Guidance-Based Appropriateness of Hemostasis Testing in the Acute Setting

Abstract

In this review, we aim to highlight the extent of inappropriate hemostasis testing and provide practical guidance on how to prevent it. We will focus on the acute setting, including but not limited to the emergency department and intensive care unit. To this end, we will first discuss the significance of inappropriateness, in the general context of laboratory medicine. This includes acknowledging the importance of the phenomenon and attempting to define it. Next, we describe the harmful consequences of inappropriate testing. Finally, we focus on the inappropriate use of hemostasis testing in the acute setting. The second section describes how interventions―in particular, the implementation of guidance for testing—can efficiently reduce inappropriateness. In the third section, we summarize the available recommendations for rational use of hemostasis testing (platelet count, activated partial thromboplastin time, prothrombin time/international normalized ratio, fibrinogen, thrombin time, D-dimer, anti-Xa assay, antithrombin, ADAMTS13 activity, antiheparin-PF4 antibodies, viscoelastometric tests, coagulation factors, and platelet function testing), as supported by guidelines, recommendations, and/or expert opinions. Overall, this review is intended to be a toolkit in the effort to promote the appropriate use of hemostasis testing. Hopefully, the new In Vitro Diagnostic Medical Device Regulation (EU) 2017/746 (IVDR) should help in improving the availability of evidence regarding clinical performance of hemostasis assays.

Keywords

laboratory tests - inappropriate - coagulation - demand management - IVDR

Inappropriateness in Laboratory Medicine

The Growing Trend

Laboratory medicine has transformed modern medical patient management.[1] A laboratory test is an accessible, objective, and efficient tool to assess a patient's physiological or pathological state. The use of laboratory tests has grown remarkably in recent years,[2] and this growth has been accompanied by a parallel increase in its misuse. The reasons for this inappropriate use are many, including increased availability of tests and ease of ordering, lack of general knowledge about laboratory tests, lack of understanding or how to interpret the tests, reflex ordering of testing, education and training of residents, use of premade bundles of tests (“panel testing”), asking for analysis instead of formulating a clinical question to be answered by the laboratory, defensive medicine behaviors, or false belief among many clinicians (e.g., we need numbers within the normal range prior to an invasive procedure).[2] [3] [4] [5] According to a large, historical meta-analysis, one-third of laboratory tests can be considered inappropriate.[6] More recently, it has been estimated that 60 to 70% of commonly performed tests (including activated partial thromboplastin time [aPTT] and prothrombin time/international normalized ratio [PT/INR]) may be of questionable clinical relevance.[7] In emergency departments (EDs), and even more so in intensive care units (ICUs), patients are closely monitored as their often critical medical condition can rapidly worsen and may require prompt interventions to avoid unfavorable clinical progression. As a result, acutely ill patients are typically tested several times a day, with extensive laboratory workup compared with other patients, with clinicians often reordering the same tests regardless of the specific half-life of the analyte or any retesting interval recommendation. This testing demand is further intensified by the increasing use of extracorporeal organ support in ICU, particularly renal replacement therapy and mechanical circulatory support such as extracorporeal membrane oxygenation, which are associated with unique hemostatic challenges.[8] These patients are exposed to parenteral antithrombotic agents and experience frequent thrombotic and hemorrhagic complications, which in turn leads to frequent hemostasis-related testing. Consequently, the number of inappropriate laboratory hemostasis-related tests is known to be essentially higher in acute patients.[9]

The Definition

Precisely defining a test as appropriate or not is challenging.[10] In its essence, an appropriate test adds value to the total patient management process. The complexity lies in the definition of the value. Value-based approaches to healthcare have focused the definition on the ratio of outcomes produced per money spent.[11] Although value-based healthcare concepts hold great promise for the future of laboratory medicine and healthcare,[12] their use does not alleviate the difficulty of defining appropriateness. Indeed, the outcomes must still be defined. It is virtually impossible to quantify the value that a single test result adds to patient care. The value of a test may be as simple as a change in patient management, either to initiate or instead to avoid potential interventions on the patient, as has long been suggested.[13] The outcome can be financial, although with clear shortcomings.[12] Other attempts have been made, such as Lundeberg's proposal to define appropriateness as the predominance of benefits over harms.[14] Nonetheless, in any definition, a scheme of trade-offs between undesirable (e.g., risk) and desirable (e.g., useful clinical information) concepts seems to emerge. Appropriateness seems to lie within the process of maintaining this rational balance rather than in the finality of the outcome. In summary, laboratory appropriateness could be defined as the “optimization of human and economic resources, contextually offering the most useful [clinical] information for improving patient outcome and maintaining the highest possible degree of patient safety.”[10]

One solution to the definition problem is to use guidelines to define appropriateness: if the test meets the indications, it is appropriate; otherwise, it is not. There are undoubtedly drawbacks to this approach. Guidelines tend to be universal by definition and thus do not capture the variability of particular clinical contexts, an aspect that has been especially highlighted in modern times, as personalized/precision medicine is the new paradigm of care. Evidence-based guidelines are also lacking for specific tests or clinical situations, for which only poorly evidence-based expert opinions can be found. However, this approach has the advantage of being objective and reproducible, two key elements for standardization. In short, if there is no universal and consensual definition of appropriateness, one must be chosen eventually.

The Consequences

Inappropriate testing is detrimental on at least three levels: human (patients and healthcare staff), financial, and environmental.[15] This is sometimes referred to as the triple bottom line or “3P” for People, Profit, and Planet.[16] The form of inappropriateness that most naturally comes to mind is performing tests that should not have been ordered, a phenomenon called overuse. However, its counterpart, underuse, is no less important. Underuse occurs when a test that should be performed is not ordered. It is by nature difficult to detect and its impact on patient care is even more difficult to quantify. Surprisingly, however, a large meta-analysis found that underuse was twice as frequent as overuse,[6] a proportion later found in other hemostasis-focused studies.[17] [18] In this section and throughout the rest of this review, we emphasize the importance of keeping in mind that inappropriateness also includes underuse.

First, inappropriateness has human consequences, both for patients and for healthcare workers. A well-described consequence of overtesting-related recurrent phlebotomies is hospital-acquired anemia, a phenomenon particularly prevalent in the ICU and neonatal ICU (NICU), and associated with poorer patient outcomes.[19] [20] [21] [22] Furthermore, overtesting mechanically results in more unexpected results—incidentalomas.[23] These incidentalomas cause anxiety for patients, unease for the clinicians, and generally lead to additional testing, which carries additional costs and risks for the patients and increased workload for healthcare staff. In general, increased staff workload correlates with an increase in medical errors, thereby compromising patient safety. A study[24] estimated that the reduction in inappropriate arterial blood gases alone saved up to 3,736 hours of clinician time in four ICUs over the course of 1 year, showing the impact of inappropriateness on healthcare staff workload. On the other hand, underuse leads to delayed or even missed diagnoses, thus also significantly impacting patient safety,[18] one of the major burdens in health care systems according to a 2024 Organization for Economic Cooperation and Development (OECD) study.[25] A typical example of underuse is the lack of a D-dimer test in patients with a low clinical probability of venous thromboembolism (VTE), which leads to pulmonary angiography being ordered, resulting in unnecessary risks for patients, a high workload for staff and high costs.[26] Finding the right balance between under- and overuse is not always easy. D-dimers are a prime example, as in addition to their aforementioned underuse, it is also known to be overused (typically, in cases where the pretest probability of VTE is high), which increases costs.[27] Missed diagnosis of antiphospholipid syndrome (APS) may be caused by the underuse of lupus anticoagulant testing (LAC), thus exposing the patient to nonprevented thrombotic risk later in life,[10] but testing patients who have a low clinical probability of APS may be considered as overuse.[28] All anticoagulants in clinical use, especially direct oral anticoagulants, interfere with the assays used to detect LAC, including aPTT and the dilute Russell viper venom time (dRVVT).[28] [29] Timing of testing in relation to the thrombotic or obstetric complication/during pregnancy is also a very important factor to consider. Testing for LA in the period close to the development of a new thrombosis can lead to false-negative results since elevation in acute phase proteins such as factor VIII and fibrinogen can lead to false-negative results. In contrast, false-positive LAC results can occur due to binding of C-reactive protein to negatively charged phospholipids in the reagent, prolonging phospholipid-dependent clotting tests.[30]

Second, inappropriate testing has a financial burden. Every test has a price, overtesting adds up to unnecessary costs. A recent analysis of 232 million medical records across both Medicare and commercial insurers in the United States found that the overuse of some specific tests (vitamin D, prostate-specific antigen, lipid panel, and hemoglobin A1c) costs the healthcare system $350 million over the course of a single year. Extrapolating their results to all laboratory tests, without accounting for downstream care costs, represented $1.9 to $3.2 billion in unnecessary costs for Medicare in 2019 alone.[31] This is also the case for hemostasis-related tests. Sarkar et al[17] estimated the burden of unnecessary laboratory testing for thrombotic or bleeding disorders at $20,000 per year in a 450-bed U.S. academic center. A recent retrospective analysis of thrombophilia testing in a 355-bed U.S. medical center estimated $150,000 per year in excess costs due to inappropriate testing in the acute care setting alone.[32] Furthermore, the aforementioned studies merely focused on primary costs, which encompass the direct expenses associated with inappropriate use of tests including reagents or calibration costs. It is noteworthy, however, that the actual cost of inappropriateness may be significantly higher. Interventions that monitor economic outcomes should ideally include the “cascade costs” of inappropriateness, such as additional personnel and material costs, prolonged patient stay in the ED or ICU, consequences of incidentalomas in terms of overtesting, overdiagnosis, and overmedication, follow-up costs due to missed diagnosis and treatment, along with environmental consequences (use of plastic tubes, waste material, major use of water, electricity, etc.). However, these consequential costs are notoriously difficult to quantify.

Finally, laboratory medicine has an environmental impact. A large survey of the environmental impact of the Australian healthcare system found that laboratory medicine was responsible for 10% of the environmental impact of healthcare.[33] While the role of laboratory medicine should be evaluated in the broader context of overall global environmental impact,[34] given the rate of inappropriateness, efforts can be made to reduce it. McAlister et al[35] estimated that a coagulation profile was responsible for an average emission of 82 g CO₂ equivalent (CO₂e). In a 936-bed academic center, it was estimated that 77,500 coagulation profiles were ordered annually, representing 6,330 kg CO₂e, or the equivalent of driving 34,000 km in a conventional passenger car.[15] While this example may seem anecdotal at the scale of a single center, it is likely to have a significant impact on the scale of all European laboratories. The exact impact of clinical laboratories is difficult to estimate due to several factors, such as the differences in the type of instrumentation or analytical techniques used to perform the tests, the formulation and origin of reagents, waste management policies, and country-dependent energy source production.[15] For example, a recent study[16] provided estimates three times higher than those previously presented by McAlister et al.[35] However, it is also possible that our current estimates are understated due to the lack of data provided by manufacturing companies.[36] ICUs inevitably contribute more than other units to the environmental impact of hospitals,[37] and laboratory testing plays its part.[38] It is therefore imperative that the environmental impact of inappropriate testing be given greater scrutiny in ICUs in the future.

Collectively, these data show that inappropriate laboratory testing has adverse financial, medical, and environmental consequences (3Ps). Some authors have raised ethical concerns about this issue.[39] One way to begin to curb the trend is to gain a deeper understanding of the underlying causes of inappropriateness, as we will explore further in the following sections.

The Hemostasis Case

Hemostasis tests are among the most commonly performed in clinical laboratories. It is therefore not surprising that a significant number of inappropriate hemostasis tests are ordered. Cadamuro et al[7] evaluated 22,186 aPTT and 36,143 PT/INR tests and reported that up to 60% of those may be of questionable clinical relevance. A similar estimate was made for coagulation testing in the ED: 64% of requests were deemed inappropriate.[40] Sarkar et al[17] reviewed 200 randomly selected cases of bleeding and thrombotic disorders and found that inappropriate testing had a prevalence of 77%. For some tests, such as those composing the thrombophilia screening, the rate of inappropriateness may be even higher. Tientadakul et al[41] examined antithrombin (AT), protein C (PC), and protein S (PS) tests in 503 medical records from a large university hospital in Thailand, showing that 91% of those were inappropriately requested. Another study[32] confirmed this trend in the acute setting of an American academic medical center, reporting an inappropriateness rate of 84% for thrombophilia testing. Another illustrative example of overuse in the acute setting is the use of assays for IgG antibodies against the platelet factor 4/heparin complex (anti-PF4/heparin) in patients with suspected heparin-induced thrombocytopenia (HIT). The 2018 American Society for Hematology guidelines[42] recommend against testing patients with low-probability 4Ts score. In a retrospective analysis of 107 patients who underwent anti-PF4/heparin testing, Jindal et al[43] demonstrated that 51 patients (48%) received a low-probability score, indicating that approximately half of the requests were inappropriate (none exhibited a strongly positive ELISA test result). In a similar study conducted by Beauverd et al,[44] the number of patients tested for anti-PF4/heparin, although labeled with a low-probability score, was as high as 73%, none being diagnosed with HIT. Publications from Canada, France, and Switzerland indicate that a small percentage (1.5–9%) of patients with “low HIT probability” with a 4T score of 3 have indeed HIT. Considering the consequences of a missed HIT diagnosis, the authors consider only 4T scores of 0 to 2 as a reason not to test for anti-PF4/heparin antibodies.[45] D-dimer is also a commonly ordered test in the acute setting, with several reports indicating overuse.[46] [47] [48]

Collectively, those studies suggest that there is a high frequency of inappropriate ordering of hemostasis tests, particularly in the acute care setting. It is possible that we are seeing only the tip of the “iceberg of inappropriateness in hemostasis testing.”[10] The authors' experience suggests that less well-studied tests such as anti-Xa assay to measure anticoagulants, ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13), TT, fibrinogen, platelet function tests, AT, or factor V levels may be overprescribed in some centers, suggesting that the reality of inappropriate hemostasis testing may be much larger than commonly appreciated.[49] [50] It is therefore crucial to focus on strategies to reduce their inappropriate use.

