Clinical Study Of Venous Thromboembolism In Children With Acute Lymphoblastic Leukemia

Objective:Acute lymphoblastic leukemia(ALL)is the most common malignant tumor in childhood,accounting for about 25% of the incidence.With the improvement of therapeutic regimens,the cure rate of ALL children has reached 80%?90%,but 10%?20% children have treatment failure.In addition to the disease itself,the cause is also related to complications in the course of treatment.Venous thromboembolism(VTE)is a rare and serious ALL related complication that not only reduces the quality of life of ALL children,but also hinders their chemotherapy process and increases the mortality of ALL children.The purpose of this study was to analyze the epidemiology of VTE in ALL children in China,clinical characteristics of different types of VTE,diagnostic methods,treatment protocols,prognosis and risk factors.Methods:This is a retrospective and multicenter clinical study.The research objects were 7640 newly diagnosed ALL children from 20 hospitals in China.From date of ALL diagnosis,we followed up to 2020.9.30.Among the ALL children,564 were treated with prophylactic anticoagulation.The basic information,clinical manifestations,tumor biogenetic information,laboratory results and survival status of ALL children were collected during the study,and the VTE occurrence,clinical characteristics,risk factors,laboratory results,imaging results and treatment prognosis of the children were recorded during the follow-up period.Statistical analysis was carried out by Chi-square or Fisher's exact test,t test,Mann-Whitney U test and binomial classification Logistic regression.Results:Part ? VTE epidemiology and occurrence characteristics of ALL children:1.VTE epidemiology:Among the 7640 ALL children,159(2.08%,159/7640)children developed VTE,and incidence density was 62.1 per 10000 person-years.It almost occurred within six months after ALL diagnosis(82.4%,131/159)and in induction therapy(56.6%,90/159).A median time for VTE was 44(28,109)days after ALL diagnosis.Up to the follow-up deadline,153(96.23%,153/159)VTE children survived,and 6(3.77%,6/159)children had ALL progression-related deaths.2.VTE occurrence characteristics:ALL children with 12?age<18 years old(P=0.027),T-ALL(P=0.015),mediastinal mass(P=0.032)and sepsis(P<0.001)had higher incidences of VTE.After development of thrombosis,the activated partial thromboplastin time(APTT)and activity of AT-? decreased significantly(P=0.009,P=0.002),but the levels of fibrinogen(FIB),fibrinogen degradation product(FDP)and D-dimer increased significantly(P<0.001,P=0.034,P<0.001).Thrombus length of 17 children with prophylactic anticoagulation was shorter than in children without prophylactic anticoagulant therapy(P<0.001).However,preventive anticoagulant therapy in this study did not reduce the incidence of VTE(3.01%vs.2.01%,P=0.107).The independent risk factor for VTE development was sepsis(OR: 2.07,95%CI:1.45?2.96).Part ? Clinical characteristics and risk factors of different types of VTE in ALL children:1.Symptomatic thrombus and asymptomatic thrombus:Among the VTE children,93 children(58.49%,93/159)developed symptomatic thrombus,and 66 children(41.51%,66/159)developed asymptomatic thrombus.Main VTE symptoms were swelling of the affected limb.Symptomatic thrombus mainly occurred in children with non-catheter related(non-CRT)(P<0.001),cerebral thrombosis(P<0.001)and 12?age<18 years old(P=0.023).And the length of thrombus was longer than that of asymptomatic thrombus(P=0.033).The independent risk factors for VTE symptoms were12?age<18 years old(OR: 4.04,95%CI: 1.12?14.57),non-CRT(OR: 5.5,95% CI:2.15?14.1),cerebral thrombosis(OR:15.6,95%CI: 3.53?68.97)and lower limb thrombosis(OR: 5.1,95%CI: 1.61?16.14).2.Catheter related(CRT)and non-catheter related(non-CRT):Among the VTE children,there were 120 cases(75.47%,120/159)of catheter-associated thrombosis(CRT),and the incidence density was 45.2 per 10000person-years.There were 39 cases(24.53%,39/159)of non-catheter-associated thrombosis(non-CRT),and the incidence density was 16.9 per 10000 person-years.The proportion of CRT in children with central venous catheter(CVC)or femoral vein and subclavian vein catheterization is higher.Compared to non-CRT,CRT children have a higher incidence of sepsis before thrombosis(P=0.033).And