Thrombosis is one of the most frequent complication in cancer and the second leading cause of death among patients with malignant diseases . The risk of thrombosis is up to seven times increased in cancer patients as compared with general population [2,3]. However, the risk of thrombosis in patients with hematologic malignancies was considered lower than in solid tumors, and much of the attention was directed towards bleeding and infectious complications due the condition of thrombocytopenia and neutropenia. Recent studies indicate that the risk of thrombosis in hematologic patients may be similar or even higher than in those with solid neoplasms. Among hematologic malignancies, the incidence of venous thromboembolism (VTE) is known in myeloma (5%), non-Hodgkin lymphoma (4.8%) and Hodgkin disease (4.6%) , whereas information in acute leukemia is sparse.
This review focuses on the current knowledge about pathogenesis, incidence, risk factors and management of thrombotic events in patients with acute leukemia.
PATHOPHYSIOLOGY OF THROMBOSIS IN ACUTE LEUKEMIA
The pathogenesis of thrombosis in leukemia is multifactorial . Blasts secrete prothrombotic products such as tissue factor (TF), cancer procoagulant  and cytokines . TF can be detected in the plasma or incorporated into cell-derived extra-vesicles (EVs). EVs are vesicular structures released by various cell types, including malignant cells, through a process of outer membrane blebbing [7▪]. TF expressed on EVs surface leads to the formation of TF/factorVIIa (FVIIa) complex  and TF-positive EVs were also found in patients with acute leukemia [9,10,11▪]. EVs also operate through TF-independent mechanisms. . Furthermore, leukemic cells activate platelets through cytokines and growth factor release [13–15]. Upon activation, platelets split in two subpopulations [16▪▪,17]. One can aggregate through several molecular interactions such as binding of P-selectin to phosphatidylserine-glycoprotein (PSGL-1) [18,19]. The other one (super-activated) externalizes P-selectin, promoting membrane-dependent activation of coagulation [17,20▪▪,21,22▪]. These super-activated platelets are thought to be central in the physiologic coagulation process  and in coagulation disturbances associated with solid cancers [24,25]. Such a platelet-regulated coagulation [26–28] is thought to occur also in hematological malignancies [29,30]. In this condition, thrombosis may result from an excess of interactions between procoagulant EVs and procoagulant platelets (Fig. 1). In acute leukemia, such an excess of interactions is also boosted by chemotherapy-induced massive cell-death , and may explain why thrombosis can paradoxically intervene in situations of thrombocytopenia [32,33]. There are also growing evidence that, upon cell-death, extracellular cell-free DNA (cfDNA) is released into circulation. Circulating cfDNA may interfere with primary and secondary hemostasis by inducing platelet aggregation, promoting coagulation activation, inhibition of fibrinolysis and altering clot stability [34–38]. Neutrophil-extracellular traps (NETs), originally described as a defense mechanism against infection , are a source of cfDNA and have been associated with cancer-related thrombosis [40–43,44▪▪]. In vitro, it was demonstrated that some category of leukemias such as promyelocytic cell lines promote formation of NET-like structures . In AML, NET formation depends on granulocyte maturation during treatment  or on the presence of EVs  In addition to EVs, circulating micro RNA (miRNA) was also detected in various types of cancers . EVs and miRNAs share the ability to transfer biological information to recipient cells. Therefore, in addition to playing a role in cancer metastasis and prognosis,  they might enforce communication between cancer cells and platelets.
In addition to procoagulant activity of malignant cells, chemotherapy, high doses of steroids, infections and central venous catheter (CVC) insertion also contribute to thrombosis in acute leukemia. Among therapeutic agents, all-trans retinoic acid (ATRA) was shown to diminish the expressions of TF and cancer procoagulants, thus attenuating procoagulant, fibrinolytic and proteolytic activity of the leukemic blasts. However, some studies also suggest that ATRA-induced modifications in the balance between procoagulant and fibrinolytic properties of leukemic promyelocytes might favor development of thrombosis, especially during ATRA syndrome and in patients with hyperleukocytosis . ATRA also seems to accelerate cfDNA release . Arsenic trioxide may also promote procoagulant activity by causing endothelial dysfunction  and platelet apoptosis  through exposure of P-selectin and microparticles. In addition to depleting the contents of asparagine in the lymphoid leukemic cells, L-asparaginase (L-ASP) deaminates circulating glutamine to glutamic acid; depletion of the glutamine levels induces alteration in the clot formation process . Moreover, as glutamine depletion inhibits platelet mitochondria function [54,55], even procoagulant platelet subpopulation participates in L-ASP-induced thrombogenesis. Finally, L-ASP in combination with steroids can suppress the natural anticoagulants antithrombin and plasminogen, thus amplifying generation of FVIII and von Willebrand factor-complex [56–58].