Guidance-Based Appropriateness of Hemostasis Testing H1

The Solutions

Education and increasing the awareness of inappropriateness and its downstream consequences have led laboratory specialists to develop interventions. An intervention can be defined as any action taken to reduce the inappropriate use of laboratory resources, in a process often referred to as laboratory demand management.[51] There are numerous examples of interventions, which have been reviewed elsewhere.[51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] Interventions with common methodology have been grouped together into distinct categories, namely, education and/or guidance (sometimes considered as a single strategy), audit and feedback, computerized physician order entry (CPOE) coupled with demand management tools, gatekeeping, multifaceted intervention when at least two different strategies are used together, and a recently coined category of artificial intelligence/machine learning-based algorithms.[9] Each type of intervention is characterized by its respective ease of implementation, its efficiency, its effectiveness over time, and its resource requirements (either temporal or economical). For example, multifaceted interventions have a higher efficiency and persistence over time than educational interventions, but they are more difficult to implement and sustain.[9] The bottom line is that most interventions are effective and feasible overall, although some more than others, and most importantly that they are safe for the patients.[9] [62]

The Examples

Fortunately, there are many examples of effective interventions to reduce the inappropriateness of hemostasis testing in the acute care setting. A comprehensive review of interventions implemented in ICUs to reduce the rate of inappropriate testing[9] found a mean reduction in inappropriate hemostasis-related tests of 41% (range: 8–64%) in the postintervention period compared with the preintervention period. In these interventions, one[63] specifically tested the effectiveness of a guideline to reduce unnecessary coagulation tests (PT/INR, aPTT, and fibrinogen) in an ICU. The authors found that the implementation of locally established guidance resulted in a 64% reduction in coagulation tests, and estimated cost savings of nearly AUS$100,000 per year for a 23-bed ICU; extrapolated to all ICUs in Australia and New Zealand, this represents savings of more than AUS$3.8 million in 1 year (as of 2014).

Illustrative examples can be found in the literature regarding anti-PF4/heparin testing in patients suspected of HIT. Cadamuro et al[64] observed that simply requiring clinicians to utilize the 4T score when ordering an anti-PF4/heparin immunoassay could effectively reduce the overuse of this test. Similarly, a study[65] that developed a clinical decision support tool, comprising a 4T score calculator and platelet count versus time graph, was able to result in the discontinuation of 25% of tests for clinicians ordering anti-PF4/heparin immunoassays. Even a relatively straightforward intervention, such as the introduction of an automatic electronic alert in the CPOE system, was shown to yield a notable reduction in the ordering of inappropriate anti-PF4/heparin tests.[66] A recent scoping review[67] on quality improvement interventions on HIT testing appropriateness retrieved 30 studies, identifying five main directions to improve HIT testing: increasing HIT recognition, reducing HIT incidence, reducing HIT overdiagnosis, promoting safer HIT management, and creating HIT task forces.

Specific, individualized interventions have also yielded substantial improvements in reducing inappropriate hemostasis testing. A study[68] of patients admitted to the emergency general surgery department of a 922-bed facility showed a 17% reduction in the ordering of coagulation tests (PT/INR and aPTT) on admission after an education and guideline-based intervention—while this study referred to the 2008 British Committee for Standards in Haematology guidelines for preoperative bleeding risk assessment,[69] it is here pertinent to advise the reader that the British Society for Haematology (BSH) guidelines have recently undergone an update,[70] and now advise against routine coagulation screening prior to invasive procedures. In another multifaceted intervention, Tawadrous et al[71] uncoupled INR and aPTT testing and provided education and reminders through the CPOE system. The intervention resulted in a 54% decrease in the total number of tests performed and an estimated savings of CAN$163,000. This number is also found in another multifaceted plan-do-study-act (PDSA)-based intervention[72] for coagulation testing in the ED. In another study, an original strategy was used. Kalsi et al[73] designed a two-part intervention: in the first part, they used an educational strategy; in the second, they physically removed the tubes needed for coagulation testing from the bedside trolleys in the ED. Interestingly, there was no change in the ordering of coagulation tests after the educational intervention. However, the rate of inappropriate coagulation testing dropped from 74 to 53% after the simple removal of tubes from the ED trolleys. In addition to highlighting the creativity of some interventions, this example illustrates how simple interventions can yield significant results.

These studies show that interventions are effective in reducing inappropriate hemostasis testing and result in cost savings, but reducing inappropriate hemostasis testing may also benefit the environment. Recently, Pilowsky et al[24] conducted a massive multifaceted intervention (education, audit, and feedback strategies) in the ICUs of four Australian centers over a 12-month period, analyzing 460,258 tests from a total of 22,210 patients. By breaking down the tests, coagulation testing alone accounted for 480 kg of CO₂e emissions and AUS$120,000 saved; the intervention resulted in a total reduction of 1.8 tons CO₂e emissions and saved nearly AUS$1 million.

While some interventions, as previously mentioned, directly address the inappropriate use of laboratory tests, others are designed to mitigate their unfavorable consequences. For example, Siegal et al[22] showed that the transition from standard to small-volume tubes in the ICU resulted in a reduction in the number of transfused red blood cell units per ICU patient-day without any impact on laboratory testing. Furthermore, a recent intensive care medicine rapid practice guideline panel has issued a “strong recommendation for the use of small-volume sample collection tubes in adult ICUs.”[74]

In conclusion, effective interventions can be designed to reduce inappropriate hemostasis testing. Such interventions reduce the rate of inappropriate testing, save costs, and reduce the environmental impact of laboratory medicine.

The Guidance

One of the most commonly used strategies is guidance-based interventions. This approach provides clinicians with precise indications for testing. In general, guidelines or guidance aims to define the “what, who, and when” of testing; inspired by the Choosing Wisely initiative,[75] they amount to answering the “6-Rs” for each test, that is, the choosing of (1) the right test, with (2) the right method, at (3) the right time, for (4) the right patient, at (5) the right cost, and for obtaining (6) the right outcome.[76] In the aforementioned review of 44 interventions conducted to reduce inappropriate testing in the ICU, 22 mentioned a guidance-based strategy.[9] Surprisingly, when examining the documents used in the interventions, none referred to international or even national guidelines. Instead, in all cases, guidance was based on local expert consensus. Closer examination of different guidance revealed discrepancies (see [Table 1] for an example regarding coagulation testing), showing (1) that we need more evidence and (2) that standardization in the context of guidance-based interventions—and more generally speaking in the ordering of laboratory tests—is certainly needed.[77] [78] [79] [80] [81]

Table 1 Discrepancies in guidance for the same test (coagulation profile) between studies in ICUs

Kumwilaisak et al[78]	Not routine
Dhannai et al[79]	Only as required (order individual tests)
Kotecha et al[80]	Bleeding, coagulopathy, on anticoagulation, planned procedure
Musca et al[63]	At admission (if not already done) Significant bleeding, coagulopathy, new thrombocytopenia (< 50 × 109/L), liver failure, or disseminated intravascular coagulation (DIC) (once and then daily if abnormal) If warfarin therapy and isolated high INR (> 1.3): INR only, daily, or less when the patient is improving If heparin therapy and isolated high aPTT: aPTT only, as per heparin protocol, or daily or less if patient improving; If the coagulation profile is abnormal but none of the above: consider ordering a coagulation profile second daily or less if the patient improving
Prat et al[81]	Upon admission to ICU When DIC or hepatic failure During ICU stay once or two times a week (if heparin treatment once a day until aPTT ok (sic) and after 2–3 times a week)

Abbreviations: aPTT, activated partial thromboplastin time; DIC, disseminated intravascular coagulation; ICU, intensive care unit; INR, international normalized ratio.

Notes: When inspecting guidance provided in the methodology of interventions aimed at reducing inappropriate testing in ICUs, none were international, standardized guidelines but instead locally established guidance. Comparing these guidance highlights discrepancies (below, for coagulation testing). Each line of this table is a guidance from one of these studies. The coagulation profile here encompasses international normalized ratio/prothrombin time, activated partial thromboplastin time, and fibrinogen testing.

There is evidence in the literature that compliance with recommended hemostasis testing is low.[82] This is mainly due to the strong beliefs of some clinicians that (1) PT and aPTT can assess hemostasis and predict the bleeding risk in patients undergoing invasive procedures; (2) abnormal laboratory test results indicate the increased risk of significant bleeding after a procedure; (3) interventions such as plasma transfusion can correct abnormal PT and/or aPTT, reducing the bleeding risk; (4) normal platelet count reassures on the low/no risk of bleeding in all patients, while platelet transfusion will modify and reduce bleeding risk in all thrombocytopenic patients; (5) risks of transfusion will not exceed the benefits of transfusion. Unfortunately, those beliefs have been continued to varying degrees in clinical practice, promoting inappropriate hemostasis testing and trying to achieve specific laboratory thresholds for prophylactic transfusions, despite generally low levels of supporting evidence.[70] [83]

In a survey of 81 Korean laboratories, only 13 reported following the correct indication for anti-factor Xa testing in low-molecular-weight heparin (LMWH) monitoring.[84] Anderson et al[85] recently showed that only 15% of inpatient thrombophilia testing met the 2023 American Society for Hematology guidelines[86] criteria for thrombophilia screening. There are many barriers to guideline implementation and compliance, including lack of awareness or accessibility of the guideline, lack of agreement, lack of practicality (i.e., when the guidelines are not appropriate for real-world practice), ‘environmental’ (i.e., institutional, political, cultural, or social) factors, or simply time constraints.[87] [88] [89] [90] In some cases, the guideline itself is a problem from a laboratory perspective. Clinical practice guidelines are often formulated for specific clinical scenarios in which laboratory medicine is not the primary focus but plays a key role. In such cases, failure to include laboratory specialists in the development process of the guidelines or care pathways may result in establishing inappropriate testing recommendations.[87]

The Future

A new type of intervention is now using artificial intelligence (AI) to help reduce inappropriate testing.[91] In 2013, Cismondi et al[92] used a predictive tool, “fuzzy modeling,” to evaluate unnecessary testing in patients with gastrointestinal bleeding in the MIMIC-II ICU database. The analysis showed that aPTT, PT, and fibrinogen tests were irrelevant in 43%, 57%, and 84% of the cases, respectively, pointing to opportunities for improvement in resorting to laboratory testing. One could imagine that the help of AI tools combined with CPOE systems could create a kind of ‘intelligent’ computerized clinical decision support[93] that would help clinicians decide which tests to order based on clinical data, patient's medical history, and previous test results. Indeed, the very essence of laboratory testing is to provide clinicians with information. If the test adds clinically useful information, it can be considered appropriate. Predicting the value that a test will add is therefore a key argument in test ordering practice. Lee and Maslove[94] have used information theory principles to examine the novelty of information that daily repetition of certain tests in ICU patients carries. Surprisingly, they concluded that platelet count was one of the tests with the least novel information on days 2 and 3 after ICU admission. The idea that AI could allow us to avoid performing certain tests by their virtual prediction is not science fiction. In 2020, a team developed a deep learning algorithm that was able to reduce the total number of laboratory tests used in ICU patients by 20%, with 98% accuracy in predicting abnormal results.[95] Interestingly, platelet count was again one of the most commonly omitted tests with this tool. AI can also provide additionally useful information. For example, Fang et al[96] used backpropagation neural networks (BPNNs) that were trained and validated with training and testing datasets to identify clotted specimens. By combining the results of five basic coagulation tests (aPTT, PT, fibrinogen, thrombin time [TT], and D-dimer) with the patient's age, the system was able to identify clotted samples with 97% accuracy, preventing unreliable results from being provided to requesting physicians.

Viewing laboratory tests as information, AI can also add value to tests already performed. In fact, there is a growing body of evidence showing that the aggregation of data coming from multiple tests (i.e., routine “bundle” testing) can accumulate into new information. This is actually not so different from what human clinicians and laboratory specialists do with test results: rather than viewing tests as separate “information givers” one at a time, they “aggregate” the information provided by multiple tests into a coherent interpretation—a diagnosis. However, with the help of AI (e.g., unsupervised algorithms), this could be brought to another scale and with a fine degree of optimization, potentially leading to a reduction in a significant number of tests.

It should be noted that AI tools have important drawbacks and present ethical challenges, notably the inherent “black box design” of unsupervised algorithms, global lack of real-world data both in terms of quantity and quality, lack of interreproducibility between different sets of data (e.g., training and real-world data), and data privacy.[9] [12] [97] Collectively, AI, while not yet mature, will certainly be a valuable tool in the future to assist clinicians and laboratory specialists in their quest to improve appropriate laboratory testing.[98]

There is a growing interest in improving the appropriate use of laboratory tests. In a survey conducted in nine European countries, the vast majority of laboratory specialists and clinicians felt that measures to ensure the appropriate use of tests were necessary, and all respondents' clinicians were interested in advice/information on their indication.[99] Close collaboration between clinicians and specialists in laboratory medicine will be essential to improve the use of laboratory testing. Recommendations or automated implementation of test profiles or laboratory diagnostic pathways, (i.e., to trigger tests based on symptoms or diagnostic hypotheses as is already the case for anemia or flow cytometry in hematology), must be based on current evidence.[12] The new In Vitro Diagnostic Medical Device Regulation (EU) 2017/746 (IVDR) requires clinical evidence, which is based on the intended use (indication) and risk class (B or C for most of the hemostasis assays).[100] We, therefore, hope that this will lead to more evidence for the correct use of hemostasis tests.

Recommendations for the Rational Use of Hemostasis Tests in the Acute Setting

The implementation of guidance-based interventions represents an effective strategy to implement in the acute care setting. However, the selection of guidelines upon which these interventions are based is critical. It is not uncommon for such interventions to make no mention of guidelines published by expert committees or national/international specialty societies. In this section, we have attempted to summarize the current guidance for commonly ordered hemostasis tests in the acute and inpatient settings, namely platelet count, aPTT, PT/INR, fibrinogen, TT, D-dimer, anti-Xa assay, AT, ADAMTS13 activity, antiheparin-PF4 antibodies, viscoelastometric tests, factor V levels and platelet function testing ([Table 2]). Additionally, we present key guidance or guideline categorized by specific clinical situations ([Table 3]).