the fibrinogen(FIB)concentration was higher in CRT than in non-CRT(P=0.001),but the prothrombin time(PT),fibrinogen degradation product(FDP)and D-dimer levels were lower(P=0.033,P=0.031,P<0.001).The occurrence of non-CRT in children was significantly affected by PEG-ASP than with that of L-ASP(P=0.011).3.Thrombosis in different sites:Among the VTE children,there were 28 cases(17.61%,28/159)of cerebral thrombosis and the incidence density was 10.9 per 10000 person-years.There were 108cases(67.92%,108/159)of upper limb thrombosis,22 cases(13.84%,22/159)of lower limb thrombosis(1 case with pulmonary embolism simultaneously),1 case of right atrial thrombosis(0.63%,1/159).Compared with limb thrombosis children,the age was older(P=0.002),leukocytes,lymphocytes,PT and activated partial thromboplastin time(APTT)were lower(P=0.006,P=0.007,P=0.04,P=0.045),platelet count was higher(P=0.043)in children with cerebral thrombosis at ALL diagnosis.Meanwhile,the concentration of FIB in cerebral thrombosis was lower(P<0.001)than limb thrombosis children,but FDP and D-dimer levels were higher(P=0.031,P<0.001).Part ? Prognosis and risk factors for VTE in ALL children:1.Bleeding associated with VTE anticoagulant therapy:Therapy methods in VTE children included anticoagulation(small molecular weight heparin is the majority)and / or thrombolysis(urokinase),a total of 6 children(4.08%,6/147)had bleeding during anticoagulation therapy.Children with non-CRT(P=0.03),prophylactic anticoagulation(P=0.021),drug-induced hepatitis(P=0.004)or longer APTT at the time of thrombosis(P=0.028)had higher bleeding rates.Independent risk factors for anticoagulation therapy related bleeding were non-CRT(OR: 8.99,95%CI: 1.13?71.49),preventive anticoagulant therapy(OR: 15.38,95%CI: 1.82?130.1)and APTT at the time of thrombosis(OR: 1.05,95%CI: 1.01?1.1).2.Outcomes after VTE children treatment:The median time of thrombosis was 25(13,55)days in VTE children.Children with12?age<18 years old(P=0.042),CRT(P=0.039),limb thrombosis(P=0.015),prophylactic anticoagulation(P=0.029)or three-cavity venous catheter(P=0.001)and PEG-ASP(P=0.038)use had shorter outcome period.3.Thrombosis recurrence in VTE children:Among the VTE children,8(5.03%,8/159)children have thrombus relapsed,and the incidence density was 2.1 per 100 person-years.All relapsed cases occurred within half a year after the first thrombus was cured.VTE recurrence was not associated with first thrombus period of outcome(P=0.062).VTE children with 6?age<9 years old(P=0.002),HR-ALL(P=0.028),no discontinuation of ASP during first thrombus duration(P=0.007),traditional intubation(P=0.02)and residual thrombus(P=0.006)had higher recurrence rates.Compared with children without recurrence,children with recurrence had more leukocytes and platelets(P=0.013,P=0.025)when initial thrombosis developed,and had shorter thrombus length(P=0.023),shorter anticoagulant period(P=0.026).The D-dimer level was higher after treatment(P=0.011).The independent risk factors for VTE recurrence were non-stop ASP during initial thrombus(OR: 6.47,95% CI: 1.17?35.89)and residual thrombus(OR: 7.11,95%CI: 1.01?1.1).Conclusions:1.The incidence rate of VTE in ALL children was 2.08%.Children with 12?age<18 years old,T-ALL,mediastinal mass and sepsis had a higher incidence.The independent risk factor for VTE development was only sepsis.Preventive anticoagulant therapy could not reduce the VTE incidence of ALL children.2.Symptomatic thrombosis accounted for 58.49%,with higher proportions in non-CRT,cerebral thrombosis and older children.CRT accounted for 75.47%,most in VTE children with CVC or femoral vein and subclavian vein catheterization.VTE in ALL children mainly occurred in upper limbs(67.92%).Cerebral thrombosis was prone to occur in older children.3.The rate of bleeding in VTE anticoagulant therapy was 4.08%.Anticoagulant therapy associated bleeding risk factors are non-CRT,prophylactic anticoagulant therapy and APTT at time of VTE development.Different age,types and locations of thrombus,different types of venous catheter and ASP,and children with or without preventive anticoagulant therapy,the time of thrombus outcome was significantly different.VTE recurrence rate was 5.03%.Recurrent risk factors were asymptomatic thrombus,non-stop ASP during thrombus and residual thrombus.