BCR/ABL tyrosine-kinase inhibitors (TKIs) can influence platelet-based hemostasis. Either dasatinib or ponatinib interferes with the formation of procoagulant platelets. Doses higher than the therapeutic levels of dasatinib, ponatinib and imatinib significantly alter thrombin generation parameters . In particular, the prothrombotic effect of ponatinib could be mediated through an excess of BCR/ABL+ cell apoptosis or a direct endothelial damage [60,61].
Endothelium injury and platelet activation is also thought to be the mechanisms leading to veno-occlusive disease (VOD) occurring during therapy with drugs such as inotuzumab ozogamicin (INO) .
Activation of coagulation can be also caused by infections. The rising levels of inflammatory cytokines induced by infections lead to TF release, thrombomodulin downregulation and upregulation of plasminogen activator inhibitor [63,64]. Furthermore, Gram-negative bacteria promote release of TF, TNF-alpha, and IL1b whereas Gram-positive can shed mucopolysaccharides that directly activate FXII .
Finally, CVC insertion is another well known risk factor for development of thrombosis in acute leukemia . CVC insertion can determine vessel damage and endothelium injury and exercises a mechanic action by engaging much of the luminal diameter of veins. Lastly, CVC-related thrombosis (CRT) may be favored by local or systemic infections .
THROMBOSIS IN ACUTE LYMPHOBLASTIC LEUKEMIA
Pathogenesis of thrombosis in acute lymphoblastic leukemia (ALL) appears to be therapy-related as most of the events occur during the induction phase. In fact, whereas at diagnosis the incidence is relatively low (1.4%), during treatment it increases up to 10% , with L-ASP being the agent most frequently associated with this complication [68–72] (Table 1). Incidence of thrombosis following L-ASP treatment appears to be higher in adults [73▪▪].
Although VTE prevails, arterial thrombosis and central nervous system (CNS) venous thrombosis were also reported . In the GRAALL (Group for Research on Adult Acute Lymphoblastic Leukemia) trial, CNS thrombosis was diagnosed in 3.1% of adult patients, in strict association with L-ASP administration. . In the UKALL2003 trial, the incidence of CNS thrombosis in the young adults treated with pegylated-ASP was 1.4%. Patients who developed CNS thrombosis were significantly older and more likely to have high-risk cytogenetics than those with no thrombosis. Other risk factors for CNS thrombosis were: hospital stay, immobility for more than 3 days, infections, dehydration and use of oral contraceptive . Intrathecal administration of methotrexate (MTX) might be an additional factor contributing to CNS thrombosis. In the HOVON (Dutch-Belgian Hemato-Oncology Cooperative Group)-37 trial, 9 (4%) of 240 patients presented CNS thrombosis . In eight of nine, thrombosis occurred in close association with L-ASP delivery, and in all patients, shortly after intrathecal injection of MTX. The inflammatory effects of MTX and diminution of cerebrospinal fluid pressure are possibly the ultimate causes of CNS thrombosis .
The advent of new drugs for the treatment of ALL contributed to expand contexts wherever thrombotic events might be observed. In fact, VTE is observed in patients with Philadelphia-positive ALL receiving ponatinib [76–78]. In a phase 2 trial of concurrent administration of hyper-CVAD and ponatinib, 8% of the patients had a VTE and 8% experienced a myocardial infarction . Many of these patients had preexisting cardiovascular disease or cardiovascular risk factors. Therefore, patients’ selection and proper management of cardiovascular risk factors appear critical to minimize the thrombotic risk of ponatinib [80,81]. In addition to these actions, it was also suggested that de-escalating the dose of ponatinib from 45 to 30 mg/day would be desirable in patients at risk of developing thrombosis, without jeopardizing the antileukemic activity of the drug. In the same line, it was found that the delivery of anti-CD22 monoclonal antibody INO, whereas being associated with a longer survival than the chemotherapy cohort, resulted in higher instances of VOD (11 vs. 1%) [62,82]. Based on this, a warning has been posed in patients for whom INO is given as a ‘bridge to transplant’ with no more than two cycles being considered the safest choice .
