Initiation of fibrinolytic therapy, if appropriate, within 1 hour of hospital arrival and 3 hours from onset of symptoms. rTpa can be administered in “well screened” patients who are at low risk for bleeding for up to 4.5 hours.
Acute promyelocytic leukemia (APL) is a distinct subtype of myeloid leukemia characterized by t(15;17) chromosomal translocation, which involves the retinoic acid receptor-alpha (RAR-alpha). APL typically presents with a life-threatening hemorrhagic diathesis. Before the introduction of all-trans retinoic acid (ATRA) for the cure of APL, fatal hemorrhages due, at least in part, to the APL-associated coagulopathy, were a major cause of induction remission failure. The laboratory abnormalities of blood coagulation found in these patients indicate the occurrence of a hypercoagulable state. Major determinants of the coagulopathy of APL are endogenous factors expressed by the leukemic cells, including procoagulant factors, fibrinolytic proteins, and non-specific proteolytic enzymes. In addition, these cells have an increased capacity to adhere to the vascular endothelium, and to secrete inflammatory cytokines [i.e. interleukin-1beta (IL-1beta) and tumor necrosis factor (TNF-alpha)], which in turn stimulate the expression of prothrombotic activities by endothelial cells and leukocytes. ATRA can interfere with each of the principal hemostatic properties of the leukemic cell, thus reducing the APL cell procoagulant potential, in parallel to the induction of cellular differentiation. This effect occurs in vivo, in the bone marrow of APL patients receiving ATRA, and is associated with the improvement of the bleeding symptoms. Therapy with arsenic trioxide (ATO) also beneficially affects coagulation in APL. However, early deaths from bleeding still remain a major problem in APL and further research is required in this field. In this review, we will summarize our current knowledge of the pathogenesis of the APL-associated coagulopathy and will overview the therapeutic approaches for the management of this complication.
Ten women (13.5%) had VWF:RCo and/or VWF:Ag
Conclusion: We conclude that the prevalence of platelet function defects and other inherited bleeding disorders is substantial in a multiracial US population of women with unexplained menorrhagia.
Coagulation laboratory abnormalities, indicating an activation of the hemostatic system, can be detected in virtually all patients with leukemias. The pathogenesis is complex and multifactorial. A prominent role is played by tumor-specific clot-promoting properties of leukemic cells themselves. In acute leukemia, bleeding manifestations prevail over localized thrombosis of large vessels. The risk of bleeding, due to thrombocytopenia and massive blood clotting activation with coagulation factors consumption, reaches a maximum in patients with APL. The coagulopathy of APL is characterized by low fibrinogen levels, prolongation of the PT and TT, and abnormal plasma levels of markers of hypecoagulation, hyperfibrinolysis and nonspecific proteolysis. Normal levels of AT and PC, coagulation inhibitors, in patients with the coagulopathy of APL cannot exclude DIC but may emphasize other features of the coagulopathy. This has raised some arguments against DIC, favoring the hypothesis of primary hyperfibrinolysis as the determinant of severe bleeding in acute leukemia. However, the nearly ubiquitous presence of elevated levels of fibrin D-dimer, and the increase of plasma levels of markers of clotting activation (F1+ 2, TAT and FPA), strongly favors the hypothesis of secondary or reactive hyperfibrinolysis occurring in response to activation of blood coagulation. Bleeding complications in patients with APL carry a high risk for mortality and, therefore, the use of prophylactic platelet transfusions is highly recommended. Although not discussed, aggressive management of infections is also very important, because viruses, Gram-negative and Gram-positive organisms can contribute to the development of DIC. In contrast, the routine use of anticoagulants and/or antifibrinolytic agents in the control or prevention of DIC cannot be recommended.
However, the use of ATRA for remission induction has changed the natural history of APL and has helped to resolve the THS in most patients. While some of the mechanisms by which ATRA regulates the aberrant hemostatic system in patients with APL have been elucidated, the rate of early hemorrhagic deaths in APL (3–10%) has not changed significantly. Additional efforts to develop therapies that rapidly correct the coagulopathy are required, as noted above. New approaches using both anticoagulant and anti-inflammatory drugs should be considered. As the molecular basis for activation of clotting in hematologic malignancies becomes better elucidated, we anticipate the development of drugs that will target both the malignant process and the resultant THS.
Modern recommendations indicate that three simultaneous actions must be immediately undertaken when a diagnosis of APL is suspected: (1) the start of ATRA therapy; (2) the administration of supportive care with plasma and platelet transfusions; (3) the confirmation of genetic diagnosis.– The mainstay of treatment of the coagulopathy of APL are shown in .
The maintenance levels of coagulation inhibitors antithrombin (AT) and protein C (PC) may distinguish the coagulopathy of APL from typical DIC complicating other clinical conditions (e.g. sepsis). Although experimental DIC can occur in the presence of normal levels of AT, such findings are not typical in clinical practice. Of interest, however, is the observation by Rodeghiero and colleagues that reduced levels of AT and PC in patients with acute leukemia tend to occur in those patients with hepatic dysfunction. Patients with acute leukemia and DIC with normal liver function in their series usually had normal levels of the inhibitors.
