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Semin Thromb Hemost 2015; 41(03): 263-266
DOI: 10.1055/s-0035-1549093
Preface
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Quality in Hemostasis and Thrombosis — Part IV

Giuseppe Lippi
1   Department of Clinical Chemistry and Hematology, Academic Hospital of Parma, Parma, Italy
,
Emmanuel J. Favaloro
2   Department of Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Westmead, Australia
,
Mario Plebani
3   Department of Laboratory Medicine, University of Padova, Padova, Italy
› Author Affiliations
Further Information

Publication History

Publication Date:
14 April 2015 (online)

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Welcome to the latest issue of Seminars in Thrombosis & Hemostasis, the fourth devoted to the concept of “quality” within the field of thrombosis and hemostasis.[1] [2] [3] The foremost goal of health care is to provide medical resources of high quality to all who need them. As such, the notion of quality in medicine is rather broad and entails the concepts of doing the right thing, at the right time, in the right way, for the right person and, last but not the least, for generating the best possible outcomes for patients/consumers/payers, clinicians, national and supranational agencies, local communities, provider organizations, and employers.[4]

Intuitively belonging to this definition, quality in health care embraces a wide spectrum of clinical actions, including prevention, diagnosis, treatment, follow-up, or prognostication of a given disorder. Recent evidence suggests that necessary care is provided in less than 50% of the cases, whereas incorrect care is administered in up to 30% of the cases, thus contributing to inappropriate patient management and an enormous waste of human and economic resources.[4] It is therefore perhaps not surprising that the editors of Seminars in Thrombosis & Hemostasis have embarked on this series of issues entitled “Quality in Hemostasis and Thrombosis.”[1] [2] [3] These issues are specifically aimed to provide overviews and updates on specific areas of quality in hemostasis and thrombosis ([Fig. 1]).

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Fig. 1 The broad loop of quality in hemostasis and thrombosis.

Point-of-care (POC) testing is a constantly growing and developing area of the laboratory industry.[5] Due to the increasing focus on this aspect of in vitro diagnostic testing, the current issue begins with an analytical evaluation of the CG02N whole blood coagulation analyzer (A&T Corporation, Kanagawa, Japan) for assessment of fibrinogen in heparinized blood drawn for blood gas analysis by Hayakawa and colleagues.[6] The major advantage of this novel instrumentation lies in the fact that the measurement entails a dry reagent method for direct assessment of thrombin-induced clot formation in an oscillating magnetic field. Importantly, the instrument uses a dry card-type single-use reagent in an aluminum-packed form and the measurement is completed in less than 2 minutes. Therefore, the CG02N can be used as a POC device in a variety of health care settings where urgent fibrinogen assessment may be required (i.e., intensive care unit) or in those where the hemostasis laboratory is not sufficiently near. Compared with a standard laboratory assay, 88% of the fibrinogen values generated by CG02N were found to be clinically acceptable, and none was considered to be in a clinically dangerous range. The area under the receiver operating characteristic curve of whole blood-fibrinogen was remarkably high compared with standard plasma fibrinogen assessment (i.e., 0.980). It could hence be concluded that the use of this POC device may be suitable in all those health care environments, where standard laboratory techniques are not rapidly available.

The second article of this issue by Kitchen and colleagues also deals with POC testing and, more specifically, with recent data of the United Kingdom National External Quality Assessment Scheme for Blood Coagulation (UK NEQAS BC) for POC international normalized ratio (INR),[7] thus extending data recently published from UK NEQAS regarding heritable bleeding disorders in this journal.[8] This sizeable program includes a large number of primary care centers (75%), in which testing is primarily performed by nurses (64%). According to the information gathered from a questionnaire of participants, it was found that a low, but still a meaningful number of centers (i.e., 2%) never performed quality control testing, that only a minority of them (i.e., 29%) were using quality control testing after accessing a new batch of test strips and, even more importantly, in only 15% of these centers was quality control testing performed according to the United Kingdom guidelines. In partial disagreement with previous evidence that in general showed excellent precision of POC INR instruments,[9] UK NEQAS BC also found that the overall 2-year imprecision of POC tests was higher than that reported in their hospital laboratory program (mean 11 vs. 7%), a finding that is most likely attributable to nonoptimal usage of instrumentation or handling of quality control material, rather than to specific analytical problems of the technique. The apparent lack of training among nonlaboratory-trained personnel performing POC INR testing was therefore identified as the leading area to be targeted for purposes of POC INR quality improvement.