THROMBOSIS IN ACUTE MYELOID LEUKEMIA
Incidence of VTE in AML varies markedly among studies, ranging from 2 to 13% [68,72,83]. Furthermore, definition of predisposing risk factors remains unclear. With the limit that no laboratory or therapeutic information is available, the study of Ku et al.  indicates that female sex, older age, number of chronic comorbidities and presence of a CVC are predictors of VTE development within 1 year from the diagnosis of AML. In a large study of 811 AML patients, advanced age (>65 years) and intermediate/high cytogenetics risk  were found to anticipate VTE development . It was hypothesized that the predictive role of adverse cytogenetics may be related to the frequent use of multiple intensive chemotherapy courses, because of the chemo-resistance profile of these AMLs. In a recent prospective study, including a cohort of 272 adult patients and an independent ‘validation’ cohort of 132 adults with newly diagnosed AML, Libourel et al. [86▪▪] measured a set of biomarkers of disseminated intravascular coagulation (DIC) (fibrinogen, D-dimer, α-2-antiplasmin, antithrombin, prothrombin time and platelet count) and calculated the DIC score (according the International Society of Thrombosis and Haemostasis) . The authors found that the incidence of thrombosis was 8.4% (4.7% venous, 4% arterial) in younger adults and 10.4% (4.4% venous, 5.9% arterial) in elderly patients. Overall, incidence of arterial thrombosis was higher than expected. The calculated DIC score  significantly predicted venous and arterial thrombosis and, among the DIC biomarkers, a high D-dimer level was the best predictor of thrombosis. As all the patients were treated by intensive chemotherapy, the authors concluded that venous and arterial thrombosis may occur in ∼10% of AML patients treated intensively. Such a complication can be largely envisaged by the presence of DIC at diagnosis. This study also confirms the potential synergism between chemotherapy and severe hyper-coagulable state intrinsic to AML [32,66–68], in determining thrombotic accidents . Finally, even in AML, the prothrombotic role of indwelled CVC must be considered. Many thrombotic episodes in AML are CRT [69,83,85]. We observed 19 (18%) instances of CRT among 106 insertions. In line with others’ experience , our CRTs were significantly associated with CVC-exit site infections and/or sepsis . At variance with what is known in solid tumors and ALL, the diagnosis of VTE in AML is not associated with reduced survival [69,83].
THROMBOSIS IN ACUTE PROMYELOCYTIC LEUKEMIA
Acute promyelocytic leukemia (APL) represents about 10% of all AML cases  and its course can be characterized by either hemorrhagic or thrombotic events . The bleeding syndrome is because of hyperfibrinolysis-associated DIC. The trigger is cancer procoagulant and TF blasts secretion and the expression of high levels of the fibrinolysis activator annexin 2 . The introduction of ATRA-based therapy substantially ameliorated the hemorrhagic coagulopathy and tipped the balance towards thrombosis. Thrombotic events are likely linked to the NETs formation due to differentiation syndrom  or to generation of tissue factor positive EVs . Reported prevalence of both arterial and vein thrombosis ranges in between 2%, in pre-ATRA era, and 10–15% in patients who received ATRA with anthracycline [50,91,92]. Finally, Breccia et al.  reporting an incidence of thrombosis of 8.8%, pointed out the relationship with high white blood cell count (WBCc) and CD2 or CD15 expression.
In general, guidelines for the prophylaxis of VTE in leukemic patients are not available. Therefore, any prophylactic interventions should be balanced against the risk of hemorrhage due to the concomitant disease- and/or therapy-related thrombocytopenia. Some authors observed that, although thromboprophylaxis appears not to increase episodes of hemorrhages, the incidence of thrombotic events was unaltered [67,93,94]. Indeed, more is known about the prophylaxis in patients treated with L-ASP. Because of its effect on the levels of natural anticoagulants, observational studies on substitutive therapy with fresh frozen plasma  or antithrombin were carried out. It was recently reported that delivery of antithrombin resulted in a significant reduction of the incidence of VTE (0/30 vs. 5/15 episodes) . Goyal et al. suggested that the prophylactic use of antithrombin (to maintain antithrombin activity >60%) or low-molecular weight heparin (LMWH) reduces the risk of VTE . At variance with this observation, it was shown that the use of enoxaparin, in ALL patients receiving L-ASP, does not attenuate incidence of VTE . A recent survey explored the spectrum of practice for VTE prevention in patients with acute leukemia. The survey showed that, during induction and consolidation, physicians provided a pharmacologic VTE prophylaxis in 47 and 45% of the cases, respectively . This reflects the lack of prospective studies to define the safest and most effective approach for VTE prevention in patients with acute leukemia.
TREATMENT OF THROMBOSIS
Management of VTE in patients with acute leukemia was addressed by several authors [99,100]. LMWH allows flexibility in the dose in order to balance effectiveness and safety, with subsequent conversion to warfarin .
