SemOpenAlex |

SemOpenAlex

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2085073510> ?p ?o ?g. }

Showing items 1 to 100 of ±153 with 100 items per page.

W2085073510 endingPage "841" @default.
W2085073510 startingPage "830" @default.
W2085073510 abstract "The guideline group was selected to include UK-based medical, scientific and laboratory representatives. Publications known to the writing group were supplemented with additional papers identified by searching MEDLINE/Pubmed using the keywords direct thrombin inhibitors (DTI), direct Xa inhibitors, apixaban, argatroban, bivalirudin, dabigatran, fondaparinux, rivaroxaban, in combination with measurement, monitoring, coagulation assays, haemostasis assays and laboratory tests. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology (BCSH). The BCSH GRADE system was not applied to this guideline as it is inappropriate for laboratory studies. The guideline was then reviewed by a sounding board of c. 50 UK haematologists, the BCSH and British Society for Haematology (BSH) Committee and comments were incorporated where appropriate. The objective of this guideline is to provide healthcare professionals with clear guidance on the clinically important issues regarding the laboratory assessment of currently used non-coumarin anticoagulants and their impact on laboratory tests of haemostasis. A short summary of the effects of rivaroxaban and dabigatran on routine coagulation screens and assessment of anticoagulation intensity on behalf of the BCSH (Baglin et al, 2012) and international recommendations related to measurement of oral direct inhibitors (Baglin et al, 2013) have recently been published. The sections on heparin and low molecular weight heparin (LMWH) represent an update of the previously issued guidance (Baglin et al, 2006). The most common anticoagulants in use in hospitals in the UK are vitamin K antagonists, of which warfarin predominates. Recent BCSH guidelines have addressed warfarin management (Keeling et al, 2011) and this is not discussed in this document. Non-coumarin anticoagulants licensed for use in the UK at the time of writing are listed in Table 1. APTT Anti-Xa, Anti-IIa Drug monitoring aims to use laboratory testing to optimize dosing to increase efficacy and/or safety. Monitoring of anticoagulants, other than warfarin, is primarily indicated for the intravenously administered drugs, such as unfractionated heparin (UFH), danaparoid, argatroban and bivalirudin. Monitoring is not required when anticoagulants are used for prophylaxis, where the anticoagulant effect is predictable and the drugs can be administered at a fixed weight-based dose. The efficacy of this approach has been established by the experience with the subcutaneously administered low molecular dose heparin (LMWH) and fondaparinux. More recently, the oral anticoagulants dabigatran, rivaroxaban and apixaban have been introduced without the intention of routine monitoring. These drugs have been shown in randomized trials to be effective and safe without monitoring (Connolly et al, 2009; Schulman et al, 2009; EINSTEIN Investigators, 2010; Patel et al, 2011). Arguments for and against laboratory monitoring of the new anticoagulants have been published (Bounameux & Reber, 2010; Mismetti & Laporte, 2010). The lack of a need for monitoring is based on the assumed similarity in pharmacokinetic and pharmacodynamic responses between individuals within a relatively wide therapeutic window. It has been estimated that the same dose of direct inhibitors of thrombin and activated factor X (Xa) can have up to 30% difference in thrombin generation inhibition (Al Dieri & Hemker, 2010). Al Dieri and Hemker (2010) also speculated that bleeding would be more likely in high responders and thrombosis more likely in low responders. Clinical trials often exclude patients with impaired renal function, children, the very elderly, those with an increased bleeding risk and those at the extremes of body weight. The lack of a need to monitor demonstrated in the trials may therefore not be applicable to groups excluded from trial entry and the questioning of the extrapolation of overall trial benefit to the individual is not new (Rothwell, 1995). More interest may be focussed on laboratory measurements following an analysis of the association between plasma concentrations and efficacy and safety outcomes, which demonstrated that the risk of ischemic events was inversely related to trough drug levels (Reilly et al, 2014). This study concluded that both ischaemic stroke and bleeding outcomes were correlated with dabigatran