tretinoin and Blood-Coagulation-Disorders

Acute promyelocytic leukemia (APL) is associated with a complex coagulopathy. In spite of substantial recent improvements in treatment regimens, hemorrhagic death remains the main cause of induction failure. In this review, we delineate recent understanding of the pathophysiology and management of the hemorrhagic diathesis of APL.. Laboratory and clinical data suggest that the malignant leukocytes mediate the hemorrhagic diathesis associated with APL through multiple mechanisms which lead to a combination of consumptive coagulopathy and primary hyperfibrinolysis. Exposure of tissue factor and Annexin II by the leukemic blasts is the main determinants of these processes. Promyelocyte-derived microparticles have recently been implicated in the coagulopathy as well. Total white cell count and platelet count have emerged as good general predictors of hemorrhagic death, along with the different routine hemostatic parameters. Prompt treatment with all-trans retinoic acid, with or without arsenic trioxide, is the most important step in preventing bleeding complications. Repletion of coagulation factors and platelets with blood products remains the mainstay of supportive treatment, whereas the role of recombinant soluble thrombomodulin is currently being investigated.. The coagulopathy of APL is multifactorial, with both disseminated intravascular coagulation and primary hyperfibrinolysis mediated largely by the malignant leukocytes.

Topics: Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation; Blood Coagulation Disorders; Humans; Leukemia, Promyelocytic, Acute; Prognosis; Remission Induction; Thrombomodulin; Treatment Outcome; Tretinoin

Despite major advances in the treatment of acute promyelocytic leukemia (APL), high-risk APL still poses unique challenges. The purpose of this review is to outline current evidence for evaluation and management of high-risk APL and discuss areas of ongoing and future investigation.. With the changing treatment paradigm in APL and increasing use of arsenic trioxide (ATO), reports have questioned the relevance of classic prognostic factors. Despite advancements in therapy, early death remains a primary reason for treatment failure. A randomized, phase III trial demonstrated that all-trans retinoic acid + ATO is at least noninferior and may be superior to all-trans retinoic acid + chemotherapy in low/intermediate-risk APL. One phase III and multiple phase II trials have suggested a benefit of adding ATO to therapy of high-risk patients. Attempts at minimizing chemotherapy in high-risk disease have proven feasible with the use of gemtuzumab ozogamicin, but it is unlikely that cytotoxic chemotherapy will be completely eliminated in this patient population.. Treatment of high-risk APL has evolved significantly over the past 10 years and current scoring systems, management, and treatment regimens have been reviewed. There are as yet unresolved questions, including how to minimize early deaths and optimal therapy in an ATO era.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Blood Coagulation Disorders; Disease Management; Humans; Leukemia, Promyelocytic, Acute; Oxides; Recurrence; Remission Induction; Treatment Outcome; Tretinoin

Coagulopathy is a unique component of the pathology of acute promyelocytic leukaemia (APL). Though many causative factors have been elucidated, therapies to rectify the coagulopathy are far from being realised. Thrombotic and bleeding complications remain the major causes of early deaths. In this chapter, the known causes of abnormalities in haemostatic function, namely the coagulopathy and changes in the fibrinolytic system, will be reviewed. Major risk factors for these complications are identified. Current available measures for correction of the coagulopathy and their effectiveness are critically examined. Unless the coagulopathy can be effectively controlled, bleeding complications will remain an obstacle to achieving a cure for this disease. The issues that need to be addressed in next phase of investigations are also discussed.

Topics: Annexin A2; Anticoagulants; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Blood Coagulation Disorders; Blood Coagulation Tests; Carboxypeptidase B2; Disseminated Intravascular Coagulation; Fibrinolysis; Forecasting; Granulocyte Precursor Cells; Hemorrhagic Disorders; Humans; Leukemia, Promyelocytic, Acute; Oxides; Recombinant Proteins; Risk Factors; S100 Proteins; Thrombomodulin; Thrombophilia; Thromboplastin; Tretinoin; Urokinase-Type Plasminogen Activator