The nonvitamin K antagonist oral anticoagulants (NOACs), such as direct inhibitors of factor Xa (apixaban, rivaroxaban) and thrombin (dabigatran), are effective and well tolerated in the treatment of lower extremity deep vein thrombosis (DVT) and pulmonary embolism but they have not been evaluated in CRT. Authors suggest that they are likely to be equally effective even in these conditions .
Few information is available about the incidence and management of clinically relevant (non CRT) VTE in high risk. The current approach to treat these patients consists in the use of unfractionated heparin or LMWH . In 22 leukemic patients with VTE, selected among a population of 1461 patients, LMWH was used at full dosage for a month followed by a period at 75% of the initial dose. All patients recovered from thrombosis without any recurrence, with 1 instance of cerebral bleeding being observed . Rickles et al. suggest modulating the dose per platelet count, discontinuing below the value of 20 × 109/l . Our experience confirms that the LMWH administration is well tolerated whenever the platelet count is more than 20 × 109/l . We agree that although laboratory monitoring is not required during therapy with LMWH, anti-Xa activity should be monitored in patients at high risk of bleeding .
Thrombosis can significantly affect morbidity and mortality in acute leukemia patients. The multifactorial pathophysiology includes both activation of contact phase and TF-dependent pathway of coagulation. In fact, factors released by blasts, EVs, chemotherapy and catheters may contribute to thrombogenesis. Guidelines for the prophylaxis of VTE in these patients are not available and the same role of thromboprophylaxis is debated. In this context of uncertainty, the most preferred approach to treat thrombosis in patients with acute leukemia remains unfractionated heparin or LMWH . Randomized clinical trials, also dealing with the role of new drugs (i.e. NOACs), are required to optimize the prophylaxis and therapy of thrombosis for these patients.
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REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
1. Khorana AA. Venous thromboembolism and prognosis in cancer. Thromb Res 2010; 125:490–493.
2. Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis
. JAMA 2005; 293:715–722.
3. Jasmijn F, Timp 1, Sigrid K, et al. Epidemiology of cancer-associated venous thrombosis
. Blood 2013; 122:1712–1723.
4. Khorana AA, Francis CW, Culakova E, et al. Frequency, risk factors, and trends for venous thromboembolism among hospitalized cancer patients. Cancer 2007; 110:2339–2346.
5. Colombo R, Gallipoli P, Castelli R. Thrombosis
and hemostatic abnormalities in hematological malignancies. Clin Lymphoma Myeloma Leuk 2014; 14:441–450.
6. Falanga A, Barbui T, Rickles FR. Hypercoagulability and tissue factor gene upregulation in hematologic malignancies. Semin Thromb Hemost 2008; 34:204–210.
7▪. Mooberry MJ, Key NS. Microparticle analysis in disorders of hemostasis and thrombosis
. Cytometry A 2016; 89:111–122.
The article is an exhaustive discussion on role of microparticle in thrombosis and on challenges in flow cytometric analysis of microparticles.
8. Lima LG, Monteiro RQ. Activation of blood coagulation in cancer: implications for tumour progression. Biosci Rep 2013; 33:e00064.
9. Van Aalderen MC, Trappenburg MC, Van Schilfgaarde M, et al. Procoagulant myeloblast-derived microparticles in AML patients: changes in numbers and thrombin generation potential during chemotherapy. J Thromb Haemost 2011; 9:223–226.
10. Ma G, Liu F, Lv L, et al. Increased promyelocytic-derived microparticles: a novel potential factor for coagulopathy in acute promyelocytic leukemia. Ann Hematol 2013; 92:645–652.
11▪. Gheldof D, Haguet H, Dogné JM, et al. Procoagulant activity of extracellular vesicles as a potential biomarker for risk of thrombosis
and DIC in patients with acute leukaemia. J Thromb Thrombolysis 2017; 43:224–232.
This article suggests a possible predictive value of procoagulant activity of extracellular in excluding the risk of thrombotic events.
12. Bang OY, Chung JW, Lee MJ, et al. Cancer cell-derived extracellular vesicles are associated with coagulopathy causing ischemic stroke via tissue factor-independent way: the OASIS-CANCER Study. PLoS One 2016; 18:e0159170.
13. Bruserud Ø, Foss B, Ulvestad E, Hervig T. Effects of acute myelogenous leukemia blasts on platelet release of soluble P-selectin and platelet-derived growth factor. Platelets 1998; 9:352–358.
14. Menter DG, Tucker SC, Kopetz S, et al. Platelets and cancer: a casual or causal relationship: revisited. Cancer Metastasis Rev 2014; 33:231–269.
