Our results showed that the rate of APL arterial thrombosis was lower than that of venous thrombosis (2.3% vs 13.6%). Venous thrombosis occurred in the disease induction treatment phase. The median time of thrombotic events occurred 14 days (range 9–26 days). Six patients with venous thrombosis were given heparin anticoagulant therapy under the premise of platelet and fibrinogen supplementation, leading to the complete recanalization of the vein, while no serious bleeding events being observed. The rate of venous thrombosis is consistent with the data reported in the previous literature [16]. Other studies showed that the rate of APL related thrombotic events increased from 2% before the adoption of all-trans retinoic acid (ATRA) to 4.5–15% after the adoption of ATRA [22,23,24].
Currently, the risk factor of thrombosis in APL patients has not been fully discovered. Previous studies reported that these factors increased the risk of APL thrombosis, including male, high score performance status (PS), high white blood cell count and platelet count, low fibrinogen levels, hypoalbuminemia, PML/RARa fusion gene variant, CD2/CD15 and FLT3-ITD positive.
Our results showed that there was no significant difference between thrombotic events and gender ratio, age, white blood cell count, hemoglobin, platelets, disease risk stratification and CD2. In addition, PML/RARa (bcr3) and CD15 were statistically significant. Moreover, in Multivariate Cox Proportional Regression, the risk factor of venous thrombosis in APL was CD15 (P = 0.043, OR 17.35, 95% CI 1.093-275.406), suggesting high-risk factors associated with thrombotic events.
In order to further explore whether the risk factors for hereditary thrombosis are involved in the event of APL thrombosis, we detected antithrombin III, protein C, protein S, antiphospholipid antibodies and homocysteine in 7 APL patients with thrombotic events. However, the results showed no positive clinical significance, suggesting that thrombotic events in 7 APL patients did not involve genetic thrombophilia.
PAI-1 is a key regulator of endogenous fibrinolytic activity [25]. It is reported that the 4G/5G polymorphism of the PAI-1 gene affects plasma levels of PAI-1 [26]. The 4G/4G genotype is associated with higher plasma PAI-1 activity, which can lead to impaired fibrinolysis, thus increasing the risk of thrombosis [27, 28]. Previous study reported that PAI-1 gene 4G/4G in APL patients receiving ATRA treatment showed high PAI-1 level in vivo and increased the frequency of APL related thrombotic events [8]. Mitrovic M et al. demonstrated [16] that the PAI 4G/4G was five and two times more frequent in Serbia population with APL-related venous and arterial TE than in those without TE (P = 0.05). Similarly, results of this study showed that PAI-1 4G/4G was detected in 71.4% (5/7) of 7 patients with thrombosis, and PAI-1 gene polymorphism was 4G/5G (28.6%, 2/7) in 2 patients. The detection rate of PAI-1 4G/4G in the patients without thrombotic events was 8.1% (3/37), and the difference was statistically significant (P = 0.0009). In Multivariate Cox Proportional Regression, the risk factor of venous thrombosis was PAI-1 4G4G (P = 0.009, OR 25.2, 95% CI 2.218-286.483), suggesting a high-risk factor related to thrombotic event.
Thrombotic events are significant complications in malignant patients. Thrombosis risk is well defined in patients with solid tumors, and Khorana score is well validated for these patients. However, the value of Khorana scoring system in predicting the thrombotic events risk of hematological malignant diseases remains to be evaluated [29, 30]. Hence, we conducted a retrospective study to validate the use of the Khorana score for thrombotic events in APL patients. The results of our study showed that the Khorana score of all APL patients with thrombotic events were 1 and 2, and there was no significant difference between the two groups.
Lee YG et al. [31] suggested that advanced age and increasing cytogenetic risk were the independent risk factors of VTE after retrospectively analyzing 811 consecutive AML patients. The expression of additional gene mutations was correlated with the pathogenesis and prognosis of acute myeloid leukemia. Recently, APL patients with epigenetic modifier genes (EMG) mutations may exert negative impact on the overall survival and disease-free survival [32]. However, the possible of EMG mutations on the risk of VTE in APL patients has not been confirmed. We have analyzed the results of EMG mutations related to prognosis of APL. As shown in Table 3, there were significant differences between the two groups in WT-1 and FLT3-ITD mutations, excluding DNMT3A, TET2, IDH1, IDH2, NRAS and ASXL1. Moreover, in Multivariate Cox Proportional Regression, the risk factors of venous thrombosis in APL were WT-1 (P = 0.043, OR 9.14, 95% CI 1.072-77.825) and FLT3/ITD (P = 0.013, OR 21.89, 95% CI 1.938-247.176), respectively (Table 4). These results suggested that WT-1 and FLT3/ITD mutations were the risk factors of thrombotic events in APL patients.