Acute promyelocytic leukaemia (APL) in children and adolescents shares many features with APL in adults. There are important distinctions, however, between these age groups in the presentation, complications and treatment outcomes. Paediatric patients are more likely to present with high risk features including elevated WBC count or microgranular variant (M3v). Yet the early death rate is lower in paediatric patients compared to adult patients. Overall outcomes such as CR, OS and EFS appear similar in paediatric and adult patients treated on similar regimens except that very young children may have a higher risk of relapse. While contemporary studies have clearly demonstrated improved survival in adults receiving ATO therapy, currently there is more limited data on the role of ATO in paediatric patients. Here we highlight the similarities and important distinctions between paediatric and adult APL while reviewing available data on treatment of paediatric APL.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Age Factors; Age of Onset; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Biomarkers, Tumor; Blood Coagulation Disorders; Bone Marrow Examination; Cell Differentiation; Child; Child, Preschool; Heart Diseases; Humans; Infant; Leukemia, Promyelocytic, Acute; Multicenter Studies as Topic; Neoplasm, Residual; Neoplasms, Second Primary; Oncogene Proteins, Fusion; Oxides; Prognosis; Pseudotumor Cerebri; Randomized Controlled Trials as Topic; Remission Induction; Risk Factors; Salvage Therapy; Tretinoin

Since the initial description of the disease, the life-threatening coagulopathy associated with acute promyelocytic leukaemia (APL) has been the defining clinical characteristic. Historically, this uncommon subtype of acute myeloid leukaemia has been associated with a high mortality rate during induction therapy, most frequently attributable to haemorrhage. Since the introduction of all-trans retinoic acid (ATRA) into the therapy of all patients with APL, disease-free survival and overall survival have improved dramatically, such that the disease is now highly curable. However, induction mortality remains a major problem and haemorrhage still accounts for the majority of such early deaths. Pathogenesis of the coagulopathy is complex and includes disseminated intravascular coagulation (DIC), fibrinolysis and proteolysis. As a result, while the predominant clinical manifestation of the coagulopathy is haemorrhage, thromboembolic events may occur both at presentation and during therapy. A major recent finding is the high expression of annexin II in the leukaemic cells from patients with APL. Annexin II is a protein with high affinity for plasminogen and tissue-type plasminogen activator (tPA), and also acts as a cofactor for plasminogen activation by tPA. As a result, both plasminogen and tPA are increased on the cell surface of the leukaemic cell, increasing plasmin activity. Annexin II is expressed in high amounts in cerebral microvascular endothelial cells, perhaps accounting for the relatively high incidence of intracranial haemorrhage in APL compared with other sites. Microparticles are cell-derived membrane fragments originating from normal cells or released from malignant cells involved in activating coagulation. Recent studies have found that microparticles containing tissue factor, tPA, plasminogen activator inhibitor-1 and annexin II have been found in the plasma of APL patients, suggesting a role in pathogenesis of the coagulopathy. Treatment of the coagulopathy remains primarily supportive. Aggressive transfusions of platelets and cryoprecipitate appear to be important. There is no clear role for the routine use of heparin or antifibrinolytic therapy. The most important factor may be the early introduction of ATRA at the first suspicion of a diagnosis of APL, before it is confirmed genetically.

Topics: Annexin A2; Blood Coagulation Disorders; Hemorrhage; Humans; Leukemia, Promyelocytic, Acute; Plasminogen; Survival Analysis; Tissue Plasminogen Activator; Tretinoin

Topics: Anticoagulants; Antifibrinolytic Agents; Blood Coagulation Disorders; Hemostasis; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Bleeding diathesis is a common complication of acute promyelocyctic leukaemia (APL). Multiple haemostatic defects are found in most patients with APL, which often worsen following cytoreductive chemotherapy. Besides thrombocytopenia, most patients develop disseminated intravascular coagulation, systemic fibrinolysis or both. A major aim in treating haemostatic defects of APL is to prevent death or disability from bleeding until chemotherapy clears the malignant promyelocytes from the blood and bone marrow. The therapeutic options are discussed in this review and practical guidelines for treatment are outlined.