15. Yan M, Jurasz P. The role of platelets in the tumor microenvironment: from solid tumors to leukemia. Biochim Biophys Acta 2016; 1863:392–400.
16▪▪. Montoro-García S, Schindewolf M, Stanford S, et al. The role of platelets in venous thromboembolism. Semin Thromb Hemost 2016; 42:242–251.
This is an elegant review that calls attention on the role of platelets in thrombogenesis.
17. McFadyen JD, Jackson SP. Differentiating haemostasis from thrombosis
for therapeutic benefit. Thromb Haemost 2013; 110:859–867.
18. Munnix IC, Cosemans JM, Auger JM, Heemskerk JW. Platelet response heterogeneity in thrombus formation. Thromb Haemost 2009; 102:1149–1156.
19. Heemskerk JW, Mattheij NJ, Cosemans JM. Platelet-based coagulation: different populations, different functions. J Thromb Haemost 2013; 11:2–16.
20▪▪. Hua VM, Chen VM. Procoagulant platelets and the pathways leading to cell death. Semin Thromb Hemost 2015; 41:405–412.
The focus of this review is the functional role of different platelet sub-population with a special attention on the procoagulant platelets in thrombus formation
21. Matarrese P, Straface E, Palumbo G, et al. Mitochondria regulate platelet metamorphosis induced by opsonized zymosan A-activation and long-term commitment to cell death. FEBS J 2009; 276:845–856.
22▪. Obydennyy SI, Sveshnikova AN, Ataullakhanov FI, Panteleev MA. Dynamics of calcium spiking, mitochondrial collapse and phosphatidylserine exposure in platelet subpopulations during activation. J Thromb Haemost 2016; 14:1867–1881.
A rigorous study that supports a model of procoagulant platelet development due to calcium intracellular movement and mitochondria collapse.
23. Podoplelova NA, Sveshnikova AN, Kotova YN, et al. Blood coagulation factors bound to procoagulant platelets are concentrated in their cap structures to promote clotting. Blood 2016; 128:1745–1755.
24. Yang C, Ma R, Jiang T, et al. Contributions of phosphatidylserine-positive platelets and leukocytes and microparticles to hypercoagulable state in gastric cancer patients. Tumour Biol 2016; 37:7881–7891.
25. Zhao L, Bi Y, Kou J, et al. Phosphatidylserine exposing-platelets and microparticles promote procoagulant activity in colon cancer patients. J Exp Clin Cancer Res 2016; 35:54.
26. de Witt SM, Verdoold R, Cosemans JM, Heemskerk JW. Insights into platelet-based control of coagulation. Thromb Res 2014; 133 (Suppl 2):S139–S148.
27. Jobe SM. Not dead yet. Blood 2015; 126:2774–2775.
28. Swieringa F, Kuijpers MJ, Lamers MM, et al. Rate-limiting roles of the tenase complex of factors VIII and IX in platelet procoagulant activity and formation of platelet-fibrin thrombi under flow. Haematologica 2015; 100:748–756.
29. Kim SH, Lim KM, Noh JY, et al. Doxorubicin-induced platelet procoagulant activities: an important clue for chemotherapy-associated thrombosis
. Toxicol Sci 2011; 124:215–224.
30. Wu Y, Dai J, Zhang W, et al. Arsenic trioxide induces apoptosis in human platelets via C-Jun NH2-terminal kinase activation. PLoS One 2014; 22:e86445.
31. Vu K, Luong NV, Hubbard J, et al. A retrospective study of venous thromboembolism in acute leukemia
patients treated at the University of Texas MD Anderson Cancer Center. Cancer Med 2015; 4:27–35.
32. Napolitano M, Valore L, Malato A, et al. Management of venous thromboembolism in patients with acute leukemia
at high bleeding risk: a multicenter study. Leuk Lymphoma 2016; 57:116–119.
33. Lebois M, Josefsson EC. Regulation of platelet lifespan by apoptosis. Platelets 2016; 27:497–504.
34. Dicke C, Amirkhosravi A, Spath B, et al. Tissue factor-dependent and -independent pathways of systemic coagulation activation in acute myeloid leukemia: a single-center cohort study. Exp Hematol Oncol 2015; 6:22.
35. Pisetsky DS. The origin and properties of extracellular DNA: from PAMP to DAMP. Clin Immunol 2012; 144:32–40.
36. Liaw PC, Ito T, Iba T, et al. DAMP and DIC. The role of extracellular DNA and DNA-binding proteins in the pathogenesis of DIC. Blood Rev 2016; 30:257–261.
