study is a multicenter survey on type 1 VWD that recruited 154 type 1 VWD families from nine European countries. The Kingston cohort recruited consecutive patients with type 1 VWD diagnosed in Kingston, Canada and includes patients screened because of bleeding symptoms or family history of VWD over a 10 year period. The Zimmerman Program for the Molecular and Clinical Biology of VWD is a multicenter study that enrolled VWD patients mostly from US clinical centres, primarily carrying a diagnosis of type 1 VWD (315 families) but also including type 2 and type 3 subjects. For the present study, only patients with a confirmed diagnosis of type 1 VWD were retained. From the three cohorts, demographic, laboratory and clinical data were abstracted, including severity of bleeding symptoms classified according to the MCMDM-1 study criteria. Only data from index cases and affected family members were retained for the present analysis. Bleeding symptoms receiving a score >=2 (and therefore requiring some type of medical intervention) were classified as "clinically relevant". VWF:Ag and VWF:RCo were measured centrally by the reference core lab of each of the three studies, against the WHO International Standard. For this purpose of the present study, Type 1 VWD is defined as VWF:Ag levels (or VWF:RCo for the Zimmerman Program) below 30 IU/dL; affected family members and index cases with VWF:Ag levels equal or above 30 IU/dL were classified as "low-VWF" patients. Pooled data from the three studies resulted in 1411 patients. At multivariate analysis, blood group O females with lower bleeding scores were the characteristics associated with the "low-VWF" patients; interestingly, the number of clinically relevant bleeding symptoms was associated with the phenotype independently from the total bleeding score. For all considered bleeding symptoms, VWD patients had a higher prevalence of relevant bleeding, with the notable exception of menorrhagia. Particularly in index cases, menorrhagia but also post-surgical bleeding was increased in patients having the "low-VWF" phenotype, although only for menorrhagia the difference was statistically significant (p=0.022). Unsupervised cluster analysis of symptom distribution disclosed three subgroups of patients. The first two were composed by males (first group) or females (second group), both having few or none bleeding symptoms. The third identified by unsupervised cluster analysis group was composed of highly symptomatic patients, predominantly women. In these patients, mucous ("wet") bleeding (epistaxis and menorrhagia) was common together with post-surgical or extraction bleeding. This pattern was not correlated with mean VWF:Ag level or "low-VWF" or Type 1 VWD phenotype. We conclude that "low-VWF" patients are more frequently blood group O, older females, with lower average bleeding scores and number of symptoms and possibly selected because of menorrhagia. A group of "severe bleeders" may be identified (n=270, 19%), having a similar distribution of "low VWF" and "VWD" phenotypes. Disclosures Tosetto: Stago, Novo-Nordisk, BMS: Speakers Bureau; Werfen: Other: Member of Advisory Board, Speakers Bureau. Eikenboom:CSL: Research Funding. James:CSL Behring: Research Funding; Shire: Research Funding; Bayer: Research Funding. Montgomery:BCW: Patents & Royalties: GPIbM assay patent to the BloodCenter of Wisconsin.