plasma concentrations (Reilly et al, 2014). Despite the fact that monitoring is not required for many anticoagulants, it is important that clinical laboratories have the capacity to rapidly measure the concentration of all anticoagulants in the circumstances listed in Table 2, as knowing the concentration of the active drug or its effect may facilitate clinical management decisions. Some published data on the effects of drugs on laboratory tests of haemostasis are based on studies where drug is added to plasma/blood in vitro and any conclusions related to this type of sample are safer if also validated by analysis of samples from patients taking the drug. Specific chromogenic anti-IIa assays are available for the measurement of drugs that inhibit thrombin, including DTIs (Shepherd et al, 2011; Harenberg et al, 2012). These assays should be calibrated with product-specific calibrators which are available commercially for dabigatran and argatroban. For recommendations and general discussion of chromogenic assay design, see the BCSH guideline (Mackie et al, 2013). Thrombin-based clotting assays are available for the assay of dabigatran or argatroban. Product-specific calibrators should be used in all cases. One commercial assay, which uses a modified thrombin time, has been successfully used and shows a linear relationship between dabigatran concentration and clotting time up to at least 0·3 mg/l (Van Ryn et al, 2010; Douxfils et al, 2012; Harenberg et al, 2012) with a stated sensitivity of 0·008 mg/l (Douxfils et al, 2012). The test plasma is diluted (normally between 1 in 8 and 1 in 20) in normal plasma, rendering the assay largely independent of the test plasma fibrinogen concentration and function. This is a rapid assay that can be applied to most coagulometers, but the test is not fully specific for DTIs given that supra-therapeutic concentrations of UFH can prolong the clotting time. Another thrombin time method that uses diluted patient plasma also shows linearity between drug concentration and clotting time up to 0·5 mg/l, and is unaffected by heparin up to 1·0 iu/ml (Jones et al, 2012). Ecarin clotting time (ECT) assays can be used as a direct measure of DTIs. There is a correlation between ECT and plasma concentration of dabigatran up to 1·0 mg/l with ECT ratios of 2–4 after 150 mg twice daily dabigatran etexilate in healthy male subjects (Van Ryn et al, 2010), with steady state plasma concentrations of dabigatran occurring after 2–3 d and peak levels at 3 h post-dose. Data obtained from in vitro samples are also available (Douxfils et al, 2012; Harenberg et al, 2012). The ECT has not been standardized and can be affected by the concentration of prothrombin in plasma (reviewed by Samama & Guinet, 2011). Other tests which can be used for assay of DTIs include amidolytic ecarin assays (Guy et al, 2008; Siegmund et al, 2008; Douxfils et al, 2012) and semi-specific assays, such as Prothrombinase Induced Clotting Time (PiCT) (Fenyvesi et al, 2002; Guy et al, 2008; Douxfils et al, 2012). Liquid chromatography can be used to determine the concentration of dabigatran in plasma (Delavenne et al, 2012). Dabigatran etexilate is a pro-drug that is hydrolysed to its active form dabigatran in vivo, and in vitro studies therefore utilize this active form. Doses recommended for clinical use are 150 mg and 220 mg once daily, and 110 mg and 150 mg twice daily. Expected plasma concentrations are shown in Table 3. The half-life is 12–17 h with normal renal function (Stangier et al, 2007; Wienen et al, 2007) and 18–27 h in the presence of moderate to severe renal impairment (Stangier et al, 2010). The APTT is usually prolonged by therapeutic doses of dabigatran, even at trough level, and the variation between results obtained with different reagents is relatively low (Van Ryn et al, 2010). Dabigatran does not always increase the APTT above the upper limit of the normal range. In one study, 18% of APTTs were normal during 150 mg twice daily dabigatran therapy (Hawes et al, 2013) in samples collected 2–3 h after dosing. The dose-response curve relating dabigatran concentration and prolongation of APTT is curvilinear, flattening at higher concentrations (Lisenfeld et al, 2006; Van Ryn et al, 2010). This effect, coupled with the lack of specificity of APTT for the presence of drug, indicates that the APTT is unsuitable for quantification of drug. The effect of dabigatran on the prothrombin time (PT) is less marked than on the APTT. Peak levels are usually associated with an International Normalized Ratio (INR) <1·5, although it should be noted that