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O਒ਉਇਉ਎ਁ਌ A਒ਔਉਃ਌ਅ Clinical relevance of isolated prolongation of the activated partial thromboplastin time in a cohort of adults undergoing surgical procedures Giuseppe Tagariello1, Paolo Radossi1, Roberta Salviato1, Milena Zardo2, Lucia De Valentin2, Marco Basso1, Giancarlo Castaman3 Transfusion Service, Haemophilia Centre and Haematology, 2Laboratory Analysis, Castelfranco Veneto Hospital, Castelfranco Veneto; 3Centre for Bleeding Disorders, Careggi University Hospital, Florence, Italy 1

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Background. Coagulation screening prior to surgery is performed routinely worldwide to identify patients at risk of bleeding during the procedure. Evidence from medical and surgical literature suggests that the activated partial thromboplastin time (aPTT) alone is suitable for predicting individual bleeding risk during surgery and it is current practice in our hospital to measure this parameter. Materials and methods. We retrospectively reviewed aPTT ratio results in 8,069 consecutive adult subjects undergoing elective surgery from January 1 to December 31, 2014 to confirm the validity of this approach. Results. In 7,606 patients (94.2%) the aPTT ratio was within the normal range while it was abnormal in 463 (5.8%). Out of these 463, 223 aPTT ratios were between 1.2 and 1.3 and we considered these results not worthy enough of further investigations. In 240 patients the aPTT ratio was higher than 1.3; in the vast majority of these cases (201/240; 83%) this abnormality was associated with oral anticoagulant treatment. Seventeen of the other 39 cases underwent detailed investigations which revealed lupus anticoagulant (n=7), decompensated chronic liver disease (n=4), factor XII deficiency (n=3), mild combined reduction of FXI and FXII (n=1) and mild haemophilia A (n=2). The other 22 patients underwent successful surgery without further investigation. Discussion. Our results from a pre-surgical setting seem to confirm the low prevalence of coagulation defects in the general population. Increased aPTT ratios were mainly attributable to oral anticoagulant therapy, with a few cases caused by mild, clinically irrelevant clotting factor deficiencies. A carefully taken personal history, including medications (i.e. oral anticoagulants) and/or previous bleeding symptoms seem more useful than coagulation screening tests to predict the risk of bleeding. Keywords: aPTT, aPTT ratio, pre-operative coagulation screening, surgery, elective surgery.

Introduction

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Coagulation screening tests are usually done preoperatively to determine the individual bleeding risk during surgery, but the real utility of this approach has been and continues to be a matter of debate1-5. The test panel includes prothrombin time as a ratio to normal plasma (PT ratio) and International Normalised Ratio (INR), activated partial thromboplastin time (aPTT) and ratio and platelet count. An increased aPTT ratio is quite common in clinical practice, but is not necessarily associated with a bleeding tendency6. Nevertheless, in daily practice detection of this abnormality may delay surgery and may be associated with increased costs because of re-testing and coagulation factor assessment as well as emotional stress for patients and their families. The "classical" splitting of the clotting cascade into intrinsic, extrinsic and common pathways has little in vivo validity, but represents a useful conceptual

categorisation for interpreting the results of laboratory investigations. Under this view the aPTT is considered a "global" coagulation test able to indicate abnormalities or deficiencies of the intrinsic and common pathways7. In 1995, in a prospective, multicentre study in the setting of routine pre-operative haemostatic screening, Houry et al.8 combined the results of standard tests, the patients' history and clinical data and divided 3,242 patients into four groups: group A had no clinical or coagulation abnormalities; group B had no clinical abnormalities, but had one or more laboratory abnormality; group C had one or more clinical abnormality without any laboratory abnormality; and group D had both clinical and laboratory abnormalities. For patient in groups B and D, the surgeon required additional haemostatic tests and postponed surgery, but specific treatment was prescribed only to those in group D, characterised by clinical and specific laboratory abnormalities. No