37. Gould TJ, Vu TT, Swystun LL, et al. Neutrophil extracellular traps promote thrombin generation through platelet-dependent and platelet-independent mechanisms. Arterioscler Thromb Vasc Biol 2014; 34:1977–1984.
38. Kimball AS, Obi AT, Diaz JA, Henke PK. The emerging role of NETs in venous thrombosis
and immunothrombosis. Front Immunol 2016; 7:236.
39. Medina E. Neutrophil extracellular traps: a strategic tactic to defeat pathogens with potential consequences for the host. J Innate Immun 2009; 1:176–180.
40. Garley M, Jabłońska E, Dąbrowska D. NETs in cancer. Tumour Biol 2016; 37:14355–14361.
41. Ma AC, Kubes P. Platelets, neutrophils, and neutrophil extracellular traps (NETs) in sepsis. J Thromb Haemost 2008; 6:415–420.
42. Urban CF, Reichard U, Brinkmann V, et al. Neutrophil extracellular traps capture and kill Candida albicans yeast and hyphal forms. Cell Microbiol 2006; 8:668–676.
43. Demers M, Krause DS, Schatzberg D, et al. Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis
. Proc Natl Acad Sci USA 2012; 109:13076–13081.
44▪▪. Carestia A, Kaufman T, Schattner M. Platelets: new bricks in the building of neutrophil extracellular traps. Front Immunol 2016; 7:271.
This excellent review reports the important role of platelets on NETs formation and thrombosis.
45. Nakayama T, Saitoh N, Morotomi-Yano K, et al. Nuclear extrusion precedes discharge of genomic DNA fibers during tunicamycin-induced neutrophil extracellular traposis (NETosis)-like cell death in cultured human leukemia cells. Cell Biol Int 2016; 40:597–602.
46. Lukášová E, Kořistek Z, Klabusay M, et al. Granulocyte maturation determines ability to release chromatin NETs and loss of DNA damage response; these properties are absent in immature AML granulocytes. Biochim Biophys Acta 2013; 1833:767–779.
47. Hell L, Thaler J, Martinod K, et al. OC-16-neutrophil extracellular traps and tissue factor-bearing microvesicles: a liaison dangereuse causing overt DIC in cancer patients? Thromb Res 2016; 140 (Suppl 1):S174–S175.
48. Tutar Y. miRNA and cancer; computational and experimental approaches. Curr Pharm Biotechnol 2014; 15:429.
49. Kinoshita T, Yip KW, Spence T, Liu FF. MicroRNAs in extracellular vesicles: potential cancer biomarkers. J Hum Genet 2017; 62:67–74.
50. Breccia M, Lo Coco F. Thrombo-hemorrhagic deaths in acute promyelocytic leukemia. Thromb Res 2014; 133 (Suppl 2):S112–S116.
51. Zhang Y, Hou J, Ge F, et al. Integrating microRNA and mRNA expression profiles of acute promyelocytic leukemia cells to explore the occurrence mechanisms of differentiation syndrome. Oncotarget 2016; 7:73509–73524.
52. Zhou J, Li H, Fu Y, et al. Arsenic trioxide induces procoagulant activity through phosphatidylserine exposure and microparticle generation in endothelial cells. Thromb Res 2011; 127:466–472.
53. Goyal G, Bhatt VR. L-asparaginase and venous thromboembolism in acute lymphocytic leukemia. Future Oncol 2015; 11:2459–2470.
54. Hua VM, Abeynaike L, Glaros E, et al. Necrotic platelets provide a procoagulant surface during thrombosis
. Blood 2015; 126:2852–2862.
55. Zakarija A, Kwaan HC. Adverse effects on hemostatic function of drugs used in hematologic malignancies. Semin Thromb Hemost 2007; 33:355–364.
56. Truelove E, Fielding AK, Hunt BJ. The coagulopathy and thrombotic risk associated with L-asparaginase treatment in adults with acute lymphoblastic leukaemia. Leukemia 2013; 27:553–559.
57. Lanvers-Kaminsky C. Asparaginase pharmacology: challenges still to be faced. Cancer Chemother Pharmacol 2017; 79:439–450.
58. Hernández-Espinosa D, Ordóñez A, Vicente V, Corral J. Factors with conformational effects on haemostatic serpins: implications in thrombosis
. Thromb Haemost 2007; 98:557–563.
59. Deb S, Sjöström C, Tharmakulanathan A, et al. PO-55 – Individual variation in hemostatic alterations caused by tyrosine kinase inhibitors – a way to improve personalized cancer therapy? Thromb Res 2016; 140 (Suppl 1):S196–S197.