Background: The type 3 Von Willebrand International RegistrieSInhibitor Prospective Study (3WINTERS-IPS) is a no-profit, investigator initiated, multicenter, European-Iranian observational, retrospective and prospective study on patients with diagnosis of type 3 VWD. Patients with type 3 von Willebrand Disease (VWD3) have markedly reduced levels of von Willebrand factor (VWF) and very severe bleeding phenotype. Due to the recessive inheritance pattern, VWD3 is by definition a rare bleeding disorder (1:Million) but its prevalence may increase in countries like Iran with consanguineous marriages. Aim: To identify the VWF genetic defects in a cohort of European and Iranian patients with previously diagnosed VWD3 enrolled into the 3WINTERS-IPS project. Methods: Patients classified locally as VWD3 were enrolled in the study following informed consent. 141 patients were from 9 different European countries and 119 patients were from the Islamic Republic of Iran. Plasma/buffy-coat samples were sent to expert labs to confirm patient's laboratory phenotype and to perform molecular analysis. PCR and Sanger sequencing/ next generation sequencing and multiplex-ligation dependent probe amplification were used in Hamburg, Sheffield and Milan to confirm previously identified variants or to seek previously unidentified variants. Results: DNA samples from 122 patients from Europe and 114 patients from Iran were analyzed at the molecular level. Of the 236 VWD3 patients under evaluation 24 are still in progress. Of the 212 fully evaluated patients 139 were homozygous (EU/IR=46/93) and 43 were compound heterozygous (EU/IR=36/7). In the remaining 30 patients no variants were identified in 19 samples (EU/IR=6/13) and only one variant was found in the remaining 11 cases (EU/IR=10/1). 135 (EU/IR=82/53) different gene defects were identified among the 375 (EU/IR=174/201) alleles found in this study. Of these 135 variants identified 51(EU/IR=22/29) were not reported on the www.ensembl.org database. The distribution of the different type of variants identified in the two populations is shown in the Figure. The two charts are showing quite similar percentages of the variants identified, with a main exception for the Small deletions and Small insertions. Only five variants are shared among the two populations. Three of these are the "hotspot" variants at the Arg codon, p.Arg1659* (EU/IR=9/8), p.Arg1853* (EU/IR=2/3) and p.Arg2535* (EU/IR=1/2). However, a missense variant , p.Cys275Ser (EU/IR=1/2) and a large deletion, delEx1_Ex5 (EU/IR=1/2) were also found in both populations. Fifteen variants were recurrent and were found in 154 alleles, whereas 49 variants were found only once in the heterozygous state (EU/IR=40/9) and 50 variants were found only twice, mainly in the homozygous state (EU/IR=25/25). Six large deletions were identified (delEx1_Ex3, delEx1_Ex5, delEx14_Ex15, delEx17, delEx35_Ex52 and delEx1_Ex52) and a duplication (dupEx1_Ex28), nevertheless 52 alleles with missense variants were identified (EU/IR=20/32). Discussion: As expected, the majority of the Iranian patients were found to be homozygous (Homozygous/Compound Heterozygous=93/7) reflecting a high rate of consanguinity, nevertheless half of the European patients were found to be homozygous (Homozygous/Compound Heterozygous=46/36). The European populations demonstrated a higher heterogeneity of variants with 82 different variants among the 175 mutated alleles vs 53 different variants among the 201 mutated alleles identified in the Iranian population. Nevertheless, a higher number of previously unreported variants was found in the Iranian population (29) vs the European one (22), probably due to bias of previous investigations performed in European patients. Figure Figure. Disclosures Peyvandi: Ablynx: Other: Member of Advisory Board, Speakers Bureau; Shire: Speakers Bureau; Roche: Speakers Bureau; Grifols: Speakers Bureau; Grifols: Speakers Bureau; Novo Nordisk: Speakers Bureau; Sobi: Speakers Bureau; Sobi: Speakers Bureau; Novo Nordisk: Speakers Bureau; Kedrion: Consultancy; Novo Nordisk: Speakers Bureau; Octapharma US: Honoraria; Novo Nordisk: Speakers Bureau; Sobi: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Kedrion: Consultancy; Novo Nordisk: Speakers Bureau; Kedrion: Consultancy; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Octapharma