Incidence Of Splanchnic Vein Thrombosis Research Articles

Efficacy and Safety of Direct Oral Anticoagulants Compared to Warfarin in Patients with Cirrhosis and Splanchnic Vein Thrombosis.

The incidence of splanchnic vein thrombosis (SVT) is reported to be <25 times lower than that of deep vein thrombosis and pulmonary emboli, which occur in 70 to 270/100,000 cases in the general population. Current guidelines recommend initial treatment with therapeutic low-molecular-weight heparin followed by a transition to a vitamin K antagonist (VKA) or a direct oral anticoagulant (DOAC) in patients with cirrhosis who develop SVT without severe liver dysfunction. This, however, is based on observational data. This study aimed to evaluate the efficacy and safety of anticoagulant therapy in patients with cirrhosis who present with SVT and receive either a DOAC or a VKA. This multicenter retrospective cohort study was conducted from December 2021 to November 2022. Patients between the ages of 18 and 75 years with cirrhosis and acute SVT who received either a VKA or a DOAC between July 2019 and July 2021 were eligible for inclusion. The primary outcome was the efficacy of treatment, defined as a new thrombotic event. The secondary outcome was the safety of treatment, defined as the development of major bleeding. Readmission data were followed up at 6 and 10 months. Bivariate analysis was conducted to assess the relationship between the medication groups and each outcome and summarized as odds ratios (ORs) with 95% confidence intervals (CIs). Statistical significance was set at 5% for all of the comparisons. A total of 80 patients from 50 hospitals were included in this study. Sixty-one patients (59.02% male) received DOACs and 19 (57.89% male) received a VKA. Of the patients who received DOACs, 41 (67.21%) received apixaban, one (1.64%) received dabigatran, and 19 (31.15%) received rivaroxaban. The results from the bivariate analysis revealed no significant differences between DOACs and warfarin for both the efficacy (OR 1.46, 95% CI 0.44-4.84, P = 0.53) and safety outcomes (OR 1.03, 95% CI 0.04-26.43, P = 1) at 10 months. The use of DOACs in patients with cirrhosis who present with SVT may be efficacious and safe compared with warfarin. The findings from our study may inform power analyses for well-conducted randomized trials to confirm these findings.

Cancer-associated splanchnic vein thrombosis: Clinical features upon diagnosis and short-term outcomes

IntroductionThe incidence of splanchnic vein thrombosis (SVT) in cancer patients has increased in recent years and its real clinical significance and management can be challenging. This study aimed to describe the clinical presentation and short-term outcomes of patients with cancer-associated SVT. Material and methodsThis was a retrospective observational study of consecutive patients with cancer-associated SVT diagnosed during the period 2015–2020. The primary objective was to describe the clinical presentation of SVT. Patients were clinically classified into two groups based on the presence of symptoms on SVT diagnosis. The main outcomes were overall and SVT-related mortality, major and non-major bleeding rates, and the thrombosis recurrence rate in the first 30 days of follow-up. ResultsThis study enrolled 203 patients. Intra-abdominal tumors (76 %) and metastatic disease (68 %) predominated. A total of 79 (39 %) patients without symptoms were diagnosed with SVT during a scheduled radiological test and were classified as “asymptomatic”, while 124 (61 %) patients presented some potential SVT symptoms and were considered as “symptomatic”. Although the 30-day outcomes showed no significant differences between the two groups, mortality in the asymptomatic group was slightly lower compared to the symptomatic group (3 % vs. 10 %, p = 0.085). ConclusionsAlmost 40 % of cases of cancer-associated SVT are asymptomatic. There were no significant differences in short-term outcomes between the symptomatic and asymptomatic patients. More studies are required to better define long-term management and outcomes in these patients.

Incidence and outcomes of splanchnic vein thrombosis after diagnosis of COVID-19 or COVID-19 vaccination: a systematic review and meta-analysis.

