The Role of Abnormal Hemostasis and Fibrinolysis in Morbidity and Mortality of Acute Promyelocytic Leukemia

Abstract

Despite the improved therapeutic advances in the management of acute promyelocytic leukemia (APL), a significant early mortality during induction, also referred to as early death (ED), remains an obstacle for further improvement in outcome. Hemorrhagic complications are the most common cause of morbidity and mortality. Perturbed hemostatic dysfunction is present as the result of abnormalities in both the coagulation and the fibrinolytic systems. The activation of coagulation is distinct from the classical disseminated intravascular coagulation. Multiple abnormalities in the fibrinolytic system have recently been identified. The most significant change is increased production of tissue plasminogen activator (tPA) and its receptor annexin A2 by the APL promyelocytes. Among the hemorrhagic complications, intracranial hemorrhage predominates. The pathogenesis of this catastrophic event is elucidated by new evidence of adverse effect of tissue plasminogen activator (tPA) on the brain, including both the plasmin-dependent and plasmin-independent pathways. In order to address the hemorrhagic complications, a thorough understanding of the hemostatic dysfunction is essential. In this article, our current concept of the abnormal hemostasis in APL is reviewed. The failure to reduce the early death rate, despite the introduction of effective therapy, will also be discussed.

Disseminated intravascular coagulation: epidemiology, biomarkers, and management

“…Primary hyper‐fibrinolysis is a common feature of acute promyelocytic leukaemia. These patients often present with severe hyper‐fibrinolysis and bleeding due to increased plasminogen activation on the malignant cell surface 44 . Hyper‐fibrinolysis has also been described among patients with solid tumours, e.g.…”

Management of Disseminated Intravascular Coagulation in Acute Leukemias

“…17 Although in APL similar thromboinflammatory mechanisms are operational, APL also has certain distinctly different features as the leukemic cells express not only tissue factor but also annexin 2 that binds and activates plasminogen, which together with a lower plasma level of thrombin-activatable fibrinolytic inhibitor aggravates fibrinolysis. 18 These factors likely contribute to the high bleeding risk in APL.…”

Emerging Cancer Epigenetic Mechanisms Regulated by All-Trans Retinoic Acid

“…While PML-RARA induced a high expression of ANXA8 in APL [ 40 , 78 , 79 ], RA-induced downregulation of ANXA2 expression in myeloid leukemia cell lines was not confined to APL. Notably, high levels of ANXA2 in hyperfibrinolysis could be corrected by RA or RA plus ATO therapy in patients with APL [ 80 , 81 , 82 ].…”