How and when to measure anticoagulant effects of direct oral anticoagulants? Practical issues.

Direct oral anticoagulants (DOACs) do not require dose adjustment based on laboratory testing. However, it might be necessary to measure their plasma concentrations in the following specific situations: 1) before thrombolytic therapy in patients with stroke; 2) before surgery or invasive procedure; 3) in case of adverse events (thrombosis or hemorrhage); 4) when immediate reversal of anticoagulation is needed; 5) in patients with extreme body weight; 6) when administering additional drugs potentially interfering with DOACs; and 7) when overdosage is suspected regardless of concomitant bleeding. Basic coagulation tests, such as prothrombin and activated partial thromboplastin time, should not be used as standalone tests to assess the levels of anticoagulation as they are not specific for DOACs and their results are dependent on the type of reagent used for testing. Plasma DOAC concentrations should be assessed by dedicated tests: dilute thrombin time or ecarin tests (for dabigatran) or anti-factor Xa assays (for anti-factor Xa inhibitors). Dedicated tests should be calibrated against their respective plasma calibrators at certified DOAC concentrations and results should be expressed as ng/ml. Caution should be exerted when interpreting the results of the most common hemostatic parameters such as antithrombin, proteins C and S, lupus anticoagulant, or individual coagulation factors, as they may be strongly affected by the presence of a DOAC. Whenever possible, these parameters should be measured 4 to 5 days after discontinuation of DOAC anticoagulation.

Harmful and Beneficial Effects of Anticoagulants in Patients With Cirrhosis and Portal Vein Thrombosis.

BACKGROUND & AIMS: Vitamin K antagonists (VKAs) promote recanalization of portal vein thrombosis (PVT) in patients with cirrhosis. However, the benefit of PVT recanalization might be offset by major and minor bleeding associated with use of anticoagulants. We evaluated harmful and beneficial effects of VKA in patients with PVT and cirrhosis. METHODS: We performed a retrospective study of 63 consecutive patients with cirrhosis given anticoagulants for the first detection of non-neoplastic PVT from 2003 to 2015 in Italy. We collected data on bleeding events in these patients and compared them with those from patients without cirrhosis with venous thromboembolism (VTE) (n = 160) for up to 4 years. Time in the therapeutic range, based on the international normalized ratio, was used to determine the quality of anticoagulation. We also collected data from 139 patients with cirrhosis who did not receive VKAs (controls), to analyze portal hypertension-related events. We performed survival analyses to determine the effects of VKA in patients with PVT vs controls. RESULTS: The group with VTE and the group with PVT were comparable in age, sex, and time in the therapeutic range, but patients with VTE received VKAs for a longer time period (31.1 ± 16.9 mo vs 23.3 ± 16.2 mo; P = .002). The incidence of major or minor bleeding was higher in patients with PVT than patients with VTE (major, 24% vs 7%; P = .012; minor, 29% vs 19%; P = .024). Patients with PVT had a higher rate of major bleeding from the upper-gastrointestinal tract than patients with VTE (P = .019), but there were no significant differences in other types of major bleeding (P = .376). Patients with PVT and controls had the same rate of upper-gastrointestinal bleeding. Complete recanalization in patients with PVT receiving VKA (n = 31) was independently associated with increased portal hypertension-related event-free and transplantation-free survival times. CONCLUSIONS: In a retrospective analysis of 63 patients with cirrhosis given anticoagulants for PVT, we found VKA use to increase risk of minor bleeding, compared with patients without cirrhosis given VKA. However, this risk is offset by the ability of VKA to increase portal hypertension-related, event-free, and transplantation-free survival of patients with PVT recanalization. Portal hypertension, rather than anticoagulants, could account for the difference in risk of major bleeding between patients with PVT vs patients with VTE.

Coagulation parameters in patients with cirrhosis and portal vein thrombosis treated sequentially with low molecular weight heparin and vitamin K antagonists.