Coronavirus disease 2019 (COVID-19) and COVID-19 vaccination may cause splanchnic vein thrombosis (SVT), which is potentially fatal. The present study aims to pool the incidence and outcomes of SVT patients with COVID-19 or having received COVID-19 vaccines. The PubMed, EMBASE, and Cochrane databases were searched. Based on the data from cohort studies, meta-analyses were performed to evaluate the incidence of SVT in COVID-19 patients or people having received COVID-19 vaccines. Pooled proportions were calculated. Based on the individual data from case reports, logistic regression analyses were performed to identify factors associated with death in SVT patients. Odds ratios (ORs) were calculated. Among 654 papers initially identified, 135 were included. Based on 12 cohort studies, the pooled incidence of SVT in COVID-19 patients was 0.6%. Data were insufficient to estimate the incidence of SVT after COVID-19 vaccination. Based on 123 case reports, the mortality was 14% (9/64) in SVT patients with COVID-19 and 25% (15/59) in those who received COVID-19 vaccines. Univariate analyses demonstrated that age (OR = 1.061; p = 0.017), diabetes mellitus (OR = 14.00; p = 0.002), anticoagulation (OR = 0.098; p = 0.004), and bowel resection (OR = 16.00; p = 0.001) were significantly associated with death in SVT patients with COVID-19; and anticoagulation (OR = 0.025; p = 0.003) and intravenous immunoglobulin (OR = 0.175; p = 0.046) were significantly associated with death in SVT patients who received COVID-19 vaccines. Multivariate analyses did not identify any independent factor for death in both patients. SVT in COVID-19 patients and in subjects who received COVID-19 vaccines carries a high mortality, but may be improved by anticoagulation. PROSPERO Identifier CRD42022315254.

Incidence and treatment of splanchnic vein thrombosis in patients with acute pancreatitis: A systematic review and meta-analysis.

This meta-analysis aimed to estimate the incidence of splanchnic vein thrombosis (SVT) in patients with acute pancreatitis and assess the effects of therapeutic anticoagulation. Systematic searches of the Medline, Embase, and Cochrane databases were undertaken to identify studies reporting the incidence and outcomes associated with SVT in patients with acute pancreatitis. The pooled incidence, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random effects model. PROSPERO database registration no. CRD 42021230912. Only 18 of the 238 studies identified met the inclusion criteria. Of the 943 patients who had SVT, 264 (28.0%) received anticoagulation. The pooled incidence of SVT at first presentation of acute pancreatitis was 15% (95% CI 5 to 26%), but was 17% (95% CI 14 to 20%) in all studies. Recanalization was more likely to occur in the anticoagulation-treated than in the untreated group (OR 0.51, 95% CI 0.31 to 0.83, P=0.007). There were no differences in hemorrhagic complications (OR 2.27, 95% CI 0.81 to 6.37, P=0.12) or overall mortality (OR 2.37, 95% CI 0.86 to 6.52, P=0.10) in relation to the use of anticoagulation. The overall incidence of portal hypertension in patients was 60% (95% CI 55 to 65%). However, it was not possible to determine the incidence in each group. The incidence of SVT in patients with acute pancreatitis is significant. Treatment with anticoagulants improved the odds of recanalization but did not increase the risk of hemorrhagic complications or overall mortality.

Splanchnic Vein Thrombosis in Liver Cirrhosis After Splenectomy or Splenic Artery Embolization: A Systematic Review and Meta-Analysis.

