A near-patient approach to combat post-partum hemorrhage

by Catherine Pedrosa

Fibrinogen is an essential part of the blood clotting process, and rapid testing of plasma fibrinogen concentrations aids decision-making in critical care situations, notably in postpartum hemorrhage. In 2020, around 1000 women in the World Health Organization European Region died owing to complications related to pregnancy or childbirth. A recently introduced point-of-care testing system now brings this facility to the near-patient setting, but, for such a vital test, accuracy and quality control are key.

Background
Fibrinogen is crucial for clot formation and has a significant impact on clinical outcomes when major bleeding occurs. Low plasma levels of functional fibrinogen are linked to inherited or acquired fibrinogen deficiency (perioperative bleeding, trauma, liver disease, abnormal fibrinolysis). Reduced levels are also the first sign of post-partum hemorrhage (PPH), the leading cause of maternal deaths during childbirth worldwide [1].

Fibrinogen is a glycoprotein synthesized in the liver and normally present at a concentration of 2–4 g/L in plasma. In the third trimester of pregnancy, higher levels (>5 g/L) can be observed. As part of the coagulation process, fibrinogen is cleaved by thrombin into fibrin monomers that, in the presence of factor XIII, are stabilized to produce the insoluble cross-linked polymer responsible for successful hemostasis.

It is no surprise, therefore, that the assessment of coagulation status, and fibrinogen testing in particular, is a prime candidate for the application of point-of-care testing (POCT). It provides several benefits for patients and also the healthcare service in general, as it aids clinical decision-making when clinicians are faced with critical hemorrhage, resulting in the need for immediate patient management and treatment.

It is recognized that PPH can be exacerbated by coagulopathy, where a decline in fibrinogen levels is known to be the first indicator of the condition. However, the clinical utility of laboratory fibrinogen testing to predict PPH progression represents a challenge because ‘time to results’ can be 60–90 minutes. Faced with PPH, this can be too long to wait. The bleed will either have stopped or results are retrospective, with the clinician having relied on empirical transfusion ratios.

The ability to monitor fibrinogen levels at the point of care within 2–10 minutes would enable clinicians to deliver early, targeted fibrinogen replacement that might stem the progression of hemorrhage. It is equally important to be able to monitor and inter-
pret other coagulation parameters at the same time, as research shows that replacing fibrinogen will not improve outcomes if levels are normal [2].

One of the barriers to understanding PPH incidence and its risk factors is the lack of a universal definition. Depending on the country or the guideline, PPH may have a different definition. For example, in the UK, PPH is defined as blood loss ≥500 mL within 24 hours of vaginal delivery, or ≥1000 mL after Caesarean-section delivery. Blood loss that is severe (>2000 mL) or massive (>2500 mL) is defined irrespective of the means of delivery [3].

Post-partum haemorrhage and fibrinogen

Figure 1. Relationship between post-partum hemorrhage and plasma fibrinogen concentration

Observational findings from two 10-year French studies have shown that fibrinogen below 2.0 g/L has a positive predictive value of 100% for PPH, and a negative predictive value of 79% if concentration is >4.0 g/L [4]. The studies also indicated that the fibrinogen level was associated with the severity of PPH, with adjusted odds ratios of 1.90 for fibrinogen between 2 and 3 g/L and 11.99 for fibrinogen below 2.0 g/L (Fig. 1) [5].

Data also showed that it was possible to achieve a 60% reduction in bleeding of more than 2500 mL and a fall in the number of hysterectomies required and intensive care unit admissions. From the laboratory perspective, there was a 30% reduction in the use of blood products [6].

The study’s overall aim was to find ways to improve maternal outcomes by assessing the value of POCT and to investigate the role of fibrinogen as a marker for increasing PPH [7]. Its findings have already led to new risk assessment strategies [8]. These start with the need to make an early, formal risk assessment of every patient, and it recommends that multidisciplinary clinical care is available at the point of care when blood loss reaches 1000 mL.

Patient blood management and POCT

The near-patient testing role in patient blood management (PBM) was one of the issues covered in a recent satellite symposium convened by the Network for the Advancement of Patient Blood Management, Haemostasis and Thrombosis (NATA), supported by iSEP and HemoSonics International, part of global hemostasis experts, Diagnostica Stago.

In a presentation given by Donat Spahn, from the Institute of Anesthesiology, University Hospital of Zürich, Switzerland, the benefits of PBM programmes were discussed, one of which was the use of POCT systems. These have been shown to decrease the use of allogeneic blood transfusion, with its associated costs and adverse events [9]. Identification of these benefits prompted the World Health Organization (WHO) to issue a policy brief in 2021 on the urgent need to implement PBM in all member states [10].

Aiding rapid decision-making

Clinicians need to know as quickly as possible if fibrinogen products have to be administered to manage coagulopathic bleeds due to hypofibrinogenemia during PPH. There was therefore urgent need for a ‘rapid and reliable’ measurement of functional fibrinogen levels from citrated whole blood.

Crucially, any near-patient solution had to compare well to the gold standard laboratory reference (Clauss) method, as well as being easy to use. In addition, built-in quality control (QC) was required to satisfy laboratory standards for consistency and reproducibility.

The launch of a novel POCT solution (qLabs FIB Monitoring system) has been developed specifically to address these concerns, taking near-patient testing solutions to a new level of accuracy and speed. It measures fibrinogen levels from a single drop of whole blood in ≤10 minutes, with a hands-on time of <60 seconds. Further, the lower a patient’s fibrinogen level, the faster it delivers the result. The time saved when using this type of innovative point-of-care device compared to the time involved in sending a sample to the laboratory and waiting for a fibrinogen result is significant. Long laboratory turnaround times can result in inappropriate or unnecessary allogeneic blood product transfusion, which may lead to further clinical complications for the patient.

