Critical laboratory values in hemostasis: toward consensus

Abstract

The term “critical values” can be defined to entail laboratory test results that significantly lie outside the normal (reference) range and necessitate immediate reporting to safeguard patient health, as well as those displaying a highly and clinically significant variation compared to previous data. The identification and effective communication of “highly pathological” values has engaged the minds of many clinicians, health care and laboratory professionals for decades, since these activities are vital to good laboratory practice. This is especially true in hemostasis, where a timely and efficient communication of critical values strongly impacts patient management. Due to the heterogeneity of available data, this paper is hence aimed to analyze the state of the art and provide an expert opinion about the parameters, measurement units and alert limits pertaining to critical values in hemostasis, thus providing a basic document for future consultation that assists laboratory professionals and clinicians alike.

KEY MESSAGES

• Critical values are laboratory test results significantly lying outside the normal (reference) range and necessitating immediate reporting to safeguard patient health.

• A broad heterogeneity exists about critical values in hemostasis worldwide.

• We provide here an expert opinion about the parameters, measurement units and alert limits pertaining to critical values in hemostasis.

Keywords:

• Laboratory
• critical values
• alert values
• patient safety
• hemostasis

Introduction

Laboratory diagnostics plays a crucial role in clinical decision making and managed care of many hemostasis disturbances (1). Total quality in the testing process entails a kaleidoscope of issues, beginning with the appropriateness of test ordering and concluding with the timely and efficient communication of test results to the physicians in charge of the patient (2). Experience acquired throughout the relatively long history of diagnostics testing supports the notion that the majority of diagnostic errors occur in the steps preceding the analysis (i.e. the preanalytical phase) or in those afterwards (i.e. the postanalytical phase), which substantially include transmission of test results and their interpretation (3).

The identification and effective communication of so-called “highly pathological” values has engaged the minds of many clinicians, health care and laboratory professionals for decades, since these activities are vital to good laboratory practice (4). Transmission of critical laboratory values is also included among the list of quality indicators developed by the Working Group on Laboratory Errors and Patient Safety (WG-LEPS) of the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) (5). Despite many efforts having been made to improving laboratory effectiveness and standardization, questions remain around the harmonization of critical values in hemostasis testing.

Definitions

A number of definitions, some specific and others diverse have been developed to outline the concept of “highly pathological” values. The first reliable definition was provided by George D. Lundberg nearly 50 years ago (6), and this has been accepted and echoed by several health care and scientific organizations thereafter. The Joint Commission (JC), an independent and not-for-profit organization aiming to improve patient safety and quality of health care, provides two different definitions of critical values (7). Briefly, “critical test results” are those results always necessitating an immediate communication, even if normal (i.e. within the reference range), whereas “critical values” are those lying significantly outside the normal (reference) range and needing immediate communication to ensure the safeguarding of patient health. This latter definition has been endorsed, with minor changes, by the Clinical and Laboratory Standards Institute (CLSI) (8) and by the Royal College of Pathologists of Australasia (RCPA) – Australasian Association of Clinical Biochemists (AACB) Working Party for High Risk Results (9).