Topics: Antineoplastic Agents; Blood Coagulation Disorders; Disseminated Intravascular Coagulation; Hemostasis; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Topics: Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation Disorders; Bone Marrow Transplantation; Cell Differentiation; Drug Resistance; Humans; Leukemia, Promyelocytic, Acute; Neoplasm, Residual; Survival Analysis; Thrombosis; Tretinoin

Topics: Blood Coagulation Disorders; Cell Differentiation; Clinical Trials as Topic; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

The antitumor effect of different retinoids focused attention in the treatment of malignant disorders on different pathways. The therapeutic effect was proved in acute promyelocytic leukaemia, but was limited in juvenile form of chronic myeloid leukaemia and in acute myelomonocytic and monoblastic leukaemia. Combined with different leukostatics, long remission could be achieved. The most important therapeutic pathway is direct growth inhibition with and without cell differentiation. Clinically, retinoids are effective in tumours, like: cutan T-cell lymphoma, mycosis fungoides, Sézary syndrome, oral leukoplakia (prevention of head and neck cancer metastases), variant form of small lung cell carcinoma, oestrogen dependent breast-carcinoma and cervix-carcinoma. The most serious complication of the retinoids' administration is the retinoic acid syndrome which is followed sometimes with thromboembolic events. Retinoids are teratogenic and hepatotoxic.

Topics: Blood Coagulation Disorders; Hematologic Diseases; Hematopoietic System; Humans; Leukemia; Neoplasms; Retinoids; Thromboembolism; Tretinoin

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.

Topics: Blood Coagulation; Blood Coagulation Disorders; Fibrinolysis; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Topics: Antineoplastic Agents; Blood Coagulation Disorders; Carrier Proteins; Gene Expression; Humans; Leukemia, Promyelocytic, Acute; Prognosis; Receptors, Retinoic Acid; Tretinoin

The clinical and laboratory features of APL are distinct. APL has been effectively treated with anthracyclines. Postremission therapy and the addition of other cytotoxic agents in induction may be beneficial. Early deaths remain a problem despite improved management of coagulopathy. The cytogenetic marker, t(15;17), reflects a molecular defect that splices two transcription factors, PML and RARA, to produce chimeric mRNA and proteins. RA, the natural ligand for RARA, is able to induce CR by stimulating differentiation and maturation of the malignant cells. The addition of RA to the therapeutic armamentarium of the hematologic oncologist will allow further refinement of the management of these patients. Diagnosis is unambiguous because the molecular defect can be readily detected. Our understanding of the biology downstream of the affected genes is incomplete. Other retinoids may be more effective than all-trans RA and may avoid the fall in plasma levels seen in patients chronically treated with RA. Combination of retinoids with other cytokines or cytotoxic agents may decrease the immediate mortality and improve long-term DFS in APL.

Topics: Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation Disorders; Cell Differentiation; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Clinical Trials as Topic; Humans; Leukemia, Promyelocytic, Acute; Neoplastic Stem Cells; Remission Induction; Translocation, Genetic; Tretinoin

Topics: Blood Coagulation Disorders; Disseminated Intravascular Coagulation; Hemostasis; Heparin; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Topics: Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation Disorders; Bone Marrow Transplantation; Cell Differentiation; Drug Resistance; Humans; Leukemia, Promyelocytic, Acute; Neoplasm, Residual; Survival Analysis; Thrombosis; Tretinoin

All-trans retinoic acid (ATRA) in acute promyelocytic leukemia (APL) represents the leading example of targetted drugs for inducing an in vivo differentiation of malignancy (1,2). A fixed dose of 45 mg/m2/day was proposed for the treatment of patients (3), according to the results obtained by retinoic acid derivatives in skin diseases. We report that 25 mg (4), and even 15 mg/m2/day are still effective dosages. Absence of drug resistance, rapid correction of fibrinogenopenia and the absence of hypoplasia are the apparent major advantages and consequently high frequency of early mortality generally reported during chemotherapy is expected to be reduced. In fact the same risk of early death (10%) is recorded in all available data (5), due to coagulation disorders and to a leukocyte activation syndrome. Management of these side-effects is based on the prevention and treatment of the irreversible state as soon as first symptoms appear. Actually the major advantage of ATRA treatment in addition to chemotherapy is the decrease of relapse rate (6), the increase of event-free survival, and thus the increase of survival.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Blood Coagulation Disorders; Child; Disease-Free Survival; Female; Humans; Leukemia, Promyelocytic, Acute; Leukocyte Count; Male; Middle Aged; Recurrence; Remission Induction; Treatment Outcome; Tretinoin