the International Sensitivity Index (ISI)/INR system, derived from patients receiving vitamin K antagonists, is not valid for patients receiving other anticoagulants. The PT was normal in 29% of samples collected 2–3 h post-dose during 150 mg twice daily dabigatran therapy (Hawes et al, 2013). Owren's PT methods, including Thrombotest, utilize a higher dilution of test plasma with lower potential for interference compared to other PT methods. There are case reports of marked elevation of the INR in the presence of dabigatran when the INR was determined using an unnamed Point-of-Care (POC) device (DeRemer et al, 2011) or the Hemochron Jr Signature device (Baruch & Sherman, 2011). The Hemochron Jr Elite POC analyser was more sensitive to the effect of dabigatran than five conventional laboratory PT methods in an ex vivo study (Hawes et al, 2013). The effect of DTIs, such as dabigatran, on tests where thrombin is directly added to plasma, including thrombin time and Clauss fibrinogen assay, depends on the concentration of thrombin in reagents and any pre-dilution of the plasma. Conventional thrombin times are very sensitive to the presence of dabigatran with greater than 10-fold prolongation at peak levels (Van Ryn et al, 2010), which do not return to normal at trough levels. In another in vitro study, plasma used in thrombin times became unclottable at dabigatran concentrations between 0·025 mg/l and 0·15 mg/l depending on the method used (Dager et al, 2012). For methods studied so far, a normal thrombin time can be used to exclude the presence of clinically relevant levels of dabigatran. Clauss fibrinogen assays without pre-dilution of plasma prior to analysis (Lindahl et al, 2011; Dager et al, 2012) underestimate fibrinogen concentrations. Methods which utilize higher thrombin concentrations and/or higher pre-dilution of plasma (typically 1 in 10 dilution or higher) are largely unaffected by dabigatran at concentrations up to 0·5 mg/l (Dager et al, 2012) or 1·0 mg/l (Lindahl et al, 2011; Douxfils et al, 2012). The effects of dabigatran on routine and specialist tests of haemostasis are summarized in Tables 4 and 5, respectively. Freyburger et al (2011) Lindahl et al (2011) Dager et al (2012) Baruch and Sherman (2011) Harenberg et al (2012) Douxfils et al (2012) Lindahl et al (2011) Douxfils et al (2012) Lindahl et al (2011) Van Ryn et al (2010) Lindahl et al (2011) Dager et al (2012) Freyburger et al (2011) Adcock et al (2013) Lindahl et al (2011) Adcock et al (2013) Lindahl et al (2011) Douxfils et al (2012) Adcock et al (2013) Halbmayer et al (2012) Martinuzzo et al (2013) High concentrations of dabigatran can cause non-parallelism in factor assays and the underestimation of clotting factor levels is reduced at higher test plasma dilutions, although the effect of dabigatran may still occur at higher dilutions (Adcock et al, 2013). Additional higher test plasma dilutions should be analysed (see Mackie et al, 2013, for a full discussion of assay design in the presence of inhibitors). Thrombophilia testing is best avoided during therapy with DTIs, but if activated protein C resistance (APCR) testing is being performed to exclude FV Leiden, genetic testing is preferred because it would not be affected by the presence of DTIs. Factor Xa-based assays of antithrombin are preferred over thrombin-based assays unless there is evidence that a particular assay is unaffected by the level of anticoagulant in the sample. Chromogenic or antigen assays are preferable to clot-based assays of protein C and protein S in the presence of DTIs. Where argatroban is given for treatment of heparin-induced thrombocytopenia (HIT) the American College of Chest Physicians (ACCP) evidence-based clinical practice guidelines (Linkins et al, 2012) recommend that the dose is adjusted to maintain an APTT ratio of 1·5–3 times patient baseline APTT. The BCSH HIT guidelines (Watson et al, 2012) recommend an APTT ratio of 1·5–3·0 (but not exceeding 100 s). Reagents used for the determination of APTT may vary in their sensitivity to DTIs (Hirsh et al, 2008). Argatroban increases the INR, which complicates the transition from argatroban to vitamin K antagonists (VKA), and the BCSH recommends that patients on argatroban undergoing transition to warfarin should have an INR of ≥4·0 for 2 d prior to discontinuing argatroban (Watson et al, 2012). A number of studies have assessed the effects of argatroban on coagulation tests (Gosselin et al, 2004; Siegmund et al, 2008; Ivandic & Zorn, 2011) and indicate that the presence of argatroban can lead to underestimation of the