US: Honoraria; Shire: Speakers Bureau; Roche: Speakers Bureau; Kedrion: Consultancy; Kedrion: Consultancy; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Octapharma US: Honoraria; Octapharma US: Honoraria; Sobi: Speakers Bureau; Roche: Speakers Bureau; Octapharma US: Honoraria; Shire: Speakers Bureau; Sobi: Speakers Bureau; Roche: Speakers Bureau; Roche: Speakers Bureau; Shire: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Grifols: Speakers Bureau; Grifols: Speakers Bureau; Grifols: Speakers Bureau; Shire: Speakers Bureau. Schneppenheim:CSL Behring: Consultancy; SHIRE: Consultancy. Berntorp:Octapharma: Consultancy; CSL Behring: Consultancy; Shire: Consultancy, Other: honoraria for lecturing . Eikenboom:CSL: Research Funding. Mannucci:Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kedrion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Grifols: Speakers Bureau; Alexion: Speakers Bureau; Baxalta/Shire: Speakers Bureau; Novo Nordisk: Speakers Bureau. Mazzucconi:Baxalta-Shire: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Novartis,: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Speakers Bureau. Oldenburg:Swedish Orphan Biovitrum: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biogen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Patients with type 3 von Willebrand Disease (VWD) usually have markedly reduced FVIII/VWF levels and very severe bleeding manifestations but, because of their rarity, their bleeding phenotype is poorly described. We aimed at evaluating the distribution of bleeding symptoms in patients with type 3 VWD, comparing them with previously available data from a cohort of type 1 patients, and describing site-specific clustering of bleeding symptoms in these patients. We analyzed clinical data from the type 3 Von Willebrand International RegistrieS Inhibitor Prospective Study (3WINTERS-IPS),a no-profit, investigators initiated, multicenter, European-Iranian observational, retrospective and prospective study on patients with diagnosis of type 3 VWD. Aims of the 3WINTERS-IPS is 3-fold: a) to identify the main phenotypic and molecular characteristics of a large cohort of VWD patients; b) to evaluate the risk factors responsible for the severe bleeding phenotype; c) to assess the efficacy and safety of the treatment with VWF concentrates with or without FVIII including the risk of anti-VWF antibodies. Retrospective information on bleeding symptoms at presentation was collected using the MCMDM-1 VWD bleeding questionnaire, and bleeding severity summarized as bleeding score. Individual bleeding symptoms were considered as relevant when having a score >1 (hence requiring medical attention). Data was compared with that retrieved from the MCMDM-1 VWD study database on patients affected by type 1 VWD (index cases and affected family members). The study enrolled a total of 260 patients, of which we analysed 243 patients with available bleeding score at recruitment. The median age at study inclusion was 29 years (interquantile range, 26.5 years); 140 were females (53.8%). There were 108 patients of Iranian descent, while the remaining of patients were from Europe. The median number of bleeding symptoms was 5, and the median bleeding score was 15 (interquantile range, 13). Only 7/243 patients (2.8%) had a single bleeding symptom. Epistaxis was the most frequent relevant symptom, being present in 195 patients (80.2%), followed by menorrhagia in 99 females (70.7%). Males had a higher frequency of hemarthroses and hematomas than females (53.4% vs 42.1% and 40.8% vs 27.1%, respectively). When comparing the clinical presentation of type 3 vs. type 1 VWD, clearly increased bleeding scores were evident for all age-classes and even in paediatric cases. The association between symptoms having a relative frequency >20% is presented in the circle diagram, showing that some symptoms appeared to cluster with others in a variable degree (e.g., menorrhagia with epistaxis, hemarthrosis or oral cavity bleeding; post-extraction bleeding again with epistaxis, hemarthrosis or oral cavity bleeding; surgical bleeding or gastrointestinal bleeding with epistaxis alone). These findings confirm the severity of type 3 VWD and extend the knowledge of symptoms distribution in the widest available cohort of type 3 VWD