Table 2 Suggested guidance or guidelines for hemostasis tests in the acute setting

Test	Half-life or time of turn-over	Main indication(s)/intended use	Key messages	Minimal retesting interval	Key references
Platelet count	4–6 d	Detection of thrombocytopenia in ICU	Many mechanisms of thrombocytopenia. Included in SIC scoring system to categorize early-phase DIC in sepsis Screening for overt DIC on the day of ICU admission was associated with lower mortality, and the association became stronger if the screening was repeated 2 days later, suggesting that DIC screening by itself might lead to improved outcomes (Umemura et al)[143] Use SIC score to detect the earlier phase of DIC (Iba et al)[144]	Daily Exception, suspicion of HIT: - Systematic platelet count before initiation of treatment by UFH/LMWH - For patients at intermediate risk of HIT, it is proposed to monitor platelet counts once to twice a week from days 4 to 14 of treatment, and then once a week for 1 mo if heparin therapy is continued - For patients at high risk of HIT, it is proposed to monitor platelet counts two to three times a week from days 4 to 14 of treatment, and then once a week for 1 mo if heparin therapy is continued	Thachil and Warkentin[145] Greinacher and Selleng[146] Greinacher[147] Cuker et al[42] Gruel et al[148] Iba et al[144] Iba et al[121] Wada et al[149] Thonon et al[49]
		Active bleeding	Monitoring is indicated to detect the threshold for platelet transfusion even if these thresholds are not validated. ESAIC guidelines recommend a goal-directed transfusion strategy (based on Hb and/or physiological red blood cell transfusion triggers, coagulation factor substitution, and platelet transfusion triggers)	According to clinical evolution (Kietaibl et al)[50]	Lang and Croal. National minimum retesting interval in pathology 2021[101] Spahn et al[151] Lippi et al[152] Lang et al[101]
aPTT	N/A	Monitoring of UFH	Use a weight-adjusted nomogram with timely laboratory monitoring Anti-Xa assay is often preferred to aPTT for this indication	Check anti-Xa UFH levels 6 h after any change in dose, or at least once per day	Lippi et al[153] Raschke et al[154] Smith and Wheeler[155] Baker et al[156] Gouin-Thibault et al[157] Thonon et al[49]
		Follow-up of DIC	No test “In bleeding patients with DIC and prolonged PT and aPTT, administration of FFP may be useful. It should not, however, be instituted based on laboratory tests alone but should be considered in those with active bleeding and in those requiring an invasive procedure. (Grade C, Level IV).” (Levi et al)[158] However, aPTT is not mentioned in ISTH guidelines (Iba et al)[121] [144] DIC is a highly dynamic situation: “it is important to repeat the tests to monitor the dynamic changes on the basis of laboratory results and clinical observations” (Wada et al)[149]	No retest	Wada et al[149] Thonon et al[49]
		Suspected bleeding disorder: - Inherited: clotting factor deficiency (intrinsic pathway), von Willebrand disease - Acquired: acquired factor inhibitors (e.g., autoantibodies to factor VIII aka “acquired hemophilia”), anticoagulants	aPTT is sensitive neither to some von Willebrand factor defects nor to platelet function defects and factor VII and factor XIII deficiencies	Confirmation required along with specific testing of coagulation factors	Lee[159] Thonon et al[49] Casini et al[160]
PT/INR	N/A	Assessment of the anticoagulant effect of VKAs in case of severe bleeding or before an invasive procedure	In a VKA-treated patient with severe bleeding and an INR > 1.5 (>1.2 if intracranial hemorrhage), it is recommended to stop anticoagulant therapy and antagonize it by administering prothrombin complex concentrate (Kuramatsu et al).[161] It is also recommended to check the INR within 30 min at 6 to 8 h and 24 h after antagonization, to decide on further administration of PCC (Schwebach et al).[162] Obtaining INR results quickly is crucial in certain conditions for patients taking VKAs. Stroke management guidelines recommend thrombolytic therapy within 4.5 h after stroke onset for patients on warfarin therapy only if their INR is below 1.7 (Powers et al).[163] Consequently, if a POCT overestimates INR, patients presenting with a stroke may be excluded from thrombolysis, whereas they might have been eligible if a standard INR measurement had been utilized.		Bonhomme et al[164] Association of Anaesthetists of Great Britain and Ireland (Anesthesia 2010)[165] Advisory panel guidance on minimum retesting intervals for laboratory tests[166] Pernod et al[167] Thonon et al[49]
		Diagnosis and follow-up of DIC (included in SIC scoring system)	DIC is a highly dynamic situation: “it is important to repeat the tests to monitor the dynamic changes on the basis of laboratory results and clinical observations” (Wada et al).[149] Included in SIC scoring system to categorize early phase DIC in sepsis “Screening for overt DIC on the day of ICU admission was associated with lower mortality, and the association became stronger if the screening was repeated 2 d later, suggesting that DIC screening by itself might lead to improved outcomes” (Umemura et al)[143]	If SIC scoring system is positive, daily (DIC)	Umemura et al[143] Iba et al[144] Iba et al[121] Wada et al[149] Thonon et al[49]
		Major bleeding	“We recommend that monitoring and measures to support coagulation be initiated immediately upon hospital admission (Grade 1B)” (Rossaint et al)[126] “We recommend that resuscitation measures be continued using a goal-directed strategy, guided by standard laboratory coagulation values and/or VEM (Grade 1B).” (Rossaint et al)[126] “If an FFP-based coagulation resuscitation strategy is used, we recommend that further use of FFP be guided by standard laboratory coagulation screening parameters (PT and/or aPTT > 1.5 times normal and/or viscoelastometric evidence of a coagulation factor deficiency) (Grade 1C)” (Rossaint et al),[126] except in cirrhotic patients (Lawrence and Siau[168] ESAIC guidelines recommend a goal-directed transfusion strategy (based on Hb and/or physiological red blood cell transfusion triggers, coagulation factor substitution and platelet transfusion triggers)	According to the clinical evolution (Kietaibl et al)[150]	Rossaint et al[126] Lang and Croal. National minimum retesting interval in pathology 2021[101] Thonon et al[49] Kietaibl et al[150] Lang et al[101]
		Suspected bleeding disorder: - Inherited: clotting factor deficiency (extrinsic pathway) - Acquired: acquired factor inhibitors, anticoagulants	PT is not sensitive to von Willebrand factor defects, platelet function disorders, factors VIII, IX, XI, and XIII deficiencies	Confirmation required along with specific testing of coagulation factors	Lee[159] Thonon et al[49] Casini et al[160]
TT		Exclusion of anti-IIa anticoagulant	Many variables affecting TT, lack of standardization between laboratories Thrombin time should not be used to assess dabigatran concentrations in the normal therapeutic range		Lippi and Favaloro[169] Lessire et al[170]
Fibrinogen		Major bleeding	“We recommend early and repeated monitoring of hemostasis, using a traditional laboratory determination such as PT/INR, Clauss fibrinogen level and platelet count and/or POC PT/INR and/or a viscoelastometric method (Grade 1C).” (Rossaint et al)[126]	According to the clinical presentation and evolution (Kietaibl et al)[150]	Rossaint et al[126] Kietaibl et al[150]
D-dimer	6–8 h	Diagnosis of DIC	D-dimer cut-off should be adapted to the reagent “Screening for overt DIC on the day of ICU admission was associated with lower mortality, and the association became stronger if the screening was repeated 2 d later, suggesting that DIC screening by itself might lead to improved outcomes” (Umemura et al)[143] DIC is a highly dynamic situation: “it is important to repeat the tests to monitor the dynamic changes on the basis of laboratory results and clinical observations” (Wada et al)[149]	Daily if SIC scoring system is positive	Wauthier et al[171] Suzuki et al[172] Wada et al[149] Thonon et al[49]
		Exclusion of venous thromboembolism	Use age-adjusted D-dimer cut-offs for diagnosing acute episodes of venous thromboembolism	No retest	Favaloro et al[173]
Anti-Xa assay	UFH: The half-life of UFH is dose-dependent, ranging from 60 to 90 min at usual IV doses	Monitoring of UFH	UFH: Use a weight-adjusted nomogram with timely laboratory monitoring (to reach more rapidly the therapeutic range, to reduce the number of dose adjustments and to reduce the number of thrombotic events)	According to a nomogram	Baker et al[156] Gouin-Thibault et al[157] Thonon et al[49]
	LMWH: - Tinzaparin, dalteparin, nadroparin: 4–6 h - Enoxaparin: 5–7 h	To detect an accumulation/overdosage of LMWH (at peak)	The LMWHs vary in their physicochemical properties, the anti-Xa:anti-IIa ratio	Only in case of persistent bleeding	Gouin-Thibault et al[174] Thonon et al[49]
	Anti-Xa DOACs (7–17 h: interindividual variability)	Measuring of DOAC levels (with dedicated calibration) in case of bleeding, antidote administration, invasive procedure	Should be measured within 30 min in case of: - Bleeding - Urgent invasive procedure - Thrombolysis On-therapy range is available at trough and peak (Douxfils et al)[175]	Only in case of persistent bleeding	Douxfils et al[175] Baker et al[156] Levy et al[176] Berge et al[177] Thonon et al[49]
AT	Several days: 66.2 h ± 1.2 according to Knot et al)[178]	Diagnosis of DIC	Disagreement between recommendations. AT is included in the revised diagnostic criteria for DIC from the Japanese Society on Thrombosis and Hemostasis (Wada et al)[179] but not in the ISTH overt DIC scoring system (Iba et al)[121]	No retest	Iba et al[121] Wada et al[179] Thonon et al[49]
		“Heparin resistance” or dampened response to UFH	Heparin resistance could be defined as UFH failure to achieve a specified anticoagulation level despite the use of what is considered to be an adequate dose of heparin There is no consensus on its definition and therefore on the reported incidence Its reality is even challenged[180] Acquired antithrombin deficiency (frequent in ICU due to sepsis, DIC, ECMO, or liver disease) can cause a dampened response to UFH, but there is no clinical benefit demonstrated when antithrombin is administered (Mansour et al)[50] In patients with large volume blood loss, although AT replacement can be considered based on levels below the normal reference range, data supporting this management strategy are needed” (Helms et al)[181] illustrating disagreement between ISTH and Extracorporeal Life Support Organization (ELSO) guidelines “Antithrombin levels [are] not significantly associated with heparin responsiveness” during venoarterial ECMO (Mansour et al)[50]	No retest (as there is no clinical benefit demonstrated when antithrombin is administered)	Van Cott et al[182] Levy et al[183] Gouin-Thibault et al[180] Thonon et al[49] Helms et al[181] McMichael et al[184]
ADAMTS13	A median half-life of 130 h was demonstrated, ranging between 82.6 and 189.5 h according to Taylor et al[185]	Diagnosis and follow-up of thrombotic thrombocytopenic purpura	Use clinical score (French or Plasmic score) to predict severe ADAMTS13 deficiency (except in specific clinical conditions like obstetric or pediatric populations)	Acute stage: diagnosis once then weekly after plasma exchange (PEX) Long-term follow-up: every 3 mo	Scully et al[186] Zheng et al[187] Graça et al[188] Coppo et al[189] Scully et al[186] Thonon et al[49]
Antiheparin-PF4 antibodies immunoassays	Undetectable levels at a median of 50–85 d after the HIT acute stage	Diagnosis of HIT if pre-test probability (e.g., 4T score) is not low	Limitations of 4T score in ICU Negative predictive value of a low 4T score (91–98.5%, only 74% of the agreement for the fourth T (other) (Crowther et al)[45] (Marchetti et al)[190]	No retest If pre-test probability is high and IA negative, a platelet activation assay may be appropriate	Cuker et al[42] Gruel et al[148] Warkentin et al[191] Crowther et al[45] Linkins et al[192] Arachchillage et al[193] Thonon et al[49]
Viscoelastometric testing (TEG, ROTEM, QUANTRA, etc.)	N/A	Might be considered to guide transfusion in case of massive bleeding (during cardiac surgery, liver disease, obstetrical bleeding and hyperfibrinolysis, etc.)	“We recommend the early and repeated monitoring of hemostasis, using a traditional laboratory determination such as PT/INR, Clauss fibrinogen level, and platelet count and/or POC PT/INR and/or a viscoelastometric method (Grade 1C).” (Rossaint et al)[126] In cases of severe (poly)trauma, there is a significant and widespread release of tPA from damaged endothelial cells throughout the body, primarily due to severe hypoperfusion and other factors. In some situations, the amount of released tPA is so substantial that it overwhelms the available levels of PAI-1. This results in an increase in free circulating plasmin, which is capable of degrading fibrinogen and other plasma proteins. (Gall et al)[194]; (Walsh et al)[195] POCTs (TEG, ROTEM) are faster but relatively insensitive for accurate diagnosis of increased fibrinolytic activation, Thus, they underestimate the incidence and severity of fibrinolytic activation in trauma (Raza et al)[196] (Gall and Davenport).[197] However, be aware of the following drawbacks of these tests: significant variability, making them non-interchangeable; lower analytical and clinical performance; higher costs compared with central laboratory devices; insufficient staff training, increasing the risk of errors; lack of systematic checks for preanalytical errors, such as hemolysis and contamination; the need for predefined algorithms and decision-making thresholds; many POC devices contribute to environmental waste due to the use of unsustainable materials. Implementation of viscoelastometric testing into an integrated transfusion algorithm during cardiac surgery, liver transplantation, or acute severe trauma, can lead to:  - Reduced red blood cell transfusions  - Reduced platelet transfusions  - Reduction in major postsurgical bleeding Be aware of the limitations of VETs  - Insensitivity for detecting von Willebrand factor and minor/moderate fibrinolytic activity   - Natural anticoagulants   - No results of interchangeability between instruments technologies Clinical evidence of the utility of VHAs largely remains to be proven through randomized clinical trials, with clinically relevant outcomes, and compared with rapid panel hemostasis testing[198]	According to the clinical situation and the treatment algorithm	Hartmann et al[199] Mansour et al[119] Thonon et al[49] Rossaint et al[126] Kietaibl et al[150]
Factor V	36 h according to Mannucci et al[200]	In cases of acute liver failure, for assessing the severity of hepatic functional impairment, where the question of liver transplantation arises	Recognized predictive criteria by Eurotransplant include the King's College criteria for acute liver failure due to paracetamol intoxication and the Clichy criteria for hepatitis B virus-induced acute liver failure. A factor V level below 20% for patients under 30 y of age, and below 30% for patients aged 30 or older, is a severity criterion indicating the need for liver transplantation. Unfortunately, factor V level measurement is not available stat in all laboratories, and some authors have recently proposed alternatives such as the Model for End Stage Liver Disease or the Liver Chronic Liver Failure-SOFA score	No retest	Müller et al[201] Goel et al[202] Thonon et al[49]
Platelet function testing	Clopidogrel: 6–8 h Prasugrel: 7 h (2–15 h)	“P2Y12 inhibitor monitoring to shorten the time window to surgery following P2Y12 inhibitor discontinuation. (Class IIa, Level B)” (Frelinger et al)[203]	Variability in platelet reactivity recovery time for clopidogrel, prasugrel and ticagrelor There are different platelet function tests that are not interchangeable Several preanalytical constraints should be managed	No retest	Frelinger et al[203] Godier et al[204] Valgimigli et al[205] Ferraris et al[206]

Abbreviations: aPTT, activated partial thromboplastin time; AT, antithrombin; d, days; DIC, disseminated intravascular coagulation; DOACs, direct oral anticoagulants; ESAIC, European Society of Anaesthesiology and Intensive Care; FFP, fresh frozen plasma; HIT, heparin-induced thrombocytopenia; ICU, intensive care unit; INR, international normalized ratio; ISTH, International Society on Thrombosis and Haemostasis; LMWH, low-molecular-weight heparin; mo, months; PAI-1, plasminogen activator inhibitor-1; POC, point-of-care; POCT, point-of-care testing; PT, prothrombin time; SIC, sepsis-induced coagulopathy; tPA, tissue plasminogen activator; TT, thrombin time; UFH, unfractionated heparin; VEM, viscoelastometric monitoring; VKA, vitamin K antagonists.

