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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