Concerning the fibrinolytic properties, it is well known that the normal balance between profibrinolytic and antifibrinolytic factors is altered in APL. Several events may contribute to an increased fibrinolysis. Secondary fibrinolysis may occur as a response to DIC at the onset of the disease. Leukemic promyelocytes contain both u-PA and t-PA.– In addition, as previously described, APL blasts express increased levels of annexin II-associated fibrinolytic activity. Additional data suggest that retinoids induce a rapid increase of u-PA activity on APL cell surface, which is promptly down-regulated by an increased production of PA inhibitors, including PAI-1 and PAI-2. These mechanisms can contribute to a reduction of fibrinolytic activity in APL cells in response to ATRA. Recent data confirm that after induction therapy with either ATRA or combination of ATRA+ATO, the levels of FDP, D-dimer, plasminogen and fibrinogen normalize in 2–3 weeks, while the expression of Annexin II in APL blast cells is downregulated and the production of plasmin in APL cells is reduced. It has been hypothesized that part of the coagulopathy of APL is related to increased proteolysis by proteases, such as elastase, that degrade fibrinogen and other clotting factors.– Increased plasma levels of elastase are indeed described in patients with acute leukemia., Elastase can degrade fibrinogen, producing a pattern of FDPs different from those produced by plasmin cleavage.– However, in an in vitro study, freshly isolated APL blasts expressed lower fibrinolytic and proteolytic activities compared to mature neutrophils.
Although ATRA increases the adhesion capacity of APL cells to the endothelium in vitro, pre-treatment of ECs with ATRA reverses this effect and actually results in impaired adhesion of APL cells to ECs. This anti-adhesive effect may be explained by the down-regulation of EC surface-specific counter-receptors by ATRA. Perhaps ATRA is unable to exert this same protective effect on the specialized endothelium of the lung, thus explaining the unusual features of the RAS. It seems likely that a further understanding of the pathogenesis of the RAS and its prevention, as well as better strategies for the treatment of the consumptive coagulopathy of APL, will evolve from an improved understanding of the biological properties of the fusion proteins of RAR-alpha.
ATO, another agent effective in the cure of APL, including the APL resistant to ATRA also reduces TF expression and PCA of APL blast cells in vitro and in vivo. ATO exerts dose-dependent dual effects on APL cells: at low concentrations (0.5 μM), ATO induces partial differentiation by degrading the PML/RAR-alpha fusion protein; while at relatively high concentrations (0.5–2.0 μM), it triggers apoptosis. Zhou et al. recently published the evidence that ATO treatment can induce rapid loss of membrane procoagulant activity and TF mRNA leading beneficial effect on the related coagulopathy in APL.– However, mechanisms by which ATRA or ATO lead to the rapid resolution of coagulopathy need further definition.
TF has been characterized in APL cells by several researchers.– Others have demonstrated that CP also is expressed in leukemic blasts of various phenotypes and is found at the highest levels in patients with APL. ATRA-induced APL cell differentiation in vitro is associated with loss of the capacity to express either CP or TF.– Further, both procoagulants are progressively reduced in vivo in the bone marrow cells of APL patients given ATRA for remission-induction therapy. Reduction of leukemic cell PCA by ATRA appears to be one important mechanism involved in the resolution of the coagulopathy. An in vitro study demonstrated that, after ATRA treatment, CP activity is down-regulated only in those NB4 cells that are sensitive to ATRA-induced cyto-differentiation, and not in ATRA-resistant cells that do not differentiate. However, TF activity was significantly reduced in all cell lines in response to ATRA, regardless of sensitivity to ATRA-induced differentiation. TF expression can be down-regulated by ATRA in both APL cells and in other types of leukemic cells and also in normally differentiated cells.– Nuclear run-on experiments in human monocytes and monocytic leukemia cells support the concept that ATRA inhibits induction of TF expression at the level of transcription, but independently of the common transcription factors AP-1 or NF-kB. Zhu et al. demonstrated destabilization of TF mRNA induced by ATRA in NB4 cells, partially dependent upon protein synthesis, and Raelson and colleagues showed that ATRA induces synthesis of a protein in NB4 cells that selectively degrades PML/RAR-alpha fusion protein. Therefore, one or more proteins induced by ATRA in leukemic cells may also destabilize TF mRNA. Furthermore, this group reported that bone marrow cells from mice transgenic for the fusion genes PLZF-RAR-alpha or NPM-RAR-alpha express the TF gene, whereas the cells derived from those mice without the fusion gene do not express the TF gene. These data link directly, for the first time, the regulation of TF gene expression in APL cells with the malignant transforming events and provide strong support for the hypothesis that down-regulation of TF gene expression is a direct result of the mechanism of the ATRA effect on oncogene expression.