level of clotting factors. However, given the relatively short half-life of c. 50 min, its effect on the measurement of clotting factors may not be so relevant. Bivalirudin has been recommended as an alternative to heparin in patients with previous HIT who are HIT antibody-positive and who require urgent cardiac surgery, and has been used for percutaneous coronary intervention in the UK (Watson et al, 2012). The half life is c. 25 min and the drug is eliminated by proteolytic cleavage and renal excretion (Koster et al, 2007). The PT, APTT and thrombin time were prolonged following addition of bivalirudin to pooled normal plasma, including concentrations that might occur in clinical use, in a study using one type of reagent in each test (Curvers et al, 2012). The results are shown in Table 6. The APTT was more sensitive than the PT and exhibited a non-linear dose response curve. Neither test is suitable to monitor therapy. The response to bivalirudin of two diluted thrombin time assays and clotting or chromogenic ecarin-based assays was linear up to at least 5 mg/l (Curvers et al, 2012). The activated clotting time (ACT) was successfully used to monitor therapy during cardiopulmonary bypass, in which anticoagulation was considered adequate if a 2·5-fold or greater prolongation of the baseline ACT was obtained using the ACT method in local use (multiple centres, ACT methods not stated) (Koster et al, 2007), though ACT results are likely to vary between different commercially available methods. The rational choice of measurement methods for direct FXa inhibitors is an anti-Xa assay. A number of in vitro and ex vivo studies indicated that anti-Xa chromogenic assays are more specific and sensitive than routine clotting test-based assays (Barrett et al, 2010; Becker et al, 2010; Samama et al, 2010, 2012). In addition, there is a better correlation between plasma concentrations, as measured by liquid chromatography/mass spectrometry, and levels estimated by anti-Xa assays than that obtained using the PT (Barrett et al, 2010). Commercial anti-Xa amidolytic assays are mainly designed for measurement of anti-Xa activity of LMWHs and some may require modifications for use with peak and trough levels of direct Xa inhibitors in treated patient plasma. In some studies, the activity of the FXa inhibitors was calibrated against a LMWH reference standard and the results expressed in iu/ml. This is not recommended as the mechanism of action of direct FXa inhibitors and LMWH is different and results showing valid comparison with LMWH are not robust. Product-specific calibrators must be used for accurate estimation of plasma level expressed in mass concentration (e.g. mg/l). The different chromogenic assays also have different dynamic ranges for rivaroxaban and apixaban (Barrett et al, 2010; Samama et al, 2012). Multiple calibrator and test plasma dilutions should be employed to ensure the test sample responses are within the range of the calibration curve and also to allow for assessment of linearity and parallelism (see Mackie et al, 2013). One study has reported overestimation of rivaroxaban levels (compared to the high performance liquid chromatography assay) with an anti- Xa assay utilizing exogenous antithrombin and the authors recommended against its use (Mani et al, 2012). The same study demonstrated the need for different calibrations for samples with high and low levels for some anti-Xa assays (Mani et al, 2012). Expected plasma concentrations of rivaroxaban and apixaban are shown in Table 3. The half-life of rivaroxaban is 7–11 h (Mueck et al, 2008) and that of apixaban is c. 12 h, with steady state occurring after 2–3 d of therapy (Frost et al, 2013). Both rivaroxaban and apixaban prolong the clotting times of clot-based assays, such as APTT, PT, dilute PT, dilute Russell viper venom time (DRVVT), PiCT and Heptest (Harder et al, 2008; Wong et al, 2008; Barrett et al, 2010; Samama et al, 2010). The effect of rivaroxaban on the APTT and PT is more pronounced than that of apixaban (Barrett et al, 2010). Due to the differing sensitivity of PT and APTT reagents to direct FXa inhibitors, the results are highly variable. For most reagents the PT is more sensitive to direct FXa inhibitors than the APTT. It should be noted that therapeutic APTT ratios established for UFH and INR for warfarin should not be used as guidance for safety and efficacy of rivaroxaban and apixaban. Rivaroxaban-associated prolongation of the PT is less marked with Owren's PT reagents (in which plasma and any drug therein is diluted) than with Quick's methods. Some ex vivo