The pathogenesis and management of the coagulopathy of acute promyelocytic leukaemia

Abstract

Summary Coagulopathy occurs in most patients with (APML) and is life‐threatening; therefore prompt diagnosis and recognition of any coagulation defect is imperative. Unfortunately haemorrhage remains a major cause of early death, preventing some from reaching treatment. The coagulopathy is caused directly or indirectly by the leukaemic cells through expression of activators of coagulation and fibrinolysis, proteases and cytokine generation, compounded by failure of platelet production due to marrow invasion. At presentation the predominant feature is usually hyperfibrinolysis. Since the introduction of all‐trans retinoic acid (ATRA), patient outcome has dramatically improved; yet, haemorrhagic complications remain the most frequent cause of mortality. Thrombotic complications occur but are less well recognized and potentially underreported. Supportive measures and prompt initiation of ATRA currently represent the mainstay of treatment of the coagulopathy in patients with suspected APML, but unanswered questions remain as to the optimal approach to further decrease the associated haemorrhagic and thrombotic risks. In particular, it is unclear how to best predict and monitor the coagulopathy; whether there is a role for the early use of antifibrinolytics; the most appropriate trigger for giving fibrinogen replacement and the value of low‐dose anticoagulation to suppress coagulation activation once fibrinolysis has been suppressed.

Acute Promyelocytic Leukemia: a Single Center Study from Southern Pakistan

“…We did not come across any such findings which is rather unusual. The incidence of thrombosis in APL is higher than in other subtypes of acute myeloid leukemia and risk of thrombosis has been associated with elevated WBC count (>10x10 9 /l) and presence of FLT3-internal tandem duplication (Breen et al, 2012). The plausible explanation of no thrombotic manifestation is possibly due to less number of patients in high risk group (15.3%).…”

The overview of brinolysis system contemporary concepts and of its disorders diagnostic methods

“…Повышенный уровень плазмин-антиплазминовых комплексов, снижение концентрации антиплазмина характеризует гиперфибринолитическое состояние, которое может быть вызвано травмами [75], ДВС [76], острым промиелоцитарным лейкозом [77]. Однако корреляции между концентрацией антиплазмина и тяжестью патологий установлено не было, видимо, в связи с высоким базовым уровнем антиплазмина.…”

Coagulopathy in APL: a step forward?

“…However, despite the progress achieved in the treatment and biologic understanding of the molecular defect of this leukemia with the introduction of the vitamin A derivative alltrans-retinoic acid (ATRA), the controversy about the respective roles of primary fibrinolysis or proteolysis and diffuse intravascular coagulation (DIC) in the pathogenesis of the APL coagulopathy still persist, suggesting that it is due to a complex interaction of the leukemic promyelocytes with the coagulation system. [2][3] The DIC theory is supported by the presence in APL of elevated levels of tissue factor and cancer procoagulant. 4 In favor of the fibrinolytic mechanism is the presence of elevated levels of annexin II (ANXII) detected on APL leukemic cells 5 and of normal antithrombin levels associated with acquired ␣2-antiplasmin deficiency.…”

“…Overall, the data favor a mechanism involving a primary activation of the fibrinolysis rather than DIC. 3 The fibrinolytic theory is clinically supported by the observation that the severe bleeding in APL is rarely associated with acute renal failure and schistocytes, which differ from other conditions associated with DIC. ANXII is a cell-surface receptor for both plasminogen and tissue plasminogen activator (tPA) present in endothelial cells, macrophages, and some tumor cells.…”

“…Patients who develop infections with Clostridium difficile are at increased risk of developing gastrointestinal (GI) tract GVHD. 3 Similarly, patients who develop GVHD are at increased risk of bacterial sepsis although the mechanisms underlying this finding, beyond those related to the immune suppression that occurs after the treatment of patients with acute GVHD, remain poorly understood. 4 In this issue of Blood, Eriguchi et al provide a new mechanism for the relationship between infectious complications and acute GVHD involving the GI tract.…”