To evaluate the safety and efficacy of all-trans retinoic acid to induce complete remission and to examine its effects on duration of remission and survival in patients with acute promyelocytic leukemia.. Phase II evaluation and comparison with historical control patients.. Tertiary care cancer referral center.. Consecutive patients with morphologic diagnoses of acute promyelocytic leukemia were treated during a 2-year period with all-trans retinoic acid (daily oral dose, 45 mg/m2). Newly diagnosed patients discontinued the drug approximately 30 days after they achieved complete remission, at which time they received three courses of combination chemotherapy. Patients treated with previous cytotoxic chemotherapy who then relapsed were continued on all-trans retinoic acid as "maintenance" therapy until they relapsed again.. 56 patients entered the study: 34 were newly diagnosed and 22 had relapsed from previous treatment. Fifty-one patients subsequently were found to have the PML/RAR-alpha gene rearrangement indicative of acute promyelocytic leukemia, and 44 of these patients achieved complete remission (86%; 95% Cl, 76% to 96%). A distinctive respiratory distress syndrome developed in 13 patients (23%) during treatment, and 5 patients (9%; Cl, 3% to 20%) died of this complication. The 5 patients who lacked PML/RAR-alpha rearrangements were withdrawn and given chemotherapy. The 13 patients given all-trans retinoic acid alone as maintenance therapy (10 of whom had relapsed from a chemotherapy-induced remission) had a median duration of remission of only 3.5 months (range, 1 to 23 months). Only 3 of 19 patients who relapsed from a remission induced by all-trans retinoic acid could be brought into remission again using this drug. The median survival time of all newly diagnosed patients has not been reached, but it now exceeds 31 months (range, 0.4 to 36+ months). No decrease in the early mortality rate was observed compared with a historical control group composed of 80 consecutive, newly diagnosed patients treated only with chemotherapy at this center; however, overall survival was superior.. All-trans retinoic acid is an effective agent to induce remission in patients with a molecular diagnosis of acute promyelocytic leukemia, but remissions are short and resistance develops rapidly. Although the incidence of early death was not reduced, the use of all-trans retinoic acid to induce remission, followed by cytotoxic chemotherapy for "consolidation," was associated with longer survival times when compared with historical controls treated only with chemotherapy. Additional studies to prevent or mitigate consequences of the "retinoic acid syndrome" and to identify specific patients who might benefit from earlier intervention with chemotherapy are needed to maximize the advantages of this approach.

Topics: Adolescent; Adult; Aged; Blood Coagulation Disorders; Child; Female; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Leukopenia; Male; Middle Aged; Recurrence; Remission Induction; Survival Analysis; Time Factors; Tretinoin

We designed a multicenter randomized trial comparing chemotherapy with daunorubicin-Ara C (chemotherapy group) and all transretinoic acid (ATRA) combined to the same chemotherapy (ATRA group) in newly diagnosed APL patients aged 65 years or less. The major endpoint of the study was event-free survival (EFS) ("events" being defined as failure to achieve complete remission [CR], occurrence of relapse, or death in CR). Early termination of the trial was decided after the first interim analysis, as EFS was significantly higher in the ATRA group. At the time, 101 patients had been randomized (54 in the ATRA group and 47 in the chemotherapy group). In the ATRA group, 49 (91%) patients achieved CR, 5 (9%) had early death, and 0 had resistant leukemia, compared with 38 (81%), 4 (8%), and 5 (10%) patients, respectively, in the chemotherapy group. The difference in CR rate between the two groups was not significant. The duration of coagulopathy was significantly reduced in the ATRA group, compared with the chemotherapy group. In the ATRA group, six patients relapsed after 7 to 15.5 months. In the chemotherapy group, 12 patients relapsed after 1 to 16 months, and 2 died in CR. Kaplan-Meier EFS was estimated at 79% +/- 7% and 50% +/- 9% at 12 months, respectively, in the ATRA and the chemotherapy group (P = .001). Kaplan-Meier estimate of relapse was 19% +/- 8% and 40% +/- 12% at 12 months (P = .005). In conclusion, ATRA followed by chemotherapy increases EFS in newly diagnosed APL. These results strongly suggest that ATRA should be incorporated in the front line therapy of newly diagnosed APL.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation Disorders; Drug Administration Schedule; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Remission Induction; Survival Rate; Tretinoin