Splenectomy and splenic artery embolization are major treatment options for hypersplenism and portal hypertension in liver cirrhosis, but may lead to splanchnic vein thrombosis (SVT), which is potentially lethal. We conducted a systematic review and meta-analysis to explore the incidence of SVT in liver cirrhosis after splenectomy or splenic artery embolization and the risk factors for SVT. All relevant studies were searched through the PubMed, EMBASE, and Cochrane Library databases. The incidence of SVT in liver cirrhosis after splenectomy or splenic artery embolization was pooled. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Sixty-six studies with 5632 patients with cirrhosis were included. The pooled incidence of SVT after splenectomy and splenic artery embolization was 24.6% (95% CI 20.2-29.3%) and 11.7% (95% CI 7.1-17.3%), respectively. A meta-analysis of three comparative studies demonstrated that the incidence of SVT after splenectomy was statistically similar to that after splenic artery embolization (OR 3.15, P = 0.290). Platelet count, mean platelet volume, preoperative splenic or portal vein diameter, preoperative or postoperative portal blood velocity, splenic volume and weight, and periesophagogastric devascularization were significant risk factors for SVT after splenectomy. Postoperative use of preventive antithrombotic therapy was a significant protective factor against SVT after splenectomy. SVT is common in liver cirrhosis after splenectomy and splenic artery embolization. Coagulation and hemostasis factors, anatomical factors, and surgery-related factors have been widely identified for the assessment of high risk of SVT after splenectomy. Prophylactic strategy after splenectomy, such as antithrombotic therapy, might be considered in such high-risk patients. This study was registered in PROSPERO with a registration number of CRD42019129673.

Splanchnic Vein Thrombosis in Acute Pancreatitis and Its Consequences.

Splanchnic vein thrombosis (SVT) is a serious vascular complication that can occur in patients with acute pancreatitis. We assessed the incidence of SVT and its relationship with acute pancreatitis (AP) and associated complications. We carried out a retrospective analysis of medical histories from patients hospitalized with AP in a single surgical center. Histories were acquired from patients with abdominal and pelvic computed tomography scans performed between the 2nd and 3rd day of hospitalization. We assessed the impact and extent of thrombosis over the disease course. We found a strong positive correlation (Cramer’s V coefficient = 0.34) between SVT and disease severity. Mortality in the study group was 7.2% (8 patients) of which 5 patients (62.5%) were diagnosed with SVT. We observed an increased incidence of death among patients with thrombosis, with results approaching significance (P = 0.056). In our study, we found that SVT has a negative effect on the course of AP and is associated with more severe disease and increased mortality.

Impact of Splanchnic Vein Thrombosis on Mortality in Patients with Advanced Pancreatic Cancer