60. Loren CP, Aslan JE, Rigg RA, et al. The BCR-ABL inhibitor ponatinib inhibits platelet immunoreceptor tyrosine-based activation motif (ITAM) signaling, platelet activation and aggregate formation under shear. Thromb Res 2015; 135:155–160.
61. Alhawiti N, Burbury KL, Kwa FA, et al. The tyrosine kinase inhibitor, nilotinib potentiates a prothrombotic state. Thromb Res 2016; 145:54–64.
62. Kantarjian HM, De Angelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med 2016; 375:2100–2101.
63. Esmon CT. The interactions between inflammation and coagulation. Br J Haematol 2005; 131:417–430.
64. Levi M, van der Poll T, Buller HR. Bidirectional relation between inflammation and coagulation. Circulation 2004; 109:2698–2704.
65. Koch A, Meesters MI, Scheller B, et al. Systemic endotoxin activity correlates with clot formation: an observational study in patients with early systemic inflammation and sepsis. Crit Care 2013; 17:R198.
66. Refaei M, Fernandes B, Brandwein J, Good, et al. Incidence
of catheter-related thrombosis
in acute leukemia
patients: a comparative, retrospective study of the safety of peripherally inserted vs. centrally inserted central venous catheters. Ann Hematol 2016; 95:2057–2064.
67. Del Principe MI, Buccisano F, Maurillo L, et al. Infections increase the risk of central venous catheter-related thrombosis
in adult acute myeloid leukemia. Thromb Res 2013; 132:511–514.
68. De Stefano V, Sora F, Rossi E, et al. The risk of thrombosis
in patients with acute leukaemia: occurrence of thrombosis
at diagnosis and during treatment. J Thromb Haemost 2005; 3:1985–1992.
69. Guzmán-Uribe P, Rosas-López A, Zepeda-León J, Crespo-Solís E. Incidence
in adults with acute leukemia
: a single center experience in Mexico. Rev Invest Clin 2013; 65:130–140.
70. Couturier MA, Huguet F, Chevallier P, et al. Cerebral venous thrombosis
in adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma during induction chemotherapy with L-asparaginase: the GRAALL experience. Am J Hematol 2015; 90:986–991.
71. Musgrave KM, van Delft FW, Avery PJ, et al. Cerebral sinovenous thrombosis
in children and young adults with acute lymphoblastic leukaemia - a cohort study from the United Kingdom. Br J Haematol 2016; [Epub ahead of print].
72. Ku GH, White RH, Chew HK, et al. Venous thromboembolism in patients with acute leukemia
, risk factors, and effect on survival. Blood 2009; 113:3911–3917.
73▪▪. Koprivnikar J, McCloskey J, Faderl S. Safety, efficacy, and clinical utility of asparaginase in the treatment of adult patients with acute lymphoblastic leukemia. Onco Targets Ther 2017; 10:1413–1422.
This comprehensive review discusses the most recent information on the use of asparaginase in acute leukemia.
74. Lee JH, Lee J, Yhim HY, et al. Venous thromboembolism following L-asparaginase treatment for lymphoid malignancies in Korea. J Thromb Haemost 2017; 15:655–661.
75. Zuurbier SM, Lauw MN, Coutinho JM, et al. Clinical course of cerebral venous thrombosis
in adult acute lymphoblastic leukemia. J Stroke Cerebrovasc Dis 2015; 24:1679–1684.
76. Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med 2012; 367:2075–2088.
77. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med 2013; 369:1783–1796.
78. Sanford DS, Kantarjian H, O’Brien S, et al. The role of ponatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia. Expert Rev Anticancer Ther 2015; 15:365–373.
79. Jabbour E, Kantarjian HM, Thomas DA, et al. Phase II Study of combination of hypercvad with ponatinib in front line therapy of patients (pts) with Philadelphia chromosome (Ph) positive acute lymphoblastic leukemia (ALL). ASH Annual Meet Abstr 2014; 124:2289.
80. Piepoli MF, Hoes AW, Agewall S, et al. European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts). Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Atherosclerosis 2016; 252:207–274.
81. Breccia M, Pregno P, Spallarossa P, et al. Identification, prevention and management of cardiovascular risk in chronic myeloid leukaemia patients candidate to ponatinib: an expert opinion. Ann Hematol 2017; 96:549–558.
82. Thota S, Advani A. Inotuzumab ozogamicin in relapsed B-cell acute lymphoblastic leukemia. Eur J Haematol 2017; 98:425–434.
