TABLE 2.

Recommendations and comments from guidelines on investigation of lupus anticoagulant (LA) while on anticoagulant therapy

Guideline	Unfractionated heparin	LMWH	VKAs	DOACs
ISTH 2009 18	Some commercial dRVVT and aPTT reagents contain neutralizers able to quench heparin up to 0.8 U/ml. LA screening not possible if heparin level exceeds reagent neutralization capacity	Screening for LA in patients treated with LMWH is possible. However, the effect on LA assays may vary depending on the ratio between FXa to FIIa activity of each LMWH preparation	Interpretation of results on patients on VKAs is difficult because of prolonged basal clotting times. Laboratory procedures should be performed 1–2 wk after treatment discontinuation or when INR <1.5. Bridging VKA discontinuation with LMWH is recommended, with the last dose of LMWH administered more than 12 h before blood is drawn for LA testing. Alternatively, for INRs between 1.5 and <3.0, a 1:1 dilution of patient plasma and PNP can be considered. However, result interpretation may be difficult, and the LA titer will be diluted twofold	The effect of direct thrombin or FXa inhibitors on LA assays is unknown
BCSH 2012 15	LA tests should not be performed in patients receiving therapeutic doses of UFH because of potential erroneous results. Low‐dose subcutaneous UFH and LMWH have less effect on the dRVVT and most commercial reagents contain heparin neutralizers sufficient to cover prophylactic doses. If positive results are obtained from aCL or aB2GPI assays, these are sufficient for the diagnosis of APS		LA testing is not recommended in patients receiving VKA. Brief discontinuation of VKA therapy for diagnostic purposes is not a high‐risk strategy in most instances. Performing testing on equal volume mixtures of patient and normal plasma may be informative. Because of the dilution effect, negative testing in mixing studies does not exclude the presence of a LA. Alternate assays to dRVVT can be considered. If positive results are obtained from aCL or aB2GPI assays, these are sufficient for the diagnosis of APS	Not mentioned
CLSI 2014 6	If possible, samples from patients treated with UFH should not be screened with the aPTT or SCT unless treated with a heparin neutralizer. Most commercially available dRVVT screening reagents contain a heparin neutralizer that permits testing in the presence of UFH. However, samples containing high UFH levels may give incorrect results	LMWHs, depending upon their composition may prolong the aPTT and therefore results should be interpreted with caution. However, in certain patient populations that are at high risk for APS and treated with LMWH, there is no alternative but to test in the presence of the drug	If possible, VKA samples should not be screened with the aPTT because correct interpretation of test results is difficult. Most patients on VKAs also have prolonged SCT and dRVVT complicating interpretation	DTIs and factor FXa inhibitors (e.g., rivaroxaban) give prolonged dRVVT results that show only partial correction in a screening mixing test
ISTH 2020 5	Whenever possible, blood for LA detection should be collected in patients not receiving any anticoagulant treatment
	Heparins interfere with LA clotting assays; however, although UFH and enoxaparin affect the dRVVT at supra‐therapeutic anti‐Xa levels, they may not lead to false‐positive LA in a three‐step procedure. Some reagents contain heparin neutralizers, but it is important to verify the levels of heparins that are quenched in these reagents. Samples should be taken, when feasible, at least 12 h after the last dose of LMWH was administered and as near as possible to the next dose		Taipan/Ecarin tests are less affected by VKAs. Recommendations for their general use awaits the provision of independent evidence. Dilution of patient plasma into PNP is not a reliable solution in patients on VKA (false‐negative or false‐positive LA results may occur)	Taipan/Ecarin tests are less affected by anti‐FXa DOACs. Recommendations for their general use awaits the provision of independent evidence. If feasible to briefly interrupt DOAC anticoagulation, LA testing can be performed after checking the level of DOAC. DOAC adsorption may be considered in DOAC treated patients
ISTH 2020 17	Some brands of LMWH, depending on their anti‐FXa/FIIa ratio, may result in sizeable prolongation of clotting tests and may affect LA detection. UFH clearly affects LA assays, especially aPTT‐based tests, with false‐positive screening and mixing results. However, at low anti‐FXa UFH activity levels, application of the three‐step procedure does not produce false‐positive LA		Although dilution of the test plasma into PNP is widely used, it is not robust enough to help making diagnosis of LA and both false‐negative or false‐positive results may occur	In patients on DOACs, on a pragmatic empirical basis, LA testing may be undertaken at least 48 h after the last dose, and longer in patients with renal impairment, although DOAC levels should also be checked. DOAC neutralizers can be considered
BCSH 2020 16	Not mentioned	Although LMWH have little effect on LA tests, this may be dependent on LMWH type and reagent. Therefore, possible interferences should be considered even if using reagents with heparin neutralizers. Samples should be taken just before the next dose of LMWH to minimize effects	Not mentioned	aPTT or dRVVT based tests should not be used to detect LA on samples from patients taking DOACs when there is a detectable drug level. There is insufficient evidence to recommend alternative tests for detection of LA in the presence of DOACs. Some studies have suggested absorption methods to remove DOACs are effective, but these methods require further validation

Text includes modifications to promote clarity and brevity. The authors apologize if this causes any misinterpretation of the original guidance. Additional descriptive text is available in Table S1.

Abbreviations: aB2GPI, anti‐beta 2 glycoprotein I antibodies; aCL, anticardiolipin antibodies; APS, antiphospholipid (antibody) syndrome; aPTT, activated partial thromboplastin time; BCSH, British Committee for Standards in Haematology; CLSI, Clinical and Laboratory Standards Institute; DOAC, direct oral anticoagulant; dRVVT, dilute Russell's viper venom time; DTIs, direct thrombin inhibitor; F, factor; INR, International Normalized Ratio; ISTH, International Society on Thrombosis and Haemostasis; LA, lupus anticoagulant; LMWH, low molecular weight heparin; PNP, pooled normal plasma; PT, prothrombin time; TT, thrombin time; UFH, unfractionated heparin; VKAs, vitamin K antagonists.