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INTRODUCTION: Coronavirus 2 (CoV-2) infection or coronavirus disease 2019 (COVID-19) is frequently associated with microvascular thrombosis.The microthrombosis in COVID-19 is the result of the interplay between inflammation and endotheliopathy. Elevated interleukin-6 (IL-6) characterizes COVID-19 inflammation resulting in endotheliopathy and coagulopathy marked by elevated D-dimer (DD). Aim of this study is to identify and to describe the coagulation changes in 100 moderate COVID-19 patients having lung involvement and to determine the association of coagulopathy with the severity and prognosis. METHODS: Inflammation, endothelial and coagulation molecules were measured in moderate and mild disease. RESULTS: IL-6 and tumor necrosis factor-α (TNF-α) and tissue factor (TF), von Willebrand factor (VWF), and tissue factor pathway inhibitor (TFPI) significantly increased in moderate disease as well as D-dimer, thrombin antithrombin complex (TAT), Fibrinogen (Fib), platelet factor-4 (PF4), s-thromboglobulin (s-TG), P-selectin, and platelet adhesion. Shortened clotting time (CT) and clot formation time (CFT), high maximum clot firmness (MCF) and low LY at 30 min were present in 100% of moderate COVID-19 patients compared with mild COVID-19 patients. CONCLUSIONS: These findings demonstrate that moderate COVID-19 has a profound inflammation associated with severee ndotheliopathy and intense coagulation activation uncontrolled by TFPI. Attention should be paid to coagulopathy in COVID-19. Closely monitoring of coagulation and application of appropriate anticoagulation may improve the prognosis of moderate COVID-19 and to prevent the progression to severe COVID-19 disease.

Essential Thrombocythemia (ET) is a myeloproliferative neoplasm characterized by high platelet count and platelet activation linked to angiogenesis. It is reported that vascular endothelial growth factor (VEGF) promotes platelet activation and that activated platelets release VEGF. Anagrelide (ANA) represents a emerging drug which decresaes platelets and inhibits platelet activation. Therefore, were studied platelet count, platelet factor 4 (PF4) levels, as indicator of platelet activation, and corrected platelet VEGF (VEGFPLT), as indicator of angiogenesis-related platelet activation, in ET patients treated either with hydroxyurea (HU) and interferon-a (IFN-a) or ANA in combination with antiaggregants. Before treatment all patients had high platelets and higher PF4 and VEGFPLT than controls. After treatment all patients had decreased platelets whereas PF4 and VEGFPLT were elevated in the HU and IFN-a group compared with controls and normal in the ANA group. There was no correlation between PF4 and platelets whereas a positive correlation there was between PF4 and VEGFPLT. These results, if confirmed in larger studies, might indicate that ANA has anti-platelet and anti-angiogenic properties.

COVID-19 vaccination campagnies with several vaccines types are currently undeway. Recently, the ASTRA ZENECA vaccine has raised public alarm with concerns regarding the development of thrombotic events known as vaccine-induced thrombotic thrombocytopenia (VITT). Early and limited studies have implicated an antibody-mediated platelet activation as the mechanism of the clotting events. Aim of this study was to investigate the platelet and coagulation activation using specialized tests. In this study we enrolled 60 patients (40 men, 20 women; mean age 55±10 years) without cardiovascular risk factors or a history of thrombosis who reported having poplitea deep vein thrombosis (35/60) and pulmonary embolism (25/60) revealed with lower-limb ultrasonography and computed tomography (CT) angiography, respectively, 7 days after vaccination with ASTRA ZENECA. All patients were evaluated for initial testing such as platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (Fib) and D-dimer (DD). Platelets were measured by automated analyzer, PT and APTT by coagulometric test, Fib using Clauss method, and DD using ELISA. Complete blood hemostasis was studied by platelet function assay (PFA-100) on Collagen/ADP (CT-ADP) and Collagen/Epinephrine (CT-EPI) cartridges and Thromboelastometry method on Clotting Time (CT), Clotting Formation Time (CFT), Maximum Clot Firmness (MCF), and clot lysis at 30 minutes (LY-30). All patients had thrombocytopenia (60±5x109/L), longer PT (28±10 s) and PTT (50±10 s), lower Fib (80±20 mg/dl), higher DD ((550±100 mg/l). All patients had shorter C/ADP and C/EPI (C/ADP, n.v. 68-121 s (42±10 s) and C/EPI n.v. 84-160 s (38±5 s) and shorter CT (CT, unit: s. n.v. 100-240 s) (INTEM 30±20 s, EXTEM 18±10 s), shorter CFT (CFT, unit: s, n.v. 30-160 s (INTEM 11±10 s, EXTEM 19±10 s), longer MCF (MCF, unit: mm, n.v. 50-72 mm (INTEM 128±10 mm, EXTEM 110±10 mm), and lower LY-30 (LY-30, %: v.n. 15% (INTEM 0.8%, EXTEM 0.7%). These interesting findings may be the novelty in the diagnostic work-up of the VITT. If these tests may aid in the diagnosis of VITT deserve to be confirmed and need reproducing in other studies. Disclosures No relevant conflicts of interest to declare.