83. Ziegler S, Sperr WR, Knobl P, et al. Symptomatic venous thromboembolism in acute leukaemia. Incidence
, risk factors, and impact on prognosis. Thromb Res 2005; 115:59–64.
84. O’Donnell MR, Abboud CN, Altman J, et al. Acute myeloid leukaemia. J Natl Compr Canc Netw 2012; 10:984–1021.
85. Lee YG, Kim I, Kwon JH, et al. Implications of cytogenetics for venous thromboembolism in acute myeloid leukaemia. Thromb Haemost 2015; 113:
86▪▪. Libourel EJ, Klerk CP, van Norden Y, et al. Disseminated intravascular coagulation at diagnosis is a strong predictor for both arterial and venous thrombosis
in newly diagnosed acute myeloid leukemia. Blood 2016; 128:1854–1861.
The original study suggests the predictive role of D-dimer thrombosis in AML patients.
87. Taylor FB Jr, Toh CH, Hoots WK, et al. Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis
and Haemostasis (ISTH). Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 2001; 86:1327–1330.
88. Lo Coco F, Ammatuna E. The biology of acute promyelocytic leukemia and its impact on diagnosis and treatment. Hematology Am Soc Hematol Educ Progr 2006; 514:151–156.
89. Hajjar KA. The biology of annexin A2: from vascular fibrinolysis to innate immunity. Trans Am Clin Climatol Assoc 2015; 126:144–155.
90. Fang Y, Garnier D, Lee TH, et al. RARa modulates the vascular signature of extracellular vesicles released by acute promyelocytic leukemia cells. Angiogenesis 2016; 19:25–38.
91. Breccia M, Avvisati G, Latagliata R, et al. Occurrence of thrombotic events in acute promyelocytic leukemia correlates with consistent immunophenotypic and molecular features. Leukemia 2007; 21:79–83.
92. Mitrovic M, Suvajdzic N, Elezovic I, et al. Thrombotic events in acute promyelocyticleukemia. Thromb Res 2015; 135:588–593.
93. Couban S, Goodyear M, Burnell M, et al. Randomized placebo-controlled study of low-dose warfarin for the prevention of central venous catheter-associated thrombosis
in patients with cancer. J Clin Oncol 2005; 23:4063–4069.
94. Cortelezzi A, Moia M, Falanga A, et al. Incidence
of thrombotic complications in patients with haematological malignancies with central venous catheters: a prospective multicentre study. Br J Haematol 2005; 129:811–817.
95. Lauw MN, Van der Holt B, Middeldorp S, et al. Venous thromboembolism in adults treated for acute lymphoblastic leukaemia: effect of fresh frozen plasma supplementation. Thromb Haemost 2013; 109:633–642.
96. Farrell K, Fyfe A, Allan J, et al. An antithrombin replacement strategy during asparaginase therapy for acute lymphoblastic leukemia is associated with a reduction in thrombotic events. Leuk Lymphoma 2016; 14:1–7.
97. Sibai H, Seki JT, Wang TQ, et al. Venous thromboembolism prevention during asparaginase-based therapy for acute lymphoblastic leukemia. Curr Oncol 2016; 23:e355–e361.
98. Lee EJ, Smith BD, Merrey JW, et al. Patterns of venous thromboembolism prophylaxis during treatment of acute leukemia
: results of a North American web-based survey. Clin Lymphoma Myeloma Leuk 2015; 15:766–770.
99. Oliver N, Short B, Thein M, et al. Treatment of catheter-related deep vein thrombosis
in patients with acute leukemia
with anticoagulation. Leuk Lymphoma 2015; 56:2082–2086.
100. Geerts W. Central venous catheter-related thrombosis
. Hematology Am Soc Hematol Educ Program 2014; 2014:306–311.
101. Kovacs MJ, Kahn SR, Rodger M, et al. A pilot study of central venous catheter survival in cancer patients using low-molecular-weight heparin (dalteparin) and warfarin without catheter removal for the treatment of upper extremity deep vein thrombosis
(the Catheter Study). J Thromb Haemost 2007; 5:1650–1653.
102. Guzmán-Uribe P1, Vargas-Ruíz ÁG. Thrombosis
in leukemia: incidence
, causes, and practical management. Curr Oncol Rep 2015; 17:444.
103. Rickles FR, Falanga A, Montesinos P, et al. Bleeding and thrombosis
in acute leukemia
: what does the future of therapy look like? Thromb Res 2007; 120 (Suppl 2):S99–S106.
104. Babin JL, Traylor KL, Witt DM. Laboratory monitoring of low-molecular-weight heparin and fondaparinux. Semin Thromb Hemost 2016; 43:261–269.