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JAMA Diagnostic Test Interpretation

September 14, 2018

Coagulation Test Interpretation in a Patient Taking Direct Oral Anticoagulant Therapy

Michelle Sholzberg, Yan Xu

JAMA. 2018;320(14):1485-1486. doi:10.1001/jama.2018.13998

Case 病例

74-year-old man presented with spontaneous, acute onset of confusion and headache. He had no preceding head trauma or falls. He had a history of atrial fibrillation with an annual stroke risk of 2.9% (based on points accrued for hypertension and age ≥65 years using the CHA2DS2-VASc score1). He was being treated with rivaroxaban, 20 mg daily. He took his last dose 14 hours prior to presentation. Other medications included ramipril and rosuvastatin.

一名74岁男性患者因急性起病的自发性意识模糊及头痛就诊。患者无颅脑外伤或摔倒病史。患者有房颤病史,年卒中风险为2.9%(根据CHA2DS2-VASc评分,高血压及年龄 ≥65岁)。患者服用利伐沙班20 mg qd,最后一次服药在就诊前14小时。其他药物包括雷米普利(ramipril)和瑞舒伐他汀(rosuvastatin)。

On physical examination, the patient’s blood pressure was 157/96 mm Hg, heart rate was 72/min, and Glasgow Coma Scale score was 14 (range, 3-15 with 15 indicating best neurological status). Head computed tomogram (CT) showed a 2.5-cm left-sided acute subdural hematoma with mass effect. He required urgent surgical evacuation and the neurosurgical team requested advice regarding his perioperative bleeding risk prior to surgery. Laboratory test results are shown in the Table.

体格检查发现,患者血压157/96 mm Hg,心率72/min,格拉斯哥昏迷评分14分(范围,3-15,15分提示最佳神经系统状态)。头颅CT显示左侧2.5-cm急性硬膜下血肿伴占位效应。患者急需手术治疗,神经外科医生要求术前评估围手术期出血风险。实验室检查结果见下表。




Discussion 讨论

Answer 答案

B. The patient’s hemostatic status is not appropriate for surgery because the abnormal PT suggests anticoagulant effect from rivaroxaban.


Test Characteristics 检查特征

Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are clot-based tests that measure the length of time required for thrombus formation in the presence of specific reagents. PT measures the activity of extrinsic (factor VII) and common (factors II, V, X) coagulation pathways and was originally introduced for monitoring vitamin K antagonist therapy (eg, warfarin).2 aPTT measures the activity of intrinsic (factors VIII, IX, XI, and XII) and common coagulation pathways and was developed as a preoperative screen for hemophilia in high-risk individuals, but later validated for monitoring therapy with unfractionated heparin.3


Direct oral anticoagulants (DOACs) dabigatran, rivaroxaban, apixaban, and edoxaban have reliable pharmacokinetics and are not affected by vitamin K intake. Therefore, unlike warfarin, they do not require coagulation test monitoring. Moreover, DOACs have short half-lives (from 7 to 20 hours), which is an additional advantage relative to warfarin in emergency settings.


Measuring the anticoagulant effect of DOACs can be useful in certain circumstances (eg, major bleeding or need for emergency invasive procedures) to inform the need for therapies to reestablish hemostasis. Based on pharmacokinetic studies, an elevated PT suggests the circulating effect of a direct Xa inhibitor (agents approved by the Food and Drug Administration [FDA] include rivaroxaban, apixaban, and edoxaban), while an elevated aPTT suggests the effect of dabigatran, a direct thrombin inhibitor, in patients receiving therapy.4 However, sensitivity of the PT to detect clinically relevant anticoagulant effect from rivaroxaban is 74% (95% CI, 70%-78%) and for apixaban is 56% (95% CI, 47%-64%).5There is substantial variability in assay sensitivity depending on the PT reagent used.4 aPTT has higher sensitivity for dabigatran effect (sensitivity, 98% [95% CI, 89%-100%]),5 but is not helpful in detecting the effect of direct Xa inhibitors. While PT and aPTT can help qualitatively assess the presence of DOAC effect, these results cannot be used to distinguish therapeutic vs supratherapeutic effects.

测定DOACs的抗凝效果在某些情况下(如大出血或需要急诊有创操作)可用于确定是否需要治疗重建止血。根据药代动力学研究,PT延长提示直接Xa抑制剂(FDA批准的药物包括利伐沙班、阿派沙班和依杜沙班)的疗效,而aPTT延长提示直接凝血酶抑制剂达比加群的疗效。然而,PT监测利伐沙班临床抗凝效果的敏感性仅为74% (95% CI, 70%-78%),监测阿派沙班抗凝效果的敏感性为56% (95% CI, 47%-64%)。根据使用的PT试剂不同,试验敏感性呈现显著差异。aPTT监测达比加群疗效敏感性较高(敏感性98% [95% CI, 89%-100%]),但无助于监测Xa直接抑制剂疗效。PT和aPTT能够定量评估是否存在DOAC疗效,而不能用于鉴别治疗及超治疗效果。

According to the Medicare fee schedule, PT costs $7.29 and aPTT costs $11.13.


Application to This Patient 在此患者的应用

The elevated PT suggests anticoagulant effect from rivaroxaban at the time of testing. The PT test result, combined with the patient’s clinical presentation and need for urgent surgery, imply that he would benefit from coagulation factors and antifibrinolytics, or a specific reversal agent to restore hemostasis. Although administration of prohemostatic agents for correcting DOAC-associated coagulopathy are recommended for life-threatening or major bleeding,6 it is considered an off-label indication. Andexanet alfa was recently approved by the FDA for the reversal of direct factor Xa inhibitors. Careful consideration of patient- and context-specific variables, such as severity of bleeding and risk of thromboembolism, is important to maximize its appropriate use.