Topics: Antineoplastic Agents; Blood Coagulation Disorders; Carrier Proteins; Gene Expression; Humans; Leukemia, Promyelocytic, Acute; Prognosis; Receptors, Retinoic Acid; Tretinoin

To explore the effect of cytokine levels on early death and coagulation function of patients with newly diagnosed acute promyelocytic leukemia (APL).. Routine examination was performed on 69 newly diagnosed APL patients at admission. Meanwhile, 4 ml fasting venous blood was extracted from the patients. And then the supernatant was taken after centrifugation. The concentrations of cytokines, lactate dehydrogenase (LDH) and ferritin were detected by using the corresponding kits.. It was confirmed that cerebral hemorrhage was a major cause of early death in APL patients. Elevated LDH, decreased platelets (PLT) count and prolonged prothrombin time (PT) were high risk factors for early death (. Elevated cytokine levels in newly diagnosed APL patients increase the risk of early bleeding and death. In addition to the interaction between cytokines themselves, ferritin and LDH positively affect the expression of cytokines, thus affecting the prognosis of APL patients.. 细胞因子对初诊急性早幼粒细胞白血病患者早期死亡的影响.. 探索细胞因子对初诊急性早幼粒细胞白血病（APL）患者早期死亡及凝血功能障碍的影响。.. 69例初诊APL患者入院时完善常规检查，采集空腹静脉血4 ml，离心后取上清液，通过相应试剂盒检测细胞因子浓度及铁蛋白、乳酸脱氢酶（LDH）的浓度。.. 初诊APL患者细胞因子水平升高导致早期出血及死亡风险增加。铁蛋白及LDH正向影响细胞因子表达，从而影响APL患者预后，细胞因子之间也相互影响。.

Topics: Blood Coagulation Disorders; Cytokines; Ferritins; Humans; Interleukin-10; Interleukin-17; Interleukin-5; Interleukin-6; Leukemia, Promyelocytic, Acute; Tretinoin

Topics: Acute Disease; Appendicitis; Blood Coagulation Disorders; Child; Humans; Leukemia, Promyelocytic, Acute; Leukemic Infiltration; Tretinoin

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation Disorders; Chromosomes, Human, Pair 16; Chromosomes, Human, Pair 8; Cytarabine; Daunorubicin; Dexamethasone; Gemtuzumab; Humans; Leukemia, Myeloid, Acute; Male; Translocation, Genetic; Tretinoin

To prevent early death, management of coagulopathy is important in patients with untreated acute promyelocytic leukemia (APL). This study aimed to clarify factors associated with in-hospital death in patients with coagulopathy during induction therapy for APL. We retrospectively identified patients with newly diagnosed APL who received induction therapy including all-trans retinoic acid (ATRA) and developed coagulopathy, using a nationwide inpatient database in Japan. Of 1115 eligible patients, 175 (15%) died at a median of 13 days (interquartile range, 7-30) after admission. In the multivariable analysis, compared with younger patients (aged < 40 years), the occurrence of in-hospital death was significantly more common among older patients (aged ≥ 40 and < 60 years: odds ratio = 2.58 [95% confidence interval: 1.29-5.19]; aged ≥ 60 and < 80 years: 7.66 [3.89-15.10]; aged ≥ 80 years: 16.83 [7.41-38.21]). Delayed initiation of ATRA and no conventional chemotherapy were significantly associated with in-hospital death (1.79 [1.16-2.76] and 2.40 [1.47-3.92], respectively). A total of 699 patients (63%) received anticoagulant therapies, but none of these was significantly associated with lower mortality. Although the present study was constrained by a lack of laboratory findings because of database limitations, the results showed that untreated patients with APL, especially the elderly, had a poor prognosis. Immediate administration of ATRA may reduce in-hospital mortality.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Blood Coagulation Disorders; Female; Hospital Mortality; Humans; Induction Chemotherapy; Japan; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Retrospective Studies; Risk Factors; Tretinoin