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Materials and methods

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Results

A total of 8,069 patients underwent coagulation screening prior to elective surgery. In 7,606 (94.2%) cases the aPTT ratio was within the normal range (≤1.20), whereas it was increased (>1.20) in 463 samples (5.8%). In 223 of these 463 patients the aPTT ratio was between 1.2 and 1.3, and the patients had not personal or family history of bleeding: no further investigations were performed in these patients. In 240 patients the aPTT ratio was >1.3. Of these 240 patients, 201 had a prolonged aPTT because of anticoagulant treatment with vitamin K antagonists. No patient was receiving treatment with "new oral anticoagulants". The remaining 39 patients with an aPTT ratio >1.3 comprised seven with LAC, four with multiple coagulation factor deficiencies due to liver disease, three with isolated FXII deficiency (levels of 38%, 8% and 2%), two with mild haemophilia A (FVIII:C levels of 9% and 13%) previously registered at the local haemophilia centre, one with mild combined FXI/FXII reduction (levels of 53% and 50%, respectively) and 22 who were not investigated for various reasons such as low-risk surgery, anaesthetists' decision, and patients' unavailability. Surgery was performed safely in all patients without any prophylaxis.

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All consecutive 8,069 patients undergoing elective surgery and coagulation screening at Castelfranco Veneto General Hospital, from 1st January to 31st December 2014, were considered. These patients attended the pre-anaesthesiology department and laboratory tests were performed within the 30 days prior to surgery. The panel of tests included platelet count, biochemistry screening, PT ratio, INR and aPTT ratio. The aPTT was determined routinely using a HemosIL aPTT SynthASil with synthetic phospholipids and silica as activator, on Automated Coagulation Laboratory (ACL) analysers (ACL TOP 700 and ACL TOP 500, Instrumentation Laboratory SpA, Milan, Italy). The range of normal aPTT ratios was 0.82-1.20. Faced with an abnormal result, the first step was to exclude pre-analytic artefacts related to sample collection such as inadequate sample volumes, heparin contamination, difficult phlebotomy, prolonged storage, and high haematocrit. Plasma samples with prolonged aPTT were also investigated by the mixing assay, which consists of measuring aPTT of a mixture (50:50) of normal pooled plasma and plasma from the patient. If the aPTT is corrected by this mixing, it means that the normal plasma added must contain the substance deficient in the patient's plasma, i.e. at least one coagulation factor (F) among FVIII, FIX, FXI and FXII. These assays are based on a comparison of the ability of dilutions of standard plasma (reference plasma) and patient's plasma to normalise ("to correct") the aPTT of a plasma totally deficient in the coagulation factor to be measured, but containing normal amounts of the other factors (e.g. FVIII-deficient plasma). The concentration

in the plasma test is determined in relationship to the reference preparation by assessing the dilutions of the plasma test able to correct the coagulation time of the substrate-specifically-deficient plasma in a suitable aPTT test system10. When the mixing assay does not correct the aPTT, the presence of an inhibitor must be taken into consideration. Inhibitors such as antiphospholipid lupus-like anticoagulants (LAC) can be revealed using silica clotting time and dilute Russell's viper venom time tests and specific acquired coagulation factor inhibitors (most frequently anti-FVIII) can be detected by the modified Nijmegen method10. A general questionnaire to explore personal and familial bleeding history was routinely administered to each patient under the responsibility of the anaesthetist in charge of the pre-operative evaluation.

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differences were observed after surgery and there were similar low incidences of bleeding complications in all groups. In 1997 Munro et al.9 published a review on the value of routine pre-operative coagulation testing in asymptomatic individuals. They considered 29 different papers; in 19 of the impact on clinical management was assessed, while in eight adverse events were surveyed. The incidence of PT abnormalities ranged from 0% to 4.8% while aPTT abnormalities were present in up to 15.6% of subjects. The impact on surgical management was significant in only 0.8% of patients. Since the management was unaltered in almost every case, the positive predictive value and utility of these tests were very low. Furthermore, there was no association between abnormal pre-operative test results and a peri-operative or post-operative outcome. We conducted a retrospective analysis of routine coagulation test results in adult patients undergoing elective surgery at our General Hospital. We focused the analysis on the incidence of prolonged aPTT and how this affected surgery and our clinical practice.

