22例获得性血友病A患者的临床特点及预后

Clinical features and prognosis of 22 patients with acquired hemophilia A

目的探讨获得性血友病A(AHA)患者的临床特点及治疗结局。方法AHA患者22例为研究对象,收集一般临床资料(人口统计学数据、基础疾病、出血部位及发病至确诊时间等);抽取AHA患者空腹静脉全血,采用凝血分析仪检测凝血功能指标[凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)、凝血酶时间(TT)、纤维蛋白原(FIB)及国际标准化比值(INR)],采用Bethesda法检测血浆凝血因子抗体并确定高低抗体滴度、凝血分析仪检测凝血因子Ⅷ活性(FⅧ:C)及判断减低程度;所有患者行人重组活化凝血因子Ⅶ(rFⅦa)、凝血酶原复合物(PCC)及1-去氨基-8-d-精氨酸血管加压素(DDAVP)等一般止血治疗及相关的清除抗体治疗[糖皮质激素(GC)单用或联合环磷酰胺(CTX),利妥昔单抗(RTX)单用或联合GC或其他免疫抑制剂如环孢素(CsA)、他克莫司(FK506)等]治疗并随访收集患者治疗、生存情况、出血情况、血常规、FⅧ抗体滴度变化、抗体清除时间、治疗相关不良事件及死因等。结果22例AHA患者男女比例为1∶2.14,起病中位年龄59.95岁;有出血表现19例,严重出血13例;诊断时FⅧ∶C中位数1.37%、FⅧ抗体平均滴度6.9×10^(-3) BU/L,高滴度FⅧ抗体组和低滴度FⅧ抗体组AHA患者出血严重程度比较、差异有统计学意义(P<0.05);rFⅦa治疗11例,低滴度抗体者加大剂量FⅧ治疗4例;使用免疫抑制清除抗体治疗15例,抗体清除患者10例,平均抗体转阴时间(47.3±14.4)d,死亡4例;GC组、GC+CTX组及GC+其他药物组AHA患者的抗体清除时间比较,差异有统计学意义(P<0.05);AHA患者出现3级以上骨髓抑制8例,感染5例,库欣综合征1例。结论AHA以育龄期女性为主,出血是其主要临床表现;高滴度抗体患者及FⅧ活性重度减低患者更容易出现严重出血;止血首选rFⅦa或PCC旁路替代治疗,清除抗体可使用GC或者GC+免疫抑制剂治疗。

Objective To investigate the clinical features and treatment outcomes of patients with acquired hemophilia A(AHA).Methods Twenty-two patients with AHA were selected as the study objects.General clinical data(demographic data,underlying disease,bleeding site,time from onset to diagnosis,etc.)were collected.Fasting venous whole blood of AHA patients was collected,and the index of coagulation function was detected by coagulation analyzer,including prothrombin time(PT),activated partial thromboplastin time(APTT),thrombin time(TT),fibrinogen(FIB),and international normalized ratio(INR);Bethesda method was used to detect plasma coagulation factor antibodies and determine high and low antibody titers,and coagulation analyzer was used to detect coagulation factor Ⅷ activity(FⅧ∶C)and determine the degree of reduction;All patients received general hemostatic treatment such as recombinant activated coagulation factorⅦ(rFⅦ),prothrombin complex(PCC),1-deamino-8-D-arginine vasopressin(DDAVP),and related alone or inantibody-scavenging therapy[glucocorticoid(GC)alone or combined with cyclophosphamide(CTX),Rituximab combination with glucocorticoids or other immunosuppressants cyclosporine(CsA),tacrolimus(FK506),etc.];After discharge,all the patients were followed up and the treatment,survival,bleeding,blood routine,change of FⅧ antibody titers,antibody clearance time,treatment-related adverse events and cause of death were collected.Results Among 22 cases involved in the study,the male-female ratio was 1∶2.14 and a median age of onset was 59.95 years.There were 19 cases of hemorrhage,and 13 cases had severe bleeding.When diagnosing,median of FⅧ∶C was 1.37%,median FⅧ antibody titer 6.9×10^(-3) BU/L.There was statistical difference in the comparison of bleeding severity between the high-and low-titer FⅧ antibody groups(P<0.05).rFⅦwas adopted in 11 cases,and FⅧ treatment in 4 cases with low titer antibody.Out of the 15 cases(68.2%)treated with immunosuppressive antibody clearance therapy,antibody was cleared up in 10 cases(66.7%),and the average time of antibody turning negative was(47.3±14.4)d,and 4 cases died(18.2%).There was statistical difference in the comparison of antibody clearance time among GC group,GC+CTX group,and GC+other drugs group were statistically significant(P<0.05).There were 8 AHA cases of myelosuppression of grade Ⅲ and above,5 case of infection,Cushing's syndrome occurred in 1 case.Conclusion AHA appears mainly in women of reproductive age,and invasive bleeding is the main clinical manifestation.Patients with high titer antibody and patients with reduced severity of FⅧ activity are more prone to suffer from severe bleeding.The first choice for hemostasis is rFⅦ or PCC bypass replacement therapy,and glucocorticoid or glucocorticoid+immunosuppressive therapy can be used to clear up antibodies.