samples obtained from patients receiving rivaroxaban samples had a normal PT using STA-Neoplastine CI Plus (Stago, Asnieres sur Siene, France) despite therapeutic rivaroxaban concentrations in one study (Mueck et al, 2011) but were prolonged at therapeutic levels in another (Patel et al, 2013). This reagent showed higher sensitivity to rivaroxaban in spiking studies compared to most other thromboplastins (Samama et al, 2010; Hillarp et al, 2011; Douxfils et al, 2012). A normal PT with Innovin (Siemens, Marburg, Germany) and Thromborel S reagents (Siemens) has been reported in the presence of up to 270 ng/ml rivaroxaban in samples from a patient with baseline PT close to the lower limit of the normal range (van Veen et al, 2013). Prothrombin times with Recombiplastin 2G were normal in all 10 ex vivo samples with <0·09 mg/l rivaroxaban (Rodgers et al, 2013). More data are needed on ex vivo samples but a baseline PT may be useful to aid interpretation of PT results during therapy. Two studies have indicated that it may be feasible to employ a rivaroxaban sensitivity index similar to the specific ISI in a PT/INR system to normalize and reduce the variability of the results obtained with different reagents (Harenberg et al, 2011 Tripodi et al, 2011) but the use of such an index is not currently recommended. The effects of rivaroxaban on routine tests of haemostasis are shown in Table 7. Samama et al (2010) Hillarp et al (2011) Samama et al (2010) Hillarp et al (2011) APTT ratio 1·4–1·6. Prolonged, 5 to10 s Samama et al (2010) Hillarp et al (2011) Asmis et al (2012) Asmis et al (2012) Mani et al (2011) Asmis et al (2012) Mani et al (2011) Commercially available PiCT and HEPTEST assay kits require modification to achieve the sensitivity needed to measure the expected trough and peak levels of these inhibitors. These clot-based assays are not specific and can be influenced by other factors, such as factor deficiency or lupus anticoagulant. The effects of rivaroxaban on specialist tests of haemostasis are shown in Table 8. Samama and Guinet (2011) Merriman et al (2011) Mani et al (2013) Martinuzzo et al (2013) Elevated ratios in one assay No effect in another Hillarp et al (2011) Mani et al (2011) The effects of apixaban on a range of routine and specific coagulation assays have been assessed using apixaban extracted from commercially available tablets and spiked into pooled normal plasma (Douxfils et al, 2013). The effects on the PT were dependent on the thromboplastin reagent used. Prolongation of the PT was minimal at concentrations of 0·2 mg/l for 6 of 7 reagents studied. The other reagent was much more sensitive to the presence of apixaban. There was some prolongation of the APTT in the presence of 0·2 mg/l apixaban for 5 reagents studied. There was a concentration - response relationship for APTT and INR (single method studied) in ex vivo samples but the limited sensitivity and large variability limited the usefulness of these tests as clinical measures of apixaban pharmacodynamic response (Frost et al, 2013). In a spiking study, apixaban at up to 0·4 mg/l had no relevant effect on Clauss fibrinogen, had some effect on the one-stage assay of factors II, V, VII and X and APCR, and was associated with dose-dependent interference in the DRVVT, Xa-based antithrombin assay, clot-based protein S assay and one-stage assays of factors VIII, IX, XI and XII (Douxfils et al, 2013). No monitoring of prophylactic use of LMWH and fondaparinux is usually required (Baglin et al, 2006; Garcia et al, 2012). For treatment of venous thromboembolism, monitoring for certain groups of patients, such as the very obese, severe renal dysfunction patients, pregnant women, infants and neonates, may provide useful information. These recommendations are supported by clinical trial data and laboratory results (Alhenc-Gelas et al, 1995; Kessler et al, 1995; Samama & Poller, 1995; Massicotte et al, 1996; Hunt et al, 1997; Abbate et al, 1998; Crowther et al, 2000; Bombeli et al, 2001). The 9th edition of the ACCP guidelines recommend that in neonates or children receiving therapeutic LMWH either once or twice daily the drug should be monitored to a target anti-Xa of 0·5–1·0 iu/ml in a sample taken 4–6 h or 0·5–0·8 iu/ml in a sample taken 2–6 h after subcuteaneous injection (Guyatt et al, 2012). The main mechanism of action of LMWH is the potentiation of the ability of antithrombin to inhibit coagulation factor proteases, with the main target being factor Xa. The anti-IIa activity of LMWH is lower than its anti-Xa activity and is cleared from circulation faster than