Patients with acute leukaemias are at high risk of both hemorrhage and thrombosis. This risk is different according to: 1. the type of leukemia, i.e, acute myeloblastic leukemia (AML), acute lymphoblastic leukemia (ALL), or acute promyelocytic leukemia (APL), and 2. the phase of treatment, i.e, onset of the disease, remission induction and consolidation .
Among bleeding complications, of particular importance, is the disseminated intravascular coagulation (DIC) syndrome, however thrombosis of large vessels is a more rare complication, although recent data indicate that it can be a relevant problem at the onset of AML, and during induction chemotherapy in ALL.
During remission induction, the prevalence of life-threatening bleeding is difficult to evaluate for the different descriptive criteria utilised and the incomplete reporting of data. In adult patients with AML, 1% of lethal bleedings on day of admission have been observed, all in the presence of hyperleukocytosis or APL.
Recent data in patients with AML show a rate of haemorrhagic death of 9.9%, whereas in studies reporting hemorrhage as a contributory cause of death, the rate increases up to 33%. In the Medical Research Council (MRC )10 trial, the mortality rate for pulmonary or cerebral hemorrhage in the early stages of treatment was 2%, and was associated with M4 and M5 morphology, high initial white cell count and concomitant infections.
During consolidation, thrombocytopenia is a direct consequence of myelosuppressive therapy, but concurrent infections may also contribute to the pathogenesis of fatal haemorrhages. The incidence of remission deaths specifically caused by hemorrhage is very low when platelet
support is adequate. In AML the cumulative rate from different studies dealing in detail with this specific aspect is 1.5% . In AML few data on the thrombotic risk are available. A recent large retrospective study shows a venous thromboembolic event rate of 2.09% at the onset of the disease, with no significant difference between AML and ALL.
Acute promyelocytic leukemia (APL) typically presents with a life-threatening haemorrhagic diathesis which is particularly severe in the microgranular variant (M3v), with marked hyperleukocytosis. Before the introduction of all-trans retinoic acid (ATRA) in the management of APL patients, fatal haemorrhages caused by the APL-associated coagulopathy were a major cause of induction remission failure, with a prevalence of haemorrhagic deaths in induction of about 10%.
A syndrome characterized by bleeding and thrombosis was first recognized in children with ALL treated with polichemotherapeutic protocols including L-Asparaginase (L-Ase). Subsequently, these observations have been confirmed: cerebral thrombo-haemorrhagic accidents and peripheral deep vein thrombosis are reported in 2.4 to 11.5 % of children with ALL. In adults, haemorrhage is also the main cause of early death during remission induction in ALL patients treated with an intensive regimen including L-Ase.
The major determinants for the pathogenesis of the coagulopathy of acute leukemia are the following: factors associated with leukemic cells, including the expression of procoagulant, fibrinolytic and proteolytic properties, and the secretion of inflammatory cytokines, Cytotoxic therapy; and concomitant infectious complications .
Many studies have characterised the procoagulant activity (PCA) expressed by leukaemic cells, particularly tissue factor (TF), the major activator of blood coagulation from normal and pathological tissues, and
‘cancer procoagulant’ (CP), more typical of malignant tissues. All AML subtypes express significant amount of PCA, with the greatest expression in the M3 type. Measurable PCA amounts are also found in ALL blasts. In AML patients CP levels appear to be related to the phase of the disease.
Abnormalities of the blood clotting system underlying the clinical pictures of DIC are observed in AML, less commonly in ALL. These abnormalities include hypofibrinogenemia, increased FDPs and prolonged prothrombin and thrombin times. These laboratory parameters often become more abnormal upon the initiation of cytotoxic chemotherapy, resulting in severe haemorrhagic complications. The advent of new laboratory tests for hypercoagulation markers clearly show that thrombin generation is a constant finding in acute leukaemia. Particularly important is the detection of the D-dimer, the lysis product of cross-linked fibrin, which definitely demonstrates that hyperfibrinolysis occurs in response to clotting activation in leukaemia.
The pathophysiology of thrombosis in patients with leukemia is complex, but can be simplified to correspond to the three categories of host defense mechanisms as described by Virchow, who emphasized abnormalities in blood flow (stasis), blood vessel wall function and “blood elements” (both soluble and cellular) as essential to the process of thrombosis. In patients with APL, the most compelling pathogenic mechanism is most likely the molecular properties of the leukemic cell itself, which releases a variety of mediators that can activate blood coagulation.
Leukaemic cells can also express fibrinolytic and proteolytic activities, which are believed to play a major role in the pathogenesis of
the bleeding syndrome. However, these activities are lower compared to mature granulocytes. A recent study demonstrates the expression of an annexin II-associated fibrinolytic activity in APL blasts, which appears increased compared to other more immature myeloid subtypes or lymphoid blasts. Leukaemic cells produce inflammatory cytokines, including TNF-α and IL-1β that increase the prothrombotic and proadhesive potential of endothelial cells.
Prophylactic platelet transfusions therapy represents an essential part of the modern supportive care for patients with acute leukemia. This practice has resulted in a marked decrease in the incidence of bleeding, prolonged survival, and allows for the intensification of therapy.
The safety of a stringent prophylactic platelet transfusion policy has been confirmed in comparative, nonrandomized studies and in randomized clinical trials. The Italian Multicenter Clinical Trial in AML showed that a threshold of 10×10L reduced platelet use of 21% without increasing major bleeding complications.
No studies or guidelines are available to guide either prophylaxis or treatment of VTE in hematologic malignancies. While the use of low molecular- weight heparin (LMWH) has improved VTE management in patients with solid tumors, no similar experience has been accumulated in patients with acute leukemia.
A therapeutic strategy based on LMWH administered for six months after a VTE episode (1 month at full dose and 5 months at approximately 75% of full dose) has proved safe and superior to warfarin in preventing VTE recurrence; this regimen has been endorsed widely as an acceptable strategy for treatment and secondary prevention of VTE in patients with solid tumours.
According to Imberti et al., 2004 we recommend the initial use of standard doses of LMWH preparations for the treatment of established VTE, but with frequent monitoring of peak anti-Xa levels, as in other high risk groups for whom good pharmacokinetic parameters are not yet available (e.g. renal failure, obesity, pregnancy, children). Tight maintenance of peak levels between 0.5 and 1.0 IU/ml may improve the risk/benefit ratio for patients with hematologic malignancies and VTE. In addition, when the platelet count drops below 50,000/ul, would advise reducing the dose of LMWH to 50%. Treatment of CVC-related VTE may not always require anticoagulants, since many of these thrombi resolve spontaneously in patients with acute leukemia following removal of the catheter