Summary Background There is no evidence that phlebotomy alone is sufficient to steadily maintain haematocrit on target level in low-risk patients with polycythaemia vera. This study aimed to compare the efficacy and safety of ropeginterferon alfa-2b on top of the standard phlebotomy regimen with phlebotomy alone. Methods In 2017, we launched the Low-PV study, a multicentre, open-label, two-arm, parallel-group, investigator-initiated, phase 2 randomised trial with a group-sequential adaptive design. The study involved 21 haematological centres across Italy. Participants were recruited in a consecutive order. Participants enrolled in the study were patients, aged 18–60 years, with a diagnosis of polycythaemia vera according to 2008–16 WHO criteria. Eligible patients were randomly allocated (1:1) to receive either phlebotomy and low-dose aspirin (standard group) or ropeginterferon alfa-2b on top of the standard treatment (experimental group). Randomisation sequence was generated using five blocks of variable sizes proportional to elements of Pascal's triangle. Allocation was stratified by age and time from diagnosis. No masking was done. Patients randomly allocated to the standard group were treated with phlebotomy (300 mL for each phlebotomy to maintain the haematocrit values of lower than 45%) and low-dose aspirin (100 mg daily), if not contraindicated. Patients randomly allocated to the experimental group received ropeginterferon alfa-2b subcutaneously every 2 weeks in a fixed dose of 100 μg on top of the phlebotomy-only regimen. The primary endpoint was treatment response, defined as maintenance of the median haematocrit values of 45% or lower without progressive disease during a 12-month period. Analyses were done by intention-to-treat principle. The study was powered assuming a higher percentage of responders in the experimental group (75%) than in the standard group (50%). Here we report results from the second planned interim analysis when 50 patients had been recruited to each group. The trial is ongoing, and registered with ClinicalTrials.gov , NCT03003325 . Findings Between Feb 2, 2017, and March 13, 2020, 146 patients were screened, and 127 patients were randomly assigned to the standard group (n=63) or the experimental group (n=64). The median follow-up period was 12·1 months (IQR 12·0–12·6). For the second pre-planned interim analysis, a higher response rate in the experimental group was seen (42 [84%] of 50 patients) than in the standard group (30 [60%] of 50 patients; absolute difference 24%, 95% CI 7–41%, p=0·0075). The observed z value (2·6001) crossed the critical bound of efficacy (2·5262), and the stagewise adjusted p value early showed superiority of experimental treatment. Thus, the data safety monitoring board decided to stop patient accrual for overwhelming efficacy and to continue the follow-up, as per protocol, for 2 years. Under the safety profile, no statistically significant difference between groups in frequency of adverse events of grade 3 or higher was observed; the most frequently reported adverse events were neutropenia (four [8%] of 50 patients) in the experimental group and skin symptoms (two [4%] of 50 patients) in the standard group. No grade 4 or 5 adverse events occurred. Interpretation Supplementing phlebotomy with ropeginterferon alfa-2b seems to be safe and effective in steadily maintaining haematocrit values on target in low-risk patients with polycythaemia vera. Findings from the current study might have implications for changing the current management of low-risk patients with polycythaemia vera. Funding AOP Orphan Pharmaceuticals, Associazione Italiana per la Ricerca sul Cancro

Although still debated, post-operative modification of hemostasis seems to be less pronounced after laparoscopy compared to open surgery. Antiphospholipid antibodies might play a role in the post-operative thromboembolic risk, although their evaluation in surgical patients has never been performed. Post-operative modification of antiphospholipid antibodies could be related to the surgical approach (laparoscopic or open). In this prospective study, the authors statistically compared the pre-operative values and post-operative modification of antiphospholipid antibodies in two homogeneous groups of patients operated on by laparoscopic and open surgery. No statistical differences within each group and between the two groups were shown comparing mean values of pre-operative and post-operative antiphospholipid antibodies. In the open group, there was a significant difference between pre-operative and post-operative LAC means (P

Highlights • A very rare case of spontaneous colon hematoma has been reported. • The rarity of our case of colon hematoma is due to the fact that it is idiopathic. • The topic is still under discussion in the Literature since the pathophysiology remains still unknown., Introduction Intestinal hematoma is usually observed after an abdominal trauma or in patients treated with anticoagulant therapy. Conversely, idiopathic bowel hematoma is very rare, being colon involvement sporadic with few reports in the Literature. Presentation of case The Authors report a case of idiopathic spontaneous large bowel hematoma. A 48-year-old man was admitted for a thoraco-abdominal pain and signs of acute abdomen and fever. After ruling out heart diseases, a CT scan revealed a marked thickening of the ascending colon wall, obstructing the bowel lumen. Leukocytosis was observed. In an emergency setting, an explorative laparotomy was performed. Hemoperitoneum and a large hematoma involving the caecum and the ascending colon were detected, together with intramesenteric and retroperitoneal blood effusion. A right hemicolectomy was accomplished. Histopathology confirmed the diagnosis of large bowel hematoma. Post-operative molecular diagnostic testing for coagulative disorders failed to demonstrate any genetic variation associate with hemorrhagic predisposition. In the post-operative course, the patient experienced a left basal bronco-pneumonia with increased unilateral pleural effusion, successfully treated by a thoracic drain and antibiotic therapy. Discussion The reported case and Literature data show that diagnosis of idiopathic colon intramural hematoma is challenging, especially in the emergency setting. Although conservative therapy is the first line treatment, surgery still has an important role when the diagnosis is uncertain, medical treatment fails or a complication, such untreatable bleeding, perforation or occlusion occur. Conclusion The Authors report a very rare case of spontaneous intramural hematoma of the right colon. Surgery still has a role in selected cases.

