Fibrinogen is essential for haemostasis and can fall to critically low levels in acute haemorrhage [1]. The long turnaround time for laboratory Clauss fibrinogen has led to interest in point-of-care viscoelastic haemostatic assays to identify hypofibrinogenemia. The ROTEM® Delta and Sigma devices (Werfen, Warrington, UK) offer the FIBTEM assay to assess fibrinogen contribution to clot strength in whole blood. FIBTEM A5, the amplitude 5 min after the clotting time, is used as a surrogate for the Clauss fibrinogen in management algorithms [2, 3]. The original FIBTEM assay used Cytochalasin D to inhibit platelets although inhibition was found to be partially influenced by the platelet count [4]. Tirofiban, a glycoprotein 2b/3a receptor antagonist, was added to reduce the influence of platelets and the dual platelet-inhibited assay received regulatory approval in 2022 [5].

Guidelines recommend that fibrinogen levels should be maintained > 2 g.l^-1 [6, 7] in obstetric haemorrhage. Since 2017, management of postpartum haemorrhage in Wales has followed the OBS Cymru ROTEM® algorithm [3] with a FIBTEM A5 > 11 mm corresponding to a Clauss fibrinogen of approximately 2 g.l^-1. In April 2023, Sigma cartridges with the dual platelet-inhibited FIBTEM assay were distributed in the UK. Clinicians at our institution became aware of this change in July 2024 following anecdotal observations of an altered relationship between FIBTEM A5 and Clauss fibrinogen, and discussions with the manufacturer.

Following local service evaluation registration, anonymised data were collected retrospectively from five obstetric units in Wales using the dual platelet-inhibited FIBTEM assay. In total, 212 paired FIBTEM and Clauss fibrinogen results were available for analysis with some patients having more than one sample during a single postpartum haemorrhage episode. Four samples from a patient with severe liver impairment were excluded. The utility of the dual platelet-inhibited FIBTEM A5 to distinguish Clauss fibrinogen ≤ 2 g.l^-1 was analysed. Fibrinogen ≤ 2 g.l^-1 is uncommon during postpartum haemorrhage and to obtain sufficient data around this level, purposive data collection was necessary (Fig. 1). Comparison was made with data from a previous study which used single platelet-inhibited Sigma FIBTEM assays [1].

There was a stronger linear correlation between FIBTEM A5 and Clauss fibrinogen (r = 0.88) (Fig. 1) in the dual platelet-inhibited FIBTEM assay compared with data from a single platelet-inhibited assay (r = 0.63) [8]. With the dual platelet-inhibited assay, FIBTEM A5 of 11 mm (as used in the algorithm with the single platelet-inhibited assay [3]) corresponded to a Clauss fibrinogen of 3.05 g.l^-1, while FIBTEM A5 of 7.8 mm corresponded to a Clauss fibrinogen of 2 g.l^-1. The area under the receiver operating characteristic curve for FIBTEM A5 to detect fibrinogen ≤ 2 g.l^-1, and sensitivity and specificity of FIBTEM A5 at different intervention points were compared between single and dual platelet-inhibited assays (Table 1). With the dual platelet-inhibited assay, a FIBTEM A5 ≤ 11 mm identified all patients with fibrinogen ≤ 2 g.l^-1, however of the 191/208 cases with fibrinogen > 2 g.l^-1, 71 had FIBTEM ≤ 11 mm and may have been inappropriately administered fibrinogen replacement therapy. With the dual platelet-inhibited assay, a threshold of FIBTEM A5 ≤ 8 mm showed near identical positive and negative predictive values to the intervention point of ≤ 11 mm with the single platelet-inhibited FIBTEM assay (Table 1). The OBS Cymru algorithm has been updated accordingly (online Supporting Information Figure S1).

The correlation between Clauss fibrinogen and FIBTEM A5 was stronger with the dual platelet-inhibited assay when compared with the single platelet-inhibited assay. We hypothesise that the enhanced platelet inhibition makes the FIBTEM assay more dependent on fibrinogen and hence a more useful surrogate marker. The change from a single to a dual platelet-inhibited FIBTEM assay could not have been detected by internal quality control or external quality assurance because these use plasma-based reagents, rather than whole blood. The difference in platelet inhibition was not detected because platelets are not present in the plasma-based reagents. This emphasises the importance of pairing laboratory and point-of-care coagulation tests to monitor device performance. The manufacturer previously compared the clinical performance of the ROTEM® Sigma FIBTEM assay (with dual platelet inhibition) and the ROTEM Delta FIBTEM assay (with single platelet inhibition) in patients undergoing cardiac and liver surgery and found a mean bias of -1.5 to -1.8 mm for FIBTEM A5 of 12 mm [5]. The change in the Sigma FIBTEM assay may also have implications for sites that use the formula ‘EXTEM amplitude minus FIBTEM amplitude’ to guide platelet transfusion, with the potential for under transfusion. These considerations do not apply to the Delta FIBTEM because the assay has not changed. Further validation is urgently required to assess the impact of the dual platelet-inhibited Sigma FIBTEM assay in other clinical settings. We highlight the importance of communicating all updates to point-of-care devices and reagents to end users so that the impact in different settings can be fully evaluated.