Abstract BACKGROUND: The incidence of venous thromboembolism in pancreatic cancer is high. Pancreatic cancer patients who develop deep venous thrombosis (DVT) or pulmonary embolism (PE) have increased mortality compared to those without. Pharmacological anticoagulation mitigates the increased mortality in these patients thus providing rationale for treatment. The incidence of splanchnic vein thrombosis (SVT) in pancreatic cancer is also high ~8% (Pachon JCO 2015, Sogaard Blood 2015). However, the correlation between SVT and mortality in pancreatic cancer is not well established. Current guidelines recommend anticoagulation for SVT on a case-to-case basis, assessing the risk-benefit of treatment and patient prognosis (Khorana J Thromb Thrombolysis 2016). Hence, we conducted the largest study to date to evaluate the impact of SVT on mortality in a cohort of United States Veterans with advanced pancreatic cancer. METHODS: Study Population: We identified patients in the Veterans Administration Central Cancer Registry (VACCR) diagnosed with unresectable or metastatic pancreatic cancer (stage II, III, IV) between October 1st, 1998 and December 31st, 2014 using ICD-O3 codes. We then identified the pancreatic cancer patients who developed SVT using ICD-9/10 codes and the CPT codes for relevant diagnostic imaging. Patients with DVT, PE and atrial fibrillation were excluded. Statistical Analyses: We compared baseline patient characteristics between pancreatic cancer patients with SVT and those without using Chi-square and Cochrane-Mantel-Haenszel tests for categorical variables, and unpaired Student's t-tests for continuous variables. Using Cox proportional hazard models, we assessed the association between SVT and overall survival in patients with pancreatic cancer while adjusting for significant prognostic indicators including: age, gender, body mass index (BMI), Charlson comorbidity index, stage of cancer (stage IV vs. stage II/III), white blood cell count (WBC), estimated glomerular filtration rate (eGFR), use of radiation or chemotherapy. A two-tailed alpha significance level of 0.05 was used for all analyses. Statistical analyses were performed using SAS version 9.2 (SAS Institute, Cary, NC). RESULTS: We identified 6296 patients with unresectable or metastatic pancreatic cancer within the VACCR, of whom 170 were diagnosed with SVT. Baseline demographics of patients with and without SVT are shown in Table 1. The median OS of the patients with SVT was 140 days as compared to 92 days for those without SVT, Figure 1. After adjusting for potential confounders, patients with SVT had a 16% reduction in mortality compared to those without (HR 0.84, p = 0.03). In addition, increasing age, male gender, BMI &lt; 18.5, increasing comorbidities, eGFR &lt; 45 mL/min, WBC &gt; 10 x 109/L, metastatic disease (stage IV) were associated with increased risk of death, while receipt of chemo or radiation therapy and BMI ≥ 25 were associated with a reduced risk of death. DISCUSSION/CONCLUSION: In this large retrospective study of patients with advanced pancreatic cancer, we found no association between SVT and increased mortality in patients with pancreatic cancer. A significant number of SVTs are detected incidentally on surveillance scans, and are thus asymptomatic at diagnosis. Anticoagulation is associated with an increased risk of hemorrhage which can be fatal in some cases. Given the lack of association between SVT and death in pancreatic cancer, future studies should assess the impact of anticoagulation on outcomes in this population with consideration given to observation only to reduce the risk of hemorrhage. Disclosures Sanfilippo: BMS/Pfizer: Speakers Bureau.

A guideline for the management of specific situations in polycythaemia vera and secondary erythrocytosis: A British Society for Haematology Guideline.

The previous BSH guideline for the management of erythrocytosis was published in 2005 (McMullin et al, 2005) and amended in 2007 (McMullin et al, 2007). Here, we re‐evaluate the literature formulate guidance on the management of specific situations encountered in polycythaemia vera (PV) and the management of the other types of secondary erythrocytosis. Recommendations for the diagnostic pathway of investigation of an erythrocytosis, risk stratification and management of PV are in the accompanying guideline (McMullin et al, 2018). We review evidence and outline guidance on management of acute thrombotic events and secondary prevention of thrombosis in PV. The unusual thrombotic events, splanchnic vein and cerebral vein thromboses are discussed and haemorrhage. The specific situations of surgery and pregnancy and guidance on management of pruritus are included. The evidence for the management of other causes of erythrocytosis, including idiopathic erythrocytosis, congenital erythrocytosis, hypoxic pulmonary disease and post‐transplant erythrocytosis, is reviewed and recommendations made.

Incidence of splanchnic vein thrombosis following abdominal surgery, a systematic review and meta-analysis

Incidence of splanchnic vein thrombosis following abdominal surgery, a systematic review and meta-analysis

Incidence of splanchnic vein thrombosis following abdominal surgery, a systematic review and meta-analysis

Incidence of splanchnic vein thrombosis following abdominal surgery, a systematic review and meta-analysis

Incidence rates and case fatality rates of portal vein thrombosis and Budd-Chiari Syndrome.