Since the introduction of all-trans retinoic acid and, more recently, arsenic trioxide into the therapy of acute promyelocytic leukemia (APL), significant improvements in patient outcomes have been achieved, and this disease has become the most curable subtype of acute myeloid leukemia. However, while primary leukemia resistance has virtually disappeared, a sizable fraction of APL patients still die before or during induction therapy. Hemorrhagic death still remains the major problem during this early phase of treatment and, to a lesser extent, deaths due to infection, differentiation syndrome and other causes. Patients with APL typically present with a range of laboratory abnormalities consistent with the diagnosis of disseminated intravascular coagulation and hyperfibrinolysis. This APL-associated coagulopathy, as a result of a dysregulation of the hemostatic system due to the imbalance between procoagulant, anticoagulant and profibrinolytic mechanisms, may show a variety of clinical manifestations, ranging from minimal bleeding or localized thrombosis to lethal or life-threatening hemorrhages or thrombotic events that sometimes occur concomitantly. Hemorrhagic events are the most common cause of death associated with APL coagulopathy, but thrombosis, a less recognized and probably underestimated life-threatening manifestation of the thrombo-hemorrhagic syndrome, is also a non-negligible cause of morbidity and mortality in patients with APL. In this article, we aim to discuss recent advances in the knowledge of pathogenesis, predictors of thrombo-hemorrhagic events, management of coagulopathy associated with APL and the controversial issues that still persist.

Topics: Blood Coagulation Disorders; Disseminated Intravascular Coagulation; Hemorrhage; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Clinical studies have shown that all-trans retinoic acid (RA), which is often used in treatment of cancer patients, improves hemostatic parameters and bleeding complications such as disseminated intravascular coagulation (DIC). However, the mechanisms underlying this improvement have yet to be elucidated. In vitro studies have reported that RA upregulates thrombomodulin (TM) expression on the endothelial cell surface. The objective of this study was to investigate how and to what extent the TM concentration changes after RA treatment in cancer patients, and how this variation influences the blood coagulation cascade.. In this study, we introduced an ordinary differential equation (ODE) model of gene expression for the RA-induced upregulation of TM concentration. Coupling the gene expression model with a two-compartment pharmacokinetic model of RA, we obtained the time-dependent changes in TM and thrombomodulin-mRNA (TMR) concentrations following oral administration of RA. Our results indicated that the TM concentration reached its peak level almost 14 h after taking a single oral dose (110 [Formula: see text]) of RA. Continuous treatment with RA resulted in oscillatory expression of TM on the endothelial cell surface. We then coupled the gene expression model with a mechanistic model of the coagulation cascade, and showed that the elevated levels of TM over the course of RA therapy with a single daily oral dose (110 [Formula: see text]) of RA, reduced the peak thrombin levels and endogenous thrombin potential (ETP) up to 50 and 49%, respectively. We showed that progressive reductions in plasma levels of RA, observed in continuous RA therapy with a once-daily oral dose (110 [Formula: see text]) of RA, did not affect TM-mediated reduction of thrombin generation significantly. This finding prompts the hypothesis that continuous RA treatment has more consistent therapeutic effects on coagulation disorders than on cancer.. Our results indicate that the oscillatory upregulation of TM expression on the endothelial cells over the course of RA therapy could potentially contribute to the treatment of coagulation abnormalities in cancer patients. Further studies on the impacts of RA therapy on the procoagulant activity of cancer cells are needed to better elucidate the mechanisms by which RA therapy improves hemostatic abnormalities in cancer.

Topics: Blood Coagulation; Blood Coagulation Disorders; Cell Line, Tumor; Computer Simulation; Endothelial Cells; Gene Expression Regulation, Neoplastic; Humans; Models, Biological; Neoplasms; Thrombin; Thrombomodulin; Tretinoin