纤维蛋白原对止血至关重要，在急性出血时可降至极低水平 [1]。实验室克劳斯纤维蛋白原的较长周转时间导致人们对即时粘弹性止血测定以识别低纤维蛋白原血症的兴趣。ROTEM® Delta 和 Sigma 设备（Werfen，Warrington，UK）提供 FIBTEM 检测，以评估纤维蛋白原对全血凝块强度的贡献。FIBTEM A5 是凝血时间后 5 分钟的振幅，在管理算法中用作 Clauss 纤维蛋白原的替代物 [2， 3]。最初的 FIBTEM 检测使用细胞松弛素 D 来抑制血小板，尽管发现抑制部分受血小板计数的影响 [4]。添加 Tirofiban 是一种糖蛋白 2b/3a 受体拮抗剂，以减少血小板的影响，双重血小板抑制测定于 2022 年获得监管批准 [5]。

指南建议，在产科出血时，纤维蛋白原水平应维持在 > 2 ^g.l-1 [6， 7]。自 2017 年以来，威尔士的产后出血管理一直遵循 OBS Cymru ROTEM® 算法 [3]，其中 FIBTEM A5 > 11 mm 对应于约 2 g.l-1 的克劳斯纤维蛋白原。2023 年 4 月，具有双重血小板抑制 FIBTEM 测定的 Sigma 卡夹在英国分发。我们机构的临床医生在 2024 年 7 月对 FIBTEM A5 和 Clauss 纤维蛋白原之间关系发生变化的轶事观察并与制造商讨论后意识到了这一变化。

在本地服务评估注册后，使用双重血小板抑制 FIBTEM 测定从威尔士的 5 个产科病房回顾性收集匿名数据。总共有 212 对 FIBTEM 和 Clauss 纤维蛋白原结果可用于分析，其中一些患者在一次产后出血发作期间有多个样本。排除了来自一名严重肝功能损害患者的 4 个样本。分析了双重血小板抑制的 FIBTEM A5 区分克劳斯纤维蛋白原 ≤ 2 ^g.l-1 的效用。纤维蛋白原 ≤ 2 ^g.l-1 在产后出血期间不常见，为了获得有关该水平的足够数据，有必要进行有目的的数据收集（图 1）。与先前使用单血小板抑制 Sigma FIBTEM 测定的研究数据进行了比较 [1]。

与单血小板抑制测定 （r = 0.63） 的数据相比，在双重血小板抑制 FIBTEM 测定中，FIBTEM A5 和克劳斯纤维蛋白原 （r = 0.88） （图 1） 之间存在更强的线性相关性 [8]。在双重血小板抑制测定中，11 mm 的 FIBTEM A5（在单血小板抑制测定的算法中使用 [3]）对应于 3.05 g.l-1 的克劳斯纤维蛋白原，而 7.8 mm 的 FIBTEM A5 对应于 2 g.l-1 的克劳斯纤维蛋白原。比较单血小板和双血小板抑制测定之间 FIBTEM A5 检测纤维蛋白原≤ 2 ^g.l-1 的受试者工作特征曲线下面积，以及 FIBTEM A5 在不同干预点的敏感性和特异性（表1）。通过双重血小板抑制试验，≤ 11 mm 的 FIBTEM A5 确定了所有纤维蛋白原≤ 2 ^g.l-1 的患者，然而，在 191/208 例纤维蛋白原 > 2 g.l-1 的病例中，71 例 FIBTEM ≤ 11 mm，可能接受了纤维蛋白原替代疗法的不当给药。在双重血小板抑制测定中，FIBTEM A5 阈值≤ 8 mm 显示出与单血小板抑制 FIBTEM 测定的 ≤ 11 mm 干预点几乎相同的阳性和阴性预测值（表 1）。OBS Cymru 算法已相应地更新（在线支持信息图 S1）。

与单血小板抑制测定相比，双重血小板抑制测定法 Clauss 纤维蛋白原和 FIBTEM A5 之间的相关性更强。我们假设增强的血小板抑制使 FIBTEM 测定更依赖于纤维蛋白原，因此是更有用的替代标志物。内部质量控制或外部质量保证无法检测到从单血小板抑制到双血小板抑制 FIBTEM 测定的变化，因为这些使用基于血浆的试剂，而不是全血。未检测到血小板抑制的差异，因为血浆试剂中不存在血小板。这强调了将实验室和床旁凝血试验配对以监测器械性能的重要性。制造商之前在接受心脏和肝脏手术的患者中比较了 ROTEM® Sigma FIBTEM 测定（双重血小板抑制）和 ROTEM Delta FIBTEM 测定（单次血小板抑制）的临床性能，发现 FIBTEM A5 的平均偏倚为 -1.5 至 -1.8 mm[5]。Sigma FIBTEM 检测的变化也可能对使用公式“EXTEM 振幅减去 FIBTEM 振幅”来指导血小板输注的部位产生影响，并可能导致输血不足。这些注意事项不适用于 Delta FIBTEM，因为测定没有改变。迫切需要进一步验证以评估双重血小板抑制 Sigma FIBTEM 测定在其他临床环境中的影响。我们强调了将床旁设备和试剂的所有更新传达给最终用户的重要性，以便可以充分评估在不同环境中的影响。