In another report related to INR testing, a team of workers from Australia has investigated results from the Royal College of Pathologists of Australasia Quality Assurance Program (RCPAQAP) with both the POC and laboratory-based programs using data from the past 8 years.[10] In contrast to UK NEQAS BC, cross-laboratory POC precision was better than that performed by laboratories (medians of 8 and 10% of laboratory-based testing based on the years 2007–2010 and 2011–2014, respectively, versus medians of 3 and 6% for CoaguChek and iSTAT POC analyzers, respectively for the years 2011–2014). Also interesting was that laboratory INR variation increased with increasing INRs, whereas POC INR variation was less dependent on the INR value (indeed, there was no relationship between variation and the INR value for the CoaguChek, and only a weak relationship for the iSTAT). In conclusion, the POC INR variation was low for the CoaguChek, indicating appropriate handling of both instrumentation and quality control material, and intermediate for the iSTAT, with a weak relationship evident according to the INR value. In contrast, the variation was greatest for laboratory-based testing, with increasing imprecision according to increasing INR value, suggesting issues related to improper assignment of international sensitivity index and mean normal prothrombin time values by laboratories leading to inaccurate INR values. The RCPAQAP has reported data on many of its external quality assessment programs in this journal.[11] [12] [13]

The next article of this issue contains the results of an international survey about d-dimer test reporting.[14] The authors designed and disseminated a simple five-item questionnaire through the platform Google drive, including information about the country and the setting of the laboratory within the health care system (i.e., university hospital, general hospital, private laboratory, other), the expression of results in term of d-dimer unit or fibrinogen equivalent unit, the measure unit (e.g., ng/mL, g/mL, mg/L, g/L, μg/L, μg/mL, or others), along with the use of a fixed or an age-dependent cutoff. Although data collection for the current article was closed at the beginning of February 2015, the questionnaire will remain open online throughout 2015 and 2016 (available at: https://docs.google.com/forms/d/1IVMqgIsZRN_rqbv2PdhPoerRB6UERXdEuCi0Czr-7m0/viewform. Last accessed: February 10, 2014), to allow other participants from a wider geographic base to provide additional useful information. The results are indeed surprising, wherein the 409 responses collected to date from around the globe underscore a dramatic situation with as many as 28 potentially different ways for expressing the results of d-dimer testing, thus making it the least standardized analyte in the entire area of diagnostic testing. It is therefore clear that international organizations and societies of the laboratory and hemostasis testing should urgently undertake more concerted efforts to pursue a comprehensive harmonization and standardization of d-dimer testing.

This initial discussion around the topic of quality in laboratory hemostasis is then closed by a speculative article discussing the changing face of hemostasis testing in modern laboratories.[15] Squeezed between an unprecedented economic crisis, that is also challenging the vast majority of national health care systems and a growing volume of laboratory testing worldwide, modern (hemostasis) laboratories are forced to find new means for providing quality testing with reduction in economic and human resources. A predictable scenario will hence be characterized by the emergence of new models strongly centered around the concepts of automation, consolidation, networking, and bedside (near patient of POC) testing. Indeed, the driving and conditioning force of these changes include several environmental, preanalytical, technological, professional, and health care issues, which are comprehensively discussed in different sections of this article, which is in part an extension of a previous article in this journal by the same authors.[16]