Little information is available on the incidence of splanchnic vein thrombosis and on mortality rates during the acute phase of the disease. We performed a large epidemiologic study on hospital admissions for portal vein thrombosis (PVT) and the Budd-Chiari syndrome (BCS) between 2002 and 2012 in Northwestern Italy. Primary and secondary discharge diagnoses of PVT and BCS were identified using the 9th edition International Classification of Diseases codes 453.0, 572.1 and 452. Hospitalisations for recurrent events were not included. Information was collected on age and gender, vital status at discharge, duration of hospitalisation, and up to five secondary discharge diagnoses. Comorbidity was evaluated using the Charlson comorbidity index (CCI). A total of 3535 patients with PVT and 287 with BCS were hospitalized. The overall gender-specific incidence rates for PVT were 3.78 per 100,000 inhabitants in males and 1.73 per 100,000 inhabitants in females; for BCS 2.0 and 2.2 per million inhabitants, respectively. In-hospital case fatality was 7.3 % in patients with PVT and 4.9 % in patients with BCS. Age, non-abdominal solid cancer, and CCI were independently associated with in-hospital mortality in both PVT and BCS after stepwise regression analysis, male gender and haematologic cancer were associated with mortality in BCS patients only. In this large study we confirmed the low incidence of BCS and we found an incidence of PVT higher than previously reported. This incidence was stable during the period of observation. In-hospital mortality is not negligible, in particular in PVT patients.

Venous Thrombotic Events After Liver Transplantation.

Thromboprophylaxis is not well defined after liver transplantation (LT). The aim of this study was to evaluate the incidence of splanchnic vein thrombosis (SVT) and nonsplanchnic vein thrombosis (NSVT) after LT. Liver transplantations performed between 2009 and 2013 in our institution were reviewed. Demographic, intraoperative, and postoperative data were recorded. Low-molecular-weight heparin was only administered postoperatively if intraoperative thrombectomy was performed or in patients preoperatively anticoagulated. Of a total of 328 patients, 72% were male with a median age of 56 years, score of model for end-stage liver disease 18 (11-23), and 88% had liver cirrhosis. The incidence of postoperative venous thrombotic events was 4.6%: 8 (2.4%) patients had SVT and 7 (2.1%) patients had NSVT. After logistic regression analysis, intraoperative thrombectomy and Child A classification emerged as risk factors for SVT (odds ratio [OR]: 77, 95% confidence interval [95% CI]: 14-421) and NSVT (OR: 20, 95% CI: 3-170), respectively. The incidence of SVT in patients who undergo intraoperative thrombectomy was 33%, whereas the incidence of NSVT in patients grouped as Child A was 7.5%. Our results suggest that thromboprophylaxis should be considered after LT in patients with cirrhosis grouped as Child A and in patients who undergo intraoperative thrombectomy.

Predictive factors of splanchnic vein thrombosis in acute pancreatitis: A 6-year single-center experience.

Splanchnic vein thrombosis (SVT) is a potentially severe complication of pancreatitis. The aim of this single-center, retrospective cohort study was to investigate the incidence of SVT and to determine the connected risk factors. All consecutive patients with acute pancreatitis (AP) managed in our hospital were included. The primary outcome was the occurrence of SVT and data was collected in accordance with Ranson's criteria. A total of 318 patients were included, of whom 124 (39.0%) were women. Biliary lithiasis was the main cause of pancreatitis (n = 156, 49.1%). A total of 19 (6.0%) SVT were identified. In univariate analysis, alcohol intake, smoking and male gender were associated with SVT (P = 0.005, 0.003 and 0.007, respectively). Biological parameters significantly associated with thrombosis were lactate dehydrogenase (LDH) < 500 U/L and hyperglycemia (≥ 10 mmol/L) (P = 0.009 and 0.016, respectively). In multivariate analysis, prothrombin time >75% was a protective factor against thrombosis (OR 0.148, P = 0.019). Leukocytes >10 × 10(9)/L (OR 6.397, P = 0.034), hyperglycemia (≥ 10 mmol/L) (OR 6.845, P = 0.023), LDH < 500 U/L ((OR 22.61, P = 0.001) and alcoholic etiology (OR 8.960, P = 0.041) were risk factors for SVT. Alcohol intake, male gender and smoking should focus the physician's attention on the risk of SVT. When further associated with certain biological parameters, the physicians should consider therapeutic anticoagulation to prevent SVT.

The Subtle Benefit of Anticoagulant Therapy for Splanchnic Vein Thrombosis.