patients. Disclosures Tosetto: Stago, Novo-Nordisk, BMS: Speakers Bureau; Werfen: Other: Member of Advisory Board, Speakers Bureau. Berntorp:Octapharma: Consultancy; CSL Behring: Consultancy; Shire: Consultancy, Other: honoraria for lecturing . Eikenboom:CSL: Research Funding. Mazzucconi:Baxalta-Shire: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Novartis,: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Speakers Bureau. Oldenburg:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biogen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Swedish Orphan Biovitrum: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Peyvandi:Kedrion: Consultancy; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Shire: Speakers Bureau; Roche: Speakers Bureau; Shire: Speakers Bureau; Kedrion: Consultancy; Kedrion: Consultancy; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Grifols: Speakers Bureau; Roche: Speakers Bureau; Octapharma US: Honoraria; Octapharma US: Honoraria; Sobi: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Kedrion: Consultancy; Shire: Speakers Bureau; Roche: Speakers Bureau; Roche: Speakers Bureau; Novo Nordisk: Speakers Bureau; Shire: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Grifols: Speakers Bureau; Shire: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Grifols: Speakers Bureau; Novo Nordisk: Speakers Bureau; Octapharma US: Honoraria; Octapharma US: Honoraria; Sobi: Speakers Bureau; Grifols: Speakers Bureau; Grifols: Speakers Bureau; Kedrion: Consultancy; Sobi: Speakers Bureau; Roche: Speakers Bureau; Novo Nordisk: Speakers Bureau; Novo Nordisk: Speakers Bureau; Novo Nordisk: Speakers Bureau; Sobi: Speakers Bureau; Octapharma US: Honoraria; Sobi: Speakers Bureau. Schneppenheim:SHIRE: Consultancy; CSL Behring: Consultancy. Tiede:Alnylam, Bayer, Biogen Idec, Biotest, Bristol-Myers-Squibb, Boehringer Ingelheim, CSL Behring, Leo Pharma, Novo Nordisk, Octapharma, Pfizer, Roche, Shire, and SOBI: Consultancy; Alnylam, Bayer, Biogen Idec, Biotest, Bristol-Myers-Squibb, Boehringer Ingelheim, CSL Behring, Leo Pharma, Novo Nordisk, Octapharma, Pfizer, Roche, Shire, and SOBI: Honoraria; Alnylam, Bayer, Biogen Idec, Biotest, Bristol-Myers-Squibb, Boehringer Ingelheim, CSL Behring, Leo Pharma, Novo Nordisk, Octapharma, Pfizer, Roche, Shire, and SOBI: Research Funding.

Background: Treatment of splanchnic vein thrombosis (SVT) is challenging, due to the increased risk of bleeding and potentially life-threatening complications. Current recommendations are based on evidence from the treatment of venous thrombosis in usual sites, but small observational studies in SVT population suggest that the bleeding risk may offset the benefit of anticoagulant treatment in this setting. The aim of this study was to evaluate the safety of vitamin K antagonists (VKAs) in SVT patients. Methods: We retrospectively included SVT patients treated with VKAs and followed by 37 Italian Anticoagulation Clinics until June 2013. All documented bleeding and thrombotic events were reviewed by a Central Independent Adjudication Committee. The primary outcome was the incidence of major bleeding (MB), according to the ISTH definition, during VKA treatment. Vascular events, including both arterial and venous thrombosis, and mortality were also documented. Results: 375 patients with SVT on VKA treatment were included (median age 53 years; 54.7% males). The most common risk factors were: hematological diseases (21.6%), hepatic cirrhosis (15.2%), solid cancer (10.7%), recent abdominal surgery (8.0%) and intra-abdominal inflammation or infection (6.7%); in 37.1% SVT was unprovoked. The therapeutic INR target range was 2.0-3.0 in 353 patients (94.1%). During a median VKA treatment duration of 1.98 years, 15 MB events occurred, corresponding to an incidence rate of 1.24 (95% CI, 0.75-2.06) per 100 patient-years. All bleeding patients were receiving warfarin with INR target range 2.0-3.0 and almost two thirds of bleeding complications occurred with therapeutic INR. One MB was fatal, corresponding to a case-fatality rate of 6.7%. Gastrointestinal bleeding represented 40% of all MB events. At multivariate analysis, adjusted for age and sex and stratified by Center, the presence of esophageal varices emerged as independent predictor of MB (HR 4.9; 95% CI, 1.4-17.1), while inflammatory bowel