Polycyhemia vera (PV) is a myeloproliferative neoplasm characterized by increased thromboxane (TX) production and thrombotic risk. It is reported that serum TXB2 concentrations in PV patients are twofold higher than healthy controls and that low-dose aspirin (ASA) therapy reduces the risk of major vascular events by 50 to 60%. To evaluate this unusual size of the effect of ASA we have studied platelet count, hematocrit (HCT), β-thromboglobulin (β-TG) and platelet factor 4 (PF4), as markers of platelet activation, TXB2, as primary indicator of platelet activation, the platelet function activity (PFA), as indicator of ASA platelet sensitivity, and the clotting time (CT), as parameter of thrombin formation. We studied 60 patients (38 men, 22 women; mean age 51 years, range 32-70) with PV according to WHO criteria. The mean duration of disease was 12 years. All patients were on ASA 100 mg once daily. All patients were on phlebotomy. None had inherited or acquired thrombotic risk factors. Of 60 patients, 30 had thrombosis (20 men, 10 women) and 30 had no thrombosis. Of 30 with thrombosis, 15 developed nonfatal myocardial infarction (10 men, 5 women) defined by chest pain of typical intensity and duration and ST-segment elevation in any limb lead on electrocardiography, 10 had nonfatal stroke (8 men, 2 women) confirmed with the use of magnetic resonance imaging, and 5 (2 men , 3 women) had deep venous thrombosis confirmed by ultrasonography. Platelet count and HCT were measured by automated analyzer. β-TG and PF4 were determined by ELISA. TXB2 was measured by radioimmunoassay technique. ASA platelet sensitivity was measured by Platelet Function Analyzer (PFA-100). CT was measured by thromboelastometry. The mean platelet count was 430±170x109/L. The mean HCT value was 42±3%. The patients with thrombosis had high β-TG, PF4 and TXB2 (110±45 IU/ml, 45±21 IU/ml, and 1.700±1.990 nmol/L, respectively), shortened C/EPI closure time (T, unit: s, n.v. 84-160 s) (55±10 s) and shortened CT (CT, unit: s. n.v. 100-240 s) (45±20 s) whereas the patients without thrombosis had normal β-TG, PF4 and TXB2 (20±11 IU/ml, 6±2 IU/ml, and 800±280 nmpl/L, respectively), prolonged C/EPI closure time (249±40 s) and normal CT (110±20 s). These findings might suggest that in PV patients and thrombotic complications might need a platelet-selective dosage of ASA. Disclosures No relevant conflicts of interest to declare.

The polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by increased hematocrit (HCT), elevated white-cell and platelet counts and splenomegaly. The most commonly used first line cytoreductive agent is hydroxyurea (HU). However, some patients have an inadequate response or have inacceptable side effects from HU. Ruxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, was shown to have a clinical benefit in patients with PV. A phase 3 study (RESPONSE) have shown that PV patients on Ruxolitinib at dose of 10 mg twice daily at week 32 had a complete hematologic remission. In this study were enrolled 40 patients with PV (30 men, 10 women; mean age 54 years, range 51-57) according to WHO criteria, assigned to Ruxolitinib at dose of 5 mg twice daily for clinical evidence of liver dysfunction. All patients were evaluated for JAK2V617F allele burden, HCT, white cells and platelets, splenomegaly and symptom burden, including pruritus, fatigue and night sweats. The mean duration of disease was 9 years. All patients received low-dose aspirin and underwent phlebotomy. Before Ruxolitinib, all patients had JAK2V617F allele burden > 50%, HCT control on phlebotomy, high white cells (12x109/L) and elevated platelets (600x109/L) and spleen volume of 450 cm3 or more as measured by magnetic resonance imaging (MRI) or computed tomography (CT). After Ruxolitinib we observed a shortened response time at week 6 marked by JAK2V617F allele burden < 50%, HCT < 45% in the absence of phlebotomy, normal white cells and platelets (6x109/L and 320x109/L, respectively) and reduced spleen size as assessed by palpation and absence of symptoms. These data suggest that the Ruxolitinib treatment at the alternative dose of 5 mg twice daily can be effective in achieving a rapid and complete hematologic remission that is still present in these patients receiving this dose of Ruxolitinib at the time of this analysis. Disclosures No relevant conflicts of interest to declare.

We analyzed 597 patients with myeloproliferative neoplasms (MPN) who presented transient ischemic attacks (TIA, n = 270) or ischemic stroke (IS, n = 327). Treatment included aspirin, oral anticoagulants, and cytoreductive drugs. The composite incidence of recurrent TIA and IS, acute myocardial infarction (AMI), and cardiovascular (CV) death was 4.21 and 19.2%, respectively at one and five years after the index event, an estimate unexpectedly lower than reported in the general population. Patients tended to replicate the first clinical manifestation (hazard ratio, HR: 2.41 and 4.41 for recurrent TIA and IS, respectively); additional factors for recurrent TIA were previous TIA (HR: 3.40) and microvascular disturbances (HR: 2.30); for recurrent IS arterial hypertension (HR: 4.24) and IS occurrence after MPN diagnosis (HR: 4.47). CV mortality was predicted by age over 60 years (HR: 3.98), an index IS (HR: 3.61), and the occurrence of index events after MPN diagnosis (HR: 2.62). Cytoreductive therapy was a strong protective factor (HR: 0.24). The rate of major bleeding was similar to the general population (0.90 per 100 patient-years). In conclusion, the long-term clinical outcome after TIA and IS in MPN appears even more favorable than in the general population, suggesting an advantageous benefit-risk profile of antithrombotic and cytoreductive treatment.