To evaluate the role of microparticle (MP) derived from acute promyelocytic leukemia (APL) cells and tissue factor (TF) carried by the MP in hypercoagulable state, and the effect of treatment with cytotoxic chemotherapy/differentiating agents on procoagulant activity (PCA) of these MP.. Bone marrow mononuclear cells (BMMNC) were extracted from 5 APL patients and 5 sex- and age- matched patients with iron deficiency anemia as controls. The cells were cultured in vitro for 48 h, then MP-rich culture medium and MP-free culture medium were harvested and MP was further obtained from certain volume of MP-rich culture medium. Subsequently, TF expression on MP was measured by ELISA. PCA of MP-rich culture medium or MP-free culture medium was assessed with thrombin generation assay. The role of TF on MP-related PCA was evaluated using anti-human TF antibody. In addition, APL cells were treated with all-trans retinoic acid (ATRA), arsenic trioxide (ATO) or daunorubicin (DNR) for 48 h, then MP-rich culture medium were harvested and the PCA was determined.. No TF expression was found in the MP released from bone marrow MNC in control group, whereas the obvious TF expression was found in the MP originated from BMMNC of APL. MP from both APL and control BM-MNC had obvious PCA. However, compared with the MP derived from control MNC, the MP from APL BM-MNC induced significantly higher PCA. TF played a crucial role in the PCA of APL BM-MNC derived MP, while played no role in that of MP from control MNCs. DNR-treating APL BM-MNC resulted in an increase in the PCA of MP, whereas ATO or ATRA exposure lead to exactly the opposite results.. MP derived from APL BM-MNC posseses obvious PCA. TF plays a crucial role in the MP-related PCA. The PCA of MP increases after treating APL BM-MNC with chemotherapy agent DNR and decreases following exposure of APL BM-MNC to differentiating agents ATRA or ATO.

Topics: Arsenicals; Blood Coagulation Disorders; Cell-Derived Microparticles; Humans; Leukemia, Promyelocytic, Acute; Oxides; Thromboplastin; Tretinoin

Topics: Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation Disorders; Humans; Leukemia, Promyelocytic, Acute; Remission Induction; Tretinoin

To study the effect of arsenic trioxide (As2O3) or all-trans retinoic acid (ATRA) on coagulopathy in patients with acute promyelocytic leukemia (APL), and the mechanism of hemorrhage in these patients.. Thrombomodulin (TM) or tissue factor (TF) transcription of mRNA of freshly isolated bone marrow blast from APL patients was detected by semi-quantitative RT-PCR. The parameters of coagulation and cell procoagulation activity (PCA) were assessed in plasmic levels. Bleeding symptom was observed during As2O3 or ATRA treatment.. TM expression in the APL cell surface was significantly upregulated from (14.31 +/- 1.60) ng/10(7) to (21.61 +/- 6.82) ng/10(7) cells. The levels of P-selectin, soluble fibrin monomer complex (SFMC) and D-dimer (D-D) decreased after ATRA or As2O3 treatment. Abnormal high expression of TF in APL cell was downregulated in patients treated with ATRA or As2O3. The expression level was (14.81 +/- 6.23) ng/L before treatment, but undetected after 20 days of treatment. In addition, the membrane PCA of fresh APL cells was predominantly FVII-dependent after ATRA or As2O3 treatment. Bleeding symptom was ameliorated during As2O3 or ATRA treatment.. Bleeding symptom was controlled in patients with APL after As2O3 or ATRA treatment.

Topics: Adult; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Blood Coagulation Disorders; Down-Regulation; Female; Hemorrhage; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Oxides; RNA, Messenger; Thrombomodulin; Thromboplastin; Tretinoin

Topics: Adult; Blood Coagulation Disorders; Hemostatics; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Among 379 patients with AML with FAB type M1, 2 and M4-7 diagnosed between 1978 and 1997 in our institution, 19 (5%) had hypofibrinogenemia (HF), ie a fibrinogen level <180 mg/dl. Compared to patients with normal fibrinogen (n = 360) patients with HF had significantly elevated markers of activation of coagulation (TAT, F1.2, FPA) and fibrinolysis (D-dimer, FDP) indicating that disseminated intravascular coagulation/hyperfibrinolysis was the cause of hypofibrinogenemia. Patients with HF had significantly longer prothrombin times, thrombin clotting and reptilase times. Factor X and VIII were significantly lower than in patients without HF. With the exception of M7, HF occurred in all FAB subtypes, but was most common in M5 (12.1%). Patients with HF did not differ from those with normal fibrinogen with regard to age, sex, leukocyte count and other hematological parameters. During induction chemotherapy fibrinogen normalized rapidly (median 5 days) and there was no increased incidence of early hemorrhagic death. The overall and disease-free survival was similar to that of patients without HF.