The next article of this issue of the journal[17] is the second of a series dedicated to the influence of dietary habits on platelet function and coagulation.[18] Herbal medicines have been for long used in patients with cardiovascular disease (CVD), as they may interact at various levels with primary and secondary hemostasis. In particular, several lines of evidence seemingly attest that many supplements, including feverfew, garlic, ginger, ginseng, motherwort, St. John wort, and willow bark, may reduce platelet reactivity and thereby impair platelet aggregation. Indeed, in vitro studies have demonstrated that Andrographis, feverfew, garlic, ginger, ginkgo, ginseng, hawthorn, horse chestnut, and turmeric may be regarded as promising natural agents for reducing platelet aggregation in patients at risk of CVD or in those with atherosclerosis, hypercholesterolemia, and hypertriglyceridemia. Moreover, cranberry, danshen, dong quai, ginkgo, ginseng, green tea, and St. John wort were also found to potently interfere with warfarin metabolism, so that their administration should require intensive monitoring of anticoagulation in patients taking warfarin and, potentially, also in those taking direct oral anticoagulants (DOACs).[19] St. John wort was also found to interplay with clopidogrel and danshen with aspirin. In regards to hemostasis testing, it thereby becomes important that repeat evaluation of platelet function be considered to rule out any influence of such herbal medicines on previous results of testing.

As a logical continuation of the former article, the same team of authors performed an experimental study aimed to establish the effect of omega-3 polyunsaturated fatty acids (PUFA) on fibrin and thrombin generation in healthy subjects and patients with CVD.[20] The generation of fibrin and thrombin was measured by overall hemostasis potential assay and calibrated automated thrombography in 40 ostensibly subjects and 16 CVD patients at baseline and 4 weeks after supplementation with 640 mg/d omega-3 PUFA. Differential outcomes were recorded in the two study populations. Specifically, omega-3 PUFA supplementation was effective to attenuate thrombin generation, as well as fibrin generation and polymerization in healthy subjects. Interestingly, although omega-3 PUFA supplementation was also effective to attenuate fibrin generation and increased the lag time of thrombin generation in CVD patients, no effect on other fibrin and thrombin generation parameters could be observed in these patients. It was hence concluded that 4-week omega-3 PUFA supplementation was more effective to mitigate the prothrombotic potential in healthy subjects than in patients with CVD. These findings have relevant clinical implications, and pave the way to further studies designed to accurately establish the minimum dietary requirement of omega-3 PUFA to produce beneficial effects in CVD patients.

In the next article, Dorgalaleh et al[21] provide a comprehensive literature review on factor XIII (FXIII) deficiency in Iran, a rare bleeding disorder with prevalence approximately of 0.5 in 1 million population worldwide,[22] and which suffers from difficult laboratory diagnosis.[23] The authors reported that nearly 473 patients have been diagnosed with a FXIII deficiency in Iran so far, and this unusually large prevalence (i.e., 12-folds higher than the overall worldwide frequency) has been attributed to the high rate of consanguineous marriages in that country. Even more interestingly, the authors found that Sistan and Baluchestan Province exhibited the highest global incidence of this condition (i.e., 1 in 7,700 individuals). As regards the specific features of FXIII deficiency in Iran patients, the Trp187Arg substitution was reported as the most common mutation, whereas umbilical cord bleeding, hematoma, and prolonged wound bleeding were found to be the most frequent symptoms. Until the recent availability of FXIII concentrate (in 2009), the therapy of this condition in Iran has been based for long on fresh-frozen plasma or cryoprecipitate. Despite being limited to a single country, this interesting overview offers meaningful insights into this condition, which can be more broadly translated for improving management and quality of life of FXIII deficient patients around the globe.