Critical values and hemostasis disturbances

Although few doubts remain about the validity of the definition of critical values, the interpretation provided by the JC of “critical test results” is perhaps more problematic and questionable. Indeed, the vast majority of test results in hemostasis and other areas of laboratory diagnostics are expected to be “normal”, meaning most of them will fall within the limits of the reference range. With the exception of point of care (bedside) testing, routine and specialized hemostasis laboratories are physically separated from the clinical wards, sometimes very distant and not directly interfaced by a laboratory information system (10), thus making it impossible for laboratories to cross check every single laboratory result against the patient’s clinical status. As paradigmatic examples, a normal platelet count (i.e. 250 × 10⁹/L) is commonly observed in daily practice and does not increase the degree of alertness of laboratory professionals. However, what if the day previously the platelet count of the same patient was 600 × 10⁹/L? After excluding preanalytical errors, this would represent a greater than 50% decrease in circulating platelets, thus potentially reflecting the presence of life-threatening conditions such as heparin-induced thrombocytopenia (HIT) (11) or disseminated intravascular coagulation (DIC) (12). Therefore, despite being within the reference range, this must be considered a critical value. Acquired hemophilia (13) and over dosage of unfractioned heparin (UFH) (14) represent other examples of critical test results, both reflecting potential causes of a substantially prolonged value of the activated partial thromboplastin time (APTT) (i.e. APTT ratio frequently over 3.0). The laboratory professional may in such cases be persuaded to contact the clinical teams as soon as possible, since the management of these conditions requires the establishment of a timely and appropriate clinical or therapeutic management. Alternatively, inherited deficiency of factor (F) XII or pre-kallikrein are rather frequent, but clinically meaningless, conditions causing highly elevated APTTs (15). FXII and kallikrein do not actively participate in physiologically meaningful hemostasis, so that individuals with severe deficiency of these proteins are unlikely to develop greater bleeding risk than individuals with normal values. In such cases, the longitudinal comparison of patient’s data would cause laboratories to consider a 3-fold prolongation as a critical test result in a patient whose APTT has always been in the normal range, as well as for a clinically meaningless finding in a totally asymptomatic patient whose APTT value has been high since birth or childhood. Such examples are useful to remind us that “critical values are not only those significantly lying outside the normal (reference) range and necessitating immediate reporting for safeguarding patient’s health,” but also “all those displaying a highly and clinically significant variation over previous data.” As specifically regards hemostasis, both scenarios may translate into an imminent risk of severe bleeding or thrombosis.

The epidemiology of critical values in laboratory and hemostasis testing

In dealing with critical values, an interesting aspect is to establish their real impact in daily laboratory practice, which has been addressed in the recent past by surveys of practice. Dighe et al carried out an interesting analysis at a large US academic medical center, aimed to establish critical value reporting by analyte, laboratory area, clinical condition, and time of day (16). Overall, critical test values represented nearly 0.25% of total results, 31.4% of which were in the domain of laboratory hematology, thereby including hemostasis testing. Predictably, potassium was the most frequent test needing urgent notification (21.2% of all cases), whereas APTT (14.6%) and platelet count (8.3%) were ranked second and third in the list, respectively. Critical values of prothrombin time (PT) were 8^th on the list (4.8%). Interestingly, the distribution of critical values calls versus the time of the day revealed a rather consistent pattern, with no significant variations for inpatients and for those admitted to the emergency department (ED) throughout the different hours of the day. Guzmán et al carried out a retrospective survey in a University Hospital of Chile (17), and reported that notification of critical potassium values was the most frequent occurrence (19%), APTT was ranked fourth (10%) and PT fifth (4%). Yang et al carried out a similar analysis in a large tertiary teaching hospital in China (18), observing an overall incidence rate of critical values of 0.96%. Interestingly, communication of critical values for APTT was ranked first (18.3%), followed by PT (15.2%), potassium (14.8%) and platelet count (11.4%). Another important aspect emerging from this study is that the leading diagnoses in inpatients with critical values for the platelet count were platelet diseases, leukemias, liver cirrhosis, gastrointestinal bleeding, and cancer. Unfortunately, no information was provided for causes explaining critical results of other hemostasis parameters. In a subsequent study, Piva et al analyzed data of critical values reporting at an Italian large academic medical center (19) and also found that potassium was the most frequent analysis needing urgent notification (49%), whereas PT (5.5%) and platelet count (4.5%) were ranked fifth and sixth on the list, respectively. Most notably, critical values reporting was associated with modification of clinical management in up to 98% of patients, institution of additional investigations in up to 70% of patients, and closer clinical monitoring in up to 26% of cases, respectively. As specifically regards hemostasis testing, Doering et al recently reported the data of a 5-year retrospective study in five US healthcare facilities (20) and found that reporting of critical values for sodium (51.7%) and potassium (18.1%) had the highest frequency, whereas notification of critical values for PT and APTT had an overall frequency of 7.1% and 3.5%, respectively. A recent survey endorsed by the College of American Pathologists (CAP) in 98 laboratories revealed that critical values reporting for the PT/International Normalized Ratio (INR) involved values comprised between 2.6–5.0 in 57% of all cases, whereas it occurred in 43% of cases for higher values (21).