Topics: Adult; Antineoplastic Agents; Blood Coagulation Disorders; Disease-Free Survival; Female; Fibrinogen; Humans; Incidence; Karyotyping; Leukemia, Myeloid, Acute; Male; Middle Aged; Neoplasm Proteins; Oncogene Proteins, Fusion; Prognosis; Tretinoin

A 22-year-old female presented with acute promyelocytic leukemia (APL). Treatment with all-trans retinoic acid (ATRA) resulted in a severe exacerbation of the coagulopathy 5 days after its introduction. This was complicated by bone marrow necrosis, parenchymal liver damage and acute tubular necrosis. Temporary cessation of the drug and subsequent dose reduction was effective in controlling the coagulopathy.

Topics: Adult; Antineoplastic Agents; Blood Coagulation Disorders; Bone Marrow; Chemical and Drug Induced Liver Injury; Female; Humans; Kidney Diseases; Leukemia, Promyelocytic, Acute; Liver Diseases; Necrosis; Tretinoin

Topics: Blood Coagulation Disorders; Humans; Leukemia, Promyelocytic, Acute; Thromboplastin; Tretinoin

APL-associated hemostasis disorders result from at least two distinct mechanisms due to the release of procoagulant activities and plasminogen activators from the leukemic cells. These two mechanisms (thrombin activation and plasmin activation) may cleave the fibrinogen molecule, but their respective roles in low fibrinogen levels and bleeding diathesis genesis remain in dispute. In vivo ATRA therapy induces a rapid correction of both low fibrinogen level and bleeding tendency, but no clear explanation of this beneficial effect has been proposed. We prospectively investigated 27 APL patients at presentation for diffuse intravascular coagulation (DIC) markers (prothrombin activation fragment and thrombin/antithrombin complexes) and plasmin-dependent primary fibrinogenolysis markers (alpha 2 plasmin inhibitor consumption +/- plasmin/alpha 2 plasmin inhibitor complexes). Fourteen of these patients were then serially studied during the first 2 weeks of ATRA therapy. Four of them, however, developed an hyperleukocytosis requiring additional chemotherapy before the end of the 2nd week. At presentation, low level of fibrinogen was clearly associated with alpha 2 plasmin inhibitor deficiency (p < 0.01), while DIC was equally present in fibrinogenopenic and non-fibrinogenopenic patients. Moreover, was observed a rapid simultaneous correction of low fibrinogen levels and plasmin activation markers in APL patients undergoing ATRA therapy (before day 5), but a more prolonged persistence of DIC markers (until day 14). Initial bleeding syndrome seemed more frequent in patients with initial low fibrinogen level. These data indicate that plasmin-dependent primary fibrinogenolysis is the major etiologic factor of low fibrinogen level in APL patients. In vivo differentiation ATRA therapy induces a rapid decrease in the plasmin activation and a normalization of fibrinogen level, while DIC may in vivo persist for several weeks. Prospective studies evaluating antifibrinolytic agents as therapy of APL-associated hemostasis disorders should be considered. Additionally, prophylactic heparin therapy might be useful after day 5 in patients undergoing ATRA therapy, since they present a prolonged procoagulant tendency.

Topics: Adolescent; Adult; Aged; alpha-2-Antiplasmin; Antifibrinolytic Agents; Blood Coagulation Disorders; Female; Fibrinogen; Fibrinolysin; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Prospective Studies; Thrombin; Tretinoin

A case of 62-year-old female with acute promyelocytic leukemia is presented, in whom in poor general condition, and with symptoms of severe haemorrhagic diathesis and biochemical signs of coagulopathy a treatment with trans-retinoic acid was induced. After three weeks of treatment with t-RA complete hematological and clinical remission was achieved, without bone marrow aplasia, worsening of hemostatic parameters, or necessity of protective or therapeutic antibiotics administration typical of conventional chemotherapy. Apart from skin allergization and increase of transaminases other side effects of the t-RA treatment were not observed.

Topics: Blood Coagulation Disorders; Female; Humans; Leukemia, Promyelocytic, Acute; Middle Aged; Remission Induction; Tretinoin

All trans retinoic acid (ATRA) in the treatment of acute promyelocytic leukemia is the first model of differentiation therapy in malignancies, and represents the first strict correlation between a genetic defect and a specific treatment. In this disease the association of differentiating agents and chemotherapy gives much better results than each type of treatment (differentiating agent or chemotherapy).

Topics: Blood Coagulation Disorders; Cell Differentiation; Drug Resistance; Humans; Leukemia, Promyelocytic, Acute; Syndrome; Tretinoin