Notes: Note that the level of evidence underpinning the use of hemostasis tests in the acute setting is highly variable according to the assay. The reader should thus refer to the key references.

Table 3 Suggested guidance for the use of hemostasis tests in the acute setting, for some clinical scenarios

Indication	Diagnosis	Follow-up	References
SIC/DIC	There is no gold standard for the diagnosis of DIC, and no single test that is, by itself, capable of accurately diagnosing DIC (ISTH/SCC 2013) SIC score is diagnosed based on platelet count, PT, and SOFA score (ISTH 2023) DIC diagnosis should include platelet count, D-dimer, fibrinogen level and PT. The utility of fibrin monomers and AT is still debated (proposed and validated by JSTH but not included in ISTH score)	According to the clinical presentation and evolution (at least daily)	BCSH 2009 guidelines (updated 2012)[158] ISTH 2023 communication[121] JSTH 2016 diagnostic criteria[207] SISET 2012 guidelines[208] ISTH/SCC 2013 harmonization guidance[149] Aota et al[209]
Cirrhosis	No test recommended (thrombomodulin-modified thrombin generation: for research use only)	No test recommended	Tripodi et al[120]
HIT	Platelet count Systematic assessment of platelet count before initiation of treatment by UFH/LMWH For patients at intermediate risk of HIT, it is proposed to monitor platelet count once to twice a week from days 4 to 14 of treatment, and then once a week for one month if heparin therapy is continued For patients at high risk of HIT, it is proposed to monitor platelet count two to three times a week from days 4 to 14 of treatment, and then once a week for one month if heparin therapy is continued. Antiheparin-PF4 antibodies Antiheparin-PF4 antibodies immunoassays if pre-test probability (e.g., 4T score) is not low Functional test If the pre-test probability is intermediate or high and a significant titer of antiheparin-PF4 antibodies is detected, a functional test should be performed. If pre-test probability is high and immunoassay is negative, a functional test may be appropriate	For patients at intermediate risk of HIT, it is proposed to monitor platelet count once to twice a week from days 4 to 14 of treatment, and then once a week for 1 mo if heparin therapy is continued For patients at high risk of HIT, it is proposed to monitor platelet count two to three times a week from days 4 to 14 of treatment, and then once a week for 1 mo if heparin therapy is continued.   No retest   No retest	ASH 2018 guidelines[42] 2020 French Working Group on Perioperative Haemostasis proposals[148] 2024 BSH guideline[193]
Thrombotic thrombocytopenic purpura	Test ADAMTS13 activity, prior to any treatment; but should not delay plasma exchange (PEX). BSH 2023 prefers testing for ADAMTS13 activity over using scoring systems (GRADE 2C), and Nine-I investigators recommend scoring systems if ADAMTS13 activity cannot be quickly measured. BSH 2023: Initial blood tests as part of TTP diagnosis include full blood count, reticulocyte count, blood film, lactate dehydrogenase, coagulation, B12/Folate, liver function, renal function, and troponin. Nine-I Investigators expert statement's laboratory workup for TTP: cardiac, neurological, renal, and gastrointestinal screening for organ dysfunction; blood cell counts and smear, lactate dehydrogenase, haptoglobin, bilirubin, direct antiglobulin test, basic coagulation tests, and tests for proteinuria and hematuria; bone marrow aspiration in patients with atypical TMA features or other diseases	Not otherwise specified (ISTH 2020). “ADAMTS13 activity 3 mo from diagnosis may […] predict the risk of subsequent relapse” (BSH 2023). French Reference Center: assessed every trimester during clinical remission. Acute stage: diagnosis once then weekly after plasma exchange (PEX) until ≥50% Long-term follow-up: every 3 mo (Coppo et al)[189]	ISTH 2020 guidelines[187] BSH 2023 guideline[186] Nine-I Investigators expert statement[210] French Reference Center for Thrombotic Microangiopathies[211] Coppo et al[189]
Major bleeding and coagulopathy following trauma	Patients treated or suspected of being treated with oral anticoagulants In VKA-treated patients undergoing an emergency moderate-to-high bleeding-risk procedure, we recommend that INR must be measured on the patient's admission to the hospital (ESAIC, 1B) We suggest the measurement of plasma levels of oral direct antifactor Xa agents such as apixaban, edoxaban or rivaroxaban in patients treated or suspected of being treated with one of these agents (pan-European, Grade 2C) Pan-European guidelines suggest the measurement of DOAC plasma levels in patients treated or suspected of being treated with DOACs (pan-European, Grade 2C). Other patients We recommend the early and repeated monitoring of haemostasis, using either a traditional laboratory determination such as PT/INR, Clauss fibrinogen level and platelet count and/or POC PT/INR and/or a viscoelastic method (pan-European, Grade 1C)	According to the clinical presentation and evolution	2023 (sixth edition) pan-European guideline[126] 2022 (second update) ESAIC guidelines[150]

Abbreviations: ASH, American Society of Hematology; AT, antithrombin; BSH (/BCSH), British Society for Haematology (/British Committee for the Standards in Haematology); DIC, disseminated intravascular coagulation; ESAIC, European Society of Anaesthesiology and Intensive Care; HIT, heparin-induced thrombocytopenia; ISTH(/SCC), International Society on Thrombosis and Haemostasis (/Scientific and Standardization Committee); JSTH, Japanese Society on Thrombosis and Hemostasis; LMWH, low-molecular-weight heparin; mo, months; POC, point of care; PT, prothrombin time; SIC, sepsis-induced coagulopathy; SISET, Italian Society on Haemostasis and Thrombosis; TTP, thrombotic thrombocytopenic purpura; UFH, unfractionated heparin; VKA, vitamin K antagonists.

A common cause of overuse is inappropriate retesting. An effective method of limiting retesting is the implementation of a minimum retesting interval (MRI),[101] which indicates the time window below which repeating the same test in the same patient is likely to be inappropriate in the absence of any significant clinical change or therapeutic intervention, e.g., transfusion. There are already valuable examples of how the use of this approach may substantially reduce the burden of potentially inappropriate retesting, such as that presented in Lippi et al,[102] where a CPOE alert system encompassing pop-up alerts based on retesting interval for 15 laboratory tests yielded a reduction of nearly 13% of the overall cost of laboratory testing. In the absence of any kind of therapeutics, either drug or transfusion, it is also inappropriate to retest the same patient below the half-life of the analyte or drug being tested (when applicable), as the effect measured is unlikely to reflect the real change in the analyte dynamics. For that reason, we have added a column to the table referring to half-life and existing MRI recommendations.

In light of this guidance, we provide below explicit examples of inappropriate (and/or debated) use of standard hemostasis assays in various clinical settings. In general, when considering clotting times, it is preferable to use PT on its own rather than in combination with aPTT, with the exception of cases where the aim is to investigate bleeding that may be caused by inherited or acquired deficiencies in factors VIII, IX, and XI. In such instances, a suitable reagent must be used that is sensitive enough to detect these deficiencies. There are several reasons to preferentially rely on PT over aPTT, given that the latter is subject to numerous drawbacks. These include a high degree of sensitivity to the preanalytical phase,[103] particularly if collected through an inserted vascular line or catheter. Additionally, aPTT is often prolonged for reasons that have no clinical impact. A shortened aPTT, however, may indicate an inflammatory state that accelerates coagulation; nevertheless, the clinical utility of such a finding remains uncertain.[104] Therefore, PT should be the preferred method for detecting acquired coagulopathies, with the exception of the rare condition of acquired hemophilia (auto-antibodies to FVIII) and exceptional auto-antibodies to FIX and FXI.[105] Additionally, in cases of anticoagulation with a vitamin K antagonist, during a bleeding event, or prior to an invasive procedure, aPTT may indicate the rare variant of FIX that renders patients hypersensitive to vitamin K antagonists (VKA), which would otherwise be undetected through INR.[106] [107] It is imperative that the aPTT be determined prior to the commencement of any anticoagulant treatment. An extended aPTT may indicate the presence of a lupus anticoagulant, which has a clinical impact. This may be the case in instances where there is a suspected catastrophic APS.[108] In such instances, when there is an acute thrombotic event, parenteral anticoagulation is switched to the oral route, VKA should be preferred over direct oral anticoagulants (DOACs).[109] [110] In the event that a basal aPTT is conducted at the time of admission or at the onset of an acute intercurrent illness and yields a normal result, retesting of aPTT is not an efficacious course of action (although it may be employed for unfractionated heparin (UFH) monitoring, for those who still utilize it, either alone or in conjunction with an anti-Xa assay).

Liver Disease

The liver is the main organ for synthetis of the majority of coagulation factors as well as for naturally occurring coagulation inhibitors such as AT, PC, or PS. Liver disease leads to a reduction in the synthesis of coagulation factors, resulting in prolonged PT as well aPTT in severe cases but also in a reduction of anticoagulants. Similarly, hypersplenism, induced thrombocytopenia is compensated by an increase in endothelium-derived von Willebrand factor (VWF), which enhances platelet function.[111] Consequently, liver diseases contribute to an rebalanced hemostatic system, resulting in a normocoagulable or hypercoagulable state that cannot be detected by conventional coagulation tests.[112] [113] In this context, prolonged PT and thrombocytopenia are not reliable predictors of bleeding risk, and current guidelines do not recommend the use of blood components (fresh frozen plasma, prothrombin complex, fibrinogen) to correct those abnormalities for management of periprocedural bleeding.[114] [115] The misconception that conventional coagulation tests indicate a hypocoagulable state in patients with cirrhosis is reinforced by the frequent hemorrhagic complications associated with this condition. Hemorrhagic events in patients with liver disease or cirrhosis are primarily due to mechanical causes in which the hemostatic state has little influence.[116] Transfusion of blood components to correct the alleged hemostatic defect is not only ineffective, but may also exacerbate bleeding by further increasing portal hypertension due to fluid overload.[117]

Another important aspect of understanding hemostasis in patients with cirrhosis is that the rebalanced hemostatic state seen in compensated cirrhotic patients can be perturbed by clinical events such as variceal bleeding, acute kidney injury, or inflammation. Such perturbations often result in a shift toward hypercoagulability.[118] At the same time, decompensation of cirrhosis may be associated with worsening disease severity or result in volume expansion, as seen in conditions such as acute kidney injury. This exacerbates portal hypertension and increases the risk of bleeding. The assessment of hemostasis in a patient with liver disease/cirrhosis must, therefore, consider its variability over time and the influence of specific clinical events. Hemostatic assessment cannot rely solely on standard coagulation tests such as PT ratio or aPTT and must take primary hemostasis, the whole coagulation system (including both pro- and anticoagulant factors), and fibrinolysis into account. Similarly, viscoelastometric assays (TEG/ROTEM) lack the sensitivity to detect VWF, as well as minor to moderate hyperfibrinolysis and natural anticoagulants. Finally, there is no standardization or interchangeability of results across different instrument technologies.[119]

Collectively, current tests for hemostasis are inadequate to assess the perioperative risk of bleeding. New tests such as thrombomodulin-modified thrombin generation validated by prospective design and clinical end points are urgently required.[120] Until results from these studies are available, clinicians should refrain from using traditional hemostasis tests and arbitrary cutoffs to make decision on perioperative prophylaxis.

Disseminated Intravascular Coagulation

It is notable that aPTT is not included in any of the scoring systems for overt DIC, the Japanese Association for Acute Medicine (JAAM) DIC, or sepsis-induced coagulopathy (SIC).[121] PT suffices. Consequently, it is inadvisable to utilize aPTT for diagnosing DIC. AT is included in the diagnostic criteria for DIC proposed by the Japanese Society on Thrombosis and Hemostasis (JSTH), but not by the International Society of Thrombosis and Hemostasis (ISTH). However, the ISTH has recently mentioned that AT activity and VWF are interesting biomarkers because changes in their plasma levels may reflect clinical severity and can be assessed easily in many clinical settings at the present.[121] Similarly, the measurement of fibrin monomers (FM)―FMs (half-life: 2–6 hours[122]), produced as a result of the action of thrombin on fibrinogen, are highly reactive molecules that assemble to form protofibrils but can also associate with two fibrinogen molecules, which limits their molecular mass so that they remain soluble, and thus accessible to measurement in plasma[122]―is included in the diagnostic criteria for DIC proposed by the JSTH but not by the ISTH. The SepsiCoag multicentric prospective observational study on patients entering an ICU with septic shock has recently evaluated the prognostic potential of fibrin generation markers (FGMs) tested at inclusion in the study, on survival at day 30. FM was the FGM best related with late prognosis.[123] FMs were higher in nonsurvivors, whereas it was not the case for D-dimers or fibrin/fibrinogen degradation product (FDP) values. Similarly, a 2017 study[124] showed that FM is a more effective indicator than D-dimers for differentiating patients with overt DIC and non-overt DIC from non-DIC patients. However, it should be noted that FM is sensitive to several preanalytical artifacts: vigorous mixing, pneumatic tube system (PTS) use, the time interval between blood collection and centrifugation, tube underfilling, and tourniquet tightening (highly tight for more than 3 minutes).[125]

Major Bleeding and Coagulopathy Following Trauma

It is inadvisable to resort to aPTT and platelet function tests in the context of significant bleeding. In accordance with the sixth edition of the European Guideline on the Management of Major Bleeding and Coagulopathy following Trauma,[126] the routine use of point-of-care (POC) platelet function testing devices in trauma patients on antiplatelet therapy or with suspected platelet dysfunction is not recommended (Grade 1C). Moreover, only PT, Clauss fibrinogen level, platelet count, and/or POC PT/INR and/or a viscoelastometric method should be used for monitoring coagulation in the event of major bleeding (Grade 1C).[126]