Discussion Laboratory assessment of blood clotting is widely used in surgical practice with the aim of predict the bleeding risk, if any, prior to an operation or other invasive procedure11-13. PT, aPTT and platelet count are typically used to screen patients undergoing surgical procedures. They are requested, in the absence of any specific clinical indication, to identify conditions that might be associated with a possible increased risk of

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recorded for 682,049 patients (65%). Overall 26.2% of patients underwent a PT test, of which 94.3% were considered not necessary, and 23% underwent aPTT testing, which was unnecessary in 99.9% of cases. In our retrospective analysis, coagulation screening was broadly used in the pre-operative setting. Among a total of 8,069 aPTT ratios, 7,606 (94.3%) were within the normal range while 463 patients (5.7%) had an increased test result. However without any relationship with the degree of increase of the aPTT ratio, the anaesthetists caring for these patients proceeded with surgery, managing the patients in different ways. Patients with an aPTT ratio below 1.3 were considered at "low risk of bleeding" irrespectively of the type of surgery. In fact, neither haematological advice nor factor assays were requested in the group of 223 patients with a slight aPTT prolongation (aPTT ratio, 1.2-1.3) and these patients were not investigated further. When the aPTT ratio was >1.3 haematological consultation and intrinsic pathway factor assays were requested. Of the 240 cases with an aPTT ratio >1.3, 201 were due to oral anticoagulant therapy. In fact PT and aPTT tests are routinely performed in patients undergoing elective surgery irrespectively of whether they are receiving anticoagulation and the latter assay is dependent on functional vitamin K-dependent coagulation factors. When a second-level coagulation test was employed (mixing assay and/or single factor detection), we diagnosed inhibitors and factors deficiencies (Figure 1). We also detected two patients affected by mild haemophilia A (0.025% of the total), regularly followed by the local haemophilia centre and already registered in the Italian Association of Haemophilia Centres' database. Their surgical procedures were performed with the administration of FVIII concentrate, without any delay and without any bleeding complications23. Some recommendations on pre-operative coagulation screening have been published. The guidelines released by the National Institute for Clinical Excellence10 are based on expert consensus due to the paucity of studies supporting the utility of coagulation tests to predict bleeding in the setting of surgical or invasive procedures. PT, aPTT and platelet count are recommended only in the case of a personal or family history positive for bleeding tendency. A laboratory assessment of blood coagulation was suggested by the American Society of Anesthesiologists (ASA) according to physical status classification system ASA grade 3 only for patients with kidney or cardiovascular disease undergoing major surgery. The British Committee for Standards in Haematology has published guidelines on the assessment of bleeding risk prior to surgery based on a systematic review of literature12: routine coagulation screening was not

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bleeding. In general, manufacturers formulate reagents so that the aPTT will be prolonged when a single coagulation factor (FVIII, IX, XI or FXII) is reduced below approximately 20-40% of normal values, which is considered a possible threshold for risk of bleeding after invasive procedures14,15. Originally the aPTT was conceived to detect deficiencies of clotting factors involved in the intrinsic coagulation pathway, such as FVIII, FIX, and FXI, which may cause a bleeding tendency (not FXII as its deficiency does not cause bleeding) or to monitor heparin treatment. Inherited coagulation defects are rare in the general population and the most frequent, haemophilia A and B, are estimated to occur in 1:10,000 and 1:30,000 males, respectively16. Severe forms of haemophilia are associated with a significant family and personal clinical history of bleeding although de novo mutations may cause the disease in individuals without a family history. Importantly, a mild haemophilia phenotype may go unrecognised until adulthood or the time of a surgical procedure. Deficiency of von Willebrand factor can lead to a prolonged aPTT, but a normal aPTT does not exclude the possibility of this defect17. Other defects are much rarer, with the prevalence of homozygous FXI deficiency being 1:1,000,000, although more common in Jewish communities18. An isolated aPTT prolongation may also be associated with a deficiency of FXII, an inherited autosomal recessive condition that can be encountered in up to 2% of the general population, without causing any bleeding tendency19. The aPTT can also indicate the presence of LAC, an antibody that partially neutralises the phospholipiddependent test in patients without a bleeding history, but is sometimes associated with a significant thrombotic tendency. The prevalence of LAC in the general population has been reported to be between 1 to 2% in the general population; this antibody is found most frequently after viral infections in children and may disappear spontaneously within 12 weeks20. A prolonged aPTT can also occur during therapy with warfarin because of this anticoagulant's effect on the vitamin-Kdependent FII, FIX and FX. There is a linear correlation between the INR and aPTT prolongation21. Recently Capoor et al. 22 evaluated data from approximately one million patients who underwent elective surgery between 2009 and 2012. They concluded that PT and aPTT were correctly used as diagnostic tests in patients with a bleeding history and/or physical symptoms. Conversely, the PT was considered unnecessary if measured in patients without a history of bleeding, warfarin therapy or liver disease, while the aPTT was considered unnecessary if measured in patients without a history of heparin use, haemophilia, LAC or von Willebrand's disease. Complete data were