Strong correlation with laboratory testing

In an article by Sanfilippo et al., published earlier this year in the journal Thrombosis Research [11], Diagnostica Stago’s scientific experts and independent laboratory scientists in France reported on the measurement of fibrinogen concentrations from 110 citrated whole blood specimens, using both the qLabs FIB and the Clauss laboratory reference methods (STA-Liquid Fib assay on STA-R Max; Stago) (Fig. 2).

Figure 2. qLabs FIB test shows a strong correlation with Stago’s STA-Liquid Fib Correlation coefficient of 0.95, an intercept of 0.02 and a slope of 0.99 (n=110). The overall coefficient of variation (CV) is 7%.

This study aimed to assess analytical performances of qLabs FIB through a comparison study with the Clauss laboratory method and the precision (reproducibility and repeatability) of the qLabs FIB using plasma QC material. In addition, single-site assays were conducted to assess the repeatability from citrated whole blood specimen covering the device’s reportable range.

A very strong correlation between the new device and the Clauss laboratory reference method was observed (r=0.95). Using a clinical cut-off value of 2.0 g/L, the area under the receiver operating characteristic curve of citrated whole blood was 0.99, and sensitivity and specificity were 100% and 93.5%, respectively.

Percentage coefficients of variation (CVs) for both reproducibility and repeatability assessed from QC material were <5%. Repeatability assessed from citrated whole blood specimen showed a CV of 2.6–6.5%. The authors concluded that the device would enable a rapid and reliable measurement of functional fibrinogen levels from citrated whole blood, exhibiting a strong prediction power at the 2 g/L clinical cut-off when compared to the Clauss laboratory reference. It also indicated that further clinical studies would be useful to demonstrate its ability to quickly confirm the diagnosis of acquired hypofibrinogenemia and help to identify other patients who may benefit from targeted hemostatic treatment.

Figure 3. qLabs FIB testing process

Technology overview

The qLabs FIB system consists of an ElectroMeter and dry-reagent test strips. The insertion of a test strip activates the process which then heats the strip to a preset operating temperature. When a drop of blood is added to the sample well, the blood flows through the test channels to the two reaction zones. Here, the blood reacts with pre-coated reagent (human thrombin) and begins to coagulate. Each reading zone contains a pair of electrodes to which a constant voltage is applied by the ElectroMeter. This detects the change of the current voltage in the test zone and determines the fibrinogen result based on the migration time (the lower a patient’s fibrinogen level, the faster the result is delivered) (Fig. 3).

The coating on the dry-reagent strips includes polybrene to inhibit heparin and abciximab to inhibit platelet aggregation. The strips are therefore insensitive to a platelet count as well as heparin therapy. They can be stored at room temperature for immediate use and have a shelf life of up to 24 months. The system includes lyophilized bi-level QC material; a touchscreen handheld rapid testing platform with the option of an eStation II docking system; and an inbuilt barcode scanner plus a communications port for printers and computer networks.

QC and governance

Studies show that POCT systems such as qLabs FIB will undoubtedly save clinical time, providing the rapid test results that enable effective patient management and treatment. In addition, they also facilitate service cost-effectiveness. When aligned with current governance standards, use of POCTs can lead to a safe, quality, and compliant-led service. Remote management of the patient, QC data and the availability of an audit trail are therefore other key demands when evaluating the performance of a new POCT system. To facilitate these requirements, the new device is supplied with its own data management solution that can be interfaced to any laboratory information management system.

Having confidence in the quality and reproducibility of results from a device such as qLabs FIB ensures transfusion of the right product at the right time. This is particularly important in cases of PPH because hemostatic impairment, such as low plasma fibrinogen, has been shown to increase the risk of progression to severe PPH [12]. Further, transfusion of inappropriate blood products during PPH has the potential to exacerbate bleeding [13], while a delay in transfusion of fibrinogen products can result in further increased blood loss [13].

Human fibrinogen blood clot (factor I) protein
(Shutterstock.com)

Precision with laboratory tests confirmed

A preliminary evaluation of qLabs FIB has also been carried out by UK National External Quality Assessment Service Blood Coagulation (UK NEQAS BC) to establish the feasibility of providing external quality assessment (EQA) for this POCT device. Lyophilized samples (citrated plasma) were tested in duplicate and compared to the median value obtained from testing by over 88 laboratories using a range of reagents.

Results of six samples showed the average of the duplicate results versus the median result from the value when the sample was dis-tributed in a UK NEQAS BC exercise. The mean values obtained were 2.67 g/L and 2.64 g/L for UK NEQAS BC and qLabs FIB, respectively, with a difference from the median of -0.2 g/L. Further testing was performed 10 times on two of the six samples to establish precision. Results showed good precision, with both samples showing coefficients of variance <5%. Overall, qLabs FIB gave good acceptance within its testing range of 1.0–4.0 g/L when compared with the Clauss fibrinogen assays used by testing laboratories. UK NEQAS BC therefore concluded that the system demonstrates good precision and shows comparable results with its EQA samples and therefore the scheme confirmed that it would provide an EQA service for this device.

Essential diagnostic support

When faced with a major PPH hemorrhage, it is accepted that rapid blood transfusion may be essential to prevent death. However, alongside the cost of such blood products, transfusion itself is associated with adverse patient outcomes, and requires significant diagnostic support prior to administration [14–17]. The arrival of a hemostasis near-patient testing system such as qLabs FIB, which has been rigorously tested for laboratory comparability and quality assurance, has the potential to improve patient outcomes.

The author

Catherine Pedrosa MSc
HemoSonics International, 92600 Asnières sur Seine, France

E-mail: catherine.pedrosa@stago.com

References

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