Department of Hematology/Oncology, Sint Franciscus Gasthuis, Rotterdam.
Clinical Trial Center - HOVON Data Center, Erasmus MC, Rotterdam; The Netherlands.
Thromb Res. 2016 Apr;140 Suppl 1:S172. doi: 10.1016/S0049-3848(16)30127-X. Epub 2016 Apr 8.
Acute myeloid leukemia (AML) is associated with a slightly increased risk of VTE with an incidence of 1.7-8.9%, but only limited data are available. The mechanism of the occurrence of thrombosis in hematological disorders is still unresolved. Disseminated intravascular coagulation (DIC) is associated with VTE and bleeding in acute promyelocytic leukemia and acute lymphoblastic leukemia. Although DIC has also been reported in AML, no data exist on the relationship between DIC and VTE in AML patients.
We hypothesized that the presence of DIC at diagnosis of AML may contribute to the risk of both venous and arterial thrombosis in AML. Therefore we studied a large cohort of adult patients with newly diagnosed AML aged <65 years by measuring DIC parameters at diagnosis prior to treatment and assessing the occurrence of both venous and arterial thrombosis during follow up. The findings of this study were validated in a second large cohort of patient with newly diagnosed AML aged >60 years.
In a prospective study we analysed markers of DIC and their association with the occurrence of thrombosis during follow up in a cohort of 272 young AML patients (aged 18-65) and a validation cohort of 132 elderly AML patients (aged >60) patients that were all treated with intensive chemotherapy. DIC parameters (fibrinogen, D-dimer, alpha-2-antiplasmin, antitrombin, prothrombin time and platelets) were measured at presentation with AML before start of induction chemotherapy. The DIC score according to the International Society of Thrombosis and Haemostasis DIC scoring systemwas calculated of all patients.
The prevalence of thrombosis was 8.7% (4.7% venous, 4.0% arterial) in young patients over a median follow up of 478 days and 10.4% (4.4% venous, 5.9% arterial) in elderly patients. Most thrombotic events (66%) occurred before start of the second course of chemotherapy. The calculated DIC score significantly predicted venous and arterial thrombosis with a Hazard Ratio (HR) for a high DIC score (=>5) of 4.79 (1.71-13.45) in the cohort of young AML patients. These results were confirmed in our validation cohort of elderly AML patients. (HR 11.08 (3.23-38.06)). Of all DIC parameters D-dimer levels are most predictive for thrombosis with a HR of 12.3 (3.39-42.64) in the cohort of young AML patients and a HR of 7.82 (1.95-31.38) in the elderly cohort for a D-dimer >4.0 mg/L.
It is concluded that both venous and arterial thrombosis occurs in around 10% of AML patients treated with intensive chemotherapy, which can be predicted by the presence of DIC, or individual DIC parameters at time of AML diagnosis.
急性髓系白血病（AML）与静脉血栓栓塞症（VTE）的风险略有增加，发生率为 1.7-8.9%，但目前仅有有限的数据。血液系统疾病中血栓形成的发生机制仍未解决。弥散性血管内凝血（DIC）与急性早幼粒细胞白血病和急性淋巴细胞白血病中的 VTE 和出血相关。尽管在 AML 中也报道了 DIC，但在 AML 患者中，DIC 与 VTE 之间的关系尚无数据。
我们假设 AML 诊断时存在 DIC 可能会增加 AML 患者静脉和动脉血栓形成的风险。因此，我们通过在治疗前测量新诊断的<65 岁 AML 成年患者的 DIC 参数，并在随访期间评估静脉和动脉血栓形成的发生情况，对 272 名年轻 AML 患者（年龄 18-65 岁）和 132 名新诊断的 AML 患者（年龄>60 岁）进行了研究。所有患者均接受强化化疗。在一项前瞻性研究中，我们分析了年轻 AML 患者队列（272 名患者）和年龄较大的 AML 患者队列（132 名患者）中 DIC 标志物及其与随访期间血栓形成的相关性。所有患者在诱导化疗前均进行了 AML 诊断时的 DIC 参数（纤维蛋白原、D-二聚体、α-2-抗纤溶酶、抗凝血酶、凝血酶原时间和血小板）检测。根据国际血栓和止血学会 DIC 评分系统计算了所有患者的 DIC 评分。
年轻患者中位随访 478 天，血栓形成发生率为 8.7%（4.7%静脉血栓形成，4.0%动脉血栓形成），老年患者为 10.4%（4.4%静脉血栓形成，5.9%动脉血栓形成）。大多数血栓形成事件（66%）发生在第二疗程化疗开始之前。计算出的 DIC 评分显著预测静脉和动脉血栓形成，在年轻 AML 患者队列中，DIC 评分高（>5）的危险比（HR）为 4.79（1.71-13.45）。这些结果在我们对年龄较大的 AML 患者队列的验证中得到了证实。（HR 11.08（3.23-38.06））。在所有 DIC 参数中，D-二聚体水平对血栓形成最具预测性，在年轻 AML 患者队列中 HR 为 12.3（3.39-42.64），在老年队列中 HR 为 7.82（1.95-31.38））D-二聚体>4.0mg/L。
接受强化化疗的 AML 患者中约有 10%发生静脉和动脉血栓形成，可通过 AML 诊断时 DIC 的存在或单个 DIC 参数来预测。