Preoperative Screening

There is a strong misbelief that coagulation screen tests can provide a general overview of the overall hemostatic system so that having normal PT and aPTT reassures about normal hemostasis during an invasive procedure or surgery. However, coagulation screen does not reliably reproduce the physiological coagulation cascade, and those tests do not completely reflect many aspects of hemostasis including abnormalities in VWF, platelet function, factor XIII, natural coagulation inhibitors, and, last but not least, endothelial dysfunction. In addition, mild coagulation deficiencies are sometimes overlooked by PT and aPTT. Similarly, VETs do not show the whole coagulation process as they are not sensitive to von Willebrand factor and minor/moderate fibrinolytic activity as well as natural anticoagulants, and have limited sensitivity to platelet function.[119] [127] In addition, POCTs are a cause of concern, because nonrestriction of ordering laboratory testing could lead to overuse. Therefore, normal or abnormal coagulation screen tests cannot make us certain that the patient will achieve adequate hemostasis during an invasive procedure or surgery.[70] Sensitivity and specificity of systematic PT, aPTT, and platelet count to identify patients with hemostasis abnormalities leading to an increased bleeding risk were only 44% (95% CI, 22–69%) and 93% (95% CI, 91–94%).[128]

Venous Thromboembolism-Thrombophilia

The large, multicenter international Computerized Registry of Patients with Venous Thromboembolism (RIETE) of >100,000 patients with VTE has recently studied the impact of heritable thrombophilia on anticoagulant management and clinical outcomes. Approximately 20% of all patients were tested for heritable thrombophilia. Clinical characteristics and VTE risk factors differed markedly between tested and untested patients with VTE. Testing for heritable thrombophilia was performed more frequently in younger patients, patients with VTE provoked by estrogen use, pregnancy or postpartum, unprovoked VTE, and prior VTE.[129] The ASH 2023 guideline[86] used a modeling approach to address 23 clinical questions. For patients with VTE, conditional recommendations for thrombophilia testing and subsequent continuation of anticoagulant treatment in those with thrombophilia were given only in the following scenarios: (1) for patients with VTE associated with nonsurgical major transient or hormonal risk factors and (2) for patients with cerebral or splanchnic venous thrombosis, in settings in which anticoagulation would otherwise be discontinued. For all other scenarios (i.e., unprovoked VTE as well as VTE provoked by major surgery), the panel provided conditional recommendations against testing for thrombophilia. However, these recommendations suffer from certain limitations that may have potentially generated inappropriate recommendations, as recently illustrated by Djulbegovic et al.[130] The BSH guideline on thrombophilia testing used more pragmatic approach, endorsing the recommendations based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature to evaluate levels of evidence and to assess the strength of recommendations.[131] Recommendations on thrombophilia testing in various clinical scenarios by the BSH and ASH guidelines are summarized in [Table 4]. The ASH-ASPHO Choosing Wisely Campaign recommends avoiding thrombophilia testing in children with venous access-associated thrombosis and no positive family history.[132] In conclusion, clinical practice data from the RIETE Registry in patients with VTE confirms that testing for inherited thrombophilia is widely performed despite lack of evidence on their clinical predictive values and no influence in clinical management. Recommendations derived from the guidelines are still based on indirect evidence, and whether and how thrombophilia testing should inform clinical decisions requires additional clinical evidence.

Table 4 Comparison of two guidelines (BSH and ASH) on recommendations for thrombophilia testing in specific acute settings

Clinical scenario	BSH 2024 guideline[193]	Level of evidence (grade)	ASH 2023 guideline[86]	Level of evidence	Comment
General	Testing for inherited thrombophilia after a venous thrombotic event is not routinely recommended to guide clinical management	2B	Patients with symptomatic VTE, unspecified type of VTE (i.e., not specified as provoked or unprovoked VTE): Do not test for thrombophilia	Conditional, very low level of evidence	Agreement
Timing of thrombophilia testing following acute thrombosis	Testing for deficiencies of physiological anticoagulants should be performed only after 3 mo of anticoagulation for acute thrombosis	2B	Not addressed	/	Nota. Disagreement between BSH and French guidelines
Testing for aPL following unprovoked VTE	Testing is recommended as results may guide clinical management including the choice of antithrombotic therapy	1B	Testing is not recommended	Conditional, very low level of evidence	Discordance
Testing for aPL following VTE provoked by a minor risk factor	Testing is suggested as results may guide clinical management including the choice of antithrombotic therapy	2C	Testing is not recommended following VTE-associated major risk surgical or non-surgical major risk factor, pregnancy/postpartum, or oral contraceptives	Conditional, very low level of evidence	The definition of a minor risk factor is not specified in BSH guidelines
Assessment of possible CAPS in patients with acute multiple thrombosis	Patients with acute multiple thrombotic events and evidence of organ failure suggestive of CAPS should be tested for antiphospholipid antibodies	1A	Not addressed	/	/
Thrombosis at unusual sites (testing for heritable thrombophilia)	Testing is not recommended as the association is weak and clinical management would not be changed if thrombophilia defects are found	2B	Testing is recommended only if anticoagulation would otherwise be discontinued after primary short-term period treatment	Conditional, very low level of evidence	Agreement
Thrombosis at unusual sites (testing for aPL)	Testing is recommended in the absence of clear provoking factors as the type and duration of anticoagulation are influenced by the presence of these antibodies	1A	Testing (including aPL) is recommended only if anticoagulation would otherwise be discontinued after primary short-term period treatment	Conditional, very low level of evidence	Discordance
Thrombosis at unusual sites (testing for PNH)	Testing for PNH is suggested with abnormal hematological parameters (i.e., cytopenia and abnormal red cell indices) or evidence of hemolysis (i.e., increased lactate dehydrogenase, bilirubin, and reticulocyte count)	2C	Does not mention about PNH testing	/	Discordance
Thrombosis at unusual sites (testing for MPN panel)	Testing for MPN panel (including JAK2 V617F, JAK2 exon 12, CALR, MPL mutation analysis) is recommended in the presence of full blood count abnormalities suggestive of an MPN	1C	Does not mention about MPN testing	/	Discordance
Thrombosis at unusual sites (testing for JAK2 mutation)	Testing for JAK2 mutation is suggested in splanchnic vein thrombosis or cerebral venous sinus thrombosis in the absence of clear provoking factors and a normal full blood count	2C	Does not mention about JAK2 mutation testing	/	Discordance
Testing for aPL in patients with RVO	Testing may be considered in the absence of any other risk factors associated with RVO	2C	Does not discuss about RVO and thrombophilia testing	/	Discordance
Arterial thrombosis	Testing for inherited thrombophilia is not recommended	1B	Not addressed	/	/
aPL testing in arterial thrombosis	Testing is recommended in the absence of other vascular risk factors	1B	Not addressed	/	/
PNH and MPN testing in arterial thrombosis	Testing is considered if abnormal blood parameters suggestive of MPN or PNH	2C	Not addressed	/	/
Ischemic stroke, all types except cerebral venous sinus thrombosis Testing for heritable thrombophilia	Testing is not recommended	1A	Not addressed	/	/
Ischemic stroke, all types except cerebral venous sinus thrombosis Testing for aPL	Testing should be considered in young (<50 years of age) in the absence of identifiable risk factors for cardiovascular disease	1A	Not addressed	/	/
Ischemic stroke, all types except cerebral venous sinus thrombosis Testing for PNH/MPN	Consider testing with an abnormal full blood count	2C	Not addressed	/	/
Thrombophilia testing in stroke and patent foramen ovale closure	Testing is not suggested	2C	Not addressed	/	/
Thrombophilia testing in children with purpura fulminans	Urgent testing for protein C and S deficiency is recommended	1B	Not addressed	/	/
Thrombophilia testing neonatal stroke	Routine testing is not recommended	2B	Not addressed	/	/
Thrombophilia testing in neonatal thrombosis	With multiple unexplained thrombosis, especially with clinical evidence suggestive of CAPS, testing for aPL and heritable thrombophilia should be considered	2D	Not addressed	/	/
Heritable thrombophilia testing in pregnancy complications	Recommended against thrombophilia testing	2B	VTE provoked by pregnancy or postpartum: test for thrombophilia	Conditional, very low level of evidence	Discordance
aPL testing in pregnancy complications	Screening for aPL can be considered with recurrent or late pregnancy loss, as the results aid risk stratification and treatment decisions	2B	Does not mention about aPL testing in pregnancy complications	Conditional, very low level of evidence	Discordance

Abbreviations: aPL, antiphospholipid antibodies; CAPS, catastrophic antiphospholipid syndrome; mo, month; MPN, myeloproliferative neoplasms; PNH, paroxysmal nocturnal hemoglobinuria; RVO, retinal vein occlusion; VTE, venous thromboembolism.

Interferences

Certain clinical circumstances have the potential to impede the accuracy of hemostasis tests. For example, according to BSH guidelines, thrombophilia testing should be avoided in patients who have experienced a recent VTE event to allow complete restoration of physiological inhibitors after the acute episode of thrombosis and avoid unreliable, namely, false positive, test results.[133] However, according to the French guidelines, thrombophilia testing may be performed in acute thrombosis but results of LAC, AT, PC, and PS testing during an acute phase response should be interpreted with caution, as false-positive and -negative results can occur.[28] Performing AT and PC at the acute phase allows the exclusion of a defect in case of normal results.[134] [135] Similarly, VKAs such as warfarin must be suspended and switched to a suitable alternative anticoagulant such as LMWH (sample for testing should be taken just prior to the next dose of LMWH) before testing for thrombophilia (especially for LAC, activated protein C resistance, PC, and PS).[136] aPTT-based assay should not be performed, whereas dRVVT may be performed but interpreted with caution if INR[137] is between 1 and 3. Furthermore, acute inflammation, which is a common occurrence in acute patients, can interfere with LAC assays based on aPTT and dRVVT.[138] Consequently, these assays should be used in such patients with much caution. Finally, when thrombophilia testing is performed at least 3 to 6 months after an acute episode of VTE results in patients requiring longer anticoagulation, DOAC removal agents may be used to avoid interference of DOACs.[139] [140] [141] [142] However, despite the use of DOAC removal agents, very low DOAC levels (below the detection threshold) may impact dRVVT.

Conclusion

Inappropriate use of laboratory resources is common and may have serious adverse consequences. Implementation of guidance-based interventions is an effective strategy to reduce inappropriate use of hemostasis testing. However, few interventions use evidence-based guidance/recommendations for testing when providing indications for testing, even when these guidance/recommendations are available. A deeper understanding of the factors contributing to the underutilization of existing guidelines (i.e., based on low evidence) would prove invaluable in the future when designing interventions to reduce inappropriate laboratory testing. In this review, we aimed to provide a summary of guidance available for the most commonly prescribed hemostasis tests in the acute setting. We emphasize the importance of involving laboratory specialists in the design of guidelines and working in close collaboration with clinicians. Diagnostic workup could be greatly enhanced if the laboratory would receive clinical information (e.g., which clinical question needs to be answered? what is the pretest probability of the condition searched for?) and test results would be given with a comment on their clinical relevance (e.g., risk profile of antiphospholipid antibodies, likelihood ratio [or even better negative predictive value/positive predictive value] of the quantitative test result).

Conflict of Interest

The authors declare that they have no conflict of interest.

Acknowledgment

None.

Authors' Contribution

L.D. and F.M. contributed to the design of the manuscript. L.D. and F.M. drafted the manuscript and tables. D.J.A., M.H., A.M., E.C., M.C., I.G-T., C.F., T.L., L.A., J.C., G.L., and F.M. substantially revised and enhanced the manuscript. All authors approved the final version of the manuscript.