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Tagariello G et al

Figure 1 - Flow chart of patients undergoing pre-operative coagulation screening.

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Patients on oral anticoagulant therapy were treated "individually" according to guidelines with suspension or continuation of treatment for minor surgery and "bridging" therapy with low molecular weight heparin for major surgery. All underwent surgery safely. OAT: oral anticoagulant therapy; LAC: lupus anticoagulant; CLD: chronic liver disease; FXII: factor XII; HA: haemophilia A; FXI: factor XI.

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recommended because of its limitations as front-line tests and because it could lead to delays in surgery and additional costs because of further blood tests. It was indicated that the pre-operative physical examination and detailed personal and family history should guide subsequent laboratory investigations. The guidelines published by the Italian Society of Haemostasis and Thrombosis13 also encourage taking a detailed personal and family history of bleeding tendencies by supporting the use of locally designed, structured questionnaires on bleeding, as well as a careful physical examination. In other settings quantitative bleeding assessment tools have been used for the diagnosis of slight bleeding disorders in previously undiagnosed patients with mild diseases and a specific questionnaire might also be very useful in the pre-operative setting24. Although this strategy cannot be applied completely in children because of the limitations to collecting their bleeding history, and more caution must be taken in this population, there are some indications that preoperative coagulation screening may be considered unnecessary in the paediatric population too25. Unfortunately, despite the fact that several national and international guidelines do not recommend

performing coagulation screening prior to surgery, the PT, aPTT and platelet count continue to be requested routinely before surgery or invasive procedures worldwide, even in the case of a negative bleeding history. This prudent attitude possibly arises from the need to have a baseline value in the case of unexpected abnormal bleeding, bearing in mind the relatively limited costs of haemostatic tests, rather than being prompted by possible medico-legal consequences.

Conclusions In conclusion, our personal experience is in keeping with that of many others. However, apart from the two patients with haemophilia who were treated with replacement therapy, all the patients in this study underwent surgery without particular haemostatic management, without mishap, and independently of the coagulation defect detected. In the light of our results, we believe that pre-operative laboratory tests are not useful for guiding the peri-operative care and that a thorough history and physical examination might be sufficient for evaluating bleeding risk, thereby saving money and improving the appropriateness of laboratory testing. Blood Transfus 2017; 15: 557-61 DOI 10.2450/2016.0047-16

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Authorship contributions GT, PR and GC designed the study, analysed data and wrote the paper. MZ, LDV, RS, and MB performed analyses, collected data and read and approved the final version of the manuscript. The Authors declare no conflicts of interest.

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We thank the Italian Association against LeukemiaLymphoma and Myeloma (AIL - Associazione Italiana contro le leucemie-linfomi e mieloma) Treviso. Marco Basso is a fellow of the AVIS per il Progresso Ematologico/AIL Treviso.

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Acknowledgements

Arrived: 29 February 2016 - Revision accepted: 31 March 2016 Correspondence: Giuseppe Tagariello Transfusion Service Haematology and Haemophilia Centre Via Ospedale 18 31033 Castelfranco Veneto, Italy e-mail: [email protected]

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