PURPOSE Presently, laparoscopic splenectomy (LS) is being performed for several indications in clinical practice. However, conversion to open surgery is occasionally required in some patients. We analyzed the intraoperative indications and potential preoperative predictors associated with conversion to open surgery in those presenting for LS. METHODS We reviewed 107 patients who underwent LS. We analyzed the surgical indications, spleen size, surgical procedure performed, operative time, rate of and indications for conversions, as well as postoperative complications. RESULTS Among the 15 patients (14.0%) who underwent conversion, the conversion was related to the occurrence of a splenic lymphoma in 10, severe bleeding in 3, a lack of anatomic definition in 1, and splenic candidiasis in 1 patient. A comparison between the results obtained in the initial 30 patients (LS performed during the learning curve) and those obtained in the remaining 77 patients, showed that conversions appeared to be related to the experience/expertise of the surgical team excluding patients with splenic malignancies. Conversion was not associated with a higher morbidity-mortality rate, but only a longer length of hospitalization. CONCLUSIONS LS is a gold standard procedure when performed by experienced and competent surgeons. However, careful patient selection is recommended before using the laparoscopic approach in those presenting with splenic malignancies.

To investigate the characteristics and clinical course of cerebral vein thrombosis (CVT) in patients with myeloproliferative neoplasms (MPN) we compared 48 patients with MPN and CVT (group MPN-CVT) to 87 with MPN and other venous thrombosis (group MPN-VT) and 178 with MPN and no thrombosis (group MPN-NoT) matched by sex, age at diagnosis of MPN (±5 years) and type of MPN. The study population was identified among 5,500 patients with MPN, from January 1982 to June 2013. Thrombophilia abnormalities were significantly more prevalent in the MPN-CVT and MPN-VT than in MPN-NoT group (P = 0.015), as well as the JAK2 V617F mutation in patients with essential thrombocythemia (P = 0.059). Compared to MPN-VT, MPN-CVT patients had a higher rate of recurrent thrombosis (42% vs. 25%, P = 0.049) despite a shorter median follow-up period (6.1 vs. 10.3 years, P = 0.019), a higher long-term antithrombotic (94% vs. 84%, P = 0.099) and a similar cytoreductive treatment (79% vs. 70%, P = 0.311). The incidence of recurrent thrombosis was double in MPN-CVT than in MPN-VT group (8.8% and 4.2% patient-years, P = 0.022), and CVT and unprovoked event were the only predictive variables in a multivariate model including also sex, blood count, thrombophilia, cytoreductive, and antithrombotic treatment (HR 1.97, 95%CI 1.05-3.72 and 2.09, 1.09-4.00, respectively).

Hereditary spherocytosis is an inherited hemolytic anemia caused by a deficiency in erythrocyte membrane proteins. Removal of the spleen may reduce the intra-splenic hemolytic process of the disease and, therefore, may correct the anemia. Furthermore, it seems to decrease the levels of serum bilirubin, thus reducing the formation of gallbladder stones. Indications and timing of splenectomy, however, are still debated. Twelve patients with severe hereditary spherocytosis operated on with laparoscopic splenectomy were retrospectively reviewed. Median age at diagnosis was 13.8 years (range 8-25 years). Male to female ratio was 5/7. Indications for laparoscopic removal of the spleen included anemia unresponsive to iron supplementation in eight patients (66.6 %) with increase need for red cells transfusions, and jaundice with symptoms related to cholelitiasis in four patients (33.3 %). Laparoscopic splenectomy was associated in four cases to laparoscopic cholecystectomy. Mean operative time was 50 min (range 40-75 min) with no conversion to open surgery. Mean hospital stay ranged from 3 to 7 days. In a 16-month follow-up, no complications were recorded and a persistent correction of anemia was observed. With the advent of laparoscopic surgery, splenectomy has been performed by this mini-invasive approach in referral centers. Laparoscopic splenectomy is an effective technique, when performed in patients with hereditary spherocytosis. Low complication rate and persistent correction of the hematologic disorders can be expected after the laparoscopic splenectomy, provided that a proper technique is performed and an experienced surgical team is available.

Only a few studies have addressed long-term results comparing laparoscopic and open splenectomy in idiopathic thrombocytopenic purpura (ITP). We analyzed the 1-year results comparing age, sex, length of preoperative steroid therapy, diagnosis-to-splenectomy interval, and preoperative platelet count in relation to postoperative response after open and laparoscopic splenectomy.Data collected from two groups, treated by laparoscopic and open splenectomy, respectively, of 20 patients each were retrospectively reviewed. Positive response to splenectomies, evaluated according to the International Working Group guidelines reported by the American Society of Hematology, was statistically related through Student's t test and the Pearson correlation test to the above-mentioned factors.Positive response to splenectomy was observed in 80% and 85% of patients, respectively, in the laparoscopic and open groups (P.10). No statistical differences were observed comparing each of the studied factors between laparoscopic and open splenectomy responder patients (P.10). When percentage increase of postoperative platelet count was related to diagnosis-to-splenectomy interval, a positive correlation was found in the laparoscopic group (r = 0.544, P.05). In addition, a significant negative correlation in both groups was observed comparing preoperative platelet count and percentage postoperative platelet increase, with a greater increase of postoperative platelet count in patients with a lower preoperative platelet count (laparoscopic group, r = -0.663; open group, r = -0.656; P.01).In this series long-term results after laparoscopic splenectomy in ITP patients were as effective as after the open approach. Higher postoperative platelet percentage increase was achieved in both groups in patients with a lower preoperative platelet count. Finally, laparoscopic splenectomy in this study seems to be superior to the open approach in patients with a longer diagnosis-to-splenectomy interval.