• References

• 1 Lippi G. The irreplaceable value of laboratory diagnostics: four recent tests that have revolutionized clinical practice. EJIFCC 2019; 30 (01) 7-13
• 2 Mrazek C, Simundic AM, Salinas M. et al. Inappropriate use of laboratory tests: how availability triggers demand - examples across Europe. Clin Chim Acta 2020; 505: 100-107
• 3 VanSpronsen AD, Zychla L, Turley E, Villatoro V, Yuan Y, Ohinmaa A. Causes of inappropriate laboratory test ordering from the perspective of medical laboratory technical professionals: implications for research and education. Lab Med 2023; 54 (01) e18-e23
• 4 Vrijsen BEL, Naaktgeboren CA, Vos LM, van Solinge WW, Kaasjager HAH, Ten Berg MJ. Inappropriate laboratory testing in internal medicine inpatients: prevalence, causes and interventions. Ann Med Surg (Lond) 2020; 51: 48-53
• 5 Lippi G, Bovo C, Ciaccio M. Inappropriateness in laboratory medicine: an elephant in the room?. Ann Transl Med 2017; 5 (04) 82
• 6 Zhi M, Ding EL, Theisen-Toupal J, Whelan J, Arnaout R. The landscape of inappropriate laboratory testing: a 15-year meta-analysis. PLoS One 2013; 8 (11) e78962
• 7 Cadamuro J, Gaksch M, Wiedemann H. et al. Are laboratory tests always needed? Frequency and causes of laboratory overuse in a hospital setting. Clin Biochem 2018; 54: 85-91
• 8 Mansour A, Flecher E, Schmidt M. et al; ECMOSARS Investigators. Bleeding and thrombotic events in patients with severe COVID-19 supported with extracorporeal membrane oxygenation: a nationwide cohort study. Intensive Care Med 2022; 48 (08) 1039-1052
• 9 Devis L, Catry E, Honore PM. et al. Interventions to improve appropriateness of laboratory testing in the intensive care unit: a narrative review. Ann Intensive Care 2024; 14 (01) 9
• 10 Lippi G, Favaloro EJ. Exploring the iceberg of inappropriateness in hemostasis testing. Diagnosis (Berl) 2017; 4 (01) 1-2
• 11 Pennestrì F, Banfi G. Value-based healthcare: the role of laboratory medicine. Clin Chem Lab Med 2019; 57 (06) 798-801
• 12 Plebani M, Cadamuro J, Vermeersch P. et al. A vision to the future: value-based laboratory medicine. Clin Chem Lab Med 2024; 62 (12) 2373-2387
• 13 Institute of Medicine, Council on Health Care Technology. Assessment of Diagnostic Technology in Health Care: Rationale, Methods, Problems, and Directions. National Academies Press; 1989
• 14 Lundberg GD. The need for an outcomes research agenda for clinical laboratory testing. JAMA 1998; 280 (06) 565-566
• 15 Devis L, Closset M, Degosserie J. et al. Revisiting the environmental impact of inappropriate clinical laboratory testing: a comprehensive overview of sustainability, economic, and quality of care outcomes. J Appl Lab Med 2024; jfae087
• 16 Spoyalo K, Lalande A, Rizan C. et al. Patient, hospital and environmental costs of unnecessary bloodwork: capturing the triple bottom line of inappropriate care in general surgery patients. BMJ Open Qual 2023; 12 (03) e002316
• 17 Sarkar MK, Botz CM, Laposata M. An assessment of overutilization and underutilization of laboratory tests by expert physicians in the evaluation of patients for bleeding and thrombotic disorders in clinical context and in real time. Diagnosis (Berl) 2017; 4 (01) 21-26
• 18 Cadamuro J, Simundic AM, von Meyer A. et al. Diagnostic workup of microcytic anemia: an evaluation of underuse or misuse of laboratory testing in a hospital setting using the AlinIQ system. Arch Pathol Lab Med 2023; 147 (01) 117-124
• 19 Koch CG, Li L, Sun Z. et al. Hospital-acquired anemia: prevalence, outcomes, and healthcare implications. J Hosp Med 2013; 8 (09) 506-512
• 20 Bodley T, Chan M, Levi O. et al. Patient harm associated with serial phlebotomy and blood waste in the intensive care unit: a retrospective cohort study. PLoS One 2021; 16 (01) e0243782
• 21 Helmer P, Hottenrott S, Steinisch A. et al. Avoidable blood loss in critical care and patient blood management: scoping review of diagnostic blood loss. J Clin Med 2022; 11 (02) 320
• 22 Siegal DM, Belley-Côté EP, Lee SF. et al. Small-volume blood collection tubes to reduce transfusions in intensive care: the STRATUS randomized clinical trial. JAMA 2023; 330 (19) 1872-1881
• 23 Lippi G, Plebani M. Laboratory “incidentalomas”: facts or fiction?. Eur J Intern Med 2010; 21 (06) 572
• 24 Pilowsky JK, Lane K, Learmonth G. et al; APTIC Investigators. Environmental impact of a blood test reduction intervention in adult intensive care units: a before and after quality improvement project. Aust Crit Care 2024; 37 (05) 761-766
• 25 The economics of diagnostic safety. OECD. September 17, 2024. Accessed October 5, 2024 at: https://www.oecd.org/en/publications/2024/09/the-economics-of-diagnostic-safety_2056205e.html
• 26 Thachil J, Lippi G, Favaloro EJ. D-dimer testing: laboratory aspects and current issues. Methods Mol Biol 2017; 1646: 91-104
• 27 Gonzaga Y, De Alencar JN. Advocating prudent D-dimer testing: constructive perspectives and comments on ‘How we manage a high D-dimer’. Haematologica 2024; 109 (10) 3452-3453
• 28 Devreese KMJ, de Groot PG, de Laat B. et al. Guidance from the Scientific and Standardization Committee for lupus anticoagulant/antiphospholipid antibodies of the International Society on Thrombosis and Haemostasis: update of the guidelines for lupus anticoagulant detection and interpretation. J Thromb Haemost 2020; 18 (11) 2828-2839
• 29 Manning JE, Arachchillage DJ. Dilemmas in the diagnosis and management of antiphospholipid syndrome. J Thromb Haemost 2024; 22 (08) 2156-2170
• 30 Schouwers SME, Delanghe JR, Devreese KMJ. Lupus anticoagulant (LAC) testing in patients with inflammatory status: does C-reactive protein interfere with LAC test results?. Thromb Res 2010; 125 (01) 102-104
• 31 Smart D, Schreier J, Singh IR. Inappropriate laboratory testing: significant waste quantified by a large-scale year-long study of Medicare and commercial payer reimbursement. Arch Pathol Lab Med 2024;
• 32 Virparia R, Brunetti L, Vigdor S, Adams CD. Appropriateness of thrombophilia testing in patients in the acute care setting and an evaluation of the associated costs. J Thromb Thrombolysis 2020; 49 (01) 108-112
• 33 Breth-Petersen M, Bell K, Pickles K, McGain F, McAlister S, Barratt A. Health, financial and environmental impacts of unnecessary vitamin D testing: a triple bottom line assessment adapted for healthcare. BMJ Open 2022; 12 (08) e056997
• 34 Lippi G, Daves M. Estimating the environmental impact of inappropriate laboratory testing. J Lab Precis Med 2017; 2: 52
• 35 McAlister S, Barratt AL, Bell KJ, McGain F. The carbon footprint of pathology testing. Med J Aust 2020; 212 (08) 377-382
• 36 Lang TF. Inappropriate laboratory testing: the hidden cost to the environment—time for a database of associated costs. J Appl Lab Med 2024; 9 (05) 1070-1072
• 37 Rabin AS, Lai PS, Maximous SI, Shankar HM. Reducing the climate impact of critical care. CHEST Crit Care 2024; 2 (01) 100037
• 38 Ostermann M, De Waele JJ, Schefold JC. The environmental impact of laboratory measurements in high-resource ICUs. Intensive Care Med 2024; 50 (03) 449-452
• 39 Pennestrì F, Tomaiuolo R, Banfi G, Dolci A. Blood over-testing: impact, ethical issues and mitigating actions. Clin Chem Lab Med 2024; 62 (07) 1283-1287
• 40 Oakman G, Anderson A, Oosthuizen JW, Olaussen A. Pathology requesting in a regional Australian Emergency Department; an observational study comparing current practice with college guidelines. Aust J Rural Health 2024; 32 (05) 1062-1067
• 41 Tientadakul P, Chinthammitr Y, Sanpakit K, Wongwanit C, Nilanont Y. Inappropriate use of protein C, protein S, and antithrombin testing for hereditary thrombophilia screening: an experience from a large university hospital. Int J Lab Hematol 2011; 33 (06) 593-600
• 42 Cuker A, Arepally GM, Chong BH. et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia. Blood Adv 2018; 2 (22) 3360-3392
• 43 Jindal V, Singh A, Siddiqui AD, Leb L. The appropriateness of testing platelet factor 4/heparin antibody in patients suspected of heparin-induced thrombocytopenia. Cureus 2018; 10 (10) e3532
• 44 Beauverd Y, Boehlen F, Tessitore E. et al. Suspicion of heparin-induced thrombocytopenia in internal medicine: How appropriate is the ordering of anti-PF4/heparin antibody testing?. Platelets 2015; 26 (07) 632-637
• 45 Crowther M, Cook D, Guyatt G. et al; PROTECT collaborators, Canadian Critical Care Trials Group, Australian and New Zealand Intensive Care Society Clinical Trials Group. Heparin-induced thrombocytopenia in the critically ill: interpreting the 4Ts test in a randomized trial. J Crit Care 2014; 29 (03) 470.e7-470.e15
• 46 Oliver M, Karkhaneh M, Karathra J, Goubran M, Wu CM. A review of inappropriate D-dimer ordering at a Canadian tertiary care centre. Blood 2019; 134 (Suppl. 01) 5778
• 47 Jones P, Elangbam B, Williams NR. Inappropriate use and interpretation of D-dimer testing in the emergency department: an unexpected adverse effect of meeting the “4-h target”. Emerg Med J 2010; 27 (01) 43-47
• 48 Franchini M, Focosi D, Pezzo MP, Mannucci PM. Response to the comment: "Advocating prudent D-dimer testing: constructive perspectives and comments on “How we manage a high D-dimer”. Haematologica 2024; 109 (10) 3454
• 49 Thonon H, Van Nieuwenhove M, Thachil J, Lippi G, Hardy M, Mullier F. Hemostasis testing in the emergency department: a narrative review. Semin Thromb Hemost 2024;
• 50 Mansour A, Berahou M, Odot J. et al. Antithrombin levels and heparin responsiveness during venoarterial extracorporeal membrane oxygenation: a prospective single-center cohort study. Anesthesiology 2024; 140 (06) 1153-1164
• 51 Mrazek C, Haschke-Becher E, Felder TK, Keppel MH, Oberkofler H, Cadamuro J. Laboratory demand management strategies-an overview. Diagnostics (Basel) 2021; 11 (07) 1141
• 52 Cadamuro J, Ibarz M, Cornes M. et al. Managing inappropriate utilization of laboratory resources. Diagnosis (Berl) 2019; 6 (01) 5-13
• 53 Bindraban RS, Ten Berg MJ, Naaktgeboren CA, Kramer MHH, Van Solinge WW, Nanayakkara PWB. Reducing test utilization in hospital settings: a narrative review. Ann Lab Med 2018; 38 (05) 402-412
• 54 Fryer AA, Smellie WSA. Managing demand for laboratory tests: a laboratory toolkit. J Clin Pathol 2013; 66 (01) 62-72
• 55 Smellie WSA. Demand management and test request rationalization. Ann Clin Biochem 2012; 49 (Pt 4): 323-336
• 56 Ezzie ME, Aberegg SK, O'Brien Jr JM. Laboratory testing in the intensive care unit. Crit Care Clin 2007; 23 (03) 435-465
• 57 Solomon DH, Hashimoto H, Daltroy L, Liang MH. Techniques to improve physicians' use of diagnostic tests: a new conceptual framework. JAMA 1998; 280 (23) 2020-2027
• 58 Yeshoua B, Bowman C, Dullea J. et al. Interventions to reduce repetitive ordering of low-value inpatient laboratory tests: a systematic review. BMJ Open Qual 2023; 12 (01) e002128
• 59 Lillo S, Larsen TR, Pennerup L, Antonsen S. The impact of interventions applied in primary care to optimize the use of laboratory tests: a systematic review. Clin Chem Lab Med 2021; 59 (08) 1336-1352
• 60 Ferraro S, Panteghini M. The role of laboratory in ensuring appropriate test requests. Clin Biochem 2017; 50 (10-11): 555-561
• 61 Panteghini M, Dolci A, Birindelli S, Szoke D, Aloisio E, Caruso S. Pursuing appropriateness of laboratory tests: a 15-year experience in an academic medical institution. Clin Chem Lab Med 2022; 60 (11) 1706-1718
• 62 Hooper KP, Anstey MH, Litton E. Safety and efficacy of routine diagnostic test reduction interventions in patients admitted to the intensive care unit: a systematic review and meta-analysis. Anaesth Intensive Care 2021; 49 (01) 23-34
• 63 Musca S, Desai S, Roberts B, Paterson T, Anstey M. Routine coagulation testing in intensive care. Crit Care Resusc 2016; 18 (03) 213-217
• 64 Cadamuro J, Mrazek C, Wiedemann H. et al. Effectiveness of a laboratory gate-keeping strategy to overcome inappropriate test utilization for the diagnosis of heparin-induced thrombocytopenia. Semin Thromb Hemost 2017; 43 (06) 645-648
• 65 Gallo T, Curry SC, Heise CW, Antonescu CC, Raschke RA. Clinical decision support to reduce unnecessary diagnostic testing for heparin-induced thrombocytopenia. Br J Haematol 2023; 202 (05) 1011-1017
• 66 Zon RL, Sylvester KW, Rubins D. et al. Electronic alerts to improve management of heparin-induced thrombocytopenia. Res Pract Thromb Haemost 2024; 8 (04) 102423
• 67 Cogan JC, McFarland MM, May JE, Lim MY. Quality improvement approaches to heparin-induced thrombocytopenia: a scoping review. Res Pract Thromb Haemost 2023; 7 (07) 102219
• 68 Thomas L, Woon E, Fong E, Parnaby C, Watson HG. Reducing the use of inappropriate coagulation testing in emergency general surgical patients. Scott Med J 2018; 63 (02) 45-50
• 69 Chee YL, Crawford JC, Watson HG, Greaves M. British Committee for Standards in Haematology. Guidelines on the assessment of bleeding risk prior to surgery or invasive procedures. Br J Haematol 2008; 140 (05) 496-504
• 70 Lester W, Bent C, Alikhan R. et al; BSH Committee. A British Society for Haematology guideline on the assessment and management of bleeding risk prior to invasive procedures. Br J Haematol 2024; 204 (05) 1697-1713
• 71 Tawadrous D, Detombe S, Thompson D, Columbus M, Van Aarsen K, Skoretz T. Reducing unnecessary testing in the emergency department: the case for INR and aPTT. CJEM 2020; 22 (04) 534-541
• 72 Murphy E, MacGlone S, McGroarty C. A novel approach to improving coagulation sample ordering in an emergency department. BMJ Qual Improv Rep 2015; 4 (01) 204785
• 73 Kalsi MS, Foo CT, Farzanehfar P, Ayoub S, Tacey M, Pearson K. Interventions to support Choosing Wisely for coagulation studies in the emergency department. Emerg Med Australas 2020; 32 (06) 1071-1073
• 74 Callum J, Putowski Z, Alhazzani W. et al. Small-volume blood sample collection tubes in adult intensive care units: a rapid practice guideline. Acta Anaesthesiol Scand 2024; 68 (10) 1319-1326