diseases were borderline statistically significant (HR 15.2; 95% CI, 0.99-233.1). The incidence rate of vascular events on treatment was 1.37 (95% CI, 0.84-2.23) per 100 patient-years, including 9 venous thrombosis and 7 arterial thrombosis. The mortality rate was 0.83 (95% CI, 0.45-1.54) per 100 patient-years. Conclusions: In designated SVT patients, oral anticoagulant treatment was safe, with a reported incidence of major bleeding less than 2% per year and a reasonable case-fatality rate. It is therefore of utmost importance to accurately select which SVT patients are suitable to be prescribed with VKAs. Disclosures Ageno: Bayer Healthcare: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; STAGO: Honoraria. Rodeghiero:GSK: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Suppremol: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Introduction Cancer-related Venous Thromboembolism (VTE) requires treatment with Low Molecular Weight Heparin (LMWH), which is more effective and safer than warfarin; however, the risk of major hemorrhage still remains clinically relevant (up to 5%). This rate is even higher in case of impaired hemostasis, such as during thrombocytopenia (due to myelosuppression or chemo-therapy) where the bleeding risk is directly related to the platelet count level. At the present, the best management of adult patients with acute or non-acute cancer-related VTE during thrombocytopenia is uncertain. Objective To develop a consensus about the platelet cut-off for a safe LMWH administration in cancer patients with acute (lasting < 1 month) or non-acute VTE and thrombocytopenia, based on RAND/UCLA Appropriateness Method (RAM). Materials and methods A systematic review of the literature was performed via electronic databases (MEDLINE, EMBASE, and Cochrane Library Central Registry). Topics and research terms were: cancer, venous thromboembolism, platelets, risk of bleeding, anticoagulant drugs, low-molecular-weight heparin, and treatments. The main study outcomes were rates of VTE (first event, recurrence, and catheter-related DVT), major and minor bleeding, thrombocytopenia, and death. A panel of experts was identified; the literature review and the list of indications were sent to all members of this panel. For each indication, the panel members rated the benefit-to-harm ratio of the procedure on a scale of 1 to 9, where 1 means that the expected harms greatly outweigh the expected benefits, and 9 means that the expected benefits greatly outweigh the expected harms. A middle rating of 5 means either that the harms and benefits are about equal or that the rater cannot make the judge for the patient described in the indication. The working group comprised 9 hematologists expert in thrombosis and haemostasis (G.S., M.M., M.C., V.D.S., A.F., A.F., F.R., A.T., S.S.) including two methodologists (G.S. and M.M.) and one coordinator (S.S.). Consensus Development the RAND was construed identifying 3 platelet count cut-offs (i.e., PLT >50.000 30.000 Results The panel of expert reached the following consensus: 1. Cancer patients with acute VTE and a platelet count 50.000 should receive full therapeutic dose LMWH ; 2. In cases of non-acute VTE with platelet count 50.000, the dose of LMWH should be reduced to 75% of the full dose; 3. In cancer patients with acute VTE and platelet count 30.000 µL, the LMWH dose should be reduced to 50% of the full therapeutic dose; 4. In case of non-acute VTE and a platelet count 30.000, the expert panel considers uncertain a treatment with a reduced dose to 50% or a low dose (i.e. 4.000 IU anti-FXa/d); 5. In case of platelet count below 30.000 µL, the expert panel agreed to suspend LMWH both in acute and non-acute VTE. Conclusions This is the first expert opinion based on RAM to establish the safe platelet cut-off to administer LMWH therapy in cancer patients affected by acute and non-acute VTE. The present panel of experts suggests as appropriate the use of dose-adjusted LMWH according to platelets count. Further investigations by means of well designed prospective clinical trials are needed to establish the best management of cancer-related VTE in patients with thrombocytopenia. Disclosures: Rodeghiero: Amgen, GSK: Honoraria; Amgen, Eisai, GSK, LFB, Suppremol: Membership on an entity’s Board of Directors or advisory committees.