anti-Xa activity (Bendetowicz et al, 1994). Fondaparinux is a synthetic pentasaccharide analogue and potentiates only the anti-Xa activity of antithrombin. An anti-IIa assay is therefore not a method of choice for measurement of LMWH and fondaparinux in clinical plasma samples. Similarly, the APTT is not a suitable method as it is largely insensitive to these two anticoagulants. The PiCT has been evaluated by a number of groups for measurement of LMWH and fondaparinux activity (Calatzis et al, 2008; Harder et al, 2008). Although PiCT is sufficiently sensitive to LMWH, it can be influenced by other inhibitors and is therefore not specific for LMWH. An anti-Xa assay is the method of choice for monitoring LMWH. There are many commercially available anti-Xa assays, some with exogenous antithrombin, which measure heparin levels, and others relying on the endogenous antithrombin present in the patient plasma, which therefore measure anticoagulant effect. Laboratories should validate the method to ensure that the standard curve covers the concentration range expected. One recent development in certain commercial products is the use of universal calibrators. Their manufacturers claim that they provide accurate estimation of a range of anticoagulants. However, the sensitivity of anticoagulants such as UFH, LMWH, indirect FXa inhibitors and direct FXa inhibitors in anti-Xa assays are different; one single calibrator cannot give accurate estimations of concentration for all anticoagulants. Fondaparinux, added to plasma in vitro at concentrations of 0·4, 0·8 and 2 mg/l, was shown to prolong the APTT by, on average, 3·8, 4·6 and 6·2 s, respectively (Smogorzewska et al, 2006). All 11 reagents investigated were affected. In other studies the APTT was almost unaffected (Samama et al, 2010) and was not prolonged by 0·8 u/ml anti-Xa activity (Linkins et al, 2002). The PT, as determined by many different methods, was prolonged by only 1–2 s and Xa-based antithrombin assays were unaffected by at least 2·0 mg/l (Smogorzewska et al, 2006). Peak levels of 0·39–0·5 mg/l after 2·5 mg od and 1·2–1·26 mg/l after 7·5 mg od have been reported (Garcia et al, 2012). This guideline replaces the relevant section in the previous BCSH guideline on the use and monitoring of heparin (Baglin et al, 2006). In contrast to the other non-coumarin anticoagulants discussed here, UFH is routinely monitored in an effort to secure maximal antithrombotic effect without excessive bleeding risk. However, there is no strong evidence to suggest that monitoring of UFH therapy improves clinical outcomes (Holbrook et al, 2012). The test of choice for routine monitoring therapeutic doses of UFH has been the APTT in most centres. There are a number of disadvantages related to the use of the APTT. APTT methods vary markedly in their responsiveness to UFH (Banez et al, 1980; Kitchen, 2000), including variation between different lot numbers of the same reagent in some cases (Shojania et al, 1988). The instrument used for clot detection contributes additional variation (D'Angelo et al, 1990). For these reasons local calibration of the APTT assay for each new lot number of reagent should be employed in the construction of the therapeutic range. In the study that established a therapeutic range for UFH monitoring using the APTT ratio (Basu et al, 1972), the range of 1·5–2·5, which was associated with reduced risk of recurrent venous thromboembolism (VTE), corresponded to a heparin level of 0·2–0·4 iu/ml by protamine titration or 0·3 to 0·7 iu/ml by anti-Xa assay (Hirsh et al, 2008). The protamine titration assay is not widely available or well standardized so an anti-Xa assay should be used for calibration. This is done by determination of the APTT ratio and anti-Xa on a series of samples from subjects receiving UFH therapy and not on spiked plasma samples. The regression relationship is then used to derive the range of APTT ratios equivalent to 0·3 to 0·7 IU/ml anti-Xa, though it should be noted that the evidence linking these plasma heparin levels to the occurrence of bleeding or thrombosis is of low quality (Holbrook et al, 2012). The correlation between heparin level and APTT is poor as a consequence of the lack of specificity of the APTT for a heparin effect, and the number of samples required for a valid assessment is not known. Between 30 and 60 samples have been used in some studies (Brill-Edwards et al, 1993; Kitchen & Preston, 1996) whereas others have suggested several hundred may be required (Rosborough, 1997). Some studies have indicated that monitoring of therapeutic UFH in the