Overall, from data obtained in these interesting surveys, it can be concluded that reporting of critical values of hemostasis testing (i.e. platelet count, APTT and PT) is a rather frequent occurrence in clinical laboratory practice.

Overview on current practices

Like other areas of diagnostic testing, the practical implementation of critical values reporting in hemostasis testing entails a number of aspects, which can be briefly summarized in three leading domains, pertaining to the type of parameters, their measurement unit and the relative alert thresholds.

At variance with other areas of laboratory medicine and beside platelet count, hemostasis testing has some peculiarities that ultimately contribute to make standardization rather challenging. This especially refers to the peculiar sample matrix (plasma anticoagulated with buffered sodium citrate) and to the high dependence of test results on reagents, instruments and potentially assay standards (e.g. reference pooled normal plasma). Indeed, the adoption of harmonized means of reporting (e.g. ratios for both APTT and PT and the INR for the PT) has greatly improved the process towards standardization but has not allowed resolution of all such problems (22). This is clearly reflected by the dramatic heterogeneity of parameters included in the panel of critical test results and the relative alert limits available in the current scientific literature. An historical survey published by the CAP in 2007 showed that the frequency of hemostasis tests within the local list of critical parameters was rather heterogeneous, with platelet count being included in 96.4% of laboratories, APTT in 94.4%, PT in 90.7%, fibrinogen in 64.8%, but also D-dimer in 25.3% of laboratories (23). In another survey published by the North American Specialized Coagulation Laboratory Association (NASCOLA), the frequency of hemostasis tests within the local list of critical parameters was 89% for APTT, 73% for PT (16% in seconds and 57% in INR), 70% for fibrinogen and only 8% for D-dimer (24). Notably, a survey disseminated by the UK Association of Clinical Biochemists (ACB) reported interesting information about critical values reporting, but was only limited to biochemical analytes (25). Campbell et al recently published a comprehensive literature analysis about the laboratory parameters with most frequently published adult- and non–age-specific alert thresholds (26). Overall, potassium was the most frequently included analyte (present in 62% documents), platelet count was placed sixth in the list (37%), APTT was tenth overall (30%), whereas PT (25%) and fibrinogen (22%) were 14th and 15th, respectively.

Summary of available recommendations

Likewise, the data about the different parameters included in the list, the alert values used for the different analytes are also dramatically varied. Table 1 summarizes the current recommendations of some scientific organizations along with mean or median limits calculated from large national surveys (8,23,24,26–29). The first aspect that emerges from comparing information is the poor consistency regarding the list of values included in the different documents. Despite APTT always being present, many documents do not include references for the other parameters. Notably, three documents also provide indications about critical values of D-dimer. The second important aspect is the acceptable consensus that has been reached for the measurement units of some parameters (e.g. APTT is always reported in seconds and platelet count in L), whereas for other analytes the situation is quite confusing (e.g. PT is reported either in seconds or as INR). Interestingly, despite current recommendations strongly supporting the reporting of results of hemostasis testing in harmonized measurement units (22), in no case are the thresholds of both the APTT and PT reported as ratios. The third and probably more challenging issue is the broad variability of threshold values. The upper limit of the listed APTT critical values ranges between 75–100 s (i.e. 25% variation), whereas the lower limit of the platelet count is comprised between 20–40 × 10⁹/L (i.e. 2-fold variation). Notably, only one document includes the concept that dynamic variation of some hemostasis tests may also be seen as critical. Specifically, according to Campbell et al., a >50% decrease of the platelet count compared to a previous result or a continual decrease over three consecutive blood collections with total drop >25% should be regarded as critical for diagnosing either HIT or DIC (26).

Table 1. Essential elements of critical laboratory values in hemostasis testing as for current literature.

