New Insights into the Pathogenesis of Coagulation Dysfunction in Acute Promyelocytic Leukemia

Abstract

Patients with acute promyelocytic leukemia (APL) are at high risk for the development of life-threatening thrombotic and hemorrhagic complications, particularly during induction chemotherapy. This propensity has been attributed to the release of tissue factor (TF)-like pro-coagulants from the leukemic cells leading to disseminated intravascular coagulation (DIC). However, recent data suggest that the pathogenesis of the coagulopathy is more complicated and may involve activation of the generalized proteolytic cascade resulting in either clotting and/or excessive fibrinolysis. Furthermore, controversy exists regarding the mechanism(s) responsible for the activation of either clotting or fibrinolysis. The malignant promyelocyte may act directly to activate coagulation and/or fibrinolysis. Alternatively, reactive inflammatory cells, which express procoagulant and/or profibrinolytic activities may play an essential role. A third possibility may involve endothelial cell expression of mediators with procoagulant/profibrinolytic properties. Putative profibrinolytic mechanisms include the release of urokinase-type and tissue-type plasminogen activators, decreases in plasminogen activator inhibitor-I and 2, and decreases in alpha-2 plasmin inhibitor. Putative procoagulant mechanisms include the release of tissue factor, Cancer Procoagulant, or cytokines such as interleukin-1, tumor necrosis factor and vascular permeability factor. Putative anticoagulant mediators include annexins, a group of proteins in human tissue which bind phospholipids and have anticoagulant activity, which have been reported in patients with APL. The current treatment of APL is rapidly evolving because of the efficacy of ail-trans retinoic acid (ATRA). All-trans retinoic acid promotes terminal differentiation of leukemic promyelocytes leading to complete remission in the majority of patients with APL with rapid resolution of the coagulopathy. Although the mechanism by which this occurs has not been established, preliminary data suggest that ATRA blocks the down regulation of the thrombomodulin gene and the up-regulation of the tissue factor gene induced by tumor necrosis factor. Since APL is a relatively uncommon disorder, the collaboration of cooperative oncology groups will be important to study patients receiving ATRA or conventional chemotherapy to further elucidate the mechanism(s) of the coagulopathy. The coagulopathy associated with APL is likely a complex interaction of several pathophysiologic processes (Fig. 2). One hypothesis suggests that excessive fibrinolysis mediated by t-PA and/or u-PA from leukemic cells is the predominant process contributing to bleeding in patients with APL. However, the coagulopathy cannot be attributed solely to fibrinolysis, since thrombin generation can be documented in many patients. A second hypothesis proposes that APL-cell derived procoagulants lead to the generation of thrombin, DIC, and bleeding. Still a third hypothesis, suggests that fibrinogenolysis and enzymatic activation and/or destruction of other coagulation factors may be mediated by leukocyte proteases such as elastase. Indirect acting procoagulants derived from leukemic cells, such as IL-I, and/or TNF, may also play an important role via their effects on endothelial cells. The mechanisms leading to bleeding may be heterogenous and may vary among patients. Since APL is a relatively uncommon disorder, the collaboration of cooperative oncology groups will be important to study patients receiving either ATRA or conventional chemotherapy to elucidate further the mechanism(s) of the coagulopathy.