Splanchnicvein thrombosis (SVT), comprising thromboses in the mesenteric, splenic, or portal veins (with or without hepatic veins), is a relativelyuncommonvenous thrombotic condition. As such, there are virtually no prospective randomized data on the appropriate therapeutic interventionsand outcomes, and most knowledge of this condition comes from retrospective case series, small prospective cohorts, or case reports. That is why the report by Ageno et al1 in this issue of JAMA Internal Medicine that assesses the outcomes of treatment for patients with SVT in the large prospective registry of the International Society on Thrombosis and Hemostasis holds importance. Even though the study is observational, it comprises a large cohort, focuses on therapeutic interventions and outcomes, and has a relatively long follow-up period. The incidence of SVT is estimated to be between 1 and 4 cases permillion people.2 The highest reported prevalence, 1%,wasdetermined inanautopsy study3of Swedish patients, although SVTmay not have been suspected during the lives of these patients. Themost common underlying conditionsassociatedwithSVTare liverdisease (cirrhosis), cancer, and idiopathic sources.Manyof the latter are oftenundetected hematologic cancer or hereditary thrombophilia. Ageno et al1 report on the outcomes of patients with SVT from a multinational registry in 11 countries. Of 604 patients enrolled during a 51⁄2-year period, the most common identifiedunderlying causes of SVTwere cirrhosis (27.8%) and solid cancer (22.7%). Idiopathic or unprovoked cases equaled those of cirrhosis (27.2%). Although systematic testing was not required for study inclusion, 20.1% of the patients were found to have the JAK2 V617Fmutation when tested, signifying an underlyingmyeloproliferative disorder, and 11%were identified as having an underlying thrombophilia (factor V Leiden in 11.2% and prothrombin gene mutation in 11.5%). Seventyseven percent (n = 465) of these patients received anticoagulant therapy; of that group, 62.4% received a vitamin K antagonist and 37.6% received only parenteral therapy (mostly low-molecular-weight heparin). Patientswho received an anticoagulant experienced less bleeding (3.9% per 100 patientyears) compared with those who did not receive treatment (5.8% per 100 patient-years). What do the results of this study from the International Society on Thrombosis and Hemostasis registry tell us, and whatare the implications?First, all of the findingsmustbeconsidered in the context of the study fromwhich they were derived. This is a prospective registry, and there are many limitations of this type of study. Nevertheless, given the lack of randomized trials, these results can be helpful to clinicians in making decisions regarding treatment for patients with SVT. Theregistryconfirms thecommonunderlyingcauses, asnoted in previous reports: liver disease and cancer.2 Most interesting, it identifies anticoagulant treatment duration as not only reducing recurrent thrombosisbutalso reducingbleeding.This was seen both in patients with as well as those without cirrhosis. Of course, selection bias might well have been a factor, and those at highest risk of bleeding might not have received anticoagulant therapy. Previous observational data of SVT tend to reporthigher ratesof bleedingvs recurrent thrombosis than seen in this registry, but Ageno et al1 suggest that this difference might be related to lower rates of anticoagulant treatment in previous studies; if such treatment reduces bleeding, the lower rates suggest that we should be using anticoagulants more frequently in SVT. Thefindingsalsohelp theclinicianassess therisksandbenefits trade-offofanticoagulant therapy.Factorsassociatedwith thehighest riskof recurrent thrombosis inpatientswithoutcirrhosis were myeloproliferative neoplasms, solid cancer, unprovoked SVT, andmale sex,whereas the risk of bleedingwas similar to that seen in patients with deep vein thrombosis or pulmonary embolism treated with anticoagulants. There are still unanswered issues regarding SVT, such as the best choice of therapy; this may depend on whether the SVT is cancer related. The new direct-acting oral anticoagulants alsomustbeconsidered; in theory, there isno reason that they would not be as effective, but their association with a higher risk of gastrointestinal tract bleeding compared with warfarin4 raises a red flag. The optimal duration of therapy is also still unclear. Because of the serious underlying disorders associatedwithmost cases of SVT, the long-term risk-benefit profile is likely to be different than those seenwith deep vein thrombosisandpulmonaryembolism,andmore long-termoutcomedata are needed. The final remaining issue is the appropriate treatment of incidental SVT. Incidental SVT can occur in patients with serious underlying conditions, such as cancer and cirrhosis,5 or as an asymptomatic complication of a transient risk factor, such as abdominal surgery. Themost recent American College of Chest Physicians Guidelines on AntithromboticTherapy6 recommendagainstanticoagulant treatment of incidental SVT, but other reports7 suggest that treatment has a beneficial risk-benefit profile. Most important, the decision to treat or not treat incidental SVTmust be guided by the underlying presumptive cause. In summary, theuseof antithrombotic therapy inanycondition is guided by the balance of the benefit of the therapy against the risk of therapy-induced bleeding. Balancing these risks is trickywhen dealingwith SVT, andmore so thanwhen dealing with deep vein thrombosis or pulmonary embolism. Theresultsof this registrystrengthentheevidence that therapy may have more net benefit than previously thought. Related article page 1474 Long-term Clinical Outcomes of Splanchnic Vein Thrombosis Original Investigation Research