The use of surgical drains after traditional splenectomy has been largely debated and several Authors have been unfavorable to their use. With the advent of laparoscopic splenectomy, their role has been re-discussed. The increased risk of undetectable pancreatic, gastric or colon injury in challenging laparoscopic removal of the spleen have induced some surgeons to reconsider the advantages related to their use.One hundred seventeen consecutive cases of laparoscopic splenectomy with routine use of surgical drains have been reviewed. Indications for surgery, length of operations, post-operative day of drain removal, post-operative complications were retrospectively analyzed.Laparoscopic splenectomy was performed for idiopathic thrombocytopenic purpura in 77 patients (65,8%), splenic lymphoma in 11 (9,4%), hereditary spherocytosis in 12 (10,2%), β-thalassemia in 6 (5.1%), other diseases in 11 (9,4%) cases. Conversion to open surgery was necessary in 11,1% of cases. Drains were removed 2-3 days after surgery in 95,8%, within 10 days in 3.4%, within 2 months in 0,8% of cases. In 2 cases a post-operative bleeding, detected through the drainage, required re-operation. One patient with myelofibrosis and massive splenomegaly developed a late post-operative subphrenic abscess, successfully treated by a percutaneous drainage.In Authors' experience, the use of drains after laparoscopic splenectomy helped detect early post-operative bleeding. Surgical drains could reduce the incidence of fluid intra-abdominal collections and infections. Their use should be recommended in the laparoscopic approach, especially in technically demanding surgical procedures.Laparoscopy, Surgical drainage, Splenectomy.L’utilizzo di drenaggi chirurgici dopo splenectomia tradizionale sono stati in gran parte discussi e diversi Autori sono stati favorevoli al loro impiego. Con l’avvento della splenectomia laparoscopica, il loro ruolo è stato nuovamente dibattuto. L’aumento del rischio di di lesioni iatrogene misconosciute del pancreas, stomaco o del colon nella rimozione laparoscopica dello stomaco difficile, hanno indotto alcuni chirurghi a riconsiderare i vantaggi connessi al loro uso.In questo studio sono stati esaminati centodiciassette pazienti consecutivi sottoposti a splenectomia laparoscopica con apposizione routinaria di drenaggio chirurgico. Sono stati analizzati retrospettivamente le indicazioni per il trattamento chirurgico, la durata dell’intervento chirurgico, la giornata post-operatoria in cui veniva rimosso il drenaggio, e le complicanze postoperatorie.La splenectomia laparoscopica è stata eseguita per la porpora trombocitopenica idiopatica in 77 pazienti (65,8%), linfoma della milza in 11 pazienti (9,4%), sferocitosi ereditaria in 12 pazienti (10,2%), β-talassemia in 6 pazienti (5,1%), altre malattie in 11 (9,4%) casi. La conversione a chirurgia open è stata necessaria in 11,1% dei casi. I drenaggi sono stati rimossi 2-3 giorni dopo l’intervento chirurgico in 95,8% dei casi, entro 10 giorni in 3,4% dei casi, ed entro 2 mesi nello 0,8% dei casi. In 2 casi un sanguinamento post-operatorio, rilevato attraverso il drenaggio, ha richiesto il re-intervento. Un paziente con mielofibrosi e massiccia splenomegalia aveva sviluppato un ascesso subfrenico nel tardo periodo post-operatorio, ed era stato trattato con successo con un drenaggio percutaneo.Nell’esperienza degli Autori, l’uso del drenaggio dopo splenectomia laparoscopica ha aiutato a individuare precocemente il sanguinamento post-operatorio. I drenaggi chirurgici potrebbero anche avere ridotto l’incidenza delle raccolte fluide e delle infezioni intraaddominali. Il loro uso dovrebbe essere raccomandato dopo approccio laparoscopico, in particolare nelle procedure chirurgiche tecnicamente impegnative.

We retrospectively studied 181 patients with polycythaemia vera (n=67), essential thrombocythaemia (n=67) or primary myelofibrosis (n=47), who presented a first episode of splanchnic vein thrombosis (SVT). Budd-Chiari syndrome (BCS) and portal vein thrombosis were diagnosed in 31 (17.1%) and 109 (60.3%) patients, respectively; isolated thrombosis of the mesenteric or splenic veins was detected in 18 and 23 cases, respectively. After this index event, the patients were followed for 735 patient years (pt-years) and experienced 31 recurrences corresponding to an incidence rate of 4.2 per 100 pt-years. Factors associated with a significantly higher risk of recurrence were BCS (hazard ratio (HR): 3.03), history of previous thrombosis (HR: 3.62), splenomegaly (HR: 2.66) and leukocytosis (HR: 2.8). Vitamin K-antagonists (VKA) were prescribed in 85% of patients and the recurrence rate was 3.9 per 100 pt-years, whereas in the small fraction (15%) not receiving VKA more recurrences (7.2 per 100 pt-years) were reported. Intracranial and extracranial major bleeding was recorded mainly in patients on VKA and the corresponding rate was 2.0 per 100 pt-years. In conclusion, despite anticoagulation treatment, the recurrence rate after SVT in myeloproliferative neoplasms is high and suggests the exploration of new avenues of secondary prophylaxis with new antithrombotic drugs and JAK-2 inhibitors. TB and AMV were supported by a grant from Associazione Italiana per la Ricerca sul Cancro (AIRC, Milano) ‘Special Program Molecular Clinical Oncology 5 × 1000’ to AGIMM (AIRC-Gruppo Italiano Malattie Mieloproliferative). VDS was supported by an unrestricted grant from the Bruno Farmaceutici Foundation.

