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 procoagulants 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-1 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 all-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 downregulation 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.

Distinct leukemia phenotypes in transgenic mice and different corepressor interactions generated by promyelocytic leukemia variant fusion genes PLZF–RAR α and NPM–RAR α

“…Transforming activity of NPM-RAR␣ fusion gene, on the other hand, was identified in transgenic animals. As part of the phenotype analysis, we also determined the expression of the tissue factor (TF) gene, which has been considered to be involved in the pathogenesis of coagulopathies typical of APL (30,31).…”

Pathogenesis of Ebola Viral Haemorrhagic Fever: TTP-like Syndrome Associated with Hepatic Coagulopathy based on "Two Activation Theory of the Endothelium"

“…True DIC is very rare but occurs perhaps in acute promyelocytic leukemia, presumably due to TF expression from leukemic cells [41]. As illustrated in Table 2, the predominant feature of true DIC is a haemorrhagic disorder without MAHA/ aMAHA or hypoxic organ dysfunction [30,41,42].…”

“…As illustrated in Table 2, the predominant feature of true DIC is a haemorrhagic disorder without MAHA/ aMAHA or hypoxic organ dysfunction [30,41,42]. In differentiating true DIC from hepatic coagulopathy, the most important test is the assay of coagulation factors, especially FVIII and FV, which are depleted in DIC.…”

Thrombocytopenia in critically ill patients due to vascular microthrombotic disease: pathogenesis based on “two activation theory of the endothelium”

“…True DIC is very rare but perhaps occurs in acute promyelocytic leukemia, presumably due to TF expression from leukemic cells [64]. The predominant feature of true DIC is hemorrhagic disorder without MAHA/aMAHA, hypoxic organ dysfunction and MODS [56][57][58].…”