In the following article of this issue, Sokol et al[24] provide an interesting update about the different models of inheritance in selected genes in patients with sticky platelet syndrome (SPS) and fetal loss. More specifically, the authors assessed the genetic variability of some specific single nucleotide polymorphisms (SNPs) within growth arrest-specific 6 (GAS6) and platelet endothelial aggregation receptor 1 (PEAR1) genes, and then investigated the potential associations between selected SNPs and the risk for fetal loss in women with this syndrome. A total of 23 female patients with SPS and history of spontaneous abortion were included in the study, along with 42 healthy women who served as controls. Two SNPs within PEAR1 (i.e., rs12041331 and rs12566888) and one within GAS6 (i.e., rs9550270) were found to be significantly associated with a positive history of abortion in SPS patients, whereas one SNP within GAS6 (i.e., rs7400002) was found to be associated with increased risk for abortion. Interestingly, the T allele of PEAR1 -9–4663G > T gene polymorphism was seemingly protective for fetal loss. Taken together, these results suggest that a polygenic heredity may be a common tract of SPS patients experimenting fetal loss. This journal recently featured a historical article on SPS[25] as well as another on SPS as a rare hereditary prothrombotic disorder.[26]

Interesting information regarding the biological and analytical variability of as many as 16 hemostasis tests is then provided by Chen et al.[27] Briefly, the study included 31 healthy volunteers who had their blood collected at three different times of the day, for 5 days. The parameters tested were prothrombin time, fibrinogen, activated partial thromboplastin time, thrombin time, INR, prothrombin time activity, activated partial thromboplastin time ratio, fibrin(-ogen) degradation products, along with the activity of clotting factors II, V, VII, VIII, IX, and X. Interestingly, the longitudinal assessment of test results helps establish that the intraindividual coefficient of variation (CVi) for all screening tests was less than 5%, except for fibrinogen. At variance, the CVi for the activity of all clotting factors appeared to be larger than 5%. Even more importantly, the index of individuality of all parameters was < 1.0, thus suggesting that the conventional reference ranges may be of little clinical utility, especially when deciding whether subjective changes may be clinically meaningful.

The last two articles of this issue are then devoted to the therapeutic management of bleeding and thrombotic disorders. In the first of these, Franchini et al[28] discuss the issue of rapid restoration of hemostasis as a primary goal for management of critical bleeding. More specifically, the current status on the use of recombinant activated factor VII (rFVIIa) and prothrombin complex concentrates (PCC) is discussed, with specific emphasis on safety and effectiveness of these hemostatic agents in reversing the anticoagulant effects of vitamin K antagonists. The role of these agents in the management of acute bleeding associated with the DOACs dabigatran, rivaroxaban, and apixaban is also analyzed in a specific section of this article.

As an ideal continuation of topics presented in the previous article, this issue of Seminars in Thrombosis & Hemostasis is closed by a comprehensive overview of the current approaches for reversing the anticoagulant effects of DOACS in the emergency department by Cervellin et al.[29] The article begins with a brief description of the pharmacokinetics properties and current indications of these drugs, and continues with an overview of the current options for urgent reversal, as it may occur in patients needing invasive procedures or in those with trauma or unexpected bleeding. Major emphasis is placed on the fact that no commercially available antidotes exist so far for any of these compounds, despite some potential agents such as idarucizumab, and exanet alfa, and aripazine being in different phases of clinical validation. It is hence emphasized that severe or life-threatening bleeding can be managed by drug withdrawal and administration of non-specific agents such as PCC. Oral charcoal and hemodialysis seem only effective for mitigating the anticoagulant effect of dabigatran, whereas the administration of desmopressin, antifibrinolytic agents, or rFVIIa may be seen as last options due to associated significant risk of prothrombotic complications with these agents. In the presence of moderate bleeding in patients taking DOACs, current evidence suggests that the most appropriate management entails the use of local or mechanical hemostasis, combined with discontinuation of the drug for a variable amount of time. Minor bleeding can be instead treated by means of local hemostatic measures and a short period of drug withdrawal, to be established according to the underlying indication for DOACs therapy. Some considerations are then presented on urgent laboratory monitoring of these drugs, a still enigmatic issue in patients undergoing therapy with DOACs.[30]

The last two articles in this issue of the journal can also be seen to provide additional context for the safe use of the DOACs, as recently explored in an entire issue of the journal,[31] as well as other recent previous entries.[32] [33] [34] As usual, we wish to thank all the authors of this issue for their unique and comprehensive contributions and hope that our readership will find interest in their content.