• 75 Baird GS. The Choosing Wisely initiative and laboratory test stewardship. Diagnosis (Berl) 2019; 6 (01) 15-23
• 76 Lippi G, Mattiuzzi C. The biomarker paradigm: between diagnostic efficiency and clinical efficacy. Pol Arch Intern Med 2015; 125 (04) 282-288
• 77 Mullier F, Closset M, Devis L, Honore PM. Which strategies should we use to reduce inappropriate use of laboratory resources in the ICU: guidelines are urgently needed!. Crit Care Med 2024; 52 (06) e327-e328
• 78 Kumwilaisak K, Noto A, Schmidt UH. et al. Effect of laboratory testing guidelines on the utilization of tests and order entries in a surgical intensive care unit. Crit Care Med 2008; 36 (11) 2993-2999
• 79 Dhanani JA, Barnett AG, Lipman J, Reade MC. Strategies to reduce inappropriate laboratory blood test orders in intensive care are effective and safe: a before-and-after quality improvement study. Anaesth Intensive Care 2018; 46 (03) 313-320
• 80 Kotecha N, Shapiro JM, Cardasis J, Narayanswami G. Reducing unnecessary laboratory testing in the medical ICU. Am J Med 2017; 130 (06) 648-651
• 81 Prat G, Lefèvre M, Nowak E. et al. Impact of clinical guidelines to improve appropriateness of laboratory tests and chest radiographs. Intensive Care Med 2009; 35 (06) 1047-1053
• 82 Vrotniakaite-Bajerciene K, Tritschler T, Jalowiec KA. et al. Adherence to thrombophilia testing guidelines and its influence on anticoagulation therapy: a single-center cross-sectional study. Thromb Res 2023; 223: 87-94
• 83 Tagariello G, Radossi P, Salviato R. et al. Clinical relevance of isolated prolongation of the activated partial thromboplastin time in a cohort of adults undergoing surgical procedures. Blood Transfus 2017; 15 (06) 557-561
• 84 Bang HI, Lee JY, Kim HY. et al. Coagulation testing in real-world setting: Insights from a comprehensive survey. Clin Appl Thromb Hemost 2024; 30: 10 760296241228239
• 85 Anderson Z, Ahsan M, Aguirre C, Ramirez M, Plowman K. Inpatient thrombophilia workup; does hematology consult prevent unnecessary testing?. J Investig Med 2024; 72 (04) 392-395
• 86 Middeldorp S, Nieuwlaat R, Baumann Kreuziger L. et al. American Society of Hematology 2023 guidelines for management of venous thromboembolism: thrombophilia testing. Blood Adv 2023; 7 (22) 7101-7138
• 87 Misra S, Moberg-Aakre K, Langlois M. et al. How useful are laboratory practice guidelines?. EJIFCC 2015; 26 (03) 190-196
• 88 Wang T, Tan JB, Liu XL, Zhao I. Barriers and enablers to implementing clinical practice guidelines in primary care: an overview of systematic reviews. BMJ Open 2023; 13 (01) e062158
• 89 Fan BE, Lippi G, Favaloro EJ. D-dimer levels for the exclusion of pulmonary embolism: making sense of international guideline recommendations. J Thromb Haemost 2024; 22 (03) 604-608
• 90 Beloeil H, Ruchard D, Drewniak N, Molliex S. Overuse of preoperative laboratory coagulation testing and ABO blood typing: a French national study. Br J Anaesth 2017; 119 (06) 1186-1193
• 91 Islam MM, Poly TN, Yang HC, Li YJ. Deep into laboratory: an artificial intelligence approach to recommend laboratory tests. Diagnostics (Basel) 2021; 11 (06) 990
• 92 Cismondi F, Celi LA, Fialho AS. et al. Reducing unnecessary lab testing in the ICU with artificial intelligence. Int J Med Inform 2013; 82 (05) 345-358
• 93 Flores E, Martínez-Racaj L, Torreblanca R. et al. Clinical decision support system in laboratory medicine. Clin Chem Lab Med 2023; 62 (07) 1277-1282
• 94 Lee J, Maslove DM. Using information theory to identify redundancy in common laboratory tests in the intensive care unit. BMC Med Inform Decis Mak 2015; 15 (01) 59
• 95 Yu L, Li L, Bernstam E, Jiang X. A deep learning solution to recommend laboratory reduction strategies in ICU. Int J Med Inform 2020; 144 (104282): 104282
• 96 Fang K, Dong Z, Chen X. et al. Using machine learning to identify clotted specimens in coagulation testing. Clin Chem Lab Med 2021; 59 (07) 1289-1297
• 97 Padoan A, Cadamuro J, Frans G. et al. Data flow in clinical laboratories: could metadata and peridata bridge the gap to new AI-based applications?. Clin Chem Lab Med 2024;
• 98 Cadamuro J, Cabitza F, Debeljak Z. et al. Potentials and pitfalls of ChatGPT and natural-language artificial intelligence models for the understanding of laboratory medicine test results. An assessment by the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group on Artificial Intelligence (WG-AI). Clin Chem Lab Med 2023; 61 (07) 1158-1166
• 99 Ibarz M, Cadamuro J, Sumarac Z. et al. Clinicians' and laboratory medicine specialists' views on laboratory demand management: a survey in nine European countries. Diagnosis (Berl) 2020; 8 (01) 111-119
• 100 Testa S, Meijer P, Lasne D, Mullier F. Implementation of the new EUR IVD regulation and relation with ISO15189 accreditation: guidance is urgently required for haemostasis testing. Int J Lab Hematol 2022; 44 (1, Suppl 1): 71-78
• 101 Lang T. Minimum retesting intervals in practice: 10 years experience. Clin Chem Lab Med 2020; 59 (01) 39-50
• 102 Lippi G, Brambilla M, Bonelli P. et al. Effectiveness of a computerized alert system based on re-testing intervals for limiting the inappropriateness of laboratory test requests. Clin Biochem 2015; 48 (16-17): 1174-1176
• 103 McPhedran P, Clyne LP, Ortoli NA, Gagnon PG, Sanders FJ. Prolongation of the activated partial thromboplastin time associated with poor venipuncture technic. Am J Clin Pathol 1974; 62 (01) 16-20
• 104 Lippi G, Salvagno GL, Ippolito L, Franchini M, Favaloro EJ. Shortened activated partial thromboplastin time: causes and management. Blood Coagul Fibrinolysis 2010; 21 (05) 459-463
• 105 Cohen AJ, Kessler CM. Acquired inhibitors. Baillieres Clin Haematol 1996; 9 (02) 331-354
• 106 Chu K, Wu SM, Stanley T, Stafford DW, High KA. A mutation in the propeptide of Factor IX leads to warfarin sensitivity by a novel mechanism. J Clin Invest 1996; 98 (07) 1619-1625
• 107 Oldenburg J, Quenzel EM, Harbrecht U. et al. Missense mutations at ALA-10 in the factor IX propeptide: an insignificant variant in normal life but a decisive cause of bleeding during oral anticoagulant therapy. Br J Haematol 1997; 98 (01) 240-244
• 108 Tripodi A, Cohen H, Devreese KMJ. Lupus anticoagulant detection in anticoagulated patients. Guidance from the Scientific and Standardization Committee for lupus anticoagulant/antiphospholipid antibodies of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2020; 18 (07) 1569-1575
• 109 Dufrost V, Risse J, Reshetnyak T. et al. Increased risk of thrombosis in antiphospholipid syndrome patients treated with direct oral anticoagulants. Results from an international patient-level data meta-analysis. Autoimmun Rev 2018; 17 (10) 1011-1021
• 110 Zuily S, Cohen H, Isenberg D. et al. Use of direct oral anticoagulants in patients with thrombotic antiphospholipid syndrome: guidance from the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2020; 18 (09) 2126-2137
• 111 Lisman T, Bongers TN, Adelmeijer J. et al. Elevated levels of von Willebrand Factor in cirrhosis support platelet adhesion despite reduced functional capacity. Hepatology 2006; 44 (01) 53-61
• 112 Tripodi A, Salerno F, Chantarangkul V. et al. Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology 2005; 41 (03) 553-558
• 113 Lisman T, Hernandez-Gea V, Magnusson M. et al. The concept of rebalanced hemostasis in patients with liver disease: communication from the ISTH SSC working group on hemostatic management of patients with liver disease. J Thromb Haemost 2021; 19 (04) 1116-1122
• 114 Northup PG, Garcia-Pagan JC, Garcia-Tsao G. et al. Vascular liver disorders, portal vein thrombosis, and procedural bleeding in patients with liver disease: 2020 practice guidance by the American Association for the Study of Liver Diseases. Hepatology 2021; 73 (01) 366-413
• 115 European Association for the Study of the Liver. Electronic address: [e-mail], European Association for the Study of the Liver. EASL Clinical Practice Guidelines on prevention and management of bleeding and thrombosis in patients with cirrhosis. J Hepatol 2022; 76 (05) 1151-1184
• 116 Rautou PE, Caldwell SH, Villa E. Bleeding and thrombotic complications in patients with cirrhosis: a state-of-the-art appraisal. Clin Gastroenterol Hepatol 2023; 21 (08) 2110-2123
• 117 Lisman T, Procopet B. Fresh frozen plasma in treating acute variceal bleeding: not effective and likely harmful. Liver Int 2021; 41 (08) 1710-1712
• 118 Zanetto A, Northup P, Roberts L, Senzolo M. Haemostasis in cirrhosis: understanding destabilising factors during acute decompensation. J Hepatol 2023; 78 (05) 1037-1047
• 119 Mansour A, Godier A, Lecompte T, Roullet S. Ten considerations about viscoelastometric tests. Anaesth Crit Care Pain Med 2024; 43 (03) 101366
• 120 Tripodi A, Primignani M, D'Ambrosio R. et al. Reappraisal of the conventional hemostasis tests as predictors of perioperative bleeding in the era of rebalanced hemostasis in cirrhosis. Hepatology 2024;
• 121 Iba T, Levi M, Thachil J, Helms J, Scarlatescu E, Levy JH. Communication from the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis on sepsis-induced coagulopathy in the management of sepsis. J Thromb Haemost 2023; 21 (01) 145-153
• 122 Hardy M, Michaux I, Bulpa P. et al. Serial fibrin monomer and D-dimer plasma levels measurements can capture thrombotic complications in critically ill COVID-19 patients: a prospective observational study. Thromb Res 2023; 221: 69-72
• 123 Gris JC, Cochery-Nouvellon E, Bouvier S. et al. Clinical value of automated fibrin generation markers in patients with septic shock: a SepsiCoag ancillary study. Br J Haematol 2018; 183 (04) 636-647
• 124 Singh N, Pati HP, Tyagi S, Upadhyay AD, Saxena R. Evaluation of the diagnostic performance of fibrin monomer in comparison to d-dimer in patients with overt and nonovert disseminated intravascular coagulation. Clin Appl Thromb Hemost 2017; 23 (05) 460-465
• 125 Bouarroudj HZ, Hardy M, Lecompte T, Mullier F. Preanalytical conditions impact fibrin monomers but not D-dimer: a study with rigorous comparisons of a broad range of simulated conditions. Int J Lab Hematol 2024;
• 126 Rossaint R, Afshari A, Bouillon B. et al. The European guideline on management of major bleeding and coagulopathy following trauma: sixth edition. Crit Care 2023; 27 (01) 80
• 127 Ranucci M, Baryshnikova E. Sensitivity of viscoelastic tests to platelet function. J Clin Med 2020; 9 (01) 189
• 128 Ajzenberg N, Longrois D, Faille D. et al. Sensitivity and specificity of strategies to identify patients with hemostasis abnormalities leading to an increased risk of bleeding before scheduled intervention: the Hemorisk study. J Thromb Haemost 2024; 22 (11) 3048-3058
• 129 Middeldorp S, Iorio A. Thrombophilia testing: does practice follow guidelines?. Blood Adv 2024; 8 (18) 4948-4949
• 130 Djulbegovic B, Hozo I, Guyatt G. Decision theoretical foundations of clinical practice guidelines: an extension of the ASH thrombophilia guidelines. Blood Adv 2024; 8 (13) 3596-3606
• 131 Arachchillage DJ, Mackillop L, Chandratheva A, Motawani J, MacCallum P, Laffan M. Thrombophilia testing: a British Society for Haematology guideline. Br J Haematol 2022; 198 (03) 443-458
• 132 O'Brien SH, Badawy SM, Rotz SJ. et al. The ASH-ASPHO Choosing Wisely Campaign: 5 hematologic tests and treatments to question. Pediatr Blood Cancer 2021; 68 (08) e28967
• 133 Connors JM. Thrombophilia testing and venous thrombosis. N Engl J Med 2017; 377 (12) 1177-1187
• 134 Trillot N, Marlu R, Suchon P. et al. Prescribing and performing a biological assessment for thrombophilia: GFHT 2022 proposals Part I: Clinical aspects and prescription in classic venous thromboembolic disease. Revue Francophone d'Hémostase et Thrombose 2022; 4 (03) 133-152
• 135 Trillot N, Dargaud Y, Gruel Y, Morange P. Prescribing and performing a biological assessment for thrombophilia: GFHT 2022 proposals Part II: Prescribing in the case of atypical thrombosis and in special situations. Revue Francophone d'Hémostase et Thrombose 2022; 4 (04) 197-230
• 136 Alameddine R, Nassabein R, Le Gal G, Sié P, Mullier F, Blais N. Diagnosis and management of congenital thrombophilia in the era of direct oral anticoagulants. Thromb Res 2020; 185: 72-77
• 137 Isert M, Miesbach W, Stoever G, Lindhoff-Last E, Linnemann B. Screening for lupus anticoagulants in patients treated with vitamin K antagonists. Int J Lab Hematol 2015; 37 (06) 758-765
• 138 Hardy M, Catry E, Pouplard M, Lecompte T, Mullier F. Is lupus anticoagulant testing with dilute Russell's viper venom clotting times reliable in the presence of inflammation?. Res Pract Thromb Haemost 2024; 8 (06) 102536
• 139 Favresse J, Lardinois B, Sabor L. et al. Evaluation of the DOAC-Stop® procedure to overcome the effect of DOACs on several thrombophilia screening tests. TH Open 2018; 2 (02) e202-e209
• 140 Favaloro EJ, Pasalic L, Selby R. Testing for the lupus anticoagulant: the good, the bad, and the ugly. Res Pract Thromb Haemost 2024; 8 (03) 102385
• 141 Slavik L, Jacova J, Friedecky D. et al. Evaluation of the DOAC-Stop procedure by LC-MS/MS assays for determining the residual activity of dabigatran, rivaroxaban, and apixaban. Clin Appl Thromb Hemost 2019; 25: 10 76029619872556
• 142 Kopatz WF, Brinkman HJM, Meijers JCM. Use of DOAC Stop for elimination of anticoagulants in the thrombin generation assay. Thromb Res 2018; 170: 97-101
• 143 Umemura Y, Yamakawa K, Hayakawa M, Hamasaki T, Fujimi S. Japan Septic Disseminated Intravascular Coagulation (J-Septic DIC) study group. Screening itself for disseminated intravascular coagulation may reduce mortality in sepsis: a nationwide multicenter registry in Japan. Thromb Res 2018; 161: 60-66