PTH-095 Portal Hypertension Due To Splanchnic Venous Thrombosis Following Open Or Skunk Wire Necrosectomy Of Acute Severe Pancreatitis

IntroductionIsolated splenic vein thrombosis (ISVT) is a well recognised complication of acute pancreatitis with incidences ranging widely but more recently in a large meta analysis reported as approximately 14% with...

Evidence that prefibrotic myelofibrosis is aligned along a clinical and biological continuum featuring primary myelofibrosis.

PurposeIn the WHO diagnostic classification, prefibrotic myelofibrosis (pre-MF) is included in the category of primary myelofibrosis (PMF). However, strong evidence for this position is lacking.Patients and MethodsWe investigated whether pre-MF may be aligned along a clinical and biological continuum in 683 consecutive patients who received a WHO diagnosis of PMF.ResultsAs compared with PMF-fibrotic type, pre-MF (132 cases) showed female dominance, younger age, higher hemoglobin, higher platelet count, lower white blood cell count, smaller spleen index and higher incidence of splanchnic vein thrombosis. Female to male ratio and hemoglobin steadily decreased, while age increased from pre-MF to PMF- fibrotic type with early and to advanced bone marrow (BM) fibrosis. Likely, circulating CD34+ cells, LDH levels, and frequency of chromosomal abnormalities increased, while CXCR4 expression on CD34+ cells and serum cholesterol decreased along the continuum of BM fibrosis. Median survival of the entire cohort of PMF cases was 21 years. Ninety-eight, eighty-one and fifty-six percent of patients with pre-MF, PMF-fibrotic type with early and with advanced BM fibrosis, respectively, were alive at 10 years from diagnosis.ConclusionPre-MF is a presentation mode of PMF with a very indolent phenotype. The major consequences of this contention is a new clinical vision of PMF, and the need to improve prognosis prediction of the disease.

Prefibrotic Myelofibrosis (PreMF) Belongs to a Continuum of Epidemiological, Clinical and Histological Characteristics Featuring Primary Myelofibrosis (PMF)