PT延长提示利伐沙班的抗凝效果。PT检查结果结合患者临床表现以及急诊手术的需求,提示患者可能获益于凝血因子和抗纤溶药物,或特异性拮抗药物恢复止血。在致命性出血或大出血时,推荐使用促止血药物纠正DOAC相关凝血异常。尽管如此,这仍然属于超适应症使用。近期,FDA批准Andexanet alfa用于逆转直接Xa因子抑制剂的作用。谨慎考虑患者及疾病特异性指标(如出血严重程度及血栓栓塞风险),对于最大程度恰当使用Andexanet alfa至关重要。

The patient’s kidney and hepatic function were normal, which is important because kidney and hepatic dysfunction can prolong the elimination half-life of DOACs. Also, the patient is not taking any medications that affect rivaroxaban metabolism. Specifically, inhibitors of p-glycoprotein (eg, verapamil, dronedarone) and CYP3A4 (eg, ritonavir) can prolong elimination half-life.7


The timing of the last dose must also be considered in assessing patients presenting with DOAC-associated bleeding; rivaroxaban reaches peak plasma concentration 2 to 3 hours following ingestion based on pharmacokinetic studies.8 Therefore, coagulation parameters can be falsely normal before complete systemic absorption has occurred, which is particularly important to consider in cases of intentional or accidental overdose. This patient took his last dose of rivaroxaban 14 hours prior to presentation, which is beyond the 9- to 12-hour window when plasma DOAC levels are expected to decline meaningfully. Repeated coagulation testing, however, may be indicated when timing of last ingestion is unclear, or to assess for a continued anticoagulant effect due to redistribution of DOAC from the extravascular space following drug reversal.


What Are Alternative Diagnostic Testing Approaches? 有无其他诊断检查?

An anti-Xa assay using a drug-specific calibrator provides estimated plasma levels of direct Xa inhibitors.9 In this test, patient plasma is added to a colorimetric commercial reagent in the presence of activated factor X, the target of direct Xa inhibitors. Similarly, the dilute thrombin time provides an estimation of plasma drug level for dabigatran. Where available, these tests should be used in the setting of major bleeding in patients taking a DOAC. In general, plasma drug levels of any DOAC below 30 ng/mL derived by the anti-Xa assay or dilute thrombin time suggest absence of a significant anticoagulant effect.6

根据药物特异性参标进行抗Xa分析可以估测直接Xa抑制剂的血浆水平。抗Xa检测时,在有活化X因子(直接Xa抑制剂的靶点)的情况下,将患者血浆加入显色试剂。与此相似,稀释凝血酶时间能够估测达比加群血浆浓度。这些检查可用于服用DOAC患者大出血时的评估。总之,根据抗Xa检测或稀释凝血酶时间估测的任何DOAC血浆浓度低于30 ng/ml时,提示没有显著的抗凝作用。

If the dilute thrombin time is not available, the thrombin clotting time, a common coagulation test that is highly sensitive (100%) to dabigatran, can be used to exclude its effect. However, an elevated thrombin clotting time cannot distinguish between clinically relevant or insignificant dabigatran levels.10 Of note, while the thrombin clotting time is sensitive to direct thrombin inhibitors, it is not useful for the detection of direct Xa inhibitor effect such as the effect of rivaroxaban or apixaban.


Patient Outcomes 患者预后

Anti-Xa assay for rivaroxaban was obtained and reported at 167.5 ng/mL (>30 ng/mL suggests rivaroxaban effect). A specific, on-label reversal agent was not available. Therefore, the patient received prothrombin complex concentrate at a dose of 2000 IU and tranexamic acid (an antifibrinolytic agent) at 1 g given the severity of bleeding, timing of last rivaroxaban dose, and need for urgent surgery. The surgeons proceeded with an uncomplicated neurosurgical intervention. Postoperative CT scan showed improvement of the subdural hematoma, the patient’s symptoms resolved over the following few days, and he was discharged home. His neurological status remained stable 1 month later. Using a shared decision model, it was decided to continue withholding anticoagulation and reevaluate antithrombotic therapy at a future appointment.

测定了利伐沙班的抗Xa检测,结果为 167.5 ng/mL(> 30 ng/mL提示存在利伐沙班疗效)。目前还没有经过批准的特异性逆转药物。因此,考虑到出血严重程度,利伐沙班的最后用药时间以及需要急诊手术的情况,患者接受了凝血酶原复合物2000 IU输注及氨甲环酸(抗纤溶药物)1 g。神经外科手术非常顺利。术后CT显示硬膜下血肿改善,此后数日患者症状消失,遂出院回家。1个月后,患者神经系统状态维持稳定。经与患者共同商议,决定继续停用抗凝药物,在随访期间重新对抗栓治疗进行评估。

Clinical Bottom Line 临床要点

An elevated PT for anti-Xa inhibitors and an elevated aPTT for dabigatran suggest clinically relevant drug effect at the time of testing.


DOAC-specific coagulation tests such as anti-Xa assay and dilute thrombin time may help guide clinical decisions in bleeding patients or in those requiring urgent surgery.


Up to 50% of people taking a direct Xa inhibitor with clinically relevant anticoagulation effect can have a normal PT. Therefore, normal PT results cannot be used to rule out the presence of circulating rivaroxaban, apixaban, or edoxaban effect.


Timing of last DOAC ingestion needs to be considered. Information on the time of the last dose, dosage taken, and the half-life of the drug are important in interpreting coagulation test results.


Serial coagulation test results can be useful when evaluating a patient with DOAC-associated bleeding, especially when the timing of last dose is unknown or following drug reversal.



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