Portal vein thrombosis (PVT) could be a life-threatening complication after splenectomy if not diagnosed promptly and treated properly. Risk factors of PVT are not completely clarified. Spleen size and underlying hematologic diseases are main potential risk factors for this complication. Laparoscopic surgery might increase the risk of developing PVT, as it reduces the blood flow in the portal system due to the pneumoperitoneum but, on the other hand, it seems to be associated with less postoperative modifications of coagulation parameters than open surgery, thus preventing PVT itself. The authors reviewed their series on open and laparoscopic splenectomies, pointing out their experience on PVT and discussing their surveillance and prophylaxis programs to prevent this complication.In this series, the authors report their experience on postsplenectomy PVT in 162 patients who have been splenectomised (102 operated on laparoscopically and 60 by open surgery).PVT was clinically observed in 1 case out of 60 open splenectomies and in 3 cases out of 102 laparoscopic procedures. Patients were treated with conservative anticoagulation therapy. In one case, additional ileal resection was needed. Mortality was 0%.Low-molecular-weight heparin should be administered to all patients who have been splenectomised, especially if they are at high risk of PVT. If symptoms appear, patients need to be treated with high-dose heparin followed, after at least 3 weeks, by oral anticoagulant therapy.

The essential thrombocythemia (ET) is a myeloid neoplasm characterized by platelet hyperreactivity and thrombotic risk. The treatment with aspirin (ASA) is recommended in ET patients at risk of first-time or recurrent thrombotic events. An unexplored topic is the optimal timing of once daily ASA intake. On the basis of the presumptions that 1) platelet aggregation is higher in the morning and that 2) the platelet inhibitory effect of ASA is not sustained during the usual 24-hour (h) dosing interval and that 3) a higher gastric mucosal resistance in the evening, we evaluated platelet count, β-thromboglobulin (β-TG) and platelet factor 4 (PF4), as markers of platelet activation, the clotting time (CT), clot formation time (CFT) and maximum clot formation/firmness (MCF), as indicators of aspirinated platelet contribution to clot formation/firmness. We studied 60 patients (20 men, 40 women; mean age 51 years, range 32-70) with ET according to WHO criteria. The mean duration of disease was 11 years. All patients were on ASA 100 mg once daily. Of these, 30 took ASA on awakening and 30 took ASA at bedtime. Of the 60 patients, 45 were on anagrelide hydrochloride (daily dose 1.5 mg) (10 men, 35 women), 15 were on hydroxyurea (daily dose 2 mg) (10 men 5 women). None had inherited or acquired thrombotic risk factors. Sixty subjects served as controls. Platelets were measured by automated analyzer. β-TG and PF4 were determined by ELISA. CT, CFT and MCF were measured by ROTEM delta. The mean platelet count was 455±200x109/L. The awakening ASA patients had normal β-TG and PF4 (12±5 IU/ml and 4±1 IU/ml), normal CT (CT, unit: s. n.v. 100-240 s) ( 110±20 s), normal CFT (CFT, unit: s, n.v. 30-110 s) (45±5 s) and normal MCF (MCF, unit: mm, n.v. 50-72 mm) (61±2 mm), whereas the bedtime ASA patients had high β-TG and PF4 (200±15 IU/ml vs 20±11 IU/ml and 170±50 IU/ml vs 6±2 IU/ml, respectively) (p Disclosures No relevant conflicts of interest to declare.

Myeloid sarcoma is a tumor composed of myeloblasts occurring at an extramedullary site. It may develop in patients with acute myeloid leukemia, myeloproliferative or myelodysplastic syndrome, sometimes preceding onset of the systemic disease. Frequent sites of myeloid sarcoma are bones or various soft tissues. Gastrointestinal involvement is very rare. We report a unique case of myeloid sarcoma presenting as a painful anal fissure, in a patient with a history of acute myeloid leukemia. The diagnosis was achieved by a surgical excisional biopsy and immunoistochemical staining.

Background We performed a retrospective study on patients with idiopathic thrombocytopenic purpura (ITP) to evaluate the response to splenectomy in relation to preoperative platelet count. Materials and methods Two groups of patients operated on with laparoscopic or open splenectomy for ITP, with a platelet count ≤30,000/μL (study group: 22 patients) and >30,000/μL (control group: 18 patients), respectively, were compared. The two groups were homogeneous in relation to age, sex, length of preoperative steroid therapy, and time interval between diagnosis and surgery (Student t test with P > .1). The results of surgery were evaluated at one year after splenectomy. Positive response to surgery, according to the American Society of Hematologic Guidelines, was considered in patients with a postoperative platelet count ≥100,000/μL or in patients with a postoperative platelet count ≥30,000/μL and a twofold increase in platelet count from baseline, in the absence of bleeding. The postoperative platelet count increase rate was statistically related to preoperative platelet count in both the study and control groups. Statistical analysis was performed using the Student's t test for independent sample and the Pearson correlation in a 2-tailed test. Results No relationship between preoperative platelet count and postoperative platelet percent increase was observed in the control group (r = -0.41; P = .089), whereas a significant negative correlation (r = -0.68; P = .0004) was found in the study group. Conclusions A higher increase of postoperative percent platelet count may be predicted in patients with a low preoperative platelet count.

Background: The incidence of deep vein thrombosis and pulmonary embolism following laparoscopic surgery is unknown and studies on alterations of hemostasis after laparoscopy are inconclusive. Methods: In this study we prospectively evaluated changes in prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen (Fg), antithrombin III (ATIII), prothrombin fragment F 1 + 2, beta-thromboglobulin (bTG) and D-dimer (D-D), preoperatively and 24 h after laparoscopic surgery in 16 patients. Results: Comparing pre- and postoperative values, no statistical differences were observed in aPTT, F1 + 2, and ATIII measurements. Postoperative PT values increased slightly (p ~ 0.05) after surgery. Conversely, Fg, bTG, and D-D values were statistically higher in the 24-h evaluation (p = 0.008, 0.01, and 0.045, respectively). Conclusions: These data suggest that laparoscopic surgery induces activation of coagulation and fibrinolytic pathways and, additionaly, bTG elevation, which has never been reported and might account for postoperative platelet activation and a greater risk of thrombogenicity. Therefore, routine thromboembolic prophylaxis in patients undergoing laparoscopic surgery is recommended.