	CLSI	IFCC	CAP^a	CCMB	NASCOLA^b	Campbell et al^b	Piva et al^b
References	(8)	(27)	(23)	(29)	(24)	(26)	(28)
APTT (sec)
Low	–	–	<16.2	–	–	<12.0	–
High	>100	>75	>92.9	>75	>100	>82.5	>85
APTT (ratio)
Low	–	–	–	–	–	–	–
High	–	–	–	–	–	–	–
PT (sec)
Low	–		–	<15	–	<8	–
High	–		–	>40	>37	>30	–
PT (ratio)
Low	–		–	–	–	–	–
High	–		–	–	–	–	–
PT (INR)
Low	–		–	–	–	–	–
High	≥5.0		–	≥5.0	>5.0	>4.75	–
Fibrinogen (g/L)
Low	–	<0.8	–	<0.8	<1.0	<1.0	–
High	–	–	–	–	–	>7.0	–
Platelet count (×10^9/L)
Low	<40^(^c^)	<20	<38.5	<20	–	<20	<30
High	>999	>1000	>963	>1000	–	>1000	>900
D-dimer
Low	–		–	–	–	–	–
High	–	Positive	–	Positive	>0.4 ng/mL	–	–

CCMB: Croatian Chamber of Medical Biochemists; CLSI: Clinical Laboratory Standards Institute; IFCC: International Federation of Clinical Chemistry and Laboratory Medicine; NASCOLA: North American Specialized Coagulation Laboratory Association.

^a Mean value from survey responses.

^b Median value from survey responses

^c <20 × 10⁹/L in patients aged <20 years.

Expert opinion

Given the heterogeneity of the currently available literature data (30), some expert guidance may be useful to help harmonize current practices across the world. Regarding the panel of putative analytes to be included in the list, we suggest that APTT and PT or INR (both upper threshold), fibrinogen (Clauss method; lower threshold) and platelet count (upper and lower threshold) should be included. Unlike these tests, the prevalence of increased D-dimer values is so high in conditions other than venous thromboembolism or DIC and especially in elderly patients and in those admitted to the ED (31) that the routine reporting of diagnostic values may be demanding but also relatively meaningless, wherein this test should always be ordered in critical patients (32,33). Another consideration that makes it reasonable to avoid including D-dimer in a critical alert test list is the current lack of standardization (34) and results reporting for this analyte (35), wherein any potential recommendation would be difficult to transfer to local practice. As regards test results reporting, in agreement with current recommendations (22), we strongly support the use of harmonized measured units, which are ratio for both the APTT and the PT, along with the INR for the PT for patients on vitamin K antagonists. The values of fibrinogen and platelet count should instead be reported by using the relative SI units (i.e. g/L and 10⁹/L, respectively). This is since test results such as APTT and PT are strongly influenced by test reagent and instrument, which in some ways can be harmonized as assay ratios, typically meaning the ratio of the patient test result over that of the midpoint of the normal range test result. For those laboratories not routinely using the ratio or the INR for expressing results of APTT and PT, the use of test results expression in seconds may still be considered a viable option. Notably, quite often no previous data to which the actual values can be compared are lacking in some populations. For example, a threshold of fibrinogen <1.0 g/L may be occasionally too low and this may need to re-evaluate the limits according to clinical history. Notably, the grade of alertness for the abnormal values should be based on the severity of the observations. More specifically, we believe that values >10 for both PT (INR and ratio) and APTT (i.e. >314 s), <0.5 g/L for fibrinogen and lower than the analytical sensitivity of the hematological analyzer (i.e. usually around 2–5 × 10⁹/L) for the platelet count are immediately life-threatening and should hence require a much greater degree of alertness, so requiring faster (virtually instant) communication. Likewise, higher alertness and immediate communication would be required when more than one of these critical values is identified in the same patient, or when the dynamic change over time is dramatically large, as in the case of a worsening DIC.

Conclusions

The determination of alert thresholds then remains the most challenging and controversial issue. A general consensus of the authors from the published literature has hence been reached for using the limits reported in Table 2, despite it needing by necessity, potential adjustments according to local availability of reagents and instrumentation of the different hemostasis laboratories. We have also introduced the concept of dynamic variation of these parameters according to biological and analytical variability (i.e. reference change value; RCV), which may help detect critical variation regardless of the results being within or outside the reference range (36). The most frequent causes generating these critical values are listed in Table 3 (37,38). Notably, before communicating the critical values, the laboratory should accurately rule out preanalytical issues that may have affected sample quality. This consideration especially refers to the possibility that the coagulation sample has been collected in an inappropriate sample matrix such as serum or EDTA-anticoagulated plasma, in both of which the clotting times of both PT and APTT may be dramatically prolonged (39). Although hemoglobin is not a hemostasis test, this parameter is critical to hemostasis management in multiple setting such as operation room and intensive care units. According to recent recommendations based on the red blood cell transfusion thresholds, <70 g/L (SI units) may be used as critical value threshold (40).