treatment of VTE may not always be needed. Unmonitored, weight-adjusted subcutaneous heparin was found to be as safe and effective as weight-adjusted LMWH in a randomized trial of patients with VTE, suggesting that APTT monitoring of subcutaneous heparin may not be needed (Kearon et al, 2006). The 9th edition of the ACCP guidelines suggests that, for outpatients with VTE treated with subcutaneous UFH, weight-adjusted dosing should be used without monitoring rather than fixed or weight-adjusted dosing with monitoring (Holbrook et al, 2012). A recent retrospective study of UFH (and warfarin) anticoagulation intensity as predictors of VTE recurrence in 1100 patients concluded that an increasing proportion of time with an APTT prolonged to the level corresponding to 0·2 iu/ml anti-Xa activity was associated with significant reductions in recurrence, and observed that patients receiving a heparin dose of at least 30 000 u/day spent a median of 92% of therapy time with this degree of APTT prolongation (Heit et al, 2011). They concluded that if their findings were confirmed by appropriate clinical trials, routine monitoring and heparin dose adjustment may be unnecessary for patients receiving doses of at least 30 000 u/day. For calibration work or treatment monitoring, samples should be collected 4–6 h after initiation or dose adjustment (reviewed by Samama, 1995). If citrate blood collection tubes are used they should have a small volume of air space in the tube after filling (Ray, 1991) and should be centrifuged within 1–2 h of collection and tested within 4 h to avoid the substantial loss of heparin over time in citrated whole blood (van den Besselaar et al, 1987). Alternatively, the sample can be collected into citrate-theophylline-adenosine- dipyridamole (CTAD), which protects the sample from loss of heparin via platelet factor 4 (PF4)-mediated neutralization (Contant et al, 1983; van den Besselaar et al, 1987). Heparin is lost more rapidly in citrate tubes that contain a large air space (after addition of blood) as a consequence of accelerated platelet activation and release of PF4, an effect that is abolished if CTAD is used (Ray et al, 1993). The APTT may be within the therapeutic range despite sub-optimal therapy where factors other than a heparin effect contribute to the prolongation of the APTT. All patients should have a baseline APTT performed before initiation of therapy. If the pre-treatment APTT is prolonged, then the APTT method used is unsafe for the purpose of monitoring. Where this baseline prolongation is caused by lupus anticoagulant, an insensitive reagent (for which the baseline APTT is normal) can be considered. The anti-Xa assay has a number of advantages over the APTT for monitoring UFH. Baseline levels of FVIII and other clotting factors and the presence of lupus anticoagulant do not affect chromogenic anti-Xa assays, which are therefore more specific for the heparin effect. There is also evidence that the variation in results obtained with different anti Xa methods is much less than that associated with different APTT techniques, including one study in which the mean anti-Xa activity in 43 samples from patients receiving UFH ranged from 0·32 to 0·42 u/ml for 8 different methods (Kitchen et al, 2000). Furthermore, there is evidence that anti-Xa assays can safely be used for monitoring UFH (Levine et al, 1994) and, when available, this could be the test of choice for monitoring UFH. Members of the writing group will inform the writing group Chair if any new pertinent evidence becomes available that would alter the strength of the recommendations made in this document or render it obsolete. The document will be archived and removed from the BCSH current guidelines website if it becomes obsolete. If new recommendations are made an addendum will be published on the BCSH guidelines website (http://www.bcshguidelines.com/). If minor changes are required due to changes in level of evidence or significant additional evidence supporting current recommendations, a new version of the current guidance will be issued on the BCSH website. While the advice and information in this guidance is believed to be true and accurate at the time of going to press, neither the authors, the BCSH nor the publishers accept any legal responsibility for the content of this guidance." @default.
W2085073510 created "2016-06-24" @default.
W2085073510 creator A5013634915 @default.
W2085073510 creator A5034822694 @default.
W2085073510 creator A5038132058 @default.
W2085073510 creator A5052873285 @default.
W2085073510 creator A5063829879 @default.