Abstract 544 Background. In patients with unprovoked venous thromboembolism (VTE) occurring in the absence of major provoking factors, the optimal duration of anticoagulation is anchored on estimating the risk for disease recurrence in the individual patient. Evidence from several studies suggests that, at least in selected patient subgroups, the risk for recurrence may approximates the annual risk for anticoagulant-related major hemorrhage, which is estimated at 1–3%, and a recent ISTH consensus considers an annual risk of recurrence below 5% as acceptable to justify stopping anticoagulant therapy. Aim. To develop a clinical prediction guide that stratifies patients according to recurrence risk and, thereby, facilitate decisions about whether to continue or stop anticoagulation. Methods. Individual patient data meta-analysis of 7 prospective studies enrolling patients with a first episode of objectively diagnosed VTE. Eligible VTE cases were those which occurred in the absence of surgery, trauma, active cancer, immobility, or pregnancy and the puerperium. Follow-up started when anticoagulant therapy was stopped and ended when one of the following occurred: symptomatic, objectively documented, recurrent VTE; death from another cause; resumption of anticoagulant therapy for another reason; or the study ended. Predictors were identified using stratified Cox regression, and the weight of predictors was obtained after model shrinkage to correct for over-optimism. The discriminative ability of the prediction rule was estimated using time-dependent c-statistics, and was internally validated by bootstrap analysis. Results. 1818 consecutively referred cases with unprovoked VTE treated for at least three months with a vitamin K antagonist were eligible for analysis. Abnormal D-dimer after stopping anticoagulation, age < 50 years, male sex and VTE not associated with hormonal therapy (in women) were the main predictors of recurrence. Optimism-corrected regression coefficients were used to derive a prognostic recurrence score (DASH, D-dimer, Age, Sex, Hormonal therapy), that showed a good predicting capability (ROC area=0.71). The DASH score attributes the following points: +2 for positive (abnormal) post-anticoagulation D-dimer, +1 for age ≤ 50 years, +1 for male sex, −2 for hormone use at time of initial VTE (in women only). The annualized recurrence risk was 3.1% (95% confidence interval [CI] 2.3 – 3.9) in patients with a DASH score ≤ 1, 6.4% (95% CI 4.8–7.9) in patients with a DASH score 2, and 12.3% (95% CI, 9.9–14.7) in patients with a DASH score ≥ 3, as reported by the Kaplan-Meier recurrence-free survival plot. By considering at low recurrence risk those patients with a DASH score ≤ 1, life-long anticoagulation might be avoided in 51.6% of patients with unprovoked VTE. Conclusions. The DASH score appears to reliably predict recurrence risk in patients with a first unprovoked VTE and may be used to decide whether anticoagulant therapy should be continued indefinitely or stopped after an initial treatment period of at last three months. Patients with a DASH score ≤ 1 appear to have an annual risk for recurrence (3.1%) that may be sufficiently low to justify stopping anticoagulation in an average patient after 3–6 months of anticoagulation, whereas a DASH score ≥ 2 appears to confer a risk of recurrent VTE that may warrant indefinite anticoagulation. Disclosures: No relevant conflicts of interest to declare.

Background. Essential Thrombocythemia (ET) and Polycythemia Vera (PV) are two chronic myeloproliferative diseases with prolonged survival, but with a high rate of vascular complications, mainly arterial thrombosis (AT). For this reason, clinical guidelines recommend the use of aspirin for primary and secondary prophylaxis. There are no data on the efficacy and safety of tienopyridine antiplatelet drugs (ticlopidine, clopidogrel), which could be useful alternatives in patients with contraindication or when aspirin is unable to prevent thrombotic event. Aims. To estimate the frequency of thrombotic and hemorrhagic complications, in ET and PV patients treated with ticlopidine in comparison with patients taking aspirin, in single institution, prospective cohort study. Patients and method. Data from 246 PV (143 males, 58%), median age at diagnosis 63 years (range 20–89) and 339 ET (114 males, 33.6%) patients, median age 62 (range 20–95) consecutively diagnosed from 1985 to 2005 were analyzed. Risk factors for arterial thrombosis (diabetes mellitus, arterial