Abstract 1743 Background:WHO diagnostic criteria of myeloproliferative neoplasms (MPNs) identify a preMF variant including patients having absence or early grade fibrosis, dual myeloid and megakaryocytic dominance, and clusters of atypical, ectopic, variable in size megakaryocytes in the bone marrow (BM). Many issues on the variant are critical, such as its distinction from essential thrombocythemia, recognisability, biological identity and true place among MPNs. Here we describe the clinical presentation of patients with preMF collected among a large cohort of patients diagnosed with PMF according WHO and for whom long-term follow-up data were available. The aim is to investigate whether there is an underlying structure of the patients' characteristics that allows to assign them to a distinct variant of MPNs or to align them along a continuum in the realm of PMF. Methods:We included in this study patients with PMF who were referred to the Center for the Study of Myelofibrosis of IRCCS Policlinico S. Matteo Foundation, Italy from 1990 to 2011. In all patients the BM biopsy taken at diagnosis was reviewed (pathologist: UM) and the diagnosis of preMF was established adopting the stringent criterion that, besides typical BM cellularity and megakaryocyte morphology, BM had less than grade 1 reticulin fibrosis (EUMNET criteria). Results:Of the 659 patients with PMF, 126 fulfilled the criteria we established for the diagnosis of preMF, thus accounting for 19.1% of the cohort. Female sex accounted for 59.5% of the preMF cohort while it accounted for 33.8% of PMF fibrotic type (P<0.0000). The mean age at diagnosis of patients with preMF was 39.2 years (range, 6 to 78 years), while it was 54.6, range 6 to 90 years (P<0.0000) in patients with PMF fibrosis type. Patients with preMF showed higher hemoglobin (14.0 vs. 11.9 g/dL; P=0.0004), higher platelet count (647 vs. 435 × 109/L; P<0.0000), lower WBC count (9.0 vs. 10.7 x109/L; P=0.02) and smaller spleen index (120 vs. 182; P<0.0000) than patients with MF fibrotic type. As a consequence, preMF displayed a greater frequency of patients with grade 0 IWG prognostic score ( 88.7% vs. 56.9%, P<0.0000). PreMF patients displayed a higher frequency of thrombotic events at the time of the diagnosis or in the year preceding the diagnosis (30.1% vs. 6.4%; P<0.0000). Both in prefibrotic and fibrotic type MF, the great majority of the thrombotic episodes were portal vein thrombosis or Budd-Chiari syndrome (89.4% in preMF and 79.4% in PMF fibrotic type). The proportion of JAK2 V617F mutated patients was not significantly different in the two categories of patients (65.2% vs. 62.1%; P=NS).In order to assign patients with PMF to groups with different degrees of BM fibrosis, we further categorized MF fibrotic type into early MF (BM fibrosis grade 1) and advanced MF (BM fibrosis grade 2 or 3). Female frequency steadily varied from 59.5% to 43.2% and 25.6% in the 3 categories of BM fibrosis, respectively. Age varied from 39.2, 50.4, 57.0 years, respectively. Hemoglobin and platelet count steadily decreased (Hb=14.0, 13.3, 11.2 g/dL, respectively; platelet count=647, 554, 346 x109/L, respectively). Spleen size steadily increased along with increasing of BM fibrosis (spleen index=120, 152, 200). All these parameters exhibited a statistically significant trend along the continuum of BM fibrosis grade (ANOVA, P<0.0001). During 993 cumulative person-years of follow-up, 4% of patients with preMF died. During 1372 cumulative person-years of follow-up, 15.4% of patients with early MF died. During 1446 cumulative person-years of follow-up, 24.5% of patients with advanced MF died. The cause of death was blast transformation in 80, 53 and 41.7% of cases, respectively. 94%, 80% and 54% of patients with preMF, early MF and advanced MF were alive at 10 years from the diagnosis. Overall, these results speak in favour to preMF belonging to a continuum of epidemiological, clinical and histological phenotypes in the realm of PMF. Splanchnic vein thrombosis, on the contrary, clusters in the category of preMF, suggesting that young age, female sex and a very indolent hematological phenotype are associated with biological characteristics that predispose to thrombosis. Conclusions:The BM picture of preMF identifies a group of patients with PMF associated with a very indolent hematologic phenotype, female dominance and very young age at presentation characterized by high incidence of splanchnic vein thrombosis. Disclosures:Barosi:Novartis: Membership on an entity's Board of Directors or advisory committees.