W2085073510 date "2014-06-14" @default.
W2085073510 modified "2023-10-13" @default.
W2085073510 title "Measurement of non-Coumarin anticoagulants and their effects on tests of Haemostasis: Guidance from the British Committee for Standards in Haematology" @default.
W2085073510 cites W1483138648 @default.
W2085073510 cites W1513455535 @default.
W2085073510 cites W1547546593 @default.
W2085073510 cites W1568662837 @default.
W2085073510 cites W168281536 @default.
W2085073510 cites W1878559559 @default.
W2085073510 cites W1884897052 @default.
W2085073510 cites W1974024236 @default.
W2085073510 cites W1974535354 @default.
W2085073510 cites W1975757685 @default.
W2085073510 cites W1977286952 @default.
W2085073510 cites W1978037800 @default.
W2085073510 cites W1981340953 @default.
W2085073510 cites W1981956866 @default.
W2085073510 cites W1984106364 @default.
W2085073510 cites W1993893409 @default.
W2085073510 cites W2001297508 @default.
W2085073510 cites W2001904766 @default.
W2085073510 cites W2002116184 @default.
W2085073510 cites W2003915795 @default.
W2085073510 cites W2004315379 @default.
W2085073510 cites W2011080889 @default.
W2085073510 cites W2015940002 @default.
W2085073510 cites W2017087558 @default.
W2085073510 cites W20197546 @default.
W2085073510 cites W2023397023 @default.
W2085073510 cites W2024241508 @default.
W2085073510 cites W2026561579 @default.
W2085073510 cites W2031581415 @default.
W2085073510 cites W2032757997 @default.
W2085073510 cites W2039989814 @default.
W2085073510 cites W2041259818 @default.
W2085073510 cites W2048491733 @default.
W2085073510 cites W2049593282 @default.
W2085073510 cites W2051126553 @default.
W2085073510 cites W2051551497 @default.
W2085073510 cites W2053361486 @default.
W2085073510 cites W2054730686 @default.
W2085073510 cites W2054769245 @default.
W2085073510 cites W2058522094 @default.
W2085073510 cites W2060578439 @default.
W2085073510 cites W2072777707 @default.
W2085073510 cites W2073510057 @default.
W2085073510 cites W2075372568 @default.
W2085073510 cites W2083713858 @default.
W2085073510 cites W2088063934 @default.
W2085073510 cites W2093492017 @default.
W2085073510 cites W2095803174 @default.
W2085073510 cites W2097854437 @default.
W2085073510 cites W2103196751 @default.
W2085073510 cites W2103247642 @default.
W2085073510 cites W2105435036 @default.
W2085073510 cites W2113166648 @default.
W2085073510 cites W2113446992 @default.
W2085073510 cites W2116930113 @default.
W2085073510 cites W2118092611 @default.
W2085073510 cites W2124882231 @default.
W2085073510 cites W2128811936 @default.
W2085073510 cites W2132953336 @default.
W2085073510 cites W2134582764 @default.
W2085073510 cites W2136489990 @default.
W2085073510 cites W2140436541 @default.
W2085073510 cites W2140895140 @default.
W2085073510 cites W2156970332 @default.
W2085073510 cites W2157100114 @default.
W2085073510 cites W2157224841 @default.
W2085073510 cites W2157601282 @default.
W2085073510 cites W2157822705 @default.
W2085073510 cites W2158014557 @default.
W2085073510 cites W2159402482 @default.
W2085073510 cites W2160160759 @default.
W2085073510 cites W2164847576 @default.
W2085073510 cites W2166437990 @default.
W2085073510 cites W2170703129 @default.
W2085073510 cites W2196887485 @default.
W2085073510 cites W2203036336 @default.
W2085073510 cites W2252446512 @default.
W2085073510 cites W2276837945 @default.
W2085073510 cites W2323559086 @default.
W2085073510 cites W2324071813 @default.
W2085073510 cites W2328155270 @default.
W2085073510 cites W2329655471 @default.
W2085073510 cites W2408536257 @default.
W2085073510 cites W2408651657 @default.
W2085073510 cites W2414467904 @default.
W2085073510 cites W2434672258 @default.
W2085073510 cites W2910798030 @default.
W2085073510 cites W4233745943 @default.