Table 2. Summary of expert opinion, opposed to consensus opinion about critical hemostasis values parameters and relative limits.

	Thresholds
Parameter	Lower	Higher	IV biological variation	Reference change value	Critical variation
APTT (ratio^a)	–	>3.5	2.7%	8.4%	15% increase in 24 hours^b
APTT (seconds^c)	–	>110	2.7%	8.4%	15% increase in 24 hours^b
PT (ratio^a)	–	>5.0	4.0%	12.4%	25% increase in 24 hours^b
PT (INR)	–	>5.0	4.0%	12.4%	25% increase in 24 hours^b
Fibrinogen (g/L)^d	<0.8 or <1.0^e	–	10.7%	33.2%	50% decrease in 24 hours
Platelet count (×10^9/L)	<20	>1000	9.1%	28.2%	50% decrease in 24 hours

The reference change value and the critical variation have been calculated according to data of Ricos et al. (36).

APTT: activated partial thromboplastin time; IV: intra-individual; PT: prothrombin time.

^a Obtained for a pooled normal plasma (PNP) run at each test occasion along with patient plasma.

^b Excluding patients on anticoagulant therapy

^c For those laboratories not reporting APTT in ratio.

^d Clauss method.

^e Depending on local protocols and method.

Table 3. Most frequent causes of critical test results in hemostasis.

Markedly prolonged APTT

• Preanalytical error (e.g. wrong sample matrix, sample contamination, inappropriate blood-to-anticoagulant ratio)

• Severe factor XII deficiency (not clinically important)

• Acquired or congenital hemophilia, potentially with inhibitors present

• Patient on anticoagulant therapy (e.g. unfractionated heparin, dabigatran, vitamin K antagonists; including overdosage)

• Disseminated intravascular coagulation (DIC)

• Strong lupus anticoagulant (LA) when using a LA-sensitive reagent

Markedly prolonged PT

• Preanalytical error (e.g. wrong sample matrix, sample contamination, inappropriate blood-to-anticoagulant ratio)

• Patient on anticoagulant therapy (e.g. vitamin K antagonists, rivaroxaban; including overdosage)

• Disseminated intravascular coagulation (DIC)

• Liver disease/vitamin K deficiency

Markedly decreased fibrinogen

• Acute liver dysfunction

• Consumption (e.g. disseminated intravascular coagulation; DIC)

• Congenital deficiency of fibrinogen

Markedly decreased platelet count (“thrombocytopenia”)

• Reduced production (drugs, bone marrow infections, leukemias, other types of cancer)

• Increased consumption (e.g. disseminated intravascular coagulation; DIC; heparin-induced thrombocytopenia; HIT)

Markedly increased platelet count (“thrombocytosis”)

• Severe acute infections

• Cancer

APTT: activated partial thromboplastin time; PT: prothrombin time.

Standardization of critical values in laboratory medicine and hemostasis is still an unmet target, as highlighted by a recent survey of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) (41). Obviously, our report has a major limitation due to the fact that it only reflects our expert opinion, and we do not intend to supplant the function and consideration of relevant scientific societies or international organizations, assuming that definitive recommendations will be released on this topic. We hence advise that international scientific organizations such as the International Society of Clinical Chemistry and Laboratory Medicine (IFCC) and the International Society of Thrombosis and Hemostasis (ISTH) should be embarked in a landmark effort to generate consensus guidance on this important issue. In the interim, we hope that our report provides a basic document for consultation that assists laboratory professionals and clinicians alike in managing unexpected results of hemostasis tests. The definition of multiple limits for the many different clinical conditions that may be encountered in routine practice is clearly unfeasible and probably misleading, since the laboratory is frequently unaware of the specific therapy used by the single patient. In this respect, we would like to reinforce the current CLSI recommendations, affirming that each organization should locally define its own list of laboratory test results needing urgent clinical review and that no list is universally mandated or applies to every health care setting (8).

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.