Background and Objectives: The aim of this study was to evaluate the results of laparoscopic surgery performed for coexisting spleen and gallbladder surgical diseases. Methods: Between May 2004 and October 2012, 12 patients underwent concomitant laparoscopic splenectomy and cholecystectomy. Indications for surgery included idiopathic thrombocytopenic purpura in 5 patients, hereditary spherocytosis in 4 patients, and thalassemia intermedia in 3 patients. Results: The mean operative time was 100 minutes (range, 80–160 minutes), and the blood loss ranged from 0 to 150 mL (mean, 50 mL). The mean longitudinal diameter of the spleen was 14 cm. One patient required conversion to open procedure. An accessory spleen was detected and removed in one case. The mean length of hospital stay was 5 days. No deaths or other major intraoperative and/or postoperative complications occurred. Conclusion: Provided that the technique is performed by an experienced surgical team, concomitant laparoscopic splenectomy and cholecystectomy is a safe and feasible procedure and may be considered for coexisting spleen and gallbladder diseases.

An increase of angiogenesis has been shown in idiopathic myelofibrosis with myeloid metaplasia (MMM) by microvessel density count method but evaluation of circulating angiogenic factors is still incomplete. In 31 patients affected by MMM and in 12 healthy subjects we evaluated the serum levels of VEGF (vascular endothelial growth factor) and correlated VEGF with clinical and laboratory features of disease. We found that MMM patients had circulating VEGF concentrations much higher than controls (Median 1208 ng/ml vs 138 ng/ml, P0.0001). No correlation was found between VEGF and Hb, WBC, PLT, LDH, creatinine, bone marrow cellularity, fibrosis, splenomegaly, hepatomegaly, and therapy. However, in the subgroup of patients with a normal or low VEGF concentration, a direct correlation between VEGF and platelet count (r = 0.90, P = 0.002) was detected. Moreover, patients with a platelet count300 x 10(9)/l had VEGF serum levels lower than patients with a higher PLT count (median VEGF 864 vs 1557 pg/ml, P = 0.001). In six patients and in eight controls we also had the opportunity to measure VEGF in the plasma and we calculated that VEGF concentration was much higher in platelet-rich than in platelet-poor plasma and that platetets of MMM patients contained four times more VEGF than those of healthy controls. These results indicate that VEGF is overproduced in MMM, thus confirming an increased angiogenic activity. Platelets are probably a major source of VEGF in MMM but not the only one.

Background: the Registro Italiano Trombocitemie (RIT) was activated mainly to evaluate the diagnosis and therapy appropriateness in the thrombocythemic patients with Ph-negative myeloproliferative neoplasm (MPN) observed in the adhering centers. Objective: to evaluate how the diagnostic and therapeutic approach changed in the RIT patients diagnosed with thrombocythemic MPN in the last two decades. Methods: the RIT centers registered by a web-based system during the years 2005-2014 their thrombocythemic MPN patients, and semesterly updated their follow-up data. For patients diagnosed before 2005, the data on diagnosis and prior follow-up were retrospectively collected. The diagnostic process and the initial treatment (started into the first year after diagnosis) were comparatively analyzed in the patients diagnosed before and after 2005. Results: the RIT centers registered 2629 patients. 2388 of them, object of this analysis, were diagnosed between1995 and 2014: 1098 (46%) in the decade 1995-2004 (Group I), and 1290 (54%) in the decade 2005-2014 (Group II). The diagnostic process in the patients of Group II and Group I included bone marrow biopsy (BMB, performed into 1 year and before any cytoreduction): 85% vs 80%, p The patients of Group II, as compared with those of Group I, showed a similar gender distribution (M/F ratio 0.61 vs 0.65, p 0.452), and had at diagnosis: a higher age (median 60 vs 57 years, p 60 years in 50% vs 45% of cases, p Moreover, they had: a lower platelet (PLT) count (median 737 vs 775 x 109/L, p 10 x 109/L in 28% vs 26% cases); a similar median levels of hematocrit (HCT %, in females 41.4 vs 41.0; in males 44.7 vs 44.6) and hemoglobin (Hb g/dL, in females 13.8 vs 13.6; in males 15.0 vs 14.9). The BMB, revised according to the WHO 2008 criteria, showed a not different distribution (p 0.21) of ET (64% vs 61%), ep-PMF (16% vs 17%), PMF (3% vs 2%), PV (4% vs 4%), and U-MPN (13% vs 16%. The JAK2 V617F mutation in patients of Group II (at diagnosis) and of Group I (after diagnosis) was found in 62% and in 58% of tested cases (p 0.054), respectively. The patients at high standard thrombotic risk were 58% vs 52%, p 0.004. In the patients of Group II and Group I the distribution of the treatment started into the first year was significantly different (p The treatment CYT ± AntiPLT was started in the patients at high standard thrombotic risk with a rate of 81% vs 80%, respectively, and in the patients at low standard thrombotic risk in 37% vs 43% of cases, respectively. The initial treatment CYT±AntiPLT was related, in multivariate analysis, both in patients of Group II and Group I, with older age (>60 and 40-60 vs 1000 and 700-1000 vs Conclusion: in the studied thrombocythemic MPN patients the real-life diagnostic approach was improved after 2005 not only due to the routine use of JAK2 tests, but also due to the higher rate of BMB done (85% vs 80%). The appropriateness of the cytoreductive treatment (CYT±AntiPLT started into one year from diagnosis) remained high in patients at high standard thrombotic risk (over 80% of cases were treated). Concomitantly, the inappropriate use of the cytoreductive drugs in patients at low standard thrombotic risk appreciably decreased (from 43% to 37% of cases). Moreover, it has to be remarked that the therapeutic approach was significantly influenced not only by older age and prior thrombosis, but also by thrombocytosis (PLT count >700 x 109/L), disease-related symptoms, and inconstantly by leukocytosis and CVRFs. Table Table. Disclosures Gugliotta: SHIRE Co.: Honoraria. Gugliotta:Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

