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Marchetti M.,Ospedali Riuniti di Bergamo | Diani E.,Ospedali Riuniti di Bergamo | ten Cate H.,Maastricht University | Falanga A.,Ospedali Riuniti di Bergamo
Haematologica | Year: 2012

Background Thrombin, the final enzyme of blood coagulation, is a multifunctional serine protease also involved in the progression of cancer. Tumor cells may activate blood coagulation proteases through the expression of procoagulant activities. However, specific information about the thrombin generation potential of malignant tissues is lacking. In this study we applied a single global coagulation test, the calibrated automated thrombogram assay, to characterize the specific procoagulant phenotypes of different tumor cells. Design and Methods Malignant hematologic cells (i.e. NB4, HEL, and K562) or solid tumor cells (i.e. MCF-7 breast cancer and H69 small cell lung cells) were selected for the study. The calibrated automated thrombogram assay was performed in normal plasma and in plasma samples selectively deficient in factor VII, XII, IX or X, in the absence or presence of a specific anti-tissue factor antibody. Furthermore, cell tissue factor levels were characterized by measuring antigen, activity and mRNA expression. Results In normal plasma, NB4 induced the highest thrombin generation, followed by MCF-7, H69, HEL, and K562 cells. The anti-tissue factor antibody, as well as deficiencies of factors VII, IX and XII affected the thrombin generation potential of malignant cells to different degrees, allowing differentiation of the two different pathways of blood clotting activation - by tissue factor or contact activation. The thrombin generation capacity of NB4 and MCF-7 cells was tissue factor-dependent, as it was highly sensitive to inhibition by anti-tissue factor antibody and factor VII deficiency, while the thrombin generation capacity of H69, HEL and K562 was contact activation-dependent, as no thrombin was generated by these cells in factor XII-deficient plasma. Conclusions This study demonstrates that the calibrated automated thrombogram assay is capable of quantifying, characterizing, and comparing the thrombin generation capacity of different tumor cells. This provides a useful tool for understanding the key factors determining the global procoagulant profile of tumors, which is important for addressing specific targeted therapy for the prevention of thrombosis and for cancer. © 2012 Ferrata Storti Foundation.


Barbui T.,Ospedali Riuniti di Bergamo | Thiele J.,University of Cologne | Vannucchi A.M.,University of Florence | Tefferi A.,Mayo Medical School
Leukemia | Year: 2013

Reproducibility and clinical usefulness of the WHO classification of chronic myeloproliferative neoplasm (MPN) persist to be a controversial issue. Major arguments are focused on the critical impact of histopathology, particularly concerning the distinction between essential thrombocythemia (ET) versus early/prefibrotic primary myelofibrosis (PMF). Regarding bone marrow morphology, WHO guidelines strictly require the recognition of characteristic histological patterns based on standardized features and a consensus of clinical and molecular-genetic data. Molecular-genetic findings as JAK2V617F, may aid to exclude reactive thrombocytosis, although in ET and PMF only 50-60% of the cases show these aberrations. Considerable doubts over the existence of early/prefibrotic PMF have been expressed with the consequence to include this entity in the ET category. On the other hand, it has to be argued that some of the critical studies failed to adhere very strictly to the WHO guidelines. Contrasting this situation, recently published retrospective and prospective clinico-pathological studies featuring the WHO criteria provided an important information on disease outcomes supporting the existence of early/prefibrotic PMF as a distinct clinico-pathologic entity in patients presenting clinically with ET. Therefore, this controversy suggests a scientific project, including the community of pathologists and hematologists, for providing sound, objective and reproducible criteria for diagnosing early/prefibrotic PMF. © 2013 Macmillan Publishers Limited All rights reserved.


Falanga A.,Ospedali Riuniti di Bergamo | Russo L.,Ospedali Riuniti di Bergamo | Verzeroli C.,Ospedali Riuniti di Bergamo
Thrombosis Research | Year: 2013

Patients with cancer are at high risk of developing thrombosis. The pathogenesis of blood coagulation activation in cancer patients is complex involves both clinical and biological factors. The thrombotic risk varies according to the type of malignancy and its disease stage, and is increased by concomitant patient-related thrombotic risk factors (i.e. advanced age, infection, heart disease). In addition, the tumor cell-specific prothrombotic properties and the host cell inflammatory response dramatically contribute to the risk of thrombosis in these patients. The current development of risk assessment models to predict thrombosis in cancer is important for identifying high-risk patients and predispose the adequate preventive measures. In this review we provide an overview of the principal mechanisms of thrombosis in cancer, including clinical and biological risk factors, and a summary of risk assessment tools to predict thrombosis in the single patient. © 2013 Elsevier Ltd. All rights reserved.