• 144 Iba T, Levy JH, Warkentin TE, Thachil J, van der Poll T, Levi M. Scientific and Standardization Committee on DIC, and the Scientific and Standardization Committee on Perioperative and Critical Care of the International Society on Thrombosis and Haemostasis. Diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation. J Thromb Haemost 2019; 17 (11) 1989-1994
• 145 Thachil J, Warkentin TE. How do we approach thrombocytopenia in critically ill patients?. Br J Haematol 2017; 177 (01) 27-38
• 146 Greinacher A, Selleng K. Thrombocytopenia in the intensive care unit patient. Hematology (Am Soc Hematol Educ Program) 2010; 2010 (01) 135-143
• 147 Greinacher A. Clinical Practice. Heparin-induced thrombocytopenia. N Engl J Med 2015; 373 (03) 252-261
• 148 Gruel Y, De Maistre E, Pouplard C. et al; Members of the French Working Group on Perioperative Haemostasis Groupe D'intérêt en Hémostase Périopératoire GIHP. Diagnosis and management of heparin-induced thrombocytopenia. Anaesth Crit Care Pain Med 2020; 39 (02) 291-310
• 149 Wada H, Thachil J, Di Nisio M. et al; The Scientific Standardization Committee on DIC of the International Society on Thrombosis Haemostasis. Guidance for diagnosis and treatment of DIC from harmonization of the recommendations from three guidelines. J Thromb Haemost 2013; 11 (04) 761-767
• 150 Kietaibl S, Ahmed A, Afshari A. et al. Management of severe peri-operative bleeding: guidelines from the European Society of Anaesthesiology and Intensive Care: Second update 2022. Eur J Anaesthesiol 2023; 40 (04) 226-304
• 151 Spahn DR, Bouillon B, Cerny V. et al. The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition. Crit Care 2019; 23 (01) 98
• 152 Lippi G, Favaloro EJ, Buoro S. Platelet transfusion thresholds: How low can we go in respect to platelet counting?. Semin Thromb Hemost 2020; 46 (03) 238-244
• 153 Lippi G, Favaloro EJ, Franchini M. Dangers in the practice of defensive medicine in hemostasis testing for investigation of bleeding or thrombosis: Part I–routine coagulation testing. Semin Thromb Hemost 2014; 40 (07) 812-824
• 154 Raschke RA, Reilly BM, Guidry JR, Fontana JR, Srinivas S. The weight-based heparin dosing nomogram compared with a “standard care” nomogram. A randomized controlled trial. Ann Intern Med 1993; 119 (09) 874-881
• 155 Smith ML, Wheeler KE. Weight-based heparin protocol using antifactor Xa monitoring. Am J Health Syst Pharm 2010; 67 (05) 371-374
• 156 Baker P, Platton S, Arachchillage DJ. et al; BSH Committee. Measurement of heparin, direct oral anti-coagulants and other non-coumarin anti-coagulants and their effects on haemostasis assays: a British Society for Haematology Guideline. Br J Haematol 2024; 205 (04) 1302-1318
• 157 Gouin-Thibault I, Mansour A, Hardy M. et al. Management of therapeutic-intensity unfractionated heparin: a narrative review on critical points. TH Open 2024; 8 (03) e297-e307
• 158 Levi M, Toh CH, Thachil J, Watson HG. British Committee for Standards in Haematology. Guidelines for the diagnosis and management of disseminated intravascular coagulation. Br J Haematol 2009; 145 (01) 24-33
• 159 Lee A. Emergency management of patients with bleeding disorders: practical points for the emergency physician. Transfus Apher Sci 2019; 58 (05) 553-562
• 160 Casini A, Al-Samkari H, Hayward C, Peyvandi F. Rare bleeding disorders: advances in management. Haemophilia 2024; 30 (Suppl. 03) 60-69
• 161 Kuramatsu JB, Gerner ST, Schellinger PD. et al. Anticoagulant reversal, blood pressure levels, and anticoagulant resumption in patients with anticoagulation-related intracerebral hemorrhage. JAMA 2015; 313 (08) 824-836
• 162 Schwebach AA, Waybright RA, Johnson TJ. Fixed-dose four-factor prothrombin complex concentrate for vitamin K antagonist reversal: Does one dose fit all?. Pharmacotherapy 2019; 39 (05) 599-608
• 163 Powers WJ, Rabinstein AA, Ackerson T. et al. Guidelines for the early management of patients with Acute Ischemic Stroke: 2019 update to the 2018 guidelines for the early management of Acute Ischemic Stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2019; 50 (12) e344-e418
• 164 Bonhomme F, Ajzenberg N, Schved JF, Molliex S, Samama CM. French Anaesthetic and Intensive Care Committee on Evaluation of Routine Preoperative Testing, French Society of Anaesthesia and Intensive Care. Pre-interventional haemostatic assessment: guidelines from the French Society of Anaesthesia and Intensive Care. Eur J Anaesthesiol 2013; 30 (04) 142-162
• 165 Thomas D, Wee M, Clyburn P. et al; Association of Anaesthetists of Great Britain and Ireland. Blood transfusion and the anaesthetist: management of massive haemorrhage. Anaesthesia 2010; 65 (11) 1153-1161
• 166 Advisory panel guidance on minimum retesting intervals for lab tests: Appropriate use recommendation [internet]. Published online June 2024. Accessed August 20, 2024 at: https://pubmed.ncbi.nlm.nih.gov/39088670/
• 167 Pernod G, Godiér A, Gozalo C, Tremey B, Sié P. French National Authority for Health. French clinical practice guidelines on the management of patients on vitamin K antagonists in at-risk situations (overdose, risk of bleeding, and active bleeding). Thromb Res 2010; 126 (03) e167-e174
• 168 Lawrence B, Siau K. Use of FFP to correct INR: time to drop this from the decompensated cirrhosis care bundle?. Frontline Gastroenterol 2022; 13 (05) 456
• 169 Lippi G, Favaloro EJ. Recent guidelines and recommendations for laboratory assessment of the direct oral anticoagulants (DOACs): Is there consensus?. Clin Chem Lab Med 2015; 53 (02) 185-197
• 170 Lessire S, Douxfils J, Baudar J. et al. Is thrombin time useful for the assessment of dabigatran concentrations? An in vitro and ex vivo study. Thromb Res 2015; 136 (03) 693-696
• 171 Wauthier L, Favresse J, Hardy M. et al. D-dimer testing: a narrative review. Adv Clin Chem 2023; 114: 151-223
• 172 Suzuki K, Wada H, Imai H, Iba T, Thachil J, Toh CH. Subcommittee on Disseminated Intravascular Coagulation. A re-evaluation of the D-dimer cut-off value for making a diagnosis according to the ISTH overt-DIC diagnostic criteria: communication from the SSC of the ISTH. J Thromb Haemost 2018; 16 (07) 1442-1444
• 173 Favaloro EJ, Franchini M, Lippi G. Aging hemostasis: changes to laboratory markers of hemostasis as we age - a narrative review. Semin Thromb Hemost 2014; 40 (06) 621-633
• 174 Gouin-Thibault I, Pautas E, Siguret V. Safety profile of different low-molecular weight heparins used at therapeutic dose. Drug Saf 2005; 28 (04) 333-349
• 175 Douxfils J, Ageno W, Samama CM. et al. Laboratory testing in patients treated with direct oral anticoagulants: a practical guide for clinicians. J Thromb Haemost 2018; 16 (02) 209-219
• 176 Levy JH, Shaw JR, Castellucci LA. et al. Reversal of direct oral anticoagulants: guidance from the SSC of the ISTH. J Thromb Haemost 2024; 22 (10) 2889-2899
• 177 Berge E, Whiteley W, Audebert H. et al. European Stroke Organisation (ESO) guidelines on intravenous thrombolysis for acute ischaemic stroke. Eur Stroke J 2021; 6 (01) I-LXII
• 178 Knot EA, de Jong E, ten Cate JW, Gie LK, van Royen EA. Antithrombin III: biodistribution in healthy volunteers. Thromb Haemost 1987; 58 (04) 1008-1011
• 179 Wada H, Takahashi H, Uchiyama T. et al; DIC subcommittee of the Japanese Society on Thrombosis and Hemostasis. The approval of revised diagnostic criteria for DIC from the Japanese Society on Thrombosis and Hemostasis. Thromb J 2017; 15 (01) 17
• 180 Gouin-Thibault I, Mullier F, Lecompte T. “Defining Heparin Resistance: Communication from the ISTH SSC Subcommittee of Perioperative and Critical Care Thrombosis and Hemostasis”: comment from Gouin-Thibault et al. J Thromb Haemost 2024; 22 (02) 572-574
• 181 Helms J, Frere C, Thiele T. et al. Anticoagulation in adult patients supported with extracorporeal membrane oxygenation: guidance from the Scientific and Standardization Committees on Perioperative and Critical Care Haemostasis and Thrombosis of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2023; 21 (02) 373-396
• 182 Van Cott EM, Orlando C, Moore GW, Cooper PC, Meijer P, Marlar R. Subcommittee on Plasma Coagulation Inhibitors. Recommendations for clinical laboratory testing for antithrombin deficiency; communication from the SSC of the ISTH. J Thromb Haemost 2020; 18 (01) 17-22
• 183 Levy JH, Frere C, Koster A. Resistance to unfractionated heparin in the ICU: evaluation and management options. Intensive Care Med 2023; 49 (08) 1005-1007
• 184 McMichael ABV, Ryerson LM, Ratano D, Fan E, Faraoni D, Annich GM. 2021 ELSO adult and pediatric anticoagulation guidelines. ASAIO J 2022; 68 (03) 303-310
• 185 Taylor A, Vendramin C, Oosterholt S, Della Pasqua O, Scully M. Pharmacokinetics of plasma infusion in congenital thrombotic thrombocytopenic purpura. J Thromb Haemost 2019; 17 (01) 88-98
• 186 Scully M, Rayment R, Clark A. et al; BSH Committee. A British Society for Haematology Guideline: diagnosis and management of thrombotic thrombocytopenic purpura and thrombotic microangiopathies. Br J Haematol 2023; 203 (04) 546-563
• 187 Zheng XL, Vesely SK, Cataland SR. et al. ISTH guidelines for the diagnosis of thrombotic thrombocytopenic purpura. J Thromb Haemost 2020; 18 (10) 2486-2495
• 188 Graça NAG, Joly BS, Voorberg J. et al. TTP: from empiricism for an enigmatic disease to targeted molecular therapies. Br J Haematol 2022; 197 (02) 156-170
• 189 Coppo P, Cuker A, George JN. Thrombotic thrombocytopenic purpura: toward targeted therapy and precision medicine. Res Pract Thromb Haemost 2018; 3 (01) 26-37
• 190 Marchetti M, Barelli S, Zermatten MG. et al. Rapid and accurate Bayesian diagnosis of heparin-induced thrombocytopenia. Blood 2020; 135 (14) 1171-1184
• 191 Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med 2001; 344 (17) 1286-1292
• 192 Linkins LA, Bates SM, Lee AYY, Heddle NM, Wang G, Warkentin TE. Combination of 4Ts score and PF4/H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia: prospective cohort study. Blood 2015; 126 (05) 597-603
• 193 Arachchillage DJ, Thachil J, Anderson JAM. et al; BSH Committee. Diagnosis and management of heparin-induced thrombocytopenia: third edition. Br J Haematol 2024; 204 (02) 459-475
• 194 Gall LS, Brohi K, Davenport RA. Diagnosis and treatment of hyperfibrinolysis in trauma (a European perspective). Semin Thromb Hemost 2017; 43 (02) 224-234
• 195 Walsh M, Shreve J, Thomas S. et al. Fibrinolysis in trauma: “Myth,” “Reality,” or “something in between”. Semin Thromb Hemost 2017; 43 (02) 200-212
• 196 Raza I, Davenport R, Rourke C. et al. The incidence and magnitude of fibrinolytic activation in trauma patients. J Thromb Haemost 2013; 11 (02) 307-314
• 197 Gall LS, Davenport RA. Fibrinolysis and antifibrinolytic treatment in the trauma patient. Curr Opin Anaesthesiol 2018; 31 (02) 227-233
• 198 Bareille M, Lecompte T, Mullier F, Roullet S. Are viscoelastometric assays of old generation ready for disposal? Comment on Volod et al. Viscoelastic hemostatic assays: a primer on legacy and new generation devices. J Clin Med 2023; 12 (02) 477
• 199 Hartmann J, Hermelin D, Levy JH. Viscoelastic testing: an illustrated review of technology and clinical applications. Res Pract Thromb Haemost 2022; 7 (01) 100031
• 200 Mannucci PM, Duga S, Peyvandi F. Recessively inherited coagulation disorders. Blood 2004; 104 (05) 1243-1252
• 201 Müller PC, Kabacam G, Vibert E, Germani G, Petrowsky H. Current status of liver transplantation in Europe. Int J Surg 2020; 82S: 22-29
• 202 Goel A, Lalruatsanga D, Himanshu D, Bharti V, Sharma D. Acute liver failure prognostic criteria: it's time to revisit. Cureus 2023; 15 (01) e33810
• 203 Frelinger III AL, Gachet C, Mumford AD. et al; Subcommittee on Platelet Physiology. Laboratory monitoring of P2Y₁₂ inhibitors: communication from the SSC of the ISTH. J Thromb Haemost 2018; 16 (11) 2341-2346
• 204 Godier A, Garrigue D, Lasne D. et al; French Working Group on Perioperative Haemostasis (GIHP). Management of antiplatelet therapy for non-elective invasive procedures or bleeding complications: Proposals from the French Working Group on Perioperative Haemostasis (GIHP) and the French Study Group on Thrombosis and Haemostasis (GFHT), in collaboration with the French Society for Anaesthesia and Intensive Care (SFAR). Arch Cardiovasc Dis 2019; 112 (03) 199-216
• 205 Valgimigli M, Bueno H, Byrne RA. et al; ESC Scientific Document Group, ESC Committee for Practice Guidelines (CPG), ESC National Cardiac Societies. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2018; 39 (03) 213-260
• 206 Ferraris VA, Saha SP, Oestreich JH. et al; Society of Thoracic Surgeons. 2012 update to the Society of Thoracic Surgeons guideline on use of antiplatelet drugs in patients having cardiac and noncardiac operations. Ann Thorac Surg 2012; 94 (05) 1761-1781
• 207 Asakura H, Takahashi H, Uchiyama T. et al; DIC subcommittee of the Japanese Society on Thrombosis and Hemostasis. Proposal for new diagnostic criteria for DIC from the Japanese Society on Thrombosis and Hemostasis. Thromb J 2016; 14 (01) 42
• 208 Di Nisio M, Baudo F, Cosmi B. et al; Italian Society for Thrombosis and Haemostasis. Diagnosis and treatment of disseminated intravascular coagulation: guidelines of the Italian Society for Haemostasis and Thrombosis (SISET). Thromb Res 2012; 129 (05) e177-e184
• 209 Aota T, Wada H, Fujimoto N. et al. Evaluation of the diagnostic criteria for the basic type of DIC established by the Japanese Society of Thrombosis and Hemostasis. Clin Appl Thromb Hemost 2017; 23 (07) 838-843
• 210 Azoulay E, Bauer PR, Mariotte E. et al; Nine-I Investigators. Expert statement on the ICU management of patients with thrombotic thrombocytopenic purpura. Intensive Care Med 2019; 45 (11) 1518-1539
• 211 Coppo P. French Reference Center for Thrombotic Microangiopathies. Management of thrombotic thrombocytopenic purpura. Transfus Clin Biol 2017; 24 (03) 148-153

Publication History

Received: 17 October 2024

Accepted: 02 December 2024

Article published online:
19 February 2025