Polycythemia vera (PV) is a myeloid neoplasm characterized by thrombotic risk related to high hematocrit (HCT) and to platelet hyperactivation. According to PVSG, the antithrombotic therapy include low dose aspirin (ASA). However, there are insensitive ASA PV patients. It is debated if enherited thrombophilia is responsible to affect platelet activation and, hence, to cause ASA insensitivity. Therefore, we evaluated gene polymorphism human platelet antigen-1 (HPA-1) as thrombophilic indicator associated with abnormal platelet activity, HCT, platelet count, b-TG and PF4, as markers of platelet activation, the platelet functional activity (PFA) and the maximum clot firmness (MCF), as direct and indirect indicators of ASA sensitivity. We studied 40 patients (28 men, 12 women; mean age 64 years, range 35-85 years) with PV according to WHO criteria. Fifty subjects served as controls. The mean duration of disease was 9 years. All patients were on phlebotomy and ASA (100 mg once daily). Platelets and HCT were measured by automated analyzer. b-TG and PF4 were determined by ELISA. PFA and MCF were measured by Platelet Function Analyzer (PFA-100) and by ROTEM delta. Of 40 patients, 24 were homozygous HPA-1a/a and 16 heterozigous HPA-1a/b. The mean HCT value was 47±3% and platelets were 428±180x109/L. All patients had high b-TG and PF4 (113±47 IU/ml vs 20±11 IU/ml and 45±21 IU/ml vs 6±2 IU/ml, respectively), prolonged C/EPI closure time (CT, unit: s, n.v. 84-160 s) (233±65 s) and normal MCF (MCF, unit: mm, n.v. 50-72 mm) (65±5 mm). These findings suggest that PFA-100 and Thromboelastometric assays may be an useful tool to detect ASA platelet sensitivity in PV patients. Disclosures No relevant conflicts of interest to declare.

In the hemopoietic system, interactions between stem cells and components of the bone marrow microenvironment play a pivotal role in blood cell proliferation and differentiation. Among the adhesion molecules, the integrins of the beta 1-subfamily are known to direct cell-cell and cell-matrix interactions and evidence has been provided that CD34-positive stem cells bind either to the bone marrow stroma or to the extracellular matrix proteins through the beta 1-integrins. It seems that changes in their expression pattern or signalling function are likely to reflect disturbances at the hemopoietic bone marrow microenvironmental level. Any alteration of their biological functions makes them attractive candidates for playing decisive roles in the leukemic processes. In this view, beta 1-integrins have been recognized to mediate those cellular interactions and migrations that are important in the biology of leukemia. In this paper we review some aspects of the role played by beta 1-integrins, especially VLA-4 and VLA-5, in adult acute lymphoblastic leukemia in relation with the expression rate of the stem cell antigen CD34.

We prospectively evaluated the effect of anagrelide (ANA) on platelets, PF4, F1+2, PAP, PAI-1, and TFPI and erythromelalgia in patients with essential thrombocythemia (ET) receiving anti-aggregants both pre- and post-ANA. At first, we observed a successful reduction of platelets, which was associated with normalization of platelet coagulant and endothelial function and disappearance of erythromelalgia. Secondly, we found a correlation between PF4 and TFPI and between TFPI and thrombosis, suggesting that erythromelalgia may be caused by platelet-mediated endothelial activation. These data may indicate that ANA may be efficacy in the treatment of symptomatic patients with ET.

Hydroxyurea (Hydroxycarbamide; HU) is commonly used for the long-term treatment of patients with Philadelphia-chromosome negative chronic myeloproliferative neoplasms (MPNs). It is considered a first-choice agent for the treatment of these disorders as underlined by the European Leukemia Net Consensus Conference [1], although it is formally approved for this indication in some countries only. The drug is reportedly well tolerated in the large majority of subjects, although systemic and/or localized toxicities have been reported. Consensus criteria for definition of “intolerance” to HU have been described; patients who develop intolerance are candidate for second-line therapy and, more recently, for investigational drugs. However, no epidemiologic information about the occurrence of the most clinically significant HU-associated adverse events is yet available. In this study, the authors report on a multicenter series of 3,411 patients who were treated with HU among which 184, accounting for 5% of total, developed significant drug-related toxicities. These data provide an estimate of the frequency and a detailed characterization of clinically significant HU-related toxicities; these information have relevance for the management of MPN patients who require second-line therapy after developing HU-related intolerance.

Essential thrombocythaemia (ET) is a myeloproliferative neoplasm characterized by elevated platelet counts and increased incidence of thrombosis and haemorrhage. Median age at diagnosis is 65-70 years. Life expectancy is similar to that of the healthy population. Symptoms and complications may affect quality of life (QoL); in particular, in elderly patients ET may represent an additional burden. We performed a survey in 494 elderly ET patients to evaluate patient-reported outcomes (PROs). Comorbidities were present in 305 (62%) patients. Factorial analysis based on survey items representing psychological aspects of daily life identified an "attitude domain" with four clusters of patients: (A) very pessimistic (n=99), (B) pessimistic (n=101), (C) optimistic (n=90), and (D) very optimistic (n=107). Patients in cluster A had more comorbidities (p=0.003) while patients in cluster D required fewer medical visits and were less disturbed by medications (p