Falanga A.,Ospedali Riuniti di Bergamo
Thrombosis research | Year: 2012

Microparticles (MP) are shed from the surface of activated or apoptotic blood cells and their levels in plasma reflect a balance between cell stimulation, proliferation, and death. MP production occurs through vesiculation of cell membranes, and involves cytoskeletal changes and a shift in the normal phospholipid asymmetry. The expression on the majority of MP of the anionic phosphatidylserine (PS) is responsible for the capacity of MP to support blood coagulation activation. In some cases, PS expression is also associated, in the same MP, with the presence of active Tissue Factor, the main activator of blood coagulation. Elevation in plasma levels of MP have been described in numerous clinical conditions, most of which also associated with an increased thrombotic risk. Particularly, MP have been found to be increased in both solid and hematological malignancies, including myeloproliferative neoplasms. A role of MP in tumor progression has been suggested by both in vitro and in vivo studies. Evidence exists that MP of platelet origin are the main players in this process, being rich in pro-angiogenic factors. The utility of measuring MP as a diagnostic and prognostic marker is currently a subject of intense investigation. The possibility to inhibit MP production by pharmacological interventions represents a future challenge. Copyright © 2012 Elsevier Ltd. All rights reserved.


Falanga A.,Ospedali Riuniti di Bergamo | Marchetti M.,Ospedali Riuniti di Bergamo | Russo L.,Ospedali Riuniti di Bergamo
Current Opinion in Oncology | Year: 2012

Purpose of Review: This review summarizes the current knowledge of the epidemiology, prophylaxis, and treatment of venous thromboembolism (VTE) in patients with lymphoma, multiple myeloma or acute leukemia. Recent Findings: Hematologic malignancies are associated with a high risk of thrombotic complications. The incidence of these events is greatly variable and is influenced by many factors, including the type and the stage of disease, antitumor therapies, and the use of central venous device (CVD). Epidemiological data allow an estimate of the incidence of VTE in acute leukemia, lymphomas, and multiple myeloma. The effect of chemotherapy on the incidence of thrombosis is particularly evident in acute leukemia as it causes the exacerbation of the clotting/bleeding syndrome typical of this disease. The role of chemotherapy is also relevant in lymphoma, and in multiple myeloma, in which the use of immunomodulating agents, in combination with chemotherapy and steroids significantly increases the risk of VTE. Summary: Thrombotic complications have a significant impact on morbidity and mortality of hematological cancer patients, therefore, in this setting, the issue of thromboprophylaxis to prevent VTE is important. However, no clear recommendation in these conditions is available, with the exception of multiple myeloma. Large prospective randomized clinical trials are needed to establish the best practice for prevention and treatment of VTE in these types of malignant diseases. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Primary antithrombotic prevention with aspirin is not indicated in asymptomatic patients with confirmed antiphospholipid (aPL) positivity without systemic autoimmune disorders because: a) the estimated prevalence of thrombosis in unselected cases is about 1% patient-years (range 0-2.8); b) this level of thrombotic risk is equivalent to that of major bleeding associated with the use of aspirin and therefore the expected benefit does not outweigh the risk; c) these expectations have been confirmed by at least one randomized clinical trial, although with methodological limits. The management of modifiable thrombotic risk factors can be an alternative and safer strategy, considering that many vascular events occur in the presence of concomitant non-aPL triggering conditions. Whether primary prophylaxis with aspirin may be useful for some subsets of aPL patients at particularly high thrombotic risk, such as those with overt systemic autoimmune disorders or with special patterns of antibodies ('triple positivity'), remains to be established. © The Author(s), 2012. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav.


Finazzi G.,Ospedali Riuniti di Bergamo
Leukemia | Year: 2012

I use the hematological, morphological and molecular criteria recently established by the World Health Organization to diagnose essential thrombocytemia. In these patients, major causes of morbidity and mortality are represented by thrombosis and bleeding, whereas progression to myelofibrosis and transformation to acute leukemia are more rare. Myelosuppressive therapy can reduce the rate of vascular complications, but there is some concern about treatment-related toxicity. Therefore, I follow a risk-oriented therapeutic approach to avoid inappropriate exposure to cytotoxic drugs on one side or suboptimal treatment on the other. Established predictors of cardiovascular events are represented by older age and previous thrombosis, whereas recent data suggest a prognostic role for novel risk factors, including leukocytosis and JAK2V617F mutational status. There is no indication for therapeutic intervention in asymptomatic, low-risk patients, while I treat high-risk patients with hydroxyurea (HU) first. Other therapeutic options, such as interferon alpha or anagrelide, may find place in selected patients including those who are resistant or intolerant to HU. I follow a risk-oriented approach also for management of pregnancy. Low-risk women are given low-dose aspirin throughout pregnancy and prophylactic low-molecular-weight heparin (LMWH) post partum, whereas LMWH throughout pregnancy and/or interferon-alpha can be required in high-risk cases. © 2012 Macmillan Publishers Limited All rights reserved.