BACKGROUND/AIMS: Information on coagulation for cirrhotics on anticoagulants is scanty. We investigated plasma from 23 cirrhotics treated with low-molecular-weight-heparin (LMWH) followed by vitamin K antagonists (VKA). METHODS: On days 1-4 patients received full-dose LMWH. On day-5 VKA was started and LMWH was terminated when INR therapeutic-interval was reached. Blood was collected at peak and trough during LMWH, LMWH+VKA and VKA. Non-cirrhotics on VKA were included as controls. RESULTS: Anti-factor Xa increased from baseline-to-peak during LMWH. During LMWH+VKA was high and reverted to zero during VKA. INR was slightly high at baseline, trough or peak during LMWH and increased to 2.2 during LMWH+VKA or VKA. Mean VKA weekly-doses for cirrhotics and controls were 28.5mg and 28.6mg. Protein C decreased upon VKA, but not to the expected extent. Endogenous-thrombin-potential (ETP) decreased from baseline (1436nMmin) to trough (1258nMmin) and peak (700nMmin) during LMWH and was further reduced during LMWH+VKA (395nMmin). CONCLUSIONS: Target-INR for cirrhotics can be reached by VKA dosages similar to those for non-cirrhotics. ETP reduction parallels the effect of LMWH and/or VKA. Whether these parameters represent the antithrombotic action elicited by these drugs remains to be determined by clinical-trials and laboratory-measurements. ETP, being a global-test reflecting both pro- and anti-coagulants targeted by antithrombotic drugs, seems the candidate for these trials.

Vitamin K antagonists in children with central venous catheter on chronic haemodialysis: a pilot study.

BACKGROUND: To date, no study has investigated the use of vitamin K antagonists (VKA) in children undergoing chronic haemodialysis (HD) with a central venous catheter (CVC). METHODS: Consecutive patients aged <18 years with a newly placed tunnelled CVC for chronic HD were enrolled over a 3-year period. Children with active nephrotic syndrome or a history of venous thrombosis received warfarin (VKA group) with therapeutic target international normalised ratios of between 2.0 and 3.0. Patients at standard risk of CVC malfunction were not treated with VKA (standard group). The primary end-point was overall CVC survival. RESULTS: The VKA group consisted of nine patients (median age 10.6 years; range 1.2-15.3 years) with 11 CVC, and the standard group comprised eight patients (11.8 years; 6.1-17.3 years) with ten CVC. The 6- and 12-month CVC survival was significantly longer in the VKA group than in the standard group (100 vs. 60 % and 83.3 vs. 16.7 %, respectively; p < 0.05), with a median survival of 369 and 195 days, respectively (p < 0.05). None of the CVC in the VKA group required removal due to malfunction, as compared to four in the standard group. No major bleeding episodes occurred in either group. CONCLUSIONS: Therapy with VKA would appear to be safe in children on chronic HD and may improve CVC survival in patients at increased risk of CVC thrombosis.

Biological variation of INR in stable patients on long-term anticoagulation with warfarin.

Within-individual biological variation of INR (CV(B)) was assessed in 245 selected stable warfarin-treated patients monitored by three thrombosis centers. Selection criteria were: treatment period of six months or longer before the observation period; at least six consecutive INRs within the therapeutic range of 2.0 - 3.0; interval between consecutive INR measurements of two weeks or longer; no change in warfarin dose; no changes in the patient's circumstances which may influence the INR, such as intercurrent diseases, invasive procedures, starting or stopping drugs interacting with warfarin. The minimum, maximum and mean within-individual coefficient of variation CV(B) of the INR measurements in the 245 selected patients were 0.4%, 14.5%, and 9.0%, respectively Analytical performance goals for the INR measurement (imprecision) could be derived from the mean CV(B). For a therapeutic range of 2.0 - 3.0 with warfarin, the desirable and optimum imprecision of INR determination is <4.5% CV and <2.25% CV, respectively. The biological variation and analytical performance goals have been derived using classic laboratory methods but should be applicable to point-of-care testing as well.