hypertension, hypercholesterolemia, smoking, cardiovascular disease, previous AT) were present in around 30% of patients. At diagnosis, median values of hemoglobin, leukocyte and platelet level in ET and PV were 137 and 180 g/L, 9.3 and 11 x 109/L, 888 and 582 x 109/L, respectively. After diagnosis, aspirin (100–300 mg daily) was given to 270 patients (155 ET, 57%), in 70 of them (25%) for secondary prophylaxis; ticlopidine (250 mg twice day) was administered to 84 patients with a previous history of gastric ulcer, gastritis or allergy to ASA (48 ET, 57%), in 19 of them (22%) for secondary prophylaxis. In 216 (137 ET, 63%) patients no antiplatelet drug was given. The two treated group had similar cardiovascular risk profile, higher than in those untreated. Cytoreductive treatment was given to 87 (32%) patients in ASA, 14 (17%) in ticlopidine and 61 (28%) in those not on antiplatelet treatment (p=0.02). An higher percentage of patients received hydroxyurea in ASA group compared with ticlopidine (19.6% vs 8.6%). Warfarin was administered to 10 patients for atrial fibrillation or venous thrombosis (not analyzed). 2 cases were lost from follow-up. All PV patients were phlebotomized to reduce hematocrit level. Results. After a median follow-up of 7.8 years (very similar in the 3 groups of patients), 29 (14.5%) thrombotic events (5 fatal) among 200 ASA patients and 18 (27.7%, 1 fatal) among 65 ticlopidine patients treated for primary prophylaxis were recorded (p=0.016). In 216 not-treated patients, 40 (18.5%) thromboses were recorded. Major hemorrhages (need of transfusions, surgical intervention or hospital admission) were 17 (8.5%) in ASA, 8 (12.3%) in ticlopidine (p= 0.299) and 25 (11.6%)) in not-treated patients (p= 0.392 between antiplatelet treated and not treated patients). Thrombotic rates for patients in primary prophylaxis were 0.4%, 0.8% and 2.5% in patients on ASA, ticlopidine and not-treated, respectively. Conclusion. In a cohort of ET and PV patients, ASA therapy appears more effective than ticlopidine in the primary prevention of thrombosis, without a significative increase of hemorrhagic risk in comparison with ticlopidine or untreated patients. This increased efficacy should be further investigated by stratifying patients accordingly to cytoreductive treatment.

Background. Desmopressin is the treatment of choice for patients with mild hemophilia A (FVIII:C 3; 5 %). However, the range of response is wide and patients with similar basal FVIII:C may respond in a significantly different way. Several clinical studies have demonstrated the clinical efficacy and safety of desmopressin, but few data are available on the relationship of biological response with a given FVIII mutation and physiological characteristics (such as age and blood group, or von Willebrand factor levels). Aim of the study. To evaluate the relationship between type of FVIII mutation, physiological caharacteristics and response to desmopressin Methods. The biological response to subcutaneous desmopressin was assessed in a group of 51 consecutive patients with FVIII:C 3 5%. Blood samples were taken at 0, 30, 60, 120 240, 480 minutes and 24 hours after injection. FVIII mutation search strategy was based on DHPLC and gene sequencing. Results Mean basal FVIII:C was 18 ± 9 U/dL (range 5 – 37) and the median increase at peak was 2.5-fold (range 1.1 – 7.1). Twelve patients with low FVIII:C and normal or increased FVIII:Ag (type II defect) had similar basal and fold increase compared to the remaining patients. By multivariate regression, VWF:Ag peak level reached after desmopressin infusion and patient age were positively related with the FVIII:C half-life (p=0.003 and p=0.002 respectively), but not with FVIII:C peak or AUC. A total of 28 different gene mutations were identified (10 novel) in 42 patients, while 9 had no detectable gene mutations even after two different complete gene sequencing with 2 different sets of primers. No mutations in exons 18–22, 24 and 27 of VWF were identified. Patients with no mutations had similar basal median FVIII:C (15 vs 19 U/dL) and VWF:Ag levels (109.1 ± 31.7 vs 133.1 ± 57.5 U/dL) compared with patients carrying missense mutations. However, the peak of FVIII:C was significantly lower in patients without mutations (median FVIII:C 26 vs 56 U/dL; P < 0.001), with only a 2-fold increase (range 1.1 – 2.7) vs 2.92-fold (range 1.6 – 7.1) in patients with mutations (P < 0.001 by ANOVA). Conclusions. A poor biological response to desmopressin was associated with the absence of an evident FVIII mutation.