Falanga A.,Ospedali Riuniti di Bergamo
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2012

Thrombosis is a leading cause of morbidity and mortality in patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), particularly polycythemia vera and essential thrombocythemia. Mechanisms involved in the pathogenesis of the acquired thrombophilic state associated with these diseases include abnormalities of MPN clone-derived blood cells, which display prothrombotic features, and abnormalities of normal vascular cells, which become procoagulant in response to inflammatory stimuli. Ultimately, the release into the blood of elevated levels of procoagulant microparticles by platelets and vascular cells and the increase in the global thrombin generation due to an acquired activated protein C resistance result in a highly prothrombotic scenario in patients with polycythemia vera and essential thrombocythemia. The acquired point mutation in the pseudokinase domain of JAK2 (JAK2V617F) in these disorders is variably associated with thrombosis and, more consistently, with elevations in WBC counts and alterations in biomarkers of blood-clotting abnormalities. The predictive value of these biomarkers for thrombosis remains to be established to identify subsets of patients at elevated risk who may benefit from prophylaxis with antithrombotic drugs.


Falanga A.,Ospedali Riuniti di Bergamo | Marchetti M.,Ospedali Riuniti di Bergamo
Thrombosis Research | Year: 2012

Venous thromboembolic (VTE) complications are common in patients with cancer and represent the second cause of death in this disease. The risk of VTE varies according to the type of malignancy and with the extent of the cancer. Patients with VTE and more advanced, metastatic disease face worse clinical outcomes. Important in this setting is the triggering role of antitumor therapies, including cancer surgery and active treatments such as chemotherapy, hormonal and anti-angiogenic therapy, which further increase the cancer-associated thrombotic risk. Predictive models for VTE in cancer patients are now available and will allow the possibility of improving outcomes for patients under chemotherapy by identifying those who would benefit most from thromboprophylaxis. © 2011 Elsevier Ltd. All rights reserved.


Barbui T.,Ospedali Riuniti di Bergamo | Finazzi M.C.,Ospedali Riuniti di Bergamo | Finazzi G.,Ospedali Riuniti di Bergamo
Blood Reviews | Year: 2012

Because the current therapy in polycythemia vera (PV) and essential thrombocythemia (ET) is aimed at lowering the risk of thrombosis, the risk classification system in these disorders is shaped according to thrombotic risk. Patients with either PV or ET can be stratified in a "high-risk" or "low-risk" category according to their age and previous history of thrombosis. Whether novel risk factors such as leukocytosis and JAK2 mutation may be included in the prognostic stratification requires confirmation in prospective future clinical studies. The identification and appropriate management of cardiovascular risk factors and the promotion of a healthy lifestyle in chronic myeloproliferative neoplasms (MPN), as in the general population, should be considered a cornerstone of vascular prevention. Blood hyperviscosity in PV is a major cause of vascular disturbances which severely impact on morbidity and mortality. An aggressive target of hematocrit lower than 45% in males and 42% in females has been advised by the European LeukemiaNet (ELN) group, although no convincing evidence of this recommendation is currently available. The efficacy and safety of low-dose aspirin (100. mg daily) in PV has been assessed in the European Collaboration on Low-dose Aspirin in Polycythemia (ECLAP) double-blind, placebo-controlled, randomized clinical trial. Translating evidence from the positive results of ECLAP to ET may be questionable. The most commonly used front-line therapy drugs for the treatment of high-risk PV and ET patients include hydroxyurea and alpha-interferon at any age while anagrelide is recommended as second line-therapy in resistant and intolerant ET patients. Busulphan is a front-line therapy in the elderly. By definition, children with ET are a population with low vascular risk unless a major thrombotic or hemorrhagic event has occurred. ELN recommends to prescribe cytoreductive drugs in children as a last resort. No results of clinical trials with JAK-2 inhibitor drugs in PV and ET are so far available. © 2012 Elsevier Ltd.

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